WO2019000224A1 - Bisindolylmaleimide derivative and preparation method and use thereof - Google Patents

Abstract

Provided are a bisindolylmaleimide derivative and a preparation method and use thereof. The bisindolylmaleimide derivative has good therapeutic effect on tumors, especially on some drug-resistant tumors, and thus precise treatment of these drug-resistant tumors can be achieved. As another embodiment, the bisindolylmaleimide derivative has good α-glucosidase inhibitory effect and can be used to prevent or treat diabetes.

Description

Bismuth maleimide derivative, preparation method and use thereof Technical field:

The present invention relates to a biguanide maleimide derivative, a process for its preparation and use.

Background technique:

Tumors are common and frequently-occurring diseases that endanger human life and health in today's world. According to the World Health Organization, there are about 76 million cancer patients in the world, 6 million deaths due to cancer, accounting for 12% of the total deaths, and their incidence is increasing every year (Tang Jun; Fu Dazhao. Targeting small molecule innovation Drugs. Progress in Modern Biomedicine. 2010, 10(20): 3997). The annual incidence of cancer in China is about 1.6 million, and the number of patients currently suffering from it is 2 million. The number of deaths per year is 1.3 million, and it is on the rise. In recent years, although the treatment of tumors such as leukemia and malignant lymphoma has made some progress, the survival time of tumor patients has been significantly prolonged, but the treatment of the most deadly solid tumor has not achieved satisfactory results.

Due to mutations, tumor cells lose sensitivity to drugs with better initial effects and produce drug resistance, which also brings new challenges to the research of innovative drugs.

Bismuth maleimide derivatives have received extensive attention due to their structural diversity and good biological activity. Zhu Weiming et al. disclosed a carbazole and biguanide maleimide alkaloid with protein kinase C (PKC) inhibitory activity and antitumor effect (Zhu Weiming, Xu Zhihong, Zhang Yapeng, Wang Wei, Liu Peipei. Preparation method and application of carbazole and biguanide maleimide. Chinese invention patent ZL201010167113.2. April 25, 2012).

The development of new and effective anti-tumor biguanide maleimide derivatives is still of great significance.

With the changes in people's living habits and dietary structure, the incidence of diabetes has increased year by year. According to data released by the WHO in 2011, about 4.6 million people worldwide die from diabetes-related diseases every year, and medical expenses for diabetes are as high as $465 billion. At present, there are nearly 100 million diabetic patients in China and about 340 million people with abnormal glucose metabolism. Diabetes has become the third biggest killer after cancer and cardiovascular disease.

Diabetes is divided into type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (non-insulin-dependent diabetes), and more than 90% of patients are type 2 diabetes. Patients with type 2 diabetes do not need insulin therapy, can regulate blood sugar, and only use drug-assisted treatment when the diet is not effective. The starch in the food is digested into oligosaccharides of glucose molecules by oral saliva and pancreatic amylase. The function of α-glucosidase is to break the α-1,4-glycosidic bond of these oligosaccharides at the non-reducing end, releasing glucose. Glucose is absorbed by the small intestine epithelium and then enters the blood circulation, becoming blood sugar. Under physiological conditions, α-glucosidase exists in the upper, middle and lower segments of the small intestine, so the body's absorption of sugar is rapid and perfect. Alpha-glucosidase inhibitors delay or slow the increase in postprandial blood glucose by reversibly or competitively inhibiting the activity of the small intestinal brush border alpha-glucosidase. In addition, fasting (when the lower small intestine has no food ingredients), after taking α-glucosidase inhibitors, intestinal carbohydrates, fats, proteins and other chyme enter the distal ileum; this part is the small intestinal glucagon-like peptide The most abundant position of 21 (GLP21) can stimulate the increase of GLP21 secretion, stimulate the release of insulin, and thus reduce postprandial blood glucose concentration. Therefore, α-glucosidase inhibitors (AGIs) are a class of oral hypoglycemic drugs that delay the absorption of intestinal saccharides to achieve diabetes.

At present, the clinically applied α-glucosidase inhibitors are mainly: acarbose, voglibose and miglitol. After taking these three drugs, they do not break down the sugars themselves. Directly reaching the large intestine, there will be adverse reactions such as abdominal discomfort, flatulence, and exhaust. Therefore, it is necessary to find a new α-glucosidase inhibitor drug.

Diabetic Kidney Disease (DKD) is one of the most common severe microvascular complications of diabetes. The incidence is about 30%-40% of diabetic patients, and it has become the first in End Stage Renal Disease (ESRD). The reason is also the leading cause of diabetes. Although some progress has been made in the research of anti-DKD drugs, the existing clinical treatments such as blood pressure control, blood sugar, blood lipids and anti-inflammatory can only delay the progression of DKD to renal failure, and cannot reverse or prevent the progression of the disease. At the same time, it faces problems such as ineffective efficacy and large side effects (Curr Diabetes Rev 2005; 1:281-286), so there is an urgent need to develop new and safe anti-DKD drugs for new targets.

Summary of the invention:

The biguanide maleimide derivative has been widely concerned due to its structural diversity and good biological activity, and the inventors have devoted themselves to the biguanide. Drug development of quinone maleimide derivatives. Moreover, the present inventors have made efforts to develop an antitumor biguanide maleimide derivative which is more effective. In addition, the inventors have found that biguanide maleimide derivatives have important prospects in the treatment of drug-resistant tumors. On the other hand, the biguanide maleimide derivative has an α-glucosidase inhibitory activity and an antidiabetic effect.

To this end, a compound of formula A, a pharmaceutically acceptable salt or prodrug thereof is provided:

among them,

The dotted line indicates that there is no chemical bond or a single bond;

R ₁ and R ₂ are each independently selected from: -H; alkyl, optionally substituted by amino, cyano, hydroxy, carboxy, alkoxy, heteroheterocyclyl, aryl, heteroaryl, - COA substituted; alkenyl group, optionally substituted by amino group, cyano group, hydroxyl group, carboxyl group, alkoxy group, aliphatic heterocyclic group, aryl group, heteroaryl group, -COA; monosaccharide group, said monosaccharide The hydroxy group of the group is optionally substituted by an alkyl group; wherein A is selected from the group consisting of hydrogen, -NR ₁₃ R ₁₄ , aryl, arylamino, alkyl optionally substituted by hydroxy, halo, alkoxy optionally substituted by hydroxy, halo base;

Alternatively, R ₁ and R ₂ together form _{- (CH 2) m1 -O- (} CH 2) m2 -, wherein the H is optionally substituted with _{- (CH 2) 0 ~ 8} -NR 13 R substituent _14, m ₁ and m ₂ are each independently an integer of 1 to 6;

Alternatively, R ₁ and R ₂ together form the following groups:

Wherein R ₉ and R _{10 are} independently -H or alkyl; or R ₉ together with R ₁₀ constitute -C(=O)-;

R _{8 is} selected from the group consisting of: -H; hydroxy; alkyl, optionally substituted by alkoxy; alkenyl; alkynyl; aryl, optionally substituted by amino, hydroxy, halo, alkoxy , alkyl, haloalkyl substituted; aliphatic heterocyclic group, optionally substituted by amino, hydroxy, halogen, alkoxy, alkyl, haloalkyl; heteroaryl, optionally substituted Substituted by amino, hydroxy, halogen, alkoxy, alkyl, haloalkyl; -C(=Y ₁ )-Y ₂ ;-S(=O) ₂ -Y ₃ ;

Y _{1 is} selected from the group consisting of: =O; =S; = NH;

Y _{2 is} selected from the group consisting of: alkyl; alkoxy; hydroxylamine; -NR ₁₃ R ₁₄ ; aryl, optionally substituted by amino, hydroxy, halogen, alkoxy, alkyl, haloalkyl; a heteroaryl group optionally substituted by an amino group, a hydroxyl group, a halogen, an alkoxy group, an alkyl group or a halogenated alkyl group; an aliphatic heterocyclic group optionally substituted with an amino group, a hydroxyl group, a halogen or an alkane An oxy group, an alkyl group, a halogenated alkyl group; an aliphatic heterocyclic group-substituted alkyl-substituted aliphatic heterocyclic group, which is optionally an amino group, a hydroxyl group, a halogen group, an alkoxy group, an alkyl group or an alkyl halide. Substituted; an alkylamino group substituted by at least one of an oxygen group, a hydroxyl group, a heteroaryl group, and an aryl group, optionally substituted with an amino group, a hydroxyl group, a halogen group, an alkoxy group, or an alkyl group. Halogenated alkyl substituted;

Y ₃ is an aryl group optionally substituted by halogen or haloalkyl;

R _{3 is} selected from -H; hydroxy; halogen; -NR ₁₃ R ₁₄ ; -(C=O)NR ₁₁ R ₁₂ ; -(C=O)R ₁₅ ; -O(C=O)R ₁₆ ;-NR ₁₇ -(C=O)R ₁₈ ;-NR ₁₉ -(COO)R ₂₀ ;-NR ₂₁ -(SO ₂ )R ₂₂ ;-O(C=O)NR ₂₃ R ₂₄ ;-SR ₂₅ ;-(S= O) R ₂₆ ; -(SO ₂ )R ₂₇ ; -(SO ₂ )NR ₃₂ R ₃₃ ; alkyl group, optionally substituted by hydroxyl group, cyano group, carboxyl group, monosaccharide group, alkoxy group, aryl group , heteroaryl, alicyclic, -NH-CO-alkylene (NH ₂ )(A ₁ ), -NR ₁₃ R ₁₄ substituted, the aryl, heteroaryl, heteroheterocyclic group optionally Alkenyl, hydroxy, halogen, alkyl, haloalkyl; alkenyl, optionally substituted by hydroxy, cyano, carboxy, monosaccharide, alkoxy, aryl, heteroaryl, heteroheterocyclyl, -NH-CO-alkylene (NH ₂ ) (A ₁ ), -NR ₁₃ R ₁₄ substituted; alkynyl, optionally substituted by hydroxy, cyano, carboxy, monosaccharide, alkoxy, aryl a heteroaryl group, an aliphatic heterocyclic group, a -NH-CO-alkylene (NH ₂ ) (A ₁ ), a -NR ₁₃ R ₁₄ substituent;

A _{1 is} selected from -H, an alkyl group optionally substituted by a heteroaryl group;

R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each is independently selected from -H; hydroxy; -NR ₁₃ R ₁₄ ; -(C=O)R ₁₅ ; -NR ₁₇ -(C= O) R ₁₈ ; -SR ₂₅ ; aryl, which is optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _{0- 2} R ₃₄ substituted; heteroaryl, which is optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; alkoxy, optionally substituted by halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ An aryloxy group optionally substituted by halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ;

G ₁ to G ₈ are each independently selected from -H; halogen; hydroxy; cyano; nitro; carboxy; -NR ₁₃ R ₁₄ ; -(C=O)NR ₁₁ R ₁₂ ;-(C=O)R ₁₅ ;-O(C=O)R ₁₆ ;-NR ₁₇ -(C=O)R ₁₈ ;-NR ₁₉ -(COO)R ₂₀ ;-NR ₂₁ -(SO ₂ )R ₂₂ ;-O(C=O NR ₂₃ R ₂₄ ; -SR ₂₅ ; -(S=O)R ₂₆ ; -(SO ₂ )R ₂₇ ; -CH=NOR ₂₈ ; -CH=NR ₂₉ ;-CH=NNR ₃₀ R ₃₁ ;-(SO ₂ ) NR ₃₂ R ₃₃ ; alkyl group, the alkyl group optionally being selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxyl, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; alkenyl, optionally substituted by halogen, hydroxy, cyano, nitro, carboxy, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; alkyne Any one selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; aryl, The aryl group is optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; heteroaryl, said heteroaryl Optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; alkoxy, which is optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _{0- 2} R ₃₄ substituted; aryloxy, optionally selected from halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ replaced;

R ₁₃ and R ₁₄ are each independently selected from -H; amino; monosaccharide group, the hydroxy hydrogen of said monosaccharide group optionally substituted by an alkyl group; alkyl group optionally selected from halogen, hydroxy group, Cyano, nitro, carboxy, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; aryl, which is optionally substituted by amino, hydroxy, halo, alkyl, The alkyl group is optionally substituted with a halogen, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an azide group, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; an aliphatic heterocyclic group, The aliphatic heterocyclic group is optionally substituted by an amino group, a hydroxyl group, a halogen, an alkyl group, which is optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxyl, azide, -NR ₁₃ R ₁₄ , -S (O) _0-2 R ₃₄ substitution;

R ₁₁ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ are each independently selected from: -H; alkyl; aryl;

The heteroheterocyclyl and heteroaryl each independently contain from 1 to 4 heteroatoms selected from the group consisting of N, O, and S.

Alternatively, in the compound of the above formula A, a pharmaceutically acceptable salt or a prodrug thereof, the alkyl group and the alkyl group in the haloalkyl group, the alkoxy group or the alkoxy group are a C ₁ - C ₂₀ alkyl group, or a C ₁ -C ₁₈ alkyl group, or a C ₁ -C ₆ alkyl group, or a C ₁ -C ₄ alkyl group; the alkenyl group being a C ₂ -C ₂₀ alkenyl group or a C ₂ -C ₁₈ alkenyl group Or a C ₂ -C ₆ alkenyl group, or a C ₂ -C ₄ alkenyl group; the alkynyl group is a C ₂ -C ₂₀ alkynyl group, or a C ₂ -C ₁₈ alkynyl group, or a C ₂ -C ₆ alkynyl, or a C ₂ -C ₄ alkynyl group; the aliphatic heterocyclic group is a 4 to 14 membered monocyclic or polycyclic heterocyclic group, the number of hetero atoms on the ring is 1 to 3, or a hetero atom on the ring The number is 1 to 2; the aryl group in the aryl group and the aryloxy group is a C ₆ -C ₁₄ monocyclic or polycyclic aryl group; the heteroaryl group is a 5 to 14 membered monocyclic or polycyclic heteroaryl group. The number of hetero atoms in the ring is 1 to 3, or the number of hetero atoms in the ring is 1 to 2.

Alternatively, in the above compound of formula A, a pharmaceutically acceptable salt or prodrug thereof:

R ₁ and R ₂ are each independently selected from: -H; C ₁ ~ C ₆ alkyl group, a C ₁ ~ C ₆ alkyl group optionally substituted by amino, cyano, hydroxy, carboxy, C ₁ ~ C ₆ alkoxy a 5-, 6- or 6-membered alicyclic, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, -COA substituted; C ₂ -C ₆ alkenyl, optionally C ₂ -C ₆ alkenyl Substituted by amino group, cyano group, hydroxyl group, carboxyl group, C ₁ -C ₆ alkoxy group, 5- or 6-membered aliphatic heterocyclic group, C ₆ -C ₁₀ aryl group, 5- to 10-membered heteroaryl group, -COA; a hydroxyl group of the monosaccharide group optionally substituted by a C ₁ -C ₆ alkyl group; wherein A is selected from the group consisting of hydrogen, -NR ₁₃ R ₁₄ , a C ₆ -C ₁₀ aryl group, a C ₆ -C ₁₀ arylamino group, a C ₁ -C ₆ alkyl group optionally substituted by a hydroxy group or a halogen, a C ₁ -C ₆ alkoxy group optionally substituted by a hydroxy group or a halogen;

Alternatively, R ₁ and R ₂ together form the following groups:

Wherein R ₉ and R _{10 are} independently -H or C ₁ -C ₆ alkyl; or R ₉ and R ₁₀ together form -C(=O)-;

R _{8 is} selected from the group consisting of: -H; hydroxy; C ₁ -C ₁₈ alkyl, said C ₁ -C ₁₈ alkyl optionally substituted by C ₁ -C ₆ alkoxy; C ₂ -C ₁₈ alkenyl; C ₂ ~ C ₁₈ alkynyl group; C ₆ ~ C ₁₀ aryl group, a C ₆ ~ C ₁₀ aryl group optionally substituted by amino, hydroxy, halo, C ₁ ~ C ₆ alkoxy group, C ₁ ~ C ₆ alkyl, C _{a 1-} to C ₆ haloalkyl group; a 5 or 6 membered alicyclic group optionally substituted with an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, or a C ₁ to C ₆ haloalkyl substituted; 5 to 10 membered heteroaryl, the heteroaryl optionally being amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl substituted; -C(=Y ₁ )-Y ₂ ; -S(=O) ₂ -Y ₃ ;

Y _{1 is} selected from the group consisting of: =O; =S; = NH;

Y _{2 is} selected from the group consisting of: C ₁ -C ₁₈ alkyl; C ₁ -C ₁₈ alkoxy; hydroxylamine; -NR ₁₃ R ₁₄ ; C ₆ -C ₁₀ aryl, optionally C ₆ -C ₁₀ aryl Substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; 5-10 membered heteroaryl, optionally substituted by amino a hydroxyl group, a halogen, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group; a 5 or 6-membered aliphatic heterocyclic group, said aliphatic heterocyclic group optionally being Amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl substituted; 5 or 6-membered aliphatic heterocyclyl substituted C ₁ -C ₆ alkyl substituted a 5- or 6-membered alicyclic group, optionally substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane substituents; C ₁ ~ C ₆ alkylamino group, a C ₁ ~ C ₆ alkylamino group is oxo, hydroxy, 5-10 membered heteroaryl, C ₆ ~ C ₁₀ aryl group substituted with at least one of the 5 ~ membered heteroaryl group, C ₆ ~ C ₁₀ aryl group optionally substituted by amino, hydroxy, halo, C ₁ ~ C ₆ alkoxy group, C ₁ ~ C ₆ alkyl group, C ₁ ~ C ₆ halogen Substituted alkyl;

Y ₃ is a C ₆ -C ₁₀ aryl group optionally substituted by halogen, halogenated C ₁ -C ₆ alkyl;

R _{3 is} selected from -H; hydroxy; halogen; -NR ₁₃ R ₁₄ ; -(C=O)NR ₁₁ R ₁₂ ; -(C=O)R ₁₅ ; -O(C=O)R ₁₆ ;-NR ₁₇ -(C=O)R ₁₈ ;-NR ₁₉ -(COO)R ₂₀ ;-NR ₂₁ -(SO ₂ )R ₂₂ ;-O(C=O)NR ₂₃ R ₂₄ ;-SR ₂₅ ;-(S= O) R ₂₆ ; -(SO ₂ )R ₂₇ ; -(SO ₂ )NR ₃₂ R ₃₃ ; C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group optionally being a hydroxyl group, a cyano group, a carboxyl group, Monosaccharide group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryl group, 5- to 10-membered heteroaryl group, 5- or 6-membered aliphatic heterocyclic group, -NH-CO-C ₁ -C ₆ -alkylene Substituted by a group of (NH ₂ )(A ₁ ), —NR ₁₃ R ₁₄ , the C ₆ —C ₁₀ aryl group, a 5- to 10-membered heteroaryl group, a 5- or 6-membered aliphatic heterocyclic group, optionally an amino group, a hydroxyl group, Halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; C ₂ -C ₆ alkenyl, the C ₂ -C ₆ alkenyl optionally being hydroxy, cyano, carboxy, monosaccharide, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, 5- or 6-membered alicyclic, -NH-CO-C ₁ -C ₆ -alkylene (NH _{2 ) (A 1), - NR} 13 R 14 substituents; C ₂ ~ C ₆ alkynyl group, a C ₂ ~ C ₆ alkynyl group optionally substituted by hydroxy, cyano, carboxy, a monosaccharide group, C ₁ ~ C ₆ alkyl alkoxy, C ₆ C ₁₀ aryl, 5- to 10-membered heteroaryl, 5 or 6-membered aliphatic heterocyclic _{group, -NH-CO-C 1 ~} C 6 alkylene group _{(NH 2) (A 1)} , - NR 13 R 14 substituents ;

A _{1 is} selected from -H, C ₁ -C ₆ alkyl optionally substituted by 5 to 10 membered heteroaryl;

R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each is independently selected from -H; hydroxy; -NR ₁₃ R ₁₄ ; -(C=O)R ₁₅ ; -NR ₁₇ -(C= _{O) R 18; -SR 25;} C 6 ~ C 10 aryl group, a C ₆ ~ C ₁₀ aryl group optionally substituted selected from halogen, hydroxy, cyano, nitro, carboxyl, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; 5 to 10 membered heteroaryl optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, - NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₁ -C ₆ alkoxy group, the C ₁ -C ₆ alkoxy group optionally being selected from the group consisting of halogen, hydroxy, cyano, nitro , carboxy, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₆ -C ₁₀ aryloxy, said C ₆ -C ₁₀ aryloxy group optionally being selected from halogen , hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted;

G ₁ to G ₈ are each independently selected from -H; halogen; hydroxy; cyano; nitro; carboxy; -NR ₁₃ R ₁₄ ; -(C=O)NR ₁₁ R ₁₂ ;-(C=O)R ₁₅ ;-O(C=O)R ₁₆ ;-NR ₁₇ -(C=O)R ₁₈ ;-NR ₁₉ -(COO)R ₂₀ ;-NR ₂₁ -(SO ₂ )R ₂₂ ;-O(C=O NR ₂₃ R ₂₄ ; -SR ₂₅ ; -(S=O)R ₂₆ ; -(SO ₂ )R ₂₇ ; -CH=NOR ₂₈ ; -CH=NR ₂₉ ;-CH=NNR ₃₀ R ₃₁ ;-(SO ₂ ) NR ₃₂ R ₃₃ ; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group optionally being selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxyl, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₂ -C ₆ alkenyl, the C ₂ -C ₆ alkenyl optionally selected from halogen, hydroxy, cyano, nitro, carboxy, azide , -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₂ -C ₆ alkynyl, optionally C ₂ -C ₆ alkynyl selected from halogen, hydroxy, cyano, nitro , carboxy, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₆ -C ₁₀ aryl, the C ₆ -C ₁₀ aryl optionally being selected from halogen, hydroxy , cyano, nitro, carboxyl, _{azido, -NR 13 R 14, -S (} O) 0-2 R 34 substituents; 5 to 10-membered heteroaryl, said heteroaryl Selected from the group selected from halogen, hydroxy, cyano, nitro, carboxyl, _{azido, -NR 13 R 14, -S (} O) 0-2 R 34 substituents; C ₁ ~ C ₆ alkoxy group, a C _{The 1} -C ₆ alkoxy group is optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; C ₆ -C ₁₀ aryloxy, said C ₆ -C ₁₀ aryloxy group optionally being selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ replacement;

R ₁₃ and R ₁₄ are each independently selected from -H; amino; monosaccharide group, the hydroxy hydrogen of said monosaccharide group is optionally substituted by C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl, said C _{The 1} -C ₆ alkyl group is optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; C ₆ - C ₁₀ an aryl group, a C ₆ ~ C ₁₀ aryl group optionally substituted by amino, hydroxy, halo, C ₁ ~ C ₆ alkyl group, a C ₁ ~ C ₆ alkyl group optionally substituted selected from halogen, hydroxy, cyano , nitro, carboxyl, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; 5 or 6-membered alicyclic group, optionally substituted with amino group, hydroxyl group, halogen, C ₁ ~ C ₆ alkyl group, a C ₁ ~ C ₆ alkyl group optionally substituted selected from halogen, hydroxy, cyano, nitro, carboxyl, azido, -NR ₁₃ R _14, -S ( O) _0-2 R ₃₄ substitution;

R ₁₁ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ are each independently selected from: -H; C ₁ -C ₆ alkyl; C ₆ -C ₁₀ aryl;

The heteroheterocyclyl and heteroaryl each independently contain from 1 to 4 heteroatoms selected from the group consisting of N, O, and S.

Alternatively, the compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, is a compound of the formula I, a compound of the formula II or a pharmaceutically acceptable salt or prodrug thereof,

Where, in formula I,

The dotted line indicates that there is no chemical bond or a single bond;

G ₁ to G ₈ are each independently selected from -H; halogen; C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl;

R _{3 is} selected from -H; -NR ₁₃ R ₁₄ ; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group optionally being hydroxy, cyano, carboxyl, monosaccharide, C ₁ -C ₆ alkane An oxy group, a C ₆ -C ₁₀ aryl group, a 5- to 10-membered heteroaryl group, a 5- or 6-membered aliphatic heterocyclic group, -NH-CO-C ₁ -C ₆ alkylene group (NH ₂ )(A ₁ ), Substituting -NR ₁₃ R ₁₄ , the 5- or 6-membered alicyclic group, 5- to 10-membered heteroaryl group, C ₆ -C ₁₀ aryl group optionally being amino group, hydroxy group, halogen, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl substituted;

Wherein A _{1 is} selected from the group consisting of: -H; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group is optionally substituted by a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is optionally Amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; R ₁₃ , R ₁₄ are each independently selected from: -H; C ₁ -C ₆ alkyl;

R ₁ and R ₂ are each independently selected from: -H; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl optionally being cyano, hydroxy, carboxy, C ₆ -C ₁₀ aryl, 5 ～10-membered heteroaryl substituted, the C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl optionally substituted by amino, hydroxy, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl ;

In formula II,

G ₁ to G ₈ are each independently selected from -H; halogen;

R _{3 is} selected from -H; C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group is optionally a hydroxyl group, a cyano group, a carboxyl group, a monosaccharide group, a C ₁ -C ₆ alkoxy group, or a C ₆ - C ₁₀ aryl, 5- to 10-membered heteroaryl, 5- or 6-membered aliphatic heterocyclic group, -NH-CO-C ₁ -C ₆ alkylene (NH ₂ )(A ₁ ), -NR ₁₃ R ₁₄ substituted The 5- or 6-membered alicyclic group, 5- to 10-membered heteroaryl group, and C ₆ -C ₁₀ aryl group are optionally amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane Base substitution

Wherein A _{1 is} selected from the group consisting of: -H; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group is optionally substituted by a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is optionally Amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; R ₁₃ , R ₁₄ are each independently selected from: -H; C ₁ -C ₆ alkyl;

R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each is independently selected from -H or -OR ₃₅ , and R ₃₅ is -H or C ₁ -C ₆ alkyl;

R ₉ and R _{10 are} independently -H or C ₁ -C ₆ alkyl; R _{8 is} selected from -C(=Y ₁ )-Y ₂ , -S(=O) ₂ -Y ₃ ;

Wherein Y _{1 is} selected from the group consisting of =O; =S; = NH;

Y _{2 is} selected from the group consisting of hydroxylamine groups; C ₆ -C ₁₀ aryl groups, and the C ₆ -C ₁₀ aryl group is optionally an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl substituted; 5-10 membered heteroaryl, the 5-10 membered heteroaryl optionally being amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkane a C ₁ -C ₆ haloalkyl group; a 5 or 6 membered alicyclic group, optionally substituted by amino, hydroxy, halo, C ₁ -C ₆ alkoxy, C ₁ ～C ₆ alkyl, C ₁ -C ₆ haloalkyl substituted; 5 or 6-membered alicyclic substituted C ₁ -C ₆ alkyl substituted 5 or 6-membered alicyclic group, said 5 or 6-membered lipid The heterocyclic group is optionally substituted by amino group, hydroxyl group, halogen, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group; C ₁ -C ₆ alkylamino group, said C _{The 1-} to C ₆ alkylamino group is substituted with at least one of oxygen, a hydroxyl group, a 5- to 10-membered heteroaryl group, and a C ₆ -C ₁₀ aryl group, and the 5- to 10-membered heteroaryl group and the C ₆ -C ₁₀ aryl group are Selected by amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

Y ₃ is a C ₆ -C ₁₀ aryl group optionally substituted by halogen, halogenated C ₁ -C ₆ alkyl;

Alternatively, R ₉ and R ₁₀ together form -C(=O)-, R _{8 is} selected from -H; C ₁ -C ₁₈ alkyl; C ₁ -C ₆ alkoxy substituted C ₁ -C ₁₈ alkyl.

In the above formula A compound, a pharmaceutically acceptable salt or prodrug thereof:

Optionally, in Formula I,

The dotted line indicates that there is no chemical bond or a single bond;

G ₁ to G _{8 are} as defined in the compound of formula I as claimed in claim 4;

R _{3 is} selected from -H; -NR ₁₃ R ₁₄ ; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group optionally being hydroxy, cyano, carboxyl, monosaccharide, C ₁ -C ₆ alkane Oxyl, morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl or -NH-CO-C ₁ -C ₆ alkylene (NH ₂ )(A ₁ ), -NR ₁₃ R ₁₄ substituted, The morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl is optionally substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

Wherein A _{1 is} selected from the group consisting of: -H; a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl group is optionally substituted with an imidazolyl group, a fluorenyl group, optionally an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group; R ₁₃ and R ₁₄ are each independently selected from: -H; a C ₁ -C ₆ alkyl group;

R ₁ and R ₂ are each independently selected from -H; C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group is optionally substituted by cyano, hydroxy, carboxy, phenyl, naphthyl, pyridyl, The phenyl, naphthyl, pyridyl group is optionally substituted with an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group;

Optionally, in Formula II,

G ₁ to G _{8 are} as defined in the compound of formula II as claimed in claim 4;

R _{3 is} selected from -H; C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group is optionally substituted with amino, hydroxy, phenyl, morpholinyl, piperidinyl, piperazinyl, said benzene The group, morpholinyl, piperidinyl, piperazinyl is optionally substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each independently selected from -H or -OH;

R ₉ and R ₁₀ are a methyl group;

R _{8 is} selected from -C(=Y ₁ )-Y ₂ ; -S(=O) ₂ -Y ₃ ;

Wherein Y _{1 is} selected from the group consisting of =O; =S; = NH;

Y _{2 is} selected from the group consisting of: hydroxylamine; phenyl, which is optionally substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; Imidazolyl; piperazinyl, said piperazinyl optionally substituted by morpholinyl; alkylamino, said alkylamino substituted by at least one of oxygen, hydroxy, thiol, phenyl;

Y ₃ is phenyl optionally substituted by halogen, C ₁ -C ₆ haloalkyl;

Alternatively, R ₉ and R ₁₀ together form -C(=O)-, R _{8 is} selected from -H; C ₁ -C ₁₈ alkyl; C ₁ -C ₆ alkoxy substituted C ₁ -C ₁₈ alkyl.

In the above formula A compound, a pharmaceutically acceptable salt or prodrug thereof:

Optionally, in Formula I,

The dotted line indicates that there is no chemical bond or a single bond;

G ₁ to G _{8 are} as defined in the compound of formula I as claimed in claim 4;

R _{3 is} selected from a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl group is morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl or -NH-CO-C ₁ -C At least one of ₆ alkylene (NH ₂ )(A ₁ ), the morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl optionally being amino, hydroxy, halogen, C ₁ -C _{a 6} alkyl group, a C ₁ -C ₆ haloalkyl group; a C ₂ -C ₆ alkyl group, the C ₂ -C ₆ alkyl group being substituted by a hydroxy group; a C ₃ -C ₆ alkyl group, the C ₃ -C ₆ alkane Substituted by -NR ₁₃ R ₁₄ ;

Wherein A _{1 is} selected from the group consisting of: -H; a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl group is optionally substituted with an imidazolyl group, a fluorenyl group, optionally an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group; R ₁₃ and R ₁₄ are each independently selected from: -H; a C ₁ -C ₆ alkyl group;

R ₁ and R ₂ are each independently selected from a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl group is substituted with at least one of a phenyl group, a naphthyl group, and a pyridyl group;

Optionally,

In formula I,

The dotted line indicates that there is no chemical bond or a single bond;

G ₁ to G ₈ are each independently selected from -H, halogen, allyl, isopentenyl;

R _{3 is} selected from -H; -Me; -(CH ₂ ) _{1 to 6} OH; -(CH ₂ ) _{0 to 6} NH ₂ ; -(CH ₂ ) _{1 to 4} NMe ₂ ; -(CH ₂ ) _{1 to 4} CN; -(CH ₂ ) _{1 to 4} CO ₂ H; -(CH ₂ ) _{1 to 4} C ₆ H ₅ OH; -(CH ₂ ) _{1 to 4} C ₆ H ₅ OMe; -(CH ₂ ) _{1 to 4} C ₆ H ₅ NH ₂ ; -(CH ₂ ) _{1 to 4} M; morpholine ethyl; piperidinyl ethyl; piperazinyl ethyl; methyl piperazinyl ethyl; pyridylethyl; halophenylethyl; (CH ₂ ) _{1 to 6} -NH-CO-CH(NH ₂ )(A ₁ ); wherein A ₁ , R ₁₃ and R _{14 are} as defined in claim 4, and M is a monosaccharide group;

Alternatively, the R _{3 is} selected from the group consisting of morpholine ethyl; piperidinyl ethyl; piperazinyl ethyl; methyl piperazinyl ethyl; pyridylethyl; aminobenzyl; aminophenethyl; hydroxybenzyl; Benzene ethyl; -(CH ₂ ) _1~6 -NH-CO-CH(NH ₂ )(A ₁ ); -(CH ₂ ) _{2 to 4} OH; -(CH ₂ ) _{3 to 6} NH ₂ ;- (CH ₂ ) _{1 to 4} NMe ₂ ; wherein A _{1 is} selected from -H; imidazole methyl;

Alternatively, said R _{3 is} selected from the group consisting of 2-(4-morpholinyl)ethyl; 2-(piperidin-1-yl)ethyl; 2-(piperazin-1-yl)ethyl; 2-(4 -methylpiperazin-1-yl)ethyl; 2-(pyridin-2-yl)ethyl; p-aminobenzyl; p-aminophenethyl; p-hydroxybenzyl; 2-(2-chloro- 6-fluorophenyl)ethyl; -(CH ₂ ) _{1 to 6} -NH-CO-CH(NH ₂ )(A ₁ ); -(CH ₂ ) _{2 to 4} OH; -(CH ₂ ) _{3 to 6} NH ₂ ; -(CH ₂ ) _{1 to 4} NMe ₂ ; wherein A _{1 is} selected from -H; (imidazol-4-yl)methyl; (indol-3-yl)methyl;

R ₁ and R ₂ are each independently selected from -H; -Et; -(CH ₂ ) _{1 to 4} CN; -(CH ₂ ) _{1 to 4} CO ₂ H; -(CH ₂ ) _{1 to 4} OH; Naphthylethyl; pyridylethyl;

Or, each of R ₁ and R _{2 is} independently selected from phenethyl; naphthylethyl; pyridylethyl;

Optionally, in Formula II,

G ₁ to G ₈ are each independently selected from -H; halogen;

R ₃ is -H;

R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each is independently selected from -H or -OR ₃₅ , and R ₃₅ is -H or C ₁ -C ₆ alkyl;

R ₉ and R ₁₀ are both methyl;

R _{8 is} selected from -C(=Y ₁ )-Y ₂ ; -S(=O) ₂ -Y ₃ ;

Wherein Y _{1 is} selected from the group consisting of =O; =S; = NH;

Y _{2 is} selected from the group consisting of: hydroxylamine; phenyl, which is optionally substituted by halogen, C ₁ -C ₆ haloalkyl; imidazolyl; oxoindenylamino; oxyphenylethylamino; (morpholine) Ethyl)piperazinyl; (halophenyl)methylamino; (halophenyl)ethylamino; (halomethylphenyl)ethylamino; phenylmethylamino; (methoxyphenyl)methylamino ; hydroxypropylamino; 4-(N,N-bis(2-chloroethyl)amino)phenylpropyl;

Alternatively, Y _{2 is} selected from the group consisting of: hydroxylamine; phenyl; halophenyl; trifluoromethyl substituted phenyl; 2-oxophenyl-2-(1H-indol-3-yl)-1-ethylamino ; imidazol-1-yl; 2-oxophenyl-2-phenyl-1-ethylamino; 4-(2(morpholin-1-yl)ethyl)piperazin-1-yl; (2,6- Difluorophenyl)methylamino; (3-chloro-4-fluorophenyl)methylamino; 2-(2-chloro-6-fluorophenyl)-1-ethylamino; 2-(4-trifluoromethyl Phenyl)-1-ethylamino; phenylmethylamino; (4-methoxyphenyl)methylamino; (S)-2-hydroxy-1-propylamino; 4-(N,N-bis(2) -chloroethyl)amino)phenylpropyl;

Y ₃ is phenyl optionally substituted by halogen, C ₁ -C ₆ haloalkyl;

Alternatively, Y _{3 is} selected from halophenyl; trifluoromethyl substituted phenyl;

or,

R ₉ together with R ₁₀ constitutes -C(=O)-;

R _{8 is} selected from -H; C ₁ -C ₁₈ alkyl; C ₁ -C ₆ alkoxy-substituted C ₁ -C ₁₈ alkyl; or R ₈ is methyl.

Optionally, a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of the following compounds, pharmaceutically acceptable salts or prodrugs thereof:

medicine:

Alternatively, in the above compound of formula A, a pharmaceutically acceptable salt or prodrug thereof, the pharmaceutically acceptable salt comprises a salt of an organic or inorganic acid; alternatively, the pharmaceutically acceptable salt is selected a salt formed from the compound of the formula A with the following acid compound: hydrochloric acid; sulfuric acid; phosphoric acid; formic acid; acetic acid; propionic acid; lactic acid; citric acid; tartaric acid; succinic acid; fumaric acid; maleic acid; ; camphorsulfonic acid;

Optionally, the pharmaceutically acceptable prodrug comprises a phosphate prodrug or carbamate prodrug of the compound of formula A.

In another aspect, there is provided a process for the preparation of a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, which comprises a compound of the formula I-1, a compound of the formula I-2, a compound of the formula I-3, II- a step of preparing a compound or a compound of II-2,

In the compound of the formula I-1, G ₁ to G ₈ , R ₁ and R _{2 are} as defined above, and the preparation steps of the compound of the formula I-1 include:

1) a preparation step of the compound of the formula a3, which is selected from the following method (1) or method (2),

Process (1): a compound of the formula a1 and a compound of the formula a2 are obtained by a Perkin condensation reaction to obtain a compound of the formula a3;

Process (2): a compound of the formula a2, a compound of the formula a6 and a compound of the formula a7 are reacted by Grignard and reacted with ethyl iodide to prepare a compound of the formula a8, and then the compound of the formula a8 is obtained by hydrolysis under basic conditions and then acidification. a compound of formula a3;

And 2) a preparation step of the compound of the formula I-1,

The compound of the formula I-1 is obtained by reacting a compound of the formula a3;

In the compound of the formula I-2, G ₁ to G ₈ , R ₁ , R ₂ and R _{3 are} as defined above, but R _{3 is} not H, and the preparation step of the compound of the formula I-2 includes: a compound of formula I-2;

In the compound of the formula I-3, G ₁ to G ₈ , R ₁ , R ₂ and R _{3 are} as defined above, and the preparation steps of the compound of the formula I-3 include:

1): a compound of the formula I-1 is obtained by a cyclization reaction or an oxidative cyclization reaction of dichlorodiacyanyl p-benzoquinone (DDQ), and a compound of the formula I-3 is obtained from a compound of the formula a5, wherein In the compound of formula I-3, R ₃ is H;

Or 2): a compound of the formula 1-2 is obtained by a photo-cyclization reaction or an oxidative cyclization reaction of dichlorodicyan-p-benzoquinone (DDQ), wherein the compound of the formula I-3 is not R ₃ H;

Wherein, when R ₁ and R ₂ are a reactive group, the protecting group is optionally protected;

In the compound of the formula II-1, R ₉ and R ₁₀ are -H or an alkyl group; and G ₁ to G ₈ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R _{8 are} as described above. The preparation step of the compound of the formula II-1 includes: a compound of the group II-1-A, a compound of the group II-1-B, a compound of the group II-1-C, a compound of the group II-1-D or a compound of the group II-1-E. Preparation steps,

The compound of the formula II-1-A is a compound of the formula II-1 as defined below: in the compound of the formula II-1, R ₈ is -C(=Y ₁ )-Y ₂ , and Y _{1 is} selected from =O or =S; ₂ is an aryl group, which is optionally substituted by an amino group, a hydroxyl group, a halogen, an alkoxy group, an alkyl group, or a halogenated alkyl group;

The preparation step of the II-1-A compound comprises: preparing the compound of the formula b1 by an acylation reaction with an arylformyl reagent or an arylsulfonyl reagent, in the arylformyl reagent or the arylsulfonyl reagent The substituent on the aryl group is the same as the substituent on the Y ₂ aryl group; in the compound of the formula b1, G ₁ to G ₈ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ as described in the class II-1-A compound;

The compound of the formula II-1-B is a compound of the formula II-1 as defined below: wherein R ₈ is -C(=Y ₁ )-Y ₂ , and Y _{1 is} selected from =O or =S; Y; ₂ is an imidazolyl group; the preparation step of the II-1-B compound comprises: reacting a compound of the formula b1 with 1,1'-thiocarbonyldiimidazole or triphosgene with imidazole to obtain a compound of the formula b2; wherein the compound of the formula b2 Where Y ₁ is =O or =S;

The compound of the formula II-1-C is a compound of the formula II-1 as defined below: in the compound of the formula II-1, R ₈ is -C(=Y ₁ )-Y ₂ , and Y _{1 is} selected from =O or =S; _{2 is} selected from the group consisting of hydroxylamine groups; -NR ₁₃ R ₁₄ ; an aliphatic heterocyclic group-substituted alkyl-substituted aliphatic heterocyclic group, which is optionally an amino group, a hydroxyl group, a halogen group, an alkoxy group, or an alkyl group. a haloalkyl group; an alkylamino group substituted with at least one of an oxygen group, a hydroxyl group, a heteroaryl group, and an aryl group, optionally substituted with an amino group, a hydroxyl group, a halogen group, an alkoxy group, Alkyl, haloalkyl substituted; wherein R ₁₃ , R _{14 are} as described above; the preparation of the II-1-C compound comprises: reacting a compound of formula b2 with methyl iodide to form a compound of formula b3, a compound of formula b3 and compound R The reaction is prepared; wherein the compound R is selected from the group consisting of an aliphatic heterocyclic group-substituted alkyl-substituted aliphatic heterocyclic ring, and the heterocyclic heterocyclic group and the heterocyclic heterocyclic ring are optionally an amino group, a hydroxyl group, a halogen, an alkoxy group. , an alkyl group, a halogenated alkyl group; an alkylamine substituted with at least one of an oxygen group, a hydroxyl group, a heteroaryl group, and an aryl group, the heteroaryl group and the aryl group being optionally an amino group , a hydroxyl group, a halogen, an alkoxy group, an alkyl group, a halogenated alkyl group;

The II-1-D compound is a compound of the formula II-1 as defined below: in the compound of the formula II-1, R ₈ is -C(=NH)-NHOH; the preparation steps of the II-1-D compound include The compound of the formula b4 is obtained from the compound of the formula b1, and the compound of the formula b4 is reacted with hydroxylamine hydrochloride;

The II-1-E compound is a compound of the formula II-1 as defined below: in the compound of the formula II-1, R ₈ is -C(=Y ₁ )-Y ₂ , Y ₁ is =O, and Y ₂ is 4- (N,N-bis(2-chloroethyl)amino)phenylpropyl; the preparation step of the II-1-E compound comprises: reacting a compound of the formula b1 with chlorambucil;

In the compound of the formula II-2, R ₉ and R ₁₀ together form -C(=O)-; G ₁ to G ₈ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R _{8 are} as claimed. 1-8, wherein the preparation of the compound of the formula II-2 comprises: reacting a compound of the formula c1 with a compound of the formula c2 to obtain a compound of the formula c3, which is then reacted to obtain a compound of the formula c4, which is then obtained by a reaction. The compound of the formula c5 is further reacted to obtain the compound of the formula c6, and the compound of the formula c7 is obtained by the reaction, and the compound of the formula c8 is obtained by the reaction, and the compound of the formula c9 is obtained by the reaction, and the compound of the formula II-2 is obtained by the reaction. ;

When R ₃ is a reactive group, it is optionally protected with a protecting group;

Optionally, the Perkin condensation reaction is carried out in the presence of oxalyl chloride, triethylamine (Et ₃ N), dichloromethane;

Optionally, the aminolysis reaction is carried out in the presence of hexamethyldisilazide (HMDS), N,N-dimethylformamide and methanol;

Optionally, the photo-cyclization reaction uses acetone as a solvent, using iodine as a catalyst, and performing under high-pressure mercury lamp illumination;

Optionally, the oxidative cyclization reaction of dichlorodicyanoquinone (DDQ) is oxidatively ring-closing with DDQ in a benzene solvent under the catalysis of p-toluenesulfonic acid;

Optionally, the compound of the formula a6 is obtained by reacting dibromomaleimide with methyl iodide;

Alternatively, the compound of the formula a8 is hydrolyzed in an alkaline solution such as KOH or NaOH, and acidified with hydrochloric acid or the like to obtain a compound of the formula a3;

Optionally, when R ₁ , R ₂ or R ₃ is a reactive group, the protecting group is selected from (Boc) ₂ O;

Optionally, in the II-1-A compound, R ₃ is -H; R ₆ and R ₇ together form =0; R ₈ is a methyl group, and the preparation steps of the II-1-A compound include: 1 acylation reaction, dissolving the cruciferine in dichloromethane, adding triethylamine, and acylation reaction with the halogenated benzoylating reagent; 2 halogenating reaction, the product obtained in step 1 in methanol and halogenated The diimide undergoes a halogenation reaction at room temperature; 3 oxidation, the product obtained in step 2 is oxidized with an oxidizing agent to obtain R ₄ , R _{5 is} independently selected from -H; -OH; or R ₄ and R ₅ together constitute =0. a compound; the acylation reaction, a halogenation reaction, an oxidation reaction are carried out in an optional order; alternatively, the oxidation reaction is carried out using the following reagents: O ₂ , DMSO, t-BuOK, and optionally NaOH;

Optionally, in the II-1-B compound, R ₃ in the compound of formula b2 is -H; R ₄ and R _{5 are} independently selected from -H; R ₆ together with R ₇ constitutes =0; R ₈ is Methyl; the preparation of the II-1-B compound is carried out by the following method: Method 1: Dissolving cruciferine in dichloromethane, then adding triethylamine, and reacting with 1,1'-thiocarbonyldiimidazole Or method 2: dissolving cruciferine in tetrahydrofuran, then adding diisopropylethylamine and triphosgene to react, dissolving the crude product in tetrahydrofuran, adding diisopropylethylamine, imidazole and p-dimethylamino Made from pyridine;

Optionally, in the II-1-C compound, R ₃ is -H; R ₄ and R ₅ are both -H; R ₆ together with R ₇ constitutes =0; R ₈ is methyl; The preparation step of the 1-C compound comprises: forming a salt of the compound of the formula b2 with iodomethane in an acetonitrile solvent, then dissolving in dichloromethane, adding triethylamine and compound R to carry out a reaction to replace the imidazole salt;

Optionally, in the II-1-D compound, R ₃ is -H; R ₄ and R ₅ are both -H; R ₆ together with R ₇ constitutes =0; R ₈ is methyl; 4) The preparation method of the compound comprises the following steps: preparing a reaction of Fradcarbazole C with hydroxylamine hydrochloride;

Optionally, in the II-1-E compound, R ₃ is -H, R ₄ and R ₅ are both -H; R ₆ together with R ₇ constitutes =0; R ₈ is methyl; The preparation step of the 1-E compound comprises: reacting staurosporine with chlorambucil;

Alternatively, in the compound of the formula II-2, R ₃ is -H; R ₄ together with R ₅ constitutes =0; R ₆ together with R ₇ constitutes =0; R ₈ is methyl; 2 The preparation steps of the compound include: 1 using glucose as a raw material, undergoing peracetylation, 1-position bromination, 1,2-position olefination reaction, deacetylation, 6-position hydroxyl group TIPS protection, 3,4-position Constructing oxazolone, methylation, reduction of sodium hydroxymercury hydride to introduce hydroxyl group at 1-position to obtain sugar donor; 2 using 2,3-dibromomaleimide as raw material, protected by BOM, and The 吲哚 氏 reagent reacts to introduce one molecule of hydrazine, and then protects the hydrazine nitrogen hydrogen with Boc, and then reacts with the 吲哚 氏 reagent to obtain a mother nucleus; 3 the sugar donor described in step 1 and step 2 The mother nucleus, using the Mitsunobu reaction for glycosidation to form the first glycosidic bond, the isomer of the glycosidic bond is separated by silica gel column chromatography, and then the Boc and TIPS protecting groups are removed, and the high pressure mercury lamp is irradiated to carry out the ring, and then The 6-position hydroxyl group is substituted with iodine, the 5,6-position deiodination is double bond, and then the second glycosidic bond is formed under iodine catalysis, and the iodine is deiodinated with tetrabutyltin hydride, 20%. Palladium hydroxide on carbon removal BOM prepared;

Alternatively, in the compound of the formula II-2, R ₃ is -H; R ₈ is a methyl group; R ₄ together with R ₅ constitutes =0, R ₆ and R ₇ are both -H; or, R ₄ , R ₅ is -H, and R ₆ and R ₇ together constitute =0; the preparation step of the compound of the formula II-2 includes: the R ₃ is -H, and R ₄ and R ₅ together constitute =0, R ₆ The compound of the formula II-2 which together with R _{7 is} =0, and R ₈ is a methyl group is obtained by reduction of sodium borohydride and reduction of zinc powder by acetic acid;

Alternatively, the compound of the formula II-2 is prepared by using a D-glucose or an L-glucose to carry out a glycosidic bond and an isomer of a different configuration of the oxazolidine.

The above compounds 1-81, 158-166 and their important intermediates 24c, 26c, 43c, 46c, 49c, 52c and 58c can be prepared from hydrazine or halogen-substituted hydrazine and hydrazine acetic acid by the following chemical synthesis methods:

In the above formula AI, in the formula A-II, G ₁ to G ₈ are each independently -H, -F, -Cl, -Br, allyl or isopentenyl; and X is -H, -Me, -NH ₂ , 2-(4-morpholinyl-)ethyl, 2-(piperidin-1-yl)ethyl, -(CH ₂ ) _n NH ₂ , -(CH ₂ ) _n NMe ₂ , -(CH _{2 n} CN, -(CH ₂ ) _n CO ₂ H, -(CH ₂ ) _n OY, -(CH ₂ ) _n C ₆ H ₅ R ₃ (Y is -H, glucosyl or amino acid group, n=1～ 4, R ₃ = -OH, -OMe); R ₁ , R ₂ represents -H, -Et, -(CH ₂ ) _m CN, -(CH ₂ ) _m CO ₂ H, -(CH ₂ ) _m OH ( m=1 to 4), -CH ₂ Ph.

Compounds 82 to 101 can be prepared from halogen-substituted anthracene and dibromomaleimide by the following chemical synthesis methods:

In the above formulae A-III, G ₅ to G ₈ are each independently -H, -F, -Cl or -Br; X is -H, -Me or -CH ₂ OH, and R ₁ and R ₂ are each independently -H, -Et or -CH ₂ OH.

Compounds 102-129 and intermediates 102f and 116c thereof can be prepared from hydrazine and dibromomaleimide by the following chemical synthesis methods:

In the above formulae A-IV, G ₅ to G ₈ are both -H; X represents -H, -Me, 2-(piperazin-1-yl)ethyl, 2-(2-chloro-6-fluoro-benzene -1-yl)ethyl, 2-(4-morpholinyl)ethyl, 2-(piperidin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, -(CH ₂ ) _n OH, -(CH ₂ ) _n NH ₂ , (n=1, 2); R ₁ is phenylethyl or 2-(naphthalen-1-yl)ethyl.

Compounds 130-157 can be prepared from staurosporine and halogen-containing benzoyl reagents and benzenesulfonyl reagents by the following chemical synthesis methods:

In the above formulas AV and A-VI, R ₁ is -H, -F, -Cl, -Br, -I or -CF ₃ ; R ₂ and R ₃ are each independently =O, -H or -OH; Is -H or -Br.

Compounds 167-184 may be prepared from staurosporine and thiocarbonyldiimidazole or triphosgene, imidazole, methyl iodide, and amine compounds; or from staurosporine and chlorambucil by the following chemical synthesis methods:

In the above formula A-VII, R ₄ represents =O, =S or =NH, and R ₅ represents 2-oxophenyl-2-(1H-indol-3-yl)-1-ethylamino, imidazole-1- , hydroxylamine, 2-oxophenyl-2-phenyl-1-ethylamino, 4-(2-(4-morpholinyl)ethyl)piperazin-1-yl, (2,6-difluoro Phenyl)methylamino, (3-chloro-4-fluorophenyl)methylamino, 2-(2-chloro-6-fluorophenyl)-1-ethylamino, 2-(3-trifluoromethylphenyl )-1-ethylamino, phenylmethylamino, (4-methoxyphenyl)methylamino, (S)-2-hydroxy-1-propylamino, 4-(N,N-bis(2-chloro) Ethyl)aminophenyl)propyl.

The compound of the formula A-VIII is 185-196, wherein the compound 185-187 can be obtained by the following chemical synthesis method from D-glucose and dibromomaleimide. In the formula A-VIII, 188-190 can be obtained from the compound 26b. It is prepared in the same manner; 191 to 195 can be obtained by the same method as L-glucose instead of D-glucose.

In the above formulae A-VIII, R _1a and R _1b are each independently -H or -OH, or R _1a and R _1b together form =0, and R _2a and R _2b are each independently -H or -OH, or R _2a and R _2b together form =0, R ₃ is -H, -Me, 2-(piperazin-1-yl)ethyl, 2-(2-chloro-6-fluorophenyl)ethyl, 2-( 4-morpholinyl)ethyl, 2-(piperidin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, -(CH ₂ ) _n OH or -(CH ₂ ) _n NH ₂ , (n = 1 or 2); R ₃ represents H, -(CH ₂ ) _n CH ₃ (n = 0 to 17) or - (CH ₂ ) _n OY, (n = 1, 2 Y=Me, Et).

As an embodiment, there is also provided an antitumor pharmaceutical composition comprising at least one of the above compound of formula A, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient; alternatively, The anti-tumor drug is an anti-drug resistant drug; optionally, the anti-tumor drug is an anti-leukemia drug, an anti-breast cancer drug, an anti-lung cancer drug or an anti-hepatocarcin drug; alternatively, the anti-tumor drug is an anti-tumor drug The leukemia drug or the anti-mutation lung cancer drug; optionally, the anti-tumor drug is an acute acute promyelocytic drug, an anti-chronic myeloid leukemia drug, an anti-T lymphocytic leukemia drug, an anti-FLT3-ITD mutation, and an acute person Double phenotype (B, mononuclear) myeloid leukemia drug, anti-adriamycin-resistant leukemia drug, anti-breast invasive ductal carcinoma drug, anti-lung adenocarcinoma drug, anti-K-ras mutant lung adenocarcinoma drug, or anti-resistant Gefitinib or erlotinib acquires the EGFR-T790M/L858R mutant lung adenocarcinoma drug.

Optionally, the anti-tumor drug is acute promyelocytic leukemia HL-60 inhibitor, chronic myeloid leukemia K562 inhibitor, T lymphocytic leukemia Jurkat inhibitor, FLT3-ITD mutant human acute double phenotype (B, Mononuclear) myeloid leukemia MV-4-11 inhibition Agent, doxorubicin-resistant leukemia K562/A02 inhibitor, breast invasive ductal carcinoma MCF-7 inhibitor, lung adenocarcinoma A549 inhibitor, gefitinib or erlotinib acquired EGFR-T790M/L858R lung Adenocarcinoma resistant mutant H1975 inhibitor or hepatoma cell HepG2 inhibitor.

The compound of the formula A, its pharmaceutically acceptable salt or prodrug or antitumor pharmaceutical composition can be administered by oral administration and injection, and is also suitable for other administration methods such as transdermal administration and the like. The above antitumor pharmaceutical composition may be in the form of a preparation such as a tablet, a capsule, a powder, a granule, a lozenge, a suppository, an oral solution or a sterile parenteral suspension. Injection forms such as injections, lyophilized powders and the like of various capacities are also included. The above dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field. In the antitumor pharmaceutical composition of the present invention, the excipients used include excipients conventional in the art, such as diluents, fillers, binders, wetting agents, absorption enhancers, surfactants, adsorption carriers, lubricants and the like.

The compound of formula A, a pharmaceutically acceptable salt or prodrug thereof, can also be used as a low molecular biological probe for inhibiting cell proliferation, for use in life science research, as a probe, a compound of formula A, a pharmaceutically acceptable salt thereof Or the prodrug may be dissolved in methanol, water or aqueous methanol, or may be dissolved in an aqueous solution of dimethyl sulfoxide.

As another embodiment, there is further provided the use of a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof for the preparation of an antitumor drug, optionally, the antitumor drug is an anti-drug resistant drug; The anti-tumor drug is an anti-leukemia drug, an anti-breast cancer drug, an anti-lung cancer drug or an anti-liver cancer drug; optionally, the anti-tumor drug is an anti-mutagenic leukemia drug or an anti-mutation lung cancer drug; The anti-tumor drug is an acute double-phenotypic (B, mononuclear) myeloid leukemia drug against acute promyelocytic leukemia drugs, anti-chronic myeloid leukemia drugs, anti-T lymphocytic leukemia drugs, anti-FLT3-ITD mutations , anti-adriamycin-resistant leukemia drugs, anti-mammary invasive ductal carcinoma drugs, anti-lung adenocarcinoma drugs, anti-K-ras mutant lung adenocarcinoma drugs, or anti-gefitinib or erlotinib-derived EGFR- T790M/L858R mutant lung adenocarcinoma drug.

In another embodiment, there is provided a method of preventing or treating a tumor comprising administering to a patient a prophylactically or therapeutically effective amount of a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, optionally, said tumor Is a drug-resistant tumor; optionally, the tumor is leukemia, breast cancer, lung cancer or liver cancer; optionally, the tumor is a mutant leukemia or a mutant lung cancer; alternatively, the tumor is acute promyelocytic Cell leukemia, chronic myelogenous leukemia, T lymphocytic leukemia, FLT3-ITD mutant human acute double phenotype (B, mononuclear) myeloid leukemia, adriamycin-resistant leukemia, breast invasive ductal carcinoma, lung adenocarcinoma , K-ras mutant lung adenocarcinoma, gefitinib or erlotinib acquired EGFR-T790M/L858R mutant lung adenocarcinoma or liver cancer.

In another embodiment, there is provided an alpha-glucosidase inhibiting composition comprising at least one of the compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

According to another embodiment, there is also provided an anti-diabetic pharmaceutical composition comprising at least one of the compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable adjuvant. Alternatively, the anti-diabetic agent is a drug that is resistant to alpha-glucosidase mediated diabetes.

In another embodiment, there is also provided a pharmaceutical composition for anti-diabetic complications comprising at least one of a compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient. Optionally, the diabetic complication is diabetic nephropathy.

The compound of the formula A, a pharmaceutically acceptable salt or prodrug thereof, the α-glucosidase inhibiting composition, or the antidiabetic pharmaceutical composition can be administered by oral administration and injection, and is also suitable for other administration methods, such as Skin administration, etc. The above antidiabetic pharmaceutical composition may be in the form of a preparation such as a tablet, a capsule, a powder, a granule, a lozenge, a suppository, an oral solution or a sterile parenteral suspension. Injection forms such as injections, lyophilized powders and the like of various capacities are also included. The above dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field. The above-mentioned anti-diabetic pharmaceutical composition, the excipients used include excipients conventional in the art, such as diluents, fillers, binders, wetting agents, absorption enhancers, surfactants, adsorption carriers, lubricants and the like.

As a further embodiment, there is also provided the use of a compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of an alpha-glucosidase inhibitor.

In another embodiment, there is also provided the use of a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, for the preparation of an anti-diabetic agent, optionally, the anti-diabetic agent is mediated by an anti-α-glucosidase Diabetes medication.

In another embodiment, there is also provided the use of a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for the prevention of diabetes complications, optionally wherein the diabetes is alpha-glucosidase mediated diabetes. Optionally, the diabetic complication is diabetic nephropathy.

As a further embodiment, there is also provided the use of a compound of formula A above, a pharmaceutically acceptable salt thereof or a prodrug as an alpha-glucosidase inhibitor.

In another embodiment, there is provided a method of preventing or treating diabetes comprising administering to a patient a prophylactically or therapeutically effective amount of a compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof. Alternatively, the diabetes is alpha-glucosidase mediated diabetes.

In another embodiment, there is provided a method of preventing or treating a diabetic complication comprising administering to a patient a prophylactically or therapeutically effective amount of a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, optionally, the complication For diabetic nephropathy.

The compound of formula A has one or more of the following beneficial effects:

Human leukemia cell inhibitory activity: strong human acute promyelocytic leukemia HL-60 inhibitory activity; strong human chronic myeloid leukemia K562 inhibitory activity; strong human T lymphocyte leukemia Jurkat inhibitory activity;

Human mutant leukemia cell inhibitory activity: strong FLT3-ITD mutant human acute double phenotype (B, mononuclear) myeloid leukemia MV-4-11 inhibitory activity, can be used for precise treatment of such leukemia patients;

Human drug-resistant leukemia cell inhibitory activity: strong doxorubicin-resistant leukemia K562/A02 inhibitory activity, can be used for precise treatment of such drug-resistant leukemia patients;

Human breast cancer cell inhibitory activity: strong human breast invasive ductal carcinoma MCF-7 inhibitory activity;

Human lung cancer inhibitory activity: strong human lung adenocarcinoma A549 inhibitory activity;

Inhibitory activity of human-resistant lung adenocarcinoma cells: the inhibitory activity of gefitinib or erlotinib-acquired EGFR-T790M/L858R lung adenocarcinoma resistant mutant H1975, which can be used for the accuracy of such lung cancer patients treatment;

Human hepatoma cell inhibitory activity: strong human hepatoma cell HepG2 inhibitory activity;

Has a higher selectivity;

Has low toxicity;

It has an α-glucosidase inhibitory activity and has anti-diabetic and anti-diabetic complications such as diabetic nephropathy.

DRAWINGS

Figure 1: H&E staining photomicrograph of renal cortical tissue sections showing the therapeutic effect of Compound 49 on diabetic nephropathy rats: x 400.

A is the normal group, B is the db/db model group, C is the model group + losartan group (positive drug), D is the model group + compound 49 (0.5 mg/kg/day) group, and E is the model group + compound Group 49 (1.0 mg/kg/day), F was the model group + compound 49 (2.0 mg/kg/day) group.

Detailed ways:

The invention is exemplified below by way of examples, but the scope of the invention is not limited to the examples.

[Example 1] Preparation of Compounds 1 to 196

Preparation of Compound 1

i) Preparation of 1-ethyl-3-indoleacetic acid (1a)

Under a argon atmosphere, 4 g of sodium hydride (60% by mass, dispersed in paraffin) and 80 mL of tetrahydrofuran were added to a 250 mL three-necked flask, and the suspension was stirred at 0 ° C, and 30 mL of tetrahydrofuran-soluble indole-3-acetic acid (3.5 g, 20mmol), after stirring for half an hour, add 30mL of tetrahydrofuran dissolved iodoethane (5mL, 60mmol), slowly rise to room temperature, after the reaction overnight, drop to 0 ° C, add 10 drops of methanol, add appropriate amount of water to obtain bright yellow solution, extracted with ethyl acetate, the aqueous layer was extracted and then added, the organic layer was combined with concentrated hydrochloric acid, and dried over anhydrous Na ₂ SO _4, evaporated to dryness in vacuo, after column chromatography on silica gel, petroleum ether: ethyl acetate = 8 The product (1a) was eluted with 1 (v/v), 3.87 g, yield 95.4%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ7.59 (d, 1H, J = 8.2Hz, Ar-H), 7.30 (d, 1H, J = 8.2Hz, Ar-H), 7.20 (dt, 1H, J = 8.2 Hz, 0.9 Hz, Ar-H), 7.10 (dt, 1H, J = 8.2 Hz, 1.0 Hz, Ar-H), 7.07 (s, 1H, Ar-H), 4.10 (q, 2H, J = 7.3 Hz, CH ₃ -C H ₂ -), 3.77 (s, 2H, -C H ₂ -CO ₂ H), 1.41 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 178.6, 135.9, 127.6, 126.1, 121.7, 119.2, 119.0, 109.4, 106.0, 40.8, 31.1, 15.4. ESI-MS m/z 202.1 [MH] ^- .

Ii) Preparation of 1-cyanomethylindole (1b)

Under a argon atmosphere, 180 mg of sodium hydride (60% by mass, dispersed in paraffin) and 30 mL of acetonitrile were added to a 100 mL three-necked flask, stirred at -5 ° C, and 10 mL of acetonitrile dissolved hydrazine (351 mg, 3.0 mmol) was added dropwise. The reaction was stirred for 30 min, and 10 mL of acetonitrile-dissolved 2-bromoacetonitrile (300 μL, 4.5 mmol) was slowly added dropwise, and the mixture was slowly warmed to room temperature. After reacting for 24 h, the reaction was quenched with saturated aqueous NH ₄ Cl and ethyl acetate (100 mL×3) times), the organic layers were combined and dried over anhydrous Na ₂ SO ₄ dried, and evaporated to dryness in vacuo, column chromatography on silica gel, petroleum ether: ethyl acetate = 15:1 (v / v) elution to give the product as a colorless oil (1b) 299 mg, yield 64%. ¹ H NMR (600MHz, CDCl ₃ ) δ 7.64 (d, 1H, J = 8.2 Hz, Ar-H), 7.33 - 7.28 (m, 2H, Ar-H), 7.19 (d, 1H, J = 6.9 Hz) , Ar-H), 7.02 ( d, 1H, J = 3.2Hz, Ar-H), 6.58 (d, 1H, J = 3.2Hz, Ar-H), 4.87 (s, 2H, -C H 2 -CN ¹³ C NMR (150 MHz, CDCl ₃ ) δ 135.6, 128.9, 127.1, 122.8, 121.5, 120.8, 114.4, 108.7, 104.1, 34.1. ESI-MS m/z 157.1 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole) maleic anhydride (1c)

Compound 1a (299 mg, 1.92 mmol) was dissolved in 25 mL of CH ₂ Cl ₂ , and 5 mL of CH ₂ Cl ₂ dissolved oxalyl chloride (366 mg, 2.88 mmol) was added dropwise at -5 ° C, and the reaction was carried out at -5 ° C for 2 h. After adding 0.5 mL of oxalyl chloride, the reaction was continued for 2.5 h, the temperature was raised to room temperature, and the solvent was evaporated in vacuo to give a crystal. Re-dissolved in 30 mL of CH ₂ Cl ₂ , added dropwise to 15 mL of CH ₂ Cl ₂ dissolved compound 1b (390 mg, 1.92 mmol) and triethylamine (388 mg, 3.84 mmol). Ester = 3:1 (v/v) eluted red powder (1c) 270 mg, yield 36%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.97 (s, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.64 (d, 1H, J = 8.2Hz, Ar-H) , 7.54 (d, 1H, J = 8.2 Hz, Ar-H), 7.22 (t, 1H, J = 7.3 Hz, Ar-H), 7.12 (t, 1H, J = 7.8 Hz, Ar-H), 6.90 (d, 1H, J = 7.7 Hz, Ar-H), 6.87 (d, 1H, J = 7.8 Hz, Ar-H), 6.85 (t, 1H, J = 7.7 Hz, Ar-H), 6.77 (t , 1H, J = 7.8 Hz, Ar-H), 5.67 (s, 2H, -C H ₂ -CN), 4.28 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.33 (t , 3H, J=7.3Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ166.2,166.1,135.7,135.6,133.2,132.5,129.9,126.1,125.5,125.3, 123.1, 122.3, 121.7, 121.6, 120.9, 120.3, 116.0, 110.6, 110.4, 106.0, 104.0, 40.9, 34.1, 15.2. ESI-MS m/z 396.2 [M+H] ⁺ .

Iv) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole)maleimide (1)

In a single-mouth bottle, compound 1c (126 mg, 0.32 mmol) was dissolved in 4 mL of DMF, and after sealing, HMDS (6.7 mL, 32 mmol) and MeOH (0.64 mL, 16 mmol) were mixed and poured into a single-necked bottle, and the reaction solution was Change from red to light yellow turbidity, and as the reaction progresses, it gradually changes to a clear liquid, and the color changes to orange-red. After the reaction overnight, poured into 25mL of cold water, extracted with ethyl acetate (50mL × 3 times), the organic layers were combined and dried over anhydrous Na ₂ SO _4, evaporated to dryness in vacuo. The oil was separated by silica gel column chromatography and eluted with chloroform to give orange-yellow powder (1) 118 mg, yield 94%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.00 (s, 1H, imide-NH), 7.87 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.57 (d, 1H, J = 8.2 Hz, Ar-H), 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.15 (t, 1H, J = 8.3 Hz, Ar-H), 7.05 (t, 1H, J = 7.4 Hz, Ar-H), 6.83 (d, 1H, J = 8.3 Hz, Ar-H), 6.80 (d, 1H, J = 8.2 Hz, Ar-H), 6.75 (t, 1H, J = 7.8 Hz, Ar-H), 6.68 (t, 1H, J = 7.8 Hz, Ar-H), 5.64 (s, 2H, NC H ₂ -CN), 4.26 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.32 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.7, 172.6, 135.5, 135.4, 131.8, 131.4, 129.1, 126.0, 125.8, 122.6, 121.8, 121.5, 121.2, 121.0, 120.4, 119.6, 116.1, 110.1, 110.0, 106.8, 104.6, 40.7, 34.0, 15.2. ESI-MS m/z 395.2 [M+H] ⁺ .

Preparation of Compound 2

i) Preparation of 1-cyanoethyl hydrazine (2b)

According to the preparation method of the compound 1b, sodium hydride (360 mg, 9.0 mmol, dispersed in paraffin, mass fraction 60%), hydrazine (702 mg, 6.0 mmol) and 3-bromopropionitrile (744 μL, 9.0 mmol) were prepared as raw materials. The product was obtained as a colorless oily product (2b) 949 mg (yield: 94%). _{^{1 H NMR (600MHz, CDCl 3}} ) δ7.65 (d, 1H, J = 7.8Hz, Ar-H), 7.30 (d, 1H, J = 7.8Hz, Ar-H), 7.25 (t, 1H, J = 7.8 Hz, Ar-H), 7.15 (t, 1H, J = 6.8 Hz, Ar-H), 7.13 (d, 1H, J = 3.2 Hz, Ar-H), 6.55 (d, 1H, J = 3.2) , Ar-H), 4.42 (t, 2H, J = 6.9 Hz, NC H ₂ -CH ₂ CN), 2.78 (t, 2H, J = J = 6.9 Hz, NCH ₂ - C H ₂ -CN). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 135.4, 129.1, 127.5, 122.3, 121.6, 120.2, 117.4, 108.7, 103.0, 42.2, 19.2.

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-cyanoethyl-3-indole) maleic anhydride (2c)

Prepared by the method of the preparation of the compound 1c, the compound 2b (988mg, 5.81mmol), oxalyl chloride (1107mg, 8.72mmol), 1a (1180mg, 5.81mmol) and triethylamine (1176mg, 11.64mmol) were separated by silica gel column chromatography The petroleum ether: ethyl acetate = 2:1 (v/v) eluted 530 mg of red powder (2c) in a yield of 23%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.84 (s, 1H, Ar-H), 7.66 (s, 1H, Ar-H), 7.35 (d, 1H, J = 8.3 Hz, Ar-H), 7.34 (d, 1H, J = 8.3 Hz, Ar-H), 7.22 (dt, 1H, J = 7.3 Hz, 1.0 Hz, Ar-H), 7.16 (dt, 1H, J = 7.5 Hz, 1.4 Hz, Ar- H), 7.11 (d, 1H, J = 7.8 Hz, Ar-H), 6.90 (dt, 1H, J = 7.8 Hz, 1.0 Hz, Ar-H), 6.89 (d, 1H, J = 8.2 Hz, Ar -H), 6.82 (dt, 1H, J = 7.3 Hz, 1.0 Hz, Ar-H), 4.47 (t, 2H, J = 6.9 Hz, NC H ₂ -CH ₂ -CN), 4.23 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 2.85 (t, 2H, J = 6.9 Hz, -NCH ₂ -C H ₂ -CN), 1.51 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 166.7, 166.6, 136.2, 135.5, 132.8, 131.5, 129.6, 126.2, 126.0, 125.6, 123.4, 122.9, 122.8, 122.5, 121.3, 120.8, 116.5 , 110.0, 109.1, 106.7, 105.0, 42.4, 41.7, 19.0, 15.1. ESI-MS m/z 410.2 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-cyanoethyl-3-indole)maleimide (2d)

Prepared according to the preparation method of compound 1 from compound 2c (230mg, 0.56mmol), HMDS (12mL, 57mmol) and MeOH (1.2mL, 28.5mmol), which was separated by silica gel column chromatography and eluted with chloroform to obtain orange-red powder (2d) 219 mg, yield 95%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.75 (s, 1H, Ar-H), 7.58 (s, 1H, s-H), 7.51 (s, 1H, -NH), 7.31 (d, 1H, J) = 8.2 Hz, Ar-H), 7.29 (d, 1H, J = 8.2 Hz, Ar-H), 7.16 (t, 1H, J = 7.3 Hz, Ar-H), 7.11 (t, 1H, J = 8.2 Hz, Ar-H), 7.09 (d, 1H, J = 8.2 Hz, Ar-H), 6.88 (d, 1H, J = 8.2 Hz, Ar-H), 6.85 (t, 1H, J = 7.4 Hz, Ar-H), 6.77 (t, 1H, J = 7.3 Hz, Ar-H), 4.45 (t, 2H, J = 6.9 Hz, NC H ₂ -CH ₂ CN), 4.20 (q, 2H, J = 7.3) Hz, -C H ₂ -CH ₃ ), 2.80 (t, 2H, J = 6.9 Hz, -NCH ₂ -C H ₂ -CN), 1.48 (t, 3H, J = 7.3 Hz, -CH ₂ C H ₃ ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.8, 171.7, 136.0, 135.4, 131.7, 130.6, 129.5, 126.6, 126.3, 125.9, 123.0, 122.7, 122.3, 122.2, 120.8, 120.2, 116.7, 109.6, 108.8 , 107.3, 105.4, 42.3, 41.5, 18.9, 15.2. ESIMS m/z 407.1 [MH] ^- .

Iv) Preparation of N-hydroxymethyl-2-(1-ethyl-3-indolyl)-3-(1-cyanoethyl-3-indole)maleimide (2)

Compound 2d (16.2 mg, 39.7 μmol) and NaHCO ₃ (6.7 mg, 79.4 μmol) were added to a 15 mL reaction flask, and a formaldehyde solution (3 mL, mass fraction: 37%) was added thereto, and the mixture was stirred at 85 ° C for 10 hours, and poured into cold water. Extracted with ethyl acetate, the organic layers were combined and dried over anhydrous Na ₂ SO ₄ dried, and evaporated to dryness in vacuo, column chromatography on silica gel, petroleum ether: ethyl acetate = 3:1 (v / v) elution to give a red powder (2) 17.1 mg, yield 98%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.93 (s, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.59 (d, 1H, J = 8.2 Hz, Ar-H) , 7.47 (d, 1H, J = 8.3 Hz, Ar-H), 7.06 (dt, 1H, J = 7.8 Hz, 0.9 Hz, Ar-H), 7.04 (dt, 1H, J = 7.3 Hz, 1.0 Hz, Ar-H), 6.83 (d, 1H, J = 8.3 Hz, Ar-H), 6.78 (d, 1H, J = 8.3 Hz, Ar-H), 6.69 (dt, 1H, J = 7.3 Hz, 1.0 Hz) , Ar-H), 6.68 (dt, 1H, J = 7.8 Hz, 0.9 Hz, Ar-H), 6.31 (t, 1H, J = 7.0 Hz, -OH), 4.98 (d, 2H, J = 6.9 Hz) _{, NC H 2 -OH), 4.59} (t, 2H, J = 6.4Hz, NC H 2 -CH 2 CN), 4.26 (q, 2H, J = 7.3Hz, C H 2 -CH 3), 3.03 (t , 2H, J = 6.4 Hz, N-CH ₂ -C H ₂ -CN), 1.34 (t, 3H, J = 7.3 Hz, -CH ₂ C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) Δ171.5,171.4,136.2,136.1,132.3,132.2,128.4,126.7,126.5,126.4,122.6,122.3,121.9,121.7,120.5,120.3,119.0,110.9,110.7,106.2,105.3,60.8,42.0,41.3, 19.1, 15.8. ESI-MS m/z 439.2 [M+H] ⁺ .

Preparation of Compound 3

i) Preparation of 1-cyanopropyl hydrazine (3b)

Prepared according to the preparation method of compound 1b, by hydrazine (1170 mg, 10 mmol), NaH (600 mg, 15 mmol, mass fraction 60%, dispersed in paraffin) and 4-bromobutyronitrile (1.6 mL, 15 mmol), silica gel column chromatography Separation, petroleum ether: ethyl acetate = 20:1 (v/v) eluted to afford the product (3b, _{^{1 H NMR (600MHz, CDCl 3}} ) δ7.70 (d, 1H, J = 7.7Hz, Ar-H), 7.38 (d, 1H, J = 8.3Hz, Ar-H), 7.29 (t, 1H, J = 7.7 Hz, Ar-H), 7.19 (t, 1H, J = 7.4 Hz, Ar-H), 7.12 (d, 1H, J = 3.3 Hz, Ar-H), 6.58 (d, 1H, J = 3.3) Hz, Ar-H), 4.28 (t, 2H, J = 6.6 Hz, NC H ₂ - (CH ₂ ) ₂ CN), 2.19 (t, 2H, J = 5.5 Hz, N(CH ₂ ) ₂ -C H _2- CN), 2.16-2.14 (m, 2H, -NCH ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 135.9, 128.9, 127.8, 122.1, 121.4, 119.9, 119.0, 109.3, 102.2, 44.5, 26.1,14.7. ESI-MS m/z 185.1 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-cyanopropyl-3-indole) maleic anhydride (3c)

Prepared according to the method for the preparation of compound 1c, 3b (407mg, 2.21mmol), oxalyl chloride (421mg, 3.32mmol), compound 1a (449mg, 2.21mmol) and triethylamine (447mg, 4.42mmol), The chloroform eluted to give a red powder (3c) of 415 mg in a yield of 45%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.89 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.57 (d, 1H, J = 8.8Hz, Ar-H) , 7.54 (d, 1H, J = 8.2 Hz, Ar-H), 7.14 (t, 1H, J = 8.2 Hz, Ar-H), 7.12 (t, 1H, J = 7.7 Hz, Ar-H), 6.94 (d, 1H, J = 8.3 Hz, Ar-H), 6.91 (d, 1H, J = 8.3 Hz, Ar-H), 6.80 (t, 1H, J = 7.1 Hz, Ar-H), 6.79 (t , 1H, J = 7.1 Hz, Ar-H), 4.33 (t, 2H, J = 7.1 Hz, NC H ₂ - (CH ₂ ) ₂ CN), 4.26 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 2.44 (t, 2H, J = 7.4 Hz, N(CH ₂ ) ₂ -C H ₂ -CN), 2.06-2.04 (m, 2H, -NCH ₂ -C H ₂ -CH ₂ CN ), 1.32 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ^{13 C NMR (150MHz, DMSO-} d 6) δ166.9 × 2,136.6,136.3,133.6,133.5,128.8,127.8,125.8,125.7,122.9,122.8,122.3,122.2,120.8,120.7,120.4,111.1,111.0 , 105.2, 104.7, 55.5, 40.4, 26.1, 15.7, 14.3. ESI-MS m/z 424.2 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-cyanopropyl-3-indole)maleimide (3)

Prepared according to the preparation method of compound 1, from 3c (205mg, 0.49mmol), HMDS (10.2mL, 48.5mmol) and MeOH (0.97mL, 24.3mmol), separated by silica gel column chromatography and eluted with chloroform to obtain orange-red powder (3) 203 mg, yield 98%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.94 (s, 1H, imide-NH), 7.78 (s, 1H, Ar-H), 7.74 (s, 1H, Ar-H), 7.50 (d, 1H, J = 8.3 Hz, Ar-H), 7.47 (d, 1H, J = 8.3 Hz, Ar-H), 7.07 (dt, 1H, J = 7.1 Hz, 1.1 Hz, Ar-H), 7.05 (dt , 1H, J = 7.1 Hz, 1.1 Hz, Ar-H), 6.86 (d, 1H, J = 7.7 Hz, Ar-H), 6.85 (d, 1H, J = 7.7 Hz, Ar-H), 6.71 ( t, 1H, J = 7.7 Hz, Ar-H), 6.69 (t, 1H, J = 7.1 Hz, Ar-H), 4.29 (t, 2H, J = 6.6 Hz, NC H ₂ - (CH ₂ ) ₂ CN), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 2.40 (t, 2H, J = 7.1 Hz, N(CH ₂ ) ₂ -C H ₂ -CN), 2.05- 2.03 (m, 2H, NCH ₂ -C H ₂ -CH ₂ CN), 1.32 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173 .4×2,136.4,136.1,132.4,132.2,128.5,127.6,126.3,126.2,122.4,122.3,122.0,121.9,120.5,120.3,120.0,110.7,110.6,105.9,105.3,45.0,41.2,26.2,15.8 , 14.3. HR-ESIMS m/z 421.1645 [MH] ^- (calcd. for C ₂₆ H ₂₁ N ₄ O ₂ , 421.1665).

Preparation of Compound 4

Prepared according to the preparation method of compound 2, compound 3 (6.3 mg, 13.9 μmol), NaHCO ₃ (2.3 mg, 27.9 μmol) and formaldehyde solution (3 mL, mass fraction: 37%), separated by silica gel column chromatography, petroleum ether: acetic acid Ester = 3:1 (v/v) eluted red powder N-hydroxymethyl-2-(1-ethyl-3-indolyl)-3-(1-cyanopropyl-3-indole) The imide (4) was 6.8 mg in a yield of 99%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.74 (s, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7.33 (d, 1H, J = 5.5 Hz, Ar-H), 7.32 (d, 1H, J = 5.5 Hz, Ar-H), 7.17-7.15 (m, 2H, Ar-H), 7.11 (t, 1H, J = 7.3 Hz, Ar-H), 6.88 (d, 2H, J = 7.3 Hz, Ar-H), 6.74 (t, 1H, J = 7.3 Hz, Ar-H), 5.25 (d, 2H, J = 7.8 Hz, NC H _{2 -} OH), 4.27 (t, 2H, J = 6.4 Hz, NC H ₂ - (CH ₂ ) ₂ CN), 4.20 (q, 2H, J = 7.3 Hz, NC H ₂ -CH ₃ ), 3.15 (brs, 1H, -OH), 2.17 (t, 2H, J = 5.9Hz, N ( CH 2) 2 -C H 2 -CN), 2.13-2.11 (m, 2H, NCH 2 -C H 2- CH 2 CN), 1.48 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.8, 171.7, 136.2, 136.1, 131.7, 131.2, 128.5, 126.4, 126.3, 125.9, 122.9, 122.8, 122.4, 122.3, 120.7, 120.2, 118.6, 109.9, 109.3, 106.7, 105.5, 61.9, 44.8, 41.6, 25.9, 15.3, 14.6. ESI-MS m/z 475.1 [M+Na] ⁺ .

Preparation of compound 5

i) Preparation of 1-cyanobutyl hydrazine (5b)

Prepared according to the preparation method of compound 1b, ruthenium (585 mg, 5 mmol), NaH (300 mg, 7.5 mmol, mass fraction 60%, dispersed in paraffin) and 5-bromovaleronitrile (880 μL, 7.5 mmol), silica gel column Chromatography, petroleum ether: ethyl acetate = 10:1 (v/v) eluted to afford 627mg of product (5b) as colorless oil. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.68 (d, 1H, J = 8.0Hz, Ar-H), 7.35 (d, 1H, J = 8.4Hz, Ar-H), 7.26 (t, 1H , J = 7.7 Hz, Ar-H), 7.16 (t, 1H, J = 7.3 Hz, Ar-H), 7.12 (d, 1H, J = 2.7 Hz, Ar-H), 6.58 (d, 1H, J) =2.7 Hz, Ar-H), 4.17 (t, 2H, J = 6.8 Hz, NC H ₂ - (CH ₂ ) ₃ CN), 2.26 (t, 2H, J = 7.3 Hz, N(CH ₂ ) ₃ - C H ₂ -CN), 1.98-1.93 (m, 2H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.61-1.54 (m, 2H, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 136.0, 128.8, 127.7, 121.8, 121.3, 119.6, 119.4, 109.3, 101.7, 45.5, 29.4, 23.0, 17.0.

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-cyanobutyl-3-indole) maleic anhydride (5c)

Prepared according to the preparation method of compound 1c, 5b (627mg, 3.17mmol), oxalyl chloride (604mg, 4.76mmol), compound 1a (644mg, 3.17mmol), and triethylamine (640mg, 6.34mmol), Elution with petroleum ether: ethyl acetate = 2:1 (v/v) afforded 712 mg of red powder (5c), yield 51%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.91 (s, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.56 (d, 1H, J = 8.3 Hz, Ar-H) , 7.53 (d, 1H, J = 8.3 Hz, Ar-H), 7.11 (dt, 1H, J = 7.5 Hz, 1.0 Hz, Ar-H), 7.10 (dt, 1H, J = 7.8 Hz, 0.9 Hz, Ar-H), 6.88 (d, 1H, J = 8.3 Hz, Ar-H), 6.86 (d, 1H, J = 8.7 Hz, Ar-H), 6.76 (dt, 1H, J = 7.8 Hz, 1.0 Hz) , Ar-H), 6.75 (dt, 1H, J = 7.4 Hz, 0.9 Hz, Ar-H), 4.30 (t, 2H, J = 6.9 Hz, NC H ₂ - (CH ₂ ) ₃ CN), 4.28 ( q, 2H, J = 7.3 Hz, NC H ₂ -CH ₃ ), 2.51 (t, 2H, J = 7.3 Hz, N(CH ₂ ) ₃ -C H ₂ -CN), 1.84-1.81 (m, 2H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.50-1.48 (m, 2H, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN), 1.34 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.9×2, 136.5, 136.3, 133.7, 133.3, 128.5, 127.9, 125.9×2, 122.8, 122.7, 122.1×2, 121.0, 120.7, 120.6, 111.2, 111.1, 104.9, 104.8, 45.7, 41.5, 29.3, 22.7, 16.4, 15.7. ESI-MS m/z 438.1 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-cyanobutyl-3-indole)maleimide (5)

Prepared by the preparation of compound 1 from 5c (616mg, 1.14mmol), HMDS (12mL, 57mmol) and MeOH (1.14mL, 28.5mmol), eluted by silica gel column chromatography, eluted with chloroform to obtain orange red powder (5) 585mg, The yield was 95%. ^{1 H NMR (600MHz, DMSO-} d 6) δ10.92 (s, 1H, imide-NH), 7.80 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.50 (d, 1H, J = 8.2 Hz, Ar-H), 7.47 (d, 1H, J = 8.2 Hz, Ar-H), 7.04 (dt, 1H, J = 7.4 Hz, 0.9 Hz, Ar-H), 7.03 (dt , 1H, J = 7.8 Hz, 1.0 Hz, Ar-H), 6.81 (d, 1H, J = 8.2 Hz, Ar-H), 6.79 (d, 1H, J = 7.8 Hz, Ar-H), 6.67 ( Dt, 1H, J = 7.4 Hz, 0.9 Hz, Ar-H), 6.65 (dt, 1H, J = 7.8 Hz, 1.0 Hz, Ar-H), 4.28 (t, 2H, J = 6.8 Hz, NC H ₂ -(CH ₂ ) ₃ CN), 4.26 (q, 2H, J = 7.3 Hz, NC H ₂ -CH ₃ ), 2.52 (t, 2H, J = 7.3 Hz, N(CH ₂ ) ₃ -C H ₂ - CN), 1.82-1.79 (m, 2H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.50-1.47 (m, 2H, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN), 1.34(t,3H,J=7.3Hz, -CH ₂ C H ₃ ). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ173.4×2,136.3,136.0,132.4,132.0,128.8,128.2×2, 127.7, 126.4, 122.3, 122.2121.8, 121.0×2, 120.0, 110.8, 110.7, 105.6, 105.4, 45.5, 41.3, 29.3, 22.7, 16.4, 15.8. ESI-MS m/z 437.1 [M+H] ⁺ .

Preparation of compound 6

Prepared according to the preparation method of compound 2, compound 5 (6.7 mg, 14.4 μmol), NaHCO ₃ (2.4 mg, 28.8 μmol) and formaldehyde solution (3 mL, mass fraction: 37%), separated by silica gel column chromatography, petroleum ether: acetic acid Ethyl ester = 5:2 (v/v) eluted red powder N-hydroxymethyl-2-(1-ethyl-3-indole)-3-(1-cyanobutyl-3-indole) Maleimide (6) 6.9 mg, yield 96%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.70 (s, 1H, Ar-H), 7.55 (s, 1H, Ar-H), 7.32 (d, 1H, J = 8.2 Hz, Ar-H), 7.27 (d, 1H, J = 8.3 Hz, Ar-H), 7.13 (dt, 1H, J = 7.8 Hz, 1.0 Hz, Ar-H), 7.11 (dt, 1H, J = 7.8 Hz, 1.0 Hz, Ar- H), 7.06 (d, 1H, J = 7.8 Hz, Ar-H), 6.91 (d, 1H, J = 7.8 Hz, Ar-H), 6.81 (d, 1H, J = 7.8 Hz, Ar-H) , 6.74 (d, 1H, J = 7.8 Hz, Ar-H), 5.25 (d, 2H, J = 7.8 Hz, NC H _{2 -} OH), 4.19 (q, 2H, J = 7.3 Hz, NC H ₂ - CH ₃ ), 4.15 (t, 2H, J = 6.4 Hz, NC H ₂ - (CH ₂ ) ₃ CN), 3.34 (t, 1H, J = 7.8 Hz, -O H ), 2.27 (t, 2H, J = 6.8 Hz, N(CH ₂ ) ₃ -C H ₂ -CN), 1.90-1.94 (m, 2H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.57-1.51 (m, 2H, N (CH ₂ ) ₂ -C H ₂ -CH ₂ CN), 1.47 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.9 × 2, 136.1×2, 131.5×2, 127.9, 126.7, 126.3, 126.0, 122.7, 122.6, 122.5, 122.3, 120.5, 120.2, 119.2, 109.7, 109.5, 106.2, 105.6, 61.8, 45.8, 41.6, 29.0, 22.8, 17.0, 15.2. ESI-MS m/z 489.1 [M+Na] ⁺ .

Preparation of Compound 7

i) Preparation of 1-cyanomethyl-3-indoleacetic acid (7a)

Under argon protection, sodium chloride (1028 mg, 25.7 mmol, mass fraction 60%, dispersed in paraffin) in a 100 mL three-necked flask was stirred in 40 mL of DMF at -5 °C, and 10 mL of DMF dissolved 3-indoleacetic acid was added. (900mg, 5.14mmol), after stirring for 30min, add 10mL of DMF dissolved bromoacetonitrile (1.03mL, 15.4mmol), slowly rise to room temperature, after the reaction overnight, drop to below 0 °C, add 10mL of methanol, add appropriate amount of water The bright yellow solution was extracted with 30 mL of diethyl ether to remove the paraffin oil. The aqueous layer was acidified to weak acid with 6N hydrochloric acid and extracted with ethyl acetate (100 mL×3 times), and the ethyl acetate layer was combined, dried over anhydrous Na ₂ SO ₄ , vacuum The mixture was evaporated to dryness, and then purified by EtOAc EtOAc. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H, -CO ₂ H ), 7.58 (d, 1H, J = 8.3 Hz, Ar-H), 7.56 (d, 1H, J = 8.2 Hz, Ar-H), 7.36 (s, 1H, Ar-H), 7.26 (dt, 1H, J = 7.8 Hz, 1.0 Hz, Ar-H), 7.13 (dt, 1H, J = 7.4 Hz, 0.9 Hz) , Ar-H), 5.52 (s, 2H, -C H ₂ -CN), 3.69 (s, 2H, -CH ₂ -CO ₂ H). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.4 , 136.3, 128.7, 127.6, 122.8, 120.4, 119.9, 117.2, 110.3, 110.2, 34.2, 31.1.

Ii) Preparation of 2,3-di(1-cyanomethyl-3-indene) maleic anhydride (7b)

Prepared according to the preparation method of Compound 1c, Compound 1b (226mg, 1.45mmol), oxalyl chloride (274mg, 2.18mmol), Compound 7a (310mg, 1.45mmol) and triethylamine (293mg, 2.9mmol) Column chromatography, petroleum ether: ethyl acetate = 3:1 (v / v) eluted to give a red powder (7b) 235 mg, yield 40%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.05 (s, 2H, Ar-H), 7.64 (d, 2H, J = 8.3 Hz, Ar-H), 7.22 (dt, 2H, J = 7.6 Hz , 1.2 Hz, Ar-H), 6.89 (d, 2H, J = 7.9 Hz, Ar-H), 6.84 (dt, 2H, J = 7.9 Hz, 0.8 Hz, Ar-H), 5.69 (s, 4H, -C H ₂ -CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.0 × 2, 135.6 × 2, 132.9 × 2, 128.6 × 2, 125.5 × 2, 123.2 × 2, 121.6 × 2, 121.1 ×2,115.9×2,110.4×2,105.8×2,34.2×2. ESI-MS m/z 407.2 [M+H] ⁺ .

Iii) Preparation of 2,3-di(1-cyanomethyl-3-indolyl)maleimide (7)

Prepared according to the preparation of compound 1 from compound 7b (200mg, 0.49mmol), HMDS (4.1mL, 19.6mmol) and MeOH (0.39mL, 9.8mmol). : 1 (v / v) eluted orange red powder (7) 183 mg, yield 92%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.10 (s, 1H, imide-NH), 7.94 (s, 2H, Ar-H), 7.58 (d, 2H, J = 8.3Hz, Ar-H) , 7.15 (dt, 2H, J = 7.4 Hz, 1.1 Hz, Ar-H), 6.82 (d, 2H, J = 8.0 Hz, Ar-H), 6.75 (dt, 2H, J = 7.0 Hz, 0.8 Hz, Ar-H), 5.65 (s, 4H, -CH ₂ -CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.4 × 2, 135.5 × 2, 131.8 × 2, 127.8 × 2, 126.1 × 2,122.7×2, 121.3×2, 120.6×2, 116.1×2, 110.1×2, 106.5×2, 34.1×2. ESI-MS m/z 406.1 [M+H] ⁺ .

Preparation of Compound 8

i) Preparation of 1-cyanopropyl-3-indoleacetic acid (8a)

According to the preparation method of the compound 7a, indole acetic acid (1.4 g, 8 mmol), NaH (1.6 g, 40 mmol, mass fraction 60%, dispersed in paraffin) and bromobutyronitrile (2.4 mL, 24 mmol) were used as raw materials. The residue was purified by silica gel column chromatography eluting elut elut elut elut eluting ^{1 H NMR (600MHz, DMSO-} d 6) δ7.54 (d, 1H, J = 7.3Hz, Ar-H), 7.42 (d, 1H, J = 7.7Hz, Ar-H), 7.22 (s, 1H , Ar-H), 7.12 (t, 1H, J = 7.3 Hz, Ar-H), 7.00 (1H, t, J = 7.3 Hz, Ar-H), 4.17 (t, 2H, J = 6.9 Hz, NC _{H 2 - (CH 2) 2} CN), 3.53 (s, 2H, -C H 2 -CO 2 H), 2.43 (t, 2H, J = 6.9Hz, N (CH 2) 2 -C HH 2 -CN ), 2.03-2.01 (2H, m, NCH 2 -C H 2 -CH 2 CN). 13 C NMR (150MHz, DMSO-d 6) δ175.0,136.3,128.6,127.2,121.6,120.7,119.9,119.0 , 110.4, 109.8, 44.5, 33.2, 26.4, 14.4. ESI-MS m/z 241.1 [MH] ^- .

Ii) Preparation of 2,3-di(1-cyanopropyl-3-indole) maleic anhydride (8b)

According to the preparation method of the compound 1c, the compound 3b (452 mg, 2.46 mmol), oxalyl chloride (469 mg, 3.69 mmol), the compound 8a (595 mg, 2.46 mmol), and triethylamine (497 mg, 4.92 mmol) were prepared as a raw material. Column chromatography, petroleum ether: ethyl acetate = 1:1 (v / v) eluted to give red powder (8b) 500 mg, yield 44% ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.88 (s, 2H, Ar-H), 7.57 (d, 2H, J = 8.4 Hz, Ar-H), 7.14 (dt, 2H, J = 7.8 Hz, 0.9 Hz, Ar-H), 6.95 (d, 2H, J = 8.4 Hz, Ar-H), 6.81 (dt, 2H, J = 7.8 Hz, 0.9 Hz, Ar-H), 4.30 (t, 4H, J = 6.9 Hz, NC H ₂ - (CH ₂ ) ₂ CN), 2.42 (t, 4H, J = 7.3 Hz, N(CH ₂ ) ₂ -C H ₂ -CN), 2.05-2.02 (m, 4H, NCH ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz , DMSO-d ₆ ) δ 166.8 × 2, 136.6 × 2, 133.7 × 2, 128.5 × 2, 125.7 × 2, 123.0 × 2, 122.2 × 2, 120.8 × 2, 120.4 × 2, 111.1 × 2, 105.1 × 2,45.3×2, 26.1×2, 14.3×2. ESI-MS m/z 463.2 [M+H] ⁺ .

Iii) Preparation of 2,3-di(1-cyanopropyl-3-indole)maleimide (8)

Prepared according to the preparation of compound 1 from compound 8b (375 mg, 0.81 mmol), HMDS (6.8mL, 32.5mmol) and MeOH (0.66mL, 16.2mmol). : 1 (v / v) eluted orange red powder (8) 341 mg, yield 91%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H, imide-NH), 7.76 (s, 2H, Ar-H), 7.50 (d, 2H, J = 8.2 Hz, Ar-H) , 7.08 (dt, 2H, J = 7.8 Hz, 0.9 Hz, Ar-H), 6.90 (d, 2H, J = 8.2 Hz, Ar-H), 6.73 (dt, 2H, J = 7.4 Hz, 0.9 Hz, Ar-H), 4.28 (t, 4H, J = 6.9 Hz, NC H ₂ - (CH ₂ ) ₂ CN), 2.38 (4H, t, J = 7.3 Hz, N(CH ₂ ) ₂ -C H ₂ - CN), 2.04-2.02 (m, 4H, NCH ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.3 × 2, 136.4 × 2, 132.5 × 2, 128.2 × 2,126.2×2,122.5×2,121.9×2,120.5×2,120.2×2,110.7×2,105.8×2,45.0×2,26.1×2,14.3×2.HR-ESIMS m/z 460.1769[ MH] ^- (calcd.for C ₂₈ H ₂₂ N ₅ O ₂ , 460.1774).

Preparation of compound 9

i) Preparation of 1-cyanobutylindole-3-acetic acid (9a)

According to the preparation method of compound 7a, indole acetic acid (1.4g, 8mmol), NaH (1.6g, 40mmol, 60% dispersed in paraffin) and bromopenteronitrile (2mL, 16mmol) were prepared and separated by silica gel column chromatography. The petroleum ether: ethyl acetate = 3:1 (v/v) eluted white crystals (9a) 1.69 g, yield 83%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.30 (s, 1H, -CO ₂ H ), 7.59 (d, 1H, J = 7.8 Hz, Ar-H), 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.27 (s, 1H, Ar-H), 7.18 (dt, 1H, J = 7.8 Hz, 0.9 Hz, Ar-H), 7.08 (dt, 1H, J = 7.8 Hz, 0.9 Hz) , Ar-H), 4.13 (t, 2H, J = 6.9 Hz, NC H ₂ - (CH ₂ ) ₃ CN), 3.72 (s, 2H, -C H ₂ -CO ₂ H), 2.44 (t, 2H) , J=6.9 Hz, N(CH ₂ ) ₃ -C H ₂ -CN), 1.81-1.79 (m, 2H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.51-1.48 (m, 2H) , N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 173.7, 136.4, 128.2, 127.7, 121.8, 121.0, 119.6, 119.2, 110.2, 107.9, 45.1, 31.4, 29.6, 22.8, 16.3. ESI-MS m/z 255.1 [MH] ^- .

Ii) Preparation of 2,3-bis(1-cyanobutyl-3-indole) maleic anhydride (9b)

According to the preparation method of the compound 1c, the compound 5b (1140 mg, 5.76 mmol), oxalyl chloride (1097 mg, 8.64 mmol), the compound 9a (1470 mg, 5.76 mmol) and triethylamine (1163 mg, 11.5 mmol) were prepared as a raw material. Chromatography, petroleum ether: ethyl acetate = 2:1 (v / v) eluted to yield product red powder (9b) 900mg, yield 32%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.93 (s, 2H, Ar-H), 7.55 (d, 2H, J = 8.3 Hz, Ar-H), 7.09 (t, 2H, J = 7.3 Hz , Ar-H), 6.83 (d, 2H, J = 8.3 Hz, Ar-H), 6.73 (2H, t, J = 7.4 Hz, Ar-H), 4.32 (t, 4H, J = 6.9 Hz, NC H ₂ -(CH ₂ ) ₃ CN), 2.52 (t, 4H, J = 7.3 Hz, N(CH ₂ ) ₃ -C H ₂ -CN), 1.85-1.83 (m, 4H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.51-1.48 (m, 4H, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.9×2, 136.4×2, 133.6×2, 128.3×2, 126.0×2, 122.8×2, 121.9×2, 121.0×2, 120.6×2, 111.2×2, 104.9×2, 45.7×2, 29.3×2, 22.7× 2,16.4×2. ESI-MS m/z 491.2 [M+H] ⁺ .

Iii) Preparation of 2,3-bis(1-cyanobutyl-3-indole)maleimide (9)

Prepared according to the preparation method of compound 1 from compound 9b (470mg, 0.96mmol), HMDS (8.1mL, 38.4mmol) and MeOH (0.77mL, 19.2mmol). = 3:2 (v/v) eluted orange-red powder (9) 426 mg, yield 90%. ^{1 H NMR (600MHz, DMSO-} d 6) δ10.93 (s, 1H, imide-NH), 7.80 (s, 2H, Ar-H), 7.48 (d, 2H, J = 8.2Hz, Ar-H) , 7.02 (dt, 2H, J = 7.8 Hz, 1.0 Hz, Ar-H), 6.77 (d, 2H, J = 8.2 Hz, Ar-H), 6.63 (dt, 2H, J = 7.4 Hz, 0.9 Hz, Ar-H), 4.29 (t, 4H, J = 6.9 Hz, NC H ₂ -(CH ₂ ) ₃ CN), 2.51 (t, 4H, J = 7.3 Hz, N(CH ₂ ) ₃ -C H ₂ - CN), 1.83-1.81 (m, 4H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.50-1.48 (m, 4H, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.4 × 2, 136.3 × 2, 132.4 × 2, 128.0 × 2, 126.5 × 2, 122.3 × 2, 121.6 × 2, 121.0 × 2, 120.0 × 2, 110.8 ×2,105.6×2, 45.5×2, 29.3×2, 22.7×2, 16.3×2. ESI-MS m/z 488.2 [MH] ^- .

Preparation of Compound 10

Compound 1 (50 mg, 0.127 mmol) was dissolved in a mixture of 10 mL acetic acid: concentrated hydrochloric acid = 3:1 (v/v) in a 25 mL single-necked flask, refluxed at 120 ° C for 30 min, then cooled to room temperature, and extracted with water and ethyl acetate. The organic layer was evaporated to dryness. Imine (10) 50 mg, yield 95%. ^{1 H NMR (600MHz, DMSO-} d 6) δ10.97 (brs, 1H, imide-NH), 7.88 (s, 1H, Ar-H), 7.66 (s, 1H, Ar-H), 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.32 (d, 1H, J = 8.2 Hz, Ar-H), 7.04 (t, 1H, J = 7.1 Hz, Ar-H), 7.02 (d, 1H, J = 8.2 Hz, Ar-H), 6.97 (t, 1H, J = 8.2 Hz, Ar-H), 6.72 (t, 1H, J = 7.1 Hz, Ar-H), 6.60 (d, 1H, J = 7.7 Hz, Ar-H), 6.58 (t, 1H, J = 7.7 Hz, Ar-H), 4.86 (s, 2H, -C H ₂ -CO ₂ H), 4.21 (q, 2H, J = 7.2 Hz) , -C H ₂ -CH ₃ ), 1.27 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.6, 173.5, 172.2, 137.2 , 135.9, 134.2, 131.7, 128.1, 127.2, 126.9, 126.0, 122.2, 122.1, 122.0, 121.7, 120.1, 119.9, 111.0, 110.5, 105.6, 105.2, 49.9, 41.1, 15.8. ESI-MS m/z 412.0 [MH. ] ^- .

Preparation of Compound 11

In a 50 mL two-necked flask, NaH (68 mg, 1.7 mmol, mass fraction 60%, dispersed in paraffin) was suspended in 10 mL of DMF, and 10 mL of DMF dissolved Compound 1 (200 mg, 0.56 mmol) was added under stirring at -5 ° C, and the reaction was carried out for 30 min after low temperature reaction. Bromoacetonitrile (114 μL, 1.7 mmol) was slowly added dropwise and reacted at low temperature for 30 min. The reaction was quenched with saturated NH ₄ Cl solution, extracted with ethyl acetate, and then evaporated. -3-(1-cyanomethyl-3-indole) maleimide (11) 161 mg, yield 66%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.93 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.60 (d, 1H, J = 8.2 Hz, Ar-H) , 7.50 (d, 1H, J = 8.2 Hz, Ar-H), 7.18 (t, 1H, J = 7.1 Hz, Ar-H), 7.08 (t, 1H, J = 7.2 Hz, Ar-H), 6.86 (d, 1H, J = 8.2 Hz, Ar-H), 6.85 (d, 1H, J = 8.3 Hz, Ar-H), 6.79 (t, 1H, J = 7.1 Hz, Ar-H), 6.72 (t , 1H, J = 7.7 Hz, Ar-H), 5.66 (s, 2H, NC H ₂ -CN), 4.75 (s, 2H, NC H ₂ -CN), 4.27 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 1.33 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 170.3, 170.2, 136.2 × 2, 133.0, 132.3, 129.5, 126.4, 126.3, 125.9, 123.4, 122.6, 122.1, 121.9, 121.2, 120.5, 116.7, 116.3, 110.9, 110.8, 107.1, 105.1, 41.4, 34.7, 26.4, 15.7. ESI-MS m/z 434.1[M+H] ⁺ .

Preparation of Compound 12

According to the preparation method of the compound 10, the compound 11 (50 mg, 0.12 mmol) was used as a starting material, and the silica gel column chromatography and dichloromethane:methanol=5:1 (v/v) eluted to obtain a red solid N-carboxymethyl group- 2-(1-Ethyl-3-indole)-3-(1-carboxymethyl-3-indole)maleimide (12) 48 mg, yield 85%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.93 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.47 (d, 1H, J = 8.3 Hz, Ar-H) , 7.38 (d, 1H, J = 8.2 Hz, Ar-H), 7.05 (t, 1H, J = 7.7 Hz, Ar-H), 7.02 (t, 1H, J = 7.1 Hz, Ar-H), 6.96 (d, 1H, J = 7.7 Hz, Ar-H), 6.72 (t, 1H, J = 7.7 Hz, Ar-H), 6.70 (d, 1H, J = 8.2 Hz, Ar-H), 6.65 (t , 1H, J = 7.1 Hz, Ar-H), 5.13 (s, 2H, NC H ₂ -CO ₂ H), 4.29 (s, 2H, -CH ₂ -CO ₂ H), 4.25 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 1.32 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.6, 171.5 , 170.5, 170.0, 137.2, 136.0, 134.0, 132.2, 127.6, 126.9, 126.6, 126.1, 122.5, 122.4, 122.1, 121.7, 120.4, 120.3, 110.9, 110.7, 105.8, 105.4, 48.1, 41.3, 39.9, 15.7. -MS m/z 470.0[MH] ^- .

Preparation of compound 13

i) Preparation of 1,2,3,4,6-D-glucopyranose pentaacetate (13a)

In a 100 mL single-mouth bottle, add glucose (2g, 11.1mmol), anhydrous sodium acetate (2.5g, 30.5mmol), acetic anhydride 12.5mL, reflux at 110 ° C, pour the reaction solution into about 100g of crushed ice while stirring, stir A large amount of a white solid was produced, the ice was melted, and then filtered, and the filter cake was recrystallized from anhydrous ethanol to give white powder (13a) 4.1 g, yield 95%. ESI-MS m/z 391.1 [M+H] ⁺ .

Ii) Preparation of 2,3,4,6-O-tetraacetyl-D-glucopyranose (13b)

Under a N ₂ protection, in a 50 mL two-necked flask, 13a (525 mg, 1.35 mmol) was dissolved in 10 mL of anhydrous THF, and benzylamine (0.22 mL, 2.02 mmol) was added dropwise at -5 ° C, and slowly warmed to room temperature overnight. The reaction was completed by TLC, and evaporated to dryness. ESI-MS m/z 349.2 [M+H] ⁺ .

Iii) Preparation of 2,3,4,6-O-tetraacetyl-D-glucopyranose trichloroacetic acid imide (13c)

In a two-necked flask, under the protection of N ₂ , 13b (390 mg, 1.12 mmol) was dissolved in 5 mL of CH ₂ Cl ₂ , trichloroacetonitrile (1.35 mL, 13.45 mmol) was added dropwise at -5 ° C, and a catalytic amount of DBU was added dropwise. The solution was changed from slightly yellowish to pale yellow. After reacting for 30 min, the mixture was evaporated to dryness mjjjjjjjjjjjjjjjjj %. ESI-MS m/z 492.0 [M+H] ⁺ .

Iv) O-2-(1-ethyl-3-indolyl)-3-(1-cyanoethyl-3-indole)maleimide-2,3,4,6-O-tetraacetyl -α-D-glucopyranoside (13d)

Compound 13c (10 mg, 22.8 μmol) and Compound 4 (7.5 mg, 16.5 μmol) were pumped dry with a gas pump, added to a 15 mL two-necked flask, and pumped in a desiccator for 3 h. The molecular sieve was dried by a muffle furnace and then pulverized. The powder was burned with an alcohol burner for 30 minutes. After the air pump was cooled, about 200 mg was added to the reaction flask. 5 mL of dry CH ₂ Cl _{2 was added} , and the air pump was changed N ₃ times to -20 ° C. After reacting for 20 min, 2 μL of BF ₃ ·Et ₂ O was added dropwise, and immediately changed from red to purple, followed by red, and the reaction was allowed to rise to room temperature for 10 h, and the reaction was completed. The reaction mixture was cooled to -5 ° C, and 10 mg of NaHCO _{3 was} added to terminate the reaction. The mixture was filtered and evaporated to dryness. , yield 95%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ7.79 (s, 1H, Ar-H), 7.61 (s, 1H, Ar-H), 7.31 (d, 1H, J = 8.2Hz, Ar-H), 7.30 (d, 1H, J = 8.2 Hz, Ar-H), 7.17 (t, 1H, J = 8.3 Hz, Ar-H), 7.11 (t, 1H, J = 8.2 Hz, Ar-H), 7.08 (d) , 1H, J = 8.2 Hz, Ar-H), 6.86 (d, 1H, J = 7.3 Hz, Ar-H), 6.85 (t, 1H, J = 7.3 Hz, Ar-H), 6.77 (t, 1H) , J = 7.3 Hz, Ar-H), 5.36/5.28 (d, 2H, J = 11.5 Hz, NC H ₂ -O), 5.19 (t, 1H, J = 10.0 Hz, Glc-C3-H), 5.10 (t, 1H, J = 10.0 Hz, Glc-C2-H), 5.00 (t, 1H, J = 10.0 Hz, Glc-C4-H), 4.86 (d, 1H, J = 8.2 Hz, Glc-C1- H), 4.46 (t, 2H, J = 7.3 Hz, NC H ₂ -CH ₂ CN), 4.21 (q, 2H, J = 7.3 Hz, NC H ₂ -CH ₃ ), 4.18/4.03 (dd, 2H, J = 12.4 Hz, 2.8 Hz, Glc-C6- H ₂ ), 3.70 (dt, 1H, J = 10.1 Hz, 3.7 Hz, Glc-C5-H), 2.82 (t, 2H, J = 7.3 Hz, NCH ₂ -C H ₂ -CN), 1.94 (s, 12H, 4-COC H ₃ ), 1.49 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) Δ171.4, 171.3, 170.8, 170.4, 169.5, 169.4, 136.2, 135.5, 131.9, 130.9, 129.0, 126.5, 125.9, 125.8, 123.2 122.8, 122.5, 122.4, 121.0, 120.5, 116.8, 109.8, 109.0, 107.3, 105.5, 100.0, 73.0, 72.1, 71.2, 68.1, 66.2, 61.6, 42.4, 41.6, 20.8, 20.7, 20.6, 20.6, 19.0, 15.3. ESI-MS m/z 791.4 [M+Na] ⁺ .

v) O-2-(1-ethyl-3-indolyl)-3-(1-cyanoethyl-3-indole)maleimide-α-D-glucopyranoside (13) preparation

In a single-mouth bottle, the sample 13d was dissolved in 1 mL of CH ₂ Cl ₂ , 4 mL of anhydrous methanol was added, NaOMe/MeOH was added dropwise with stirring at 0 ° C, to pH 9-10, and the reaction was allowed to rise to room temperature for 30 min, and no residual material was detected by TLC. The reaction was stopped by adding a saturated NH ₄ Cl solution at 0 °C. The mixture was extracted with ethyl acetate and evaporated to dryness. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.94 (s, 1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.60 (d, 1H, J = 8.2 Hz, Ar-H) , 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.06 (t, 1H, J = 7.8 Hz, Ar-H), 7.04 (t, 1H, J = 7.3 Hz, Ar-H), 6.82 (d, 1H, J = 7.8 Hz, Ar-H), 6.78 (d, 1H, J = 8.3 Hz, Ar-H), 6.68 (t, 2H, J = 7.8 Hz, Ar-H), 5.20/5.14 (d, 2H, J = 11.0 Hz, NC H ₂ -O), 5.10 (d, 1H, J = 5.5 Hz, Glc-C1-H), 4.99 (d, 1H, J = 3.7 Hz, Glc-C2- O H ), 4.92 (d, 1H, J = 3.7 Hz, Glc-C3-O H ), 4.60 (t, 2H, J = 6.7 Hz, NC H ₂ -CH ₂ CN), 4.47 (t, 1H, J) =6.0 Hz, Glc-C6-O H ), 4.41 (d, 1H, J = 8.2 Hz, Glc-C4-O H ), 4.27 (q, 2H, J = 7.3 Hz, NC H ₂ -CH ₃ ), 3.62 (m, 1H, Glc-C2-H), 3.48 (m, 1H, Glc-C3-H), 3.11 (m, 2H, Glc-C6- H ₂ ), 3.09 (m, 1H, Glc-C4- H), 3.04 (t, 2H, J = 6.7 Hz, NCH ₂ -CH ₂ -CN), 2.95 (m, 1H, Glc-C5-H), 1.34 (t, 3H, J = 7.3 Hz, N- ^{_{CH 2 -C H 3). 13}} C NMR (150MHz, DMSO-d 6) δ171.5,171.4,136.1,136.0,132.5,132.4,128.4,126.7,126.4,126.3,122.6,122.4,122.0 , 121.8, 120.5, 120.4, 119.0, 110.9, 110.7, 106.2, 105.3, 103.0, 77.6, 77.3, 73.8, 70.2, 66.2, 61.4, 41.9, 41.3, 19.1, 15.8. HR-ESIMS m/z 623.2139 [M+Na ] ⁺ (C ₃₃ H ₃₅ N ₄ O ₈ Na, 623.2118).

Preparation of compound 14

Dissolve 1c (20mg, 50.6μmol) with 2mL DMF, add 0.5mL of ethylenediamine with stirring, react overnight at room temperature, add appropriate amount of water, extract with ethyl acetate, dry the organic layer, separate by silica gel column chromatography, dichloromethane: methanol =10:1 (v/v) eluted orange-red powder N-(2-aminoethyl)-2-(1-ethyl-3-indole)-3-(1-cyanomethyl-3-吲哚) Maleimide (14) 22 mg, yield 99%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.89 (s, 1H, Ar-H), 7.84 (s, 1H, Ar-H), 7.60 (d, 1H, J = 8.2Hz, Ar-H) , 7.49 (d, 1H, J = 8.2 Hz, Ar-H), 7.17 (t, 1H, J = 7.8 Hz, Ar-H), 7.07 (t, 1H, J = 7.4 Hz, Ar-H), 6.88 (d, 1H, J = 7.8 Hz, Ar-H), 6.86 (d, 1H, J = 7.6 Hz, Ar-H), 6.78 (t, 1H, J = 7.4 Hz, Ar-H), 6.71 (t , 1H, J = 7.6 Hz, Ar-H), 5.67 (s, 2H, -C H ₂ -CN), 4.26 (q, 2H, J = 7.3 Hz, NC H ₂ -CH ₃ ), 3.71 (t, 2H, J=6.2 Hz, NC H ₂ -CH ₂ -NH ₂ ), 2.94 (t, 2H, J = 6.2 Hz, N-CH ₂ -C H ₂ -NH ₂ ), 1.32 (t, 3H, J = 7.3 Hz, N-CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.9×2, 136.0, 135.9, 132.4, 132.0, 129.0, 126.4, 126.2, 125.7, 123.1, 122.4, 122.1, 121.9, 121.0, 120.2, 116.7, 110.7, 110.6, 107.3, 105.2, 41.2, 40.0, 39.0, 34.6, 15.7. ESI-MS m/z 438.1 [M+H] ⁺ .

Preparation of compound 15

Prepared according to the preparation method of compound 14, using compound 2c (60mg, 146.7μmol) as raw material, silica gel column chromatography, dichloromethane: methanol = 10:1 (v / v) eluted to obtain red crystal N-(2-ammonia Ethyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanoethyl-3-indole)maleimide (15) 74.5 mg, yield 100%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.89 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.60 (d, 1H, J = 8.3Hz, Ar-H) , 7.48 (d, 1H, J = 8.3 Hz, Ar-H), 7.07 (t, 1H, J = 7.8 Hz, Ar-H), 7.05 (t, 1H, J = 7.3 Hz, Ar-H), 6.87 (d, 1H, J = 8.0 Hz, Ar-H), 6.83 (d, 1H, J = 8.0 Hz, Ar-H), 6.70 (t, 1H, J = 7.3 Hz, Ar-H), 6.69 (t , 1H, J = 7.8 Hz, Ar-H), 4.59 (t, 2H, J = 6.4 Hz - C H ₂ -CH ₂ -CN), 4.27 (q, 2H, J = 7.2 Hz, NC H ₂ -CH ₃ ), 3.76 (t, 2H, J = 6.1 Hz, NC H ₂ -CH ₂ -NH ₂ ), 3.03 (t, 2H, J = 6.1 Hz, N-CH ₂ -C H ₂ -NH ₂ ), 3.00 (t, 2H, J = 6.4 Hz, -C H ₂ -CN), 1.33 (t, 3H, J = 7.2 Hz, N-CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) Δ171.4, 171.3, 135.5, 135.4, 131.5, 131.4, 127.7, 126.4, 125.9, 125.8, 121.9, 121.7, 121.5, 121.2, 119.7, 119.6, 118.3, 110.2, 110.0, 105.7, 104.9, 41.3, 40.6, 38.5, 37.4, 18.4, 15.1. ESI-MS m/z 452.3 [M+H] ⁺ .

Preparation of Compound 16

Compound 15 (20 mg, 0.044 mmol) was dissolved in 4N hydrochloric acid / ethyl acetate solution, stirred at room temperature for 6 h, evaporated to dryness and lyophilized for 5h, then recrystallized from anhydrous ethanol/ petroleum ether (v/v, 5:1) Deep red crystal N-(2-aminoethyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanoethyl-3-indole) maleimide hydrochloride (16) 17 mg, yield 79.2%. ^{1 H NMR (600MHz, DMSO-} d 6) δ8.15 (brs, 3H, -NH 3 +), 7.92 (s, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.65 (d , 1H, J = 8.0 Hz, Ar-H), 7.52 (d, 1H, J = 8.0 Hz, Ar-H), 7.07 (t, 1H, J = 7.8 Hz, Ar-H), 7.15 (t, 1H) , J = 7.6 Hz, Ar-H), 6.89 (d, 1H, J = 8.0 Hz, Ar-H), 6.81 (d, 1H, J = 8.0 Hz, Ar-H), 6.72 (t, 1H, J = 7.3 Hz, Ar-H), 6.70 (t, 1H, J = 7.8 Hz, Ar-H), 4.58 (t, 2H, J = 6.4 Hz NC H ₂ -CH ₂ CN), 4.27 (q, 2H, J = 7.2 Hz, NC H ₂ -CH ₃ ), 3.96 (t, 2H, J = 6.2 Hz, NC H ₂ -CH ₂ -NH ₃ ⁺ ), 3.73 (t, 2H, J = 6.2 Hz, N-CH ^{_{2 -C H 2 -NH 3 +)}} , 3.01 (t, 2H, J = 6.4Hz, NCH 2 -C H 2 -CN), 1.32 (t, 3H, J = 7.2Hz, NCH 2 -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.4, 171.2, 135.6, 135.4, 131.5, 131.3, 127.7, 127.4, 125.9, 125.8, 121.9, 121.6, 121.5, 121.2, 119.7, 119.5, 118.3, 110.2, 110.1, 105.7, 104.7, 45.3, 42.6, 38.5, 37.4, 18.4, 15.1. ESI-MS m/z 452.2 [M-Cl] ⁺ .

Preparation of compound 17

According to the preparation method of the compound 14, the compound 3c (24 mg, 56.7 μmol) and ethylenediamine were used as a raw material, and the column chromatography on silica gel and dichloromethane:methanol=10:1 (v/v) eluted to obtain a dark red solid N. -(2-Aminoethyl)-2-(1-ethyl-3-indole)-3-(1-cyanopropyl-3-indole)maleimide (17) 26 mg, yield 98 %. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.79 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.53 (d, 1H, J = 8.3 Hz, Ar-H) , 7.50 (d, 1H, J = 8.3 Hz, Ar-H), 7.09 (t, 1H, J = 8.5 Hz, Ar-H), 7.07 (t, 1H, J = 8.5 Hz, Ar-H), 6.90 (t, 2H, J = 7.9 Hz, Ar-H), 6.75 (d, 1H, J = 7.4 Hz, Ar-H), 6.72 (d, 1H, J = 7.4 Hz, Ar-H), 4.31 (t , 2H, J = 6.7 Hz, NC H ₂ - (CH ₂ ) ₂ CN), 4.25 (q, 2H, J = 7.2 Hz, NC H ₂ -CH ₃ ), 3.76 (t, 2H, J = 5.7 Hz, _{NC H 2 -CH 2 -NH 2)} , 3.01 (t, 2H, J = 5.7Hz, NCH 2 -C H 2 -NH 2), 2.41 (t, 2H, J = 7.2Hz, N (CH 2) 2 -C H ₂ -CN), 2.02 (m, 2H, NCH ₂ -C H ₂ -CH ₂ CN), 1.31 (t, 3H, J = 7.2 Hz, N-CH ₂ -C H ₃ ). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ171.5×2, 135.9, 135.6, 131.9, 131.8, 127.4, 126.4, 125.6×2, 122.0, 121.8, 121.6×2, 120.0, 119.8, 119.6, 110.3, 110.2, 105.4, 104.9,44.5,40.7,38.5,37.2,25.6,15.2,13.7.HR-ESIMS m / z 466.2266 [ m + H] + (calcd.for C 28 H 28 N 5 O 2, 466.2243).

Preparation of Compound 18

Prepared according to the preparation method of compound 14, using compound 4c (24mg, 54.9μmol) as a starting material, eluted by silica gel column chromatography, dichloromethane:methanol=10:1 (v/v) to obtain red solid N-(2-Ammonia Ethyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanobutyl-3-indole)maleimide (18) 30 mg, yield 100%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.82 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.51 (d, 1H, J = 8.4 Hz, Ar-H) , 7.47 (d, 1H, J = 8.4 Hz, Ar-H), 7.05 (t, 1H, J = 7.5 Hz, Ar-H), 7.04 (t, 1H, J = 7.4 Hz, Ar-H), 6.83 (d, 1H, J = 8.5 Hz, Ar-H), 6.82 (d, 1H, J = 8.7 Hz, Ar-H), 6.68 (t, 1H, J = 7.5 Hz, Ar-H), 6.66 (t , 1H, J = 7.4 Hz, Ar-H), 4.30 (t, 2H, J = 6.8 Hz, NC H ₂ - (CH ₂ ) ₃ CN), 4.26 (q, 2H, J = 7.2 Hz, NC H ₂ -CH ₃ ), 3.60 (t, 2H, J = 6.4 Hz, NC H ₂ -CH ₂ -NH ₂ ), 2.82 (t, 2H, J = 6.4 Hz, N-CH ₂ -C H ₂ -NH ₂ ) , 2.51 (t, 2H, J = 7.2 Hz, N(CH ₂ ) ₃ -C H ₂ -CN), 1.82 (m, 2H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.46 (m , 2H, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN), 1.33 (t, 3H, J = 7.2 Hz, N-CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆₎ ) δ 172.2 × 2, 136.2, 136.0, 132.4, 132.0, 127.9, 127.3, 126.8, 126.3, 122.3, 122.2, 121.8, 121.0, 120.0, 119.9, 114.3, 110.7, 110.6, 105.6, 105.4, 45.4, 41.2, 40.8 , 40.0, 29.2, 22.6, 16.3, 15.7. ESI-MS m/z 480.2 [M+H] ⁺ .

Preparation of Compound 19

i) Preparation of N-tert-butyloxycarbonylglycine (19a)

In a 15 mL single-mouth bottle, glycine (1.0 g, 13 mmol) was dissolved in 4 mL of 10% Na ₂ CO ₃ aqueous solution, and 2 mL of acetonitrile dissolved Boc anhydride (2.84 g, 13 mmol) was added dropwise at -5 ° C, and the mixture was allowed to warm to room temperature and stirred. After overnight, the filtrate was extracted with petroleum ether, the petroleum ether layer was discarded, the aqueous layer was acidified with hydrochloric acid, ethyl acetate was evaporated, dried, evaporated in vacuo, silica gel column chromatography, methylene chloride:methanol = 30:1 (v /v) 0.8 g of white needle crystals (19a) was eluted in a yield of 35%. ESI-MS m/z 389.3 [2M+K] ⁺ .

Ii) N-(N-tert-Butoxycarbonylglycylethyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole)maleyl Preparation of imine (19b)

In two 25mL flask to dissolve 2mL CH ₂ Cl ₂ Compound 19a (26mg, 0.15mmol), compound 14 (50mg, 0.11mmol) and DMAP (4mg, 0.03mmol), was added 0.5mL CH ₂ Cl ₂ dissolved DCC ( 35mg, 0.17mmol), reacted at room temperature overnight, the reaction was completed by TLC, filtered, filtered, evaporated to dryness, eluted with silica gel column eluting with petroleum ether: ethyl acetate = 1:3 (v/v) to give an orange-red solid (19b 47 mg, yield 69%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.05 (t, 1H, J = 5.5 Hz, -NH), 7.78 (s, 1H,,,,,,,,,,,,,, , 7.59 (d, 1H, J = 8.2 Hz, Ar-H), 7.50 (d, 1H, J = 8.2 Hz, Ar-H), 7.17 (dt, 1H, J = 7.2 Hz, 1.1 Hz, Ar-H ), 7.07 (dt, 1H, J = 7.2 Hz, 1.1 Hz, Ar-H), 6.90 (t, 1H, J = 5.9 Hz, -NH), 6.86 (d, 1H, J = 8.2 Hz, Ar-H) ), 6.85 (d, 1H, J = 8.2 Hz, Ar-H), 6.79 (t, 1H, J = 7.7 Hz, Ar-H), 6.70 (t, 1H, J = 7.7 Hz, Ar-H), 5.64 (s, 2H, -C H ₂ -CN), 4.27 (q, 2H, J = 7.1 Hz, NC H ₂ -CH ₃ ), 3.65 (t, 2H, J = 6.1 Hz, NC H ₂ -CH ₂ -NH), 3.51 (m, 2H , N-CH 2 -C H 2 -NH), 3.35 ( 'q'like, J = 5.5Hz, 6.1Hz, -CO-C H 2 -NH -), 1.35 ( s, 9H, -C(C H ₃ ) ₃ ), 1.33 (t, 3H, J = 7.1 Hz, N-CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.9, 171.8, 171.0, 169.0, 136.1 × 2, 132.5, 132.0, 129.1, 126.6, 126.3, 125.6, 123.3, 122.5, 122.2, 121.9, 121.1, 120.3, 116.7, 110.8, 110.6, 107.5, 105.3, 78.6, 60.4, 41.3, 38.1, 37.8, 34.6, 28.7, 15.8. ESI-MS m/z 495.3 [M+H] ⁺ .

Iii) Preparation of N-glycylethyl-2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole)maleimide (19)

The compound 19b (30 mg, 0.05 mmol) was dissolved in 8 mL of toluene, and an appropriate amount of 100-200 mesh silica gel was added thereto, and the condensed water at 110 ° C under reflux of N ₂ was refluxed for 3.5 hours, cooled to room temperature, filtered under reduced pressure, and the organic layer was evaporated to dryness. Chromatography, dichloromethane:methanol = 50:1 (v/v) eluted to give a red solid (19) 23.5mg, yield 95%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.87 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.59 (d, 1H, J = 8.3 Hz, Ar-H) , 7.49 (d, 1H, J = 8.3 Hz, Ar-H), 7.17 (dt, 1H, J = 7.7 Hz, 1.1 Hz, Ar-H), 7.07 (dt, 1H, J = 7.7 Hz, 1.1 Hz, Ar-H), 6.86 (d, 1H, J = 7.7 Hz, Ar-H), 6.84 (d, 1H, J = 7.1 Hz, Ar-H), 6.79 (t, 1H, J = 7.7 Hz, Ar- H), 6.71 (t, 1H, J = 7.7 Hz, Ar-H), 5.65 (s, 2H, -CH ₂ -CN), 4.25 (q, 2H, J = 7.1 Hz, NC H ₂ -CH ₃ ), 3.66 (t, 2H, J = 5.5 Hz, NC H ₂ -CH ₂ NH), 3.50-3.60 (brs. 2H, -NH ₂ ), 3.49 (t, 2H, J = 5.5 Hz, NCH ₂ -C H ₂ -NH), 3.23 (s, 2H, -CO-C H ₂ -NH ₂ ), 3.15 (s, 1H, NCH ₂ -CH ₂ -N H ), 1.31 (t, 3H, J = 7.1 Hz, N-CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.9×2, 170.7, 136.1×2, 132.5, 132.0, 129.1, 126.5, 126.3, 125.7, 123.3, 122.5, 122.2 , 122.0, 121.1, 120.3, 116.7, 110.8, 110.7, 107.4, 105.3, 63.2, 43.1, 38.1, 37.8, 34.6, 15.8. ESI-MS m/z 495.3 [M+H] ⁺ .

Preparation of Compound 20

i) Preparation of N-tert-butyloxycarbonyl-L-alanine (20a)

According to the preparation method of the compound 19a, white needle-like crystals (20a) (0.66 g) were obtained from L-alanine (1.3 g, 15 mmol). ESI-MS m/z 212.2 [M+Na] ⁺ .)

Ii) N-(N-tert-Butoxycarbonyl-L-alanylethyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole) Preparation of maleimide (20b)

According to the preparation method of the compound 19b, the compound 20a (30 mg, 0.16 mmol), the compound 14 (50 mg, 0.11 mmol), DMAP (4 mg, 0.03 mmol) and DCC (35 mg, 0.17 mmol) were used as raw materials to obtain an orange-red solid (20b) 45 mg, yield 65%. ^{1 H NMR (600MHz, DMSO-} d 6) δ8.05 (t, 1H, J = 5.5Hz, -NH), 7.85 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.58 (d, 1H, J = 8.2 Hz, Ar-H), 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.16 (dt, 1H, J = 7.1 Hz, 1.1 Hz, Ar-H) , 7.06 (dt, 1H, J = 7.1 Hz, 1.1 Hz, Ar-H), 6.85 (d, 2H, J = 7.7 Hz, Ar-H), 6.77 (t, 1H, J = 7.2 Hz, Ar-H ), 6.70 (t, 1H, J = 7.7 Hz, Ar-H), 5.64 (s, 2H, -C H ₂ -CN), 4.24 (q, 2H, J = 7.1 Hz, NC H ₂ -CH ₃ ) , 3.87 (q, 1H, J = 8.3 Hz, CH ₃ -C H -NH-), 3.62 (m, 2H, NC H ₂ -CH ₂ NH), 3.47 (m, 1H, J = 6.1 Hz, NCH ₂ -C H ₂ -NH-), 3.26 (m, 1H, J = 6.1 Hz, NCH ₂ -C H ₂ -NH-), 1.32 (s, 9H, -C(CH ₃ ) 3 ), 1.30 (t, 3H, J=7.1 Hz, N-CH ₂ -C H ₃ ), 1.13 (d, 3H, J = 6.6 Hz, -NH-CH-C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171 .9,171.8,171.0,169.0,136.1×2,132.5,132.0,129.1,126.6,126.3,125.6,123.3,122.5,122.2,121.9,121.1,120.3,116.7,110.8,110.6,107.5,105.3,78.6,60.4 , 41.3, 38.1, 37.8, 34.6, 28.7, 15.8. ESI-MS m/z 1219.2 [2 M+H] ⁺ .

Iii) N-(L-alanylethyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole)maleimide (20) Preparation

According to the preparation method of the compound 19, the compound (20) (23.4 mg) was obtained from the compound 20b (30 mg, 0.049 mmol). ^{1 H NMR (600MHz, DMSO-} d 6) δ8.41 (t, 1H, J = 5.5Hz, -NH), 7.84 (s, 1H, Ar-H), 7.67 (s, 1H, Ar-H), 7.46 (d, 1H, J = 8.3 Hz, Ar-H), 7.33 (d, 1H, J = 8.3 Hz, Ar-H), 7.06 (t, 2H, J = 7.1 Hz, Ar-H), 7.03 ( d, 1H, J = 8.3 Hz, Ar-H), 6.74 (t, 1H, J = 7.1 Hz, Ar-H), 6.65 (dd, 2H, J = 7.1 Hz, 8.3 Hz, Ar-H), 4.90 (s, 2H, -C H ₂ -CN), 4.21 (q, 2H, J = 7.1 Hz, NC H ₂ -CH ₃ ), 3.66 (m, 2H, NC H ₂ -CH ₂ NH), 3.49 (m) , 2H, NCH ₂ -C H ₂ -NH-), 3.53 (m, 1H, J = 6.6 Hz, -CO-C H -NH ₂ ), 1.28 (t, 3H, J = 7.1 Hz, -NCH ₂ - _{C H 3), 1.18 (d} , 3H, J = 7.1Hz, H 2 NCH-C H 3). 13 C NMR (150MHz, DMSO-d 6) δ173.4,172.1,169.4,137.1,136.0,134.1, 131.9, 127.2 × 2, 126.7, 126.0, 122.4, 122.3 × 2, 122.2, 121.9, 120.2 × 2, 110.8, 110.6, 105.6 × 2, 49.7, 49.1, 41.2, 38.0, 37.4, 19.7, 15.7. ESI-MS m /z 509.2[M+H] ⁺ .

Preparation of Compound 21

i) Preparation of N,N-di-tert-butyloxycarbonyl-L-histidine (21a)

According to the preparation method of the compound 18a, 0.92 g of white needle crystals (21a) was obtained from histidine (1.0 g, 7 mmol), and the yield was 37%. ESI-MS m/z 356.4 [M+H] ⁺ .

Ii) N-(N,N-di-tert-butyloxycarbonyl-L-histidylethyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3- Preparation of maleimide (21b)

According to the preparation method of the compound 18b, the compound (21b) was obtained from the compound 21a (80.9 mg, 0.16 mmol), the compound 14 (50 mg, 0.11 mmol), DMAP (4.2 mg, 0.03 mmol) and DCC (35 mg, 0.17 mmol). 35 mg, yield 45%. ESI-MS m/z 775.5 [M+H] ⁺ .

Iii) N-(L-histylethyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole)maleimide (21) Preparation

According to the preparation method of the compound 18, the compound (21) (20.2 mg) was obtained from the compound 21b (30 mg, 0.039 mmol), and the yield was 90%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.85 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.58 (d, 1H, J = 8.2Hz, Ar-H) , 7.54 (s, 1H, imidazole-H), 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.16 (t, 1H, J = 7.1 Hz, Ar-H), 7.05 (t, 1H, J = 7.1 Hz, Ar-H), 6.84 (d, 2H, J = 8.2 Hz, Ar-H), 6.77 (t, 1H, J = 6.6 Hz, Ar-H), 6.76 (s, 1H, imidazole- H), 6.68 (t, 1H, J = 7.7 Hz, Ar-H), 5.63 (s, 2H, -CH ₂ -CN), 4.23 (q, 2H, J = 7.1 Hz, NC H ₂ -CH ₃ ), 3.65 (m, 2H, NC H 2 -CH 2 -NH), 3.59 (m, 1H, NCH 2 -C H 2 -NH -), 3.53 (m, 1H, J = 4.4Hz, -CO-C H -NH ₂ ), 3.4 (m, 2H, imidazole-C H ₂ -CHNH ₂ ), 1.29 (t, 3H, J = 7.1 Hz, NCH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ173.6, 172.0, 171.9, 136.1, 135.4, 135.3, 132.7, 132.5, 131.9, 129.2, 126.6, 126.3, 123.3, 122.5, 122.2, 122.0, 121.1, 120.3, 116.7, 110.8, 110.7, 107.5, 105.3, 70.3, 60.4, 55.4, 42.3, 38.2, 34.6, 29.5, 22.6, 15.7. ESI-MS m/z 575.3 [M+H] ⁺ .

Preparation of Compound 22

i) Preparation of N-tert-butyloxycarbonyl-L-tryptophan (22a)

According to the preparation method of the compound 18a, white needle-like crystals (22a) (1.3 g) were obtained from tryptophan (1.0 g, 5 mmol), yield 63.3%. ESI-MS m/z 305.3 [M+H] ⁺ .

Ii) N-(N-tert-Butyloxycarbonyl-L-tryptophanyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole) Preparation of maleimide (22b)

According to the preparation method of the compound 18b, the compound (22b) 80 mg was obtained from the compound 22a (72 mg, 0.17 mmol), the compound 13 (50 mg, 0.11 mmol), DMAP (4.2 mg, 0.03 mmol) and DCC (35 mg, 0.17 mmol). The yield was 89%. ESI-MS m/z 724.2 [M+H] ⁺ , 746.2 [M+Na] ⁺ .

Iii) N-(L-tryptophanyl)-2-(1-ethyl-3-indolyl)-3-(1-cyanomethyl-3-indole)maleimide (22) Preparation

According to the preparation method of Compound 18, Compound 22b (30 mg, 0.041 mmol) was used as a starting material to obtain the product (22) 23.2 mg, yield 90%. ^{1 H NMR (600MHz, DMSO-} d 6) δ10.81 (brs, 1H, -NH), 8.22 (t, 1H, J = 6.1Hz, -NH), 7.86 (s, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.58 (d, 1H, J = 8.3 Hz, Ar-H), 7.46 (dd, 2H, J = 8.2 Hz, 7.7 Hz, Ar-H), 7.32 (d, 2H) , J = 8.2 Hz, Ar-H), 7.16 (t, 1H, J = 8.8 Hz, Ar-H), 7.04-7.02 (m, 2H, Ar-H), 6.88-6.86 (m, 3H, Ar- H), 6.74 (t, 1H, J = 7.7 Hz, Ar-H), 6.67 (t, 1H, J = 7.2 Hz, Ar-H), 5.61 (s, 2H, -CH ₂ -CN), 4.21. (q, 2H, J = 7.1 Hz, NC H ₂ -CH ₃ ), 3.67 (m, 2H, -NC H ₂ -CH ₂ -NH), 3.43 (m, 2H, -CH-CH ₂ -indole) , 3.1 (d, 2H, J = 3.8 Hz, -CH-C H ₂ -indole), 2.68-2.65 (m, 2H, NCH ₂ -C H ₂ -NH-), 1.26 (t, 3H, J = 7.1 Hz, NCH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 175.2, 172.0, 171.9, 136.8, 136.6, 136.1, 132.4, 132.0, 129.2, 127.9, 126.6, 126.3, 125.7, 124.1 , 123.2, 122.4, 122.2, 122.0, 121.4, 121.1, 120.3, 119.0, 118.7, 116.7, 111.8, 111.1, 110.8, 110.6, 107.5, 105.3, 60.3, 55.8, 41.3, 38.2, 34.6, 31.3, 15.7. ESI-MS m/z 624.4 [M+H] ⁺ .

Preparation of Compound 23

According to the preparation method of compound 16, the compound N-(2-aminoethyl)-2-(1-ethyl-3-indolyl)-3-(3-indole)maleimide (930 mg, 2.34) Methyl acetate (23 mg, yield 88%) was obtained from the crude material. ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.84 (s, 1H, indole-NH), 8.19 (brs, 3H, -NH ₃ ⁺ ), 7.77 (d, 1H, J = 2.5 Hz, Ar-H ), 7.70 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.39 (d, 1H, J = 8.1 Hz, Ar-H), 7.05 (t, 1H) , J = 7.6 Hz, Ar-H), 6.99 (dd, 2H, J = 7.1 Hz, 5.0 Hz, Ar-H), 6.74 (t, 1H, J = 8.7 Hz, Ar-H), 6.73 (t, 1H, J = 7.9 Hz, Ar-H), 6.63 (t, 1H, J = 7.5 Hz, Ar-H), 4.25 (q, 2H, J = 7.2 Hz, -NC H ₂ -CH ₃ ), 3.84 ( t, 2H, J = 5.7 Hz, NC H ₂ -CH ₂ NH ₃ ⁺ ), 3.10 (t, 2H, J = 5.7 Hz, NCH ₂ -C H ₂ -NH ₃ ⁺ ), 1.29 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 172.2, 172.1, 136.5, 135.9, 131.8, 129.8, 127.6, 126.9, 126.4, 125.4, 122.2, 122.1, 121.9, 121.5, 120.0, 119.8, 112.3, 110.5, 106.0, 105.5, 41.1, 40.2, 39.4, 15.7. HR-ESIMS m/z 399.1826 [M-Cl] ⁺ (calcd. for C ₂₄ H ₂₃ N ₄ O ₂ , 399.1815).

Preparation of Compound 24

i) Preparation of 1-benzyl hydrazine (24a)

In a 100 mL three-necked flask, NaH (300 mg, 7.5 mmol, 60% by mass, dispersed in paraffin) was suspended in 30 mL of DMF, and 10 mL of DMF-dissolved hydrazine (585 mg, 5 mmol) was slowly added dropwise at -5 °C. The reaction was allowed to react at room temperature for 30 min and then decreased to -5 °C. Add benzyl bromide (0.89 mL, 7.5 mmol) dropwise, complete the dropwise addition, stir the reaction at -5 ° C for 30 min, complete the reaction, add 10 mL of methanol, then add 100 mL of saturated ammonium chloride solution, extract with CH ₂ Cl ₂ (100 mL × 3 The organic layer was combined, dried over anhydrous sodium sulfate and evaporated to dryness. %. ¹ H NMR (600MHz, CDCl ₃ ) δ 7.76 (d, 1H, J = 7.7 Hz, Ar-H), 7.38-7.33 (m, 4H, Ar-H), 7.27 (dt, 1H, J = 6.8 Hz) , 0.9 Hz, Ar-H), 7.22 (dt, 1H, J = 6.9 Hz, 0.9 Hz, Ar-H), 7.20 (t, 1H, J = 3.2 Hz, Ar-H), 7.18 (d, 2H, J = 6.8 Hz, Ar-H), 6.65 (dd, 1H, J = 3.2 Hz, 0.9 Hz, Ar-H), 5.37 (s, 2H, Ph-CH ₂ -). ¹³ C NMR (150 MHz, CDCl _{3 )} δ 137.7, 136.5, 128.9, 128.9, 128.4, 127.8, 127.0, 126.9, 121.9, 121.2, 119.7×2, 109.9, 101.9, 50.2. ESI-MS m/z 208.2 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-3-indole) maleic anhydride (24b)

According to the preparation method of the compound 1c, the compound 24a (356 mg, 1.72 mmol), oxalyl chloride (328 mg, 2.58 mmol), the compound 1a (349 mg, 1.72 mmol) and Et ₃ N (347 mg, 3.44 mmol) were used as raw materials to obtain a red solid ( 24b) 299 mg, yield 39%. ^{1 H NMR (600MHz, DMSO-} d 6) δ8.02 (s, 1H, Ar-H), 7.94 (s.1H, Ar-H), 7.53 (d, 1H, J = 7.3Hz, Ar-H) , 7.44 (d, 1H, J = 7.8 Hz, Ar-H), 7.33 (t, 2H, J = 6.4 Hz, Ar-H), 7.27 (t, 1H, J = 6.8 Hz, Ar-H), 7.20 (d, 2H, J = 5.9 Hz, Ar-H), 7.11 (t, 1H, J = 7.3 Hz, Ar-H), 7.05 (t, 1H, J = 6.8 Hz, Ar-H), 6.91 (d , 1H, J = 7.3 Hz, Ar-H), 6.88 (d, 1H, J = 7.3 Hz, Ar-H), 6.75 (t, 1H, J = 7.3 Hz, Ar-H), 6.73 (t, 1H) , J = 7.3 Hz, Ar-H), 5.52 (s, 2H, Ph-CH ₂ -), 4.29 (q, 2H, J = 6.8 Hz, -C H ₂ -CH ₃ ), 1.34 (t, 3H, J = 6.8 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 167.0, 166.9, 137.9, 136.6, 136.3, 133.9, 133.3, 129.2 × 2, 128.8, 128.1, 127.8 , 127.6 × 2, 126.2, 125.9, 122.9, 122.8, 122.2, 122.0, 120.8, 120.7, 111.5, 111.1, 105.3, 104.7, 50.0, 40.5, 15.7. ESI-MS m/z 447.2 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-3-indole)maleimide (24c)

248 mg of a red powdery solid (24c) was obtained from compound 24b (260 mg, 0.58 mmol), HMDS (2.44 mL, 11.7 mmol) and MeOH (0.23 mL, 5.8 mmol). ^{1 H NMR (600MHz, DMSO-} d 6) δ10.95 (s, 1H, imide-NH), 7.90 (s, 1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.46 (d, 1H, J = 8.2 Hz, Ar-H), 7.36 (d, 1H, J = 8.2 Hz, Ar-H), 7.32 (t, 2H, J = 7.6 Hz, Ar-H), 7.26 (t, 1H, J = 7.3 Hz, Ar-H), 7.17 (d, 2H, J = 7.3 Hz, Ar-H), 7.04 (t, 1H, J = 7.8 Hz, Ar-H), 6.97 (t, 1H, J = 7.3 Hz, Ar-H), 6.84 (d, 1H, J = 8.2 Hz, Ar-H), 6.82 (d, 1H, J = 7.7 Hz, Ar-H), 6.65 (t, 1H, J = 7.8 Hz) , Ar-H), 6.64 (t, 1H, J = 7.4 Hz, Ar-H), 5.49 (s, 2H, Ph-CH ₂ -), 4.26 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.34 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.4 × 2, 138.2, 136.4, 136.0, 132.8, 132.0, 129.1 × 2, 128.5, 128.0, 127.5, 127.4 × 2, 126.7, 126.4, 122.4, 122.2, 121.8, 121.7, 120.2, 120.1, 111.1, 110.7, 106.0, 105.4, 49.9, 41.3, 15.8. ESI-MS m /z 446.2[M+H] ⁺ .

Iv) Preparation of 2-(1-ethyl-3-indolyl)-3-(3-indole)maleimide (24d)

The compound 24c (100 mg, 0.225 mmol) was dissolved in DMSO (0.85 mL), and 1 M t-BuOK/THF solution (8.4 mL, 8.4 mmol) was added dropwise with stirring, and the addition was completed, and O was added to the reaction solution. ₂ about 30min, saturated ammonium chloride solution was added to terminate the reaction, extracted with ethyl acetate (100mL × 3 times), the organic layer was combined and dried over anhydrous Na ₂ SO _4, evaporated to dryness in vacuo. The oil was separated by silica gel column chromatography eluting with methylene chloride:ethyl acetate=6:1 (v/v) to yield 70.5 mg of red powder (24d), yield 89%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.66 (s, 1H, indole-NH), 10.90 (s, 1H, imido-NH), 7.76 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.46 (d, 1H, J = 8.2 Hz, Ar-H), 7.37 (d, 1H, J = 8.1 Hz, Ar-H), 7.04 (t, 1H, J = 7.6 Hz, Ar-H), 6.98 (t, 1H, J = 7.5 Hz, Ar-H), 6.90 (d, 1H, J = 8.0 Hz, Ar-H), 6.74 (d, 1H, J = 8.1 Hz, Ar- H), 6.69 (t, 1H, J = 7.5 Hz, Ar-H), 6.62 (t, 1H, J = 7.5 Hz, Ar-H), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.31 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.6, 173.5, 136.6, 136.0, 131.9, 129.8, 128.4, 127.7, 126.6, 125.7, 122.2, 122.1, 121.9, 121.6, 120.1, 119.9, 112.3, 110.6, 106.1, 105.5, 41.2, 15.8. ESI-MS m/z 356.1 [M+H] ⁺ .

v) Preparation of 2-(1-ethylindole)-3-(3-indole) maleic anhydride (24e)

In a 50 mL single-mouth flask, the compound was suspended in 20 mL of 10% aqueous KOH solution for 24 days (50 mg, 0.14 mmol), refluxed at 110 ° C for 40 min, cooled to room temperature, acidified with 2N hydrochloric acid, extracted with ethyl acetate, and combined with organic layer. Dry over anhydrous sodium sulfate, EtOAc (EtOAc m.) ^{1 H NMR (600MHz, DMSO-} d 6) δ11.96 (s, 1H, indole-NH), 7.89 (d, 1H, J = 2.8Hz, Ar-H), 7.83 (s, 1H, Ar-H) , 7.52 (d, 1H, J = 8.3 Hz, Ar-H), 7.44 (d, 1H, J = 8.3 Hz, Ar-H), 7.10 (t, 1H, J = 7.4 Hz, Ar-H), 7.05 (t, 1H, J = 7.7 Hz, Ar-H), 6.98 (d, 1H, J = 7.7 Hz, Ar-H), 6.78 (t, 1H, J = 7.6 Hz, Ar-H), 6.77 (d , 1H, J = 7.6 Hz, Ar-H), 6.70 (t, 1H, J = 7.1 Hz, Ar-H), 4.25 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.30 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 167.1, 167.0, 136.8, 136.2, 133.1, 131.3, 128.7, 127.9, 126.1, 125.2, 122.7 × 2, 122.2, 121.9, 120.7, 120.5, 112.8, 111.0, 105.5, 104.8, 41.4, 15.7. ESI-MS m/z 357.1 [M+H] ⁺ .

Vi) Preparation of N-(N,N-dimethylaminoethyl)-2-(1-ethyl-3-indolyl)-3-(3-indole)maleimide (24)

The compound 24d (55mg, 0.154mmol), N,N-dimethylethylenediamine (84.4μL, 0.772mmol) and catalytic amount Et ₃ N were dissolved in 30mL of toluene, dissolved in toluene, and condensed water at 110 ° C under nitrogen protection. After refluxing for 17 h, the solvent was evaporated to dryness. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.73 (s, 1H, indole-NH), 7.80 (d, 1H, J = 2.7Hz, Ar-H), 7.77 (s, 1H, Ar-H) , 7.47 (d, 1H, J = 8.3 Hz, Ar-H), 7.39 (d, 1H, J = 8.1 Hz, Ar-H), 7.05 (t, 1H, J = 7.7 Hz, Ar-H), 6.99 (t, 1H, J = 7.6 Hz, Ar-H), 6.89 (d, 1H, J = 7.9 Hz,), 6.74 (d, 1H, J = 8.1 Hz, Ar-H), 6.70 (d, 1H, J = 7.4 Hz, Ar-H), 6.62 (d, 1H, J = 7.8 Hz, Ar-H), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.66 (t, 2H, J=6.4 Hz, NC H ₂ -CH ₂ N(CH ₃ ) ₂ ), 2.49 (t, J = 6.4 Hz, 2H, NCH ₂ -C H ₂ -N(CH ₃ ) ₂ ), 2.18 (s , 6H, -N(CH ₃ ) ₂ ), 1.31 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.1 × 2, 136.6 , 136.0, 132.1, 130.0, 127.4, 126.8, 126.5, 125.6, 122.3, 122.2, 121.9, 121.6, 120.2, 120.0, 112.4, 110.7, 106.1, 105.5, 57.3, 45.7 × 2, 41.3, 36.3, 15.8. HR-ESIMS m/z 427.2140 [M+H] ⁺ (calcd. for C ₂₆ H ₂₇ N ₄ O ₂ , 427.2134).

Preparation of compound 25

According to the preparation method of the compound 16, the compound hydrochloride (N-(N,N-dimethylaminoethyl)-2-(1-ethyl-3-indole) was obtained from the compound 24 (50 mg, 0.117 mmol).哚)-3-(3-indole) maleimide hydrochloride (25) (48 mg, yield 90%). ^{1 H NMR (500MHz, DMSO-} d 6) δ11.94 (s, 1H, indole-NH), 10.61 (brs, 1H, (CH 3) 2 N H +), 7.77 (d, 1H, J = 2.4Hz , Ar-H), 7.69 (s, 1H, Ar-H), 7.47 (d, 1H, J = 8.2 Hz, Ar-H), 7.40 (d, 1H, J = 8.1 Hz, Ar-H), 7.05 (t, 1H, J = 7.6 Hz, Ar-H), 6.99 (d, 1H, J = 7.8 Hz, Ar-H), 6.98 (t, 1H, J = 7.8 Hz, Ar-H), 6.76 (d , 1H, J = 8.0 Hz, Ar-H), 6.72 (t, 1H, J = 7.5 Hz, Ar-H), 6.62 (t, 1H, J = 7.5 Hz, Ar-H), 4.23 (q, 2H) , J=7.0 Hz, -C H ₂ -CH ₃ ), 3.93 (t, 2H, J = 5.7 Hz, NC H ₂ -CH ₂ (CH ₃ ) ₂ NH ⁺ ), 3.36 (t, 2H, J = 6.0) Hz, NCH ₂ -C H ₂ -(CH ₃ ) ₂ NH ⁺ ), 2.84 (s, 6H, (C H ₃ ) ₂ NH ⁺ ), 1.28 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.9×2, 136.5, 135.9, 131.8, 129.9, 128.0, 127.1, 126.4, 125.3, 122.2, 122.1×2, 121.7, 120.0, 119.8, 112.4 , 110.9, 105.9, 105.5, 54.8, 42.6 × 2, 41.1, 33.9, 15.7. HR-ESIMS m/z 427.2141 [M-Cl] ⁺ (calcd. for C ₂₆ H ₂₆ N ₄ O ₂ , 426.2056).

Preparation of Compound 26

i) Preparation of 1-benzyl-6-bromoindole (26a)

Prepared according to the synthesis method of compound 24a, using 6-bromoindole (980 mg, 5 mmol), NaH (300 mg, 7.5 mmol, 60% by mass, dispersed in paraffin) and benzyl bromide (1283 mg, 7.5 mmol) as raw materials. The residue was purified by silica gel column chromatography eluting elut elut elut elut eluting ¹ H NMR (600MHz, CDCl ₃ ) δ 7.54 (d, 1H, J = 8.8 Hz, Ar-H), 7.47 (s, 1H, Ar-H), 7.35-7.31 (m, 3H, Ar-H) , 7.25 (dd, 1H, J = 8.8 Hz, 1.9 Hz, Ar-H), 7.10-7.12 (m, 3H, Ar-H), 6.56 (d, 1H, J = 3.8 Hz, Ar-H), 5.27 (s, 2H, Ph-C H ₂ -). ¹³ C NMR (150MHz, CDCl ₃ ) δ 137.3, 137.1, 129.0 × 2, 127.9, 127.7, 126.8 × 2, 123.0, 122.3, 115.5, 112.8, 102.1, 50.2. ESI-MS m/z 286.0/288.0 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-6-bromo-3-indole) maleic anhydride (26b)

According to the preparation method of the compound 24b, the compound 24a (1100 mg, 3.86 mmol), (COCl) ₂ (500 μL, 5.79 mmol), the compound 1c (783 mg, 3.86 mmol) and Et ₃ N (1070 μL, 7.72 mmol) were prepared as a starting material. The methanol was recrystallized to give 652 mg of red powder (26b), yield: 32.2%. ^{1 H NMR (600MHz, DMSO-} d 6) δ8.02 (s, 1H, Ar-H), 7.99 (s, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.54 (d, 1H, J = 8.2 Hz, Ar-H), 7.35 (t, 2H, J = 7.7 Hz, Ar-H), 7.29 (t, 1H, J = 6.6 Hz, Ar-H), 7.19 (d, 2H, J = 7.1 Hz, Ar-H), 7.12 (t, 1H, J = 7.7 Hz, Ar-H), 6.90 (d, 1H, J = 8.2 Hz, Ar-H), 6.88 (d, 1H, J = 7.7 Hz, Ar-H), 6.76 (d, 1H, J = 7.7 Hz, Ar-H), 6.71 (t, 1H, J = 7.7 Hz, Ar-H), 5.53 (s, 2H, Ph-CH ₂ -), 4.32 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.37 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO -d ₆ ) δ166.9,166.8,137.6,137.3,136.3,134.4,133.6,130.0,129.2×2,128.2,127.5×2,126.8,125.7,125.4,123.6,123.5,122.9,122.0,120.8,115.8, 114.3, 111.2, 105.5, 104.5, 50.0, 41.6, 15.8. ESI-MS m/z 525.1/527.1 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-6-bromo-3-indole)maleimide (26c)

Prepared according to the preparation method of compound 24c, Compound 26b (600mg, 1.14mmol), HMDS (12mL, 57.3mmol) and MeOH (1.2mL, 28.7mmol), which were separated by silica gel column chromatography and eluted with dichloromethane. The powdery solid (26c) was 218 mg in a yield of 95%. ^{1 H NMR (600MHz, DMSO-} d 6) δ10.99 (s, 1H, imide-NH), 7.90 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.65 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.3 Hz, Ar-H), 7.34 (t, 2H, J = 7.7 Hz, Ar-H), 7.28 (t, 1H, J = 7.1 Hz, Ar-H), 7.17 (d, 2H, J = 7.1 Hz, Ar-H), 7.05 (t, 1H, J = 7.7 Hz, Ar-H), 6.82 (d, 1H, J = 8.8 Hz, Ar- H), 6.79 (d, 1H, J = 7.1 Hz, Ar-H), 6.72 (d, 1H, J = 8.3 Hz, Ar-H), 6.63 (t, 1H, J = 7.1 Hz, Ar-H) , 5.51 (s, 2H, Ph-CH ₂ -), 4.29 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 1.37 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.3, 173.1, 137.9, 137.2, 136.1, 133.4, 132.3, 129.3, 129.2 × 2, 128.1, 127.4, 127.4, 126.5, 126.2, 125.9, 123.3 , 123.0, 122.3, 121.7, 120.2, 115.3, 113.9, 110.8, 106.3, 105.1, 49.8, 41.3, 15.8. ESI-MS m/z 524.1/526.1 [M+H] ⁺ .

Iv) Preparation of 2-(1-ethyl-3-indolyl)-3-(6-bromo-3-indolyl)maleimide (26d)

Prepared according to the method for the preparation of compound 24d, Compound 26c (538 mg, 1.03mmol), DMSO (1.7mL), 1M t-BuOK/THF solution (16.8mL, 16.8mmol) and O ₂ as starting material. The mixture was chromatographed on silica gel eluting with EtOAc EtOAc (EtOAc) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.81 (s, 1 H, Ar-H), 7.76 (d, 1H, J = 2.8 Hz, Ar-H), 7.57 (s, 1H, Ar-H) , 7.46 (d, 1H, J = 8.3 Hz, Ar-H), 7.04 (dt, 1H, J = 8.2 Hz, 1.1 Hz, Ar-H), 6.78 (d, 1H, J = 8.0 Hz, Ar-H ), 6.75 (dd, 1H, J = 8.6 Hz, 1.8 Hz, Ar-H), 6.71 (d, 1H, J = 8.8 Hz, Ar-H), 6.69 (dt, 1H, J = 7.3 Hz, 0.9 Hz) , Ar-H), 4.26 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 1.34 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR ( 150MHz, DMSO-d ₆ ) δ173.4×2, 137.4, 136.0, 132.2, 130.6, 128.6, 127.4, 126.4, 125.0, 123.1, 122.6, 122.3, 121.7, 120.2, 115.0, 114.9, 110.7, 106.3, 105.3, 41.3 , 15.8. ESI-MS m/z 434.0 / 436.0 [M+H] ⁺ , HR-ESI MS m/z 434.0506 [M+H] ⁺ (calcd. for C ₂₂ H ₁₇ N ₃ O ₂ Br, 434.0504).

v) Preparation of 2-(1-ethyl-3-indolyl)-3-(6-bromo-3-indole) maleic anhydride (26e)

According to the preparation method of the compound 24e, Compound 26d (80 mg, 0.185 mmol) was used as a starting material to obtain an orange-red solid (26e) 60 mg, yield 75%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.99 (s, 1H, indole-NH), 7.88 (d, 1H, J = 2.7Hz, Ar-H), 7.84 (s, 1H, Ar-H) , 7.62 (s, 1H, Ar-H), 7.49 (d, 1H, J = 8.0 Hz, Ar-H), 7.08 (t, 1H, J = 7.6 Hz, Ar-H), 6.80 (t, 2H, J = 7.1 Hz, Ar-H), 6.73 (t, 2H, J = 7.5 Hz, Ar-H), 4.26 (q, 2H, J = 8.2 Hz, -C H ₂ -CH ₃ ), 1.32 (t, 3H, J=7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.8×2, 137.4, 136.1, 133.2, 131.7, 128.9, 127.5, 125.8, 124.4, 123.2 , 123.0, 122.7, 121.9, 120.7, 115.7, 115.2, 111.0, 105.5, 104.5, 41.4, 15.8. ESI-MS m/z 435.0/437.0 [M+H] ⁺ .

Vi) N-(N,N-Dimethylaminoethyl)-2-(1-ethyl-3-indolyl)-3-(6-bromo-3-indolyl)maleimide (26) Preparation

According to the preparation method of the compound 24, compound 26e (50 mg, 0.115 mmol), N,N-dimethylethylenediamine (81 μL, 0.575 mmol) and a catalytic amount of Et ₃ N were used as raw materials to obtain a red solid (26) 46.4. Mg, yield 80%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.79 (s, 1H, indole-NH), 7.84 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.56 (d, 1H, J = 1.4 Hz, Ar-H), 7.47 (d, 1H, J = 8.2 Hz, Ar-H), 7.03 (t, 1H, J = 7.6 Hz, Ar-H), 6.74 (d, 2H, J = 8.5 Hz, Ar-H), 6.69 (d, 1H, J = 6.5 Hz, Ar-H), 6.68 (t, 1H, J = 62 Hz, Ar-H), 4.26 (q, 2H, J = 7.2) Hz, -C H ₂ -CH ₃ ), 3.64 (t, 2H, J = 6.4 Hz, -NC H ₂ CH ₂ -N(CH ₃ ) ₂ ), 2.46 (t, 2H, J = 6.5 Hz, -NCH ₂ C H ₂ -N(CH ₃ ) ₂ ), 2.16 (s, 6H, -N(CH ₃ ) ₂ ), 1.33 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.8×2, 137.3, 136.0, 132.2, 130.5, 127.6, 126.3, 126.2, 124.8, 122.9, 122.6, 122.3, 121.6, 120.1, 114.9, 114.8, 110.7, 106.2, 105.1 , 57.2, 45.6, 41.2, 36.2, 15.7. HR-ESIMS m/z 505.1250 [M+H] ⁺ (calcd. for C ₂₆ H ₂₆ N ₄ O ₂ Br, 505.1239).

Preparation of Compound 27

According to the preparation method of the compound 16, the compound hydrochloride (N,N-N-dimethylaminoethyl)-2-(1-ethyl-3-indole) was obtained from the compound 26 (100 mg, 0.198 mmol).哚)-3-(6-Bromo-3-indole) maleimide hydrochloride (27) (91 mg, yield 85%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H, indole-NH), 10.63 (brs, 1H, -(CH ₃ ) ₂ N H ⁺ ), 7.79 (s, 1H, Ar-H ), 7.74 (s, 1H, Ar-H), 7.60 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.05 (t, 1H, J = 7.5 Hz) , Ar-H), 6.84 (d, 1H, J = 8.0 Hz, Ar-H), 6.76 (d, 1H, J = 7.2 Hz, Ar-H), 6.74 (s, 1H, Ar-H), 6.70 (d, 1H, J = 7.4 Hz, Ar-H), 4.26 (q, 2H, J = 6.9 Hz, -C H ₂ -CH ₃ ), 3.92 (t, 2H, J = 4.9 Hz, NC H ₂ - CH ₂ N(CH ₃ ) ₂ H ⁺ ), 3.04 (t, 2H, J = 4.9 Hz, NCH ₂ -C H ₂ -N(CH ₃ ) ₂ H ⁺ ), 2.83 (s, 6H, -(C H ₃ ) ₂ NH ⁺ ), 1.32 (t, 3, J = 6.9 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.8, 171.6, 137.4, 136.0, 132.1, 130.5, 128.0, 126.9, 126.1, 124.7, 123.1, 122.5, 122.3, 121.8, 120.1, 115.0, 114.8, 110.7, 106.2, 105.2, 54.8, 45.6, 42.6 × 2, 41.2, 33.5, 15.7. HR-ESIMS m/z 505.1246[M-Cl] ⁺ (calcd.for C ₂₆ H ₂₇ N ₄ O ₂ Br, 505.1250).

Preparation of Compound 28

According to the preparation method of the compound 14, a red solid N-(2-aminoethyl)-2-(1-ethyl-3-indole) was obtained from the compound 26e (49 mg, 0.114 mmol) and ethylenediamine. 3-(6-Bromo-3-indole) maleimide (28) 49 mg, yield 90%. ^{1 H NMR (500MHz, DMSO-} d 6) δ7.81 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.56 (s, 1H, Ar-H), 7.46 (d, 1H, J = 8.3 Hz, Ar-H), 7.03 (t, 1H, J = 7.6 Hz, Ar-H), 6.77 (d, 1H, J = 8.0 Hz, Ar-H), 6.74 (dd, 1H, J = 8.6 Hz, 1.4 Hz, Ar-H), 6.70 (d, 1H, J = 8.6 Hz, Ar-H), 6.67 (t, 1H, J = 7.5 Hz, Ar-H), 4.25 (q, 2H) , J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.56 (t, 2H, J = 6.5 Hz, NC H ₂ -CH ₂ NH ₂ ), 2.77 (t, 2H, J = 6.5 Hz, NCH ₂ - C H ₂ -NH ₂ ), 1.32 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 172.1 × 2, 137.3, 135.9, 132.0 , 130.4, 127.7, 126.4, 126.2, 124.8, 123.0, 122.5, 122.2, 121.6, 120.1, 114.9, 114.8, 110.7, 106.3, 105.2, 41.3, 41.2, 40.6, 15.7. HR-ESIMS m/z 477.0934 [M+H ] ⁺ (calcd.for C ₂₄ H ₂₂ N ₄ O ₂ Br, 477.0926).

Preparation of Compound 29

According to the preparation method of the compound 16, the compound hydrochloride (N-(2-aminoethyl)-2-(1-ethyl-3-indole)-3- was obtained from the compound 28 (200 mg, 0.42 mmol). (6-Bromo-3-indole) Maleimide hydrochloride (29) 172 mg, yield 80%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.03 (s, 1H, indole-NH), 8.20 (brs, 3H, -NH ₃ ⁺ ), 7.80 (s, 1H, Ar-H), 7.75 (s , 1H, Ar-H), 7.60 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.1 Hz, Ar-H), 7.05 (t, 1H, J = 7.4 Hz, Ar-H) , 6.83 (d, 1H, J = 7.9 Hz, Ar-H), 6.76 (d, 1H, J = 8.5 Hz, Ar-H), 6.73 (d, 1H, J = 8.8 Hz, Ar-H), 6.72 (t, 1H, J = 7.8 Hz, Ar-H), 4.26 (q, 2H, J = 6.9 Hz, -C H ₂ -CH ₃ ), 3.83 (t, 2H, J = 6.4 Hz, NC H ₂ - CH ₂ NH ₃ ⁺ ), 3.08 (t, 2H, J = 6.5 Hz, NCH ₂ -C H _μ -NH ₃ ⁺ ), 1.32 (t, 3H, J = 6.9 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.9, 171.8, 137.4, 136.9, 132.0, 130.5, 127.9, 126.8, 126.1, 124.7, 123.1, 122.5, 122.3, 121.8, 120.1, 115.0, 114.8, 110.7, 106.2 , 105.2, 41.2, 38.1, 36.1, 15.7. HR-ESIMS m/z 477.0932 [M-Cl] ⁺ (calcd. for C ₂₄ H ₂₂ N ₄ O ₂ Br, 477.0934).

Preparation of Compounds 30, 31, 32

NaH (13.5 mg, 0.563 mmol, 60% by mass, dispersed in paraffin) was suspended in DMF at 0 ° C. DMF-dissolved compound 24d (40 mg, 0.113 mmol) was added dropwise, and NaH (338 mg, 14.1 mmol) was suspended in DMF. , mass fraction 60%, dispersed in paraffin), dropwise addition of chlorohydrin (38 μL, 0.563 mmol), low temperature reaction for 20 min, piped into the suspension of compound 24d, reacted for 20 min, raised to room temperature, condensed The water was refluxed for 4.5 h. The mixture was cooled to -5 ° C, MeOH was added dropwise, and aq. Methanol = 100:1 (v/v) eluted red solid N-(2-hydroxyethyl)-2-(1-ethyl-3-indole)-3-(3-indole)maleyl Imine (30), 2-(1-ethyl-3-indolyl)-3-(1-(2-hydroxyethyl)-3-indole)maleimide (31) and N-( 2-Hydroxyethyl)-2-(1-ethyl-3-indolyl)-3-(1-(2-hydroxyethyl)-3-indole) maleimide (32) 23 mg, respectively 5mg and 4mg, the yields were 51%, 11% and 8%, respectively.

Compound ^{30: 1 H NMR (600MHz,} DMSO-d 6) δ11.67 (s, 1H, indole-NH), 7.78 (d, 1H, J = 2.1Hz, Ar-H), 7.73 (s, 1H, Ar -H), 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.37 (d, 1H, J = 8.1 Hz, Ar-H), 7.03 (t, 1H, J = 7.6 Hz, Ar-H ), 6.97 (t, 1H, J = 7.6 Hz, Ar-H), 6.91 (d, 1H, J = 8.0 Hz, Ar-H), 6.73 (d, 1H, J = 8.0 Hz, Ar-H), 6.68 (t, 1H, J = 7.5 Hz, Ar-H), 6.61 (t, 1H, J = 7.6 Hz, Ar-H), 4.89 (t, 1H, J = 5.5 Hz, imide-NCH ₂ CH ₂ O H ), 4.22 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.62-3.59 (m, 4H, imide-N(CH ₂ ) ₂ -), 1.29 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.1×2, 136.5, 135.9, 131.8, 129.7, 127.5, 126.8, 126.4, 125.5, 122.1×2, 121.8 , 121.5, 120.0, 119.8, 112.2, 110.5, 106.0, 105.5, 58.7, 41.1, 40.9, 15.6. HR-ESIMS m/z 400.1666 [M+H] ⁺ (calcd.for C ₂₄ H ₂₂ N ₃ O ₃ , 400.1661 ).

Compound ^{31: 1 H NMR (600MHz,} DMSO-d 6) δ10.92 (s, 1H, imide-NH), 7.82 (s, 1H, Ar-H), 7.70 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.46 (d, 1H, J = 8.2 Hz, Ar-H), 7.05 (t, 1H, J = 7.6 Hz, Ar-H), 7.02 (t , 1H, J = 7.1 Hz, Ar-H), 6.92 (d, 1H, J = 8.0 Hz, Ar-H), 6.72 (d, 1H, J = 7.3 Hz, Ar-H), 6.71 (t, 1H) , J = 6.9 Hz, Ar-H), 6.64 (t, 1H, J = 7.7 Hz, Ar-H), 4.95 (t, 1H, J = 5.2 Hz, indole-NCH ₂ CH ₂ O H ), 4.26 ( t, 2H, J = 5.6 Hz, indole-NC H ₂ CH ₂ -), 4.23 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ) 3.71-3.69 (m, 2H, indole-NCH ₂ C H ₂ -), 1.30 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.5 × 2, 136.7, 136.0, 133.4, 131.9 , 128.0, 127.5, 126.9, 126.1, 122.2, 122.1, 122.0, 121.9, 120.1, 120.0, 111.0, 110.6, 105.5, 105.2, 60.6, 49.1, 41.2, 15.8. HR-ESIMS m/z 400.1668 [M+H] ⁺ (calcd.for C ₂₄ H ₂₂ N ₃ O ₃ ).

Compound 32: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.84 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.48 (d, 1H, J = 7.8 Hz, Ar -H), 7.46 (d, 1H, J = 7.8 Hz, Ar-H), 7.05 (t, 1H, J = 7.2 Hz, Ar-H), 7.02 (t, 1H, J = 7.4 Hz, Ar-H ), 6.93 (d, 1H, J = 8.0 Hz, Ar-H), 6.73 (d, 1H, J = 7.8 Hz, Ar-H), 6.71 (t, 1H, J = 7.5 Hz, Ar-H), 6.65 (t, 1H, J = 7.3 Hz, Ar-H), 4.93 (t, 1H, J = 4.7 Hz, indole-NCH ₂ CH ₂ O H ), 4.88 (t, 1H, J = 4.8 Hz, imide- NCH ₂ CH ₂ O H ), 4.26 (t, 2H, J = 5.3 Hz, indole-NC H ₂ CH ₂ -), 4.22 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 3.70 (t, 2H, J = 5.3 Hz, indole-NCH ₂ C H ₂ -), 3.65-3.57 (m, 4H, imide-N(CH ₂ ) ₂ -), 1.29 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 172.0×2, 136.6, 135.9, 133.3, 131.8, 127.1, 126.7, 126.4, 125.9, 122.1, 122.0×2, 121.8, 120.0,119.9,110.9,110.5,105.9,105.2,60.5,58.6,49.0,41.1,40.9,15.6.HR-ESIMS m/z 444.1934(calcd.for C ₂₆ H ₂₆ N ₃ O ₄ ,444.1923[M+H] ⁺ ).

Preparation of Compound 33

According to the preparation method of the compound 24, 4-methoxybenzylamine (185 μL, 1.4 mmol) and the compound 24e (50 mg, 0.14 mmol) were used to obtain N-(4-methoxybenzyl)-2-(1- Ethyl-3-indolyl-3-(3-indole)maleimide (33) 48 mg, yield 72%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.75 (s, 1H, indole-NH), 7.82 (d, 1H, J = 2.7Hz, Ar-H), 7.77 (s, 1H, Ar-H) , 7.45 (d, 1H, J = 8.3 Hz, Ar-H), 7.39 (d, 1H, J = 8.1 Hz, Ar-H), 7.29 (d, 2H, J = 8.7 Hz, Ar-H), 7.04 (t, 1H, J = 7.6 Hz, Ar-H), 6.98 (t, 1H, J = 7.6 Hz, Ar-H), 6.90 (d, 2H, J = 6.7 Hz, Ar-H), 6.89 (d , 1H, J = 2.1 Hz, Ar-H), 6.74 (d, 1H, J = 8.1 Hz, Ar-H), 6.69 (t, 1H, J = 7.5 Hz, Ar-H), 6.62 (t, 1H) , J = 7.5 Hz, Ar-H), 4.68 (s, 2H, -C H ₂ -), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.70 (s, 3H, -OCH ₃ ), 1.29 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.0, 171.9, 159.1, 136.6, 136.0, 132.2, 130.1, 129.9, 129.6 × 2, 127.5, 127.3, 126.9, 126.5, 125.6, 122.3 × 2, 121.9, 121.6, 120.2, 112.0, 114.5, 112.4, 110.7, 106.1, 105.5, 55.6, 41.2, 41.1, 15.7. MS m/z 498.2 [M+Na] ⁺ .

Preparation of compound 34

Prepared according to the preparation method of compound 2, using compound 33 (60mg, 0.126mmol) and NaHCO ₃ (42mg, 0.5mmol) and HCHO (3mL, mass fraction 37%) as raw materials, gel column chromatography, methanol elution Dark red solid N-(4-methoxybenzyl)-2-(1-ethyl-3-indolyl)-3-(1-hydroxymethyl-3-indole)maleimide (34 ) 51 mg, yield 78%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.79 (s, 1H, ar-H), 7.74 (s, 1H, Ar-H), 7.55 (d, 1H, J = 8.3 Hz, Ar-H) , 7.47 (d, 1H, J = 8.2 Hz, Ar-H), 7.39 (t, 1H, J = 8.1 Hz, Ar-H), 7.29 (d, 2H, J = 8.8 Hz, Ar-H), 7.05 (m, 2H, Ar-H), 6.99 (d, 1H, J = 8.1 Hz, Ar-H), 6.91 (d, 2H, J = 8.8 Hz, Ar-H), 6.72 (d, 1H, J = 7.2 Hz, Ar-H), 6.69 (t, 1H, J = 8.1 Hz, -CH ₂ O H ), 6.63 (d, 1H, J = 7.0 Hz, Ar-H), 5.60 (d, 2H, J = 7.2 Hz, -C H2 OH), 4.70 (s, 2H, -CH ₂ -), 4.23 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.71 (s, 3H, -OCH ₃ ), 1.30 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.9, 171.8, 159.2, 136.1, 136.0, 132.6 × 2, 132.2 , 129.8, 129.6, 127.4, 126.9, 126.8, 126.4, 122.4 × 2, 121.9, 121.8, 120.5, 120.3, 114.6, 111.4, 110.7, 105.9, 105.5, 100.0, 69.7, 60.3, 41.7, 41.3, 15.7. ESI-MS m/z 528.1 [M+Na] ⁺ .

Preparation of Compound 35

According to the preparation method of the compound 24, 4-hydroxybenzylamine (86 mg, 0.7 mmol) and the compound 24e (50 mg, 0.14 mmol) were used as a starting material to obtain N-(4-hydroxybenzyl)-2-(1-ethyl). -3-吲哚)-3-(3-indole) maleimide (35) 35 mg, yield 60%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.72 (s, 1H, indole-NH), 9.26 (s, 1H, Ar-OH), 7.80 (d, 1H, J = 2.3Hz, Ar-H) , 7.77 (s, 1H, Ar-H), 7.45 (d, 1H, J = 8.3 Hz, Ar-H), 7.38 (d, 1H, J = 8.1 Hz, Ar-H), 7.17 (d, 1H, J = 8.5 Hz, Ar-H), 7.11 (d, 2H, J = 8.3 Hz, Ar-H), 7.03 (t, 1H, J = 7.4 Hz, Ar-H), 6.97 (d, 1H, J = 7.5 Hz, Ar-H), 6.89 (d, 1H, J = 8.0 Hz, Ar-H), 6.71 (d, 2H, J = 8.4 Hz, Ar-H), 6.68 (d, 1H, J = 7.4 Hz) , Ar-H), 6.61 (t, 1H, J = 7.4 Hz, Ar-H), 4.64 (s, 2H, -NCH ₂ Ar), 4.22 (q, 2H, J = 7.2 Hz, -C H ₂ - CH ₃ ), 1.30 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.0×2, 156.7, 136.6, 136.0, 134.1, 132.1 , 132.0, 130.1, 129.9, 129.7, 129.2, 128.1, 127.9, 127.5, 126.9, 126.5, 125.6, 115.8 × 2, 115.5 × 2, 112.4, 110.7, 106.1, 105.5, 56.6, 41.2, 15.7. ESI-MS m/ z 462.3[M+H] ⁺ .

Preparation of Compound 36

According to the preparation method of compound 2, compound 35 (59 mg, 0.128 mmol) and NaHCO ₃ (53.7 mg, 0.64 mmol) were used as raw materials to obtain a dark red solid N-(4-hydroxybenzyl)-2-(1-B Methyl-3-indole-3-(1-hydroxymethyl-3-indole) maleimide (36) 50 mg, yield 80%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H, Ar-OH), 8.00 (s, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.56 (d, 1H, J = 8.3 Hz, Ar-H), 7.47 (d, 1H, J = 8.3 Hz, Ar-H), 7.19 (d, 2H, J = 8.5 Hz, Ar-H), 7.05 (m, 2H, Ar-H), 7.00 (d, 1H, J = 8.1 Hz, Ar-H), 6.74 (d, 2H, J = 8.6 Hz, Ar-H), 6.72 (d, 1H, J = 7.4 Hz, Ar- H), 6.69 (t, 1H, J = 7.4 Hz, -CH ₂ O H ), 6.63 (d, 1H, J = 3.3 Hz, Ar-H), 5.61 (d, 2H, J = 7.4 Hz, -C H ₂ OH), 4.65 (s, 2H, -NCH ₂ Ar), 4.03 (q, 2H, J = 7.1 Hz, -CH ₂ -CH ₃ ), 1.17 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.9 × 2, 157.3, 136.1, 136.0, 132.7, 132.6, 132.2, 129.7, 128.1, 127.3, 126.8 × 2, 126.4, 122.4 × 2,121.9,121.8,120.5,120.3,115.8,111.4,110.7,105.9,105.5,100.0,69.7,60.3,41.3,15.7. ESI-MS m/z 514.1[M+Na] ⁺ .

Preparation of Compound 37

According to the preparation method of the compound 24, 4-(2-aminoethyl)morpholine (771 μL, 0.59 mmol) and the compound 24e (50 mg, 0.14 mmol) were used as a starting material to obtain N-(2-(4-morpholine). Ethyl)-2-(1-ethyl-3-indolyl)-3-(3-indole)maleimide (37) 41 mg, yield 61%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.68 (s, 1H, indole-NH), 7.78 (s, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.46 (d, 1H, J = 8.3 Hz, Ar-H), 7.37 (d, 1H, J = 8.1 Hz, Ar-H), 7.04 (t, 1H, J = 7.6 Hz, Ar-H), 6.98 (t, 1H, J = 7.5 Hz, Ar-H), 6.90 (d, 1H, J = 8.0 Hz, Ar-H), 6.71 (d, 1H, J = 8.3 Hz, Ar-H), 6.70 (t, 1H, J = 7.5 Hz, Ar-H), 6.62 (t, 1H, J = 7.5 Hz, Ar-H), 4.23 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.68 (t, 2H, J=6.4 Hz, imide-NC H ₂ CH ₂ -), 3.53 (t, 4H, J = 4.4 Hz, morpholine-N(CH ₂ -C H ₂ ) ₂ O), 2.53 (t, 2H, J = 6.4 Hz, imide-NCH ₂ C H ₂ -), 2.44 (t, 4H, J = 4.4 Hz, morpholine-N(C H ₂ -CH ₂ ) ₂ O), 1.30 (t, 3H, J = 7.2 Hz, - CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 172.0×2, 136.5, 135.9, 131.9, 129.8, 127.4, 126.8, 126.4, 125.4, 122.2, 122.1, 121.7, 121.4, 120.0 ,119.8,112.3,110.5,106.0,105.3,66.7×2,56.3,53.6×2,41.1,35.2,15.6.HR-ESIMS m/z 469.2247[M+H] ⁺ (calcd.for C ₂₈ H ₂₉ N ₄ O ₃ , 469.2240 [M+H] ⁺ ).

Preparation of Compound 38

According to the preparation method of the compound 2, compound 37 (33 mg, 0.071 mmol) and NaHCO ₃ (30 mg, 0.35 mmol) were used as a starting material to obtain a dark red solid N-(2-(4-morpholine)ethyl)-2- (1-Ethyl-3-indole)-3-(1-hydroxymethyl-3-indole)maleimide (38) 29 mg, yield 82%. ^{1 H NMR (500MHz, DMSO-} d 6) δ7.96 (s, 1H, Ar-H), 7.70 (s, 1H, Ar-H), 7.55 (d, 1H, J = 8.2Hz, Ar-H) , 7.47 (d, 1H, J = 8.2 Hz, Ar-H), 7.05 (t, 1H, J = 8.1 Hz, Ar-H), 7.02 (t, 1H, J = 8.4 Hz, Ar-H), 6.73 (t, 1H, J = 7.5 Hz, Ar-H), 6.67 (t, 1H, J = 7.3 Hz, Ar-H), 6.62 (d, 1H, J = 8.5 Hz, Ar-H), 6.60 (d , 1H, J=8.0Hz, Ar-H), 5.59 (d, 2H, J=7.3Hz, indole-C H ₂ -OH), 4.22 (q, 2H, J=7.2Hz, -CH ₂ -CH ₃ ), 3.72 (t, 2H, J = 6.4 Hz, imide-NC H ₂ CH ₂ -), 3.56 (t, 4H, J = 4.5 Hz, morpholine-N(CH ₂ -C H ₂ ) ₂ O), 2.57 (t, 2H, J = 6.4 Hz, imide-NCH ₂ C H ₂ -), 2.47 (t, 4H, J = 4.5 Hz, morpholine-N(C H ₂ -CH ₂ ) ₂ O), 1.29 (t , 3H, J=7.2Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ171.9×2, 136.0, 135.9, 132.4, 131.9, 127.3, 126.9, 126.6, 126.2, 122.3, 122.2, 121.8, 121.6, 120.3, 120.1, 111.9, 110.6, 105.7, 105.4, 69.5, 66.6 × 2, 56.3, 53.5 × 2, 41.1, 35.3, 15.6. HR-ESIMS m/z 499.2352 [M+H] ⁺ (calcd.for C ₂₉ H ₃₁ N ₄ O ₄ ,499.234 5).

Preparation of Compound 39

According to the preparation method of the compound 24, 2-(2-aminoethyl)pyridine (50 μL, 0.421 mmol) and the compound 24e (30 mg, 0.084 mmol) were used as a starting material to obtain N-(2-(2-pyridyl)ethyl. 2-(1-Ethyl-3-indene)-3-(3-indole)maleimide (39) 25 mg, yield 64%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.71 (s, 1H, indole-NH), 8.48 (d, 1H, J = 4.7Hz, Ar-H), 7.75 (d, 1H, J = 2.7Hz , Ar-H), 7.73-7.70 (m, 2H, Ar-H), 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.38 (d, 1H, J = 8.1 Hz, Ar-H) , 7.31 (d, 1H, J = 7.7 Hz, Ar-H), 7.23 (dd, 1H, J = 7.4, 4.9 Hz, Ar-H), 7.05 (t, 1H, J = 7.6 Hz, Ar-H) , 6.99 (t, 1H, J = 7.5 Hz, Ar-H), 6.88 (d, 1H, J = 8.1 Hz, Ar-H), 6.71 (t, 2H, J = 8.0 Hz, Ar-H), 6.64 (d, 1H, J = 7.7 Hz, Ar-H), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.93 (t, 2H, J = 7.1 Hz, imide-NC H ₂ CH ₂ -), 3.09 (t, 2H, J = 7.1 Hz, imide-NCH ₂ C H ₂ -), 1.30 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.0, 171.9, 158.9, 149.7, 137.2, 136.6, 136.0, 132.0, 129.9, 127.6, 126.9, 126.5, 125.6, 123.8, 122.3, 122.2, 121.9, 121.6, 120.1, 119.9, 112.4, 110.7, 106.0, 105.5, 100.0, 41.2, 38.2, 36.7, 15.8. HR-ESIMS m/z 461.1981 [M+H] ⁺ (calcd.for C ₂₉ H ₂₅ N ₄ O ₂ , 461.1978).

Preparation of Compound 40

According to the preparation method of the compound 16, the compound (39 mg, 0.435 mmol) was used as a starting material to prepare the hydrochloride salt: N-(2-(2-pyridyl)ethyl)-2-(1-ethyl-3-indole哚)-3-(3-indole) maleimide hydrochloride (40) 173 mg, yield 80%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.88 (s, 1H, indole-NH), 10.60 (brs, 1H, -pryidine-H +), 8.82 (s, 1H, Ar-H), 8.45 ( t, 1H, J = 7.2 Hz, Ar-H), 7.99 (d, 1H, J = 6.4 Hz, Ar-H), 7.87 (t, 1H, J = 7.0 Hz, Ar-H), 7.68 (d, 1H, J = 7.1 Hz, Ar-H), 7.61 (d, 1H, J = 7.6 Hz, Ar-H), 7.45 (d, 1H, J = 7.7 Hz, Ar-H), 7.37 (d, 1H, J = 7.4 Hz, Ar-H), 7.04 (t, 1H, J = 6.8 Hz, Ar-H), 6.97 (t, 1H, J = 7.1 Hz, Ar-H), 6.87 (d, 1H, J = 7.5 Hz, Ar-H), 6.70 (t, 1H, J = 6.6 Hz, Ar-H), 6.65 (d, 1H, J = 7.1 Hz, Ar-H), 6.61 (d, 1H, J = 6.6 Hz) , Ar-H), 4.20 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 4.02 (t, 2H, J = 7.1 Hz, imide-NC H ₂ CH ₂ -), 3.39 (t , 2H, J = 7.1 Hz, imide-NCH ₂ C H ₂ -), 1.26 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171 .7×2,155.0,145.7,142.4,136.5,135.9,131.8,129.9,127.9,127.6,126.7,126.3,125.4,125.9,122.2,122.1,121.9,121.6,120.0,119.8,112.3,110.6,105.8,105.3 , 45.7, 41.1, 37.6, 15.6. HR-ESIMS m /z 461.1989[M-Cl] ⁺ (calcd.for C ₂₉ H ₂₅ N ₄ O ₂ , 461.1978).

Preparation of Compound 41

Compound 24e (52 mg, 0.146 mmol) was dissolved in 10 mL of THF, and hydrazine hydrate (73 μL, 1.46 mmol) was added dropwise. The reaction mixture was heated to 45 ° C for 15 min, and the solvent was evaporated in vacuo. EtOAcjjjjjjjjjjjjjjjjj N-amino-2-(1-ethyl-3-indene)-3-(3-indole)maleimide (41) 45 mg, yield 83.3%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.71 (d, 1H, J = 2.2Hz, indole-NH), 7.81 (d, 1H, J = 2.2Hz, Ar-H), 7.73 (s, 1H , Ar-H), 7.46 (d, 1H, J = 8.3 Hz, Ar-H), 7.40 (d, 1H, J = 8.3 Hz, Ar-H), 7.05 (t, 1H, J = 7.1 Hz, Ar -H), 6.99 (t, 1H, J = 7.1 Hz, Ar-H), 6.93 (d, 1H, J = 7.7 Hz, Ar-H), 6.74 (d, 1H, J = 8.2 Hz, Ar-H ), 6.71 (t, 1H, J = 7.7 Hz, Ar-H), 6.63 (t, 1H, J = 7.7 Hz, Ar-H), 4.85 (s, 2H, -NH ₂ ), 4.22 (q, 2H) , J = 7.7 Hz, -C H ₂ -CH ₃ ), 1.30 (t, 3H, J = 7.7 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.5, 171.4, 136.6, 136.0, 131.9, 129.9, 126.6, 126.1, 125.6, 125.4, 122.3, 122.2, 121.9, 121.5, 120.1, 119.9, 112.4, 110.7, 106.2, 105.6, 41.2, 15.8. HR-ESIMS m/z 371.1511 [ M+H] ⁺ (calcd.for C ₂₂ H ₁₉ N ₄ O ₂ , 371.1508).

Preparation of Compound 42

The compound 24d (22 mg, 0.05 mmol) was suspended in a 10 mL one-necked flask with HCHO (4 mL, mass fraction 37%) and allowed to react overnight at room temperature. After the TLC was detected, the reaction was completed, poured into ice water (30 mL), ethyl acetate (2×50 mL), and brine (2×50 mL). Separation by silica gel column chromatography, methylene chloride:methanol=80:1 (v/v)哚) Maleimide (42) 12 mg, yield 60%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.71 (s, 1H, indole-NH), 7.81 (d, 1H, J = 2.7Hz, Ar-H), 7.76 (s, 1H, Ar-H) , 7.48 (d, 1H, J = 8.2 Hz, Ar-H), 7.39 (d, 1H, J = 8.1 Hz, Ar-H), 7.06 (t, 1H, J = 7.0 Hz, Ar-H), 6.99 (t, 1H, J = 7.4 Hz, Ar-H), 6.92 (d, 1H, J = 8.0 Hz, Ar-H), 6.73 (dd, 2H, J = 7.7 Hz, 4.6 Hz, Ar-H), 6.64 (d, 1H, J = 7.4 Hz, Ar-H), 6.30 (t, 1H, J = 7.0 Hz, -CH ₂ -O H ), 4.97 (d, 2H, J = 7.0 Hz, -C H ₂ -OH), 4.25 (q, 2H, J = 7.2 Hz, -CH ₂ -CH ₃ ), 1.32 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.7 × 2, 136.6, 136.1, 132.1, 130.1, 128.0, 127.3, 126.6, 125.6, 122.3 × 2, 121.9, 121.5, 120.2, 120.0, 112.4, 110.7, 106.0, 105.4, 60.8, 41.6 , 15.7. HR-ESIMS m/z 386.1490 [M+H] ⁺ (calcd. for C ₂₃ H ₂₀ N ₃ O ₃ , 386.1499 [M+H] ⁺ ).

Preparation of Compound 43

i) Preparation of 1-benzyl-6-fluoroindole (43a)

According to the synthesis method of the compound 24a, 6-fluoroindole (675 mg, 5 mmol), NaH (300 mg, 7.5 mmol, 60% by mass, dispersed in paraffin) and benzyl bromide (1283 mg, 7.5 mmol) were used as raw materials. The crystalline powder (43a) was 1.01 g, and the yield was 90%. ¹ H NMR (600MHz, CDCl ₃ ) δ 7.53 (dd, 1H, J = 8.7 Hz, 5.5 Hz, Ar-H), 7.29-7.24 (m, 3H, Ar-H), 7.06-7.09 (m, 3H) , Ar-H), 6.92 (dd, 1H, J = 9.6 Hz, 2.3 Hz, Ar-H), 6.86 (dt, 1H, J = 9.6 Hz, 2.3 Hz, Ar-H), 6.51 (d, 1H, J = 3.2 Hz, Ar-H), 5.21 (s, 2H, -CH ₂ -Ph). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 159.9 (d, ¹ J _CF = 240 Hz), 137.2, 136.5 (d) , ³ J _CF = 12 Hz), 129.0, 128.9 × 2, 127.9, 126.9 × 2, 125.3, 121.7 (d, ³ J _CF = 10 Hz), 108.5 (d, ² J _CF = 25 Hz), 102.0, 96.3 (d, ² J _CF = 26 Hz), 50.4. ESI-MS m/z 225.1 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-6-fluoro-3-indole) maleic anhydride (43b)

According to the synthesis method of the compound 24b, the compound 43a (600 mg, 2.67 mmol), (COCl) ₂ (345 μL, 4.00 mmol), the compound 1a (541 mg, 2.67 mmol), and Et ₃ N (738 μL, 5.33 mmol) were used as a raw material. A red solid (43b) of 400 mg was obtained in a yield of 32%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.00 (s, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.53 (d, 1H, J = 8.3 Hz, Ar-H) , 7.36 (dd, 1H, J = 8.7 Hz, 2.3 Hz, Ar-H), 7.34 (t, 2H, J = 7.3 Hz, Ar-H), 7.28 (t, 1H, J = 7.3 Hz, Ar-H ), 7.22 (d, 2H, J = 7.3 Hz, Ar-H), 7.11 (t, 1H, J = 6.9 Hz, Ar-H), 6.89 (dd, 1H, J = 8.7 Hz, 5.5 Hz, Ar-) H), 6.78 (d, 1H, J = 7.8 Hz, Ar-H), 6.69 (t, 1H, J = 7.8 Hz, Ar-H), 6.63 (dt, 1H, J = 9.2 Hz, 2.3 Hz, Ar -H), 5.49 (s, 2H, -CH ₂ -Ph), 4.32 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.36 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 166.9, 166.8, 155.9 (d, ¹ J _CF = 235 Hz), 137.6, 136.6 (d, ³ J _CF = 12 Hz), 136.3, 134.3, 133.5, 129.6, 129.2 × 2, 128.2, 127.6 × ² , 127.1, 125.8, 123.1 (d, ³ J _CF = 13 Hz), 123.0, 122.8, 122.1, 120.7, 111.2, 109.2 (d, ² J _CF = 23 Hz ), 105.5, 104.6, 98.0 (d, ² J _CF = 26 Hz), 50.0, 41.5, 15.8. ESI-MS m/z 465.2 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-6-fluoro-3-indolyl)maleimide (43c)

According to the preparation method of the compound 24c, Compound 43b (317 mg, 0.68 mmol), HMDS (7.2 mL, 34.3 mmol) and MeOH (0.68 mL, 17.2 mmol) were used as a starting material to obtain 287 mg of a red powdery solid (43c). 91%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.00 (s, 1H, imide-NH), 7.89 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.46 (d, 1H, J = 8.3 Hz, Ar-H), 7.33 (t, 2H, J = 7.3 Hz, Ar-H), 7.28 (dd, 1H, J = 8.7 Hz, 2.3 Hz, Ar-H), 7.27 (t , 1H, J = 7.8 Hz, Ar-H), 7.19 (d, 2H, J = 7.3 Hz, Ar-H), 7.04 (t, 1H, J = 8.2 Hz, Ar-H), 6.83 (dd, 1H) , J = 8.7 Hz, 5.5 Hz, Ar-H), 6.76 (d, 1H, J = 8.2 Hz, Ar-H), 6.63 (t, 1H, J = 7.8 Hz, Ar-H), 6.53 (dt, 1H, J=9.2 Hz, 2.3 Hz, Ar-H), 5.47 (s, 2H, -CH ₂ -Ph), 4.26 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.34 ( t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.3 × 2, 159.4 (d, ¹ J _CF = 235 Hz), 137.9, 136.5 ( d, ³ J _CF = 12 Hz), 136.0, 133.2, 132.2, 129.2, 129.0 × 2, 128.1, 127.5 × 2, 126.8, 126.3, 123.5, 122.7 (d, ³ J _CF = 11 Hz), 122.3, 121.8, 120.1, 110.8, 108.6 (d, ² J _CF = 24 Hz), 106.3, 105.2, 97.6 (d, ² J _CF = 26 Hz), 49.9, 41.3, 15.8. ESI-MS m/z 464.2 [M+H] ⁺ .

Iv) Preparation of 2-(1-ethyl-3-indolyl)-3-(6-fluoro-3-indolyl)maleimide (43)

Prepared according to the preparation method of compound 24d, using compound 43c (247mg, 0.53mmol), DMSO (0.85mL), 1M t-BuOK/THF solution (8.4mL, 8.4mmol) and O ₂ as raw materials, and separated by silica gel column chromatography. Petroleum ether: ethyl acetate = 3:1 (v/v) eluted to give a red powdery solid (43) 118 mg, yield 60%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.69 (s, 1H, indole-NH), 10.92 (s, 1H, imide-NH), 7.76 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.14 (d, 1H, J = 8.6 Hz, Ar-H), 7.04 (t, 1H, J = 7.9 Hz, Ar-H), 6.81 (d, 1H, J = 8.1 Hz, Ar-H), 6.71 (dd, 1H, J = 8.5 Hz, 5.9 Hz, Ar-H), 6.67 (d, 1H, J = 7.3 Hz) , Ar-H), 6.47 (t, 1H, J = 8.6 Hz, Ar-H), 4.24 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 1.32 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 173.4 × 2, 159.3 (d, ¹ J _CF = 235 Hz), 136.5 (d, ³ J _CF = 12 Hz) , 136.0, 132.1, 130.4, 128.2, 127.7, 126.4, 122.6, 122.4 (d, ³ J _CF = 11 Hz), 122.3, 121.8, 120.1, 110.7, 108.2 (d, ² J _CF = 24 Hz), 106.2, 105.3, 98.4 (d, ² J _CF = 27 Hz), 41.3, 15.8. HR-ESIMS m/z 374.1314 [M+H] ⁺ (calcd. for C ₂₂ H ₁₇ N ₃ O ₂ F, 374.1305).

Preparation of Compound 44

The compound was synthesized by the method of the compound 42 (20 mg, 0.05 mmol) and HCHO (5 mL, mass fraction: 37%), eluted by silica gel column chromatography, eluting with dichloromethane:methanol=70:1 (v/v) A red solid N-hydroxymethyl-2-(1-ethyl-3-indene)-3-(6-fluoro-3-indole)maleimide (44) 12 mg was obtained in a yield of 60%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.74 (s, 1H, indole-NH), 7.81 (s, 1H, Ar-H), 7.79 (d, 1H, J = 2.7Hz, Ar-H) , 7.49 (d, 1H, J = 8.3 Hz, Ar-H), 7.17 (dd, 1H, J = 8.7 Hz, 2.3 Hz, Ar-H), 7.06 (s, 1H, Ar-H), 6.84 (d) , 1H, J = 8.0 Hz, Ar-H), 6.73 - 6.69 (m, 2H, Ar-H), 6.50 (td, J = 8.4 Hz, 2.4 Hz, 1H, Ar-H), 6.30 (t, 1H) _{, J = 7.0Hz, -CH 2 -O} H), 4.97 (d, 2H, J = 7.0Hz, -C H 2 -OH), 4.27 (q, 2H, J = 7.2Hz, -C H 2 -CH ₃ ), 1.34 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.6, 171.5, 159.4 (d, ¹ J _CF = 235 Hz) , 136.62 (d, ³ J _CF = 12 Hz), 136.1, 132.2 × 2, 130.6, 128.2, 127.9, 127.3, 126.4, 122.5 (d, ³ J _CF = 11 Hz), 121.8, 120.3, 110.8, 108.3 (d, ² J _CF = 25 Hz), 106.1, 105.2, 98.5 (d, ² J _CF = 27 Hz), 60.8, 41.3, 15.6. HR-ESIMS m/z 404.1393 [M+H] ⁺ (calcd.for C ₂₃ H ₁₉ N ₃ O ₃ F, 404.1405).

Preparation of Compound 45

Prepared according to the preparation method of compound 2, using compound 43 (30mg, 0.08mmol), formaldehyde solution (3mL, mass fraction 37%) and NaHCO ₃ (13.5mg, 0.16mmol) as raw materials, silica gel column chromatography, petroleum ether: acetic acid Ethyl ester = 2:1 (v/v) eluted red solid N-hydroxymethyl-2-(1-ethyl-3-indole)-3-(1-hydroxymethyl-6-fluoro-3 -吲哚) Maleimide (45) 35 mg, yield 99%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.95 (s, 1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.3Hz, Ar-H) , 7.41 (dd, 1H, J = 9.0 Hz, 1.5 Hz, Ar-H), 7.06 (t, 1H, J = 7.7 Hz, Ar-H), 6.91 (d, 1H, J = 8.1 Hz, Ar-H ), 6.73 (t, 1H, J = 7.9 Hz, Ar-H), 6.61 (dd, J = 8.8 Hz, 5.4 Hz, Ar-H), 6.51 (dd, 1H, J = 8.8 Hz, 2.0 Hz), 5.57 (s, 2H, -C H ₂ -OH), 4.95 (s, 2H, -CH ₂ -OH), 4.25 (q, 2H, J = 7.3 Hz, -CH ₂ -CH ₃ ), 1.31 ( t,3H,J=7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.5×2, 159.4 (d, ¹ J _CF = 235 Hz), 136.2 (d, ³ J _CF = 12 Hz), 136.1, 133.0, 132.2, 128.3, 126.7, 126.6, 123.2, 122.6 (d, ³ J _CF = 11 Hz), 122.5, 121.8, 120.4, 110.8, 108.8 (d, ² J _CF = 25 Hz) , 106.0, 105.3, 98.0 (d, ² J _CF = 26 Hz), 69.8, 60.8, 41.3, 15.8. HR-ESIMS m/z 456.1342 [M+Na] ⁺ (calcd.for C ₂₄ H ₂₀ N ₃ O ₄ FNa , 456.1336).

Preparation of Compound 46

i) Preparation of 1-benzyl-6-chloropurine (46a)

According to the synthesis method of compound 24a, 6-chloroindole (303 mg, 2 mmol), NaH (120 mg, 3 mmol, 60% by mass, dispersed in paraffin) and benzyl bromide (513 mg, 3 mmol) were used as raw materials. Chromatography, petroleum ether: ethyl acetate = 60:1 (v/v) eluted to yield white powdery solid (46a) 483mg, yield 100%. ¹ H NMR (600MHz, CDCl ₃ ) δ 7.55 (d, 1H, J = 8.22 Hz, Ar-H), 7.26-7.33 (m, 4H, Ar-H), 7.12 (d, 1H, J = 3.2 Hz) , Ar-H), 7.09 (d, 2H, J = 7.7 Hz, Ar-H), 7.08 (d, 1H, J = 1.8 Hz, Ar-H), 6.53 (dd, 1H, J = 3.4 Hz, 0.9 Hz, Ar-H), 5.28 (s, 2H, Ph-CH ₂ -). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 137.1, 136.8, 129.1, 129.0, 127.9, 127.8, 127.3, 126.8 × 2, 121.9 , 120.4, 109.8, 102.0 × 2, 50.2. ESI-MS m/z 242.1/244.1 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-6-chloro-3-indole) maleic anhydride (46b)

Prepared according to the synthesis method of compound 24b, using compound 46a (419 mg, 1.73 mmol), (COCl) ₂ (446 μL, 5.20 mmol), Compound 1a (352 mg, 1.73 mmol) and Et ₃ N (480 μL, 3.47 mmol) as starting materials. The methanol was recrystallized to give 278 mg of red powder (46b), yield: 33.4%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.01 (s, 2H, Ar-H), 7.59 (s, 1H, Ar-H), 7.54 (d, 1H, J = 8.2 Hz, Ar-H) , 7.34 (t, 2H, J = 7.8 Hz, Ar-H), 7.29 (t, 1H, J = 7.3 Hz, Ar-H), 7.19 (d, 2H, J = 7.8 Hz, Ar-H), 7.11 (t, 1H, J = 7.7 Hz, Ar-H), 6.92 (d, 1H, J = 8.7 Hz, Ar-H), 6.77 (d, 1H, J = 8.7 Hz, Ar-H), 6.75 (d , 1H, J = 7.3 Hz, Ar-H), 6.69 (t, 1H, J = 7.3 Hz, Ar-H), 5.53 (s, 2H, Ph-CH ₂ -), 4.32 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.37 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.9, 166.8, 137.6 , 136.9, 136.3, 134.5, 133.6, 129.9, 129.3 × 2, 128.2, 127.7, 127.5 × 2, 126.8, 125.7, 125.2, 123.2, 122.9, 122.0, 121.0, 120.8, 111.4, 111.2, 105.5, 104.5, 50.0, 41.5 , 15.8. ESI-MS m/z 481.2/483.2 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-6-chloro-3-indole)maleimide (46c)

Prepared according to the preparation method of compound 24c, Compound 46b (240mg, 0.5mmol), HMDS (4.2mL, 20mmol) and MeOH (0.4mL, 10mmol). The powdery solid (46c) was 218 mg in a yield of 91%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.00 (s, 1H, imide-NH), 7.91 (s, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.51 (d, 1H, J = 1.9 Hz, Ar-H), 7.47 (d, 1H, J = 8.2 Hz, Ar-H), 7.34 (t, 2H, J = 7.4 Hz, Ar-H), 7.28 (t, 1H, J = 7.3 Hz, Ar-H), 7.17 (d, 2H, J = 7.3 Hz, Ar-H), 7.05 (t, 1H, J = 7.7 Hz, Ar-H), 6.84 (d, 1H, J = 8.2 Hz, Ar-H), 6.72 (d, 1H, J = 7.8 Hz, Ar-H), 6.67 (dd, 1H, J = 8.7 Hz, 1.9 Hz, Ar-H), 6.62 (t, 1H, J) = 7.3 Hz, Ar-H), 5.50 (s, 2H, Ph-CH ₂ -), 4.28 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.36 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.3 × 2, 137.9, 136.8, 136.1, 133.5, 132.3, 129.3, 129.2 × 2, 128.1, 127.4 × 2 , 127.2, 126.5, 126.2, 125.6, 122.9, 122.3, 121.7, 120.5, 120.2, 111.0, 110.8, 106.3, 105.1, 49.8, 41.3, 15.8. ESI-MS m/z 480.1/482.2 [M+H] ⁺ .

Iv) Preparation of 2-(1-ethyl-3-indolyl)-3-(6-chloro-3-indolyl)maleimide (46)

Prepared according to the preparation method of compound 23d, using compound 46c (160mg, 0.33mmol), DMSO (0.85mL), 1M t-BuOK/THF solution (8.4mL, 8.4mmol) and O ₂ as raw materials, and separated by silica gel column chromatography. Petroleum ether: ethyl acetate = 3:1 (v/v) eluted to give red powder (46) 128 mg, yield 99%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.75 (s, 1H, indole-NH), 10.94 (s, 1H, imide-NH), 7.79 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.45 (d, 1H, J = 8.3 Hz, Ar-H), 7.41 (s, 1H, Ar-H), 7.02 (t, 1H, J = 7.6 Hz, Ar-H), 6.77 (d, 1H, J = 7.7 Hz, Ar-H), 6.73 (d, 1H, J = 8.2 Hz, Ar-H), 6.66 (t, 1H, J = 7.5 Hz, Ar-H), 6.61 ( Dd, 1H, J = 8.5 Hz, 1.1 Hz, Ar-H), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.32 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 173.3 × 2, 136.8, 135.9, 132.0, 130.5, 128.4, 127.2, 126.6, 126.2, 124.6, 122.5, 122.2, 121.6, 120.0, 119.9,111.8,110.6,106.1,105.1,41.1,15.7.HR-ESIMS m / z390.1014 [m + H] + (calcd.for C 22 H 17 N 3 O 2 Cl, 390.1009).

Preparation of Compound 47

Compound 46 (19 mg, 0.05 mmol) and HCHO (5 mL, mass fraction: 37%) were purified by silica gel column chromatography eluting with dichloromethane:methanol=80:1 (v/v) The red solid N-hydroxymethyl-2-(1-ethyl-3-indolyl)-3-(6-chloro-3-indole)maleimide (47) was obtained as a 10% yield. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.78 (s, 1H, indole-NH), 7.83 (s, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.3 Hz, Ar-H), 7.42 (d, 1H, J = 1.3 Hz, Ar-H), 7.04 (t, 1H, J = 7.5 Hz, Ar-H), 6.77 (d, 1H, J = 8.0 Hz, Ar-H), 6.71 (d, 1H, J = 8.6 Hz, Ar-H), 6.68 (t, 1H, J = 7.5 Hz, Ar-H), 6.62 (dd, 1H, J = 8.6 Hz, 1.5 Hz, Ar-H), 6.30 (t, 1H, J = 6.9 Hz, imide-CH ₂ -O H ), 4.94 (d, 2H, J = 6.9 Hz, imide-C H ₂ -OH) , 4.28 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.33 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ171.5×2, 137.0, 136.1, 132.3, 130.9, 128.2, 127.0, 126.9, 126.4, 124.6, 122.6, 122.4, 121.7, 120.3, 120.2, 112.1, 110.9, 106.2, 105.2, 60.8, 41.3, 15.8. HR-ESIMS m/z 420.1107 [M+H] ⁺ (calcd. for C ₂₃ H ₁₉ N ₃ O ₃ Cl, 420.1109).

Preparation of Compound 48

According to the preparation method of compound 2, compound 46 (14 mg, 36.0 μmol), formaldehyde solution (3 mL, mass fraction 37%) and NaHCO ₃ (7 mg, 0.083 mmol) were prepared as raw materials, and separated by silica gel column chromatography, petroleum ether: acetic acid Ester = 3:1 (v/v) eluted red solid N-hydroxymethyl-2-(1-ethyl-3-indole)-3-(1-hydroxymethyl-6-chloro-3-吲哚) Maleimide (48) 16 mg, yield 99%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.79 (s, 1H, ar-H), 7.83 (s, 1H, Ar-H), 7.69 (d, 1H, J = 1.8 Hz, Ar-H) , 7.50 (d, 1H, J = 8.2 Hz, Ar-H), 7.06 (t, 1H, J = 7.8 Hz, Ar-H), 6.89 (d, 1H, J = 8.2 Hz, Ar-H), 6.75 (t, 1H, J = 7.3 Hz, -CH ₂ -O H ), 6.72 (t, 1H, J = 7.7 Hz, Ar-H), 6.66 (dd, 1H, J = 8.2 Hz, 1.8 Hz, Ar- H), 6.62 (d, 1H, J = 8.2 Hz, Ar-H), 6.35 (t, 1H, J = 6.8 Hz, -CH ₂ -O H ), 5.61 (d, 2H, J = 7.3 Hz, - NC H ₂ -OH), 4.97 (d, 2H, J = 6.8 Hz, -NC H ₂ -OH), 4.28 (q, 2H, J = 6.8 Hz, -CH ₂ -CH ₃ ), 1.32 (t, 3H, J=6.8Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ171.4×2, 136.5, 136.0, 133.3, 132.4, 128.6, 127.2, 126.6, 126.3, 125.4 , 122.7, 122.5, 121.7, 120.6, 120.4, 111.5, 110.9, 105.9, 105.2, 69.8, 60.9, 41.3, 15.8. HR-ESIMS m/z 472.1046 [M+Na] ⁺ (calcd.for C ₂₄ H ₂₀ N ₃ O ₄ ClNa, 472.1040).

Preparation of Compound 49

i) Preparation of 1-benzyl-4-bromoindole (49a)

According to the preparation method of the compound 24a, the compound 4-bromoindole (700 mg, 3.59 mmol), NaH (129 mg, 5.38 mmol, 60% by mass, dispersed in paraffin) and benzyl bromide (0.64 mL, 5.38 mmol) were used. The preparation of the starting material was separated by silica gel column chromatography, eluting with petroleum ether: ethyl acetate=100:1 (v/v) to yield white crystals (49a), 0.88 g, yield 86%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.64 (d, 1H, J = 3.3 Hz, Ar-H), 7.49 (d, 1H, J = 8.3 Hz, Ar-H), 7.29-7.27 (m , 2H, Ar-H), 7.25-7.23 (m, 2H, Ar-H), 7.19-7.18 (m, 2H, Ar-H), 7.03 (t, 1H, J = 7.7 Hz, Ar-H), 6.45 (d, 1H, J = 2.8 Hz, Ar-H), 5.43 (s, 2H, Ph-CH ₂ -). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 138.4, 136.7, 130.9, 129.2, 129.1, 128.0, 127.6, 127.4, 123.0 × 2, 122.4, 114.2, 110.5, 101.4, 50.0. ESI-MS m/z 286.0/288.0 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-4-bromo-3-indole) maleic anhydride (49b)

Prepared according to the preparation method of compound 24b, using compound 49a (400mg, 1.4mmol), (COCl) ₂ (214μL, 2.25mmol), compound 1a (548mg, 2.7mmol) and Et ₃ N (626μL, 4.5mmol) as raw materials, The oil was separated by silica gel column chromatography, eluted with petroleum ether: ethyl acetate=7:1 (v/v) to afford red powder (49b) 220 mg, yield 30.0%. ¹ H NMR (600 MHz, pyridine-d ₅ ) δ 8.37 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.41 (d, 1H, J = 3.8 Hz, Ar-H) , 7.42 (m, 3H, Ar-H), 7.24-7, 22 (m, 4H, Ar-H), 7.06-7.04 (m, 4H, Ar-H), 6.77 (t, 1H, J = 7.2 Hz , Ar-H), 5.3 (d, 1H, J = 15.9 Hz, Ph-C H ₂ -), 5.24 (d, 1H, J = 15.9 Hz, Ph-CH ₂ -), 4.05 (q, 2H, J = 8.2 Hz, -C H ₂ -CH ₃ ), 1.37 (t, 3H, J = 8.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, pyridine-d ₅ ) δ 166.0, 165.6, 148.5 × 2, 136.4, 135.5, 135.4, 133.2, 130.6, 127.5, 126.4, 125.5, 125.4, 124.5, 124.1, 123.8, 122.5, 122.1, 121.5, 121.2, 119.9, 113.4, 109.3, 109.2, 104.4, 103.8, 48.8, 40.1, 13.5. ESI-MS m/z 525.1/527.1 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-4-bromo-3-indole)maleimide (49c)

Prepared according to the preparation method of compound 24c, Compound 49c (110mg, 0.21mmol), HMDS (4.5mL, 21mmol) and MeOH (0.4mL, 10.5mmol) as a starting material, silica gel column chromatography, petroleum ether: dichloromethane = 1 4 (v/v) eluted to obtain 100 mg of red powder (49c) in a yield of 91%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.02 (s, 1H, imide-NH), 8.05 (s, 1H, Ar-H), 7.53 (s, 1H, Ar-H), 7.47 (t, 2H, J=8.7 Hz, Ar-H), 7.27 (d, 1H, J = 7.6 Hz, Ar-H), 7.19 (dd, 3H, J = 5.0 Hz, 1.8 Hz, Ar-H), 7.09 (dt , 2H, J = 8.2 Hz, 2.0 Hz, Ar-H), 6.99-6.95 (m, 2H, Ar-H), 6.68 (d, 1H, J = 8.1 Hz, Ar-H), 6.58 (t, 1H) , J = 7.6 Hz, Ar-H), 5.42 (d, 1H, J = 15.9 Hz) / 5.38 (d, 1H, J = 15.9 Hz) (Ph-CH ₂ -), 4.25 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.35 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.9, 173.2, 137.9 , 137.6, 136.5, 134.3, 133.3, 132.0, 129.0, 127.9, 127.1, 126.9, 126.7, 125.7, 124.6, 123.7, 122.5, 121.9, 120.6, 114.4, 111.0 × 2, 110.9, 106.2, 105.0, 49.8, 49.2, 41.4 , 15.8. ESI-MS m/z 524.1/526.1 [M+H] ⁺ .

Iv) Preparation of 2-(1-ethyl-3-indolyl)-3-(4-bromo-3-indolyl)maleimide (49)

Prepared according to the preparation method of compound 24d, using compound 49c (110mg, 0.21mmol), DMSO (1.24mL), 1M t-BuOK/THF solution (0.97mL, 0.97mmol) and O ₂ as raw materials, and separated by silica gel column chromatography. Petroleum ether: ethyl acetate = 3:1 (v/v) eluted to give a red powder (49), 63 mg, yield 70%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.65 (s, 1H, indole-NH), 10.93 (s, 1H, imide-NH), 8.00 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.3 Hz, Ar-H), 7.45 (d, 1H, J = 8.3 Hz, Ar-H), 7.30 (d, 1H, J = 2.8 Hz, Ar-H), 7.24 (d, 1H, J = 7.7 Hz, Ar-H), 7.09 (t, 1H, J = 7.7 Hz, Ar-H), 7.01 (t, 1H, J = 6.6 Hz, Ar-H), 6.58 (d, 1H, J = 7.9 Hz, Ar-H), 6.53 (t, 1H, J = 7.3 Hz, Ar-H), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.34 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 174.0, 173.4, 137.9, 136.4, 134.3, 133.3, 128.6, 127.4, 126.4, 125.8, 124.1, 123.5 , 122.4, 121.8, 120.4, 114.1, 112.2, 110.8, 106.5, 105.1, 41.3, 15.8. HR-ESIMS m/z 434.0514 [M+H] ⁺ (calcd.for C ₂₂ H ₁₇ N ₃ O ₂ Br, 434.0504) .

Preparation of Compound 50

The compound was synthesized by the method of the compound 42 (20 mg, 0.05 mmol) and HCHO (5 mL, mass fraction: 37%), eluted by silica gel column chromatography eluting with dichloromethane:methanol=70:1 (v/v) A red solid N-hydroxymethyl-2-(1-ethyl-3-indene)-3-(4-bromo-3-indole)maleimide (50) 11 mg was obtained in a yield of 50%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.70 (s, 1H, indole-NH), 8.03 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.1Hz, Ar-H) , 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.34 (d, 1H, J = 2.5 Hz, Ar-H), 7.22 (d, 1H, J = 7.5 Hz, Ar-H), 7.07 (t, 1H, J = 7.9 Hz, Ar-H), 7.02 (t, 1H, J = 7.3 Hz, Ar-H), 6.56 (d, 2H, J = 7.5 Hz, Ar-H), 6.34 (t , 1H, J = 7.0 Hz, -CH ₂ -O H ), 4.95 (d, 2H, J = 7.0 Hz, -C H ₂ -OH), 4.27 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.33 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.9, 171.4, 137.8, 136.4, 133.9, 133.3, 128.6, 126.7, 126.2, 125.6, 124.0, 123.4, 122.4, 121.6, 120.4, 113.8, 112.1, 110.8, 106.1, 105.0, 60.7, 41.2, 15.6. HR-ESIMS m/z 464.0602 [M+H] ⁺ (calcd. For C ₂₃ H ₁₉ N ₃ O ₃ Br, 464.0604).

Preparation of Compound 51

Prepared according to the preparation method of compound 2, using compound 49 (100 mg, 0.23 mmol), formaldehyde solution (3 mL, mass fraction: 37%) and NaHCO ₃ (97 mg, 1.15 mmol) as a starting material, silica gel column chromatography, petroleum ether: acetic acid Ester = 4:1 (v/v) elution to give red solid N-hydroxymethyl-2-(1-ethyl-3-indole)-3-(1-hydroxymethyl-4-bromo-3 -吲哚) Maleimide (51) 67 mg, yield 59%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8. s (s, 1 H, Ar-H), 7.68 (d, 1H, J = 8.1 Hz, Ar-H), 7.48 (s, 1H, Ar-H) , 7.45 (d, 1H, J = 8.3 Hz, Ar-H), 7.28 (d, 1H, J = 7.5 Hz, Ar-H), 7.15 (d, 1H, J = 7.9 Hz, Ar-H), 7.06 (t, 1H, J = 7.4 Hz, Ar-H), 6.73 (d, 1H, J = 8.2 Hz, Ar-H), 6.62 (t, 1H, J = 6.8 Hz, Ar-H), 6.60 (t , 1H, J = 7.2 Hz, indole-CH ₂ -O H ), 6.37 (t, 1H, J = 6.5 Hz, imide-CH ₂ -O H ), 5.53 (d, 2H, J = 7.2 Hz, indole- C H ₂ -OH), 4.97 (d, 2H, J = 6.5 Hz, imide-C H ₂ -OH), 4.24 (q, 2H, J = 7.1 Hz, -CH ₂ -CH ₃ ), 1.33 (t , 3H, J=7.1Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 172.0, 171.5, 137.4, 136.5, 134.6, 133.5, 131.3, 127.2, 126.2, 125.9, 124.8, 123.8, 122.6, 121.9, 120.7, 114.1, 111.2, 110.9, 106.0, 105.1, 69.6, 60.8, 41.4, 15.7. HR-ESIMS m/z 516.0540 [M+Na] ⁺ (calcd.for C ₂₄ H ₂₀ N ₃ O ₄ BrNa, 516.0535).

Preparation of Compound 52

i) Preparation of 1-benzyl-5-bromoindole (52a)

According to the preparation method of the compound 24a, the compound 5-bromoindole (700 mg, 3.59 mmol), NaH (129 mg, 5.38 mmol, 60% by mass, dispersed in paraffin) and benzyl bromide (0.64 mL, 5.38 mmol) were used. The preparation of the starting material was separated by silica gel column chromatography, eluting with petroleum ether: ethyl acetate=60:1 (v/v) to afford white crystal powder (52a), 0.88 g, yield 86%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.75 (d, 1H, J = 1.6Hz, Ar-H), δ7.56 (d, 1H, J = 3.3Hz, Ar-H), 7.42 (d , 2H, J = 8.8 Hz, Ar-H), 7.30 (t, 2H, J = 7.7 Hz, Ar-H), 7.24 - 7.16 (m, 3H, Ar-H), 6.48 (d, 1H, J = 2.2 Hz, Ar-H), 5.41 (s, 2H, -CH ₂ -). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 138.5, 135.0, 131.3, 130.7 × 2, 129.1, 128.0, 127.6, 127.5 , 124.2, 123.2, 112.8, 112.4, 101.3, 49.8. ESI-MS m/z 286.0/288.0 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-5-bromo-3-indole) maleic anhydride (52b)

According to the preparation method of the compound 24b, the compound 52a (1100 mg, 3.86 mmol), (COCl) ₂ (500 μL, 5.79 mmol), the compound 1a (783 mg, 3.86 mmol) and Et ₃ N (1.07 mL, 7.72 mmol) were prepared. The pure methanol was recrystallized to give a red powder (52b) 652 mg, yield 32.2%. ^{1 H NMR (600MHz, DMSO-} d 6) δ8.06 (s, 1H, Ar-H), 7.99 (s, 1H, Ar-H), 7.55 (d, 1H, J = 8.1Hz, Ar-H) , 7.39 (d, 1H, J = 8.7 Hz, Ar-H), 7.33 (t, 2H, J = 7.5 Hz, Ar-H), 7.28 (d, 1H, J = 6.7 Hz, Ar-H), 7.17 (d, 2H, J = 7.4 Hz, Ar-H), 7.14 (d, 1H, J = 8.8 Hz, Ar-H), 7.10 (t, 1H, J = 7.7 Hz, Ar-H), 6.98 (s , 1H, Ar-H), 6.76 (d, 1H, J = 8.1 Hz, Ar-H), 6.69 (d, 1H, J = 8.2 Hz, Ar-H), 5.52 (s, 2H, -CH ₂ - Ph), 4.33 (q, 2H, J = 6.6 Hz, -C H ₂ -CH ₃ ), 1.39 (t, 3H, J = 6.6 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO -d ₆ ) δ 166.8 × 2, 137.6, 136.2, 135.2, 134.8, 133.2, 129.5, 129.2, 128.2, 128.0, 127.6, 127.5, 127.4, 125.8, 125.3, 124.4, 122.9, 121.7, 120.7, 113.5, 113.4, 111.2, 104.8, 104.6, 99.9, 50.2, 41.5, 16.1. ESI-MS m/z 525.1/527.0 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-5-bromo-3-indole)maleimide (52c)

Prepared according to the preparation method of compound 24c, Compound 52b (110mg, 0.21mmol), HMDS (4.5mL, 21mmol) and MeOH (0.4mL, 11mmol) as a starting material. The solid (52c) was 100 mg in a yield of 91%. ^{1 H NMR (600MHz, DMSO-} d 6) δ10.98 (s, 1H, imide-NH), 7.96 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.3 Hz, Ar-H), 7.34 (dt, 3H, J = 7.2 Hz, 1.7 Hz, Ar-H), 7.27 (t, 1H, J = 7.3 Hz, Ar-H), 7.14 (d) , 2H, J = 7.1 Hz, 2H, Ar-H), 7.06 (dd, 1H, J = 6.8 Hz, 2.0 Hz, Ar-H), 6.90 (d, 1H, J = 1.9 Hz, Ar-H), 6.72 (d, 1H, J = 8.0 Hz, Ar-H), 6.62 (t, 1H, J = 7.2 Hz, Ar-H), 5.49 (s, 2H, -CH ₂ -Ph), 4.30 (q, 2H) , J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.38 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.2 × 2,137.9,136.0,135.0,133.9,132.0,129.2,128.8,128.4,128.19,127.4,127.0×2,126.7,124.8,124.2×2,122.4,121.4,120.1,113.1,112.9,110.8,105.6,105.1, 50.0, 41.3, 16.1. ESI-MS m/z 524.1/526.1 [M+H] ⁺ .

Iv) Preparation of 2-(1-ethyl-3-indolyl)-3-(5-bromo-3-indolyl)maleimide (52)

Prepared according to the method for the preparation of compound 24d, Compound 52c (90 mg, 0.172 mmol), DMSO (0.85mL) and 1M t-BuOK/THF solution (7mL, 7mmol) and O ₂ as starting material. The oil was separated by silica gel column chromatography eluting with methylene chloride: ethyl acetate = 4:1 (v/v) to give a red powder (52) 54 mg, yield 73%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.82 (s, 1H, indole-NH), 10.92 (s, 1H, imide-NH), 7.80 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.49 (d, 1H, J = 8.3 Hz, Ar-H), 7.31 (d, 1H, J = 8.6 Hz, Ar-H), 7.05 (d, 1H, J = 8.0 Hz, Ar-H), 7.03 (d, 1H, J = 8.0 Hz, Ar-H), 6.79 (s, 1H, Ar-H), 6.77 (d, 1H, J = 8.0 Hz, Ar-H), 6.67 ( t, 1H, J = 7.2 Hz, Ar-H), 4.28 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.36 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 173.4, 173.3, 136.0, 135.2, 131.9, 131.0, 128.1, 127.8, 127.5, 126.5, 124.6, 124.0, 122.4, 121.4, 120.1, 114.2, 112.4 , 110.7, 105.8, 105.3, 41.3, 16.1. HR-ESIMS m/z 434.0514 [M+H] ⁺ (calcd. for C ₂₂ H ₁₇ N ₃ O ₂ Br, 434.0504).

Preparation of Compound 53

The compound was synthesized according to the method of compound 42 from Compound 52 (21 mg, 0.05 mmol) and HCHO (5 mL, mass fraction: 37%), eluted on silica gel column chromatography eluting with dichloromethane:methanol=70:1 (v/v) The red solid N-hydroxymethyl-2-(1-ethyl-3-indolyl)-3-(5-bromo-3-indole)maleimide (53) 12 mg was obtained in a yield of 55%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.86 (s, 1H, indole-NH), 7.83 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.49 (d, 1H, J = 8.4 Hz, Ar-H), 7.32 (d, 1H, J = 8.7 Hz, Ar-H), 7.06 (d, 1H, J = 8.3 Hz, Ar-H), 7.03 (d, 1H, J = 7.7 Hz, Ar-H), 6.81 (s, 1H, Ar-H), 6.77 (t, 1H, J = 8.2 Hz, Ar-H), 6.67 (t, 1H, J = 7.7 Hz, Ar- H), 6.31 (t, 1H, J = 6.7 Hz, -CH ₂ -O H ), 4.95 (d, 2H, J = 6.4 Hz, -CH ₂ -OH), 4.28 (q, 2H, J = 7.0) Hz, -C H ₂ -CH ₃ ), 1.36 (t, 3H, J = 6.8 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.4, 171.3, 136.0, 135.1, 131.9, 131.1, 127.6, 127.3, 127.2, 126.2, 124.6, 123.9, 122.3, 121.3, 120.1, 114.1, 112.4, 110.7, 105.5, 105.0, 60.7, 41.2, 15.9. HR-ESIMS m/z 464.0600 [M+ H] ⁺ (calcd.for C ₂₃ H ₁₉ N ₃ O ₃ Br, 464.0604).

Preparation of Compound 54

Prepared according to the preparation method of compound 2, using compound 53 (53mg, 0.122mmol), NaHCO ₃ (51mg, 0.62mmol) and formaldehyde solution (3mL, mass fraction 37%) as raw materials, silica gel column chromatography, petroleum ether: acetic acid Ester = 4:1 (v/v) eluted red solid N-hydroxymethyl-2-(1-ethyl-3-indole)-3-(1-hydroxymethyl-5-bromo-3-吲哚) Maleimide (54) 60 mg, yield 99%. ^{1 H NMR (500MHz, DMSO-} d 6) δ8.04 (s, 1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.50 (d, 2H, J = 8.6Hz, Ar-H) , 7.13 (d, 1H, J = 8.6 Hz, Ar-H), 7.06 (t, 1H, J = 7.5 Hz, Ar-H), 6.87 (d, 1H, J = 7.9 Hz, Ar-H), 6.75 (t, 1H, J = 6.8 Hz, indole-CH ₂ -O H ), 6.71 (d, 1H, J = 7.6 Hz, Ar-H), 6.68 (s, 1H, Ar-H), 6.34 (t, 1H, J=6.4 Hz, imide-CH ₂ -O H ), 5.58 (d, 2H, J = 6.8 Hz, indole-C H ₂ -OH), 4.96 (d, 2H, J = 6.4 Hz, imide-C H ₂ -OH), 4.28 (q, 2H, J = 6.9 Hz, -CH ₂ -CH ₃ ), 1.35 (t, 3H, J = 6.9 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR ( 125MHz, DMSO-d ₆ ) δ171.4×2, 136.0, 134.8, 133.6, 132.0, 128.2, 128.1, 126.9, 126.6, 124.8, 124.3, 122.5, 121.4, 120.4, 113.3, 113.2, 110.8, 105.4, 105.2, 69.9 ,60.8,41.4,16.1.HR-ESIMS m/z 516.0547[M+Na] ⁺ (calcd.for C ₂₄ H ₂₀ N ₃ O ₄ BrNa, 516.0535),.

Preparation of Compound 55 (Compound 26d)

See the preparation of compound 26d.

Preparation of Compound 56

The compound was synthesized according to the method of compound 42 from Compound 55 (21 mg, 0.05 mmol) and HCHO (5mL, mass fraction: 37%), eluted on silica gel column chromatography eluting with dichloromethane:methanol=70:1 (v/v) A red solid N-hydroxymethyl-2-(1-ethyl-3-indene)-3-(6-bromo-3-indole)maleimide (56) 12 mg was obtained in a yield of 53%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.81 (s, 1H, indole-NH), 7.85 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.58 (d, 1H, J = 1.8 Hz, Ar-H), 7.50 (d, 1H, J = 8.3 Hz, Ar-H), 7.38 (dd, 1H, J = 7.6 Hz, 1.5 Hz, Ar-H), 7.06 (t , 1H, J = 7.6 Hz, Ar-H), 6.79 (d, 1H, J = 8.0 Hz, Ar-H), 6.76 (dd, 1H, J = 8.6 Hz, 1.8 Hz, Ar-H), 6.71 ( d, 1H, J = 3.9 Hz, Ar-H), 6.69 (t, 1H, J = 3.9 Hz, Ar-H), 6.32 (t, 1H, J = 7.0 Hz, -CH ₂ -O H ), 4.96 (d, 2H, J = 7.0 Hz, -C H ₂ -OH), 4.29 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.35 (t, 3H, J = 7.2 Hz, - CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.5×2, 137.5, 136.1, 132.3, 130.7, 128.2, 127.0, 126.3, 124.9, 123.0, 122.8, 122.4, 121.7, 120.3 , 115.1,115.0,110.9,106.2,105.1,60.8,41.3,15.8.HR-ESIMS m / z464.0591 [ m + H] + (calcd.for C 23 H 19 N 3 O 3 Br, 464.0604).

Preparation of Compound 57

Prepared according to the preparation method of compound 2, compound 56 (50mg, 0.115mmol), NaHCO ₃ (29mg, 0.345mmol) and formaldehyde solution (3mL, mass fraction 37%) as raw materials, silica gel column chromatography, petroleum ether: acetic acid Ester = 4:1 (v/v) eluted red solid N-hydroxymethyl-2-(1-ethyl-3-indole)-3-(1-hydroxymethyl-6-bromo-3-吲哚) Maleimide (57) 48 mg, yield 85%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H, ar-H), 7.83 (s, 2H, Ar-H), 7.49 (d, 1H, J = 8.2 Hz, Ar-H) , 7.07 (t, 1H, J = 7.7 Hz, Ar-H), 6.89 (d, 1H, J = 7.7 Hz, Ar-H), 6.78 (d, 1H, J = 8.2 Hz, Ar-H), 6.76 (t, 1H, J = 6.8 Hz, -CH ₂ -O H ), 6.72 (t, 1H, J = 7.7 Hz, Ar-H), 6.60 (d, 1H, J = 8.2 Hz, Ar-H), 6.35 (t, 1H, J = 6.6 Hz, -CH ₂ -O H ), 5.61 (d, 2H, J = 6.6 Hz, -NC H ₂ -OH), 4.98 (d, 2H, J = 6.6 Hz, - C H ₂ -OH), 4.27 (q, 2H, J = 6.6 Hz, -CH ₂ -CH ₃ ), 1.34 (t, 3H, J = 6.6 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ171.4×2, 136.9, 136.1, 133.1, 132.3, 128.7, 126.6, 126.3, 125.7, 123.2, 123.1, 122.5, 121.7, 120.4, 115.3, 114.4, 110.9, 106.0, 105.2, 69.8,60.9,41.4,15.8.HR-ESIMS m / z 516.0544 [ m + Na] + (calcd.for C 24 H 20 N 3 O 4 BrNa, 516.0535).

Preparation of Compound 58

i) Preparation of 1-benzyl-7-bromoindole (58a)

According to the preparation method of the compound 24a, the compound 7-bromoindole (700 mg, 3.59 mmol), NaH (129 mg, 5.38 mmol, 60% by mass, dispersed in paraffin) and benzyl bromide (0.64 mL, 5.38 mmol) were used. Preparation of the starting material, silica gel column chromatography, petroleum ether: ethyl acetate = 60:1 (v / v) eluted to yield white crystal powder (58a) 1.0 g, yield 98%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.61 (d, 1H, J = 7.8Hz, Ar-H), 7.54 (d, 1H, J = 3.2Hz, Ar-H), 7.29 (d, 1H , J = 7.5 Hz, Ar-H), 7.26 (t, 2H, J = 7.5 Hz, Ar-H), 7.21 (d, 1H, J = 7.1 Hz, Ar-H), 6.95 (d, 1H, J = 7.7 Hz, Ar-H), 6.93 (dd, 2H, J = 7.6 Hz, 2.7 Hz, Ar-H), 6.61 (d, 1H, J = 3.2 Hz, Ar-H), 5.81 (s, 2H, -CH ₂ -). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 140.2 × 2, 133.3, 132.4, 129.1 × 2, 127.6, 127.0, 126.3, 121.4 × 2, 121.1, 103.6, 102.6, 51.0. -MS m/z 286.0/288.0 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-7-bromo-3-indole) maleic anhydride (58b)

According to the preparation method of the compound 24b, Compound 58a (700 mg, 2.5 mmol), (COCl) ₂ (714 μL, 7.5 mmol), Compound 1a (686 mg, 3.3 mmol) and Et ₃ N (0.723 mL, 5.2 mmol) were used as starting materials. The pure methanol was recrystallized to obtain 380 mg of a red powder (58b) in a yield of 30%. ^{1 H NMR (600MHz, DMSO-} d 6) δ8.04 (s, 1H, Ar-H), 8.01 (s, 1H, Ar-H), 7.50 (d, 1H, J = 8.0Hz, Ar-H) , 7.31 (t, 2H, J = 7.0 Hz, Ar-H), 7.25 (t, 1H, J = 7.4 Hz, Ar-H), 7.21 (d, 1H, J = 7.6 Hz, Ar-H), 7.09 (t, 1H, J = 7.6 Hz, Ar-H), 6.99 (d, 2H, J = 7.4 Hz, Ar-H), 6.94 (d, 1H, J = 8.0 Hz, Ar-H), 6.77 (d , 1H, J = 8.0 Hz, Ar-H), 6.71 (t, 1H, J = 7.5 Hz, Ar-H), 6.63 (t, 1H, J = 7.8 Hz, Ar-H), 5.90 (s, 2H) , -CH ₂ -Ph), 4.31 (q, 2H, J = 5.8 Hz, -C H ₂ -CH ₃ ), 1.34 (t, 3H, J = 5.8 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 166.8, 166.7, 139.4, 136.4, 136.3, 133.8, 132.6, 131.1, 129.8, 129.2, 128.2, 127.8, 127.3, 126.2, 125.9, 125.8, 123.0, 121.8, 121.4, 120.9 , 120.8, 119.4, 111.2, 105.8, 104.6, 103.9, 51.7, 41.6, 15.8. ESI-MS m/z 525.1/527.0 [M+H] ⁺ .

Iii) Preparation of 2-(1-ethyl-3-indolyl)-3-(1-benzyl-7-bromo-3-indole)maleimide (58c)

Prepared according to the preparation method of compound 24c, Compound 58b (110mg, 0.45mmol), HMDS (4.5mL, 21mmol) and MeOH (0.4mL, 11mmol). The solid (58c) was 100 mg in a yield of 91%. ^{1 H NMR (600MHz, DMSO-} d 6) 11.04 (s, 1H, imide-NH), 7.93 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.45 (d, 1H, J = 8.3 Hz, Ar-H), 7.31 (t, 2H, J = 7.5 Hz, Ar-H), 7.25 (s, 1H, J = 7.4 Hz, Ar-H), 7.15 (dd, 1H, J = 7.6 Hz, 1.0 Hz, Ar-H), 7.04 (d, 1H, J = 1.1 Hz, Ar-H), 6.97 (d, 2H, J = 7.2 Hz, Ar-H), 6.88 (dd, 1H, J) = 8.0 Hz, 1.0 Hz, Ar-H), 6.76 (d, 1H, J = 8.0 Hz, Ar-H), 6.67 (d, 1H, J = 7.9 Hz, Ar-H), 6.56 (t, 1H, J = 7.8 Hz, Ar-H), 5.88 (s, 2H, -CH ₂ -Ph), 4.27 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.35 (t, 3H, J) = 7.2 Hz, -CH ₂ -C H ₃ _). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.2 × 2, 139.7, 136.0, 135.6, 135.5, 132.5, 132.4, 130.3, 130.2, 129.1, 127.7 ×2,126.3,126.2,125.7,122.4,121.7,121.6,121.1×2,120.2,110.8,106.5,105.1,103.7,51.5,41.4,15.8.ESI-MS m/z 523.8/525.8[M+H] ⁺ .

Iv) Preparation of 2-(1-ethyl-3-indolyl)-3-(7-bromo-3-indolyl)maleimide (58)

Prepared according to the method for the preparation of compound 24d, Compound 58c (292mg, 0.558mmol), DMSO (0.85mL) and 1M t-BuOK/THF solution (8.4mL, 8.4mmol) and O ₂ as starting material. The oil was separated by silica gel column chromatography eluting with methylene chloride: ethyl acetate = 4:1 (v/v) to yield 150 mg of red powder (58). ^{1 H NMR (500MHz, DMSO-} d 6) δ11.86 (s, 1H, indole-NH), 10.96 (s, 1H, imide-NH), 7.78 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.46 (d, 1H, J = 8.2 Hz, Ar-H), 7.19 (d, 1H, J = 7.5 Hz, Ar-H), 7.03 (t, 1H, J = 7.6 Hz, Ar-H), 6.82 (d, 1H, J = 8.0 Hz, Ar-H), 6.76 (d, 1H, J = 8.0 Hz, Ar-H), 6.69 (t, 1H, J = 7.5 Hz, Ar- H), 6.57 (t, 1H, J = 7.7 Hz, Ar-H), 4.24 (q, 2H, J = 7.1 Hz, -CH ₂ -CH ₃ ), 1.31 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 173.1×2, 135.9, 134.7, 132.1, 130.3, 128.9, 127.4, 127.1, 126.2, 124.6, 122.2, 121.5, 121.1, 120.8,120.1,110.6,107.2,105.1,104.6,41.1,15.7.HR-ESIMS m / z 434.0509 [ m + H] + (calcd.for C 22 H 17 N 3 O 2 Br, 434.0504).

Preparation of Compound 59

The compound was synthesized by the method of the compound 42 (21 mg, 0.05 mmol) and HCHO (5 mL, mass fraction: 37%), eluted by silica gel column chromatography eluting with dichloromethane: methanol = 70:1 (v/v) A red solid N-hydroxymethyl-2-(1-ethyl-3-indene)-3-(7-bromo-3-indole)maleimide (59) 9 mg was obtained in a yield of 40%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.94 (s, 1H, indole-NH), 7.84 (s, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.49 (d, 1H, J = 8.3 Hz, Ar-H), 7.22 (d, 1H, J = 7.5 Hz, Ar-H), 7.06 (t, 1H, J = 7.6 Hz, Ar-H), 6.86 (d, 1H, J = 8.1 Hz, Ar-H), 6.77 (d, 1H, J = 8.0 Hz, Ar-H), 6.73 (d, 1H, J = 7.6 Hz, Ar-H), 6.59 (t, 1H, J = 7.8 Hz, Ar-H), 6.34 (t, 1H, J = 7.0 Hz, N-CH ₂ -O H ), 4.97 (d, 2H, J = 7.0 Hz, NC H _{2 -} OH), 4.27 (q, 2H, J=7.2 Hz, -C H ₂ -CH ₃ ), 1.33 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.5 ×2,136.1,134.9,132.4,130.6,128.7,127.4,126.8,126.3,124.9,122.5,121.7,121.4,120.9,120.4,110.9,107.2,105.1,104.9,60.8,41.3,15.8.HR-ESIMS m/ z 464.0592 [M+H] ⁺ (calcd.for C ₂₃ H ₁₉ N ₃ O ₃ Br, 464.0604).

Preparation of Compound 60

Prepared according to the preparation method of compound 2, compound 59 (75mg, 0.173mmol), NaHCO ₃ (73mg, 0.866mmol) and formaldehyde solution (3mL, mass fraction 37%) as raw materials, silica gel column chromatography, petroleum ether: acetic acid Ester = 4:1 (v/v) eluted red solid N-hydroxymethyl-2-(1-ethyl-3-indole)-3-(1-hydroxymethyl-7-bromo-3-吲哚) Maleimide (60) 20 mg, yield 25%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.64 (s, 1H, Ar-H), 7.61 (s, 1H, Ar-H), 7.25 (d, 1H, J = 6.6 Hz, Ar-H), 7.21. (d, 1H, J = 7.6 Hz, Ar-H), 7.07 (t, 1H, J = 7.6 Hz, Ar-H), 6.90 (d, 1H, J = 8.2 Hz, Ar-H), 6.77 (d , 1H, J = 8.0 Hz, Ar-H), 6.74 (t, 1H, J = 7.9 Hz, Ar-H), 6.50 (t, 1H, J = 7.9 Hz, Ar-H), 5.86 (d, 2H) , J = 7.2 Hz, -C H ₂ OH), 5.14 (d, 2H, J = 6.1 Hz, -C H ₂ OH), 4.26 (t, 1H, J = 7.2 Hz, -CH ₂ O H ), 4.17 (t, 1H, J = 6.1 Hz, -CH ₂ O H ), 4.09 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 1.38 (t, 3H, J = 7.3 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150MHz, CDCl ₃ ) δ 172.0, 171.7, 136.0, 134.1, 132.3, 132.0, 129.9, 129.7, 127.7, 126.3, 124.6, 122.5, 122.2, 121.7, 121.6, 120.6, 109.7,106.7,105.5,103.5,71.1,61.5,41.6,15.2.HR-ESIMS m / z 516.0540 [ m + Na] + (calcd.for C 24 H 20 N 3 O 4 BrNa, 516.0535).

Preparation of Compound 61

Compound 55 (300 mg, 0.693 mmol) was dissolved in a 50 ml single-necked flask with 6 mL of DMF, and PPh ₃ (36.3 mg, 0.139 mmol), PdCl ₂ (6.1 mg, 0.0346 mmol) and propylenetributyltin (258 μL, 0.83 mmol) were added. Under argon protection, the reaction was stirred for 23 h in a 110 ° C oil bath. It was cooled to room temperature, extracted with diethyl ether and washed with aq. The PdCl _{2 was} removed by suction filtration, and purified by silica gel column chromatography eluting with EtOAc (EtOAc:EtOAc: Allyl-3-indole maleimide (61) 171 mg, yield 62%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.60 (s, 1H, indole-NH), 10.90 (s, 1H, imide-NH), 7.70 (d, 1H, J = 2.9Hz, Ar-H) , 7.70 (s, 1H, Ar-H), 7.46 (d, 1H, J = 8.3 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (t, 1H, J = 7.1 Hz, Ar-H), 6.92 (d, 1H, J = 8.1 Hz, Ar-H), 6.71 (t, 1H, J = 7.5 Hz, Ar-H), 6.64 (d, 1H, J = 8.1 Hz, Ar- H), 6.47 (d, 1H, J = 8.3 Hz, Ar-H), 5.94-5.86 (m, 1H, ArCH ₂ C H = CH ₂ ), 5.00 - 4.97 (m, 1H, ArCH ₂ CH = C H ₂ ), 4.96-4.94 (m, 1H, ArCH ₂ CH=C H ₂ ), 4.23 (q, 2H, J = 7.3 Hz, -C H ₂ -CH ₃ ), 3.32 (d, 2H, J = 6.7 Hz) , Ar-C H ₂ CH=CH ₂ ), 1.30 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.6, 173.5, 138.8 , 137.0, 136.0, 133.7, 131.9, 129.6, 128.6, 127.4, 126.6, 124.1, 122.2, 121.9, 121.5, 121.1, 120.1, 115.9, 111.8, 110.6, 106.0, 105.5, 41.2, 39.0, 15.8. HR-ESIMS m/ z 396.1718[M+H] ⁺ (calcd.for C ₂₅ H ₂₂ N ₃ O ₂ , 396.1712).

Preparation of Compound 62

Compound 61 (128 mg, 0.324 mmol) was dissolved in a 50 ml single-necked flask in 20 mL of CH ₂ Cl ₂ , and the condensed water was refluxed at 40 ° C for 0.5 h to dissolve all the compound, cooled to room temperature, and added 2-methyl-2-butene ( 1.2 mL, 11.34 mmol) and Grubbs '2 generation catalyst (27.5 mg, 0.0324 mmol), under argon atmosphere, condensed water was refluxed at 40 ° C for 2 h, cooled to room temperature, and evaporated to dryness under vacuum. Separation by silica gel column chromatography, eluting with petroleum ether: ethyl acetate=6:1 (v/v) to give red solid 2-(1-ethyl-3-indole)-3-(6-isopentenyl-3 -吲哚) Maleimide (62) 91 mg, yield 66%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.50 (s, 1H, indole-NH), 10.87 (s, 1H, imide-NH), 7.67 (d, 1H, J = 1.7Hz, Ar-H) , 7.66 (s, 1H, Ar-H), 7.47 (d, 1H, J = 8.3 Hz, Ar-H), 7.14 (s, 1H, Ar-H), 7.06 (t, 1H, J = 7.1 Hz, Ar-H), 6.96 (d, 1H, J = 8.0 Hz, Ar-H), 6.74 (t, 1H, J = 7.2 Hz, Ar-H), 6.64 (d, 1H, J = 8.2 Hz, Ar- H), 6.47 (dd, 1H, J = 8.3 Hz, 1.4 Hz, Ar-H), 5.27-5.22 (m, 1H, ArCH ₂ C H = C(CH ₃ ) ₂ ), 4.22 (q, 2H, J) = 7.2 Hz, -C H ₂ -CH ₃ ), 3.27 (d, 2H, J = 7.4 Hz, ArC H ₂ CH=C(CH ₃ ) ₂ ), 1.67 (s, 3H, ArCH ₂ CH=C (C) H ₃ ) ₂ ), 1.64 (s, 3H, ArCH ₂ CH=C(C H ₃ ) ₂ ), 1.29 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz , DMSO-d ₆ ) δ 172.9, 172.8, 136.4, 135.4, 134.8, 131.2, 131.1, 128.9, 128.0, 126.7, 125.9, 123.8, 123.1, 121.6, 121.3, 120.8, 120.3, 119.4, 101.0, 105.3, 104.8, 100.0,40.5,33.6,25.4,17.5,15.0.HR-ESIMS m / z 424.2029 [ m + H] + (calcd.for C 27 H 26 N 3 O 2, 424.2025).

Preparation of Compound 63

According to the preparation method of the compound 2, compound 62 (43 mg, 0.1088 mmol), a formaldehyde solution (3 mL, mass fraction: 37%) and NaHCO ₃ (46 mg, 0.544 mmol) were used as raw materials to obtain a deep red solid N-hydroxymethyl group- 2-(1-Ethyl-3-indole)-3-(1-hydroxymethyl-6-isopentenyl-3-indole) maleimide (63) 17 mg, yield 34%. ^{1 H NMR (600MHz, DMSO-} d 6) δ7.90 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.48 (d, 1H, J = 8.3Hz, Ar-H) , 7.34 (s, 1H, Ar-H), 7.10 (d, 1H, J = 7.9 Hz, Ar-H), 7.08 (d, 1H, J = 8.3 Hz, Ar-H), 6.79 (t, 1H, J = 7.0 Hz, -CH ₂ O H ), 6.73 (t, 1H, J = 7.2 Hz, Ar-H), 6.48 (q, 2H, J = 8.2 Hz, Ar-H), 6.38 (t, 1H, J = 6.9 Hz, imide-CH ₂ O H ), 5.55 (d, 2H, J = 7.0 Hz, indole-C H ₂ OH), 5.23 (t, 1H, J = 7.2 Hz, ArCH ₂ C H = C ( CH ₃ ) ₂ ), 4.96 (d, 2H, J = 6.9 Hz, -C H ₂ OH), 4.22 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.28 (d, 2H, J = 7.4 Hz, ArC H ₂ CH=C(CH ₃ ) ₂ ), 1.65 (s, 3H, ArCH ₂ CH=C(C H ₃ ) ₂ ), 1.63 (s, 3H, ArCH ₂ CH=C (C) H ₃ ) ₂ ), 1.26 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.6 × 2, 136.6, 136.0, 135.9, 132.4 , 132.0, 131.8, 127.7, 127.5, 126.8, 124.4, 122.4, 121.9, 121.7, 121.5, 120.4, 110.8, 110.6, 105.6, 105.4, 100.0, 69.5, 60.8, 41.2, 34.5, 26.1, 18.2, 15.6. ESI-MS m/z 484.2 [M+H] ⁺ .

Preparation of Compound 64

In an open quartz bottle, compound 1 (40 mg, 0.1 mmol) was dissolved in 1.0 L of acetone, and a catalytic amount of I _{2 was} added thereto. The mixture was stirred under a 250 W mercury lamp for 24 hours, and most of the solvent was evaporated in vacuo, and then poured into 100 mL of Na _{2 .} S ₂ O ₃ saturated aqueous solution, stirred for 10min, extracted with ethyl acetate (50mL × 3 times), the organic layers combined and dried over anhydrous Na ₂ SO _4, evaporated in vacuo, column chromatography on silica gel, petroleum ether: ethyl acetate Ester = 3:1 (v/v) eluted yellow fluorescent powder 12-ethyl-13-cyanomethyl-12,13-dihydro-5H-indole [2,3-a]pyrrole [3,4 -c] oxazole-5,7(6H)-dione (64) 28 mg, yield 71%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.27 (s, 1H, indole-NH), 9.12 (d, 1H, J = 8.3Hz, Ar-H), 9.11 (d, 1H, J = 8.3Hz , Ar-H), 7.96 (d, 1H, J = 8.2 Hz, Ar-H), 7.91 (d, 1H, J = 8.2 Hz, Ar-H), 7.73 (t, 1H, J = 7.7 Hz, Ar -H), 7.67 (t, 1H, J = 7.9 Hz, Ar-H), 7.53 (t, 1H, J = 7.3 Hz, Ar-H), 7.43 (t, 1H, J = 7.3 Hz, Ar-H ), 5.79 (s, 2H, -NC H ₂ -CN), 4.75 (q, 2H, J = 6.8 Hz, -C H ₂ -CH ₃ ), 1.10 (t, 3H, J = 6.8 Hz, -CH _{2 )} -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.0, 170.9, 152.0, 145.5, 144.4, 133.1, 132.9, 128.8, 128.5, 125.5, 125.4, 124.5, 123.6, 123.5, 123.0, 122.1 , 121.5, 121.0, 116.4, 113.3, 113.0, 43.3, 31.0, 14.0. HR-ESIMS m/z 391.1206 [MH] ^- (calcd.for C ₂₄ H ₁₅ N ₄ O ₂ , 391.1195).

Preparation of Compound 65

Prepared according to the preparation method of compound 2, using compound 2 (10 mg, 24.6 μmol) and NaHCO ₃ (4.1 mg, 49.2 μmol) as a starting material, and separated by silica gel column chromatography, petroleum ether: ethyl acetate = 3:1 (v/v) Elected yellow fluorescent powder 6-hydroxymethyl-12-ethyl-13-cyanoethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]咔Imidazole-5,7(6H)-dione (65) 10.1 mg, yield 94%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.24 (d, 1H, J = 7.8Hz, Ar-H), 9.22 (d, 1H, J = 7.8Hz, Ar-H), 7.66 (dt, 1H, J = 7.5 Hz, 1.4 Hz, Ar-H), 7.65 (d, 1H, J = 6.9 Hz, Ar-H), 7.64 (dt, 1H, J = 7.8 Hz, 0.9 Hz, Ar-H), 7.59 (d , 1H, J = 7.8 Hz, Ar-H), 7.49 (dt, 1H, J = 7.8 Hz, 0.9 Hz, Ar-H), 7.46 (dt, 1H, J = 7.5 Hz, 1.4 Hz, Ar-H) , 5.40 (d, 2H, J = 7.8 Hz, -NC H ₂ -OH), 4.96 (t, 2H, J = 7.8 Hz, NC H ₂ -CH ₂ CN), 4.66 (q, 2H, J = 7.3 Hz) _{, -C H 2 -CH 3),} 3.18 (t, 1H, J = 7.8Hz, NCH 2 -O H), 2.21 (t, 2H, J = 7.8Hz, NCH 2 -C H 2 -CN), 1.12 (t, 3H, J = 7.3 Hz, -CH ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.0, 168.9, 145.0, 143.8, 133.9, 132.7, 128.9, 128.4, 128.3, 126.5, 126.1, 125.4, 124.5, 123.3, 122.5, 122.4, 121.5, 120.2, 116.4, 112.2, 111.7, 61.8, 44.4, 43.9, 15.7, 13.6. ESI-MS m/z 437.2 [M+H] ⁺ .

Preparation of Compound 66

According to the preparation method of the compound 64, the compound 3 (30 mg, 0.072 mmol) was used as a raw material, and it was separated by silica gel column chromatography, petroleum ether: ethyl acetate=3:1 (v/v) to obtain yellow fluorescent powder 12-B. Benzyl-13-cyanopropyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (66) 20.6 Mg, yield 68%. ¹ H NMR (600MHz, CDCl ₃ ) δ 9.25 (d, 1H, J = 8.2 Hz, Ar-H), 9.24 (d, 1H, J = 8.3 Hz, Ar-H), 7.77 (s, 1H, imide -NH), 7.64 (t, 1H, J = 7.4 Hz, Ar-H), 7.63 (d, 1H, J = 7.4 Hz, Ar-H), 7.62 (t, 1H, J = 7.7 Hz, Ar-H ), 7.60 (d, 1H, J = 7.8 Hz, Ar-H), 7.48 (dt, 1H, J = 6.8 Hz, 1.7 Hz, Ar-H), 7.46 (dt, 1H, J = 7.4 Hz, 1.7 Hz) , Ar-H), 4.84 (t, 2H, J = 7.1 Hz, NC H ₂ - (CH ₂ ) ₂ CN), 4.68 (q, 2H, J = 7.1 Hz, NC H ₂ -CH ₃ ), 1.77 ( t, 2H, J = 6.9 Hz, N(CH ₂ ) ₂ -C H ₂ -CN), 1.26-1.24 (m, 2H, NCH ₂ -C H ₂ -CH ₂ CN), 1.10 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.5×2, 145.0, 144.1, 133.7, 133.4, 128.1, 128.0, 126.4, 126.1, 124.6, 124.5, 122.6, 122.3, 122.1, 121.6, 121.5, 121.2, 118.2, 112.2, 111.8, 46.9, 44.1, 29.8, 24.0, 14.7. HR-ESIMS m/z 419.1498 [MH] ^- (calcd.for C ₂₆ H ₁₉ N ₄ O ₂ , 419.1508).

Preparation of Compound 67

Prepared according to the preparation method of compound 2, using compound 66 (10.2 mg, 23.8 μmol) and NaHCO ₃ (4 mg, 47.6 μmol) as a starting material, and separated by silica gel column chromatography, petroleum ether: ethyl acetate = 5:1 (v/v) Elected yellow fluorescent powder 6-hydroxymethyl-12-ethyl-13-cyanopropyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]咔Imidazole-5,7(6H)-dione (67) 10.5 mg, yield 96%. ¹ H NMR (600MHz, CDCl ₃ ) δ 9.25 (d, 1H, J = 7.7 Hz, Ar-H), 9.23 (d, 1H, J = 7.7 Hz, Ar-H), 7.65-7.61 (m, 4H) , Ar-H), 7.47 (t, 1H, J = 7.7 Hz, Ar-H), 7.44 (t, 1H, J = 6.6 Hz, Ar-H), 5.41 (d, 2H, J = 7.7 Hz, NC H ₂ -OH), 4.84 (t, 2H, J = 7.7 Hz, NC H ₂ -(CH ₂ ) ₂ CN), 4.68 (q, 2H, J = 7.7 Hz, NC H ₂ -CH ₃ ), 3.17 ( t, 1H, J = 7.7 Hz, -OH), 1.74-1.78 (m, 4H, NCH ₂ -C H ₂ -C H ₂ -CN), 1.11 (t, 3H, J = 7.7 Hz, CH ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.1× ₂ , 144.9, 144.1, 133.7, 133.4, 132.7, 128.1, 128.0, 126.3, 126.0, 124.6, 124.5, 122.6, 122.3, 122.2, 121.6, 120.3, 118.2, 112.2 , 111.8, 61.8, 46.9, 44.1, 24.0, 14.7, 13.6. HR-ESIMS m/z 473.1575 [M+H] ⁺ (calcd. for C ₂₇ H ₂₂ N ₄ O ₃ Na, 473.1590).

Preparation of Compound 68

According to the preparation method of the compound 64, the compound 5 (40 mg, 0.092 mmol) was prepared as a raw material, which was separated by silica gel column chromatography and petroleum ether: ethyl acetate=3:1 (v/v) to obtain yellow fluorescent powder 12-B. -13-cyanobutyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (68) 28.7 Mg, yield 72%. ¹ H NMR (600MHz, CDCl ₃ ) δ 9.26 (d, 1H, J = 7.7 Hz, Ar-H), 9.24 (d, 1H, J = 7.7 Hz, Ar-H), 7.72 (s, 1H, imide -NH), 7.64 (t, 1H, J = 7.3 Hz, Ar-H), 7.63 (d, 1H, J = 7.4 Hz, Ar-H), 7.62 (t, 1H, J = 7.7 Hz, Ar-H ), 7.60 (d, 1H, J = 7.8 Hz, Ar-H), 7.463 (dt, 1H, J = 7.6 Hz, 1.1 Hz, Ar-H), 7.462 (dt, 1H, J = 7.4 Hz, 0.9 Hz) , Ar-H), 4.75 (t, 2H, J = 6.9 Hz, NC H ₂ - (CH ₂ ) ₃ CN), 4.65 (q, 2H, J = 7.4 Hz, NC H ₂ -CH ₃ ), 1.99 ( t, 2H, J = 6.8 Hz, N(CH ₂ ) ₃ -C H ₂ -CN), 1.67 (m, 2H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.10 (t, 3H, J = 7.4 Hz, -CH ₂ -C H ₃ ), 1.00-0.98 (m, 2H, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.5 ×2,145.0,144.1,133.8,133.6,127.9,127.8,126.3,126.1,124.7,124.4,122.3,122.2,122.0,121.7,121.3,121.2,118.9,112.1,111.9,47.6,44.1,29.8,27.3,22.3 , 16.7. HR-ESIMS m/z 433.1663 [MH] ^- (calcd.for C ₂₇ H ₂₁ N ₄ O ₂ , 433.1665).

Preparation of Compound 69

Prepared according to the preparation method of Compound 2, Compound 68 (9.8 mg, 22.6 μmol) and NaHCO ₃ (4 mg, 45.2 μmol) were separated by silica gel column chromatography, petroleum ether: ethyl acetate = 4:1 (v/v) Elected yellow fluorescent powder 6-hydroxymethyl-12-ethyl-13-cyanobutyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]咔Oxazol-5,7(6H)-dione (70) 10 mg, yield 95%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.26 (d, 1H, J = 7.7 Hz, Ar-H), 9.24 (d, 1H, J = 8.8 Hz, Ar-H), 7.64-7.60 (m, 4H) , Ar-H), 7.45 (t, 2H, J = 7.7 Hz, Ar-H), 5.41 (d, 2H, J = 7.2 Hz, NC H _{2 -} OH), 4.75 (t, 2H, J = 6.6 Hz) , NC H ₂ -(CH ₂ ) ₃ CN), 4.66 (q, 2H, J = 6.6 Hz, NC H ₂ -CH ₃ ), 3.15 (t, 1H, J = 7.2 Hz, -OH), 1.97 (t , 2H, J=7.8Hz, N(CH ₂ ) ₃ -C H ₂ -CN), 1.68-1.64 (m, 2H, NCH ₂ -C H ₂ -(CH ₂ ) ₂ CN), 1.10(t,3H , J = 6.6 Hz, -CH ₂ -C H ₃ ), 0.98 (m, 2H, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.2 × 2,144.9,144.1,133.8,133.6,128.9,127.9,127.8,126.2,126.0,124.7,122.6,122.3×2,122.1,120.5,119.3,118.9,112.2,111.9,61.8,47.5,44.1,27.3,22.3, 16.7, 13.6. ESI-MS m/z 465.3 [M+H] ⁺ .

Preparation of Compound 70

According to the preparation method of the compound 64, the compound 7 (60 mg, 0.15 mmol) was used as a raw material, and it was separated by silica gel column chromatography, petroleum ether: ethyl acetate=2:1 (v/v) to obtain yellow fluorescent powder 12,13 -Dicyanomethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (70) 25 mg, The rate is 42%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.40 (s, 1H, imide-NH), 9.12 (d, 2H, J = 7.8 Hz, Ar-H), 8.02 (d, 2H, J = 8.3 Hz , Ar-H), 7.77 (dt, 2H, J = 7.3 Hz, 1.1 Hz, Ar-H), 7.56 (t, 2H, J = 7.3 Hz, Ar-H), 5.75 (s, 4H, -C H ₂ -CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 170.0 × 2, 144.5 × 2, 132.3 × 2, 128.6 × 2, 125.1 × 2, 123.6 × 2, 123.2 × 2, 122.2 × 2, 121.5×2, 115.3×2, 112.8×2, 37.4×2. ESI-MS m/z 404.1 [M+H] ⁺ .

Preparation of Compound 71

According to the preparation method of compound 64, the compound 2,3-di(1-cyanoethyl-1H-indol-3-yl)maleimide (30mg, 0.07mmol) was prepared as a raw material, and separated by silica gel column chromatography, petroleum ether: ethyl acetate =2:1 (v/v) eluted yellow fluorescent powder 12,13-dicyanoethyl-12,13-dihydro-5H-indole [2,3-a]pyrrole [3,4-c] Indazole-5,7(6H)-dione (71) 12 mg, yield 40%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.27 (s, 1H, imide-NH), 9.14 (d, 2H, J = 8.3 Hz, Ar-H), 8.00 (d, 2H, J = 8.2 Hz , Ar-H), 7.69 (t, 2H, J = 7.7 Hz, Ar-H), 7.49 (d, 2H, J = 7.7 Hz, Ar-H), 5.07 (t, 4H, J = 6.6 Hz, NC _{H 2 -CH 2 CN), 2.64} (4H, t, J = 6.6Hz, NCH 2 -C H 2 -CN). 13 C NMR (150MHz, DMSO-d 6) δ171.2 × 2,143.8 × 2, 133.6×2, 128.3×2, 125.6×2, 124.5×2, 122.7×2, 121.8×2, 121.2×2, 118.2×2, 113.6×2, 44.3×2, 21.5×2. ESI-MS m/z430 .0[MH] ^- .

Preparation of Compound 72

Prepared by the preparation of compound 65, using compound 9 (45 mg, 0.09 mmol) as a starting material, and eluted by silica gel column chromatography, petroleum ether: ethyl acetate=2:1 (v/v) to obtain yellow fluorescent powder 12,13 -Dicyanobutyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (74) 17 mg, The rate is 43%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H, imide-NH), 9.15 (d, 2H, J = 7.8 Hz, Ar-H), 7.93 (d, 2H, J = 8.2 Hz , Ar-H), 7.66 (dt, 2H, J = 7.8 Hz, 1.0 Hz, Ar-H), 7.44 (t, 2H, J = 7.8 Hz, Ar-H), 4.78 (t, 4H, J = 7.4 Hz, NC H ₂ -(CH ₂ ) ₃ CN), 2.26 (t, 4H, J = 7.3 Hz, N(CH ₂ ) ₃ -C H ₂ -CN), 1.53-1.50 (m, 4H, NCH ₂ - C H ₂ -(CH ₂ ) ₂ CN), 1.11-1.09 (4H, m, N(CH ₂ ) ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.2 ×2,144.6×2, 133.4×2, 128.0×2, 125.4×2, 123.7×2, 122.0×2, 121.4×2, 120.7×2, 120.3×2, 113.4×2, 48.1×2, 27.6×2 , 22.5 × 2, 16.1 × 2. ESI-MS m / z 486.1 [MH] ^- .

Preparation of Compound 73

i) Preparation of 12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (73a)

Compound 24d (400mg, 1.13mmol), DDQ (282mg, 1.24mmol) and p-TsOH (214mg, 1.13mmol) was dissolved in 100mL of benzene was refluxed for 30min under N ₂ conditions, the solvent was evaporated to dryness, redissolved in ethyl acetate 100mL , with saturated NaHSO ₃ solution, water, saline, dried organic layer over anhydrous Na ₂ SO _4, evaporated to dryness and after column chromatography on silica gel, petroleum ether: ethyl acetate = 2:1 (v / v) as eluent afforded Yellow powder (73a) 280 mg, yield 70%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.96 (s, 1H, indole-NH), 10.99 (s, 1H, imido-NH), 9.12 (d, 1H, J = 8.1Hz, Ar-H) , 9.07 (d, 1H, J = 8.1 Hz, Ar-H), 7.79 (d, 2H, J = 8.0 Hz, Ar-H), 7.59 (t, 1H, J = 7.9 Hz, Ar-H), 7.56 (t, 1H, J = 9.0 Hz, Ar-H), 7.36 (d, 1H, J = 8.2 Hz, Ar-H), 7.34 (d, 1H, J = 8.1 Hz, Ar-H), 4.94 (q) , 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 1.42 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171. 6×2, 141.5, 141.0, 129.6, 128.6, 127.3, 125.1, 124.7, 121.7, 121.4, 120.7×2, 120.4, 120.2, 117.2, 116.3, 112.5, 110.2, 110.1, 39.8, 16.1. HR-ESIMS m/z 354.1249 [M+H] ⁺ (calcd.for C ₂₂ H ₁₆ N ₃ O ₂ , 354.1243).

Ii) 6-(2-Aminoethyl)-12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7 ( Preparation of 6H)-dione (73)

The compound 73a (470 mg, 1.33 mmol) was suspended in 100 mL of 10% KOH aqueous solution, and the mixture was refluxed at 110 ° C for 1.5 h, dissolved in a pale yellow clear solution, cooled to room temperature, acidified with 2N hydrochloric acid, ethyl acetate (100 mL×3 times), organic The layer was evaporated to dryness to give 465 mg of crude 12-ethyl-12,13-dihydrofuran[3,4-c]indole[2,3-a]oxazol-5,7-dione (73b). Very poor, but the reaction is complete, the product is single, so directly into the next step without separation. According to the preparation method of the compound 14, the crude product 73b and 2 mL of ethylenediamine were used as a raw material to obtain 510 mg of a yellow powder (73) in a yield of 97%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9. s (t, 2H, J = 8.5 Hz, Ar-H), 7.80 (d, 1H, J = 8.1 Hz, Ar-H), 7.74 (d, 1H) , J = 8.1 Hz, Ar-H), 7.57 (t, 1H, J = 7.8 Hz, Ar-H), 7.53 (t, 1H, J = 7.6 Hz, Ar-H), 7.33 (d, 1H, J) = 8.1 Hz, Ar-H), 7.31 (d, 1H, J = 8.0 Hz, Ar-H), 4.86 (q, 2H, J = 6.9 Hz, -C H ₂ -CH ₃ ), 3.75 (t, 2H) , J = 6.1 Hz, -NC H ₂ CH ₂ NH ₂ ), 2.97 (t, 2H, J = 6.1 Hz, -NCH ₂ C H ₂ -NH ₂ ), 1.36 (t, 3H, J = 6.9 Hz, - CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.1×2, 141.5, 140.9, 129.4, 128.3, 127.3, 127.2, 124.9, 124.5, 121.5, 121.2, 120.6×2, 119.2 , 119.0, 117.2, 116.3, 112.6, 110.1, 39.9, 39.6, 38.7, 16.1. HR-ESIMS m/z 397.1671 [M+H] ⁺ (calcd. for C ₂₄ H ₂₁ N ₄ O ₂ , 397.1665).

Preparation of Compound 74

According to the preparation method of compound 16, a yellow powder 6-(2-aminoethyl)-12-ethyl-12,13-dihydro-5H-indole[2] was obtained from compound 73 (510 mg, 1.26 mmol). , 3-a] pyrrole [3,4-c]oxazol-5,7(6H)-dione hydrochloride (74) 540 mg, yield 99%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.07 (s, 1H, indole-NH), 9.11 (d, 1H, J = 8.2 Hz, Ar-H), 9.08 (d, 1H, J = 8.2 Hz , Ar-H), 7.90 (brs, 3H, -NH ₃ ⁺ ), 7.84 (d, 2H, J = 8.1 Hz, Ar-H), 7.63 (t, 1H, J = 7.1 Hz, Ar-H), 7.58 (t, 1H, J = 7.7 Hz, Ar-H), 7.38 (t, 1H, J = 7.8 Hz, Ar-H), 7.35 (t, 1H, J = 7.7 Hz, Ar-H), 4.98 ( q, 2H, J = 6.9 Hz, -C H ₂ -CH ₃ ), 3.98 (t, 2H, J = 5.9 Hz, NC H ₂ -CH ₂ NH ₃ ⁺ ), 3.19 (t, 2H, J = 6.0 Hz) , NCH ₂ -C H ₂ -NH ₃ ⁺ ), 1.41 (t, 3H, J = 6.9 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 170.1 × 2, 141.6, 141.1, 129.6, 128.5, 127.5 × 2, 124.9, 124.5, 121.6, 121.2, 120.8, 120.8, 119.5, 119.3, 117.3, 116.5, 112.7, 110.4, 39.6, 38.5, 35.8, 16.1. HR-ESIMS m/z 397.1670[M-Cl] ⁺ (calcd.for C ₂₄ H ₂₁ N ₄ O ₂ , 397.1665).

Preparation of Compound 75

At 0 ° C, NaH was suspended in a 250 mL two-necked flask with 15 mL of DMF, and 1 mL of the dissolved compound 73a (40 mg, 0.113 mmol) was added dropwise, and reacted for 10 min at low temperature, and allowed to react at room temperature for 30 min. The temperature was lowered to 0 ° C, and ClCH ₂ CH ₂ OH (0.092 mL, 1.36 mol) was added dropwise. Under an oil bath of 55 ° C, Ar gas was protected, and the condensed water was refluxed for 5 h. The reaction was not completely carried out by TLC, and the temperature was raised to 85 ° C for 6 h. After cooling to room temperature, 10 mL of methanol and 20 mL of a saturated aqueous solution of ammonium chloride were added at low temperature. Extracted with ethyl acetate, the organic layer was dried over anhydrous Na ₂ SO _4, evaporated to dryness in vacuo. The THF was dissolved, and the residue was purified by silica gel column chromatography eluting with ethyl ether: ethyl acetate=4:1 (v/v) to give a yellow solid 6-(2-hydroxyethyl)-12-ethyl-12,13-dihydro- 5H-吲哚[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (75) 11 mg, yield 25%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.95 (s, 1H, indole-NH), 9.09 (d, 1H, J = 8.1Hz, Ar-H), 9.08 (d, 1H, J = 8.1Hz , Ar-H), 7.79 (d, 1H, J = 7.8 Hz, Ar-H), 7.77 (d, 1H, J = 7.6 Hz, Ar-H), 7.59 (t, 1H, J = 7.4 Hz, Ar -H), 7.56 (t, 1H, J = 7.4 Hz, Ar-H), 7.35 (t, 1H, J = 8.1 Hz, Ar-H), 7.33 (t, 1H, J = 7.4 Hz, Ar-H ), 4.90 (q, 2H, J = 6.9 Hz, -C H ₂ -CH ₃ ), 3.73 - 3.71 (m, 2H, -NCH ₂ C H ₂ -OH), 3.69 (t, 2H, J = 5.4 Hz) , -NC H ₂ CH ₂ OH), 1.41 (t, 3H, J = 6.9 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.1 × 2, 141.8, 141.0 , 129.5, 128.4, 127.3, 125.0, 124.6, 121.6, 121.3, 120.7 × 2, 119.3, 119.1, 117.2, 116.4, 112.5, 110.1 × 2, 58.8, 40.5, 39.5, 16.1. HR-ESIMS m/z 398.1508 [ M+H] ⁺ (calcd.for C ₂₄ H ₂₀ N ₃ O ₃ , 398.1505).

Preparation of Compound 76

According to the preparation method of the compound 24, the compound 73b (49 mg, 0.14 mmol), 4-hydroxybenzylamine (51 mg, 0.42 mmol) and a catalytic amount of Et ₃ N were used as raw materials to obtain a yellow solid 6-(4-hydroxybenzyl). -12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (76) 15 mg, The rate is 23%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.03 (d, 1H, J = 7.0 Hz, Ar-H), 9.03 (d, 1H, J = 6.8 Hz, Ar-H), 7.77 (d, 1H) , J = 8.2 Hz, Ar-H), 7.70 (d, 1H, J = 8.4 Hz, Ar-H), 7.56 (d, 1H, J = 7.0 Hz, Ar-H), 7.55 (d, 1H, J = 6.9 Hz, Ar-H), 7.34 (dd, 1H, J = 7.0 Hz, 0.9 Hz, Ar-H), 7.32 (dd, 1H, J = 7.0 Hz, 0.9 Hz, Ar-H), 7.20 (d) , 2H, J = 8.2 Hz, Ar-H), 6.71 (d, 2H, J = 8.2 Hz, Ar-H), 4.81 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 4.63 (s, 2H, -NCH ₂ -Ar), 1.38 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ CNMR (150 MHz, DMSO-d ₆ ) δ 169.8, 169.7, 157.2, 141.7, 141.0, 129.6 × 2, 128.5, 128.4, 127.4, 125.0, 124.9, 124.7, 121.5, 121.3, 120.9, 120.8, 119.0, 118.8, 117.4, 116.4, 115.8 × 2, 112.6, 110.1, 100.0, 40.7, 39.6, 16.3. ESI-MS m/z 460.1 [M+H] ⁺ .

Preparation of Compound 77

According to the preparation method of the compound 24, the compound 73b (35 mg, 0.098 mmol), 4-(2-aminoethyl)morpholine (104 μL, 0.79 mmol) and a catalytic amount of Et ₃ N were used as raw materials to obtain a yellow solid 6-( 2-(4-morpholine)ethyl)-12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7 ( 6H)-dione (77) 33 mg, yield 72%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.01 (s, 1H, indole-N H ), 9.09 (t, 1H, J = 8.1 Hz, Ar-H), 9.07 (t, 1H, J = 7.9 Hz, Ar-H), 7.81 (d, 2H, J = 8.0 Hz, Ar-H), 7.59 (t, 1H, J = 8.0 Hz, Ar-H), 7.56 (t, 1H, J = 7.8 Hz, Ar-H), 7.38 (d, 1H, J = 8.0 Hz, Ar-H), 7.35 (t, 1H, J = 8.0 Hz, Ar-H), 4.94 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 3.79 (t, 2H, J = 6.2 Hz, imide-NC H ₂ CH ₂ -), 3.50 (t, 4H, J = 4.5 Hz, morpholine-N (CH ₂ -C H ₂ ) ₂ O), 2.62 (t, 2H, J = 6.2 Hz, imide-NCH ₂ C H ₂ -), 2.46 (t, 4H, J = 4.5 Hz, morpholine-N(C H ₂ -CH ₂ ) ₂ O) , 1.37 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.0 × 2, 141.7, 140.9, 129.4, 128.5, 127.5, 127.3, 125.0, 124.7, 121.6, 121.5, 121.4, 121.2, 120.9, 119.0, 117.4, 116.5, 112.7, 110.2, 66.8 × 2, 56.6, 53.7 × 2, 39.6, 34.9, 16.2. HR-ESIMS m/z 467.2088 [M+ H] ⁺ (calcd.for C ₂₈ H ₂₇ N ₄ O ₃ , 467.2083).

Preparation of Compound 78

According to the preparation method of the compound 24, the compound 73b (100 mg, 0.282 mmol), N,N-dimethylethylenediamine (247.7 μL, 2.256 mmol) and a catalytic amount of Et ₃ N were used as raw materials to obtain a yellow solid 6-( 2-(N,N-dimethylaminoethyl))-12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5 , 7(6H)-dione (78) 95.7 mg, yield 80%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.88 (s, 1H, indole-NH), 9.01 (d, 2H, J = 7.4Hz, Ar-H), 7.76 (d, 1H, J = 8.1Hz , Ar-H), 7.69 (d, 1H, J = 8.3 Hz, Ar-H), 7.56 (d, 1H, J = 8.1 Hz, Ar-H), 7.53 (d, 1H, J = 7.9 Hz, Ar -H), 7.33 (td, 2H, J = 7.8 Hz, 2.3 Hz, Ar-H), 4.80 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 3.63 (t, 2H, J) = 6.4 Hz, imide-NC H ₂ CH ₂ N(CH ₃ ) ₂ ), 2.49 (t, 2H, J = 6.4 Hz, imide-NCH ₂ C H ₂ -N(CH ₃ ) ₂ ), 2.18 (s, 6H, -N(CH ₃ ) ₂ ), 1.38 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 169.9 × 2, 141.6, 141.0, 129.5, 128.4, 127.4 × 2, 125.0, 124.8 × 2, 121.6, 121.3, 120.7, 119.1, 118.9, 117.3, 116.4, 112.6, 110.1, 57.5, 45.7 × 2, 39.7, 35.7, 16.2. HR-ESIMS m /z 425.1988[M+H] ⁺ (calcd.for C ₂₆ H ₂₅ N ₄ O ₂ , 425.1978).

Preparation of Compound 79

According to the preparation method of the compound 24, the compound 73b (80 mg, 0.226 mmol), 2-(2-aminoethyl)pyridine (135.3 μL, 1.13 mmol) and a catalytic amount of Et ₃ N were used as raw materials to obtain a yellow solid 6-( 2-(2-pyridyl)ethyl)-12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H )-Dione (79) 25 mg, yield 64%. 72.5 mg, yield 70%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.92 (s, 1H, indole-NH), 9.02 (d, 1H, J = 6.5Hz, Ar-H), 9.01 (t, 1H, J = 6.5Hz , Ar-H), 8.43 (d, 1H, J = 3.2 Hz, Ar-H), 7.77 (t, 2H, J = 7.4 Hz), 7.66 (t, 1H, J = 8.0 Hz, Ar-H), 7.58 (t, 1H, J = 8.0 Hz, Ar-H), 7.55 (t, 1H, J = 7.8 Hz, Ar-H), 7.33 - 7.28 (m, 3H, Ar-H), 7.18 (t, 1H) , J = 6.3 Hz, Ar-H), 4.88 (q, 2H, J = 7.0 Hz, -C H ₂ -CH ₃ ), 4.00 (t, 2H, J = 6.5 Hz, imide-NC H ₂ CH ₂ - ), 3.13 (t, 2H, J = 6.5 Hz, imide-NCH ₂ C H ₂ -), 1.39 (t, 3H, J = 7.0 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO) -d ₆ ) δ169.8×2, 159.0, 149.7, 141.6, 141.0, 137.1, 129.5, 128.4, 127.3, 125.0, 124.7, 123.8, 123.7, 122.9, 122.2, 121.6, 121.3, 120.7, 119.1, 118.9, 117.3, 116.4, 112.5, 110.1, 39.6, 37.7, 36.9, 16.2. HR-ESIMS m/z 459.1831 [M+H] ⁺ (calcd. for C ₂₉ H ₂₃ N ₄ O ₂ , 459.1821).

Preparation of Compound 80

According to the preparation method of the compound 64, the compound 62 (41 mg, 0.09 mmol) was used as a starting material to obtain a yellow solid 2-isopentenyl-12-ethyl-12,13-dihydro-5H-indole [2,3- a] Pyrrole [3,4-c]carbazole-5,7(6H)-dione (80) 38 mg, yield 90%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.80 (s, 1H, indole-NH), 10.95 (s, 1H, imide-NH), 9.06 (d, 1H, J = 7.6Hz, Ar-H) , 8.88 (d, 1H, J = 8.1 Hz, Ar-H), 7.75 (d, 1H, J = 8.3 Hz, Ar-H), 7.58 (td, 1H, J = 7.1 Hz, 1.1 Hz, Ar-H ), 7.50 (s, 1H, Ar-H), 7.33 (t, 1H, J = 7.5 Hz, Ar-H), 7.13 (dd, 1H, J = 8.1 Hz, 1.3 Hz, Ar-H), 5.40 ( t, 1H, J = 7.5 Hz, ArCH ₂ C H = C(CH ₃ ) ₂ ), 4.87 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 3.48 (d, 2H, J = 7.5 Hz, ArC H ₂ CH=C(CH ₃ ) ₂ ), 1.75 (s, 6H, ArCH ₂ CH=C(C H ₃ ) ₂ ), 1.39 (t, 3H, J = 7.2 Hz, -CH ₂ - C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 170.7, 170.6, 141.0, 140.0, 139.9, 131.5, 128.6, 127.5, 126.2, 124.0, 123.5, 122.8, 120.7, 119.6, 119.1, 118.8, 118.4,116.3,115.1,110.3,109.0,106.5,33.6,28.3,25.1,17.2,15.2.HR-ESIMS m / z 422.1879 [ m + H] + (calcd.for C 27 H 24 N 3 O 2, 422.1869) .

Preparation of Compound 81

According to the preparation method of compound 2, compound 80 (30 mg, 0.071 mmol) and formaldehyde solution (3 mL, mass fraction: 37%) were used as raw materials to obtain a yellow solid 2-isopentenyl-6-hydroxymethyl-12-ethyl -12,13-Dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (81) 13 mg, yield 25%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.78 (s, 1H, indole-NH), 9.03 (d, 1H, J = 7.8Hz, Ar-H), 8.86 (d, 1H, J = 8.1Hz , Ar-H), 7.72 (d, 1H, J = 8.3 Hz, Ar-H), 7.57 (t, 1H, J = 7.0 Hz, Ar-H), 7.51 (s, 1H, Ar-H), 7.34 (t, 1H, J = 7.4 Hz, Ar-H), 7.14 (d, 1H, J = 8.2 Hz, Ar-H), 6.28 (t, 1H, J = 7.0 Hz, -CH ₂ O H ), 5.44 (t, 1H, J = 7.6 Hz, ArCH ₂ C H = C(CH ₃ ) ₂ ), 4.92 (d, 2H, J = 6.1 Hz, -C H ₂ OH), 4.80 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.53 (d, 2H, J = 7.5 Hz, ArC H ₂ CH=C(CH ₃ ) ₂ ), 1.78 (s, 6H, ArCH ₂ CH=C (C H _{3 2} ), 1.39 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 168.6 × 2, 141.3, 140.3, 140.2, 131.8, 128.8 , 127.7, 126.6, 124.1, 123.6, 123.0 × 2, 120.8, 112.0, 118.6, 118.1, 117.7, 116.5, 115.4, 110.6, 109.3, 59.4, 38.8, 33.9, 25.4, 17.5, 15.4. HR-ESIMS m/z 450.1821 [MH] ^- (calcd.for C ₂₈ H ₂₄ N ₃ O ₃ , 450.1812).

Preparation of Compound 82

i) Preparation of N-methyl-2,3-dibromomaleimide (82a)

In a 50 mL two-necked flask, NaH (30 mg, 0.75 mmol, 60% by mass, dispersed in paraffin) was suspended and stirred with 5 mL of DMF, and 5 mL of DMF dissolved 2,3-dibromomaleimide was added dropwise at -5 °C. (127.5mg, 0.5mmol), after 30min reaction at low temperature, add methyl iodide (47μL, 0.75mmol), react at low temperature for 30min, stop the reaction by adding saturated NH ₄ Cl solution, extract with CH ₂ Cl ₂ , and evaporate the organic layer. Column chromatography, petroleum ether: ethyl acetate = 30:1 (v / v) eluted to afford white crystals (82a): ¹ H NMR (600 MHz, CDCl ₃ ) δ 3.12 (s, 3H, -CH ₃ ). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 164.1×2, 129.5×2, 25.6. ESI-MS m/z 267.9 [M+H] ⁺ .

Ii) Preparation of N-methyl-2,3-bis(6-chloro-3-indolyl)maleimide (82)

Place a magnesium wire (200 mg, 8.35 mmol) in a 50 mL two-necked flask, stir and stir with 5 mL of THF at room temperature, add bromoethane (620 μL, 8.35 mmol) dropwise, react at room temperature for 20 min, increase to 45 ° C, continue the reaction for 30 min, add 8 mL. 6-chloroindole (1.27 g, 8.35 mmol) dissolved in toluene, reacted for 1 h, slowly added 8 mL of toluene dissolved in 82a (448 mg, 1.67 mmol), and the mixture was refluxed to 110 ° C for 2 h, and dropped to -5 ° C. dropwise addition of saturated NH ₄ Cl solution to terminate the reaction, extracted with ethyl acetate, the organic layer was concentrated and column chromatography on silica gel, petroleum ether: ethyl acetate = 3:1 (v / v) as eluent afforded a red solid powder (82) 300mg, The yield was 44%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.80 (s, 2H, indole-NH), 7.80 (s, 2H, Ar-H), 7.43 (s, 2H, Ar-H), 6.71 (d, 2H, J=8.6 Hz, Ar-H), 6.65 (d, 2H, J = 8.6 Hz, Ar-H), 3.02 (s, 3H, -CH ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) Δ171.9×2, 136.8×2, 130.7×2, 127.4×2, 126.8×2, 124.4×2, 122.3×2, 120.1×2, 112.0×2, 106.0×2, 24.4. HR-ESIMS m/z 410.0467[M+H] ⁺ (calcd.for C ₂₁ H ₁₄ N ₃ O ₂ Cl ₂ , 410.0463).

Preparation of Compound 83

In a 25 mL two-necked flask, compound 82 (257 mg, 0.63 mmol) was dissolved in 10 mL of DMF, and NaH (28 mg, 0.69 mmol, mass fraction 60%, dispersed in paraffin) was added under stirring at -5 ° C. After 30 min of low temperature reaction, slowly drip. EtI (108 mg, 0.69 mmol) was added and the reaction was carried out at low temperature for 30 min. Dropwise addition of saturated NH ₄ Cl solution to terminate the reaction, extracted with ethyl acetate, the organic layer was concentrated and column chromatography on silica gel, petroleum ether: ethyl acetate = 4:1 (v / v) as eluent afforded an orange-red powder N- methyl - 2-(1-Ethyl-6-chloro-3-indolyl)-3-(6-chloro-3-indole)maleimide (83) 100 mg, yield 38%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.84 (d, 1H, J = 2.2Hz, indole-NH), 7.83 (d, 1H, J = 2.2Hz, Ar-H), 7.79 (s, 1H , Ar-H), 7.64 (d, 1H, J = 1.6 Hz, Ar-H), 7.45 (d, 1H, J = 1.7 Hz, Ar-H), 6.81 (d, 1H, J = 8.8 Hz, Ar -H), 6.72 (dd, 1H, J = 8.3 Hz, 1.7 Hz, Ar-H), 6.66-6.64 (m, 2H, Ar-H), 4.25 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 3.03 (s, 3H, N-CH ₃ ), 1.31 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 172 .0,171.9,137.1,136.5,132.9,131.0,127.7,127.3,127.0,126.9,125.1,124.3,122.9,122.6,120.5,120.3,112.2,110.8,106.0,105.6,41.4,24.6,15.8.HR-ESIMS m/z 438.0780 [M+H] ⁺ (calcd. for C ₂₃ H ₁₈ N ₃ O ₂ Cl ₂ , 438.0776).

Preparation of Compound 84

i) Preparation of 2-(1-ethyl-6-chloro-3-indolyl)-3-(6-chloro-3-indole) maleic anhydride (84a)

In a 50 mL single-mouth flask, compound 83 (100 mg, 0.23 mmol) was suspended in 10 mL of ethanol, 10 mL of 5 M KOH solution was added, refluxed at 78 ° C for 8 h, cooled to room temperature, acidified with 6N hydrochloric acid, extracted with ethyl acetate, The organic layer was dried over anhydrous sodium sulfate and evaporated. ^{1 H NMR (600MHz, DMSO-} d 6) δ12.06 (d, 1H, J = 2.8Hz, indole-NH), 7.92 (d, 1H, J = 3.3Hz, Ar-H), 7.88 (s, 1H , Ar-H), 7.69 (d, 1H, J = 1.6 Hz, Ar-H), 7.49 (d, 1H, J = 1.6 Hz, Ar-H), 6.85 (d, 1H, J = 8.8 Hz, Ar -H), 6.79 (dd, 1H, J = 8.2 Hz, 1.6 Hz, Ar-H), 6.73 (dd, 1H, J = 8.2 Hz, 1.6 Hz, Ar-H), 6.70 (d, 1H, J = 8.8 Hz, Ar-H), 4.26 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 1.31 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 166.8, 166.7, 137.2, 136.7, 134.0, 132.3, 128.8, 128.1, 127.7, 127.4, 124.7, 124.0, 123.2, 122.9, 121.0, 120.7, 112.5, 111.1, 105.4, 104.8 , 41.6, 15.7. ESI-MS m/z 425.0/427.0 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-6-chloro-3-indolyl)-3-(6-chloro-3-indolyl)maleimide (84)

According to the preparation method of the compound 24c, the compound 84a (53 mg, 0.125 mmol), HMDS (2.6 mL, 12.5 mmol) and MeOH (0.25 mL, 6.25 mmol) were used as raw materials to obtain an orange-red powder (84) 52 mg, yield 98. %. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.80 (s, 1H, indole-NH), 10.97 (s, 1H, imide-NH), 7.81 (d, 1H, J = 2.8Hz, Ar-H) , 7.79 (s, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 6.80 (d, 1H, J = 8.8 Hz, Ar-H), 6.71 (dd, 1H, J = 8.8 Hz, 1.1 Hz, Ar-H), 6.69 (d, 1H, J = 8.8 Hz, Ar-H), 6.65 (dd, 1H, J = 8.8 Hz, 1.7 Hz, Ar -H), 4.25 (q, 2H, J = 7.1 Hz, -CH ₂ -CH ₃ ), 1.31 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 173.2 × 2, 137.0, 136.5, 132.9, 130.9, 128.3, 127.7, 127.2, 126.9, 125.2, 124.5, 122.9, 122.6, 120.4, 120.2, 112.1, 110.0, 106.0, 105.6, 41.4, 15.8 .HR-ESIMS m/z 424.0629 [M+H] ⁺ (calcd. for C ₂₂ H ₁₆ N ₃ O ₂ Cl ₂ , 424.0620).

Preparation of Compound 85

Prepared according to the preparation method of compound 2, using compound 84 (20 mg, 47 μmol), formaldehyde solution (3 mL, mass fraction: 37%) and NaHCO ₃ (11.9 mg, 140 μmol) as a starting material, silica gel column chromatography, petroleum ether: ethyl acetate = 2:1 (v/v) eluted red solid N-hydroxymethyl-2-(1-ethyl-6-chloro-3-indole)-3-(1-hydroxymethyl-6-chloro -3-吲哚) Maleimide (85) 22 mg, yield 97%. ^{1 H NMR (500MHz, DMSO-} d 6) δ8.00 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.68 (s, 1H, Ar-H), 7.64 (s, 1H, Ar-H), 6.86 (d, 1H, J = 8.6 Hz, Ar-H), 6.74 (t, 1H, J = 7.2 Hz, indole-CH ₂ -O H ), 6.70 (d, 1H, J) =8.7 Hz, Ar-H), 6.67 (d, 1H, J = 8.6 Hz, Ar-H), 6.55 (d, 1H, J = 8.6 Hz, Ar-H), 6.33 (t, 1H, J = 7.0) Hz, imide-CH ₂ -O H ), 5.60 (d, 2H, J = 7.2 Hz, indole-C H ₂ -OH), 4.95 (d, 2H, J = 7.0 Hz, imide-C H ₂ -OH) , 4.25 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.29 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ171.3×2, 136.6×2, 133.5, 133.1, 127.8, 127.4×2, 127.3, 125.3, 125.2, 122.9, 122.7, 120.8, 120.6, 111.6, 110.9, 105.7, 105.4, 69.9, 60.9, 41.5, 15.8. HR-ESIMS m/z 506.0656 [M+Na] ⁺ (calcd. for C ₂₄ H ₁₉ N ₃ O ₄ Cl ₂ Na, 506.0650).

Preparation of Compound 86

Prepared according to the preparation method of compound 82, using compound 82a (710mg, 2.64mmol), Mg (317mg, 13.2mmol), bromoethane (982μL, 13.2mmol) and 4-bromoindole (2g, 132mmol) as raw materials, The solid N-methyl-2,3-bis(4-bromo-3-indolyl)imide was eluted by silica gel column chromatography eluting with dichloromethane:ethyl acetate=9:1 (v/v). (86) 500 mg, yield 30%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.84 (s, 2H, indole-NH), 7.84 (d, 2H, J = 7.4Hz, Ar-H), 7.42 (d, 2H, J = 8.1Hz , Ar-H), 7.18 ( d, 2H, J = 7.5Hz, Ar-H), 7.02 (t, 2H, J = 7.8Hz, Ar-H), 3.07 (s, 3H, -CH 3). 13 C NMR (125 MHz, DMSO-d ₆ ) δ 172.3 × 2, 137.8 × 2, 137.3 × 2, 130.4 × 2, 127.1 × 2, 126.1 × 2, 123.6 × 2, 113.9 × 2, 112.4 × 2, 104.8 × 2,24.8. ESI-MS m/z 519.9/521.9/523.9 [M+Na] ⁺ .

Preparation of Compound 87

According to the preparation method of compound 83, compound 86 (506 mg, 1.02 mmol), NaH (81 mg, 2.04 mmol, 60% by mass, dispersed in paraffin) and ethyl iodide (90 μL, 1.2 mmol) were used as raw materials, and silica gel column was prepared. Chromatography, petroleum ether: ethyl acetate = 2:1 (v / v) eluted to give an orange-red solid N-methyl-2-(1-ethyl-4-bromo-3-indole)-3- 4-bromo-3-indole maleimide (87) 182 mg, yield 34%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.85 (s, 1H, indole-NH), 7.92 (s, 1H, Ar-H), 7.85 (d, 1H, J = 2.7Hz, Ar-H) , 7.52 (d, 1H, J = 8.3 Hz, Ar-H), 7.41 (d, 1H, J = 8.1 Hz, Ar-H), 7.19 (dd, 2H, J = 7.2 Hz, 1.6 Hz, Ar- H), 7.06 (t, 1H, J = 7.9 Hz, Ar-H), 7.02 (t, 1H, J = 7.8 Hz, Ar-H), 4.22 (q, 2H, J = 7.2 Hz, -CH ₂ -CH ₃ ), 3.06 (s, 3H, -NCH ₃ ), 1.34 (t, J = 7.2 Hz, 3H, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 172.3 ×2,137.7×2,135.3,134.7,132.7,130.4,126.3,126.1,124.2,124.1,123.6,123.5,114.1,113.9,111.9,110.4,104.2,103.5,41.4,24.8,15.8.ESI-MS m/ z 525.9/527.9/529.9[M+H] ⁺ .

Preparation of Compound 88

i) Preparation of 2-(1-ethyl-4-bromo-3-indolyl)-3-(4-bromo-3-indole) maleic anhydride (88a)

Prepared according to the method of the compound 84a, Compound 87 (100 mg, 0.23 mmol) was used as a starting material, and silica gel column chromatography (dichloromethane elution) yielded an orange-red solid (88a) 58 mg, yield 60%. ^{1 H NMR (600MHz, DMSO-} d 6) δ12.06 (s, 1H, indole-NH), 8.00 (s, 1H, Ar-H), 7.95 (d, 1H, J = 2.7Hz, Ar-H) , 7.57 (d, 1H, J = 8.2 Hz, Ar-H), 7.46 (d, 1H, J = 8.1 Hz, Ar-H), 7.25 (dd, 2H, J = 7.2 Hz, 7.1 Hz, Ar-H ), 7.10 (t, 1H, J = 7.9 Hz, Ar-H), 7.06 (t, 1H, J = 7.9 Hz, Ar-H), 4.25 (q, 2H, J = 7.2 Hz, -C H ₂ - CH ₃ ), 1.35 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.7×2, 137.8, 137.3, 136.9, 136.3, 133.6 , 131.4, 125.8, 125.6, 124.7, 124.6, 124.0 × 2, 113.9, 113.7, 112.3, 110.7, 102.9, 102.2, 41.6, 15.8. ESI-MS m/z 513.1/515.0/517.1 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-4-bromo-3-indolyl)-3-(4-bromo-3-indolyl)maleimide (88)

Prepared according to the preparation method of compound 24c, Compound 88a (126mg, 0.32mmol), HMDS (6.7mL, 32mmol) and MeOH (0.64mL, 16mmol) were prepared by silica gel column chromatography and eluted with dichloromethane to obtain orange-red powder. 88 (118 mg, yield 94%). ^{1 H NMR (500MHz, DMSO-} d 6) δ11.83 (s, 1H, indole-NH), 10.98 (s, 1H, imide-NH), 7.92 (s, 1H, Ar-H), 7.85 (d, 1H, J = 2.7 Hz, Ar-H), 7.52 (t, 1H, J = 8.0 Hz, Ar-H), 7.41 (d, 1H, J = 8.0 Hz, Ar-H), 7.20 (t, 1H, J = 7.5 Hz, Ar-H), 7.18 (d, 1H, J = 7.5 Hz, Ar-H), 7.06 (d, 1H, J = 7.9 Hz, Ar-H), 7.01 (t, 1H, J = 7.8 Hz, Ar-H), 4.21 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.35 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 173.5×2, 137.7, 137.2, 135.8, 135.3, 132.6, 130.3, 126.4, 124.1, 124.0, 123.5, 114.2, 113.9, 113.7, 111.9, 110.3, 104.4, 103.7, 100.0 , 41.4, 15.8.1. ESI-MS m/z 512.1/514.0/516.1 [M+H] ⁺ .

Preparation of Compound 89

Prepared according to the preparation method of compound 1, using compound 88 (36 mg, 70.5 μmol), formaldehyde solution (3 mL, mass fraction: 37%) and NaHCO ₃ (30 mg, 352 μmol) as a starting material, silica gel column chromatography, petroleum ether: ethyl acetate =1:2 (v/v) eluted orange-yellow solid N-hydroxymethyl-2-(1-ethyl-4-bromo-3-indole)-3-(1-hydroxymethyl-4- Bromo-3-indole maleimide (89) 39 mg, yield 97%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.79 (s, 1H, ar-H), 7.92 (s, 1H, Ar-H), 7.61 (d, 1H, J = 8.2 Hz, Ar-H) , 7.53 (d, 1H, J = 8.2 Hz, Ar-H), 7.24 (d, 1H, J = 7.8 Hz, Ar-H), 7.21 (d, 1H, J = 7.6 Hz, Ar-H), 7.09 (t, 1H, J = 8.0 Hz, Ar-H), 7.06 (t, 1H, J = 7.6 Hz, Ar-H), 6.69 (t, 1H, J = 7.3 Hz, -CH ₂ O H ), 6.40 (t, 1H, J = 7.0 Hz, -CH ₂ O H ), 5.56 (d, 2H, J = 7.3 Hz, -C H ₂ OH), 4.97 (d, 2H, J = 7.0 Hz, -C H ₂ OH), 4.02 (q, 2H, J = 7.1 Hz, -CH ₂ -CH ₃ ), 1.17 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO -d ₆ ) δ171.6×2, 137.2, 137.1, 135.5, 135.0, 133.2, 132.9, 126.8, 126.3, 124.7, 124.2, 123.8, 123.6, 114.0, 113.9, 111.0, 110.4, 103.9, 103.3, 69.7, 60.3, 41.5, 15.8. ESI-MS m/z 554.1/556/1/558.1 [MH ₂ O+H] ⁺ .

Preparation of Compound 90

According to the preparation method of the compound 82, the compound 5-bromoindole (2g, 13.2mmol), Mg (317mg, 13.2mmol) and the compound 82a (710mg, 2.64mmol) were prepared as a raw material, and the silica gel column chromatography, petroleum ether: acetic acid Ethyl ester = 3:1 (v/v) eluted to an orange-red solid N-methyl-2,3-bis(5-bromo-3-indole)maleimide (90) 500 mg, yield 30 %. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.91 (s, 2H, indole-NH), 7.80 (s, 2H, Ar-H), 7.36 (d, 2H, J = 8.6Hz, Ar-H) , 7.10 (d, 2H, J = 8.6 Hz, Ar-H), 6.84 (s, 2H, Ar-H), 3.04 (s, 3H, -CH ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) Δ171.9×2, 135.2×2, 130.9×2, 127.5×2, 127.3×2, 124.7×2, 123.6×2, 114.2×2, 112.4×2, 105.5×2, 24.5. HR-ESIMS m/z 497.9458 [M+H] ⁺ (calcd.for C ₂₁ H ₁₄ N ₃ O ₂ Br ₂ , 497.9453).

Preparation of Compound 91

According to the preparation method of compound 84, compound 90 (506 mg, 1.2 mmol), NaH (81 mg, 2.04 mmol, 60% by mass, dispersed in paraffin) and EtI (90 μL, 1.2 mmol) were prepared as silica gel column chromatography. , petroleum ether: ethyl acetate = 3:1 (v / v) eluted to obtain an orange-red solid N-methyl-2-(1-ethyl-5-bromo-3-indole)-3-(5- Bromo-3-indole maleimide (91) 200 mg, yield 36%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.95 (s, 1H, indole-NH), 7.88 (s, 1H, Ar-H), 7.75 (d, 1H, J = 1.4Hz, Ar-H) , 7.48 (d, 1H, J = 8.1 Hz, Ar-H), 7.37 (d, 1H, J = 8.5 Hz, Ar-H), 7.18 (d, 1H, J = 8.5 Hz, Ar-H), 7.09 (d, 1H, J = 7.9 Hz, Ar-H), 6.99 (s, 1H, Ar-H), 6.68 (s, 1H, Ar-H), 4.24 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 3.03 (s, 3H, -CH ₃ ), 1.31 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 172 .0,171.9,135.4,134.8,133.0,131.3,128.1,127.9,127.1,126.8,124.8×2,124.0,123.7,114.3,112.8×2,112.6,105.6,105.0,41.5,24.6,16.0.HR-ESIMS m/z 525.9776 [M+H] ⁺ (calcd. for C ₂₃ H ₁₈ N ₃ O ₂ Br ₂ , 525.9766).

Preparation of Compound 92

i) Preparation of 2-(1-ethyl-5-bromo-3-indolyl)-3-(5-bromo-3-indole) maleic anhydride (92a)

Prepared according to the method of the compound 84a, Compound 91 (120 mg, 0.229 mmol) was used as a starting material. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.16 (s, 1H, indole-NH), 7.97 (d, 1H, J = 1.4 Hz, Ar-H), 7.87 (s, 1H, Ar-H) , 7.53 (d, 1H, J = 8.7 Hz, Ar-H), 7.40 (d, 1H, J = 8.5 Hz, Ar-H), 7.23 (d, 1H, J = 8.8 Hz, Ar-H), 7.16 (d, 1H, J = 8.4 Hz, Ar-H), 7.01 (s, 1H, Ar-H), 6.72 (s, 1H, Ar-H), 4.28 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.33 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.8, 166.7, 135.5, 134.9, 134.0, 132.4, 129.1, 128.0, 127.7, 126.8, 125.2 × 2, 124.2, 124.0, 114.6, 113.3, 113.0 × 2, 104.8, 104.2, 41.7, 16.0. ESI-MS m/z ESI-MS m/z 512.9/514.9/ 516.9[M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-5-bromo-3-indolyl)-3-(5-bromo-3-indolyl)maleimide (92)

Prepared according to the preparation of compound 23c, Compound 92a (88mg, 0.172mmol), HMDS (4mL, 17.2mmol) and MeOH (0.5mL, 8.6mmol). 92 (85 mg, yield 97%). ^{1 H NMR (500MHz, DMSO-} d 6) δ11.93 (s, 1H, indole-NH), 10.98 (s, 1H, imide-NH), 7.86 (d, 1H, J = 2.8Hz, Ar-H) , 7.77 (s, 1H), 7.48 (d, 1H, J = 8.7 Hz, Ar-H), 7.35 (d, 1H, J = 8.5 Hz, Ar-H), 7.15 (dd, 1H, J = 8.7 Hz) , 1.8 Hz, Ar-H), 7.08 (dd, 1H, J = 8.6 Hz, 1.9 Hz, Ar-H), 6.94 (d, 1H, J = 7.8 Hz, Ar-H), 6.68 (d, 1H, J = 1.7 Hz, Ar-H), 4.25 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.32 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 173.2, 173.1, 135.3, 134.7, 133.0, 131.2, 128.5, 128.1, 127.4, 127.2, 124.8, 124.7, 123.9, 123.8, 114.3, 112.8, 112.7, 112.5, 105.4 , 105.0, 41.5, 16.0. HR-ESIMS m/z 511.9617 [M+H] ⁺ (calcd. for C ₂₂ H ₁₆ N ₃ O ₂ Br ₂ , 511.9609).

Preparation of Compound 93

Prepared according to the preparation method of compound 2, using compound 92 (55 mg, 107.6 μmol), formaldehyde solution (3 mL, mass fraction: 37%) and NaHCO ₃ (45 mg, 538 μmol) as a starting material, silica gel column chromatography, petroleum ether: ethyl acetate =1:2 (v/v) eluted orange-yellow solid N-hydroxymethyl-2-(1-ethyl-5-bromo-3-indole)-3-(1-hydroxymethyl-5- Bromo-3-indole maleimide (93) 58 mg, yield 95%. ^{1 H NMR (500MHz, DMSO-} d 6) δ8.04 (s, 1H, Ar-H), 7.71 (s, 1H, Ar-H), 7.55 (d, 1H, J = 8.7Hz, Ar-H) , 7.50 (d, 1H, J = 8.7 Hz, Ar-H), 7.18 (dt, 2H, J = 8.9 Hz, 1.5 Hz, Ar-H), 7.12 (d, 1H, Ar-H, J = 1.5 Hz) ), 6.58 (d, 1H, Ar-H J = 1.5 Hz), 5.60 (s, 2H, indole-C H ₂ -OH), 4.97 (s, 2H, imide-C H ₂ -OH), 4.23 (q) , 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 3.78 (s, 1H, N-CH ₂ -O H ), 3.15 (s, 1H, N-CH ₂ -O H ), 1.29 (t , 3H, J=7.1Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ171.2×2, 134.9, 134.8, 133.9, 133.2, 128.2, 128.1, 127.6, 127.5, 127.0,125.0,124.1,124.0,113.5,113.2,113.1,112.8,104.9,104.8,69.9,60.9,41.5,16.0.HR-ESIMS m/z 593.9647[M+Na] ⁺ (calcd.for C ₂₄ H ₁₉ N ₃ O ₄ Br ₂ Na, 593.9640).

Preparation of Compound 94

According to the preparation method of compound 82, 6-bromoindole (850 mg, 5.58 mmol), Mg (134 mg, 5,58 mmol) and compound 82 (300 mg, 1.12 mmol) were used as raw materials to obtain an orange-red solid N-methyl- 2,3-bis(6-bromo-3-indolyl)maleimide (94) 180 mg, yield 30%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.83 (s, 2H, indole-NH), 7.78 (d, 2H, J = 7.7Hz, Ar-H), 7.58 (d, 2H, J = 7.7Hz , Ar-H), 6.78 (d, 1H, J = 7.8 Hz, Ar-H), 6.77 (d, 1H, J = 7.8 Hz, Ar-H), 6.68 (s, 1H, Ar-H), 6.67 (s, 1H, Ar-H), 3.02 (s, 3H, -CH ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.0 × 2, 137.4 × 2, 130.8 × 2, 127.5 × 2, 124.8×2, 122.9×2, 122.8×2, 115.1×2, 115.0×2, 106.1×2, 24.6. HR-ESIMS m/z 497.9458[M+H] ⁺ (calcd.for C ₂₁ H ₁₄ N ₃ O ₂ Br ₂ , 497.9453).

Preparation of Compound 95

According to the preparation method of the compound 83, the compound 94 (155 mg, 0.312 mmol), NaH (14 mg, 0.343 mmol, 60% by mass, dispersed in paraffin) and EtI (28 μL, 0.343 mmol) were prepared as a raw material, and separated by silica gel column chromatography. , petroleum ether: ethyl acetate = 4:1 (v / v) eluted to obtain an orange-red solid N-methyl-2-(1-ethyl-6-bromo-3-indole)-3-(6- Bromo-3-indole maleimide (95) 56 mg, yield 34%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.81 (s, 1H, indole-NH), 7.79 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 6.82 (d, 1H, J = 8.6 Hz, Ar-H), 6.75 (t, 2H, J = 7.7 Hz, Ar-H), 6.61 (d, 1H, J = 8.6 Hz, Ar-H), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.02 (s, 3H, -NCH ₃ ), 1.29 (t, 3H, J = 7.2 Hz, -CH _{2 )} -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.9, 171.8, 137.4, 136.8, 132.6, 130.8, 127.6, 126.9, 125.2, 124.4, 123.1, 122.9, 122.8, 122.7, 115.2, 115.0 , 114.9, 113.5, 105.9, 105.4, 41.3, 24.4, 15.7. HR-ESIMS m/z 525.9771 [M+H] ⁺ (calcd. for C ₂₃ H ₁₈ N ₃ O ₂ Br ₂ , 525.9766).

Preparation of Compound 96

i) Preparation of 2-(1-ethyl-6-bromo-3-indolyl)-3-(6-bromo-3-indole) maleic anhydride (96a)

Prepared according to the method of the compound 84a, Compound 95 (240 mg, 0.46 mmol) was used as a starting material, which was purified by silica gel column chromatography and eluted with dichloromethane to give an orange-red solid 96a (144 mg, yield 61%). ^{1 H NMR (600MHz, DMSO-} d 6) δ12.04 (s, 1H, indole-NH), 7.89 (d, 1H, J = 1.5Hz, Ar-H), 7.87 (s, 1H, Ar-H) , 7.82 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 6.91 (d, 1H, J = 8.6 Hz, Ar-H), 6.85 (d, 1H, J = 8.6 Hz, Ar-H), 6.80 (d, 1H, J = 8.6 Hz, Ar-H), 6.67 (d, 1H, J = 8.6 Hz, Ar-H), 4.27 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 1.30 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.8, 166.7, 137.7, 137.1, 133.9, 132.2, 128.8, 128.1, 124.9, 124.2, 123.6, 123.5, 123.3, 123.2, 115.8, 115.5 × 2, 114.0, 105.4, 104.8, 41.6, 15.7. ESI-MS m/z 535.1/537.0/539.1 [M+Na] ⁺ .

Ii) Preparation of 2-(1-ethyl-6-bromo-3-indolyl)-3-(6-bromo-3-indole)maleimide (96)

Prepared according to the preparation of compound 24c, Compound 96a (100mg, 0.195mmol), HMDS (4ml, 17.2mmol) and MeOH (0.5ml, 8.6mmol). 96 (97 mg, yield 97%). ^{1 H NMR (500MHz, DMSO-} d 6) δ11.82 (s, 1H, indole-NH), 11.00 (s, 1H, imide-NH), 7.79 (d, 1H, J = 0.9Hz, Ar-H) , 7.78 (s, 1H, Ar-H), 7.76 (d, 1H, J = 7.5 Hz, Ar-H), 7.57 (d, 1H, J = 7.6 Hz, Ar-H), 6.82 (dd, 1H, J = 8.6 Hz, 1.6 Hz, Ar-H), 6.76 (dd, 1H, J = 8.6 Hz, 1.7 Hz, Ar-H), 6.73 (d, 1H, J = 8.5 Hz, Ar-H), 6.63 ( d, 1H, J = 8.6 Hz, Ar-H), 4.25 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 1.30 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 173.2×2, 137.5, 136.9, 132.8, 130.9, 128.3, 127.6, 125.4, 124.7, 123.2, 123.0, 122.9, 122.8, 115.3, 115.1, 114.9 , 113.6, 106.0, 105.5, 41.4, 15.8. HR-ESIMS m/z 511.9617 [M+H] ⁺ (calcd. for C ₂₂ H ₁₆ N ₃ O ₂ Br ₂ , 511.9609).

Preparation of Compound 97

Prepared according to the preparation method of compound 2, using compound 96 (14mg, 27.4μmol), formaldehyde solution (3mL, mass fraction 37%) and NaHCO ₃ (12mg, 137μmol) as raw materials, silica gel column chromatography, petroleum ether: ethyl acetate =3:1 (v/v) eluted red solid N-hydroxymethyl-2-(1-ethyl-6-bromo-3-indole)-3-(1-hydroxymethyl-6-bromo -3-吲哚) Maleimide (97) 14.1 mg, yield 90%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.78 (s, 2H, Ar-H), 6.85-6.82 ( m, 2H, Ar-H), 6.79 (d, 1H, J = 8.8 Hz, Ar-H), 6.74 (t, 1H, J = 7.5 Hz, indole-CH ₂ -O H ), 6.51 (d, 1H) , J = 8.5 Hz, Ar-H), 6.32 (t, 1H, J = 6.0 Hz, imide-CH ₂ -O H ), 5.59 (d, 2H, J = 7.5 Hz, indole-C H ₂ -OH) , 4.95 (d, 2H, J = 6.0 Hz, imide-C H ₂ -OH), 4.25 (q, 2H, J = 6.8 Hz, -C H ₂ -CH ₃ ), 1.29 (d, 3H, J = 6.8 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.3, 171.2, 137.0, 136.9, 133.4, 133.0, 127.8, 127.2, 125.5, 125.4, 123.4, 123.3, 123.2, 123.0×2,115.4,114.5,113.8,105.6,105.4,69.8,60.9,41.4,15.8.HR-ESIMS m/z 593.9650[M+Na] ⁺ (calcd.for C ₂₄ H ₁₉ N ₃ O ₄ Br ₂ Na , 593.9640).

Preparation of Compound 98

According to the preparation method of the compound 82, 7-bromoindole (850 mg, 5.6 mmol), Mg (134 mg, 5.6 mmol) and the compound 82a (286 mg, 1.1 mmol) were used as raw materials to obtain an orange-red solid N-methyl-2. , 3-bis(7-bromo-3-indole) maleimide (98) 180 mg, yield 32%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.94 (s, 2H, indole-NH), 7.77 (d, 2H, J = 2.7Hz, Ar-H), 7.20 (d, 2H, J = 7.5Hz , Ar-H), 6.77 ( d, 2H, J = 8.0Hz, Ar-H), 6.60 (t, 2H, J = 7.8Hz, Ar-H), 3.04 (s, 3H, -CH 3). 13 C NMR (125 MHz, DMSO-d ₆ ) δ 171.8 × 2, 134.7 × 2, 130.5 × 2, 127.7 × 2, 127.4 × 2, 124.9 × 2, 121.3 × 2, 120.6 × 2, 107.0 × 2, 104.8 × 2,24.5.HR-ESIMS m/z 497.9464 [M+H] ⁺ (calcd. for C ₂₁ H ₁₄ N ₃ O ₂ Br ₂ , 497.9453).

Preparation of Compound 99

According to the preparation method of the compound 83, compound 98 (317 mg, 0.638 mmol), NaH (28.1 mg, 0.702 mmol, 60% by mass, dispersed in paraffin) and EtI (57 μL, 0.702 mmol) were used as raw materials, and silica gel column chromatography was used. Separation, petroleum ether: ethyl acetate = 5:1 (v / v) eluted to give an orange-red solid N-methyl-2-(1-ethyl-7-bromo-3-indole)-3-(7 -Bromo-3-indole) Maleimide (99) 110 mg, yield 33%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.96 (s, 1H, indole-NH), 7.83 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.24 (d, 1H, J = 7.5 Hz, Ar-H), 7.20 (d, 1H, J = 7.5 Hz, Ar-H), 6.95 (d, 1H, J = 7.9 Hz, Ar-H), 6.64 (t, 1H, J = 6.7 Hz, Ar-H), 6.62 (d, 1H, J = 6.6 Hz, Ar-H), 6.57 (t, 1H, J = 7.8 Hz, Ar-H), 4.59 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.04 (s, 3H, -NCH ₃ ), 1.31 (d, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO -d ₆ ) δ171.7×2, 134.8×2, 131.9, 130.8, 129.8, 128.7, 127.5, 127.0, 126.6, 124.9, 121.5, 121.3, 121.1, 120.6, 106.9, 105.6, 104.8, 103.4, 43.5, 24.5, 17.9. HR-ESIMS m/z 525.9772 [M+H] ⁺ (calcd. for C ₂₃ H ₁₈ N ₃ O ₂ Br ₂ , 525.9766).

Preparation of Compound 100

i) Preparation of 2-(1-ethyl-7-bromo-3-indole)-3-(7-bromo-3-indole) maleic anhydride (100a)

Prepared according to the method of the compound 84a, Compound 99 (200 mg, 0.38 mmol) was used as a starting material, which was purified by silica gel column chromatography and eluted with dichloromethane to give an orange-red solid 100a (84 mg, yield 43%). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H, indole-NH), 7.90 (d, 1H, J = 2.5 Hz, Ar-H), 7.87 (s, 1H, Ar-H) , 7.29 (d, 1H, J = 7.5 Hz, Ar-H), 7.26 (d, 1H, J = 7.3 Hz, Ar-H), 7.00 (d, 1H, J = 8.0 Hz, Ar-H), 6.71 -6.68 (m, 1H, Ar-H), 6.68-6.62 (m, 2H, Ar-H), 4.60 (q, 2H, J = 7.1 Hz, -CH ₂ -CH ₃ ), 1.32 (t, 3H) , J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 166.6, 166.5, 135.9, 135.1, 132.2, 130.0, 129.5, 128.1, 127.8, 126.7, 125.5, 122.1, 122.0, 121.4, 121.0, 106.4, 105.2, 104.9, 103.7, 43.8, 17.9. ESI-MS m/z 512.9/514.9/516.9 [M+H] ⁺ .

Ii) Preparation of 2-(1-ethyl-7-bromo-3-indolyl)-3-(7-bromo-3-indolyl)maleimide (100)

Prepared according to the preparation of compound 24c, Compound 100a (150 mg, 0.293 mmol), HMDS (4 mL, 17.2 mmol) and MeOH (0.5 mL, 8.6 mmol). 100 (123 mg, yield 82%). ^{1 H NMR (500MHz, DMSO-} d 6) δ11.94 (s, 1H, indole-NH), 11.03 (s, 1H, imide-NH), 7.80 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.23 (d, 1H, J = 7.6 Hz, Ar-H), 7.19 (d, 1H, J = 7.4 Hz, Ar-H), 6.92 (d, 1H, J = 8.0 Hz, Ar-H), 6.64 (d, 1H, J = 7.9 Hz, Ar-H), 6.62 (t, 1H, J = 7.9 Hz, Ar-H), 6.56 (t, 1H, J = 7.7 Hz, Ar- H), 4.58 (d, 2H, J = 7.1 Hz, -CH ₂ -CH ₃ ), 1.32 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz, DMSO -d ₆ ) δ 172.9, 172.8, 134.8 × 2, 131.9, 130.8, 129.9, 129.2, 127.5, 127.2, 127.1, 124.8, 121.4, 121.3, 121.1, 120.6, 106.9, 105.6, 104.8, 103.3, 43.5, 17.9. HR-ESIMS m/z 511.9613 [M+H] ⁺ (calcd. for C ₂₂ H ₁₆ N ₃ O ₂ Br ₂ , 511.9609).

Preparation of Compound 101

Prepared according to the preparation method of compound 2, using compound 100 (55 mg, 107 μmol), formaldehyde solution (3 mL, mass fraction: 37%) and NaHCO ₃ (45 mg, 537 μmol) as the starting materials, silica gel column chromatography, petroleum ether: ethyl acetate = 3:1 (v/v) eluted red solid N-hydroxymethyl-2-(1-ethyl-7-bromo-3-indole)-3-(1-hydroxymethyl-7-bromo- 3-吲哚) Maleimide (101) 20.2 mg, yield 33%. ^{1 H NMR (500MHz, DMSO-} d 6) δ12.06 (s, 1H, indole-NH), 7.87 (s, 1H,), 7.82 (s, 1H, Ar-H), 7.26 (d, 2H, J = 7.6 Hz, Ar-H), 7.22 (d, 1H, J = 7.4 Hz, Ar-H), 6.95 (d, 1H, J = 8.0 Hz, Ar-H), 6.65 (d, 1H, J = 7.8) Hz, Ar-H), 6.63 (d, 1H, J = 6.0 Hz, Ar-H), 5.82 (t, 1H, J = 7.0 Hz, -CH ₂ O H ), 4.97 (d, 2H, J = 7.0) Hz, -C H ₂ OH), 4.62 (q, 2H, J = 7.0 Hz, -C H ₂ -CH ₃ ), 1.33 (t, 3H, J = 7.0 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 170.5, 170.4, 134.3 × 2, 134.2, 131.3, 130.4, 129.2, 128.2, 126.9, 126.9, 126.4 × 2, 126.1 × 2, 120.9, 120.8, 119.9, 104.8, 104.2, 60.1, 42.9, 17.2. HR-ESIMS m/z 541.9725 [M+H] ⁺ (calcd. for C ₂₃ H ₁₈ N ₃ O ₃ B _r2 , 541.9715).

Preparation of Compound 102

i) Preparation of N-methyl-2-(3-indole)-3-bromomaleimide (102a)

The magnesium chips (360 mg, 15 mmol) were suspended in THF (5 mL) in a 50 mL two-necked flask. Ethyl bromide (1.12 mL, 15 mmol) was slowly added dropwise, stirred at room temperature for 20 min, then warmed to 45 ° C, stirred for 20 min, and dissolved in THF (5 mL) The hydrazine (1.75 g, 15 mmol) was stirred for 30 min. After cooling to room temperature, compound 82a (2 g, 7.5 mmol) dissolved in THF (10 mL) was evaporated. After the TLC was detected, the reaction was completed, and the reaction was quenched with saturated aqueous ammonium chloride (50 mL), ethyl acetate (2××100 mL), and brine (2××100 mL). The organic layer was dried (MgSO4), EtOAc (EtOAc) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.12 (s, 1H, indole-NH), 8.06 (d, 1H, J = 8.0 Hz, Ar-H), 7.91 (d, 1H, J = 8.0 Hz , Ar-H), 7.55 (dt, 1H, J = 8.0 Hz, 0.6 Hz, Ar-H), 7.23 (dt, 1H, J = 7.9 Hz, 0.9 Hz, Ar-H), 7.15 (dt, 1H, J = 7.7 Hz, 1.0 Hz, Ar-H), 3.01 (s, 3H, -NCH ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 169.7, 167.1, 138.2, 137.1, 131.6, 125.1, 123.1 , 122.8, 121.0, 114.1, 112.9, 104.4, 25.1. ESI-MS m/z 304.9 [M+H] ⁺ .

Ii) Preparation of N-methyl-2-(1-tert-butyloxycarbonyl-3-indole)-3-bromomaleimide (102b)

Compound 102a (2 g, 6.58 mmol) was dissolved in THF (80 mL), and a catalytic amount of DMAP was added at 0 ° C, and THF (20 mL) dissolved (Boc) ₂ O (2.9 g, 13.16) was slowly added dropwise. Methyl), warmed to room temperature and stirred for 2 h. The reaction was completed by TLC, and the solvent was evaporated in vacuo. m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ^{1 H NMR (500MHz, DMSO-} d 6) δ8.13 (d, 1H, J = 8.4Hz, Ar-H), 8.08 (s, 1H, Ar-H), 7.77 (d, 1H, J = 7.9Hz , Ar-H), 7.43 (dt, 1H, J = 7.9 Hz, 0.9 Hz, Ar-H), 7.36 (dt, 1H, J = 7.7 Hz, 1.0 Hz, Ar-H), 3.02 (s, 3H, -NCH ₃ ), 1.65 (s, 9H, -C(CH ₃ ) ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 168.9, 166.4, 149.0, 136.3, 135.1, 129.4, 127.2, 125.8, 123.7 , 123.0, 122.1, 115.5, 109.0, 85.7, 28.1, 25.3. ESI-MS m/z 405.0 [M+H] ⁺ .

Iii) Preparation of N-methyl-2-(1-tert-butyloxycarbonyl-3-indole)-3-(3-indole)maleimide (102c)

According to the synthesis method of compound 102a, compound 102b (1.8 g, 4.46 mmol), magnesium powder (321 mg, 13.37 mmol), bromoethane (1 mL, 13.37 mmol) and hydrazine (1.57 g, 13.37 mmol) were synthesized, silica gel column Chromatography, petroleum ether: ethyl acetate = 4:1 (v/v) eluted to yield a yellow solid (102c) 1.6 g, yield 81%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.83 (s, 1H, indole-NH), 8.03 (d, 1H, J = 8.3Hz, Ar-H), 7.91 (s, 1H, Ar-H) , 7.85 (d, 1H, J = 2.8 Hz, Ar-H), 7.37 (d, 1H, J = 8.1 Hz, Ar-H), 7.18 (t, 1H, J = 7.7 Hz), 6.98 (t, 1H) , J = 7.6 Hz, Ar-H), 6.87 (d, 1H, J = 8.2 Hz, Ar-H), 6.86 (d, 1H, J = 8.3 Hz, Ar-H), 6.82 (t, 1H, J = 7.5 Hz, 1H, Ar-H), 6.67 (t, 1H, J = 7.6 Hz, Ar-H), 3.04 (s, 3H, -NCH ₃ ), 1.60 (s, 9H, -C(CH ₃ ) ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.6, 171.5, 149.1, 136.6, 134.7, 132.5, 131.0, 128.4, 128.1, 125.5, 125.0, 123.4, 122.9, 122.4, 121.7, 121.2, 120.3, 115.1, 112.4, 111.2, 105.7, 85.0, 28.0, 24.5. ESI-MS m/z 442.2 [M+H] ⁺ .

Iv) Preparation of p-toluenesulfonate (102d)

Phenylethanol (2 g, 16.3 mmol) was dissolved in dichloromethane (50 mL) in a 250 mL two-necked flask at 0 ° C, triethylamine (3.38 mL, 24.5 mmol) was added, and dichloromethane (20 mL) was added dropwise to dissolve toluene. Sulfonyl chloride (4.67 g, 24.5 mmol) was added dropwise to room temperature and allowed to react overnight. After the reaction was completed by TLC, the solvent was evaporated in vacuo, and purified by silica gel column chromatography, eluting with petroleum ether: ethyl acetate=25:1 (v/v) to afford 3.6 g (yel. ESI-MS m/z 277.1 [M+H] ⁺ .

v) Preparation of N-methyl-2-(1-tert-butyloxycarbonyl-3-indene)-3-(1-phenylethyl-3-indole)maleimide (102e)

In a 25 mL three-neck reaction flask, sodium hydride (11 mg, 0.272 mmol, 60% dispersion in paraffin oil) was suspended in DMF (5 mL), and stirred at -5 ° C for 30 min, then DMF (5 mL) dissolved compound 102c was slowly added dropwise ( 60 mg, 0.136 mmol), stirring was continued for 45 min at low temperature, and compound 102d (100 μL, 0.272 mmol) dissolved in DMF (2 mL) was slowly added dropwise, and allowed to warm to room temperature overnight. After the TLC was detected, the reaction was completed, and the mixture was cooled to 0° C., and then the mixture was evaporated to dryness with saturated aqueous ammonium chloride (50 mL), and the mixture was extracted with ethyl acetate (3××100 mL), brine (2××100 mL), and the organic phase was combined. The organic layer was dried over anhydrous sodium sulfate and evaporated. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.03 (d, 1H, J = 8.4 Hz, Ar-H), 7.93 (s, 1H, Ar-H), 7.72 (s, 1H, Ar-H) , 7.47 (d, 1H, J = 8.3 Hz, Ar-H), 7.22 (t, 1H, J = 6.6 Hz, Ar-H), 7.18 (m, 2H, Ar-H), 7.14 (m, 2H, Ar-H), 7.03-6.98 (dt, 1H, J = 7.8 Hz, 0.9 Hz, Ar-H), 6.81 (m, 3H, Ar-H), 6.66 (dd, 1H, J = 7.0 Hz, 7.1 Hz , Ar-H), 4.47 (t, 2H, J = 7.1 Hz, NC H ₂ -CH ₂ Ph), 3.01 (s, 3H, -NCH ₃ ), 2.99 (t, 2H, J = 7.1 Hz, NCH ₂ -C H ₂ -Ph), 1.61 (s, 9H, -C(CH ₃ ) ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.5, 171.4, 149.2, 138.7, 136.2, 134.7, 133.7, 131.7, 129.2 × 2, 128.7 × 2, 128.6, 128.2, 126.9, 126.1, 125.1, 123.3, 122.8, 122.6, 121.7, 121.4, 120.5, 115.1, 111.2, 110.9, 104.9, 85.1, 47.8, 36.1, 28.1 × 3, 24.5. ESI-MS m/z 546.3 [M+H] ⁺ .

Vi) Preparation of N-methyl-2-(3-indolyl)-3-(1-phenylethyl-3-indole)maleimide (102f)

Compound 102e (34 mg, 0.062 mmol) was dissolved in toluene (10 mL) in EtOAc (EtOAc) The mixture was cooled to room temperature, and the reaction was completed by TLC. The solvent was evaporated in vacuo, and purified by silica gel column chromatography, eluting with petroleum ether: ethyl acetate=3:1 (v/v) to yield a red solid (102f) 26mg, yield 94% . ^{1 H NMR (500MHz, DMSO-} d 6) δ11.68 (s, 1H, indole-NH), 7.76 (s, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.45 (d, 1H, J = 8.3 Hz, Ar-H), 7.36 (d, 1H, J = 8.1 Hz, Ar-H), 7.25 (d, 1H, J = 7.8 Hz, Ar-H), 7.24 (d, 2H, J = 7.2 Hz, Ar-H), 7.18-7.16 (m, 3H, Ar-H), 6.99 (d, 1H, J = 7.9 Hz, Ar-H), 6.95 (d, 1H, J = 7.8 Hz, Ar-H), 6.75 (d, 1H, J = 8.3 Hz, Ar-H), 6.73 (d, 1H, J = 8.0 Hz, Ar-H), 6.64 (d, 1H, J = 8.1 Hz, Ar- H), 6.60 (d, 1H, J = 8.1 Hz, Ar-H), 4.46 (t, 2H, J = 7.3 Hz, NC H ₂ -CH ₂ Ph), 3.03 (t, 2H, J = 7.3 Hz, NCH ₂ -C H ₂ -Ph), 3.01 (s, 3H, -NCH ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 172.2, 172.1, 138.8, 136.4, 136.0, 134.7, 132.3, 129.6, 129.2×2, 128.7×2, 127.4, 126.9, 126.7, 126.4, 125.8, 122.1, 121.6, 121.4, 119.9, 119.7, 112.2, 110.6, 106.1, 105.3, 47.7, 36.2, 24.4. ESI-MS m/z 446.3[ M+H] ⁺ .

Vii) 6-Methyl-12-phenethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-di Preparation of ketone (102)

Synthesis of compound 102f (406 mg, 0.912 mmol), DDQ (269 mg, 1.19 mmol) and p-TsOH (154 mg, 0.81 mmol). 1 (v/v) eluted yellow solid (102) 340 mg, yield 84%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H, indole-NH), 9.03 (d, 1H, J = 8.0 Hz, Ar-H), 9.00 (d, 1H, J = 7.8 Hz , Ar-H), 7.77 (d, 1H, J = 8.1 Hz, Ar-H), 7.55 (t, 1H, J = 7.5 Hz, Ar-H), 7.50 (d, 1H, J = 8.1 Hz, Ar -H), 7.44 (t, 1H, J = 7.0 Hz, Ar-H), 7.33 (t, 1H, J = 6.9 Hz, Ar-H), 7.27 (t, 1H, J = 6.9 Hz, Ar-H ), 7.03-7.00 (m, 5H, Ar-H), 5.07 (t, 2H, J = 7.4 Hz, NC H ₂ -CH ₂ Ph), 3.05 (s, 3H, NCH ₃ ), 3.03 (t, 2H) , J = 7.4 Hz, NCH ₂ -C H ₂ -Ph). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.1 × 2, 141.7, 141.6, 138.4, 129.8, 129.6, 129.5, 128.7 × 2, 128.6 , 128.5, 127.4, 127.2, 126.8, 124.8, 124.7, 121.5, 120.8, 120.7 × 2, 119.7, 117.5, 116.6, 112.6, 110.6, 45.8, 36.9, 24.1. ESI-MS m/z 444.2 [M+H] ⁺ .

Preparation of Compound 103

i) Preparation of 12-phenethyl-12,13-dihydrofuran[3,4-c]indole [2,3-a]oxazol-5,7-dione (103a)

Synthesis of Compound 102 (200 mg, 0.45 mmol) and KOH (5M, 30 mL) Since the solubility of the product is extremely poor and the reaction is relatively complete, it is directly input to the next reaction without separation and purification.

Ii) 12-phenethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]carbazole-5,7(6H)-dione (103) preparation

Synthesis of compound 103a (20 mg, 0.047 mmol), HMDS (500 μL, 2.35 mmol) and methanol (50 μL, 1.18 mmol), eluted on silica gel column chromatography, petroleum ether: ethyl acetate = 3:1 ( v/v) eluted yellow solid (103) 16 mg, yield 90%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.83 (s, 1H, indole-NH), 11.02 (s, 1H, imide-NH), 9.08 (d, 1H, J = 7.8Hz, Ar-H) , 9.06 (d, 1H, J = 7.8 Hz, Ar-H), 7.79 (d, 1H, J = 8.1 Hz, Ar-H), 7.62 (d, 1H, J = 8.3 Hz, Ar-H), 7.56 (t, 1H, J = 7.6 Hz, Ar-H), 7.47 (t, 1H, J = 7.7 Hz, Ar-H), 7.35 (t, 1H, J = 7.5 Hz, Ar-H), 7.30 (t , 1H, J = 7.5 Hz, Ar-H), 7.10-6.98 (m, 5H, Ar-H), 5.20 (t, 2H, J = 7.1 Hz, NC H ₂ -CH ₂ -Ph), 3.07 (t , 2H, J=7.1Hz, N-CH ₂ -C H ₂ -Ph). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ171.6,171.5,141.6,141.5,138.2,133.0,129.5×2,128.9 , 128.4 × 2, 127.3, 127.1, 126.7, 124.9, 124.7, 123.5, 121.6, 121.4, 120.7 × 2, 120.3, 117.4, 116.6, 112.5, 110.6, 45.8, 36.5. ESI-MS m/z 430.2 [M+H ] ⁺ .

Preparation of Compound 104

According to the preparation method of the compound 2, the compound 103 (18 mg, 0.06 mmol) was used as a raw material, and it was eluted by silica gel column chromatography, petroleum ether: ethyl acetate=3:1 (v/v) to obtain yellow fluorescent powder 6-hydroxyl -12-phenethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (104) 21 mg The yield is 80%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.92 (s, 1H, indole-NH), 9.07 (d, 1H, J = 7.9Hz, Ar-H), 9.06 (d, 1H, J = 7.8Hz , Ar-H), 7.79 (d, 1H, J = 8.1 Hz, Ar-H), 7.58 (d, 1H, J = 8.2 Hz, Ar-H), 7.56 (d, 1H, J = 8.1 Hz, Ar -H), 7.47 (t, 1H, J = 7.6 Hz, Ar-H), 7.35 (t, 1H, J = 7.4 Hz, Ar-H), 7.30 (t, 1H, J = 7.4 Hz, Ar-H ), 7.00-6.97 (m, 5H), 6.29 (t, 1H, J = 7.0 Hz, -CH ₂ O H ), 5.16 (t, 2H, J = 6.8 Hz, NC H ₂ -CH ₂ Ph), 5.04 (d, 2H, J = 7.0 Hz, -C H ₂ OH), 3.08 (t, 2H, J = 6.8 Hz, NCH ₂ - C H ₂ -Ph). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 169 .5,169.4,141.6,141.5,138.2,130.0,129.4×2,128.9,128.4,127.4,127.2,126.7,124.9,124.7,124.5,123.5,121.4,121.3,120.8,120.7,119.1,117.4,116.6,112.6 , 110.6, 60.2, 45.8, 36.4. ESI-MS m/z 460.2 [M+H] ⁺ .

Preparation of Compound 105

The compound was synthesized by the method of the synthesis of compound 14a (40 mg, 0.09 mmol) and ethylenediamine (75 μL, 0.9 mmol), eluted by silica gel column chromatography, methylene chloride:methanol=50:1 (v/v) Yellow solid 6-(2-aminoethyl)-12-phenethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7 (6H)-dione (105) 34 mg, yield 80%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.07 (s, 1H, indole-NH), 9.08 (d, 1H, J = 7.2 Hz, Ar-H), 9.07 (d, 1H, J = 7.9 Hz , Ar-H), 7.83 (d, 1H, J = 8.0 Hz, Ar-H), 7.62 (d, 1H, J = 8.1 Hz, Ar-H), 7.58 (t, 1H, J = 7.8 Hz, Ar -H), 7.47 (t, 1H, J = 7.3 Hz, Ar-H), 7.35 (t, 1H, J = 7.3 Hz, Ar-H), 7.30 (t, 1H, J = 7.2 Hz, Ar-H ), 7.01 (m, 5H, Ar-H), 5.23 (t, 2H, J = 6.6 Hz, NC H ₂ -CH ₂ -Ph), 3.90 (t, 2H, J = 5.7 Hz, NC H ₂ -CH ₂ NH ₂ ), 3.10 (t, 2H, J = 5.7 Hz, NCH ₂ -C H ₂ -NH ₂ ), 3.09 (t, 2H, J = 6.6 Hz, N-CH ₂ -C H ₂ -Ph). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.2×2, 141.7, 141.6, 138.2, 129.5×2, 128.8, 128.4×2, 127.4, 127.2, 126.7, 124.7, 124.6, 121.9, 121.4, 120.9, 120.7 , 119.4, 119.3, 117.5, 116.7, 112.7, 111.6, 110.7, 45.9, 40.9, 40.9, 36.5. ESI-MS m/z 473.3 [M+H] ⁺ .

Preparation of Compound 106

A yellow solid 6-(2-aminoethyl)-12-phenethyl-12,13-dihydro-5H-indole[2, was obtained from compound 105 (25 mg, 0.05 mmol). 3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione hydrochloride (106) 173 mg, yield 90%. ^{1 H NMR (500MHz, DMSO-} d 6) δ12.24 (s, 1H, indole-NH), 9.05 (d, 1H, J = 7.5Hz, Ar-H), 9.04 (d, 1H, J = 7.0Hz , Ar-H), 8.21 (brs, 3H, -NH ₃ ⁺ ), 7.87 (d, 1H, J = 8.1 Hz, Ar-H), 7.56 (d, 1H, J = 7.7 Hz, Ar-H), 7.55 (d, 1H, J = 8.1 Hz, Ar-H), 7.45 (d, 1H, J = 7.3 Hz, Ar-H), 7.34 (t, 1H, J = 7.5 Hz, Ar-H), 7.28 ( t,1H,J=7.4Hz,Ar-H),7.03-6.93(m,5H),5.23(t,2H,J=6.4Hz,NC H ₂ -CH ₂ Ph),3.97(t,2H,J = 6.4 Hz, NC H ₂ -CH ₂ NH ₃ ⁺ ), 3.18 (t, 2H, J = 6.4 Hz, NCH ₂ -C H ₂ -NH ₃ ⁺ ), 3.07 (t, 2H, J = 6.4 Hz, NCH ^{_{2 -C H 2 -Ph). 13}} C NMR (125MHz, DMSO-d 6) δ170.1 × 2,141.8,141.6,138.2,129.8,129.4,128.7,128.3,127.4,127.1,126.6,124.6,124.5, 121.4, 120.9, 121.2, 120.7, 120.6, 119.3 × 2, 117.4, 116.7, 112.8, 110.7, 110.6.45.8, 38.2, 36.6, 35.7. ESI-MS m/z 473.2 [M-Cl] ⁺ .

Preparation of Compound 107

The compound was synthesized according to the method of the compound 14 from compound 103a (25 mg, 0.06 mmol) and 1,3-propanediamine (99 μL, 1.2 mmol), and purified by silica gel column chromatography, methylene chloride:methanol = 50:1 (v/v The yellow solid 6-(3-aminopropyl)-12-phenethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]carbazole -5,7(6H)-dione (107) 22 mg, yield 75%. ^{1 H NMR (500MHz, DMSO-} d 6) δ12.19 (s, 1H, indole-NH), 9.05 (d, 1H, J = 7.8Hz, Ar-H), 9.03 (d, 1H, J = 7.8Hz , Ar-H), 7.87 (d, 1H, J = 8.1 Hz, Ar-H), 7.57 (dt, 1H, J = 8.1 Hz, 1.1 Hz, Ar-H), 7.54 (d, 1H, J = 8.1 Hz, Ar-H), 7.45 (dt, 1H, J = 8.1 Hz, 1.1 Hz, Ar-H), 7.35 (dt, 1H, J = 8.1 Hz, 1.1 Hz, Ar-H), 7.28 (t, 1H) , J=7.9 Hz, Ar-H), 7.05-7.03 (m, 5H, Ar-H), 5.20 (t, 2H, J = 7.0 Hz, NC H ₂ -CH ₂ Ph), 3.76 (t, 2H, J = 6.6 Hz, NC H ₂ -(CH ₂ ) ₂ NH ₂ ), 3.07 (t, 2H, J = 7.0 Hz, NCH ₂ -C H ₂ -Ph), 2.90 (t, 2H, J = 6.6 Hz, _{N (CH 2) 2 -C H} 2 -NH 2), 2.04-2.00 (m, 2H, NCH 2 -C H 2 -CH 2 NH 2). 13 C NMR (125MHz, DMSO-d 6) δ170.2 ×2,141.9,141.7,138.4,130.0,129.6×2,128.9,128.5×2,127.5,127.3,126.8,124.8,124.6,121.5,121.4,120.8×2,119.1×2,117.6,116.8,112.9,110.7 , 45.9, 37.5, 36.7, 35.2, 27.4. ESI-MS m/z 487.1 [M+H] ⁺ .

Preparation of Compound 108

A yellow solid 6-(3-aminopropyl)-12-phenethyl-12,13-dihydro-5H-indole[2, was obtained from compound 107 (23 mg, 0.05 mmol). 3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione hydrochloride (108) 20 mg, yield 90%. ^{1 H NMR (500MHz, DMSO-} d 6) δ12.18 (s, 1H, indole-NH), 9.06 (d, 2H, J = 7.9Hz, Ar-H), 8.01 (brs, 3H, -NH 3 + ), 7.85 (d, 1H, J = 8.1 Hz, Ar-H), 7.59 (d, 1H, J = 8.1 Hz, Ar-H), 7.56 (d, 1H, J = 8.1 Hz, Ar-H), 7.45 (t, 1H, J = 7.6 Hz, Ar-H), 7.34 (t, 1H, J = 7.5 Hz, Ar-H), 7.29 (t, 1H, J = 7.5 Hz, Ar-H), 7.04- 6.97 (m, 5H), 5.22 (t, 2H, J = 6.8 Hz, NC H ₂ -CH ₂ Ph), 3.77 (d, 2H, J = 6.8 Hz, NC H ₂ -(CH ₂ ) ₂ N H ₃ ⁺ ), 3.07 (t, 2H, J = 6.7 Hz, NCH ₂ -C H ₂ -Ph), 2.93 (t, 2H, J = 6.7 Hz, N(CH ₂ ) ₂ -C H ₂ -NH ₃ ⁺ ) , 2.05-1.97 (m, 2H, NCH ₂ -C H ₂ -CH ₂ NH ₃ ⁺ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 170.2, 170.1, 141.8, 141.6, 138.3, 130.0, 129.8, 129.5, 128.8, 128.4, 127.4, 127.3, 127.2, 126.7, 124.7, 124.5, 121.4, 121.2, 120.7 × 2, 119.0 × 2, 117.5, 116.7, 112.8, 110.7, 45.8, 37.4, 36.5, 35.1, 27.3. MS m/z 487.1 [M-Cl] ⁺ .

Preparation of Compound 109

According to the synthesis method of compound 24, compound 103a (21 mg, 0.049 mmol), 4-(2-aminoethyl)-morpholine (50 μL, 0.49 mmol) and catalytic amount of triethylamine were synthesized, and separated by silica gel column chromatography. Ethyl chloride:methanol = 50:1 (v/v) eluted as a yellow solid 6-(2-(4-morpholine)ethyl)-12-phenethyl-12,13-dihydro-5H-indole [2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (109) 19 mg, yield 80%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.91 (s, 1H, indole-NH), 9.05 (d, 1H, J = 7.9Hz, Ar-H), 9.04 (d, 1H, J = 7.8Hz , Ar-H), 7.78 (d, 1H, J = 8.1 Hz), 7.57 (d, 1H, J = 7.8 Hz, Ar-H), 7.57 (t, 1H, J = 7.3 Hz, Ar-H), 7.46 (d, 1H, J = 7.2 Hz, Ar-H), 7.34 (t, 1H, J = 7.2 Hz, Ar-H), 7.29 (t, 1H, J = 7.4 Hz, Ar-H), 7.03- 7.01 (m, 5H, Ar-H), 5.16 (t, 2H, J = 7.0 Hz, NC H ₂ -CH ₂ Ph), 3.78 (t, 2H, J = 6.5 Hz, imide-NC H ₂ -CH ₂ -morpholine), 3.50 (t, 4H, J = 3.9 Hz, morpholine-N(CH ₂ -C H ₂ ) ₂ O), 3.07 (t, 2H, J = 7.0 Hz, NCH ₂ -C H ₂ -Ph) , 2.61 (t, 2H, J = 6.5 Hz, imide-NCH ₂ - C H ₂ -morpholine), 2.47 (t, 4H, J = 3.9 Hz, morpholine-N (C H ₂ -CH ₂ ) ₂ O). ^{13 C NMR (125 MHz, DMSO} -d 6) δ170.0,169.9,141.6,141.5,138.2,130.0,129.8,129.5 × 2,128.8,128.7,128.4 × 2,127.4,127.2,126.7,124.6,121.4, 121.3, 120.8, 120.1, 119.0, 117.4, 116.7, 112.6, 110.6, 66.6 × 2, 56.5 × 2, 53.6, 45.8, 36.5, 34.9. ESI-MS m/z 543.2 [M+H] ⁺ .

Preparation of Compound 110

According to the synthesis method of compound 24, compound 103a (23 mg, 0.054 mmol), 4-(2-aminoethyl)-piperazine (60 μL, 0.54 mmol) and catalytic amount of triethylamine were synthesized, and separated by silica gel column chromatography. Ethyl chloride:methanol = 50:1 (v/v) eluted as a yellow solid 6-(2-piperazinethyl)-12-phenethyl-12,13-dihydro-5H-indole[2,3 -a] Pyrrole [3,4-c]carbazole-5,7(6H)-dione (110) 16 mg, yield 80%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.12 (s, 1H, indole-NH), 10.24 (s, 1H, piperazin-NH), 9.04 (d, 1H, J = 7.1 Hz, Ar-H) , 9.03 (d, 1H, J = 6.9 Hz, Ar-H), 7.83 (d, 1H, J = 8.1 Hz, Ar-H), 7.58-7.52 (m, 2H, Ar-H), 7.44 (t, 1H, J = 7.5 Hz, Ar-H), 7.33 (t, 1H, J = 7.4 Hz, Ar-H), 7.28 (t, 1H, J = 7.4 Hz, Ar-H), 7.05-6.94 (m, 5H, Ar-H), 5.19 (t, 2H, J = 7.0 Hz, NC H ₂ -CH ₂ Ph), 3.80 (t, 2H, J = 6.5 Hz, imide-NC H ₂ -CH ₂ -piperazine), 3.07 (t, 2H, J = 7.0 Hz, NCH ₂ -C H ₂ -Ph), 3.01 (t, 4H, J = 4.4 Hz, piperazine-N(C H ₂ -CH ₂ ) ₂ NH), 2.75 (t , 4H, J = 4.4 Hz, piperazine-N (CH ₂ -C H ₂ ) ₂ NH), 2.48 (t, 2H, J = 6.5 Hz, imide-NCH ₂ -C H ₂ -piperazine). ¹³ C NMR ( 125 MHz, DMSO-d ₆ ) δ 170.0, 169.9, 141.7, 141.6, 138.2, 129.9, 129.5 × 2, 128.7, 128.4 × 2, 127.4, 127.1, 126.7, 124.7, 124.5, 121.4, 121.2, 120.7, 120.6, 119.0 , 118.9, 117.4, 116.6, 112.7, 110.6, 55.6 × 2, 53.6, 49.5 × 2, 43.1, 36.5, 34.8. ESI-MS m/z 542.3 [M+H] ⁺ .

Preparation of Compound 111

According to the synthesis method of compound 24, compound 103a (15 mg, 0.035 mmol), 2-chloro-6-fluorophenethylamine (20 μL, 0.35 mmol) and catalytic amount of triethylamine were synthesized by silica gel column chromatography and dichloromethane. : methanol = 50:1 (v / v) eluted to give a yellow solid 6-(2-chloro-6-fluorophenethyl)-12-phenethyl-12,13-dihydro-5H-indole[2 3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (111) 13 mg, yield 68%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.93 (s, 1H, indole-NH), 9.00 (d, 1H, J = 7.8Hz, Ar-H), 8.98 (d, 1H, J = 7.9Hz , Ar-H), 7.78 (d, 1H, J = 8.1 Hz, Ar-H), 7.60 (d, 1H, J = 8.4 Hz, Ar-H), 7.55 (t, 1H, J = 7.6 Hz, Ar -H), 7.46 (t, 1H, J = 7.4 Hz, Ar-H), 7.35 (t, 1H, J = 7.7 Hz, Ar-H), 7.29 (d, 1H, J = 7.6 Hz, Ar-H ), 7.25 (m, 2H, Ar-H), 7.11 (dd, J = 7.1 Hz, 5.9 Hz, 1H), 7.08-6.95 (m, 5H, Ar-H), 5.17 (t, 2H, J = 7.0) Hz, NC H ₂ -CH ₂ Ph), 3.94 (t, 2H, J = 6.5 Hz, imide-NC H ₂ -CH ₂ -C ₆ H ₃ FCl), 3.19 (t, 2H, J = 6.5 Hz, imide -NCH ₂ -C H ₂ -C ₆ H ₃ FCl), 3.07 (t, 2H, J = 7.0 Hz, NCH ₂ -C H ₂ -Ph). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 169.8 , 169.7, 161.8 (d, ¹ J _CF = 244 Hz), 141.6 (d, ³ J _CF = 11 Hz), 138.2, 135.0, 129.8 (d, ² J _CF = 11 Hz), 129.4 × 2, 128.7, 128.4 × 2, 127.4, 127.2, 126.7, 125.8 × ² , 124.8, 124.7, 124.6, 124.5 × ² , 121.4 (d, ² J _CF = 22 Hz), 120.8, 120.7, 119.0, 118.9, 117.4, 116.6, 114.7 (d, ² J _CF =23Hz), 112.6, 110.6, 45 .8,36.9,36.5,25.9. ESI-MS m/z 586.2 [M+H] ⁺ .

Preparation of Compound 112

According to the synthesis method of compound 24, compound 103a (15 mg, 0.035 mmol), 1-(2-aminoethyl)piperidine (50 μL, 0.47 mmol) and catalytic amount of triethylamine were synthesized, and separated by silica gel column chromatography. Methane:methanol = 50:1 (v/v) eluted as a yellow solid 6-(2-piperidinyl)-12-phenethyl-12,13-dihydro-5H-indole[2,3- a] Pyrrole [3,4-c]carbazole-5,7(6H)-dione (112) 17 mg, yield 67%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.92 (s, 1H, indole-NH), 9.04 (d, 1H, J = 8.2Hz, Ar-H), 9.02 (d, 1H, J = 8.5Hz , Ar-H), 7.78 (d, 1H, J = 8.1 Hz, Ar-H), 7.56 (d, 1H, J = 7.3 Hz, Ar-H), 7.54 (d, 1H, J = 8.0 Hz, Ar -H), 7.45 (d, 1H, J = 7.2 Hz, Ar-H), 7.34 (d, 1H, J = 7.3 Hz, Ar-H), 7.28 (d, 1H, J = 7.3 Hz, Ar-H ), 7.08-6.96 (m, 5H, Ar-H), 5.14 (t, 2H, J = 6.6 Hz, NC H ₂ -CH ₂ Ph), 3.77 (t, 2H, J = 5.4 Hz, imide-NC H ₂ -CH ₂ -piperidine), 3.06 (t, 2H, J = 6.6 Hz, NCH ₂ -C H ₂ -Ph), 2.65 (t, 2H, J = 6.5 Hz, imide-NCH ₂ -C H ₂ -piperidine ), 2.49 (t, 4H, J = 3.1 Hz, piperididine-N(C H ₂ -CH ₂ ) ₂ CH ₂ ), 1.45 (m, 4H, piperididine-N(CH ₂ -C H ₂ ) ₂ CH ₂ ) , 1.34 (t, 2H, J = 3.4 Hz, piperididine-N(CH ₂ -CH ₂ ) ₂ C H ₂ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 169.9 × 2, 141.6, 141.5, 138.2 , 129.8, 129.4 × 2, 128.7, 128.4 × 2, 127.4, 127.1, 126.7, 124.7, 124.6, 121.4, 121.3, 120.7, 120.6, 119.1, 119.0, 117.4, 116.5, 112.6, 110.6, 56.5 × 2, 54.2, 45.8 , 36.5, 25.9, 25.6×2, 24.1. ESI-MS m/z 541.2 [M+H] ⁺ .

Preparation of Compound 113

According to the synthesis method of compound 24, compound 103a (23 mg, 0.054 mmol), 4-methyl-1-piperazine ethylamine (50 μL, 0.55 mmol) and catalytic amount of triethylamine were synthesized, and separated by silica gel column chromatography. Methane:methanol = 50:1 (v/v) eluted as a yellow solid 6-(2-(4-methylpiperazine)ethyl)-12-phenethyl-12,13-dihydro-5H-indole [2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (113) 19 mg, yield 65%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.94 (s, 1H, indole-NH), 9.06 (d, 1H, J = 7.3Hz, Ar-H), 9.05 (d, 1H, J = 7.0Hz , Ar-H), 7.79 (d, 1H, J = 8.2 Hz, Ar-H), 7.59 (d, 1H, J = 7.7 Hz, Ar-H), 7.56 (d, 1H, J = 7.7 Hz, Ar -H), 7.46 (t, 1H, J = 7.6 Hz, Ar-H), 7.35 (t, 1H, J = 7.5 Hz, Ar-H), 7.07-6.97 (m, 5H, Ar-H), 5.17 (t, 2H, J = 6.8 Hz, NC H ₂ -CH ₂ Ph), 3.79 (t, 2H, J = 6.3 Hz, NC H ₂ -CH ₂ -piperazine), 3.07 (t, 2H, J = 6.9 Hz) , NCH ₂ -C H ₂ -Ph), 2.62 (t, 2H, J = 6.5 Hz, NCH ₂ -C H ₂ -piperazine), 2.48 (t, 4H, J = 4.5 Hz, piperazine-N (C H ₂ -CH ₂ ) ₂ NCH ₃ ), 2.35 (t, 4H, J = 4.5 Hz, piperazine-N(CH ₂ -C H ₂ ) ₂ NCH ₃ ), 2.15 (s, 3H, piperazine-N (CH ₂ -CH) ₂ ) ₂ NC H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 169.9 × 2, 141.6 × 2, 138.2, 129.9, 129.5 × 2, 128.7, 128.4 × 2, 127.5, 127.2, 126.7, 124.7 , 124.6, 121.4, 121.3, 120.8, 120.7, 119.1, 119.0, 117.4, 116.7, 112.6, 110.6, 55.9 × 2, 54.8 × 2, 52.6, 45.8, 45.6, 36.5, 35.2. ESI-MS m/z 556.3 [M +H] ⁺ .

Preparation of Compound 114

According to the synthesis of compound 24, compound 103a (40 mg, 0.093 mmol), ethanolamine (102 μL, 1.86 mmol) and a catalytic amount of triethylamine were synthesized by silica gel column chromatography, dichloromethane:methanol = 50:1 (v/ v) Yellow solid 6-(2-hydroxyethyl)-12-phenethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indole Oxazol-5,7(6H)-dione (114) 28 mg, yield 67%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.86 (s, 1H, indole-NH), 9.06 (d, 1H, J = 8.0Hz, Ar-H), 9.04 (d, 1H, J = 7.9Hz , Ar-H), 7.78 (d, 1H, J = 8.1 Hz, Ar-H), 7.57 (t, 1H, J = 7.3 Hz, Ar-H), 7.53 (d, 1H, J = 8.1 Hz, Ar -H), 7.45 (t, 1H, J = 7.3 Hz, Ar-H), 7.35 (d, 1H, J = 7.0 Hz, Ar-H), 7.28 (t, 1H, J = 7.5 Hz, Ar-H ), 7.07-7.00 (m, 5H, Ar-H), 5.12 (t, 2H, J = 6.6 Hz, NC H ₂ -CH ₂ Ph), 4.93 (t, 1H, J = 5.7 Hz, -O H ) , 3.72 (t, 2H, J = 5.7 Hz, NC H ₂ -CH ₂ OH), 3.69 (t, 2H, J = 5.7 Hz, -C H ₂ OH), 3.07 (t, 2H, J = 6.6 Hz, NCH ₂ -C H ₂ -Ph). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ170.2×2, 141.7, 141.6, 138.4, 129.8, 129.5×2,128.8,128.5×2,127.5,127.2,126.8 , 124.9, 124.8, 121.5, 121.4, 120.8, 120.7, 119.3 × 2, 117.5, 116.7, 112.6, 110.6, 58.9, 45.9, 45.8, 36.6. ESI-MS m/z 474.3 [M+H] ⁺ .

Preparation of Compound 115

According to the synthesis of compound 24, compound 103a (30 mg, 0.07 mmol), 3-hydroxypropylamine (100 μL, 1.4 mmol) and a catalytic amount of triethylamine were synthesized by silica gel column chromatography, dichloromethane:methanol = 50:1 (v/v) eluted yellow solid 6-(3-hydroxypropyl)-12-phenethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole [3,4- c] oxazole-5,7(6H)-dione (115) 24 mg, yield 70%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.93 (s, 1H, indole-NH), 9.07 (d, 1H, J = 7.9Hz, Ar-H), 9.05 (d, 1H, J = 7.9Hz , Ar-H), 7.80 (d, 1H, J = 8.1 Hz, Ar-H), 7.58 (dd, 1H, J = 8.3 Hz, 1.1 Hz, Ar-H), 7.57 (t, 1H, J = 7.7 Hz, Ar-H), 7.48 (dt, 1H, J = 8.1 Hz, 1.1 Hz, Ar-H), 7.35 (d, J = 8.3 Hz, 1H, Ar-H), 7.29 (t, 1H, J = 7.5 Hz, Ar-H), 7.08-7.01 (m, 5H, Ar-H), 5.15 (t, 2H, J = 7.1 Hz, NC H ₂ -CH ₂ Ph), 4.59 (t, 1H, J = 5.1) Hz, N(CH ₂ ) ₂ CH ₂ -O H ), 3.73 (t, 2H, J = 7.2 Hz, NC H ₂ -CH ₂ CH ₂ OH), 3.53-3.51 (m, 2H, N (CH ₂ ) _{2 -C H 2 -OH), 3.07} (t, 2H, J = 7.1Hz, NCH 2 -C H 2 -Ph), 1.88-1.83 (m, 2H, NCH 2 -C H 2 -CH 2 OH). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.2×2, 141.8, 141.7, 138.4, 129.9, 129.6×2, 128.8, 128.5×2, 127.5, 127.3, 126.9, 124.9, 124.8, 121.6, 121.4, 120.8 , 120.7, 119.2 × 2, 117.5, 116.8, 112.9, 110.7, 59.3 × 2, 45.9, 36.6, 32.3. ESI-MS m/z 488.1 [M+H] ⁺ .

Preparation of Compound 116

i) Preparation of p-toluenesulfonic acid (1-naphthylethyl) ester (116a)

According to the synthesis method of compound 102d, it was synthesized from naphthylethanol (5 g, 0.029 mmol), p-toluenesulfonyl chloride (11.65 g, 0.061 mmol) and triethylamine (8.46 mL, 0.061 mmol). Ethyl ester = 3:1 (v/v) eluted 9.6 g of a white solid, yield 85%. ESI-MS m/z 278.1 [M+H] ⁺ .

Ii) N-methyl-2-(1-tert-butyloxycarbonyl-3-indole)-3-(1-(1-naphthalenyl)-3-indole maleimide (116b) Preparation

The compound 102c (1 g, 2.27 mmol), sodium hydride (200 mg, 4.54 mmol) and compound 116a (1.13 g, 3.41 mmol) were synthesized according to the procedure of compound 102e. The oil was separated by silica gel column chromatography eluting with EtOAc (EtOAc) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.08 (d, 1H, J = 8.0 Hz, Ar-H), 8.07 (d, 1H, J = 8.0 Hz, Ar-H), 7.97 (s, 1H) , Ar-H), 7.94 (d, 1H, J = 7.8 Hz, Ar-H), 7.80 (d, 1H, J = 8.2 Hz, Ar-H), 7.74 (s, 1H, Ar-H), 7.59 (dd, 1H, J = 8.3 Hz, 1.4 Hz, Ar-H), 7.56 (d, 1H, J = 6.9 Hz, Ar-H), 7.44 (d, 1H, J = 8.3H, Ar-H), 7.38 (t, 1H, J = 7.2 Hz, Ar-H), 7.24 (d, 1H, J = 7.2 Hz, Ar-H), 7.19 (d, 1H, J = 7.1 Hz, Ar-H), 7.04 ( t, 1H, J = 7.6 Hz, Ar-H), 6.95 (d, 1H, J = 8.0 Hz, Ar-H), 6.89 (d, 1H, J = 7.9 Hz, Ar-H), 6.85 (d, 1H, J=7.9 Hz, Ar-H), 6.74 (t, 1H, J = 7.6 Hz, Ar-H), 4.58 (t, 2H, J = 7.3 Hz, NC H ₂ -CH ₂ -Nap), 3.46 (t, 2H, J = 7.3 Hz, NCH ₂ -C H ₂ -Nap), 3.04 (s, 3H, NCH ₃ ), 1.64 (s, 9H, -C(CH ₃ ) ₃ ). ¹³ C NMR (125 MHz , DMSO-d ₆ ) δ 171.5 × 2, 149.3, 136.4, 134.9, 134.8, 134.0, 133.9, 131.9, 131.8, 129.3, 128.4, 128.3, 127.8, 127.4, 126.9, 126.3, 125.9, 125.2, 124.0, 123.6, 123.0, 122.8, 122.0, 121.7, 120.7, 115.3, 111.3, 110.9, 105. 1,85.2, 47.2, 33.3, 28.2 × 3, 24.9. ESI-MS m/z 596.2 [M+H] ⁺ .

Iii) Preparation of N-methyl-2-(3-indolyl)-3-(1-(1-naphthalenyl)-3-indole)maleimide (116c)

The compound 116b (100 mg, 0.168 mmol) and silica gel (400 mg) were synthesized by chromatography, eluting with silica gel column eluting with petroleum ether: ethyl acetate = 4:1 (v/v) ) 79 mg, yield 95%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.72 (d, 1H, J = 2.5Hz, indole-NH), 8.09 (d, 1H, J = 8.2Hz, Ar-H), 7.94 (s, 1H , Ar-H), 7.80 (d, 1H, J = 8.2 Hz, Ar-H), 7.75 (d, 1H, J = 2.8 Hz, Ar-H), 7.62 (s, 1H, Ar-H), 7.58 (t, 1H, J = 7.7 Hz, Ar-H), 7.54 (t, 1H, J = 7.7 Hz, Ar-H), 7.43-7.40 (m, 2H, Ar-H), 7.36 (dd, 1H, J = 8.2 Hz, 7.0 Hz, Ar-H), 7.25 (d, 1H, J = 7.0 Hz, Ar-H), 7.01 (dt, 2H, J = 7.5 Hz, 1.1 Hz, Ar-H), 6.84 ( d, 1H, J = 8.0 Hz, Ar-H), 6.80 (d, 1H, J = 8.1 Hz, Ar-H), 6.69 (dt, 1H, J = 7.5 Hz, 1.1 Hz, Ar-H), 6.66 (dt, 1H, J = 7.5 Hz, 1.1 Hz, Ar-H), 4.57 (t, 2H, J = 7.3 Hz, NC H ₂ -CH ₂ -Nap), 3.51 (t, 2H, J = 7.3 Hz, NCH ₂ -C H ₂ -Nap), 3.02 (s, 3H, NCH ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 172.3, 172.2, 136.6, 136.2, 134.9, 134.0, 132.5, 131.9, 129.9 , 129.3, 127.7, 127.5, 126.9, 126.4, 126.3, 126.0, 125.7, 124.1, 122.3 × 2, 121.9, 121.6, 120.1, 119.9, 112.4, 110.6, 106.2, 105.6, 47.2, 33.3, 24.5. ESI-MS m/ z 496.2[M+H] ⁺ .

Iv) 6-Methyl-12-(1-naphthalenyl)-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7 ( Preparation of 6H)-dione (116)

Synthesis of compound 116c (400 mg, 0.808 mmol), DDQ (238 mg, 1.05 mmol) and p-TsOH (154 mg, 0.81 mmol). 1 (v/v) eluted as a yellow solid (116) 270 mg, yield 65%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.85 (s, 1H, indole-NH), 9.07 (d, 1H, J = 7.9Hz, Ar-H), 9.00 (d, 1H, J = 7.8Hz , Ar-H), 8.00 (d, 1H, J = 7.9 Hz, Ar-H), 7.83 (d, 1H, J = 7.3 Hz, Ar-H), 7.73 (d, 1H, J = 8.1 Hz, Ar -H), 7.62 (d, 1H, J = 8.1 Hz, Ar-H), 7.60 (dt, 1H, J = 7.7 Hz, 1.1 Hz, Ar-H), 7.48-7.40 (m, 2H, Ar-H) ), 7.39 (t, 1H, J = 7.7 Hz, Ar-H), 7.33 (t, 1H, J = 7.7 Hz, Ar-H), 7.23 (d, 1H, J = 7.7 Hz, Ar-H), 7.22 (d, 1H, J = 8.1 Hz, Ar-H), 7.16 (t, 1H, J = 7.4 Hz, Ar-H), 7.02 (d, 1H, J = 6.6 Hz, Ar-H), 5.24 ( t, 2H, J = 7.0 Hz, NC H ₂ -CH ₂ -Nap), 3.53 (t, 2H, J = 7.0 Hz, NCH ₂ -C H ₂ -Nap), 3.12 (s, 3H, NCH ₃ ). ^{13 C NMR (150MHz, DMSO-} d 6) δ170.2,170.1,141.8,141.7,134.5,133.8,132.0,129.9,129.0,128.8,127.6,127.5 × 2,127.0,126.6,126.1,125.7,124.8,124.7 , 123.8, 121.6 × 2, 120.9, 120.7, 119.4, 119.3, 117.7, 117.0, 112.6, 110.2, 45.3, 33.4, 24.1. ESI-MS m/z 494.2 [M+H] ⁺ .

Preparation of Compound 117

i) Preparation of 12-(1-naphthylethyl)-12,13-dihydrofuran[3,4-c]indole[2,3-a]oxazol-5,7-dione (117a)

The compound 116 (200 mg, 0.45 mmol) and KOH (5M, 30 mL) were obtained to give a yellow solid (117a) 164 mg (yield: 84%). Since the solubility of the product is extremely poor and the reaction is relatively complete, it is directly input to the next reaction without separation and purification.

Ii) 12-(1-Naphthylethyl)-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione Preparation of (117)

Synthesis of compound 117a (26 mg, 0.054 mmol), HMDS (500 μL, 2.35 mmol) and methanol (50 μL, 1.18 mmol), eluted on silica gel column chromatography, petroleum ether: ethyl acetate = 4:1 v/v) eluted as a yellow solid (117) 22 mg, yield 87%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.91 (s, 1H, indole-NH), 11.03 (s, 1H, imide-NH), 9.10 (d, 1H, J = 7.9Hz, Ar-H) , 9.04 (d, 1H, J = 7.8 Hz, Ar-H), 8.00 (d, 1H, J = 8.0 Hz, Ar-H), 7.80 (d, 1H, J = 7.3 Hz, Ar-H), 7.75 (d, 1H, J = 7.5 Hz, Ar-H), 7.62 (d, 1H, J = 8.1 Hz, Ar-H), 7.60 (t, 1H, J = 7.8 Hz, Ar-H), 7.47-7.42 (m, 2H, Ar-H), 7.37 (t, 1H, J = 7.7 Hz, Ar-H), 7.33-7.30 (m, 2H, Ar-H), 7.25 (d, 1H, J = 7.6 Hz, Ar-H), 7.15 (t, 1H, J = 7.8 Hz, Ar-H), 7.05 (d, 1H, J = 7.0 Hz, Ar-H), 5.32 (t, 2H, J = 7.0 Hz, NC H _{2 -CH 2 -Nap), 3.54 (} t, 2H, J = 7.0Hz, NCH 2 -C H 2 -Nap). 13 C NMR (125MHz, DMSO-d 6) δ171.7,171.6,141.8,134.5, 133.8, 132.0, 130.2, 129.1, 129.0, 127.7, 127.6, 127.5, 127.1, 126.6, 126.4, 126.1, 125.7, 125.0, 124.9, 123.8, 121.8, 121.7, 120.9, 120.8, 120.5, 120.4, 117.6, 117.0, 112.6, 110.3, 45.4, 33.3. ESI-MS m/z 480.3 [M+H] ⁺ .

Preparation of Compound 118

According to the synthesis method of compound 2, compound 117 (20 mg, 0.04 mmol) and formaldehyde (3 mL, mass fraction: 37%) were synthesized by silica gel column chromatography eluting with petroleum ether: ethyl acetate = 4:1 (v/v) A yellow solid 6-hydroxymethyl-12-(1-naphthalenyl)-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5, 7(6H)-dione (118) 16 mg, yield 80%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.90 (s, 1H, imide-NH), 9.08 (d, 1H, J = 7.9Hz, Ar-H), 9.00 (d, 1H, J = 7.4Hz , Ar-H), 7.96 (d, 1H, J = 7.6 Hz, Ar-H), 7.77 (d, 1H, J = 8.4 Hz, Ar-H), 7.72 (d, 1H, J = 8.2 Hz, Ar -H), 7.59 (d, 1H, J = 8.1 Hz, Ar-H), 7.56 (d, J = 7.4 Hz, 1H), 7.45-7.39 (m, 2H), 7.36 (t, 1H, J = 7.5) Hz, Ar-H), 7.29 (t, 1H, J = 7.8 Hz, Ar-H), 7.22 (t, 2H, J = 7.0 Hz, Ar-H), 7.10 (t, 1H, J = 7.6 Hz, Ar-H), 6.98 (d, 1H, J = 6.9 Hz, Ar-H), 6.30 (t, 1H, J = 6.6 Hz, -CH ₂ O H ), 5.26 (t, 2H, J = 6.9 Hz, _{NC H 2 -CH 2 -Nap),} 5.03 (d, 2H, J = 6.6Hz, -C H 2 OH), 3.53 (t, 2H, J = 6.9Hz, NCH 2 -C H 2 -Nap). 13 C NMR (150MHz, DMSO-d ₆ ) δ 169.4, 169.3, 141.7, 141.6, 134.3, 133.6, 131.9, 130.1, 128.9 × 2, 127.5, 127.4, 127.0, 126.4, 126.3, 126.0, 125.5, 124.6, 124.5, 123.7, 122.3, 121.5, 121.4, 120.8, 120.6, 119.1, 119.0, 117.5, 116.8, 112.6, 110.2, 60.3, 45.3, 33.2. ESI-MS m/z 510.2 [M+H] ⁺ .

Preparation of Compound 119

The compound 117a (36 mg, 0.074 mmol) and ethylenediamine (500 μL, 7.5 mmol) were synthesized according to the method of the compound 14 and eluted with silica gel column chromatography, methylene chloride:methanol=3:1 (v/v) Yellow solid 6-(2-aminoethyl)-12-(1-naphthalenyl)-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]carbazole -5,7(6H)-dione (119) 35 mg, yield 90%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.10 (d, 1H, J = 7.9 Hz, Ar-H), 9.02 (d, 1H, J = 7.7 Hz, Ar-H), 8.02 (dd, 1H) , J = 6.7 Hz, 2.2 Hz, Ar-H), 7.82 (dd, 1H, J = 6.4 Hz, 2.5 Hz, Ar-H), 7.81 (d, 1H, J = 8.3 Hz, Ar-H), 7.62 (d, 1H, J = 8.2 Hz, Ar-H), 7.61 (t, 1H, J = 7.6 Hz, Ar-H), 7.48 (dd, 2H, J = 6.6 Hz, 3.2 Hz, Ar-H), 7.40 (t, 1H, J = 7.7 Hz, Ar-H), 7.31 (t, 1H, J = 8.1 Hz, Ar-H), 7.23 (t, 1H, J = 8.2 Hz, Ar-H), 7.20 ( d, 1H, J = 7.8 Hz, Ar-H), 7.11 (t, 1H, J = 8.1 Hz, Ar-H), 6.96 (d, 1H, J = 6.9 Hz, Ar-H), 5.33 (t, 2H, J=6.1 Hz, NC H ₂ -CH ₂ -Nap), 3.93 (t, 2H, J = 6.7 Hz, NC H ₂ -CH ₂ NH ₂ ), 3.54 (t, 2H, J = 6.1 Hz, NCH _{2 -C H 2 -Nap), 3.14} (t, 2H, J = 6.7Hz, NCH 2 -C H 2 -NH 2). 13 C NMR (125MHz, DMSO-d 6) δ170.3,170.2,142.0, 141.9, 134.5, 133.8, 132.0, 130.0, 129.1, 129.0, 127.7, 127.6, 127.1, 126.6, 126.4, 126.1, 125.7, 124.8, 124.7, 123.8, 121.6, 121.5, 121.0, 120.7, 119.6, 119.5, 117.7, 117.1, 112.9, 110.3, 45.4, 3 9.1, 37.1, 33.5. ESI-MS m/z 523.4 [M+H] ⁺ .

Preparation of Compound 120

According to the synthesis of compound 16 from compound 119 (23 mg, 0.04 mmol) and ethyl acetate (3N, 3mL), 20 mg of yellow solid 6-(2-aminoethyl)-12-(1-naphthalene) ,12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione hydrochloride (120), yield 90%. ^{1 H NMR (500MHz, DMSO-} d 6) δ12.16 (s, 1H, indole-NH), 9.07 (d, 1H, J = 7.9Hz, Ar-H), 9.00 (d, 1H, J = 7.6Hz , Ar-H), 8.13 (s, 3H, -NH ₃ ⁺ ), 8.00 (d, 1H, J = 5.6 Hz, Ar-H), 7.79 (d, 2H, J = 7.7 Hz, Ar-H), 7.59 (d, 1H, J = 8.0 Hz, Ar-H), 7.56 (d, 1H, J = 7.5 Hz, Ar-H), 7.45 (d, 1H, J = 7.5 Hz, Ar-H), 7.43 ( d, 1H, J = 7.5 Hz, Ar-H), 7.36 (t, 1H, J = 7.4 Hz, Ar-H), 7.28 (t, 1H, J = 7.6 Hz, Ar-H), 7.22 (d, 1H, J = 7.4 Hz, Ar-H), 7.18 (t, 1H, J = 6.8 Hz, Ar-H), 7.07 (t, 1H, J = 7.5 Hz, Ar-H), 6.92 (d, 1H, J=6.9 Hz, Ar-H), 5.33 (t, 2H, J=6.9 Hz, NC H ₂ -CH ₂ -Nap), 3.97 (t, 2H, J = 6.7 Hz, NC H ₂ -CH ₂ NH ₃ ⁺ ), 3.52 (t, 2H, J = 6.9 Hz, NCH ₂ -C H ₂ -Nap), 3.19 (t, 2H, J = 6.7 Hz, NCH ₂ -C H ₂ -NH ₃ ⁺ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ170.1, 170.0, 141.8×2, 134.3, 133.6, 131.8, 129.8, 129.0, 128.8, 127.5, 127.4, 127.0, 126.5, 126.0, 125.5, 124.6, 124.5, 123.7, 121.4, 121.3, 120.8, 120.6, 119.4, 119.3, 117.6, 116.9, 112.8 110.2,45.3,38.3,35.7,33.4.ESI-MS m / z 523.3 [ M-Cl] +.

Preparation of Compound 121

According to the synthesis method of compound 14, from compound 117a (25 mg, 0.05 mmol), 1,3-propanediamine (60 μL, 0.78 mmol), 25 mg of yellow solid 6-(3-aminopropyl)-12-(1- Naphthylethyl)-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (121), yield 90 %. ^{1 H NMR (500MHz, DMSO-} d 6) δ12.16 (s, 1H, indole-NH), 9.08 (d, 1H, J = 8.0Hz, Ar-H), 9.01 (d, 1H, J = 7.7Hz , Ar-H), 7.97 (d, 1H, J = 7.4 Hz, Ar-H), 7.81-7.79 (m, 2H, Ar-H), 7.62 (t, 1H, J = 7.5 Hz, Ar-H) , 7.61 (d, 1H, J = 7.6 Hz, Ar-H), 7.59 (t, 1H, J = 7.5 Hz, Ar-H), 7.48-7.42 (m, 2H, Ar-H), 7.37 (t, 1H, J = 7.4 Hz, Ar-H), 7.31 (t, 1H, J = 7.6 Hz, Ar-H), 7.23 (t, 1H, J = 7.7 Hz, Ar-H), 7.21 (t, 1H, J = 7.4 Hz, Ar-H), 7.11 (t, 1H, J = 7.8 Hz, Ar-H), 6.99 (d, 1H, J = 7.0 Hz, Ar-H), 5.33 (t, 2H, J = 6.8 Hz, NC H ₂ -CH ₂ -Nap), 3.79 (t, 2H, J = 7.2 Hz, NC H ₂ -(CH ₂ ) ₂ -NH ₂ ), 3.54 (t, 2H, J = 6.8 Hz, NCH ₂ -C H ₂ -Nap), 2.91 (t, 2H, J = 7.2 Hz, N(CH ₂ ) ₂ -C H ₂ -NH ₂ ), 2.11-1.93 (m, 2H, NCH ₂ -C H ₂ - CH ₂ NH ₂ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 170.3, 170.2, 142.0, 141.9, 134.5, 133.8, 132.0, 130.1, 129.0×2, 127.7, 127.6, 127.5, 127.1, 126.6, 126.1 , 125.7, 124.8, 124.7, 123.8, 121.6, 121.5, 120.9, 120.7, 119.2, 119.1, 117.7, 117.1, 112.9, 110.4, 45.9, 45.4, 37.6, 35.2, 27.4. ESI-MS m/z 537.4 [M+H] ⁺ .

Preparation of Compound 122

A yellow solid 6-(3-aminopropyl)-12-(1-naphthylethyl) was synthesized from compound 121 (25 mg, 0.04 mmol) )-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione hydrochloride (122) 20 mg, yield 90%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H, indole-NH), 9.07 (d, 1H, J = 7.8 Hz, Ar-H), 9.01 (d, 1H, J = 7.8 Hz , Ar-H), 7.99 (s, 3H, -NH ₃ ⁺ ), 7.96 (d, 1H, J = 9.0 Hz, Ar-H), 7.78 (d, 2H, J = 7.9 Hz, Ar-H), 7.59 (d, 1H, J = 8.0 Hz, Ar-H), 7.56 (d, 1H, J = 7.9 Hz, Ar-H), 7.46-7.40 (m, 2H, Ar-H), 7.35 (t, 1H) , J = 7.5 Hz, Ar-H), 7.28 (d, 1H, J = 7.2 Hz, Ar-H), 7.24 (d, 1H, J = 7.9 Hz, Ar-H), 7.22 (d, 1H, J) = 7.2 Hz, Ar-H), 7.11 (t, 1H, J = 7.5 Hz, Ar-H), 6.98 (d, 1H, J = 6.8 Hz, Ar-H), 5.34 (t, 2H, J = 6.8 Hz, NC H ₂ -CH ₂ -Nap), 3.81 (t, 2H, J = 7.2 Hz, NC H ₂ -(CH ₂ ) ₂ -NH ₃ ⁺ ), 3.52 (t, 2H, J = 6.8 Hz, NCH ₂ -C H ₂ -Nap), 2.93 (t, 2H, J = 7.2 Hz, N(CH ₂ ) ₂ -C H ₂ -NH ₃ ⁺ ), 2.05-1.99 (m, 2H, NCH ₂ -C H ₂ -CH ₂ NH ₂ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 170.1, 170.0, 141.8, 141.7, 134.3, 133.6, 131.8, 130.0, 129.3, 128.9 × 2, 127.5, 127.4, 127.0, 126.4, 125.9, 125.5, 124.6, 124.5, 123.6, 121.4, 121.3, 120.8, 120.6, 119.1, 119.0 , 117.6, 116.9, 112.7, 110.3, 45.3, 37.4, 35.1, 33.3, 27.3. ESI-MS m/z 573.3 [M-Cl] ⁺ .

Preparation of Compound 123

According to the synthesis method of compound 24, compound 117a (20 mg, 0.04 mmol), 4-(2-aminoethyl)-morpholine (50 μL, 0.42 mmol) and a catalytic amount of triethylamine were synthesized and separated by silica gel column chromatography. Ethyl chloride:methanol = 3:1 (v/v) eluted as a yellow solid 6-(2-morpholinethyl)-12-(1-naphthalenethyl)-12,13-dihydro-5H-indole [2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (123) 19 mg, yield 76%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.90 (s, 1H, indole-NH), 9.07 (d, 1H, J = 8.0Hz, Ar-H), 9.00 (d, 1H, J = 7.8Hz , Ar-H), 7.97 (d, 1H, J = 7.7 Hz, Ar-H), 7.79 (dd, 1H, J = 6.9 Hz, 2.4 Hz, Ar-H), 7.72 (d, 1H, J = 8.1 Hz, Ar-H), 7.60 (d, 1H, J = 8.2 Hz, Ar-H), 7.57 (t, 1H, J = 7.7 Hz, Ar-H), 7.47-7.40 (m, 2H, Ar-H ), 7.36 (t, 1H, J = 7.5 Hz, Ar-H), 7.29 (d, 1H, J = 6.9 Hz, Ar-H), 7.25 (d, 1H, J = 8.6 Hz, Ar-H), 7.23 (t, 1H, J = 7.3 Hz, Ar-H), 7.14 (t, 1H, J = 7.7 Hz, Ar-H), 7.02 (d, 1H, J = 6.9 Hz, Ar-H), 5.28 ( t, 2H, J = 6.4 Hz, NC H ₂ -CH ₂ -Nap), 3.80 (t, 2H, J = 5.8 Hz, NC H ₂ -CH ₂ -morpholine), 3.54 (t, 2H, J = 6.4 Hz) , NCH ₂ -C H ₂ -Nap), 3.56 (t, 4H, J = 3.9 Hz, morpholine-N(CH ₂ -C H ₂ ) ₂ O), 2.63 (t, 2H, J = 5.8 Hz, imide- NCH ₂ -C H ₂ -morpholine), 2.49 (t, 4H, J = 3.9 Hz, morpholine-N(C H ₂ -CH ₂ ) ₂ O). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 169.9 , 169.8, 141.7, 134.4, 133.6, 131.9, 129.9, 128.9 × 2, 127.5, 127.4, 127.0, 126.4, 126.0, 1 25.6, 124.7, 124.6, 123.7, 121.5, 121.4, 120.8, 120.6, 119.1 × 2, 117.6, 116.9, 112.5, 110.2, 66.6 × 2, 56.5, 53.6 × 2, 45.3, 34.9, 33.2. ESI-MS m/z 593.3[M+H] ⁺ .

Preparation of Compound 124

According to the synthesis method of compound 24, compound 117a (20 mg, 0.042 mmol), 4-(2-aminoethyl)piperazine (45 μL, 0.42 mmol) and catalytic amount of triethylamine were synthesized, and separated by silica gel column chromatography. Methane:methanol = 10:1 (v/v) eluted as a yellow solid 6-(2-piperazinethyl)-12-(1-naphthalenethyl)-12,13-dihydro-5H-indole [ 2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (124) 20 mg, yield 80%. ^{1 H NMR (500MHz, DMSO-} d 6) δ9.05 (d, 1H, J = 7.9Hz, Ar-H), 8.97 (d, 1H, J = 7.6Hz, Ar-H), 7.94 (d, 1H , J=8.0Hz, Ar-H), 7.84 (d, 1H, J=8.0Hz, Ar-H), 7.80 (d, 1H, J=7.8Hz, Ar-H), 7.59(d,1H,J = 8.7 Hz, Ar-H), 7.57 (d, 1H, J = 7.6 Hz, Ar-H), 7.46-7.39 (m, 2H, Ar-H), 7.35 (dd, 1H, J = 11.4 Hz, 4.3 Hz, Ar-H), 7.23 (dd, 1H, J = 8.1 Hz, 1.2 Hz, Ar-H), 7.20 (t, 1H, J = 7.6 Hz, Ar-H), 7.11 (d, 1H, J = 8.2 Hz, Ar-H), 7.10 (t, 1H, J = 8.2 Hz, Ar-H), 6.98 (d, 1H, J = 6.9 Hz, Ar-H), 5.33 (t, 2H, J = 6.6 Hz) , NC H ₂ -CH ₂ -Nap), 3.78 (t, 2H, J = 6.5 Hz, NC H ₂ -CH ₂ -piperazine), 3.56 (t, 2H, J = 6.6 Hz, NCH ₂ -C H ₂ - Nap), 2.97 (t, 4H, J = 5.1 Hz, piperazine-N(C H ₂ -CH ₂ ) ₂ NH), 2.70 (t, 4H, J = 5.1 Hz, piperazine-N (CH ₂ -C H _{2 2} NH), 2.68 (t, 2H, J = 6.5 Hz, NCH ₂ -C H ₂ -piperazine). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.1, 170.0, 142.0, 141.8, 134.6, 134.3 , 133.7, 133.3, 131.9, 131.5, 130.0, 129.0 × 2, 128.1, 127.6, 127.0, 126.5 126.0, 125.6, 124.7, 123.8, 121.5, 120.8, 120.6, 119.2, 119.0, 117.6, 116.9, 112.9, 110.2, 55.9 × 2, 50.0, 45.4 × 2, 43.5, 35.0, 33.5. ESI-MS m/z 592.3 [ M+H] ⁺ .

Preparation of Compound 125

According to the synthesis method of compound 24, compound 117a (20 mg, 0.042 mmol), 2-chloro-6-fluorophenethylamine (30 μL, 0.42 mmol) and catalytic amount of triethylamine were synthesized by silica gel column chromatography and dichloromethane. : methanol = 25:1 (v / v) eluted to give a yellow solid 6-(2-chloro-6-fluorophenethyl)-12-(1-naphthalenyl)-12,13-dihydro-5H- [2,3-a]pyrrole[3,4-c]carbazole-5,7(6H)-dione (125) 12 mg, yield 60%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.90 (s, 1H, indole-NH), 9.02 (d, 1H, J = 7.8Hz, Ar-H), 8.95 (d, 2H, J = 7.8Hz , Ar-H), 7.95 (d, 1H, J = 8.2 Hz, Ar-H), 7.80 (d, 1H, J = 7.9 Hz, Ar-H), 7.73 (d, 1H, J = 8.1 Hz, Ar -H), 7.62 (d, 1H, J = 8.1 Hz, Ar-H), 7.58 (t, 1H, J = 7.5 Hz, Ar-H), 7.47 (t, 1H, J = 7.2 Hz, Ar-H ), 7.42 (dd, 1H, J = 8.2 Hz, 1.8 Hz, Ar-H), 7.36 (t, 1H, J = 7.5 Hz, Ar-H), 7.31 (d, 1H, J = 7.3 Hz, Ar-) H), 7.29-7.27 (m, 2H, Ar-H), 7.23 (t, 1H, J = 7.0 Hz, Ar-H), 7.17 (d, 1H, J = 7.1 Hz, Ar-H), 7.15 ( t, 1H, J = 7.0 Hz, Ar-H), 7.14 (dd, 1H, J = 7.4 Hz, 1.2 Hz, Ar-H), 7.07 (d, 1H, J = 6.9 Hz, Ar-H), 5.29 (t, 2H, J = 6.8 Hz, NC H ₂ -CH ₂ -Nap), 3.95 (t, 2H, J = 6.7 Hz, NC H ₂ -CH ₂ -C ₆ H ₃ FCl), 3.54 (t, 2H) , J = 6.8 Hz, NCH ₂ -C H ₂ -Nap), 3.21 (t, 2H, J = 6.7 Hz, NCH ₂ -C H ₂ -C ₆ H ₃ FCl). ¹³ C NMR (125 MHz, DMSO-d ^{_{6) δ169.9,169.8,162.7 (d, 1 J}} CF = 244Hz), 141.8 (d, 3 J CF = 11Hz), 135.1,134.8,134.5,133.7,133.4,132.0 _{^{130.1,129.9 (d, 3 J CF =}} 11Hz), 128.9,128.8,127.6,127.5,127.1,126.5,126.1,125.9,125.7,124.9,124.8,123.8,122.8,121.6 (d, 2 J CF = 22Hz), 120.9, 120.8, 119.1, 119.0, 117.7, 117.0, 114.9 (d, ² J _CF = 23 Hz), 112.6, 110.3, 90.3, 45.4, 36.5, 33.3, 29.4. ESI-MS m/z 636.2 [M+H] ⁺ .

Preparation of Compound 126

According to the synthesis method of compound 24, compound 117a (20 mg, 0.042 mmol), 1-(2-aminoethyl)piperidine (50 μL, 0.42 mmol) and a catalytic amount of triethylamine were synthesized by silica gel column chromatography and dichlorobenzene. Methane:methanol = 10:1 (v/v) eluted as a yellow solid 6-(2-piperidinylethyl)-12-(1-naphthalenethyl)-12,13-dihydro-5H-indole [ 2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (126) 19 mg, yield 67%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.89 (s, 1H, indole-NH), 9.05 (d, 1H, J = 7.9Hz, Ar-H), 8.97 (d, 1H, J = 7.6Hz , Ar-H), 7.95 (d, 1H, J = 8.9 Hz, Ar-H), 7.78 (d, 1H, J = 7.4 Hz, Ar-H), 7.71 (d, 1H, J = 8.1 Hz, Ar -H), 7.59 (d, 1H, J = 8.2 Hz, Ar-H), 7.56 (t, 1H, J = 7.6 Hz, Ar-H), 7.44 - 7.40 (m, 2H, Ar-H), 7.34 (t, 1H, J = 7.5 Hz, Ar-H), 7.26 (d, 1H, J = 7.0 Hz, Ar-H), 7.20 (d, 1H, J = 8.0 Hz, Ar-H), 7.18 (d) , 1H, J = 7.5 Hz, Ar-H), 7.13 (t, 1H, J = 7.5 Hz, Ar-H), 7.00 (d, 1H, J = 6.8 Hz, Ar-H), 5.29 (t, 2H) , J = 6.8 Hz, NC H ₂ -CH ₂ -Nap), 3.73 (t, 2H, J = 6.6 Hz, NC H ₂ -CH ₂ -piperidine), 3.51 (t, 2H, J = 6.8 Hz, NCH _{2 -C H 2 -Nap), 2.58 (} t, 2H, J = 6.2Hz, NCH 2 -C H 2 -piperidine), 2.44 (t, 4H, J = 3.3Hz, piperidine-N (C H 2 -CH 2 ₂ CH ₂ ), 1.45-1.41 (m, 4H, piperididine-N(CH ₂ -C H ₂ ) ₂ CH ₂ ), 1.33 (t, 2H, J = 4.4 Hz, piperididine-N (CH ₂ -CH _{2 ) 2} C H ₂ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 169.9, 169.8, 141.7, 141.6, 135.1, 134.4, 133.6, 13 1.9, 129.9, 128.9, 128.8, 127.5, 127.4, 127.4, 126.9, 126.4, 126.0, 125.6, 125.1, 124.7, 124.6, 123.7, 121.4, 121.4, 120.7, 120.6, 119.1, 119.0, 117.5, 116.9, 112.5, 110.1, 56.6 × 2, 54.3, 45.2, 35.2, 33.3, 25.9 × 2, 24.3. ESI-MS m/z 591.3 [M+H] ⁺ .

Preparation of Compound 127

According to the synthesis method of compound 24, compound 117a (22 mg, 0.046 mmol), 4-methyl-1-piperazine ethylamine (50 μL, 0.55 mmol) and catalytic amount of triethylamine were synthesized, and separated by silica gel column chromatography, dichloro Methane:methanol = 10:1 (v/v) eluted as a yellow solid 6-(2-(4-methylpiperazine)ethyl)-12-(1-naphthalenyl)-12,13-dihydro -5H-吲哚[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (127) 22 mg, yield 80%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.95 (s, 1H, indole-NH), 9.06 (d, 1H, J = 7.0Hz, Ar-H), 8.98 (d, 1H, J = 7.2Hz , Ar-H), 7.95 (d, 1H, J = 6.7 Hz, Ar-H), 7.78 (d, 1H, J = 6.8 Hz, Ar-H), 7.73 (d, 1H, J = 8.1 Hz, Ar -H), 7.62 - 7.54 (m, 2H, Ar-H), 7.42 (d, 2H, J = 7.8 Hz, Ar-H), 7.34 (t, 1H, J = 7.8 Hz, Ar-H), 7.27 (t, 1H, J = 7.3 Hz, Ar-H), 7.20 (d, 2H, J = 6.9 Hz, Ar-H), 7.11 (d, 1H, J = 7.6 Hz, Ar-H), 7.01 (d , 1H, J = 7.6 Hz, Ar-H), 5.27 (t, 2H, J = 6.3 Hz, NC H ₂ -CH ₂ -Nap), 3.75 (t, 2H, J = 6.3 Hz, NC H ₂ -CH ₂ -piperazine), 3.51 (t, 2H, J = 6.3 Hz, NCH ₂ -C H ₂ -Nap), 2.60 (d, 2H, J = 5.8 Hz, NCH ₂ -C H ₂ -piperazine), 2.48 (t , 4H, J=4.6Hz, piperazine-N(C H ₂ -CH ₂ ) ₂ NCH ₃ ), 2.25 (t, 4H, J=4.6Hz, piperazine-N(CH ₂ -C H ₂ ) ₂ NCH ₃ ) , 2.07 (s, 3H, piperazine-N(CH ₂ -CH ₂ ) ₂ NC H ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 169.9, 169.8, 141.7, 141.6, 134.4, 133.6, 131.8, 129.9, 128.9, 127.5, 127.4, 126.9, 126.4, 125.9, 125.6, 124.7, 124.6, 123.7, 121.4, 121.4, 120.8, 120.6, 119.15, 119.0, 117.5, 116.9, 112.6, 110.1, 56.1, 55.1 × 2, 53.0 × 2, 46.1, 45.3, 35.2, 33.3. ESI-MS m/z 605.4 [ M+H] ⁺ .

Preparation of Compound 128

According to the synthesis of compound 24, compound 117a (30 mg, 0.063 mmol), ethanolamine (55 μL, 0.94 mmol) and a catalytic amount of triethylamine were synthesized by silica gel column chromatography, dichloromethane: methanol = 50:1 (v/ v) Yellow solid 6-(2-hydroxyethyl)-12-(1-naphthalenyl)-12,13-dihydro-5H-indole[2,3-a]pyrrole [3,4] -c] oxazole-5,7(6H)-dione (128) 26 mg, yield 89%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.95 (s, 1H, indole-NH), 9.11 (d, 1H, J = 7.8Hz, Ar-H), 9.05 (d, 1H, J = 7.9Hz , Ar-H), 8.02 (d, 1H, J = 7.7 Hz, Ar-H), 7.83 (d, 1H, J = 8.1 Hz, Ar-H), 7.75 (d, 1H, J = 8.1 Hz, Ar -H), 7.63 (d, 1H, J = 8.0 Hz, Ar-H), 7.59 (t, 1H, J = 7.8 Hz, Ar-H), 7.47 (m, 2H, Ar-H), 7.38 (t , 1H, J = 7.5 Hz, Ar-H), 7.34 (t, 1H, J = 7.8 Hz, Ar-H), 7.26-7.24 (m, 2H, Ar-H), 7.15 (t, 1H, J = 7.8 Hz, Ar-H), 7.00 (d, 1H, J = 7.2 Hz, Ar-H), 5.32 (t, 2H, J = 7.0 Hz, NC H ₂ -CH ₂ -Nap), 4.94 (t, 1H) , J = 6.1 Hz, NC H ₂ -CH ₂ -OH), 4.2 (brs, -O H ), 3.80 (t, 2H, J = 6.1 Hz, NCH ₂ -C H ₂ -OH), 3.56 (t, 2H, J=7.0 Hz, NCH ₂ -C H ₂ -Nap). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.3, 170.2, 141.9, 134.5, 133.8, 132.0, 130.1, 129.1, 129.0, 127.7, 127.6, 127.5, 127.1, 126.6, 126.1, 125.7, 124.9, 124.8, 123.8, 121.6, 121.6, 120.9, 120.8, 119.8, 119.4, 117.7, 117.0, 112.7, 112.4, 110.3, 58.9, 45.4, 40.7, 33.4. MS m/z 524.4 [M+H ] ⁺ .

Preparation of Compound 129

The compound 117a (25 mg, 0.052 mmol), 3-hydroxypropylamine (50 μL, 0.52 mmol) and a catalytic amount of triethylamine were synthesized according to the method of the synthesis of compound 24, and separated by silica gel column chromatography, methylene chloride:methanol = 50:1 (v/v) eluted as a yellow solid 6-(3-hydroxypropyl)-12-(1-naphthalenyl)-12,13-dihydro-5H-indole[2,3-a]pyrrole [ 3,4-c]oxazol-5,7(6H)-dione (129) 24 mg, yield 80%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.91 (s, 1H, indole-NH), 9.10 (d, 1H, J = 7.9Hz, Ar-H), 9.04 (d, 1H, J = 7.7Hz , Ar-H), 8.01 (d, 1H, J = 8.0 Hz, Ar-H), 7.82 (dd, 2H, J = 7.6 Hz, 3.2 Hz, Ar-H), 7.74 (d, 1H, J = 8.1 Hz, Ar-H), 7.62 (d, 1H, J = 8.2 Hz, Ar-H), 7.59 (dt, 1H, J = 8.2 Hz, 1.2 Hz, Ar-H), 7.48-7.43 (m, 2H, Ar-H), 7.39 (dt, 1H, J = 7.8 Hz, 1.1 Hz, Ar-H), 7.34 (t, 1H, J = 7.8 Hz, Ar-H), 7.27 (d, 1H, J = 8.1 Hz) , Ar-H), 7.27 (t, 1H, J = 7.6 Hz, Ar-H), 7.14 (t, 1H, J = 7.7 Hz, Ar-H), 7.03 (d, 1H, J = 6.6 Hz, Ar -H), 5.30 (t, 2H, J = 6.9 Hz, NC H ₂ -CH ₂ -Nap), 4.57 (brs, -O H ), 3.77 (t, 2H, J = 7.2 Hz, NC H ₂ -CH ₂ CH ₂ OH), 3.54 (t, 2H, J = 6.9 Hz, NCH ₂ -C H ₂ -Nap), 3.53 (t, 2H, J = 6.2 Hz, N(CH ₂ ) ₂ -C H ₂ -OH ), 1.90- 1.84 (m, 2H, NCH ₂ -C H ₂ -CH ₂ OH). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 170.2, 170.1, 141.8, 134.5, 133.8, 132.0, 130.1, 129.1 , 129.0, 127.7, 127.6, 127.1, 126.6, 126.1, 125.7, 124.9, 124.8, 123.8, 121.7, 121.6 120.9,120.8,119.3,119.3,117.7,117.0,112.7,112.4,110.3,59.3,45.4,35.5,33.3,32.3.ESI-MS m / z 538.5 [ M + H] +.

Preparation of Compound 130

Under argon protection, add staurosporine (46.6 mg, 0.1 mmol) in a 25 mL two-neck reaction flask, dissolve it with 3 mL of dichloromethane, add an excess of triethylamine, then add p-fluorobenzenesulfonyl chloride, stir at room temperature. 4h, quenched with water, extracted with dichloromethane, and dried over anhydrous Na ₂ SO _4, evaporated to dryness in vacuo, after separation by gel column chromatography, eluting with methanol to give 3'-N- fluorobenzenesulfonyl staurosporine ( 130) 52.0 mg, yield 83.3%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.40 (d, 1H, J = 7.4Hz, Ar-H), 7.92 (m, 2H, Ar-H), 7.85 (d, 1H, J = 7.3Hz, Ar -H), 7.72 (d, 1H, J = 7.8 Hz, Ar-H), 7.47 (t, 1H, J = 7.3 Hz, Ar-H), 7.46 (t, 1H, J = 7.3 Hz, Ar-H ), 7.43 (d, 2H, J = 7.3 Hz, Ar-H), 7.32 (m, 2H, J = 7.3 Hz, Ar-H), 7.06 (d, 1H, J = 7.8 Hz, Ar-H), 6.84 (brs, 1H, -NH), 6.56 (m, 1H, H-1'), 4.95 (d, 1H, J = 16.0 Hz, H-7a), 4.89 (d, 1H, J = 16.0 Hz, H -7b), 4.53 (dd, 1H, J = 12.4 Hz, 5.5 Hz, H-3'), 3.94 (s, 1H, H-4'), 2.71 (s, 3H, 4'-OCH ₃ ), 2.47 (s, 3H, 3'-NCH ₃ ), 2.43 (m, 1H, H-1'a), 2.37 (s, 3H, H-6'), 2.27 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 173.5, 164.6 (d, ¹ J _CF = 247.2 Hz), 138.4, 136.5, 136.5, 132.5, 130.5, 129.7 × 2 (d, ³ J _CF = 9.2 Hz), 126.9 , 126.3, 125.5, 125.3, 124.8, 123.6, 121.7, 120.8, 120.2, 119.2, 116.8 × 2 (d, ² J _CF = 13.7 Hz), 116.3, 114.6, 112.2, 107.6, 94.7, 86.5, 82.4, 60.3, 52.1 , 46.0, 30.8, 29.1, 28.3. ESI-MS m/z 625.3 [M+H] ⁺ .

Preparation of Compound 131

According to the synthesis method of Compound 130, it was synthesized from staurosporine (46.6 mg, 0.1 mmol), triethylamine and p-chlorobenzenesulfonyl chloride. After separation by gel column chromatography and methanol elution, 51.3 mg of 3'-N-p-chlorobenzenesulfonyl staurosporine (131) was obtained in a yield of 80.1%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.41 (d, 1H, J = 7.7 Hz, Ar-H), 7.86 (d, 1H, J = 7.8 Hz, Ar-H), 7.84 (d, 2H, J = 8.2 Hz, Ar-H), 7.72 (d, 1H, J = 8.7 Hz, Ar-H), 7.61 (d, 2H, J = 8.2 Hz, Ar-H), 7.48 (t, 1H, J = 8.3) Hz, Ar-H), 7.44 (t, 1H, J = 6.8 Hz, Ar-H), 7.36 (t, 1H, J = 7.8 Hz, Ar-H), 7.34 (t, 1H, J = 7.8 Hz, Ar-H), 7.09 (d, 1H, J = 8.2, Ar-H), 6.61 (br s, 1H, -NH), 6.58 (dd, 1H, J = 9.2 Hz, 4.1 Hz, H-1') , 4.93 (m, 2H, H-7), 4.52 (ddd, 1H, J = 12.8 Hz, 5.5 Hz, 1.9 Hz, H-3'), 3.96 (s, 1H, H-4'), 2.72 (s , 3H, 4'-OCH ₃ ), 2.48 (s, 1H, 3'-NCH ₃ ), 2.44 (m, 1H, H-2'a), 2.41 (s, 3H, H-6'), 2.26 ( m,1H,H-2'a). ¹³ C NMR (150MHz, CDCl ₃ ) δ 173.3, 139.8, 138.5, 137.7, 136.5, 132.5, 130.5, 129.9 × 2, 128.5 × 2, 126.9, 126.3, 125.6, 125.3, 124.8, 123.7, 121.7, 120.8, 120.3, 119.3, 116.4, 114.7, 112.2, 107.6, 94.7, 86.6, 82.4, 60.4, 52.2, 45.9, 30.8, 29.2, 28.3. ESI-MS m/z 641.4/643.4[ M+H] ⁺ .

Preparation of Compound 132

According to the synthesis method of Compound 130, it was synthesized from staurosporine (46.6 mg, 0.1 mmol), triethylamine and p-bromobenzenesulfonyl chloride. After separation by gel column chromatography and methanol elution, 5'-N-p-bromobenzenesulfonyl staurosporine (132) was obtained in a yield of 76.8%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.40 (d, 1H, J = 7.1Hz, Ar-H), 7.99 (d, 1H, J = 6.9Hz, Ar-H), 7.83 (d, 1H, J = 7.7 Hz, Ar-H), 7.72 (d, 1H, J = 8.3 Hz, Ar-H), 7.61 (d, 2H, J = 6.9 Hz, Ar-H), 7.47 (t, 1H, J = 7.7) Hz, Ar-H), 7.42 (t, 1H, J = 7.2 Hz, Ar-H), 7.34 (t, 2H, J = 7.1 Hz, Ar-H), 7.04 (d, 2H, J = 7.7, Ar -H), 6.51 (br s, 1H, -NH), 4.99 (d, 1H, J = 18.0 Hz, H-7a), 4.92 (d, 1H, J = 16.4 Hz, H-7b), 4.50 (dd , 1H, J = 5.5 Hz, 12.7 Hz, H-3'), 3.91 (s, 1H, H-4'), 2.69 (s, 3H, 4'-OCH ₃ ), 2.47 (s, 1H, 3' -NCH ₃ ), 2.45 (t, 1H, J = 12.6 Hz, H-2'a), 2.35 (s, 3H, H-6'), 2.45 (t, 1H, J = 12.4 Hz, H-2'a); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 173.4, 138.4, 132.9 × 2, 138.3, 136.4, 132.5, 130.5, 128.6 × 2, 128.2, 126.8, 126.3, 125.5, 125.3, 124.7, 123.6, 121.7, 120.7, 120.3, 119.0, 116.2, 114.6, 112.2, 107.7, 94.6, 86.6, 82.4, 60.3, 52.2, 46.1, 30.8, 29.1, 28.3. ESI-MS m/z 685.3/687.3 [M+H] ⁺ .

Preparation of Compound 133

According to the synthesis method of Compound 130, it was synthesized from staurosporine (46.6 mg, 0.1 mmol), triethylamine and benzenesulfonyl chloride. After separation by gel column chromatography and methanol elution, 5'-N-benzenesulfonyl staurosporine (133) 50.4 mg was obtained in a yield of 83.2%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.40 (d, 1H, J = 7.8Hz, Ar-H), 7.91 (d, 2H, J = 7.4Hz, Ar-H), 7.87 (d, 1H, J = 7.3 Hz, Ar-H), 7.70 (d, 1H, J = 7.8 Hz, Ar-H), 7.64 (t, 2H, J = 7.8 Hz, Ar-H), 7.46 (t, 1H, J = 7.8) Hz, Ar-H), 7.42 (t, 1H, J = 7.8 Hz, Ar-H), 7.34 (t, 1H, J = 7.3 Hz, Ar-H), 7.32 (t, 1H, J = 7.3 Hz, Ar-H), 7.07 (d, 1H, J = 8.2 Hz, Ar-H), 6.71 (br s, 1H, -NH), 6.69 (dd, 1H, J = 9.2 Hz, 4.6 Hz, H-1' ), 4.94 (m, 2H, H-7), 4.54 (dd, 2H, J = 12.8 Hz, 5.5 Hz, H-3'), 3.91 (s, 1H, H-4'), 2.73 (s, 3H) , 4'-OCH ₃ ), 2.45 (s, 3H, 3'-NCH ₃ ), 2.43 (br m, 1H, H-2'a), 2.39 (s, 3H, H-6'), 2.25 (br m,1H,H-2'b). ¹³ C NMR (150MHz, CDCl ₃ ) δ 173.3, 139.1, 138.4, 136.4, 133.3, 132.4, 130.4, 129.5 × 2, 127.0 × 2, 126.8, 126.2, 125.4, 125.1, 124.7, 123.6, 121.5, 120.6, 120.2, 119.1, 116.2, 114.5, 112.1, 107.5, 94.6, 86.2, 82.4, 60.3, 51.9, 45.9, 30.7, 29.1, 28.1. ESI-MS m/z 607.3 [M+ H] ⁺ .

Preparation of Compound 134

Under argon protection, 3'-N-p-fluorobenzoyl staurosporine (15.0 mg, 0.025 mmol) was added to a 25 mL two-neck reaction flask, dissolved in 1 mL of methanol, and then brominated succinimide (5.0) was added. mg, 0.027mmol), the reaction was stirred at room temperature 2h, quenched with water, extracted with dichloromethane, and dried over anhydrous Na ₂ SO _4, evaporated to dryness in vacuo, after gel column chromatography, eluting with methanol to give 3-bromo-3 '-N-p-fluorobenzoyl staurosporine (134) 8.4 mg, yield 49.0%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.51 (s, 1H, Ar-H), 7.86 (d, 1H, J = 7.8 Hz, Ar-H), 7.75 (d, 1H, J = 7.3 Hz, Ar -H), 7.46 (t, 2H, J = 7.8 Hz, Ar-H), 7.43 (m, 2H, J = 7.3 Hz, Ar-H), 7.36 (t, 1H, J = 7.8 Hz, Ar-H ), 7.34 (d, 1H, J = 7.8 Hz, Ar-H), 7.09 (d, 2H, J = 7.3 Hz, Ar-H), 7.02 (br s, 1H, -NH), 6.66 (br s, 1H, H-1'), 5.18 (d, 1H, J = 7.8 Hz, H-3'), 4.93 (br s, 2H, H-7), 4.17 (s, 1H, H-4'), 2.82 (s, 3H, 4'-OCH ₃ ), 2.71 (dt, 1H, J = 12.5 Hz, 3.2 Hz, H-2'a), 2.56 (s, 3H, 3'-NCH ₃ ), 2.44 (dt, 1H, J = 12.5 Hz, 3.2 Hz, H-2'b), 2.36 (s, 3H, H-6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.6, 171.4, 163.5 (d, ¹ J _CF = 247.2 Hz), 138.5 × 2, 132.9, 132.1, 131.5, 130.4, 129.4 × 2 (d, ³ J _CF = 6.9 Hz), 129.0, 128.1, 126.8, 125.4, 125.1, 124.6, 121.8, 120.8, 119.2, 115.7 × 2 (d, ² J _CF = 13.7 Hz), 115.5, 115.0, 112.3, 109.1, 94.7, 84.7, 82.6, 60.5, 49.8, 46.2, 34.6, 29.2, 28.1. ESI-MS m/z 667.3/669.3 [ M+H] ⁺ .

Preparation of Compound 135

i) Preparation of compound 135a

In a 25 mL two-necked reaction flask filled with oxygen, add staurosporine (6.6 mg, 0.1 mmol), dissolve in 3 mL of DMSO, add an excess of potassium t-butoxide, react at room temperature for 6 h, terminate the reaction with water, and extract three times with ethyl acetate. The mixture was evaporated to dryness in vacuo, and then purified by gel column chromatography and eluted with methanol to afford 4 s. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.04 (s, 1H, -NH), 9.21 (d, 1H, J = 8.8Hz, Ar-H), 9.08 (d, 1H, J = 7.7Hz, Ar-H), 8.03 (d, 1H, J = 8.8 Hz, Ar-H), 7.71 (t, 1H, J = 8.8 Hz, Ar-H), 7.60 (t, 1H, J = 7.7 Hz, Ar- H), 7.51 (t, 1H, J = 7.7 Hz, Ar-H), 7.41 (t, 1H, J = 7.7 Hz, Ar-H), 7.33 (d, 1H, J = 7.7 Hz, Ar-H) , 6.77 (br s, 1H, H-1'), 4.14 (m, 1H, H-3'), 3.38 (s, 1H, H-4'), 3.36 (s, 3H, 4'-OCH ₃ ) , 2.55 (m, 2H, H-2'), 2.34 (s, 1H, 3'-NCH ₃ ), 1.22 (s, 3H, H-6'). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171 .4,171.2,142.1,139.2,132.3,131.7,127.5,126.5,126.4,125.6,124.4,122.8,121.2,121.1,120.6,120.2,117.2,116.4,115.8,109.2,92.1,84.5,81.3,57.4,51.5 , 33.6, 30.4, 30.1. ESI-MS m/z 481.1 [M+H] ⁺ .

Ii) Preparation of Compound 135

According to the synthesis of Compound 130, it was synthesized from 135a (10.0 mg, 0.021 mmol), triethylamine and p-fluorobenzoyl chloride. After separation by gel column chromatography and methanol elution, 7-oxophenyl-3'-N-p-fluorobenzoylsporine (135) 10.8 mg was obtained in a yield of 86.1%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.33 (d, 1H, J = 7.7 Hz, Ar-H), 9.17 (d, 1H, J = 7.8 Hz, Ar-H), 7.73 (d, 1H, J) = 7.7 Hz, Ar-H), 7.68 (t, 1H, J = 7.4 Hz, Ar-H), 7.56 (t, 1H, J = 7.8 Hz, Ar-H), 7.51 (t, 1H, J = 7.8) Hz, Ar-H), 7.42 (t, 1H, J = 7.8 Hz, Ar-H), 7.41 (d, 2H, J = 7.7 Hz, Ar-H), 7.41 (t, 1H, J = 7.8 Hz, Ar-H), 7.11 (d, 2H, J = 7.4 Hz, Ar-H), 6.72 (br s, 1H, H-1'), 5.20 (d, 1H, J = 5.8 Hz, H-3') , 4.16 (s, 1H, H-4'), 2.86 (s, 3H, 4'-OCH ₃ ), 2.80 (m, 1H, H-2'a), 2.53 (s, 3H, 3'-NCH ₃ ), 2.38 (m, 1H, H-2'b), 2.35 (s, 3H, H-6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.8, 169.6, 163.8 (d, ¹ J _CF = 270.0 Hz), 139.3, 139.2, 137.8, 133.2 × 2, 130.3, 129.6 × 2 (d, ³ J _CF = 6.9 Hz), 127.0 × 2 (d, ² J _CF = 13.7 Hz), 126.5, 126.3, 123.8, 122.5, 121.4, 121.3, 121.0, 119.4, 117.4, 116.3, 114.7, 111.3, 108.2, 94.7, 86.0, 82.5, 60.1, 51.9, 30.7, 28.9, 28.3. ESI-MS m/z 603.2 [M+H] ⁺ .

Preparation of Compound 136

According to the synthesis of Compound 130, it was synthesized from 135a (10.0 mg, 0.021 mmol), triethylamine and p-chlorobenzoyl chloride. After separation by gel column chromatography and methanol elution, 7-oxophenyl-3'-N-p-chlorobenzoylsporine (136) 10.6 mg was obtained in a yield of 82.3%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.38 (d, 1H, J = 7.7Hz, Ar-H), 9.24 (d, 1H, J = 7.8Hz, Ar-H), 7.94 (t, 1H, J = 7.4 Hz, Ar-H), 7.76 (t, 1H, J = 7.8 Hz, Ar-H), 7.61 (t, 1H, J = 7.8 Hz, Ar-H), 7.54 (d, 2H, J = 7.7 Hz, Ar-H), 7.52 (d, 2H, J = 7.7 Hz, Ar-H), 7.51 (br s, 1H, -NH), 7.41 (t, 1H, J = 7.8 Hz, Ar-H), 7.40 (d, 1H, J = 7.8 Hz, Ar-H), 7.11 (d, 1H, J = 7.4 Hz, Ar-H), 6.80 (br s, 1H, H-1'), 5.26 (dd, 1H) , J = 5.4 Hz, 12.3 Hz, H-3'), 4.22 (s, 1H, H-4'), 2.88 (s, 3H, 4'-OCH ₃ ), 2.83 (dt, 1H, J = 3.2 Hz) , 10.8 Hz, H-2'a), 2.74 (dt, 1H, J = 3.2 Hz, 10.8 Hz, H-2'b), 2.58 (s, 3H, 3'-NCH ₃ ), 2.44 (s, 3H) , H-6'). ¹³ C NMR (150MHz, CDCl ₃ ) δ 171.4, 169.9, 169.7, 139.5, 137.9, 136.3, 131.6, 130.2, 129.0, 128.6, 129.6 × 2, 127.1 × 2, 126.5, 126.4, 123.8, 122.6, 121.4, 121.3, 121.0, 119.5, 117.4, 116.4, 111.7, 111.6, 108.3, 94.8, 84.7, 82.5, 60.5, 49.7, 30.4, 29.0, 28.1. ESI-MS m/z 619.5/621.5 [M+ H] ⁺ .

Preparation of Compound 137

According to the synthesis of Compound 130, it was synthesized from 135a (10.0 mg, 0.021 mmol), triethylamine and p-bromobenzoyl chloride. After separation by gel column chromatography and methanol elution, 7-oxophenyl-3'-N-p-bromobenzoyl staurosporine (137) 11.1 mg was obtained in a yield of 80.3%. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.34 (d, 1H, J = 7.7 Hz, Ar-H), 9.19 (d, 1H, J = 7.8 Hz, Ar-H), 7.74 (t, 1H, J) = 7.4 Hz, Ar-H), 7.71 (t, 1H, J = 7.8 Hz, Ar-H), 7.56 (t, 1H, J = 7.8 Hz, Ar-H), 7.54 (d, 2H, J = 7.7) Hz, Ar-H), 7.52 (d, 2H, J = 7.7 Hz, Ar-H), 7.51 (br s, 1H, -NH), 7.41 (t, 1H, J = 7.8 Hz, Ar-H), 7.40 (d, 1H, J = 7.8 Hz, Ar-H), 7.29 (d, 1H, J = 7.4 Hz, Ar-H), 6.71 (br s, 1H, H-1'), 5.21 (dd, 1H) , J=5.5 Hz, 12.4 Hz, H-3'), 4.15 (s, 1H, H-4'), 2.84 (s, 3H, 4'-OCH ₃ ), 2.80 (dt, 1H, J = 3.2 Hz) , 10.8 Hz, H-2'a), 2.67 (dt, 1H, J = 3.2 Hz, 10.8 Hz, H-2'b), 2.53 (s, 3H, 3'-NCH ₃ ), 2.35 (s, 3H) , H-6'). ¹³ C NMR (150MHz, CDCl ₃ ) δ 171.4, 170.0, 169.7, 139.4, 137.8, 134.8, 131.5, 130.1, 129.0, 128.6, 128.7 × 2, 127.1 × 2, 126.5, 126.3, 126.2, 123.8, 122.5, 121.4, 121.3, 121.1, 119.5, 117.4, 116.3, 111.6, 108.3, 94.7, 84.7, 82.5, 60.4, 49.7, 34.4, 28.9, 28.1. ESI-MS m/z 663.5/665.5 [M+ H] ⁺ .

Preparation of Compound 138

According to the synthesis of Compound 130, it was synthesized from 135a (10.0 mg, 0.021 mmol), triethylamine and p-iodobenzoyl chloride. After separation by gel column chromatography and methanol elution, 7-oxophenyl-3'-N-p-iodobenzoyl staurosporine (138) was obtained in a yield of 78.5%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.38 (d, 1H, J = 7.7Hz, Ar-H), 9.24 (d, 1H, J = 7.8Hz, Ar-H), 7.94 (t, 1H, J = 7.4 Hz, Ar-H), 7.76 (t, 1H, J = 7.8 Hz, Ar-H), 7.61 (t, 1H, J = 7.8 Hz, Ar-H), 7.54 (d, 2H, J = 7.7 Hz, Ar-H), 7.52 (t, 2H, J = 7.7 Hz, Ar-H), 7.51 (br s, 1H, -NH), 7.41 (t, 1H, J = 7.8H, Ar-H), 7.40 (d, 1H, J = 7.8 Hz, Ar-H), 7.11 (d, 1H, J = 7.4 Hz, Ar-H), 6.80 (dd, 1H, J = 3.7 Hz, 9.2 Hz, H-1' ), 5.26 (dd, 1H, J = 5.5 Hz, 12.4 Hz, H-3'), 4.22 (s, 1H, H-4'), 2.88 (s, 3H, 4'-OCH ₃ ), 2.83 (dt , 1H, J = 3.2 Hz, 10.8 Hz, H-2'a), 2.74 (dt, 1H, J = 3.2 Hz, 10.8 Hz, H-2'b), 2.58 (s, 3H, 3'-NCH ₃ ), 2.44 (s, 3H, H-6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.4, 170.0, 169.8, 139.5, 137.9, 136.3, 131.9, 130.2, 129.0, 128.6, 129.6 × 2, 127.1 ×2,126.5,126.4,123.8,122.6,121.4,121.3,121.0,120.9,119.5,117.4,116.4,111.7,108.3,94.8,84.7,82.5,60.5,49.7,30.4,29.0,28.1.ESI-MS m/ z 711.5[M+H] ⁺ .

Preparation of Compound 139

Under argon protection, add 3'-N-p-fluorobenzoyl staurosporine (20.0 mg, 0.034 mmol) in a 25 mL two-neck reaction flask, dissolve in 1 mL of DMSO, then add 0.03 mL of 2N NaOH solution and stir at room temperature. the reaction 4h, quenched with water, extracted with ethyl acetate, and dried over anhydrous Na ₂ SO _4, evaporated to dryness in vacuo, after separation by gel column chromatography, eluting with methanol to give 7α- hydroxy -3'-N- p-fluorophenyl a Acyl staurosporine (139) 7.6 mg, yield 37.0%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.00 (d, 1H, J = 7.7Hz, Ar-H), 8.64 (d, 1H, J = 7.7Hz, -NH), 7.50 (t, 1H, J = 8.2 Hz, Ar-H), 7.49 (t, 2H, J = 8.2 Hz, Ar-H), 7.44 (t, 2H, J = 7.3 Hz, Ar-H), 7.37 (t, 1H, J = 7.7 Hz) , Ar-H), 7.36 (t, 1H, J = 7.7 Hz, Ar-H), 7.25 (d, 1H, J = 7.7 Hz, Ar-H), 7.19 (t, 1H, J = 7.7 Hz, Ar -H), 7.11 (t, 2H, J = 7.7 Hz, Ar-H), 7.10 (s, 1H, H-7), 6.71 (br s, 1H, -OH), 6.47 (br s, 1H, H -1'), 5.19 (d, 1H, J = 8.2 Hz, H-3'), 3.84 (s, 1H, H-4'), 2.70 (s, 3H, 4'-OCH ₃ ), 2.35 (m , 1H, H-2'a), 2.24 (m, 1H, H-2'b), 2.19 (s, 3H, 3'-NCH ₃ ), 2.04 (s, 3H, H-6'). ¹³ C NMR (150MHz, CDCl ₃ ) δ 173.3, 171.5, 163.6 (d, ¹ J _CF = 247.2 Hz), 136.5 × 2, 132.5, 132.2, 130.6, 129.5 × 2 (d, ³ J _CF = 6.9 Hz), 126.7 , 126.4, 125.5, 125.2, 124.9, 123.8, 121.6, 120.6, 120.3, 119.2, 116.3, 115.8 × 2 (d, ² J _CF = 13.7 Hz), 114.6, 112.4, 107.6, 94.7, 84.8, 82.5, 79.4, 60.5 , 49.8, 34.5, 29.2, 28.2. ESI-MS m/z 605.3 [M+H ] ⁺ .

Preparation of Compounds 140 and 141

According to the synthesis of Compound 139, it was synthesized from 3'-N-p-chlorobenzoylsporine (20.0 mg, 0.034 mmol), DMSO and NaOH. After separation by gel column chromatography and methanol elution, 7α-hydroxy-3′-N-p-chlorobenzoyl staurosporine (140) 7.2 mg (yield 35.1%) and 7β-hydroxy-3′-N-pair were obtained. Chlorobenzoyl staurosporine (141) 5.4 mg (yield 26.3%).

Compound 140: ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.25 (d, 1H, J = 7.8 Hz, Ar-H), 8.87 (s, 1H, -NH), 8.46 (d, 1H, J = 7.7 Hz, Ar-H), 7.99 (d, 1H, J = 7.8 Hz, Ar-H), 7.68 (d, 2H, J = 7.8 Hz, Ar-H), 7.52 (d, 2H, J = 7.3 Hz) , Ar-H), 7.50 (t, 1H, J = 8.0 Hz, Ar-H), 7.49 (t, 2H, J = 7.3 Hz, Ar-H), 7.34 (t, 1H, J = 7.8 Hz, Ar -H), 7.31 (t, 1H, J = 7.8 Hz, Ar-H), 7.19 (s, 1H, -OH), 6.54 (d, 1H, J = 10.0 Hz, H-7), 6.44 (d, 1H, J = 8.0 Hz, H-1'), 5.19 (d, 1H, J = 9.2 Hz, H-3'), 4.50 (s, 1H, H-4'), 2.84 (s, 3H, 4' -OCH ₃ ), 2.73 (m, 1H, H-2'a), 2.67 (m, 1H, H-2'b), 2.54 (s, 3H, 3'-NCH ₃ ), 2.48 (s, 3H, H-6'). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 171.0, 171.1, 137.4, 136.6, 134.8, 133.8, 132.5, 130.6, 129.1 × 2, 128.6 × 2, 126.9, 126.5, 125.6, 125.2 , 124.8, 123.7, 121.6, 120.7, 120.3, 119.3, 116.4, 114.7, 112.5, 109.6, 95.1, 84.7, 82.7, 79.1, 60.6, 49.8, 34.5, 29.9, 27.0. ESI-MS m/z 605.3/607.3 [M +H] ⁺ .

Compound 141: ¹ H NMR (600MHz, CDCl ₃ ) δ 9.25 (d, 1H, J = 7.8 Hz, Ar-H), 8.46 (d, 1H, J = 7.7 Hz, -NH), 7.72 (d, 1H) , J = 7.8 Hz, Ar-H), 7.49 (t, 1H, J = 7.8 Hz, Ar-H), 7.46 (t, 2H, J = 7.8 Hz, Ar-H), 7.40 (d, 2H, J = 7.3 Hz, Ar-H), 7.38 (d, 2H, J = 7.3 Hz, Ar-H), 7.35 (t, 2H, J = 7.8 Hz, Ar-H), 7.22 (d, 1H, J = 7.8 Hz, Ar-H), 6.68 (s, 1H, H-7), 6.66 (s, 1H, -OH), 6.41 (d, 1H, J = 8.0 Hz, H-1'), 5.19 (d, 1H) , J=9.2 Hz, H-3'), 4.21 (s, 1H, H-4'), 2.81 (s, 3H, 4'-OCH ₃ ), 2.71 (m, 1H, H-2'a), 2.61 (m, 1H, H-2'b), 2.51 (s, 3H, 3'-NCH ₃ ), 1.66 (s, 3H, H-6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.3 , 171.2, 136.9, 136.4, 133.4, 132.5, 130.9, 130.6, 129.0 × 2, 128.6 × 2, 126.9, 126.5, 125.6, 125.2, 124.8, 123.7, 121.6, 120.7, 120.3, 119.3, 115.9, 115.6, 112.5, 107.8 , </ RTI>^< / RTI>^<RTIgt;

Preparation of Compounds 142 and 143

According to the synthesis of Compound 139, it was synthesized from 3'-N-p-trifluoromethylbenzoylsporine (20.0 mg, 0.031 mmol), DMSO and NaOH. After separation by gel column chromatography and methanol elution, 7α-hydroxy-3'-N-p-trifluoromethylbenzoyl staurosporine (142) 7.5 mg (yield 36.6%) and 7β-hydroxy-3'- N-p-trifluoromethylbenzoyl staurosporine (143) 5.4 mg (yield 26.3%).

Compound 142: ¹ H NMR (600MHz, CDCl ₃ ) δ 8.93 (d, 1H, J = 7.4 Hz, Ar-H), 8.62 (d, 1H, J = 7.4 Hz, -NH), 7.69 (m, 3H) , Ar-H), 7.60 (d, 1H, J = 7.9 Hz, Ar-H), 7.51 (m, 2H, Ar-H), 7.43 (t, 2H, J = 7.8 Hz, Ar-H), 7.37 (t, 2H, J = 7.8 Hz, Ar-H), 7.16 (d, 1H, J = 7.8 Hz, Ar-H), 6.89 (s, 1H, H-7), 6.87 (m, 1H, H- 1'), 6.49 (br s, 1H, -OH), 5.19 (m, 1H, H-3'), 3.90 (s, 1H, H-4'), 2.70 (s, 3H, 4'-OCH ₃ ), 2.54 (m, 1H, H-2'a), 2.35 (m, 1H, H-2'b), 2.09 (s, 3H, 3'-NCH ₃ ), 2.06 (s, 3H, H-6) '). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.2, 170.1, 141.1, 139.7, 138.3, 134.8 × 2, 132.8, 130.1, 128.8 × 2 (q, ² J _CF = 27.0 Hz), 127.9, 127.1, 127.3, 126.7, 125.8, 125.3 (q, ³ J _CF = 8.0 Hz), 125.1, 124.6, 122.7 (q, ¹ J _CF = 270.0 Hz), 121.8, 120.1 (q, ³ J _CF = 7.1 Hz), 119.6, 115.0, 114.7, 113.2, 109.0, 94.5, 83.0, 82.0, 78.2, 60.3, 48.8, 33.7, 29.3, 28.2. ESI-MS m/z 655.2 [M+H] ⁺ .

Compound 143: ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.28 (d, 1H, J = 7.4 Hz, Ar-H), 8.88 (s, 1H, -NH), 8.51 (d, 1H, J = 6.6 Hz, Ar-H), 7.99 (d, 1H, J = 7.7 Hz, Ar-H), 7.83 (d, 1H, J = 7.1 Hz, Ar-H), 7.70 (d, 1H, J = 7.3 Hz) , Ar-H), 7.66 (d, 1H, J = 7.3 Hz, Ar-H), 7.49 (m, 3H, Ar-H), 7.34 (t, 1H, J = 8.3 Hz, Ar-H), 7.30 (m, 2H, Ar-H), 7.09 (d, 1H, J = 9.0 Hz, H-7), 6.46 (br s, 1H, -OH), 6.45 (m, 1H, H-1'), 5.09 (d, 1H, J = 10.0 Hz, H-3'), 4.53 (s, 1H, H-4'), 2.90 (s, 3H, 4'-OCH ₃ ), 2.78 (m, 1H, H-2) 'a), 2.73 (s, 3H, 3'-NCH ₃ ), 2.57 (m, 1H, H-2'b), 2.39 (s, 3H, H-6'). ¹³ C NMR (150 MHz, DMSO- d ₆ ) δ 170.9, 170.8, 139.8, 137.1, 138.3, 134.8 × 2, 132.8, 130.1, 128.7 × 2 (q, ² J _CF = 27.0 Hz), 127.9, 127.1, 127.3, 126.7, 125.8, 125.0 (q , ³ J _CF = 8.0 Hz), 125.1, 124.6, 122.6 ( ¹ J _CF = 270.0 Hz), 121.8, 120.1 (q, ³ J _CF = 7.1 Hz), 119.6, 115.0, 114.7, 113.2, 109.0, 94.5, 83.0 , 82.0, 78.3, 60.3, 48.9, 33.8, 29.2, 28.1. ESI-MS m/z 655.2 [M+H] ⁺ .

Preparation of Compounds 144 and 145

According to the synthesis of Compound 139, it was synthesized from 130 (25.0 mg, 0.040 mmol), DMSO and NaOH solution. After separation by gel column chromatography and methanol elution, 7α-hydroxy-3′-N-p-fluorobenzenesulfonyl staurosporine (144) 8.4 mg (yield 32.8%) and 7β-hydroxy-3′-N-pair were obtained. Fluorobenzenesulfonyl staurosporine (145) 6.0 mg (yield 23.4%).

Compound 144: ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.22 (d, 1H, J = 7.9 Hz, Ar-H), 8.86 (s, 1H, -NH), 8.45 (d, 1H, J = 8.6 Hz, Ar-H), 9.07 (m, 2H, Ar-H), 7.99 (d, 1H, J = 8.4 Hz, Ar-H), 7.56 (m, 2H, Ar-H), 7.50 (m, 3H, Ar-H), 7.34 (t, 1H, J = 7.3 Hz, Ar-H), 7.30 (d, 1H, J = 7.7 Hz, H-7), 6.95 (m, 1H, H-1') , 6.44 (br s, 1H, -OH), 4.53 (d, 1H, J = 13.4 Hz, H-3'), 4.18 (s, 1H, H-4'), 2.63 (s, 3H, 4'- OCH ₃ ), 2.59 (s, 3H, 3'-NCH ₃ ), 2.57 (m, 1H, H-2'a), 2.43 (m, 1H, H-2'b), 2.40 (s, 3H, H -6'). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 170.3, 163.5 (d, ¹ J _CF = 85.7 Hz), 138.8, 136.5, 134.9, 130.2 × 2 (d, ³ J _CF = 9.9 Hz ), 129.6, 126.0, 125.6, 125.6, 125.4, 123.5, 123.4, 123.4, 122.6, 120.3, 119.7, 118.8, 117.0 × 2 (d, ² J _CF = 11.1 Hz), 115.1, 114.8, 113.0, 109.1, 94.8, 85.1, 82.1, 60.3, 51.8, 40.1, 30.60, 29.0, 26.9. ESI-MS m/z 641.2 [M+H] ⁺ .

Compound 145: ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.19 (d, 1H, J = 8.2 Hz, Ar-H), 8.37 (d, 1H, J = 7.9 Hz, -NH), 7.87 (m, 2H) , Ar-H), 7.65 (d, 1H, J = 8.3 Hz, Ar-H), 7.44 (ddd, 1H, J = 1.3, 7.3, 8.0 Hz, Ar-H), 7.36 (ddd, 1H, J = 1.5, 6.9, 8.1 Hz, Ar-H), 7.31 (d, 1H, J = 7.3 Hz, Ar-H), 7.29 (dt, 2H, J = 2.8, 8.2 Hz, Ar-H), 7.26 (m, 1H, Ar-H), 7.24 (t, 1H, J = 7.4 Hz, Ar-H), 6.99 (d, 1H, J = 8.1 Hz, Ar-H), 6.82 (s, 1H, H-7), 6.48 (dd, 1H, J=4.5, 8.9 Hz, H-1'), 6.27 (s, 1H, -O H ), 4.49 (ddd, 1H, J = 2.1, 5.5, 13.0 Hz, H-3') , 3.87 (s, 1H, H-4), 2.57 (s, 3H, 4'-OCH ₃ ), 2.44 (s, 3H, 3'-NCH ₃ ), 2.34 (dt, 1H, J = 4.6, 13.3 Hz , H-2'a), 2.27 (s, 3H, H-6'), 2.22 (m, 1H, H-2'b). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.3, 165.4 (d, ¹ J _CF = 254.9 Hz), 138.8, 136.8, 135.3, 133.5, 130.7, 129.7 × 2 (d, ³ J _CF = 9.2 Hz), 127.2, 126.6, 125.8, 125.7, 124.1, 123.9, 123.2, 120.9, 120.4, 118.1, 115.9 × 2 (d, ² J _CF = 22.8 Hz), 115.8, 115.5, 112.0, 107.7, 94.7, 86.6, 82.3, 79.3, 60.4, 52.1, 33.7, 29.3, 28.2. ESI-MS m/z 641.2 [M+H] ⁺ .

Preparation of Compounds 146 and 147

According to the synthesis of compound 139, it was synthesized from 131 (25.0 mg, 0.039 mmol), DMSO and NaOH solution. After separation by gel column chromatography and methanol elution, 7α-hydroxy-3′-N-p-chlorobenzenesulfonyl staurosporine (146) 8.2 mg (yield 32.0%) and 7β-hydroxy-3′-N-pair Chlorobenzenesulfonyl staurosporine (147) 5.9 mg (yield 23.0%).

Compound 146: ¹ H NMR (600MHz, CDCl ₃ ) δ 8.63 (d, 2H, J = 7.7 Hz, Ar-H), 8.23 (s, 1H, -NH), 7.84 (m, 2H, Ar-H) , 7.61 (m, 2H, Ar-H), 7.49 (d, 1H, J = 8.4 Hz, Ar-H), 7.43 (t, 1H, J = 7.3, Ar-H), 7.36 (t, 1H, J) = 7.7 Hz, Ar-H), 6.87 (t, 1H, J = 7.7 Hz, Ar-H), 6.80 (d, 1H, J = 7.7 Hz, Ar-H), 6.79 (dd, 1H, J = 3.7 , 11.7 Hz, Ar-H), 6.54 (d, 1H, J = 7.7 Hz, H-7), 6.53 (m, 1H, H-1'), 5.43 (br s, 1H, -OH), 4.53 ( Dd, 1H, J = 6.3, 12.4 Hz, H-3'), 3.60 (s, 1H, H-4'), 2.58 (s, 3H, 4'-OCH ₃ ), 2.47 (s, 3H, 3' -NCH ₃ ), 2.34 (m, 1H, H-2'a), 2.22 (dt, 1H, J = 4.2, 12.3 Hz, H-2'b), 1.92 (s, 3H, H-6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 173.3, 139.7, 138.3, 138.0, 135.8, 133.7, 130.4, 129.9× ₂ , 128.5× ₂ , 126.7, 125.9, 125.5, 124.6, 124.4, 124.3, 122.5, 120.7, 119.6 , 117.9, 116.3, 114.9, 111.0, 107.1, 94.3, 86.2, 82.2, 80.3, 59.7, 52.2, 30.6, 29.2, 28.7. ESI-MS m/z 657.6 / 659.6 [M+H] ⁺ .

Compound 147: ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.14 (d, 1H, J = 7.9 Hz, Ar-H), 8.28 (d, 1H, J = 7.8 Hz, -NH), 7.76 (brd, 2H, J=8.0Hz, Ar-H), 7.62 (d, 1H, J=8.5Hz, Ar-H), 7.54 (br d, 2H, J=8.7Hz, Ar-H), 7.40(t, 1H , J = 7.3 Hz, Ar-H), 7.30 (t, 1H, J = 7.8 Hz, Ar-H), 7.25 (m, 2H, Ar-H), 7.19 (t, 1H, J = 7.7 Hz, Ar -H), 7.06 (s, 1H, H-7), 6.92 (d, 1H, J = 8.0 Hz, Ar-H), 6.41 (dd, 1H, J = 4.5, 8.9 Hz, H-1'), 6.16 (s, 1H, -OH), 4.44 (dd, J = 5.4, 11.9 Hz H-3'), 3.79 (s, 1H, H-4'), 2.51 (s, 3H, 4'-OCH ₃ ) , 2.43 (s, 3H, 3'-NCH ₃ ), 2.28 (m, 1H, J = 4.2, 13.2 Hz, H-2'a), 2.19 (m, 1H, H-2'b), 2.15 (s , 3H, H-6'). ¹³ C NMR (150MHz, CDCl ₃ ) δ 171.5, 139.7, 138.6, 137.7, 136.7, 133.5, 130.6, 119.9 × 2, 118.4 × 2, 127.0, 126.4, 135.7, 125.6, 124.1, 123.9, 123.1, 120.8, 120.3, 118.0, 115.6, 115.5, 111.8, 107.7, 94.6, 86.6, 82.2, 79.3, 60.2, 52.1, 30.6, 29.2, 28.2. ESI-MS m/z 657.6/659.6 [M+ H] ⁺ .

Preparation of Compounds 148 and 149

According to the synthesis of compound 139, it was synthesized from 132 (25.0 mg, 0.036 mmol), DMSO and NaOH solution. After separation by gel column chromatography and methanol elution, 7α-hydroxy-3′-N-p-bromobenzenesulfonyl staurosporine (148) 7.8 mg (yield 30.5%) and 7β-hydroxy-3′-N-pair were obtained. Bromobenzenesulfonyl staurosporine (149) 5.5 mg (yield 21.5%).

Compound 148: ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.90 (s, 1H, Ar-H), 8.66 (d, 1H, J = 7.4 Hz, -NH), 8.59 (d, 1H, J = 7.8 Hz , Ar-H), 7.77 (m, 4H, Ar-H), 7.46 (d, 1H, J = 8.1 Hz, Ar-H), 7.42 (d, 1H, J = 8.5 Hz, Ar-H), 7.36 (t, 1H, J = 7.7 Hz, Ar-H), 6.82 (dd, 1H, J = 3.5, 9.8 Hz, Ar-H), 6.78 (m, 2H, Ar-H), 6.56 (d, 1H, J = 10.9 Hz, H-7), 6.46 (t, 1H, J = 7.2 Hz, H-1'), 5.78 (d, 1H, J = 11.1 Hz, -OH), 4.52 (dd, 1H, J = 6.2, 12.8 Hz, H-3'), 3.56 (s, 1H, H-4'), 2.56 (s, 3H, 4'-OCH ₃ ), 2.48 (s, 3H, 3'-NCH ₃ ), 2.35 (m, 1H, H-2'a), 2.19 (dt, 1H, J = 2.5, 13.5 Hz, H-2'b), 2.86 (s, 3H, H-6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 173.2, 138.5, 138.2, 135.6, 133.8, 132.9 × ₂ , 130.3, 128.6 × 2, 128.1, 126.5, 125.8, 125.4, 124.8, 124.4, 124.2, 122.4, 120.6, 119.5, 117.9, 116.2, 114.8 , 110.8, 107.0, 94.2, 86.2, 82.4, 80.5, 59.6, 52.2, 30.5, 29.1, 28.7. ESI-MS m/z 701.5/703.5 [M+H] ⁺ . Compound 149: ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.07 (d, 1H, J = 7.8 Hz, Ar-H), 8.36 (d, 1H, J = 7.8 Hz, -NH), 7.77 (m, 4H) , Ar-H), 7.64 (d, 1H, J = 8.2 Hz, Ar-H), 7.43 (t, 1H, J = 6.8 Hz, Ar-H), 7.37 (d, 1H, J = 3.9 Hz, Ar -H), 7.31 (m, 2H, Ar-H), 7.13 (t, 1H, J = 7.7 Hz, Ar-H), 7.08 (s, 1H, H-7), 6.99 (d, 1H, J = 8.1 Hz, Ar-H), 6.51 (dd, 1H, J = 4.0, 9.2 Hz, H-1'), 6.34 (s, 1H, -OH), 4.49 (ddd, 1H, J = 1.9, 5.5, 12.8) Hz, H-3'), 3.86 (s, 1H, H-4'), 2.58 (s, 3H, 4'-OCH ₃ ), 2.48 (s, 3H, 3'-NCH ₃ ), 2.44 (m, 1H, H-2'a), 2.25 (s, 3H, H-6'), 2.22 (m, 1H, H-2'b). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.6, 138.7, 138.3 , 136.7, 134.4, 132.9 × 2, 130.6, 128.5 × 2, 128.2, 127.1, 126.1, 126.5, 125.7, 125.7, 124.2, 123.1, 120.9, 120.3, 118.0, 115.7, 115.6, 111.8, 107.6, 94.6, 86.6, 82.3 , 79.4, 60.3, 52.1, 33.7, 29.3, 28.2. ESI-MS m/z 701.5/703.5 [M+H] ⁺ .

Preparation of Compound 150

According to the synthesis of Compound 139, it was synthesized from 3'-N-p-iodobenzenesulfonyl staurosporine (25.0 mg, 0.034 mmol), DMSO and NaOH. After separation by gel column chromatography and methanol elution, 8.1 mg (yield 31.7%) of 7α-hydroxy-3'-N-p-iodobenzenesulfonyl staurosporine (150) was obtained. _{^{1 H NMR (600MHz, CDCl 3}} ) δ8.65 (d, 1H, J = 7.4Hz, Ar-H), 8.60 (d, 1H, J = 7.9Hz, Ar-H), 8.57 (s, 1H, - NH), 7.99 (m, 2H, Ar-H), 7.60 (m, 2H, Ar-H), 7.47 (d, 1H, J = 8.0 Hz, Ar-H), 7.43 (t, 1H, J = 7.3) Hz, Ar-H), 7.36 (t, 1H, J = 7.3 Hz, Ar-H), 6.83 (t, 1H, J = 7.8 Hz, Ar-H), 6.79 (t, 2H, J = 8.0 Hz, Ar-H), 6.54 (d, 1H, J = 11.8 Hz, H-7), 6.49 (t, 1H, J = 7.8 Hz, H-1'), 5.62 (d, 1H, J = 12.2 Hz, - OH), 4.50 (dd, 1H, J = 5.8, 12.8 Hz, H-3'), 3.57 (s, 1H, H-4'), 2.57 (s, 3H, 4'-OCH ₃ ), 2.47 (s , 1H, 3'-NCH ₃ ), 2.34 (m, 1H, H-2'a), 2.20 (dt, 1H, J = 3.2, 12.4 Hz, H-2'b), 1.90 (s, 3H, H -6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 173.5, 139.3 × 2, 138.8 × 2, 138.3, 135.7, 133.8, 130.4, 128.5 × 2, 126.6 × 2, 125.8, 125.4, 124.4, 122.4, 120.6, 119.6, 117.9, 116.3, 114.9, 110.9, 109.4, 100.5, 94.3, 86.2, 82.2, 80.4, 59.6, 52.3, 30.6, 29.1, 28.7. ESI-MS m/z 749.6 [M+H] ⁺ .

Preparation of Compounds 151 and 152

According to the synthesis of Compound 139, it was synthesized from 133 (25.0 mg, 0.034 mmol), DMSO and NaOH solution. After separation by gel column chromatography and methanol elution, 7α-hydroxy-3'-N-benzenesulfonyl staurosporine (151) 7.9 mg (yield 30.8%) and 7β-hydroxy-3'-N-benzenesulfonyl group were obtained. Crucyanine (152) 5.4 mg (yield 21.1%).

Compound 151: ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.66 (s, 1H, -NH), 8.63 (t, 2H, J = 7.4 Hz, Ar-H), 7.91 (d, 2H, J = 7.4 Hz , Ar-H), 7.70 (t, 1H, J = 7.8 Hz, Ar-H), 7.64 (m, 2H, Ar-H), 7.40 (m, 2H, Ar-H), 7.34 (t, 1H, J = 7.4 Hz, Ar-H), 6.77 (m, 2H, Ar-H), 6.73 (d, 1H, J = 7.6 Hz, Ar-H), 6.54 (d, 1H, J = 10.0 Hz, H- 7), 6.48 (d, 1H, J = 8.0 Hz, H-1'), 5.75 (d, 1H, J = 10.0 Hz, -OH), 4.53 (dd, 1H, J = 12.8, 5.5 Hz, H- 3'), 3.48 (s, 1H, H-4'), 2.58 (s, 3H, 4'-OCH ₃ ), 2.42 (s, 3H, 3'-NCH ₃ ), 2.36 (m, 1H, H-) 2'a), 2.18 (m, 1H, H-2'b), 1.82 (s, 3H, H-6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 173.5, 139.5, 138.2, 135.7, 133.7 , 133.2, 130.4, 129.6 × 2, 127.0 × 2, 126.6, 125.7, 125.3, 124.7, 124.3, 124.2, 122.4, 120.5, 119.5, 117.8, 116.1, 114.8, 110.8, 107.0, 94.2, 85.8, 82.2, 80.4, 59.4 , 52.1, 30.5, 29.0, 28.6. ESI-MS m/z 623.2 [M+H] ⁺ .

Compound 152: ¹ H NMR (600MHz, CDCl ₃ ) δ 9.19 (d, 1H, J = 7.8 Hz, Ar-H), 8.38 (d, 1H, J = 7.4 Hz, -NH), 7.88 (d, 2H) , J = 7.3 Hz, Ar-H), 7.70 (d, 1H, J = 7.8 Hz, Ar-H), 7.62 (m, 3H, Ar-H), 7.43 (t, 1H, J = 7.8 Hz, Ar -H), 7.36 (t, 1H, J = 7.8 Hz, Ar-H), 7.30 (t, 1H, J = 7.3 Hz, Ar-H), 7.24 (t, 1H, J = 7.3 Hz, Ar-H ), 6.99 (d, 1H, J = 7.9 Hz, ArH), 6.83 (s, 1H, H-7), 6.47 (dd, 1H, J = 9.2, 4.6 Hz, H-1'), 6.31 (br s , 1H, -OH), 4.50 (ddd, 1H, J = 1.9, 5.3, 13.0 Hz, H-3'), 3.83 (s, 1H, H-4'), 2.61 (s, 3H, 4'-OCH ₃ ), 2.42 (s, 3H, 3'-NCH ₃ ), 2.34 (m, 1H, H-2'a), 2.29 (s, 3H, H-6'), 2.22 (m, 1H, H-2) 'b). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.3, 139.2, 138.8, 136.8, 133.4, 133.2, 130.7, 129.5 × ₂ , 127.2, 127.1 × 2, 126.6, 125.6, 125.8, 125.7, 124.1, 124.0 , 123.3, 120.9, 120.4, 118.1, 115.6, 112.0, 107.7, 94.7, 86.3, 82.4, 79.4, 60.3, 52.1, 20.7, 29.3, 28.1. ESI-MS m/z 623.2 [M+H] ⁺ .

Preparation of Compound 153

According to the synthesis method of Compound 130, it was synthesized from staurosporine (46.6 mg, 0.1 mmol), triethylamine and p-fluorobenzoyl chloride. After separation by gel column chromatography and methanol elution, 5'-N-p-fluorobenzoylsporine (153) 53.8 mg was obtained in a yield of 91.5%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.45 (d, 1H, J = 8.2Hz, Ar-H), 7.87 (d, 1H, J = 7.8Hz, Ar-H), 7.78 (d, 1H, J = 7.8 Hz, Ar-H), 7.48 (t, 1H, J = 7.8 Hz, Ar-H), 7.46 (t, 1H, J = 7.3 Hz, Ar-H), 7.43 (m, 2H, J = 7.3) Hz, Ar-H), 7.37 (t, 1H, J = 7.3 Hz, Ar-H), 7.33 (t, 1H, J = 7.3 Hz, Ar-H), 7.21. (d, 1H, J = 7.3 Hz, Ar-H), 7.10 (d, 2H, J = 7.3 Hz, Ar-H), 6.94 (br s, 1H, -NH), 6.66 (br s, 1H, H-1'), 5.17 (d, 1H) , J = 7.8 Hz, H-3'), 4.97 (d, 1H, J = 16.0 Hz, H-7a), 4.93 (d, 1H, J = 16.0 Hz, H-7b), 4.21 (s, 1H, H-4'), 2.84 (s, 3H, 4'-OCH ₃ ), 2.72 (m, 1H, H-2'a), 2.65 (m, 1H, H-2'b), 2.53 (s, 3H) , 3'-NCH ₃ ), 2.45 (s, 3H, H-6'). ¹³ C NMR (150MHz, CDCl ₃ ) δ 173.5, 171.5, 163.6 (d, ¹ J _CF = 247.2 Hz), 136.6 × 2 , 132.5, 132.2, 130.6, 129.4 × 2 (d, ³ J _CF = 6.9 Hz), 126.9, 126.4, 125.5, 125.1, 124.8, 123.7, 121.6, 120.6, 120.2, 119.2, 116.3, 115.8 × 2 (d, ² J _CF = 13.7 Hz), 114.6, 112.4, 107.8, 94.7, 84.8, 82.4, 60.5, 49. 8, 46.1, 34.6, 29.2, 28.2. ESI-MS m/z 589.2 [M+H] ⁺ .

Preparation of Compound 154

Compound 153 (15.0 mg, 0.025 mmol) and chlorosuccinimide (7.5 mg, 0.056 mmol) were synthesized according to the procedure of compound 134. After separation by gel column chromatography and methanol elution, 10.5 mg of 3-chloro-3'-N-p-fluorobenzoyl staurosporine (154) was obtained in a yield of 33.2%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.38 (s, 1H, Ar-H), 7.89 (d, 1H, J = 7.8 Hz, Ar-H), 7.77 (d, 1H, J = 7.3 Hz, Ar -H), 7.48 (d, 2H, J = 7.8 Hz, Ar-H), 7.43 (d, 2H, J = 7.3, Ar-H), 7.36 (t, 1H, J = 7.8 Hz, Ar-H) , 7.35 (d, 1H, J = 7.8 Hz, Ar-H), 7.12 (t, 2H, J = 7.3 Hz, Ar-H), 7.10 (br s, 1H, -NH), 6.74 (br s, 1H) , H-1'), 5.20 (d, 1H, J = 7.8 Hz, H-4'), 4.98 (br s, 2H, H-7), 4.22 (s, 1H, H-3'), 2.86 ( s, 3H, 4'-OCH ₃ ), 2.75 (m, 1H, H-2'a), 2.62 (m, 1H, H-2'b), 2.57 (s, 3H, 3'-NCH ₃ ), 2.44(s,3H,H-6'). ¹³ C NMR (150MHz, CDCl ₃ ) δ 173.0, 171.5, 163.6 (d, ¹ J _CF = 247.2 Hz), 134.8 × 2, 132.8, 132.2, 130.4, 129.3 ×2(d, ³ J _CF = 6.9 Hz),, 127.1, 126.1, 125.7, 125.4, 124.7, 124.6, 121.7, 120.8, 119.2, 115.9 × 2 (d, ² J _CF = 13.7 Hz), 115.4, 115.0, 112.4, 108.6 x 2, 94.8, 84.7, 82.5, 60.5, 49.8, 46.1, 34.5, 29.2, 28.1. ESI-MS m/z 623.3/625.3 [M+H] ⁺ .

Preparation of Compound 155

This was synthesized from Compound 153 (20.0 mg, 0.034 mmol), DMSO and NaOH. After separation by gel column chromatography and methanol elution, 7β-hydroxy-3′-N-p-fluorobenzoyl staurosporine (155) 7.6 mg was obtained in a yield of 37.0%. ¹ H NMR (600 MHz, DMSO) δ 9.28 (d, 1H, J = 7.7 Hz, Ar-H), 8.52 (d, 1H, J = 7.7 Hz, -NH), 7.77 (d, 1H, J = 7.7 Hz, Ar-H), 7.50 (t, 1H, J = 8.2 Hz, Ar-H), 7.49 (t, 1H, J = 8.2 Hz, Ar-H), 7.44 (d, 2H, J = 7.3 Hz, Ar-H), 7.39 (t, 1H, J = 7.7 Hz, Ar-H), 7.37 (t, 1H, J = 7.7 Hz, Ar-H), 7.35 (t, 1H, J = 7.7 Hz, Ar- H), 7.11 (d, 2H, J = 7.7 Hz, Ar-H), 7.06 (s, 1H, H-7), 6.71 (br s, 1H, -OH), 6.50 (br s, 1H, H- 1'), 5.20 (d, 1H, J = 8.2 Hz, H-3'), 4.26 (s, 1H, H-4'), 2.87 (s, 3H, 4'-OCH ₃ ), 2.74 (m, 1H, H-2'a), 2.68 (m, 1H, H-2'b), 2.54 (s, 3H, 3'-NCH ₃ ), 1.67 (s, 3H, H-6'); ¹³ C NMR (150MHz, DMSO) δ171.0, 170.9, 163.9 (d, ¹ J _CF = 247.2 Hz), 137.1 × 2, 135.4, 133.5, 130.2, 129.9 × 2 (d, ³ J _CF = 6.9 Hz), 126.1 × 2 , 125.8, 124.0, 123.9, 123.1, 120.7, 120.2, 119.3 × 2, 116.1, 115.7 × 2 (d, ² J _CF = 13.7 Hz), 113.9, 112.7, 109.6, 95.2, 82.7, 82.7, 78.9, 61.0, 49.9 , 34.6, 29.9, 27.5; ESI-MS m/z 604.2 [M+H] ⁺ .

Preparation of Compound 156

According to the synthesis of compound 130, it was synthesized from 135a (48.0 mg, 0.1 mmol), triethylamine and p-trifluoromethylbenzoyl chloride. After separation by gel column chromatography and methanol elution, 7-oxophenyl-3'-N-p-trifluoromethylbenzoylsporine (156) 59.5 mg was obtained in a yield of 91.3%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.34 (d, 1H, J = 7.7 Hz, Ar-H), 9.17 (d, 1H, J = 7.8 Hz, Ar-H), 7.91 (d, 2H, J = 7.7 Hz, Ar-H), 7.71 (t, 1H, J = 7.4 Hz, Ar-H), 7.66 (t, 1H, J = 7.8 Hz, Ar-H), 7.63 (t, 1H, J = 7.8) Hz, Ar-H), 7.53 (t, 2H, J = 7.7 Hz, Ar-H), 7.52 (br s, 1H, -NH), 7.41 (t, 1H, J = 7.8 Hz, Ar-H), 7.40 (d, 1H, J = 7.8 Hz, Ar-H), 7.12 (d, 1H, J = 7.4 Hz, Ar-H), 6.60 (dd, 1H, J = 3.7 Hz, 9.2 Hz, H-1' ), 4.56 (dd, 1H, J = 5.5 Hz, 12.4 Hz, H-3'), 3.83 (s, 1H, H-4'), 2.74 (s, 3H, 4'-OCH ₃ ), 2.47 (m) , 1H, H-2'a), 2.42 (s, 3H, 3'-NCH ₃ ), 2.38 (m, 1H, H-2'b), 2.26 (s, 3H, H-6'). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.8, 169.6, 167.8, 139.3, 139.2, 137.8 × ² , 133.2 × ² , 131.4 (q, ² J _CF = 27.3 Hz), 130.0, 129.6 × ² , 127.1 × 2, 126.5 (q, ³ J _CF = 8.4 Hz), 126.3, 123.8 (q, ¹ J _CF = 270.0 Hz), 122.5, 121.4, 121.3, 121.0 (q, ³ J _CF = 7.8 Hz), 119.4, 117.4, 116.4, 114.7 , 111.3, 108.2, 94.7, 86.0, 82.5, 60.1, 51.9, 30.7 , 28.9, 28.3; ESI-MS m/z 653.2 [M+H] ⁺ .

Preparation of Compound 157

According to the synthesis method of Compound 130, it was synthesized from staurosporine (46.6 mg, 0.1 mmol), triethylamine and p-iodobenzenesulfonyl chloride. After separation by gel column chromatography and methanol elution, 62.1 mg of 3'-N-p-iodobenzenesulfonyl staurosporine (157) was obtained in a yield of 84.8%. _{^{1 H NMR (600MHz, CDCl 3}} ) δ9.42 (d, 1H, J = 7.8Hz, Ar-H), 7.99 (d, 2H, J = 6.9Hz, Ar-H), 7.89 (d, 1H, J = 7.8 Hz, Ar-H), 7.72 (d, 1H, J = 8.3 Hz, Ar-H), 7.61 (d, 2H, J = 6.9 Hz, Ar-H), 7.48 (t, 1H, J = 7.3) Hz, Ar-H), 7.45 (t, 1H, J = 7.3 Hz, Ar-H), 7.37 (t, 1H, J = 7.8 Hz, Ar-H), 7.35 (t, 1H, J = 7.8 Hz, Ar-H), 7.10 (d, 1H, J = 8.2 Hz, Ar-H), 6.61 (br s, 1H, -NH), 6.57 (dd, 1H, J = 4.6 Hz, 9.2 Hz, H-1' ), 4.99 (d, 1H, J = 16.5 Hz, H-7a), 4.92 (d, 1H, J = 16.5 Hz, H-7b), 4.50 (m, 1H, H-4'), 3.96 (s, 1H, H-3'), 2.72 (s, 3H, 4'-OCH ₃ ), 2.47 (s, 1H, 3'-NCH ₃ ), 2.45 (m, 1H, H-2'a), 2.43 (s , 3H, H-6'), 2.45 (m, 1H, H-2'a); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 173.3, 138.9 × ₂ , 138.5, 136.6 × 2, 132.5, 130.5, 128.4 ×2,127.0,126.4,125.6,125.3,124.8,123.7,121.7,120.8,120.3,119.3,116.4,114.7,112.3,107.7,100.6,94.7,86.6,82.5,60.5,52.2,46.0,30.9,29.2, 28.2 .ESI-MS m/z 733.3 [M+H] ⁺ .

Preparation of Compound 158

i) Preparation of N-methyl-3,4-di(3-indolyl)maleimide (158a)

According to the synthesis method of compound 82, it was synthesized from magnesium wire (128 mg, 5.3 mmol), bromoethane (396 μL, 5.3 mmol) and hydrazine (622 mg, 5.3 mmol), and separated by silica gel column chromatography, petroleum ether: ethyl acetate = 3:1 (v/v) eluted 263 mg of a red solid (158a), yield 73%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.70 (s, 2H, indole-NH), 7.77 (d, 2H, J = 2.3Hz, Ar-H), 7.38 (d, 2H, J = 8.2Hz , Ar-H), 6.98 (t, 2H, J = 7.7 Hz, Ar-H), 6.82 (d, 2H, J = 7.8 Hz, Ar-H), 6.64 (t, 2H, J = 7.8 Hz, Ar -H), 3.04 (s, 3H, -CH ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.4 × 2, 136.6 × 2, 129.7 × 2, 127.6 × 2, 125.9 × 2, 122.2 × 2, 121.5 × 2, 119.9 × 2, 112.3 × 2, 106.2 × 2, 24.5. ESI-MS m/z 342.1 [M+H] ⁺ .

Ii) Preparation of 3,4-bis(3-indole) maleic anhydride (158b)

The compound 158a (120 mg, 0.35 mmol) was combined with a 10% KOH solution. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.93 (d, 2H, J = 2.8Hz, indole-NH), 7.86 (d, 2H, J = 2.8Hz, Ar-H), 7.44 (d, 2H , J = 8.2 Hz, Ar-H), 7.04 (t, 2H, J = 8.2 Hz, Ar-H), 6.87 (d, 2H, J = 7.7 Hz, Ar-H), 6.71 (t, 2H, J = 7.7 Hz, Ar-H). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 167.1 × 2, 136.7 × 2, 131.1 × 2, 125.8 × 2, 125.5 × 2, 122.6 × 2, 121.7 × 2, 120.4×2, 112.7×2, 105.5×2. ESI-MS m/z 329.1 [M+H] ⁺ .

Iii) Preparation of 3,4-bis(3-indolyl)maleimide (158c)

According to the preparation method of Compound 1, 70 mg of an orange-red powder (158c) was obtained from Compound 158b (100 mg, 0.3 mmol), HMDS (6.4 mL, 30.5 mmol), MeOH (0.61 mL, 15.2 mmol), yield 71%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.65 (brs, 2H, indole-NH), 10.89 (brs, 1H, imide-NH), 7.72 (d, 2H, J = 2.8Hz, Ar-H) , 7.36 (d, 2H, J = 8.2 Hz, Ar-H), 6.96 (dt, 2H, J = 8.2 Hz, 1.0 Hz, Ar-H), 6.79 (d, 2H, J = 7.8 Hz, Ar-H ), 6.61 (dt, 2H, J = 8.2 Hz, 1.0 Hz, Ar-H). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 173.6 × 2, 136.4 × 2, 129.6 × 2, 128.2 × 2, 125.9 × 2, 122.1 × 2, 121.4 × 2, 119.8 × 2, 112.3 × 2, 106.1 × 2. ESI-MS m/z 328.2 [M+H] ⁺ .

Iv) Preparation of N-hydroxymethyl-3,4-bis(1-hydroxymethyl-3-indole)maleimide (158)

According to the preparation method of the compound 4, a red powdery solid (158) 96 mg was obtained from 158c (76.5 mg, 0.23 mmol), NaHCO ₃ (98 mg, 1.17 mmol), and a formaldehyde solution (3 mL, mass fraction: 37%). %. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.95 (s, 2H, Ar-H), 7.55 (d, 2H, J = 8.2 Hz, Ar-H), 7.03 (t, 2H, J = 7.3 Hz , Ar-H), 6.76 (d, 2H, J = 8.2 Hz, Ar-H), 6.64 (t, 2H, J = 7.3 Hz, Ar-H), 5.60 (s, 4H, indole-C H ₂ - OH), 4.98 (s, 2H, imide-C H ₂ -OH). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.6 × 2, 136.0 × 2, 132.4 × 2, 127.6 × 2, 127.0 × 2 , 122.4 × 2, 121.5 × 2, 120.6 × 2, 111.4 × 2, 105.9 × 2, 69.7, 60.9 × 2. HR-ESIMS m / z 440.1236 [M + H ^{] +} (calcd. for C ₂₃ H ₁₉ N ₃ O ₅ Na, 440.1222).

Preparation of Compound 159

According to the preparation method of the compound 14, the compound 8b (30 mg, 0.055 mmol) and ethylenediamine (0.5 mL) were reacted, and the mixture was separated by silica gel column chromatography and dichloromethane: methanol = 8:1 (v/v) to obtain a deep red color. Solid N-(2-aminoethyl)-2,3-bis(1-cyanopropyl-3-indole)maleimide (159) 30 mg, yield 94%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.76 (s, 2H, Ar-H), 7.50 (d, 2H, J = 8.2 Hz, Ar-H), 7.07 (t, 2H, J = 7.6 Hz , Ar-H), 6.89 (d, 2H, J = 7.9 Hz, Ar-H), 6.72 (s, 2H, Ar-H), 4.28 (t, 4H, J = 5.5 Hz, -NC H ₂ - ( CH ₂ ) ₂ CN), 3.63 (t, 2H, J = 5.7 Hz, -NC H ₂ -CH ₂ NH ₂ ), 2.86 (t, 2H, J = 5.7 Hz, -NCH ₂ -C H ₂ -NH ₂ ), 2.37 (t, J = 6.8 Hz, 4H, N(CH ₂ ) ₂ -C H ₂ -CN), 2.03-1.98 (m, 4H, N-CH ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.9 × 2, 136.3 × 2, 132.4 × 2, 127.4 × 2, 126.0 × 2, 122.5 × 2, 121.9 × 2, 120.3 × 2, 120.1 × 2, 110.6 × 2,105.7×2,54.0,45.0×2,39.9,26.0×2, 14.2×2. ESI-MS m/z 505.1 [M+H] ⁺ .

Preparation of Compound 160

According to the preparation method of the compound 24, the compound 8b (60 mg, 0.129 mmol), 4-(2-aminoethyl)morpholine (120 μL, 0.909 mmol) and a catalytic amount of Et ₃ N were synthesized by silica gel column chromatography and dichloromethane. : methanol = 30:1 (v/v) eluted to give a red solid N-(2-(4-morpholine)ethyl)-2,3-di(1-cyanopropyl-3-indole) Malay The imide (160) was 44 mg in a yield of 59%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.77 (s, 2H, Ar-H), 7.51 (d, 2H, J = 8.3 Hz, Ar-H), 7.07 (t, 2H, J = 7.6 Hz) , Ar-H), 6.87 (d, 2H, J = 8.0 Hz, Ar-H), 6.73 (t, 2H, J = 7.5 Hz, Ar-H), 4.27 (t, 4H, J = 6.6 Hz, - NC H ₂ -(CH ₂ ) ₂ CN), 3.69 (t, 2H, J = 6.0 Hz, -NC H ₂ -CH ₂ -morpholine), 3.52 (t, 4H, J = 4.5 Hz, morpholine-N (CH) ₂ C H ₂ ) ₂ O), 2.53 (t, 2H, J = 6.0 Hz, -NCH ₂ -C H ₂ -morpholine), 2.42 (t, 4H, J = 5.3 Hz, N(CH ₂ ) ₂ -C H ₂ -CN), 2.37 (t, 4H, J = 3.9 Hz, morpholine-N(C H ₂ CH ₂ ) ₂ O), 2.03-1.98 (m, 4H, NCH ₂ -C H ₂ -CH ₂ CN) ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 171.8 × 2, 136.3 × 2, 132.5 × 2, 127.2 × 2, 126.0 × 2, 122.5 × 2, 121.8 × 2, 120.4 × 2, 120.2 × 2, 110.6×2, 105.6×2, 66.7×2, 56.4, 53.6×2, 45.0×2, 35.3, 26.0×2, 14.2×2. ESI-MS m/z 575.2 [M+H] ⁺ .

Preparation of Compound 161

According to the synthesis method of compound 24, compound 8b (60 mg, 0.129 mmol), 4-(2-aminoethyl)piperazine (100 μL, 0.90 mmol) and catalytic amount of Et ₃ N were synthesized by silica gel column chromatography and dichloromethane. : methanol = 10:1 (v/v) eluted as red solid N-(2-piperazinylethyl)-2,3-di(1-cyanopropyl-3-indole)maleimide ( 161) 44 mg, yield 75%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.77 (s, 2H, Ar-H), 7.51 (d, 2H, J = 8.3 Hz, Ar-H), 7.07 (t, 2H, J = 7.6 Hz) , Ar-H), 6.87 (d, 2H, J = 8.0 Hz, Ar-H), 6.73 (t, 2H, J = 7.5 Hz, Ar-H), 4.27 (t, 4H, J = 6.5 Hz, - NC H ₂ -(CH ₂ ) ₂ CN), 3.67 (t, 4H, J = 6.1 Hz, piperazine-N(CH ₂ CH ₂ ) ₂ NH), 2.73 (t, 4H, J = 4.9 Hz, piperazine-N (CH ₂ C H ₂ ) ₂ NH), 2.52 (t, 2H, J = 6.1 Hz, imide-NC H ₂ -CH ₂ -piperazine), 2.43 (t, 2H, J = 4.9 Hz, imide-NCH ₂ - C H ₂ -piperazine), 2.37 (t, 4H, J = 7.1 Hz, N(CH ₂ ) ₂ -C H ₂ -CN), 1.99-2.02 (m, 4H, NCH ₂ -C H ₂ -CH ₂ CN ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.8 × 2, 136.3 × 2, 132.5 × 2, 127.3 × 2, 126.0 × 2, 122.5 × 2, 121.8 × 2, 120.3 × 2, 120.2 × 2 , 110.6 × 2, 105.6 × 2, 56.4, 53.2 × 2, 45.3 × 2, 45.0 × 2, 35.4, 26.0 × 2, 14.2 × 2. ESI-MS m / z 574.2 [M + H] ⁺ .

Preparation of Compound 162

Compound 8b (55 mg, 0.119 mmol) was dissolved in 6 ml of dry pyridine, and hydroxylamine hydrochloride (17 mg, 0.238 mmol) was added, and the reaction was carried out at 100 ° C for 1.5 h under nitrogen atmosphere. The reaction was stopped until TLC detected, cooled to room temperature and then evaporated to dryness. Separation by silica gel column chromatography, methylene chloride:methanol=15:1 (v/v) eluted to give red solid N-hydroxy-2,3-di(1-cyanopropyl-3-indole)maleimide (162) 51 mg, yield 89%. ^{1 H NMR (600MHz, DMSO-} d 6) δ10.46 (s, 1H, -OH), 7.78 (s, 2H, Ar-H), 7.51 (d, 2H, J = 8.3Hz, Ar-H), 7.07 (t, 2H, J = 7.6 Hz, Ar-H), 6.86 (d, 2H, J = 8.0 Hz, Ar-H), 6.72 (t, 2H, J = 7.5 Hz, Ar-H), 4.28 ( t, 4H, J = 6.5 Hz, -NC H ₂ -(CH ₂ ) ₂ CN), 2.37 (t, 4H, J = 7.1 Hz, N(CH ₂ ) ₂ -C H ₂ -CN), 2.04-1.98 (m, 4H, NCH ₂ -C H ₂ -CH ₂ CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 168.6 × 2, 136.3 × 2, 132.6 × 2, 125.9 × 2, 124.7 × 2, 122.5 × 2, 121.8 × 2, 120.4 × 2, 120.3 × 2, 110.7 × 2, 105.5 × 2, 45.0 × 2, 26.0 × 2, 14.2 × 2. ESI-MS m / z 478.2 [M + H] ⁺ .

Preparation of Compound 163

According to the synthesis of compound 162, compound 26e (55 mg, 0.13 mmol) and hydroxylamine hydrochloride (25 mg, 0.25 mmol) were synthesized, eluted with silica gel column chromatography, dichloromethane:methanol=20:1 (v/v) Solid N-hydroxy-2-(1-ethyl-3-indolyl)-3-(6-bromo-3-indole) Maleimide (162) 58 mg, yield 99%. ^{1 H NMR (600MHz, DMSO-} d 6) δ11.83 (s, 1H, indole-NH), 10.50 (brs, 1H, -OH), 7.84 (s, 1H, Ar-H), 7.79 (s, 1H , Ar-H), 7.57 (s, 1H, Ar-H), 7.47 (d, 1H, J = 8.2 Hz, Ar-H), 7.03 (t, 1H, J = 7.6 Hz, Ar-H), 6.76 (t, 1H, J = 7.6 Hz, Ar-H), 6.74 (d, 1H, J = 7.1 Hz, Ar-H), 6.68 (t, 1H, J = 6.2 Hz, Ar-H), 6.67 (d , 1H, J = 8.1 Hz, Ar-H), 4.25 (q, 2H, J = 7.0 Hz, -C H ₂ -CH ₃ ), 1.32 (t, 3H, J = 7.1 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 168.7×2, 137.3, 136.0, 132.3, 130.7, 126.1, 125.2, 124.7, 124.3, 122.9, 122.7, 122.3, 121.6, 120.2, 114.9×2, 110.7,106.1,105.0,41.2,15.7.HR-ESIMS m / z 450.0459 [ m + H] + (calcd.for C 22 H 16 N 3 O 3 Br, 449.0375).

Preparation of Compound 164

According to the preparation method of the compound 24, the compound 26e (30 mg, 0.069 mmol), 4-(2-aminoethyl)morpholine (64 μL, 0.484 mmol) and a catalytic amount of Et ₃ N were synthesized by silica gel column chromatography and dichloromethane. : methanol = 25:1 (v/v) eluted red solid N-(2-(4-morpholinyl)ethyl)-2-(1-ethyl-3-indole)-3-(6- Bromo-3-indole maleimide (164) 33 mg, yield 88%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.78 (s, 1H, indole-NH), 7.81 (s, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.56 (d, 1H, J = 1.5 Hz, Ar-H), 7.46 (d, 1H, J = 8.3 Hz, Ar-H), 7.03 (t, 1H, J = 7.6 Hz, Ar-H), 6.78 (d, 1H, J = 7.7 Hz, Ar-H), 6.74 (dd, 1H, J = 8.4 Hz, 1.6 Hz, Ar-H), 6.69 (d, 1H, J = 8.4 Hz, Ar-H), 6.67 (t, 1H) , J = 8.2 Hz, Ar-H), 4.24 (q, 2H, J = 7.2 Hz, -C H ₂ -CH ₃ ), 3.67 (t, 2H, J = 6.5 Hz, imide-NC H ₂ CH ₂ - ), 3.51 (t, 4H, J = 4.2 Hz, morpholine-N(CH ₂ -C H ₂ ) ₂ O), 2.52 (t, 2H, J = 6.5 Hz, imide-NCH ₂ C H ₂ -), 2.40 (t, 4H, J = 4.2 Hz, morpholine-N(C H ₂ -CH ₂ ) ₂ O), 1.32 (t, 3H, J = 7.2 Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125 MHz , DMSO-d ₆ ) δ 171.9, 171.8, 137.3, 136.0, 132.1, 130.5, 127.7, 126.4, 126.2, 124.7, 122.9, 122.6, 122.3, 121.6, 120.1, 114.9, 114.8, 110.7, 106.2, 105.1, 66.6 × 2,56.3,53.6×2,41.2,35.3,15.7.HR-ESIMS m/z 547.1354[M+H] ⁺ (calcd.for C ₂₈ H ₂₇ N ₄ O ₃ Br, 546.1267).

Preparation of Compound 165

According to the synthesis method of compound 24, compound 26e (30 mg, 0.069 mmol), 4-(2-aminoethyl)piperazine (93 μL, 0.712 mmol) and catalytic amount of Et ₃ N were synthesized by silica gel column chromatography and dichloromethane. : methanol = 8:1 (v/v) eluted to give red solid N-(2-piperazinethyl)-2-(1-ethyl-3-indole)-3-(6-bromo-3-吲哚) Maleimide (165) 55 mg, yield 99%. ^{1 H NMR (500MHz, DMSO-} d 6) δ11.78 (s, 1H, indole-NH), 7.81 (s, 1H, Ar-H), 7.76 (d, 1H, J = 2.6Hz, Ar-H) , 7.57 (d, 1H, J = 1.5 Hz, Ar-H), 7.48 (d, 1H, J = 8.3 Hz, Ar-H), 7.04 (t, 1H, J = 7.6 Hz, Ar-H), 6.78 (d, 1H, J = 8.0 Hz, Ar-H), 6.76 (dd, 1H, J = 8.4 Hz, 1.6 Hz, Ar-H), 6.69 (d, 1H, J = 8.5 Hz, Ar-H), 6.68 (t, 1H, J = 7.8 Hz, Ar-H), 4.25 (q, 2H, J = 7.1 Hz, -C H ₂ -CH ₃ ), 3.67 (d, 2H, J = 6.2 Hz, imide-NC H ₂ CH ₂ -), 3.15 (brs, 1H, piperazine-NH), 3.03 (t, 4H, J = 4.9 Hz, piperazine-N(C H ₂ -CH ₂ ) ₂ NH), 2.64 (t, 4H, J=4.9 Hz, piperazine-N(CH ₂ -C H ₂ ) ₂ NH), 2.60 (t, 2H, J = 5.8 Hz, imide-NCH ₂ C H ₂ -), 1.32 (t, 3H, J = 7.2) Hz, -CH ₂ -C H ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.9, 171.8, 137.3, 136.0, 132.2, 130.6, 127.7, 126.4, 126.1, 124.7, 122.9, 122.6, 122.3, 121.6, 120.2, 114.9, 114.8, 110.8, 106.2, 105.1, 55.5 × 2, 49.6, 43.5 × 2, 41.2, 35.3, 15.7. HR-ESIMS m/z 546.1515 [M+H] ⁺ (calcd.for C ₂₈ H ₂₈ N ₅ O ₂ Br,545 .1426).

Preparation of Compound 166

According to the synthesis method of compound 64, compound 8 (50.0 mg, 0.108 mmol) and I ₂ (2.0 mg, 0.008 mmol) were synthesized by silica gel column chromatography, petroleum ether: ethyl acetate = 3:1 (v/v) Decolorized yellow powder 12,13-dicyanopropyl-6H-indole [2,3-a]pyrrole [3,4-c]oxazol-5,7-dione (166) 23 mg, yield 45% . ^{1 H NMR (600MHz, DMSO-} d 6) δ11.2 (s, 1H, -NH), 9.14 (d, 2H, J = 7.8Hz, Ar-H), 7.89 (d, 2H, J = 8.2Hz, Ar-H), 7.66 (t, 2H, J = 7.8 Hz, Ar-H), 7.44 (t, 2H, J = 7.8 Hz, Ar-H), 4.81 (t, 4H, J = 6.9 Hz, NC H _{2 - (CH 2) 2 CN} ), 2.13 (t, 4H, J = 6.9Hz, N (CH 2) 2 -C H 2 -CN), 1.71 (m, 4H, NCH 2 -C H 2 -CH 2 CN). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.2 × 2, 144.3 × 2, 133.2 × 2, 128.1 × 2, 125.5 × 2, 123.9 × 2, 122.2 × 2, 121.6 × 2, 120.5 × 2,120.2×2,113.3×2,47.5×2, 24.2×2, 14.2×2. HR-ESIMS m/z 458.1604[MH] ^- (calcd.for C ₂₈ H ₂₀ N ₅ O ₂ , 458.1617).

Preparation of Compound 167

Dissolve the staurosporine (60 mg, 0.129 mmol) in THF (5 mL) at 0 ° C, add diisopropylethylamine (64 μL, 0.38 mmol) and triphosgene (19 mg, 0.064 mmol), stir at room temperature for 2 h, pour into ice In water, ethyl acetate was extracted (2××30 mL), brine (2××30 mL), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was dissolved in THF (3 mL), diisopropylethylamine (127 μL, 0.77 mmol), imidazole (18 mg, 0.25 mmol) and p-dimethylaminopyridine (31.5 mg, 0.258 mmol). Pour into ice water, extract with ethyl acetate (2××30 mL), wash with brine (2××30 mL), dry organic Separation by silica gel column chromatography, methylene chloride:methanol = 50:1 (v/v) to give a pale yellow solid: 3?-N-(1-imidazolylyl) sporine (167) 56 mg, yield 80% . [α] _D ¹⁸ +176 (c 0.07, CHCl ₃ ); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.31 (d, J = 7.9 Hz, 1H, ArH), 8.68 (s, 1H, ArH) , 8.61 (s, 1H, NH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 8.01 (d, J = 8.5 Hz, 1H, ArH), 7.79 (brs, 1H, ArH), 7.59 (d , J = 8.2 Hz, 1H, ArH), 7.51 (t, J = 8.2 Hz, 1H, ArH), 7.49 (t, J = 8.2 Hz, 1H, ArH), 7.37 (t, J = 7.7 Hz, 1H, ArH), 7.35 (brs, 1H, ArH), 7.31 (t, J = 7.5 Hz, 1H, ArH), 7.04 (dd, J = 8.5, 5.6 Hz, 1H, H-1'), 5.00 (s, 2H) , H-7), 4.68 (m, 1H, H-3'), 4.50 (brs, 1H, H-4'), 2.94-2.99 (m, 1H, H-2'a), 2.89 (s, 3H) , 3'-NCH ₃ ), 2.61 (s, 3H, 6'-CH ₃ ), 2.36-2.43 (m, 1H, H-2'b), 2.39 (s, 3H, 6'-CH ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 172.0, 150.8, 138.6, 137.2, 136.3, 132.6, 129.5, 125.9, 125.8, 125.5, 125.5, 125.3, 123.9, 122.8, 121.7, 120.6, 119.7, 119.6, 119.5, 115.2, 114.3, 113.2, 109.0, 94.7, 83.2, 82.1, 60.2, 52.3, 45.5, 33.2, 28.9, 27.0. HRESI-MS m/z 561.2242 [M+H] ⁺ (calcd for C ₃₂ H ₂₉ N ₆ O ₄ , 561.2245).

Preparation of Compound 168

The staurosporine (186 mg, 0.4 mmol) was dissolved in 10 mL of dichloromethane, and 1 mL of triethylamine and N,N'-thiocarbonyldiimidazole (214 mg, 1.2 mmol) were added at room temperature overnight. The reaction solution was poured into 20 mL of ice water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, and then concentrated, and then purified by silica gel column chromatography, methylene chloride:methanol=20:1 (v/v) to give 3'-N- (1-Imidazolylthioformyl) Staurosporine (168) 180 mg, yield 78%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.32 (d, J = 7.9 Hz, 1H), 8.63 (s, 1H, NH), 8.12 (s, 1H, ArH), 8.07 (d, J = 7.7 Hz, 1H, ArH), 8.03 (d, J = 8.5 Hz, 1H, ArH), 7.64 (d, J = 7.2 Hz, 1H, ArH), 7.59 (brs, 1H, ArH), 7.51 (t, J = 7.4 Hz, 1H, ArH), 7.50 (t, J = 7.7, 1H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.32 (t, J = 7.5 Hz, 1H, ArH), 7.13 (brs, 1H, ArH), 7.06 (brs, 1H, H-1'), 5.47 (brs, 1H, H-3'), 5.01 (s, 2H, H-7), 4.79 (brs, 1H, H) -4'), 3.06 (s, 3H, 3'-NCH ₃ ), 3.02-3.09 (m, 1H, H-2'a), 2.73 (s, 3H, 4'-OCH ₃ ), 2.44 (s, 3H,6'-CH ₃ ), 2.41-2.47 (m,1H,H-2'b); ¹³ C NMR (125MHz, DMSO-d ₆ ) δ179.3,171.9,138.8,137.7,136.2,132.7,129.3 , 129.0, 125.8, 125.4, 125.2 × 2, 123.9, 122.7, 121.6, 120.5, 119.9, 119.6, 119.6, 115.3, 114.3, 113.5, 108.9, 94.8, 81.9 × 2, 60.4, 58.1, 45.5, 38.2, 29.4, 27.1 ;HRESI-MS m/z 577.2031 [M+H] ⁺ (calcd for C ₃₂ H ₂₉ N ₆ O ₃ S, 577.2022).

Preparation of Compound 169

Compound 168 (80 mg, 0.14 mmol) was dissolved in 10 mL of acetonitrile, methylene chloride (.sub. The reaction solution was directly concentrated, and washed with 50 ml of a mixed solution of petroleum ether:dichloromethane=4:1 (v/v) to obtain 75 mg of the imidazolium salt of the imidazole moiety of Compound 168, yield 76%; HRESI-MS m/ z 591.2164 [MI] ⁺ (calcd for C ₃₃ H ₃₁ N ₆ O ₃ S, 591.2173). The tryptamine (2.0 g, 12.5 mmol) was dissolved in 20 mL of tetrahydrofuran, reduced to 10 ° C, and then triethylamine (3.5 mL, 25 mmol) and tert-butoxybenzoic anhydride (3.03 g, 15.0 mmol) were added, and reacted at 10 ° C The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then evaporated. -[2-(3-Indolyl)ethyl]carbamic acid tert-butyl ester 3.16 g,yield: 97%; ESI-MS m/z 261.3 [M+H] ⁺ . tert-Butyl N-[2-(3-indene)ethyl]carbamate (1.8 g, 6.92 mmol) was dissolved in 110 mL THF / H ₂ O (10:1), reduced to 0 ° C, DDQ (3.1) g, 13.8 mmol) and reacted at this temperature for two hours. The reaction mixture was poured into ethyl acetate (200 mL), EtOAc (EtOAc m. v/v) eluted to give 1.2 g of N-[2-oxophenyl-2-(3-indolyl)ethyl]carbamic acid tert-butyl ester, yield 63%; ESI-MS m/z 275.4 [M+ H] ⁺ . N-[2-Oxophenyl-2-(3-indolyl)ethyl]carbamic acid tert-butyl ester (200 mg, 0.73 mmol) was dissolved in 5 mL of trifluoroacetic acid, and reacted at 10 ° C for one hour, and benzene (5 mL) was added. ×3 times) Arotropy removal of trifluoroacetic acid gave 185 mg of N-[2-oxophenyl-2-(3-indole)ethyl]trifluoroacetic acid, yield 93%. The imidazolium salt of the imidazole moiety of compound 168 (75.0 mg, 0.105 mmol) was dissolved in 2 mL of DMF, and triethylamine (73.0 μL, 0.525 mmol) and N-[2-oxyphenyl-2-(3-indole) were added.哚)ethyl]ammonium trifluoroacetate (85.4 mg, 0.315 mmol, 3.0 equiv) was reacted at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Semi-preparative HPLC separation, elution with MeOH:H ₂ O=9:1 (v/v) afforded 3'-N-[N-(2-oxophenyl-2-(3-indole)ethyl)aminosulfide Mesoyl] staurosporine (169) 40 mg, yield 56%. [α] _D ^{18 +} 248 (c 0.07, CHCl ₃ ); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.02 (d, J = 2.0 Hz, 1H, NH), 9.30 (d, J = 8.0 Hz) , 1H, ArH), 8.59 (s, 1H, NH), 8.49 (d, J = 2.9 Hz, 1H, ArH), 8.19 (d, J = 7.0 Hz, 1H, ArH), 8.05 (d, J = 7.8) Hz, 1H, ArH), 7.98 (d, J = 8.5 Hz, 1H, ArH), 7.92 (t, J = 6.0 Hz, 1H, NH), 7.72 (d, J = 8.3 Hz, 1H, ArH), 7.52 (d, J = 7.2 Hz, 1H, ArH), 7.49 (t, J = 7.5 Hz, 2H, ArH), 7.36 (t, J = 7.4 Hz, 1H, ArH), 7.31 (t, J = 7.5 Hz, 1H, ArH), 7.25 (dt, J = 7.7, 1.6 Hz, 1H, ArH), 7.21 (dt, J = 7.6, 1.5 Hz, 1H, ArH), 7.07 (t, J = 7.4 Hz, 1H, H- 1'), 5.94 (d, J = 12.2 Hz, 1H, H-3'), 4.97-5.09 (m, 2H, H-3"), 5.01 (s, 2H, H-7), 4.51 (brs, 1H, H-4'), 2.96 (s, 3H, 3'-NCH ₃ ), 2.84 (s, 3H, 4'-OCH ₃ ), 2.72-2.76 (m, 1H, H-2'a), 2.36 (s, 3H, 6'-CH ₃ ), 2.31 (ddd, J = 12.5, 12.5, 6.5 Hz 1H, H-2'b); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 190.2, 182.5, 172.1, 139.1, 136.5, 136.4, 133.4, 132.8, 129.2, 125.7, 125.5 × 2, 12 5.1, 125.1, 123.9, 123.0, 122.7, 121.9, 121.5, 121.3, 120.4, 119.6, 119.4, 115.4, 114.3 × 2, 113.9, 112.3, 109.2, 95.1, 83.1, 82.5, 60.5, 54.3, 52.0, 45.6, 32.8, 29.6, 27.8; HRESI-MS m/z 683.2462 [M+H] ⁺ (calcd for C ₃₉ H ₃₅ N ₆ O ₄ S, 683.2441).

Preparation of Compound 170

Bromoacetophenone (1.97 g, 10.0 mmol) was dissolved in 40 mL of chloroform, and hexamethylenetetramine (1.47 g, 10.5 mmol) was added and allowed to react at room temperature for 4 hours. After filtering the reaction mixture, the residue was dissolved in 80 mL of methanol, and 4 mL of concentrated hydrochloric acid was added thereto, and the mixture was refluxed for 3 hours. After concentrating the reaction mixture, methanol was recrystallized to give the compound N-(2- oxyphenyl-2-phenethyl) ammonium chloride 1.5 g, yield: 88%; ESI-MS m/z 136.3 [M-Cl] ⁺ . The imidazolium salt of the imidazole moiety of compound 168 (49.0 mg, 0.068 mmol) was dissolved in 2 mL of DMF, and triethylamine (47.2 [mu]L, 0.34 mmol) and N-(2-oxophenyl-2-phenethyl) Ammonium chloride (34.9 mg, 0.204 mmol) was reacted at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Flash column chromatography, petroleum ether: ethyl acetate = 1:1 (v/v) eluted to give 3'-N-[N-(2-oxyphenyl-2-phenethyl)aminothioformyl] Staurosporine (170) 18.0 mg, yield 41%. [α] _D ¹⁸ + 257 (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.29 (d, J = 8.1 Hz, 1H, ArH), 8.61 (s, 1H, NH) , 8.06 (d, J = 7.8 Hz, 1H, ArH), 8.04 (d, J = 7.7 Hz, 2H, ArH), 8.00 (d, J = 8.5 Hz, 1H, ArH), 7.74 (d, J = 8.2) Hz, 1H, ArH), 7.68 (t, J = 7.3 Hz, 1H, ArH), 7.58 (t, J = 7.6 Hz, 2H, ArH), 7.49 (t, J = 7.6 Hz, 2H, ArH), 7.36 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH), 7.08 (t, J = 7.7 Hz, 1H, H-1'), 5.85 (m, 1H, H-3'), 5.02-5.15 (m, 2H, H-3"), 5.01 (s, 2H, H-7), 4.51 (brs, 1H, H-4'), 2.93 (s, 3H, 3) '-NCH ₃ ), 2.85 (s, 3H, 4'-OCH ₃ ), 2.70-2.74 (m, 1H, H-2'a), 2.34 (s, 3H, 6'-CH ₃ ), 2.28 (ddd , J = 13.0, 13.0, 7.2 Hz, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 195.4, 182.5, 171.9, 139.1, 136.3, 135.5, 133.4, 132.8, 129.0, 128.8×2, 127.8×2, 125.7, 125.4, 125.0, 124.9, 123.8, 122.6, 121.4, 120.3, 119.5, 119.4, 115.3, 114.2, 114.0, 109.1, 94.9, 82.7, 82.3, 60.4, 54.4, 51.9, 4 5.5, 32.9, 29.6, 27.6; HRESI-MS m/z 644.2351 [M+H] ⁺ (calcd for C ₃₇ H ₃₄ N ₅ O ₄ S, 644.2332).

Preparation of Compound 171

Compound 167 (50 mg, 0.089 mmol) was dissolved in 10 mL of acetonitrile, EtOAc (EtOAc (EtOAc) The reaction solution was directly concentrated, and washed with 50 ml of a mixed solution of petroleum ether:dichloromethane=4:1 (v/v) to obtain the imidazolium salt of compound 167 (yield: 77%, yield 77%; HRESI-MS m/z 575.2393 [MI ] ⁺ (calcd for C ₃₃ H ₃₁ N ₆ O ₄ , 575.2401). The imidazolium salt of the imidazole moiety of compound 167 (48.0 mg, 0.068 mmol) was dissolved in 2 mL of DMF, and triethylamine (47.2 [mu]L, 0.34 mmol) and N-[2-oxyphenyl-2-(3-)哚)ethyl]ammonium trifluoroacetate (55.2 mg, 0.204 mmol) was reacted at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Flash column chromatography, dichloromethane: ethyl acetate = 1:3 (v / v) eluted to give 3'-N-[N-(2-oxyphenyl-2-(3-indole)ethyl) Carbamoyl] staurosporine (171) 36.0 mg, yield 79%. [α] _D ¹⁸ +105 (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 12.08 (d, J = 2.5 Hz, 1H, NH), 9.29 (d, J = 8.0 Hz) , 1H, ArH), 8.61 (s, 1H, NH), 8.49 (d, J = 3.1 Hz, 1H, ArH), 8.21 (d, J = 7.7 Hz, 1H, ArH), 8.04 (d, J = 7.9) Hz, 1H, ArH), 7.96 (d, J = 8.4 Hz, 1H, ArH), 7.70 (d, J = 8.4 Hz, 2H, ArH), 7.52 (d, J = 8.0 Hz, 1H, ArH), 7.48 (t, J = 7.6 Hz, 2H, ArH), 7.35 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH), 7.24 (t, J = 7.3 Hz, 1H, ArH), 7.21 (t, J = 7.6 Hz, 1H, ArH), 7.02 (t, J = 7.6 Hz, 1H, H-1'), 6.84 (t, J = 5.3 Hz, 1H, NH), 5.00 (s, 2H, H-7), 4.85 (d, J = 12.5 Hz, 1H, H-3'), 4.50 (d, J = 5.7 Hz, 2H, H-3"), 4.24 (brs, 1H) , H-4'), 2.84 (s, 3H, 3'-NCH ₃ ), 2.75 (s, 3H, 4'-OCH ₃ ), 2.61-2.65 (m, 1H, H-2'a), 2.30 ( s, 3H, 6'-CH ₃ ), 2.22 (ddd, J = 12.5, 12.5, 7.0 Hz, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 192.0, 172.2, 158.4, 139.2, 136.6, 136.5, 133.5, 132.9, 129.4, 125.9, 125.7, 125.6, 1 25.2×2, 124.0, 123.1, 122.8, 122.0, 121.6, 121.4, 120.5, 119.7, 119.5, 115.4, 114.3×2, 114.0, 112.4, 109.3, 95.1, 84.1, 82.7, 60.6, 49.1, 47.6, 45.7, 30.0, 29.7, 27.6; HRESI-MS m/z 667.2661 [M+H] ⁺ (calcd for C ₃₉ H ₃₅ N ₆ O ₅ , 667.2669).

Preparation of Compound 172

The imidazolium salt of the imidazole moiety of compound 167 (48.0 mg, 0.068 mmol) was dissolved in 2 mL DMF, and triethylamine (47.2 [mu]L, 0.34 mmol) and N-(2-oxophenyl-2-phenylethyl) were added. Ammonium chloride (34.9 mg, 0.204 mmol) was reacted at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Flash column chromatography, dichloromethane: ethyl acetate = 2:1 (v / v) eluted to give 3'-N-[N-(2-oxyphenyl-2-phenethyl)carbamoyl] cross Sporamide (172) 20.0 mg, yield 47.0%. [α] _D ¹⁸ +174 (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.28 (d, J = 7.9 Hz, 1H, ArH), 8.60 (s, 1H, NH) , 8.04 (t, J = 8.2 Hz, 1H, ArH), 8.03 (d, J = 8.1 Hz, 1H, ArH), 8.03 (d, J = 8.3 Hz, 1H, ArH), 7.96 (t, J = 8.7) Hz, 1H, ArH), 7.70 (d, J = 8.5 Hz, 1H, ArH), 7.68 (t, J = 7.6 Hz, 1H, ArH), 7.58 (d, J = 7.6 Hz, 1H, ArH), 7.57 (d, J = 7.6 Hz, 1H, ArH), 7.49 (t, J = 6.8 Hz, 2H, ArH), 7.35 (t, J = 7.5 Hz, 1H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH), 7.02 (t, J = 7.6 Hz, 1H, H-1'), 6.90 (t, J = 5.3 Hz, 1H, NH), 5.00 (s, 2H, H-7), 4.81 (d , J = 12.5 Hz, 1H, H-3'), 4.59 (d, J = 5.6 Hz, 2H, H-3"), 4.20 (brs, 1H, H-4'), 2.83 (s, 3H, 3) '-NCH ₃ ), 2.72 (s, 3H, 4'-OCH ₃ ), 2.59-2.63 (m, 1H, H-2'a), 2.29 (s, 3H, 6'-CH ₃ ), 2.20 (ddd , J = 12.5, 12.5, 6.9 Hz, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 196.9, 172.2, 158.2, 139.2, 136.5, 135.4, 133.6, 132.9, 129.3, 129.0×2, 128.0×2, 125.8, 125.6, 125.1×2, 123.9, 12 2.8, 121.6, 120.5, 119.7, 119.5, 115.4, 114.3, 114.0, 109.2, 95.0, 84.0, 82.6, 60.6, 49.1, 47.7, 45.6, 30.0, 29.7, 27.5; HRESI-MS m/z 628.2568 [M+H] ⁺ (calcd for C ₃₇ H ₃₄ N ₅ O ₅ , 628.2560).

Preparation of Compound 173

According to the preparation of Compound 169, (15.0mg, 0.021mmol) and DMF, Et ₃ N and 4- (2-piperazin-ethyl) morpholine by the iodide salt of the imidazole moiety of compound 168. Semi-preparative HPLC separation, elution with MeOH:H ₂ O = 4:1 (v/v) afforded 3'-N-[4-(2-(4-morpholine)ethyl)piperazine thioformyl] cross Sporamide (173) 8.0 mg, yield 47.1%. [α] _D ²⁰ +101° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.29 (d, J = 7.9 Hz, 1H, ArH), 8.52 (s, 1H, NH) ), 8.03 (d, J = 7.8 Hz, 1H, ArH), 7.94 (d, J = 8.6 Hz, 1H, ArH), 7.56 (d, J = 8.2 Hz, 1H, ArH), 7.48 (t, J = 7.8 Hz, 1H, ArH), 7.45 (t, J = 7.8 Hz, 1H, ArH), 7.34 (t, J = 7.4 Hz, 1H, ArH), 7.27 (t, J = 7.5 Hz, 1H, ArH), 7.00 (dd, J=8.7, 5.5 Hz, 1H, H-1'), 5.23-5.27 (m, 1H, H-3'), 4.98 (s, 2H, H-7), 4.68 (brs, 1H, H-4'), 3.91 (brs, 4H, morpholine-N(CH ₂ -C H ₂ ) ₂ O), 3.50-3.75 (m, 16H, -N(C H ₂ -C H ₂ ) ₂ N,piperazine -C H ₂ -C H ₂ -morpholine, -N(C H ₂ -CH ₂ ) ₂ O), 3.01 (s, 3H, 3'-NCH ₃ ), 2.94 - 2.98 (m, 1H, H-2' a), 2.56 (s, 3H, 4'-OCH ₃ ), 2.44 (s, 3H, 6'-CH ₃ ), 2.37-2.41 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 193.5, 172.0, 138.5, 136.2, 132.4, 129.6, 125.8, 125.5, 125.2, 125.1, 123.9, 122.7, 121.4, 120.4, 119.5, 119.4, 115.2, 114.2, 113.1, 108.8, 94.9, 83.0 , 82.2, 63.3 × 2, 59.9 56.3,51.6 × 2,51.0 × 2,49.8 × 2,49.2,47.6,45.5,37.3,29.2,27.6; ESI-MS m / z 708.4 [M + H] +.

Preparation of Compound 174

According to the preparation of Compound 169, (18.0mg, 0.021mmol) and DMF, Et ₃ N and trimethylamine synthesized from 2,6-difluorophenyl methyl iodide salt of the imidazole moiety of compound 168. Flash column chromatography, dichloromethane: ethyl acetate = 4:1 (v/v) eluted to give 3'-N-[N-(2,6-difluorobenzyl)aminothioformyl] cross Sporamide (174) 8.0 mg, yield 48.0%. [α] _D ²⁰ +128° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.27 (d, J = 7.9 Hz, 1H, ArH), 8.60 (s, 1H, NH) ), 8.04 (d, J = 7.8 Hz, 1H, ArH), 7.99 (d, J = 8.5 Hz, 1H, ArH), 7.93 (t, J = 4.2 Hz, 1H, NH), 7.70 (d, J = 8.3 Hz, 1H, ArH), 7.47 (t, J = 7.6 Hz, 2H, ArH), 7.39 (m, 1H, ArH), 7.35 (t, J = 7.5 Hz, 1H, ArH), 7.29 (t, J) = 7.5 Hz, 1H, ArH), 7.06 (t, J = 7.7 Hz, 2H, ArH), 7.03-7.06 (m, 1H, H-1'), 5.90 (d, J = 12.5 Hz, 1H, H- 3'), 4.99 (s, 2H, H-7), 4.75-4.88 (m, 2H, H-3"), 4.47 (brs, 1H, H-4'), 2.82 (s, 3H, 3'- NCH ₃ ), 2.74 (s, 3H, 4'-OCH ₃ ), 2.66-2.71 (m, 1H, H-2'a), 2.35 (s, 3H, 6'-CH ₃ ), 2.20-2.27 (m , 1H, H-2'b); ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 181.6, 172.0, 161.3 × 2 (dd, ¹ J _CF = 247.7 Hz, ³ J _CF = 8.2 Hz), 139.0, 136.4, 132.8, 129.6 (t, ³ J _CF = 10.5 Hz), 129.2, 125.7, 125.4, 125.1, 125.0, 123.8, 122.7, 121.5, 120.4, 119.6, 119.4, 115.3, 114.3 (t, ² J _CF =18.1 Hz ), 114.2, 113.9, 111.5 × 2(d, ² J _CF = 20.1 Hz), 109.2, 95.0, 83.0, 82.4, 60.3, 54.2, 45.5, 38.3, 32.9, 29.5, 27.7; ESI-MS m/z 652.3 [M+H] ⁺ .

Preparation of Compound 175

According to the preparation of Compound 169, (, 0.021mmol 18.0mg) and DMF, Et synthesized from methyl iodide and methylamine salt of the imidazole moiety of Compound 168 ₃ N 3- chloro-4-fluorophenyl. Flash column chromatography, dichloromethane: ethyl acetate = 4:1 (v/v) eluted to give 3'-N-[N-(3-chloro-4-fluorobenzyl)aminothioformyl] Staurosporine (175) 8.0 mg, yield 48.0%. [α] _D ²⁰ +166° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.28 (d, J = 7.9 Hz, 1H, ArH), 8.62 (s, 1H, NH) ), 8.26 (t, J = 4.5 Hz, 1H, NH), 8.05 (d, J = 7.8 Hz, 1H, ArH), 8.00 (d, J = 8.5 Hz, 1H, ArH), 7.71 (d, J = 8.2 Hz, 1H, ArH), 7.51 (d, J = 7.1 Hz, 1H, ArH), 7.48 (t, J = 7.7 Hz, 2H, ArH), 7.38 (t, J = 7.8 Hz, 1H, ArH), 7.32-7.37 (m, 2H, ArH), 7.29 (t, J = 7.5 Hz, 1H, ArH), 7.07 (t, J = 7.6 Hz, 1H, H-1'), 5.92 (d, J = 12.9 Hz) , 1H, H-3'), 5.00 (s, 2H, H-7), 4.79-4.87 (m, 2H, H-3"), 4.50 (brs, 1H, H-4'), 2.88 (s, 3H,3'-NCH ₃ ), 2.79 (s,3H,4'-OCH ₃ ), 2.68-2.72 (m,1H,H-2'a), 2.36 (s,3H,6'-CH ₃ ), 2.26 (ddd, J = 12.9, 12.9, 6.9 Hz, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 182.1, 172.0, 156.1 (d, ¹ J _CF = 244.8 Hz) , 139.1, 137.8, 136.4, 132.8, 129.2, 129.1 (d, ³ J _CF = 7.4 Hz), 127.9 (d, ³ J _CF = 7.4 Hz), 125.7, 125.4, 125.1, 125.0, 123.8, 122.7, 121.5, 120.4 , 119.6, 119.4, 119.0 (d, ² J _CF = 17.8 Hz), 116.6 (d, ² J _CF = 20.9 Hz), 115.3, 114.2, 113.9, 109.2, 95.0, 83.0, 82.4, 60.4, 54.4, 45.5, 35.9, 33.0, 29.6, 27.7; ESI-MS m /z 668.4/670.4[M+H] ⁺ .

Preparation of Compound 176

Compound 169 was prepared according to the method, the iodide salt (18.0mg, 0.021mmol) imidazole moiety of Compound 168 with DMF, Et ₃ N, and the synthesis of 2-chloro-6-fluoro-phenethylamine. Flash column chromatography, dichloromethane: ethyl acetate = 4:1 (v / v) eluted to give 3'-N-[N-(2-chloro-6-fluorophenethyl)aminothioformyl] Staurosporine (176) 6.0 mg, yield 35.0%. [α] _D ²⁰ +96° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.29 (d, J = 8.0 Hz, 1H, ArH), 8.60 (s, 1H, NH) ), 8.06 (d, J = 7.7 Hz, 1H, ArH), 8.01 (d, J = 8.5 Hz, 1H, ArH), 7.75 (t, J = 5.4 Hz, 1H, NH), 7.69 (d, J = 8.3 Hz, 1H, ArH), 7.48 (m, 1H, ArH), 7.36 (t, J = 7.5 Hz, 1H, ArH), 7.27-7.32 (m, 3H, ArH), 7.15-7.19 (m, 1H, ArH), 7.06 (dd, J = 8.3, 6.6 Hz, 1H, H-1'), 5.98 (d, J = 12.1 Hz, 1H, H-3'), 5.00 (s, 2H, H-7), 4.39 (brs, 1H, H-4'), 3.89-3.96 (m, 1H, H-3" a), 3.70-3.76 (m, 1H, H-3"b), 3.03-3.16 (m, 2H, H-4"), 2.77 (s, 3H, 3'-NCH ₃ ), 2.68 (s, 3H, 4'-OCH ₃ ), 2.67-2.71 (m, 1H, H-2'a), 2.40 (s) , 3H,6'-CH ₃ ), 2.25 (ddd, J = 12.9, 12.9, 6.4 Hz, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 181.8, 172.0, 161.4 (d, ¹ J _CF = 246.5 Hz), 138.9, 136.3, 134.7 (d, ³ J _CF = 6.6 Hz), 132.7, 129.3, 128.9 (d, ³ J _CF = 10.4 Hz), 125.7, 125.4 × 2, 125.3 (d, ² J _CF = 25.6 Hz), 125.1 × ² , 123.8, 122.7, 121.5, 12 0.4, 119.5, 119.4, 115.2, 114.3 (d, ² J _CF = 22.3 Hz), 114.2, 113.7, 109.2, 95.0, 83.3, 82.4, 60.2, 53.9, 45.5, 43.9, 32.6, 29.4, 27.7, 26.2; MS m/z 682.4/684.4 [M+H] ⁺ .

Preparation of Compound 177

Compound 169 was prepared according to the method, the iodide salt (18.0mg, 0.021mmol) imidazole moiety of Compound 168 with DMF, Et ₃ N and 2-m-trifluoromethyl phenylethylamine synthesis. Flash column chromatography, dichloromethane: ethyl acetate = 4:1 (v/v) eluted to give 3'-N-[N-(2-m-trifluoromethylphenethyl)aminothioformyl] Staurosporine (177) 6.0 mg, yield 35.0%. [α] _D ²⁰ +132° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.29 (d, J = 8.0 Hz, 1H, ArH), 8.61 (s, 1H, NH) ), 8.05 (d, J = 7.8 Hz, 1H, ArH), 7.99 (d, J = 8.5 Hz, 1H, ArH), 7.71 (t, J = 5.6 Hz, 1H, NH), 7.70 (d, J) = 8.0 Hz, 1H, ArH), 7.52 - 7.58 (m, 4H, ArH), 7.48 (t, J = 6.3 Hz, 2H, ArH), 7.36 (t, J = 7.4 Hz, 1H, ArH), 7.30 ( t, J = 7.5 Hz, 1H, ArH), 7.06 (t, J = 7.3 Hz, 1H, H-1'), 5.95 (d, J = 12.4 Hz, 1H, H-3'), 5.00 (s, 2H, H-7), 4.44 (brs, 1H, H-4'), 3.86-3.92 (m, 1H, H-3" a), 3.74-3.80 (m, 1H, H-3"b), 3.98 -3.10 (m, 2H, H-4"), 2.76 (s, 3H, 3'-NCH ₃ ), 2.70 (s, 3H, 4'-OCH ₃ ), 2.65-2.70 (m, 1H, H-2 'a), 2.38 (s, 3H, 6'-CH ₃ ), 2.24 (ddd, J = 12.9, 12.9, 6.8 Hz, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) Δ181.5, 172.0, 141.0, 139.0, 136.3, 133.1, 132.8, 129.4, 129.3 (q, ² J _CF = 27.2 Hz), 128.9, 125.7, 125.4, 125.2 (q, ³ J _CF = 5.0 Hz), 125.1, 125.0, 123.8, 123.4 (q, ¹ J _CF = 274.7 Hz) 122.9 (q, ³ J _CF = 5.7 Hz), 122.7, 121.5, 120.4, 119.5, 119.4, 115.3, 114.2, 113.8, 109.2, 95.0, 83.1, 82.4, 60.2, 53.9, 46.4, 45.4, 34.3, 32.6, 29.5, 27.6; MS m/z 698.3 [M+H] ⁺ .

Preparation of Compound 178

According to the preparation method of Compound 169, the imidazolium salt of the imidazole moiety of Compound 168 (18.0 mg, 0.021 mmol) was synthesized with DMF, Et ₃ N and benzylamine. Flash column chromatography, dichloromethane: ethyl acetate = 1:1 (v / v) eluted to give 9.0 mg of 3'-N-(N-benzylaminothiocarbamoyl) staurosporine (178). The yield was 73.2%. [α] _D ²⁰ +54° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.28 (d, J = 8.0 Hz, 1H, ArH), 8.58 (s, 1H, NH) ), 8.20 (brs, 1H, NH), 8.05 (d, J = 7.9 Hz, 1H, ArH), 8.00 (d, J = 8.3 Hz, 1H, ArH), 7.70 (d, J = 8.0 Hz, 1H, ArH), 7.48 (t, J = 7.8 Hz, 2H, ArH), 7.36 (t, J = 7.8 Hz, 1H, ArH), 7.28-7.33 (m, 5H, ArH), 7.21 - 7.25 (m, 1H, ArH), 7.06 (t, J = 7.4 Hz, H-1'), 5.98 (d, J = 13.5 Hz, 1H, H-3'), 5.00 (s, 2H, H-7), 4.89 (d, J = 5.6 Hz, 2H, H-3"), 4.49 (s, 1H, H-4'), 2.89 (s, 3H, 3'-NCH ₃ ), 2.72 (s, 3H, 4'-OCH ₃ ) , 2.68-2.74 (m, 1H, H-2'a), 2.38 (s, 3H, 6'-CH ₃ ), 2.24-2.30 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 182.2, 172.0, 139.8, 139.0, 136.4, 132.8, 129.2, 128.2 × 2, 127.2 × 2, 126.6, 125.7, 125.4, 125.1, 125.1, 123.8, 122.7, 121.5, 120.4, 119.6, 119.4 , 115.3, 114.2, 113.8, 109.2, 95.1, 83.2, 82.5, 60.4, 54.3, 48.4, 45.6, 32.9, 29.5, 27.8; ESI-MS m/z 616.3 [M+H] ⁺ .

Preparation of Compound 179

Compound 169 was prepared according to the method, the iodide salt (18.0mg, 0.021mmol) imidazole moiety of Compound 168 with DMF, Et ₃ N and Synthesis methoxybenzylamine. Flash column chromatography, dichloromethane: ethyl acetate = 1:1 (v/v) eluted to give 3'-N-[N-(4-methoxybenzyl)aminothioformyl] The base (179) was 9.0 mg, and the yield was 69.8%. [α] _D ²⁰ +40° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.28 (d, J = 7.9 Hz, 1H, ArH), 8.58 (s, 1H, NH) ), 8.13 (t, J = 5.4 Hz, 1H, NH), 8.05 (d, J = 7.8 Hz, 1H, ArH), 7.99 (d, J = 8.5 Hz, 1H, ArH), 7.69 (d, J = 8.2 Hz, 1H, ArH), 7.48 (t, J = 7.5 Hz, 2H, ArH), 7.35 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.6 Hz, 1H, ArH), 7.27 (d, J = 8.6 Hz, 2H, ArH), 7.05 (t, J = 7.5 Hz, 1H, H-1'), 6.88 (d, J = 8.6 Hz, 2H, ArH), 5.00 (s, 2H) , H-7), 4.80 (d, J = 12.5 Hz, 1H, H-3'), 4.47 (brs, 1H, H-4'), 3.73 (brs, 2H, H-3"), 2.86 (s , 3H, 3'-NCH ₃ ), 2.74 (s, 3H, 4'-OCH ₃ ), 2.67-2.73 (m, 1H, H-2'a), 2.37 (s, 3H, 6'-CH ₃ ) , 2.23-2.29 (m, 1H, H-2'b); ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 182.0, 172.0, 158.2, 139.0, 136.4, 132.8, 131.7, 129.3, 128.6 × 2, 125.7 , 125.5, 125.2, 125.1, 123.9, 122.7, 121.5, 120.4, 119.6, 119.4, 115.3, 114.2, 113.8, 113.6 × 2, 109.2, 95.1, 83.2, 82.5, 60.4, 55.2, 54.3, 47.9, 45.6, 32.8, 2 9.5, 27.8; ESI-MS m/z 646.3 [M+H] ⁺ .

Preparation of Compound 180

According to the preparation method of Compound 171, the imidazolium salt of the imidazole moiety of Compound 167 (15.0 mg, 0.021 mmol) was synthesized with DMF, Et ₃ N and 4-(2-piperazinethyl)morpholine. Flash column chromatography, dichloromethane: ethyl acetate = 1:3 (v/v) eluted to give 3'-N-[4-(2-(4-morpholine)ethyl)piperazine formyl] cross Sporamide (180) 8.0 mg, yield 55.1%. [α] _D ²⁰ +72° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.29 (d, J = 7.9 Hz, 1H, ArH), 8.58 (s, 1H, NH) ), 8.06 (d, J = 7.5 Hz, 1H, ArH), 8.00 (d, J = 8.5 Hz, 1H, ArH), 7.59 (d, J = 8.3 Hz, 1H, ArH), 7.50 (t, J = 7.6 Hz, 1H, ArH), 7.47 (t, J = 7.7 Hz, 1H, ArH), 7.36 (t, J = 7.5 Hz, 1H, ArH), 7.30 (t, J = 7.7 Hz, 1H, ArH), 6.97 (dd, J=8.8, 5.2 Hz, 1H, H-1'), 5.00 (s, 2H, H-7), 4.44 (ddd, J = 13.0, 4.9, 2.2 Hz, 1H, H-3') , 4.36 (brs, 1H, H-4'), 3.79 (brs, 4H, -N(CH ₂ -C H ₂ ) ₂ O), 3.33 (brs, 8H, -N(C H ₂ -C H ₂ ) ₂ N), 3.14 (brs, 8H, piperazine-C H ₂ -C H ₂ -morpholine, -N(C H ₂ -CH ₂ ) ₂ O), 2.78-2.83 (m, 1H, H-2'a) , 2.71 (s, 3H, 3'-NCH ₃ ), 2.55 (s, 3H, 4'-OCH ₃ ), 2.39 (s, 3H, 6'-CH ₃ ), 2.28-2.34 (m, 1H, H- 2'b); ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 172.4, 163.6, 139.0, 136.7, 133.0, 130.0, 126.1, 126.0, 125.8, 125.6, 124.2, 123.1, 122.0, 120.9, 119.9, 119.8, 115.4, 114.5, 113.7, 109.4, 95.1, 84.4 82.7,64.2 × 2,60.3,52.3 × 2,51.8 × 2,51.3,51.1,50.6,45.9,44.4 × 2,33.4,29.4,27.8; ESI-MS m / z 708.4 [M + H] +.

Preparation of Compound 181

The production method of compound 171, (15.0mg, 0.021mmol) and DMF, Et ₃ N and trimethylamine synthesized from 2,6-difluorophenyl methyl iodide salt of the imidazole moiety of compound 167. Flash column chromatography, dichloromethane: ethyl acetate = 1:2 (v / v) eluted to give 3'-N-[N-(2,6-difluorobenzyl)carbamoyl]sporine (181) 9.0 mg, yield 67.6%. [α] _D ²⁰ +48° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.28 (d, J = 7.9 Hz, 1H, ArH), 8.60 (s, 1H, NH) ), 8.04 (d, J = 7.7 Hz, 1H, ArH), 7.95 (d, J = 8.6 Hz, 1H, ArH), 7.65 (d, J = 8.2 Hz, 1H, ArH), 7.45-7.48 (m, 2H, ArH), 7.33-7.38 (m, 2H, ArH), 7.29 (t, J = 7.5 Hz, 1H, ArH), 7.06 (t, J = 7.8 Hz, 2H, ArH), 6.98 (t, J = 7.6 Hz, 1H, H-1'), 6.93 (t, J = 4.6 Hz, 1H, NH), 4.99 (s, 2H, H-7), 4.82 (d, J = 12.7 Hz, 1H, H-3 '), 4.34 - 4.44 (m, 2H, H-3"), 4.21 (brs, 1H, H-4'), 2.73 (s, 3H, 3'-NCH ₃ ), 2.61 (s, 3H, 4' -OCH ₃ ), 2.55-2.60 (m, 1H, H-2'a), 2.31 (s, 3H, 6'-CH ₃ ), 2.16 (ddd, J = 13.0, 13.0, 6.7 Hz, 1H, H- 2'b); ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 172.1, 161.3 × 2 (dd, ¹ J _CF = 247.5 Hz, ³ J _CF = 9.2 Hz), 157.7, 139.1, 136.4, 132.8, 129.5 (t, ³ J _CF = 11.0 Hz), 129.3, 125.8, 125.5, 125.2, 125.1, 123.8, 122.7, 121.5, 120.4, 119.6, 119.4, 115.6 (t, ² J _CF = 18.1 Hz), 115.3, 114.2, 113.8 , 111.5 × 2 (d, ² J _CF =19.9 Hz), 109.1, 95.0, 84.0, 82.5, 60.3, 48.9, 45.6, 32.7, 29.9, 29.5, 27.5; ESI-MS m/z 636.5 [M+H] ⁺ .

Preparation of Compound 182

According to the preparation method of Compound 169, the imidazolium salt of the imidazole moiety of Compound 168 (50.0 mg, 0.070 mmol) was synthesized with DMF, Et ₃ N and 2S-hydroxy-1-propylamine. Semi-preparative HPLC separation, elution with MeOH:H ₂ O = 4:1 (v/v) afforded 3'-N-[N-(2S-hydroxypropyl)aminothioformyl]sporine (182) 12.0 Mg, yield 28.5%. [α] _D ²⁰ +31° (c 0.07, CHCl ₃ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.30 (d, J = 8.0 Hz, 1H, ArH), 8.59 (s, 1H, NH) ), 8.05 (d, J = 7.8 Hz, 1H, ArH), 8.00 (d, J = 8.5 Hz, 1H, ArH), 7.69 (d, J = 8.2 Hz, 1H, ArH), 7.48 (t, J = 7.6 Hz, 1H, ArH), 7.47 (d, J = 7.6 Hz, 1H, ArH), 7.35 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH), 7.06 (t, J = 7.6 Hz, 1H, H-1'), 5.99 (d, J = 12.8 Hz, 1H, H-3'), 5.01 (s, 2H, H-7), 4.75 (s, 1H) , OH), 4.45 (s, 1H, H-4'), 3.97 (brs, 1H, H-4"), 3.61-3.66 (m, 1H, H-3" a), 3.40-3.46 (m, 1H) , H-3"b), 2.85 (s, 3H, 3'-NCH ₃ ), 2.71 (s, 3H, 4'-OCH ₃ ), 2.66-2.71 (m, 1H, H-2'a), 2.39 (s, 3H, 6'-CH ₃ ), 2.24-2.30 (m, 1H, H-2'b), 1.07 (d, J = 6.2 Hz, 3H, H-5"); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 181.7, 172.0, 138.9, 136.3, 132.7, 129.3, 125.7, 125.4, 125.1 × 2, 123.8, 122.7, 121.5, 120.4, 119.5, 119.4, 115.3, 114.2, 113.7, 109.1, 95.0, 83.3 , 82.4, 64.6, 60.2, 54.0, 53.1, 45.5, 32 .5, 29.4, 27.7, 21.2; ESI-MS m/z 584.7 [M+H] ⁺ .

Preparation of Compound 183

Fradcarbazole C (16.0 mg, 0.032 mmol) was dissolved in 5 mL of methanol, and 100.0 μL of triethylamine and 100 mg of hydroxylamine hydrochloride were added and allowed to react at room temperature overnight. The reaction mixture was diluted with ethyl acetate. Semi-preparative HPLC separation, elution with MeOH:H ₂ O=9:1 (v/v) afforded 12.0 mg of 3'-N-(N-hydroxyaminoiminomethyl)sporine (183), yield 71.8%. . [α] _D ²⁰ +15° (c 0.07, MeOH); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 10.32 (s, 1H, NH), 9.27 (d, J = 7.9 Hz, 1H, ArH) , 8.63 (s, 1H, NH), 8.30 (s, 1H, NH), 8.05 (d, J = 7.8 Hz, 1H, ArH), 7.94 (d, J = 8.5 Hz, 1H, ArH), 7.70 (d , J = 8.2 Hz, 1H, ArH), 7.50 (t, J = 7.3 Hz, 2H, ArH), 7.36 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH), 6.98 (t, J = 7.6 Hz, 1H, H-1'), 5.00 (s, 2H, H-7), 4.47 (brs, 1H, H-3'), 4.18 (brs, 1H, H) -4'), 3.16 (s, 1H, OH), 2.93 (s, 3H, 3'-NCH ₃ ), 2.73 (s, 3H, 4'-OCH ₃ ), 2.70-2.75 (m, 1H, H- 2'a), 2.35 (s, 3H, 6'-CH ₃ ), 2.27-2.32 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 172.0, 158.6, 139.4, 136.4, 132.9, 128.9, 125.8, 125.5, 125.1, 124.9, 123.9, 122.7, 121.5, 120.5, 119.7, 119.5, 115.4, 114.4, 114.3, 109.1, 95.0, 82.5, 82.0, 60.6, 52.0, 45.6, 31.6, 29.4, 27.2; ESI-MS m/z 525.2 [M+H] ⁺ .

Preparation of Compound 184

The staurosporine (46.6 mg, 0.1 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of a catalytic amount of DMAP, dicyclohexylcarbodiimide (24.7 mg, 0.12 mmol) and chlorambucil (36.4 mg, The mixture was reacted for 2 hours at room temperature, poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate and evaporated. 3'-N-[4-[4-(N,N-bis(2-chloroethyl)amino)phenyl]butyryl]crosporin (184) 60.1 mg, yield 80%. [α] _D ²⁰ +99° (c 0.07, CHCl ₃ ); ¹ H NMR (CD ₃ OD) δ 9.27 (d, J = 8.0 Hz, 1H, ArH), 7.85 (d, J = 7.7 Hz, 1H) , ArH), 7.73 (d, J = 8.5 Hz, 1H, ArH), 7.40-7.44 (m, 2H, ArH), 7.27-7.30 (m, 2H, ArH), 7.22 (d, J = 8.1 Hz, 1H) , ArH), 7.03 (d, J = 8.5 Hz, 2H, ArH), 6.65 (dd, J = 9.0, 4.9 Hz, 1H, H-1'), 6.59 (d, J = 8.5 Hz, 2H, ArH) , 5.10-5.14 (m, 1H, H-3'), 4.86-4.95 (m, 2H, H-7), 3.95 (brs, 1H, H-4'), 3.65 (t, J = 6.7 Hz, 4H , -N(C H ₂ -CH ₂ Cl) ₂ ), 3.57 (t, J = 6.7 Hz, 4H, -N(CH ₂ -C H ₂ Cl) ₂ ), 2.76 (s, 3H, 3'-NCH ₃ ), 2.56 (t, J = 7.9 Hz, 2H, H-2"), 2.43 (s, 3H, 4'-OCH ₃ ), 2.43-2.49 (m, 1H, H-2'a), 2.39 ( s, 3H, 6'-CH ₃ ), 2.30-2.33 (m, 1H, H-2'b), 1.90 (t, J = 7.8 Hz, 2H, H-4"), 1.53-1.56 (m, 2H) , H-3"); ¹³ C NMR (CD ₃ OD) δ 175.0, 174.5, 144.9, 139.1, 137.0, 133.1, 131.0, 130.8, 130.0 × 2, 126.7, 126.6, 125.9, 125.5, 124.9, 123.8, 121.8 , 121.0, 120.3, 119.2, 116.4, 114.9, 112.9, 112.6 × 2, 108.4, 95. 1,85.1,82.9,60.7,53.9×2,48.9,46.5,40.9×2,34.1,31.7,29.3,28.4,26.0,25.3; ESI-MS m/z 752.2/754.3/756.2 [M+H] ⁺ .

Preparation of Compound 185

i) Preparation of N-benzyloxymethyl-2-(3-indole)-3-bromomaleimide (185a)

2,3-Dibromomaleimide (2.55 g, 10.0 mmol) was placed in a 100 mL three-necked flask, dissolved in 30 mL of dry DMF, protected with nitrogen, reduced to 0 ° C, and sodium hydride (480 mg). 12 mmol, 60% by mass dispersed in paraffin). After 1 h, 10 mL of dry DMF-dissolved chloromethylbenzyl ether (2.08 mL, 15 mmol) was added and the mixture was warmed to room temperature for 2 h. After the temperature was lowered to 0 ° C, the reaction was terminated by adding 20 mL of a saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated, and then purified by column chromatography, petroleum ether: ethyl acetate = 50:1 (v/v The compound N-benzyloxymethyl-2,3-dibromomaleimide 3.55 g was eluted in a yield of 94%. ESIMS m/z 395.4, 397.3, 399.5 [M+Na] ⁺ . Magnesium wire (432 mg, 18.0 mmol) was placed in a 100 mL dry three-necked flask, 4 mL of dry tetrahydrofuran was added, and the mixture was replaced with argon. After the introduction of ethyl bromide (1.35 mL, 18.0 mmol), the mixture was stirred at room temperature for 15 min and then raised to 40. The reaction was carried out at ° C for 30 min. The crucible (2.11 g, 18.0 mmol) was introduced through a catheter and reacted for 1 h. After that, N-benzyloxymethyl-2,3-dibromomaleimide (3.29 g, 8.9 mmol) was added, and the mixture was reacted at room temperature for 4 h. The reaction was quenched by the addition of 20 mL of a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated, and then purified by column chromatography eluting with petroleum ether: ethyl acetate = 4:1 (v/v) 185a 3.46 g, yield 94%. ¹ H-NMR (600MHz, DMSO-d ₆ ) δ 8.93 (brs, 1H, NH), 8.03 (t, J = 7.8 Hz, 1H, ArH), 7.99 (t, J = 7.8 Hz, 1H, ArH) , 7.44 (d, J = 7.8 Hz, 1H, ArH), 7.37 (s, 1H, ArH), 7.27-7.36 (m, 5H, ArH), 7.25 (d, J = 7.8 Hz, 1H, ArH), 5.17 (s, 2H, PhCH ₂ O CH ₂ N), 4.67 (s, 2H, Ph CH ₂ OCH ₂ N); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 168.8, 166.2, 137.8, 137.8, 136.6, 131.5, 128.2 × 2, 127.6, 127.5 × 2, 124.5, 122.6, 122.4, 120.6, 114.1, 112.4, 103.7, 70.5, 67.5; ESIMS m/z 433.0, 435.0 [M+Na] ⁺ .

Ii) Preparation of N-benzyloxymethyl-2-(1-tert-butoxycarbonyl-3-indole)-3-bromomaleimide (185b)

Compound 185a (3.15 g, 8.39 mmol) was dissolved in 50 mL of tetrahydrofuran, and 3.81 mL of tert-butoxy anhydride (ie di-tert-butyldicarbonate Boc ₂ O, 16.78 mmol) and 100 mg of p-dimethylaminopyridine were added and reacted at room temperature. 4h. After direct concentration and column chromatography, petroleum ether: ethyl acetate = 20:1 (v/v) eluted to yield compound 185b 3.90 g, yield 91%. ¹ H-NMR (600MHz, CDCl ₃ ) δ 8.23 (s, 1H, arH), 8.20 (d, J = 8.2 Hz, 1H, ArH), 7.80 (dd, J = 7.3, 8.2 Hz, 1H, ArH) , 7.41 (t, J = 7.3, 1H, ArH), 7.26 (d, J = 7.3 Hz, 1H, ArH), 7.30-7.36 (m, 5H, ArH), 5.17 (s, 2H, PhCH ₂ O CH ₂ N), 4.68 (s, 2H, Ph CH ₂ OCH ₂ N), 1.71 (s, 9H, -C(CH ₃ ) ₃ ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 168.2, 165.6, 148.9, 137.4 , 136.7, 135.4, 130.0, 128.5 × 2, 127.9, 127.6 × 2, 126.8, 125.4, 123.3, 122.5, 120.9, 115.4, 108.4, 85.2, 71.9, 67.8, 28.1 × 3; ESIMS m/z 511.2, 513.0 [M +H] ⁺ .

Iii) Preparation of N-benzyloxymethyl-2-(1-tert-butoxycarbonyl-3-indole)-3-(3-indole)maleimide (185c)

Magnesium wire (366.7 mg, 15.32 mmol) was placed in a 100 mL dry three-necked flask, 4 mL of dry tetrahydrofuran was added, and the mixture was replaced with argon. After the introduction of ethyl bromide (1.15 mL, 15.32 mmol), the mixture was stirred at room temperature for 15 min. The reaction was carried out at 40 ° C for 30 min. The crucible (1.8 g, 15.32 mmol) was introduced through a catheter and reacted for 1 h. Compound 185b (3.9 g, 7.66 mmol) was then added and allowed to react at room temperature for 4 h. The reaction was quenched by the addition of 20 mL of a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated, and then purified by column chromatography eluting with petroleum ether: ethyl acetate = 4:1 (v/v) 185c (3.98 g, yield 95%). ¹ H-NMR (600MHz, CDCl ₃ ) δ 8.60 (brs, 1H, NH), 8.19 (d, J = 7.8 Hz, 1H, ArH), 8.09 (s, 1H, ArH), 8.02 (s, 1H, ArH); 7.81 (t, J = 7.8 Hz, 1H, ArH); 7.29 to 7.41 (m, 5H, ArH); 7.16 (dt, J = 8.0, 3.0 Hz, 1H, ArH), 7.10 (t, J = 8.2 Hz, 1H, ArH), 7.05 (d, J = 7.8, 1H, ArH), 6.77 to 6.83 (m, 3H, ArH), 5.23 (s, 2H, PhCH ₂ O CH ₂ N), 4.72 (s, 2H,Ph CH ₂ OCH ₂ N), 1.68 (s, 9H, -C(CH ₃ ) ₃ ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.4, 171.2, 149.2, 137.6, 136.0, 135.0, 131.6, 129.9, 128.6, 128.4 × 2, 128.0, 127.8, 127.7 × 2, 125.3, 124.6, 124.4, 122.7, 122.6, 121.7, 121.6, 120.7, 115.0, 111.6, 110.7, 106.4, 84.5, 71.7, 67.3, 28.1 × 3; ESIMS m/z 546.2 [MH] ^- .

Iv) Preparation of 6-O-triisopropylsilyl-D-glucoenose (185d)

0.206 mL of perchloric acid was slowly added to 40 mL of acetic anhydride, stirred at 40 ° C for 30 min, then the temperature was lowered to 30 ° C, and 10 g of D-glucose was slowly added and stirred for 30 min. The reaction solution was cooled to 10 ° C, 3.1 g of red phosphorus, 5.8 mL of liquid bromine and 3.6 mL of water were slowly added in sequence, and then the temperature was raised to 30 ° C and stirring was continued for 2 hours. The reaction mixture was quenched with 50 mL of EtOAc. The concentrate was dissolved in 50 mL of ethyl acetate, and the temperature was lowered to 0 ° C. 16.1 g of zinc powder, 212 mg of CuSO ₄ ·5H ₂ O and 1.06 g of sodium acetate were mixed with 130 mL of 60% aqueous acetic acid, and added to the reaction liquid. After reacting at 0 ° C for 1 h, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered, and then ethyl acetate was evaporated. (v/v) elution gave 10.4 g of 3,4,6-tris(O-acetyl)-D-glucoenose (yield 68% in two steps), ESI MS m/z 273.2 [M+H] ⁺ . 5.2 g of 3,4,6-tris(O-acetyl)-D-glucoenose (19.1 mmol) was dissolved in 100 mL of methanol, 300 mg of sodium methoxide was added, and the reaction was carried out for 1 hour at room temperature, and the pH of the reaction solution was adjusted to 7 with a cationic resin. filtered and concentrated, pressure column chromatography (ethyl acetate) to give 2.5 g of D-glucal, yield 90%; ESIMS m / z 147.1 [m + H] +. 5.6 g of D-glucoenose (38.4 mmol) was dissolved in 100 mL of pyridine, cooled to 0 ° C, 11.34 mL of triisopropylchlorosilane (54.22 mmol) and 15.6 g of imidazole (230.4 mmol) were added and reacted at room temperature for 2 h with 50 mL of ice. The mixture was quenched with EtOAc (EtOAc). The rate is 46%. ¹ H-NMR (600MHz, CDCl ₃ ) δ 6.30 (d, J = 6.0, 1H, H-1), 4.72-4.74 (m, 1H, H-2), 4.27-4.29 (m, 1H, H- 4), 4.09 (dd, J = 12.0, 4.8 Hz, 1H, H-6a), 3.98 (dd, J = 12.00, 4.8 Hz, 1H, H-6b), 3.85 (dd, J = 6.0, 3.6 Hz, 1H, H-3), 3.81-3.84 (1H, m, H-5), 3.35 (brs, 1H, OH), 2.35 (brs, 1H, OH), 1.12-1.16 (m, 3H, -Si(C) H (CH ₃ ) ₂ ) ₃ ), 1.08 (d, J = 6.0 Hz, 18H, -Si(CH(C H ₃ ) ₂ ) ₃ ). ESIMS m/z 303.2 [M+H] ⁺ .

v) Preparation of Compound 185e

1.43g of compound 185d (4.7mmol) was placed in a 100mL three-necked flask, protected with argon, dissolved in 20mL of dry dichloromethane, reduced to -5 ° C, added sodium hydride (751mg, 31.3mmol, 60%) Disperse in paraffin), raise to 0 ° C for 20 min, slowly increase to room temperature for 1.5 h. The mixture was again reduced to -5 ° C, and trichloroacetonitrile (5.59 mL, 56.4 mmol) was dissolved in 10 mL of dry dichloromethane. The reaction solution was cooled to -78 ° C, boron trifluoride diethyl ether (17.3 mL, 141 mmol) was added dropwise, and the mixture was reacted at this temperature for 6 h, then 20 mL of saturated sodium bicarbonate solution was added, slowly warmed to room temperature, and extracted with dichloromethane. After drying over anhydrous sodium sulfate, the mixture was concentrated and evaporated tolulululululululululululululululululululu [α] _D ²⁰ +121° (c 2.02, CH ₂ Cl ₂ ); ¹ H-NMR (600MHz, CDCl ₃ ) δ 7.02 (brs, 1H, NH), 6.45 (d, J = 4.8, 1H, H-1), 4.92-4.94 (m, 1H, H-2), 4.46-4.48 (m, 1H, H-4), 4.16-4.18 (m, 1H, H-3), 4.06 (dd, J = 12.0, 5.4 Hz, 1H, H-6a), 3.96 (dd, J = 12.0, 5.4 Hz, 1H, H-6b), 3.84 - 3.86 (m, 1H, H-5), 3.17 (brs, 1H, OH ), 1.12-1.16 (m, 3H, -Si(C H (CH ₃ ) ₂ ) ₃ ), 1.08 (d, J = 6.0 Hz, 18H, -Si(CH(C H ₃ ) ₂ ) ₃ ); ¹³ C-NMR (150 MHz, CDCl ₃ ): δ 162.3, 145.8, 97.3, 92.6, 74.5, 67.1, 63.4, 45.8, 17.8 × ₃ , 11.7×6; ESIMS m/z 444.0 [MH] ^- .

Vi) Preparation of compound 185f

1.1 g of compound 185e (2.4 mmol) was dissolved in 30 mL of dichloromethane, reduced to 0 ° C, sodium hydride (244 m g, 10.2 mmol, 60% disperse in paraffin) was added, and the mixture was slowly warmed to room temperature for 3 h, then reduced to The reaction was quenched by the addition of water, and the mixture was combined with methylene chloride. EtOAc (EtOAc) The rate is 75%. [α] _D ²⁰ +108° (c 3.00, CH ₂ Cl ₂ ); ¹ H-NMR (500MHz, CDCl ₃ ) δ 6.58 (d, J = 7.2, 1H, H-1), 5.96 (brs, 1H) , NH), 4.85-4.87 (m, 2H, H-2 and H-4), 4.34 (1H, dd, J = 7.2, 4.2 Hz, H-3), 4.06 (dd, J = 10.2, 3.6 Hz, 1H , H-6a), 3.96 (dd, J = 10.2, 3.6 Hz, 1H, H-6b), 3.80-3.82 (m, 1H, H-5), 1.12-1.16 (m, 3H, -Si (C H (CH ₃ ) ₂ ) ₃ ), 1.08 (d, J = 6.0 Hz, 18H, -Si(CH(C H ₃ ) ₂ ) ₃ ); ¹³ C-NMR (125 MHz, CDCl ₃ ): δ 158.7, 147.2 , 98.5, 74.0, 71.0, 61.7, 46.1, 17.9 × 3, 11.9 × 6; ESIMS m/z 326.0 [MH] ^- .

Vii) Preparation of Compound 185g

595 mg of compound 185f (1.8 mmol) was transferred to a two-necked flask, dissolved in 20 mL of dichloromethane, lowered to -5 ° C, sodium hydride (218 mg, 9.1 mmol, 60% dispersed in paraffin) was added, and the reaction was allowed to rise to room temperature. After the hour, the dimethyl sulfate (0.87mL, 9.1mmol) was added, and the reaction was carried out for 16h at room temperature. The reaction was terminated by adding ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography, petroleum ether: acetic acid The ester = 6:1 (v/v) eluted to give 185 g of a compound (yield: 97%). [α] _D ²⁰ +75° (c 1.00, CH ₂ Cl ₂ ); ¹ H-NMR (500MHz, CDCl ₃ ) δ 6.68 (d, J = 7.2 Hz, 1H, H-1), 4.93 (1H, Dd, J = 7.2, 4.8 Hz, H-2), 4.74 - 4.76 (m, 1H, H-4), 4.09 (dd, J = 13.2, 3.6 Hz, 1H, H-6a), 4.07-4.10 (m , 1H, H-3), 3.98 (dd, J = 13.2, 3.6 Hz, 1H, H-6b), 3.61-3.63 (m, 1H, H-5), 2.84 (s, 3H, N-CH ₃ ) , 1.12-1.16 (m, 3H, -Si(C H (CH ₃ ) ₂ ) ₃ ), 1.08 (d, J = 6.0 Hz, 18H, -Si(CH(C H ₃ ) ₂ ) ₃ ); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 157.3, 148.5, 96.0, 74.4, 67.7, 61.6, 51.0, 28.8, 17.9 × ₃ , 11.9 × 6. ESIMS m/z 342.2 [M+H] ⁺ .

Viii) Preparation of mixture 185h

415 mg of the compound 185 g (1.22 mmol) was dissolved in 20 mL of tetrahydrofuran, and the mixture was cooled to 0 ° C, and 20 mL of water-dissolved Mercury acetate (781 mg, 2.44 mmol) was added. The solution turned yellow and was allowed to react to room temperature for 2 h. After dropping to 0 ° C, 60 mL of water was added, and then sodium borohydride (371 mg, 9.76 mmol) was slowly added, which was formed in black. After 10 min, carbon dioxide was passed until the solution was neutral. After suction filtration, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography, eluting with petroleum ether: ethyl acetate=2:1 (v/v) to give a pair of undivided C-1 The epimer was 185 h (337 mg, yield 77%). ¹ H-NMR (600MHz, CDCl ₃ ) δ 5.31 (m, 1H, H-1), 5.15 (dd, J = 6.0, 4.8 Hz, 1H, H-1), 4.63 (t, J = 8.4 Hz, 1H, H-4), 4.57 (t, J = 8.4 Hz, 1H, H-4), 4.03-3.97 (m, 2H, H-6a), 3.91-3.94 (m, 2H, H-6b), 3.86 -3.90 (m, 2H, H-3), 3.78-3.81 (m, 1H, H-5), 3.58-3.61 (m, 1H, H-5), 2.86 (s, 3H, N-CH ₃ ), 2.83(s,3H,N-CH ₃ ),2.22-2.26(m,1H,H-2a),2.04-2.08(m,1H,H-2a),1.96-2.01(m,1H,H-2b) , 1.81 (ddd, J = 13.2, 8.4, 6.0 Hz, 1H, H-2b), 1.07-1.12 (m, 6H, -Si(C H (CH ₃ ) ₂ ) ₃ ), 1.05 (d, J = 7.2 Hz, 36H, -Si(CH(C H ₃ ) ₂ ) ₃ ); ¹³ C-NMR (150MHz, CDCl ₃ ) δ 158.4, 158.0, 91.7, 90.6, 74.7, 69.0, 68.8, 68.1, 63.2, 63.1, 53.9, 52.9, 31.2, 29.9, 29.2, 28.9, 18.0 x 3, 17.8 x 3, 12.4 x 6, 12.0 x 6; ESIMS m/z 360.2 [M+H] ⁺ .

Ix) Preparation of Compounds 185i and 185j

712.5 mg of compound 185c (1.253 mmol) was placed in a 250 mL three-neck reaction flask, dissolved in 20 mL of dry tetrahydrofuran, argon-protected, cooled to -78 ° C, and 10 mL of dry tetrahydrofuran-dissolved triphenylphosphine (655 mg, 2.515 mmol) was added. After that, 0.5 mL of DIAD (2.515 mmol) was dissolved in 10 mL of tetrahydrofuran, and the reaction solution was added dropwise. After reacting at -78 ° C for 1 h, 10 mL of tetrahydrofuran-dissolved compound 185 h (300 mg, 0.835 mmol) was added, and the reaction was carried out at -78 ° C for 2 h. The reaction was carried out overnight at room temperature. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, and the mixture was evaporated to ethylamine. 210 mg of compound 185j (yield 28%).

185i: [α] _D ²⁰ +14.1° (c 0.59, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 8.15 (d, J = 7.8 Hz, 1H, ArH), 8.11 (s, 1H) , ArH), 7.77 (s, 1H, ArH), 7.40-7.10 (m, 9H, ArH), 6.86 (t, J = 7.8 Hz, 1H, ArH), 6.80-6.77 (m, 2H, ArH), 5.72 (dd, J = 10.8, 1.8 Hz, 1H, H-1'), 5.23 (s, 2H, PhCH ₂ O CH ₂ N), 4.59 (dd, J = 9.0, 7.2 Hz, 1H, H-4') , 4.72 (s, 2H, Ph CH ₂ OCH ₂ N), 4.06-4.08 (m, 1H, H-3'), 4.01 (dd, J = 12.0, 1.8 Hz, 1H, H-6'a), 3.95 (dd, J = 12.0, 2.4 Hz, 1H, H-6'b), 3.82-3.84 (m, 1H, H-5'), 2.87 (s, 3H, N-CH ₃ ), 2.39-2.41 (m , 1H, H-2'a), 2.27-2.30 (m, 1H, H-2'b), 1.69 (s, 9H, -C(C H ₃ ) ₃ ), 1.04-1.10 (m, 3H, - Si(C H (CH ₃ ) ₂ ) ₃ ), 1.02 (d, J = 6.0 Hz, -Si(CH(C H ₃ ) ₂ ) ₃ ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.1, 171.0 , 158.5, 149.1, 137.6, 135.7, 135.1, 130.5, 129.0, 128.6, 128.3 × 2, 127.7, 127.6 × 2, 126.5, 125.7, 124.6, 123.2, 122.4 × 2, 121.7, 121.5, 121.0, 115.1, 110.6, 110.4 , 107.0, 84.6, 79.4, 78.3 , 71.7, 67.3, 67.0, 62.9, 55.7, 29.5, 29.3, 28.1 × 3, 17.8 × 3, 11.8 × 6; ESIMS m/z 889.6 [M+H] ⁺ , 911.6 [M+Na] ⁺ ; HR-ESIMS m/z 889.4195 [M+H] ⁺ (calcd for C ₅₀ H ₆₁ N ₄ O ₉ Si, 889.4208).

185j: [α] _D ²⁰ -9.1° (c 0.10, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 8.15 (d, J = 7.2 Hz, 1H, ArH), 8.13 (s, 1H) , ArH), 7.63 (s, 1H, ArH), 7.39-7.42 (m, 3H, ArH), 7.28-7.32 (m, 3H, ArH), 7.22-7.25 (m, 1H, ArH), 7.15-7.19 ( m, 2H, ArH), 6.95 (t, J = 7.2 Hz, 1H, ArH), 6.78 (t, J = 7.8 Hz, 1H, ArH), 6.70 (d, J = 7.8 Hz, 1H, ArH), 6.10 (dd, J = 10.7, 4.5 Hz, 1H, H-1'), 5.23 (s, 2H, PhCH ₂ O CH ₂ N), 4.75 (t, J = 7.8 Hz, 1H, H-4'), 4.72 (s, 2H, Ph CH ₂ OCH ₂ N), 3.99-4.03 (m, 1H, H-3'), 3.85-3.93 (m, 2H, H-6'), 3.80-3.83 (m, 1H, H -5'), 2.87 (s, 3H, N-CH ₃ ), 2.40-2.44 (m, 1H, H-2'a), 2.06-2.11 (m, 1H, H-2'b), 1.69 (s , 9H, -C(C H ₃ ) ₃ ), 1.06-1.12 (m, 3H, -Si(C H (CH ₃ ) ₂ ) ₃ ), 1.02 (d, J = 6.0 Hz, 18H, -Si(CH) (C H ₃ ) ₂ ) ₃ ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.2, 171.0, 157.3, 149.2, 137.8, 136.0, 135.4, 130.8, 129.4, 128.5 × ₃ , 127.9, 127.8 × 2, 127.3 , 126.7, 126.0, 124.7, 123.3, 122.5 × 2, 122.0, 121.7, 115 .4,110.6,110.4,107.1,84.8,78.6,72.5,71.8,68.8,67.4,63.6,53.7,29.8,29.2,28.2×3,18.0×3,11.9×6.ESIMS m/z 889.5[M+H ] ⁺ .

x) Preparation of compounds 185l and 188b

Compound 185i (311 mg, 0.350 mmol) was dissolved in 40 mL of toluene. After bringing back to room temperature, filtered over silica gel, eluting with ethyl acetate to give compound 185k (262mg, yield 95%); HR-ESIMS m / z 787.3499 [MH] - (calcd for C 45 H 51 N 4 O 7 Si, 787.3572 ). 188a (180 mg, yield 96%) was prepared in the same manner as the compound 185j (210 mg), HR-ESIMS m/z 787.3496 [MH] ^- (calcd for C ₄₅ H ₅₁ N ₄ O ₇ Si,787.3572 ). 262 mg of the compound 185k (0.333 mmol) was dissolved in 30 mL of tetrahydrofuran, and the mixture was reduced to 0 ° C, and tetrabutylammonium fluoride (1.0 mL, 1.0 mmol, 1.0 M tetrahydrofuran solution) was added to deprotect the group. After washing with water, the ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated. 188b (136 mg, yield 95%) was obtained in the same manner using 188a (179 mg).

185l: [α] _D ²⁰ -2.5° (c 0.01, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.40 (s, 1H, NH), 7.67 (d, J = 3.0 Hz, 1H) , ArH), 7.59 (s, 1H, ArH), 7.36-7.37 (m, 2H, ArH), 7.27-7.32 (m, 4H, ArH), 7.22-7.24 (m, 1H, ArH), 7.17-7.17 ( m, 2H, ArH), 7.04 (t, J = 7.8 Hz, 1H, ArH), 6.87-6.90 (m, 2H, ArH), 6.76 (t, J = 7.8 Hz, 1H, ArH), 5.67 (dd, J = 10.2, 1.2 Hz, 1H, H-1'), 5.14 (s, 2H, PhCH ₂ O CH ₂ N), 4.67 (s, 2H, Ph CH ₂ OCH ₂ N), 4.30 (t, J = 7.8) Hz, 1H, H-4'), 3.86-3.87 (m, 1H, H-3'), 3.81 (dd, J = 12.00, 2.4 Hz, 1H, H-6'a), 3.72-3.75 (m, 1H, H-5'), 3.64 (dd, J = 12.0, 2.4 Hz, 1H, H-6'b), 2.77 (s, 3H, N-CH ₃ ), 2.24 - 2.29 (m, 1H, H- 2'a), 2.12-2.16 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 171.7, 171.6, 158.6, 137.7, 136.3, 136.0, 129.7, 129.2, 128.5 × 2,128.0,127.8×2,127.7,126.6,126.5,124.9,123.3,122.9,122.6,122.2,121.5,120.4,111.8,110.0,107.6,106.5,78.9,77.6,71.7,67.2,62.1,60. 5,55.7,29.6,28.8; HR-ESIMS m/z 631.2216 [MH] ^- (calcd for C ₃₆ H ₃₁ N ₄ O ₇ , 631.2193).

188b: [α] _D ²⁰ -10° (c 0.10, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 8.90 (s, 1H, NH), 7.80 (m, 1H, ArH), 7.46 -7.21 (m, 10H, ArH), 7.80 (d, J = 3.0 Hz, 1H, ArH), 7.45-7.46 (m, 2H, ArH), 7.38-7.40 (m, 3H, ArH), 7.34-7.36 ( m,1H,ArH), 7.29-7.32 (m, 2H, ArH), 7.20-7.25 (m, 2H, ArH), 7.07-7.10 (m, 1H, ArH), 7.01 (t, J = 7.2 Hz, 1H) , ArH), 6.72-6.74 (m, 2H, ArH), 6.05 (dd, J = 10.4, 5.4 Hz, 1H, H-1'), 5.14 (s, 2H, PhCH ₂ O CH ₂ N), 4.71 ( s, 2H, Ph CH ₂ OCH ₂ N), 4.60 (t, J = 8.4 Hz, 1H, H-4'), 3.92-3.97 (brs, 1H, H-3'), 3.69 (dd, J = 12.0) , 2.4 Hz, 1H, H-6'a), 3.60 (dd, J = 12.0, 4.2 Hz, 1H, H-6'b), 3.52-3.54 (m, 1H, H-5'), 2.80 (s , 3H, N-CH ₃ ), 2.39-2.43 (m, 1H, H-2'a), 2.25-2.30 (m, 1H, H-2'b); ¹³ C NMR (150MHz, CDCl ₃ ): δ171 .7×2,157.3,137.8,136.4,135.8,129.7,129.1,128.5×2,127.9,127.8×2,127.7,127.0,126.8,124.3,123.3,123.0,122.7,122.3,121.6,120.4,112.0,110.1 , 107.6, 106. 5,78.4,76.5,71.8,68.9,62.1,59.2,53.2,29.8,28.9;HR-ESIMS m/z 631.2218[MH] ^- (C ₃₆ H ₃₁ N ₄ O ₇ , calculated 631.2193).

Xi) Preparation of Compounds 185m and 188c

30 mg of compound 185 l (0.047 mmol) was dissolved in 1750 mL of acetone, catalyzed by 3 mg of iodine, and irradiated by a 250-W high-pressure mercury lamp for 12 h. The solution changed from red to green fluorescence, concentrated, and then added with saturated sodium thiosulfate solution and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was evaporated, evaporated, mjjjjjjjjj Compound 188c (70 mg, yield 51%) was obtained in the same manner from Compound 188b (136 mg).

185m: [α] _D ²⁰ +71.7° (c 0.05, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 11.0 (s, 1H, NH), 9.23 (d, J = 7.8 Hz, 1H) , ArH), 8.77 (d, J = 7.8 Hz, 1H, ArH), 7.54 - 7.57 (m, 1H, ArH), 7.46-7.48 (m, 2H, ArH), 7.39-7.41 (m, 2H, ArH) , 7.35-7.38 (m, 2H, ArH), 7.28-7.31 (m, 3H, ArH), 6.97 (d, J = 8.4 Hz, 1H, ArH), 6.16 (dd, J = 9.0, 1.8 Hz, 1H, H-1'), 5.18 (t, J = 7.8 Hz, 1H, H-4'), 5.13-5.17 (m, 2H, PhCH ₂ O CH ₂ N), 4.80 (s, 2H, Ph CH ₂ OCH ₂ N), 4.40 (d, J = 12.0 Hz, 1H, H-3'), 4.10-4.13 (m, 2H, H-6'), 3.35-3.38 (m, 1H, H-5'), 2.91 ( s, 3H, N-CH ₃ ), 2.29-2.34 (m, 1H, H-2'a), 1.98-2.01 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, CDCl ₃ ): Δ169.5,169.0,158.7,140.7,139.7,137.5,129.7,128.6×2,128.3,128.1×3,128.0,127.6,127.2,126.2,125.0,122.7,121.7,120.7,120.5,119.5,118.4,118.1, 111.2, 108.6, 79.3, 78.3, 71.9, 66.8, 66.2, 60.9, 56.2, 29.7, 29.0; ESIMS m/z 629.3 [MH] ^- .

188c: [α] _D ²⁰ -25.7° (c 0.16, CH ₂ Cl ₂ ); ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.4 (s, 1H, NH), 9.22 (d, J = 7.8 Hz) , 1H, ArH), 9.10 (d, J = 7.8 Hz, 1H, ArH), 7.95 (d, J = 8.4 Hz, 1H, ArH), 7.79 (d, J = 8.4 Hz, 1H, ArH), 7.73 7.74 (m, 1H, ArH), 7.67-7.68 (m, 1H, ArH), 7.61-7.64 (m, 2H, ArH), 7.46 (t, J = 7.8 Hz, 1H, ArH), 7.40 (t, J = 7.2 Hz, 1H, ArH), 7.32 (d, J = 7.2 Hz, 1H, ArH), 7.31 (t, J = 7.8 Hz, 1H, ArH), 7.24 (t, J = 7.2 Hz, 1H, ArH) , 6.94 (dd, J = 11.4, 4.8 Hz, 1H, H-1'), 5.45 (t, J = 5.4 Hz, 1H, H-4'), 5.20 (s, 2H, PhCH ₂ O CH ₂ N) , 4.83-4.85 (m, 1H, H-3'), 4.77-4.79 (m, 1H, OH), 4.69 (s, 2H, Ph CH ₂ OCH ₂ N), 4.44 - 4.48 (m, 1H, H- 5'), 3.90-3.96 (m, 2H, H-6'), 2.67 (s, 3H, N-CH ₃ ), 2.48-2.52 (m, 1H, H-2'a), 2.43-2.46 (m) , 1H, H-2'b); ¹³ C NMR (150MHz, DMSO-d ₆ ) δ169.6,169.5,157.2,141.2,140.0,138.4,132.3,132.1,129.3×2,129.1,128.8×2,128.1 ×3,128.0,125.3,124.9,122.6,122.0,121.512 1.3, 120.3, 118.8, 118.2, 112.8, 79.5, 75.1, 70.1, 67.3, 65.6, 61.4, 53.4, 29.6, 29.0; ESIMS m/z 629.2 [MH] ^- .

Xii) Preparation of Compounds 185o and 188e

307 mg of triphenylphosphine (1.171 mmol) and 159 mg of imidazole (2.342 mmol) were dissolved in 20 mL of dichloromethane, reduced to 0 ° C, and 287 mg of iodine (2.342 mmol) was added and stirred for 1 h. The compound 185 m (123 mg, 0.195 mmol) was dissolved in dichloromethane (20 mL), and slowly added to the reaction mixture, and the mixture was allowed to react at room temperature for 6 h. After being reduced to 0 ° C, it was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography, eluting with petroleum ether: ethyl acetate=2:1 (v/v) to give compound 185n (80mg, yield 56%); HR-ESIMS m / z 741.1221 [m + H] + (C 36 H 30 N 4 O 6 I, calc. 741.1210). Compound 188d (54 mg, yield 65%) was obtained in the same manner using compound 188c (70 mg), HR-ESIMS m/z 741.1225 [M+H] ⁺ (calcd for C ₃₆ H ₃₀ N ₄ O ₆ I, 741.1210). 30 mg of the compound 185n (0.041 mmol) was dissolved in 10 mL of tetrahydrofuran, and the mixture was dropped to 0 ° C, and 0.4 mL of DBU (2.67 mmol) was added thereto, and the reaction was carried out at 0 ° C for 1 h, and the reaction was carried out at 40 ° C for 1 h. The reaction mixture was diluted with EtOAc. EtOAc EtOAc EtOAc. Compound 188e (40 mg, yield 90%) was obtained in the same manner from Compound 188d (54 mg).

185o: [α] _D ²⁰ +141.3° (c 0.34, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.1 (s, 1H, NH), 9.22 (d, J = 7.8 Hz) , 1H, ArH), 9.08 (d, J = 8.4 Hz, 1H, ArH), 7.86 (d, J = 8.4 Hz, 1H, ArH), 7.71 (d, J = 8.4 Hz, 1H, ArH), 7.60- 7.63 (m, 2H, ArH), 7.47 (d, J = 7.2 Hz, 1H, ArH), 7.41 - 7.36 (m, 3H, ArH), 7.31 (t, J = 7.2 Hz, 2H, ArH), 7.24 ( t, J = 7.2 Hz, 1H, ArH), 7.20 (dd, J = 12.0, 2.4 Hz, 1H, H-1'), 5.40 (d, J = 9.6, 1H, H-4'), 5.15-5.19 (m, 2H, PhCH ₂ O CH ₂ N), 5.07-5.09 (m, 2H, H-6'), 4.67 (s, 2H, Ph CH ₂ OCH ₂ N), 4.33-4.36 (m, 1H, H -3'), 2.69 (s, 3H, N-CH ₃ ), 2.44-2.51 (m, 1H, H-2'a), 2.10-2.14 (m, 1H, H-2'b); ¹³ C NMR (150MHz, DMSO-d ₆ ) δ169.6,169.5,157.0,152.9,142.2,140.6,138.4,129.8,129.4,128.8×2,128.2,128.1×3,128.0,125.6,124.9,123.7,122.5,121.8, 121.4, 120.5, 119.2, 118.8, 118.4, 113.7, 112.9, 101.2, 81.0, 71.4, 70.9, 67.3, 53.1, 28.8, 28.0; ESIMS m/z 611.3 [MH] ^- .

188e: [α] _D ²⁰ -21.4° (c 0.7, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.62 (s, 1H, NH), 9.27 (d, J = 8.4 Hz, 1H) , ArH), 9.10 (d, J = 8.4 Hz, 1H, ArH), 7.62 - 7.66 (m, 1H, ArH), 7.51 - 7.56 (m, 2H, ArH), 7.38-7.46 (m, 4H, ArH) , 7.29-7.36 (m, 3H, ArH), 7.22 (t, J = 7.2 Hz, 1H, ArH), 6.27 (dd, J = 11.4, 2.4 Hz, 1H, H-1'), 5.43 (d, J =2.0 Hz, 1H, H-6'a), 5.30 (d, J = 2.0 Hz, 1H, H-6'b), 5.16-5.22 (m, 2H, PhCH ₂ O CH ₂ N), 5.07 (d , 1H, J = 7.2 Hz, H-4'), 4.73 (s, 2H, Ph CH ₂ OCH ₂ N), 4.14 - 4.18 (m, 1H, H-3'), 2.76 (s, 3H, N- CH ₃ ), 2.47-2.53 (m, 1H, H-2'a), 2.38-2.42 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.4, 169.2, 156.7 , 151.3, 140.8, 139.7, 137.7, 129.3, 128.5 × 2, 128.2, 128.0 × 3, 127.8, 127.5, 126.3, 125.3, 122.6, 122.2, 121.9, 121.6, 121.0, 119.5, 119.3, 118.8, 111.9, 108.7, 100.1 , 81.9, 71.6, 70.1, 66.9, 54.4, 32.8, 29.2; ESIMS m/z 611.4 [MH] ^- .

Xiii) Preparation of Compounds 185p and 188f

30 mg of compound 1850 (0.05 mmol) was dissolved in tetrahydrofuran / methanol 10 mL / 1 mL, cooled to 0 ° C, 22 mg of potassium t-butoxide (0.2 mmol) was added, the solution changed from yellow to red, slowly warmed to room temperature, stirred for 2 h, added 38 mg of iodine (0.15 mmol), the solution darkened and reacted overnight. The mixture was cooled to 0 ° C, poured into saturated sodium thiosulfate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography, petroleum ether: ethyl acetate = 1:2 (v/v) The product was eluted 185p (20 mg, yield 54%). Compound 188f (20 mg, yield 42%) was obtained in the same manner from Compound 188e (40 mg).

185p: [α] _D ²⁰ +45.9° (c 0.05, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.28 (d, J = 7.8 Hz, 1H, ArH), 9.03 (d) , J = 7.8 Hz, 1H, ArH), 8.11 (d, J = 9.0 Hz, 1H, ArH), 8.07 (d, J = 8.4 Hz, 1H, ArH), 7.70 - 7.66 (m, 2H, ArH), 7.56 (t, J = 7.2 Hz, 1H, ArH), 7.47 (t, J = 7.2 Hz, 1H, ArH), 7.36-7.40 (m, 2H, ArH), 7.31 (t, J = 7.2 Hz, 2H, ArH), 7.24 (t, J = 7.2 Hz, 1H, ArH), 7.08 (dd, J = 9.6, 7.2 Hz, 1H, H-1'), 5.91 (d, J = 12.0 Hz, 1H, H-4) '), 5.26 (s, 2H, PhCH ₂ O CH ₂ ), 4.70 (s, 2H, Ph CH ₂ OCH ₂ ), 4.63 (1H, d, J = 12.6 Hz, H-6'a), 4.48-4.51 (m, 1H, H-3'), 3.79 (1H, d, J = 12.6 Hz, H-6'b), 2.99 (s, 3H, N-CH ₃ ), 2.58-2.63 (m, 1H, H -2'a), 2.36-2.42 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 169.2, 169.0, 156.7, 138.1, 135.5, 132.4, 131.0, 128.9, 128.5×2, 127.9, 127.8×2, 127.5, 126.2, 126.0, 125.4, 122.7, 121.9, 121.4, 119.7, 119.1, 118.5, 117.9, 116.7, 112.5, 108.0, 93.5, 77.7, 71.8, 70.5, 67.0 53.2,29.8,27.8,9.3; ESIMS m / z 761.1 [ M + Na] +.

188f: [α] _D ²⁰ -73.4° (c 0.21, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.41 (d, J = 8.4 Hz, 1H, ArH), 9.23 (d, J) = 8.4 Hz, 1H, ArH), 8.05 (d, J = 8.4 Hz, 1H, ArH), 7.61 (t, J = 7.2 Hz, 2H, ArH), 7.49 (t, J = 7.2 Hz, 1H, ArH) , 7.43-7.46 (m, 4H, ArH), 7.30 (t, J = 7.2 Hz, 2H, ArH), 7.22 (t, J = 7.2 Hz, 1H, ArH), 6.63 (dd, J = 10.8, 6.0 Hz) , 1H, H-1'), 5.34 (s, 2H, PhCH ₂ O. CH ₂ ), 5.31 (d, J = 9.0 Hz, 1H, H-4'), 4.73 (s, 2H, Ph CH ₂ OCH ₂ ), 4.52 (d, J = 11.4 Hz, 1H, H-6'a), 4.27-4.32 (m, 1H, H-3'), 3.96 (1H, d, J = 11.4 Hz, H-6' b), 2.84-2.89 (m, 1H, H-2'a), 2.80 (s, 3H, N-CH ₃ ), 2.41-2.48 (m, 1H, H-2'b); ¹³ C NMR (150 MHz , CDCl ₃ ) δ 169.4, 169.2, 155.4, 141.7, 137.8 × 2, 131.8, 128.7, 128.4 × 2, 128.0, 127.9 × 2, 127.8, 127.6, 126.6, 126.1, 125.1, 122.8, 122.3, 121.7, 121.3, 119.7×2, 115.0, 114.1, 107.1, 92.2, 79.4, 73.5, 71.6, 67.0, 53.4, 29.5, 29.0, 14.2; ESIMS m/z 761.1 [M+Na] ⁺ .

Vix) Preparation of Compounds 185q and 188g

25 mg of the compound 185p (0.034 mmol) was dissolved in 20 mL of benzene, argon gas, and AIBN (3 mg) and tetrabutyltin hydride (0.1 mL) were added and heated to reflux for 1 h. After concentrating to room temperature, it was concentrated, and purified by column chromatography eluting with EtOAc (EtOAc:EtOAc) Using the compound 188f (20 mg) as a starting material, 188 g (15 mg, yield: 96%) of compound was obtained in the same procedure.

185q: [α] _D ²⁰ +87.3° (c 0.29, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.35 (d, J = 7.2 Hz, 1H, ArH), 9.10 (d, J) = 7.8 Hz, 1H, ArH), 7.64 - 7.57 (m, 3H, ArH), 7.47 - 7.42 (m, 4H, ArH), 7.35 (t, J = 7.2 Hz, 1H, ArH), 7.31 (t, J = 7.8 Hz, 2H, ArH), 7.23 (t, J = 7.2 Hz, 1H, ArH), 6.49 (dd, J = 9.6, 7.2 Hz, 1H, H-1'), 5.63 (d, J = 9.6 Hz) , 1H, H-4'), 5.25-5.33 (m, 2H, PhCH ₂ O CH ₂ ), 4.76 (s, 2H, Ph CH ₂ OCH ₂ ), 4.32-4.35 (m, 1H, H-3') , 3.10 (s, 3H, N-CH ₃ ), 2.69-2.73 (m, 1H, H-2'a), 2.36-2.40 (m, 1H, H-2'b), 1.94 (s, 3H, 6 '-CH ₃ ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.4, 169.2, 157.3, 140.1, 138.1, 137.7, 130.1, 128.9, 128.5 × ₂ , 128.0 × ₂ , 127.8, 127.6, 127.5, 126.7, 126.3 , 124.7, 122.2, 122.1, 121.5, 121.0, 119.6, 118.5, 117.5, 112.3, 107.8, 94.0, 77.2, 71.7, 71.4, 66.9, 52.7, 29.6, 26.2, 24.6; ESIMS m/z 613.5 [M+H] ⁺ .

188g: [α] _D ²⁰ -24.0° (c 0.19, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.40 (d, J = 7.8 Hz, 1H, ArH), 9.24 (d, J) = 7.8 Hz, 1H, ArH), 8.09 (d, J = 7.8 Hz, 1H, ArH), 7.72 - 7.74 (m, 1H, ArH), 7.59 - 7.62 (m, 2H, ArH), 7.53 - 7.55 (m , 1H, ArH), 7.43-7.47 (m, 3H, ArH), 7.31 (t, J = 7.8 Hz, 2H, ArH), 7.25 (t, J = 7.2 Hz, 1H, ArH), 6.59 (dd, J = 9.6, 6.6 Hz, 1H, H-1'), 5.37 (s, 2H, PhCH ₂ O CH ₂ ), 5.11 (d, J = 8.4 Hz, 1H, H-4'), 4.77 (s, 2H, Ph CH ₂ OCH ₂ ), 4.26-4.31 (m, 1H, H-3'), 2.79-2.85 (m, 1H, H-2'a), 2.77 (s, 3H, N-CH ₃ ), 2.42 2.48 (m, 1H, H-2'b), 2.08 (s, 3H, 6'-CH ₃ ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.5, 169.3, 155.8, 142.1, 137.7×2, 131.0 , 128.9, 128.7, 128.4 × 2, 127.9 × 2, 127.8, 127.7, 127.6, 126.6, 125.8, 124.6, 122.3, 122.2, 121.6, 119.7, 119.5, 116.4, 114.1, 107.5, 93.3, 79.0, 71.9, 71.6, 67.0 , 53.0, 30.0, 29.7, 29.5; ESIMS m/z 635.2 [M+Na] ⁺ .

Xx) Preparation of Compounds 185 and 188

Compound 185q (10 mg, 0.016 mmol) was dissolved in 20 mL of ethyl acetate:methanol =1:1 (v/v). After argon gas, 5 mg of 20% palladium hydroxide carbon was added, followed by hydrogen replacement and overnight reaction. Filtration with silica gel, concentration, semi-preparative HPLC separation, eluting with MeOH:H ₂ O = 9:1 (v/v) to give 4'-O-desmethyl-(4'-O,3'-N)carbonyl- 7-Oxophenyl-3',4'-bis-sporoline (185) 7 mg, yield 89%. The enantio[4'-O-desmethyl-(4'-O,3'-N)carbonyl-7-oxophenyl]aspartate was prepared in the same manner using 188 g (15 mg) of the compound. 188) 11.3 mg, yield 96%.

185: [α] _D ²⁰ +33.5° (c 0.04, CH ₂ Cl ₂ ); ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.2 (s, 1H, NH), 9.22 (d, J = 7.8 Hz) , 1H, ArH), 9.00 (d, J = 7.8 Hz, 1H, ArH), 8.08 (d, J = 7.8 Hz, 1H, ArH), 7.95 (d, J = 7.8 Hz, 1H, ArH), 7.65 ( t, J = 7.8 Hz, 1H, ArH), 7.63 (t, J = 7.2 Hz, 1H, ArH), 7.49 (t, J = 7.8 Hz, 1H, ArH), 7.42 (t, J = 7.8 Hz, 1H) , ArH), 6.99 (dd, J = 10.2, 6.6 Hz, 1H, H-1'), 5.76 (d, J = 9.6 Hz, 1H, H-4'), 4.43-4.46 (m, 1H, H- 3'), 2.99 (s, 3H, N-CH ₃ ), 2.80 (ddd, J = 9.6, 6.0, 2.4 Hz, 1H, H-2'a), 2.18 (ddd, J = 9.6, 6.0, 2.4 Hz) , 1H, H-2'b), 1.80 (s, 3H, 6'-CH ₃ ); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.2 × 2, 157.4, 140.4, 135.9, 130.2, 129.1, 127.8, 127.7, 125.8, 125.3, 124.3, 122.0 × 2, 121.5, 121.4, 120.7, 117.6, 116.5, 114.4, 114.3, 94.1, 77.9, 71.4, 52.4, 29.5, 24.9 × 2; ESIMS m/z 491.3 [MH] ⁺ .

188: [a] _D ²⁰ -50.2 ° (c 0.08, CH ₂ Cl ₂ ); ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.23 (d, J = 9.0 Hz, 1H, ArH), 9.04 (d) , J = 10.2 Hz, 1H, ArH), 8.09 (d, J = 9.6 Hz, 1H, ArH), 7.88 (d, J = 10.8 Hz, 1H, ArH), 7.64 (t, J = 9.0 Hz, 1H, ArH), 7.57-7.60 (m, 1H, ArH), 7.41-7.44 (m, 2H, ArH), 7.01 (dd, J = 12.0, 7.2 Hz, 1H, H-1'), 5.33 (d, J = 10.8 Hz, 1H, H-4'), 4.32-4.36 (m, 1H, H-3'), 2.93-2.99 (m, 1H, H-2'a), 2.57 (s, 3H, N-CH ₃ ), 2.04-2.11 (m, 1H, H-2'b), 2.05 (s, 3H, 6'-CH ₃ ); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 170.8, 170.5, 155.7, 141.4 , 137.7, 130.0, 128.2, 127.3, 126.7, 125.0, 124.7, 123.5, 121.3, 121.1 × 2, 121.0, 119.9, 117.5, 116.7, 115.8, 109.4, 92.6, 79.0, 75.3, 52.0, 29.8, 28.3 × 2; m/z 515.2 [M+Na] ⁺ .

Preparation of Compound 186, 187, 189, 190

Compound 185 (15 mg, 0.030 mmol) was dissolved in 10 mL of MeOH. EtOAc (EtOAc, EtOAc. After dilution, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated. The crude product was dissolved in 5 mL of glacial acetic acid, zinc powder (20 mg, 0.32 mmol) was added, and the mixture was heated to 40 ° C for 1.5 hours. After being cooled to room temperature, diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution, anhydrous sulfuric acid. The sodium is dried and concentrated. Semi-preparative HPLC chromatography, acetonitrile:water = 2:3 (v / v) eluted to give 5.2 mg of 4'-O-demethyl-(4'-O,3'-N)carbonyl-3',4' - Bisporin (186) (yield 36%) and 5.2 mg of 5-deoxy-7-oxophenyl-4'-O-desmethyl-(4'-O,3'-N)carbonyl- 3', 4'-Bisphine (187) (yield 36%). Using compound 188 (11 mg) as a starting material, 4.0 mg of enantiomer [4'-O-desmethyl-(4'-O,3'-N)carbonyl]asporine (189) was obtained in the same manner. Rate of 38%) and 4.0 mg of enantiomer [5-deoxy-7-oxophenyl-4'-O-desmethyl-(4'-O,3'-N)carbonyl]aspartate (190) ( The yield was 38%).

186: [α] _D ²⁰ +101.0° (c 0.10, MeOH); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.32 (d, J = 8.0 Hz, 1H, ArH), 7.97 (d, J = 7.7 Hz) , 1H, ArH), 7.68 (d, J = 8.3 Hz, 1H, ArH), 7.56 (m, 1H, ArH), 7.52-7.58 (m, 2H, ArH), 7.43-7.48 (m, 2H, ArH) , 7.38 (t, J = 7.5 Hz, 1H, ArH), 6.57 (s, 1H, NH), 6.49 (dd, J = 9.6, 6.8 Hz, 1H, H-1'), 5.59 (d, J = 9.4 Hz, 1H, H-4'), 5.04 (d, J = 16.7 Hz, 1H, H-7a), 4.92 (d, J = 16.7 Hz, 1H, H-7b), 4.28-4.30 (m, 1H, H-3'), 3.06 (s, 3H, N-CH ₃ ), 2.49-2.55 (m, 1H, H-2'a), 2.22 - 2.28 (m, 1H, H-2'b), 1.94 ( s, 3H, 6'-CH ₃ ); ¹³ C NMR (125MHz, CDCl ₃ ) δ 172.7, 157.4, 139.2, 137.2, 133.2, 129.3, 127.2, 126.3, 125.8 × 2, 125.5, 123.5, 122.1, 121.8, 120.8, 120.3, 117.8, 115.8, 113.0, 107.5, 93.9, 77.2, 71.7, 52.9, 46.1, 29.6, 26.2, 24.7; HR-ESIMS m/z 479.1738 [M+H] ⁺ (calcd for C ₂₈ H ₂₃ N ₄ O ₄ 479.1719).

187: [α] _D ²⁰ +102.6° (c 0.05, MeOH); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.60 (d, J = 7.7 Hz, 1H, ArH), 7.98 (d, J = 7.7 Hz) , 1H, ArH), 7.61 (d, J = 8.4 Hz, 1H, ArH), 7.56 (t, J = 7.7 Hz, 1H, ArH), 7.54 (t, J = 8.4 Hz, 1H, ArH), 7.51 ( d, J = 8.4 Hz, 1H, ArH), 7.44 (t, J = 7.3 Hz, 1H, ArH), 7.40 (t, J = 7.4 Hz, 1H, ArH), 6.50 (dd, J = 9.4, 6.9 Hz) , 1H, H-1'), 6.40 (s, 1H, NH), 5.67 (d, J = 9.5 Hz, 1H, H-4'), 4.99-5.07 (m, 2H, H-5), 4.30 ( d, J = 9.5 Hz, 1H, H-3'), 3.08 (s, 3H, N-CH ₃ ), 2.59 - 2.64 (m, 1H, H-2'a), 2.37 - 2.43 (m, 1H, H-2'b), 1.90 (s, 3H, 6'-CH ₃ ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 173.1, 157.5, 139.3, 137.3, 134.7, 128.2, 127.7, 126.8, 126.2 × 2 , 125.9, 123.2, 122.0, 121.5, 121.1, 119.6, 118.9, 115.3, 111.9, 108.4, 94.0, 77.2, 71.8, 52.9, 45.7, 29.6, 26.4, 24.4; HR-ESIMS m/z 479.1706 [M+H] ⁺ (calcd for C ₂₈ H ₂₃ N ₄ O ₄ , 479.1719).

189: [α] _D ²⁰ -72.8° (c 0.10, MeOH); ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.23 (d, J = 7.6 Hz, 1H, ArH), 8.67 (s, 1H, NH), 8.06 (d, J = 8.5 Hz, 1H, ArH), 8.03 (d, J = 7.4 Hz, 1H, ArH), 7.79 (d, J = 8.4 Hz, 1H, ArH), 7.50-7.53 (m) , 2H, ArH), 7.37-7.40 (m, 1H, ArH), 7.29-7.32 (m, 1H, ArH), 6.96 (dd, J = 9.9, 6.3 Hz, 1H, H-1'), 5.31 (d , J = 8.8 Hz, 1H, H-4'), 4.95-5.03 (m, 2H, H-7), 4.34 (ddd, J = 12.1, 8.8, 5.1 Hz, 1H, H-3'), 2.90- 2.94 (m, 1H, H-2'a), 2.58 (s, 3H, N-CH ₃ ), 2.03 (s, 3H, 6'-CH ₃ ), 1.97-2.02 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.7, 155.7, 140.4, 136.5, 133.0, 128.7, 125.8, 125.6, 125.1, 125.0, 124.7, 122.4, 121.3, 121.1, 120.4, 119.7, 116.7, 115.9,115.5,108.8,92.6,79.2,75.5,52.1,45.4,29.6,28.8,28.3; HR-ESIMS m / z 479.1708 [m + H] + (calcd for C 28 H 23 N 4 O 4 479.1719).

190: [α] _D ²⁰ -75.6 ° (c 0.10, MeOH); ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.51 (d, J = 7.9 Hz, 1H, ArH), 8.62 (s, 1H, NH), 8.10 (d, J = 7.8 Hz, 1H, ArH), 8.01 (d, J = 8.5 Hz, 1H, ArH), 7.84 (d, J = 8.2 Hz, 1H, ArH), 7.56 (t, J) = 7.7 Hz, 1H, ArH), 7.45-7.48 (m, 1H, ArH), 7.38 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH), 6.96 ( Dd, J = 9.8, 6.3 Hz, 1H, H-1'), 5.29 (d, J = 8.7 Hz, 1H, H-4'), 4.96-5.01 (m, 2H, H-5), 4.34 (ddd , J = 12.1, 8.8, 5.1 Hz, 1H, H-3'), 2.91-2.96 (m, 1H, H-2'a), 2.59 (3H, s, N-CH ₃ ), 2.05-2.10 (m , 1H, H-2'b), 1.99 (s, 3H, 6'-CH ₃ ); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.9, 155.8, 140.4, 136.6, 134.4, 127.0, 126.6, 125.70,125.5,125.1×2,122.1,121.9,120.6,120.1,119.4,117.6,116.1,114.3,109.3,92.6,79.2,75.5,52.2,44.9,29.5,28.8,28.3;HR-ESIMS m/z 479.1722[ M+H] ⁺ (calcd for C ₂₈ H ₂₃ N ₄ O ₄ 479.1719).

Preparation of Compound 191

i) Preparation of 6-O-triisopropylsilyl-L-glucoenose (191a)

0.041 mL of perchloric acid was slowly added to 40 mL of acetic anhydride, stirred at 40 ° C for 30 min, then the temperature was lowered to 30 ° C, 2 g of L-glucose was added slowly and stirring was continued for 30 min. The reaction solution was cooled to 10 ° C, and 0.62 g of red phosphorus, 1.16 mL of liquid bromine and 0.72 mL of water were slowly added in that order, and the mixture was heated to 30 ° C and stirred for 2 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The concentrate was dissolved in 50 mL of ethyl acetate, and the temperature was lowered to 0 ° C. 3.22 g of zinc powder, 42.4 mg of CuSO ₄ ·5H ₂ O and 0.21 g of sodium acetate were mixed with 30 mL of a 60% by volume aqueous solution of acetic acid, and then added to the reaction liquid. After reacting at 0 ° C for 1 h, it was allowed to react to room temperature for 1 h. The reaction solution was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,,,,, 6-Tris(O-acetyl)-L-glucoenose, yield of 82% in two steps; ESIMS m/z 273.3 [M+H] ⁺ . 3,4,6-tris(O-acetyl)-L-glucoenose (2.5 g, 9.19 mmol) was dissolved in 100 mL of methanol, 60 mg of sodium methoxide was added, and reacted at room temperature for 1 h. The reaction solution was adjusted to pH 7 with a cationic resin. , filtered and concentrated, pressure column chromatography (ethyl acetate) to give 1.3g L--glucal, yield 97%; ESIMS m / z 147.2 [m + H] +. The compound L-glucoenose (1.3 g, 8.9 mmol) was dissolved in 30 mL of pyridine, cooled to 0 ° C, triisopropylchlorosilane (3.78 ml, 17.8 mmol) and imidazole (3.61 g, 53.4 mmol) were added and reacted at room temperature for 2 h. It was quenched with 50 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated. The yield was 52%. ¹ H-NMR (500MHz, CDCl ₃ ) δ 6.27 (d, J = 6.0 Hz, 1H, H-1), 4.67-4.70 (m, 1H, H-2), 4.26 (brs, 1H, H-4) ), 4.04 (dd, J = 12.0, 4.8 Hz, 1H, H-6a), 3.98 (dd, J = 12.00, 4.8 Hz, 1H, H-6b), 3.79-3.82 (m, 2H, H-3 and H) -5), 1.09-1.16 (m, 3H, ((CH ₃ ) ₂ CH) ₃ Si-), 1.06 (d, J = 6.0 Hz, 18H, ((C H ₃ ) ₂ CH) ₃ Si-). ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 143.9, 102.5, 76.5, 72.5, 69.4, 64.4, 17.8× ₃ , 11.8×6; ESIMS m/z 325.1 [M+Na] ⁺ .

Ii) Preparation of Compound 191b

1.41 g of compound 191a (4.7 mmol) was placed in a 100 mL three-necked flask, and argon-protected by adding 20 mL of dry dichloromethane to dissolve, to -5 ° C, and sodium hydride (740 mg, 18.5 mmol, 60%) was added in two portions. The mass fraction was dispersed in paraffin, and the reaction was raised to 0 ° C for 20 min, and slowly raised to room temperature to continue the reaction for 1.5 h. The mixture was again reduced to -5 ° C, and trichloroacetonitrile (5.51 mL, 55.6 mmol) was dissolved in 10 mL of dry dichloromethane. The reaction solution was cooled to -78 ° C, boron trifluoride etherate (17.0 mL, 139 mmol) was added dropwise, and the reaction was carried out at this temperature for 6 h, then the reaction was quenched by adding 20 mL of saturated sodium hydrogen carbonate solution, and slowly warmed to room temperature, dichloromethane The extract was dried over anhydrous sodium sulfate and concentrated. EtOAc EtOAc m. [α] _D ²⁰ -71.6° (c 0.90, CH ₂ Cl ₂ ); ¹ H-NMR (500MHz, CDCl ₃ ) δ 7.02 (brs, 1H, NH), 6.45 (d, J = 6.0, 1H, H) -1), 4.93 (dd, J = 6.0, 5.0 Hz, 1H, H-2), 4.46-4.49 (m, 1H, H-4), 4.16-4.18 (m, 1H, H-3), 4.06 ( Dd, J = 12.0, 5.4 Hz, 1H, H-6a), 3.96 (dd, J = 12.00, 5.4 Hz, 1H, H-6b), 3.82-3.86 (m, 1H, H-5), 1.10-1.17 (m, 3H, ((CH ₃ ) ₂ CH) ₃ Si-), 1.07 (d, J = 6.0 Hz, 18H, ((C H ₃ ) ₂ CH) ₃ Si-); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 162.4, 145.8, 97.3, 92.6, 74.6, 67.3, 63.5, 45.9, 17.9 × ₃ , 11.8 × 6; ESIMS m/z 446.1/448.2/490.1 [M+H] ⁺ .

Iii) Preparation of Compound 191c

Compound 191b (0.88 g, 1.98 mmol) was dissolved in 30 mL of dichloromethane, and then dropped to 0 ° C, sodium hydride (194 mg, 4.95 mmol, 60% dispersion in paraffin) was added, and the mixture was slowly warmed to room temperature for 3 h, then reduced to The reaction was quenched by the addition of water, and the mixture was combined with methylene chloride, dried over anhydrous sodium sulfate and evaporated. The rate is 84%. [α] _D ²⁰ -86.0° (c 0.50, CH ₂ Cl ₂ ); ¹ H-NMR (500MHz, CDCl ₃ ) δ 6.59 (d, J = 6.0, 1H, H-1), 5.87 (brs, 1H) , NH), 4.85-4.88 (m, 2H, H-2/H-4), 4.34 (dd, J = 7.5, 4.0 Hz, 1H, H-3), 4.04 (dd, J = 11.0, 3.0 Hz, 1H, H-6a), 3.99 (dd, J = 11.0, 3.60 Hz, 1H, H-6b), 3.82-3.84 (m, 1H, H-5), 1.09-1.16 (m, 3H, ((CH _{3) 2} C H ) ₃ Si-), 1.06 (d, J = 6.0 Hz, 18H, ((C H ₃ ) ₂ CH) ₃ Si-); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 158.5, 147.2 , 98.5, 74.1, 71.1, 61.8, 46.1, 17.9 × 3, 11.9 × 6; ESIMS m/z 326.1 [MH] ^- .

Iv) Preparation of Compound 191d

Compound 191c (537 mg, 1.64 mmol) was transferred to a two-necked flask, dissolved in 20 mL of dichloromethane, and lowered to -5 ° C. Sodium hydride (197 mg, 4.92 mmol, 60% dispersion in paraffin) was added and the mixture was allowed to react to room temperature. After two hours, dimethyl sulfate (0.79 mL, 8.21 mmol) was added, and the reaction was carried out for 16 h at room temperature. The reaction was quenched with ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated. Ethyl ester = 6:1 (v/v) eluted 467 mg of compound 191d, yield 83%. [α] _D ²⁰ -77° (c 1.00, CH ₂ Cl ₂ ); ¹ H-NMR (500MHz, CDCl ₃ ) δ 6.67 (d, J = 6.0 Hz, 1H, H-1), 4.93 (dd, J=6.0, 4.0 Hz, 1H, H-2), 4.74 (1H, dd, J=9.0, 7.5 Hz, H-4), 4.05-4.07 (m, 1H, H-3), 4.04 (dd, J =12.0, 2.5 Hz, 1H, H-6a), 4.00 (dd, J = 12.0, 2.5 Hz, 1H, H-6b), 3.60-3.63 (1H, m, H-5), 2.84 (s, 3H, N-CH ₃ ) 1.08-1.15 (m, 3H, ((CH ₃ ) ₂ C H ) ₃ Si-), 1.06 (d, J = 6.0 Hz, 18H, ((C H ₃ ) ₂ CH) ₃ Si- ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 157.3, 148.4, 96.0, 74.5, 67.8, 61.7, 51.0, 28.6, 17.9 × ₃ , 11.9×6; ESIMS m/z 342.2 [M+H] ⁺ .

v) Preparation of Compound 191e

Compound 191d (467 mg, 1.37 mmol) was dissolved in 20 mL of tetrahydrofuran, and then reduced to 0 ° C, 20 mL of water-dissolved Mercury acetate (876 mg, 2.74 mmol) was added, the solution turned yellow, and the mixture was allowed to react to room temperature for 2 h. After dropping to 0 ° C, 60 mL of water was added, and then sodium borohydride (416 mg, 11.0 mmol) was slowly added. After 10 min, carbon dioxide was passed until the solution was neutral. After suction filtration, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography, eluted with petroleum ether: ethyl acetate = 2:1 (v/v) to give 400 mg of a 1-bit difference Isomer mixture 191e, yield 81%. ¹ H-NMR (500MHz, CDCl ₃ ): δ 5.30-5.33 (m, 1H, H-1), 5.15-5.18 (m, 1H, H-1), 4.64 - 4.68 (m, 1H, H-4) ), 4.556-4.60 (m, 1H, H-4), 4.04-3.86 (m, 6H, H-3, H-6a, H-6b,), 3.77-3.82 (m, 1H, H-5), 3.60-3.63 (m, 1H, H-5), 2.87 (s, 3H, N-CH ₃ ), 2.84 (s, 3H, N-CH ₃ ), 2.22 - 2.27 (m, 1H, H-2a), 2.05-2.09 (m, 1H, H-2a), 1.97-2.02 (m, 1H, H-2b), 1.79-1.85 (m, 1H, H-2b), 1.08-1.15 (m, 6H, ((CH) ₃ ) ₂ C H ) ₃ Si-), 1.07 (d, J = 7.2 Hz, 36H, ((C H ₃ ) ₂ CH) ₃ Si-). ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 158.2, 157.8, 91.6, 90.6, 74.5, 69.0, 68.7, 68.1, 63.2, 63.0, 53.7, 52.8, 31.1, 29.9, 29.1, 28.8, 17.9 x 6, 12.0 x 12; ESIMS m/z 360.2 [M+H] ⁺ .

Vi) Preparation of compounds 191f and 191g

870 mg of compound 185c (1.59 mmol) was placed in a 250 mL three-neck reaction flask, dissolved in 20 mL of dry tetrahydrofuran, argon-protected, cooled to -78 ° C, and 10 mL of dry tetrahydrofuran dissolved triphenylphosphine (833 mg, 3.18 mmol) was added. Then, 0.62 mL of DIAD (3.18 mmol) was dissolved in 10 mL of tetrahydrofuran, and the reaction solution was added dropwise. After reacting at -78 ° C for 1 h, 10 mL of tetrahydrofuran-dissolved compound 191e (380 mg, 1.06 mmol) was added, and the reaction was carried out at -78 ° C for 2 h. The reaction was carried out overnight at room temperature. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. EtOAc EtOAc EtOAc EtOAc EtOAc And 230 mg of compound 191 g (yield 25%).

191f: [α] _D ²⁰ -14.2° (c 1.0, CH ₂ Cl ₂ ); ¹ H NMR (500MHz, CDCl ₃ ) δ 8.15 (d, J = 7.8 Hz, 1H, ArH), 8.11 (s, 1H) , ArH), 7.77 (s, 1H, ArH), 7.36-7.40 (m, 3H, ArH), 7.29-7.32 (m, 2H, ArH), 7.23-7.25 (m, 1H, ArH), 7.15-7.18 ( m, 1H, ArH), 7.10-7.12 (m, 2H, ArH), 6.86 (t, J = 7.8 Hz, 1H, ArH), 6.77-6.81 (m, 2H, ArH), 5.71 (dd, J = 10.5) , 2.0 Hz, 1H, H-1'), 5.20-5.25 (m, 2H, PhCH ₂ OC H ₂ N), 4.71 (s, 2H, PhC H ₂ OCH ₂ N), 4.69 (dd, J = 9.0, 7.5 Hz, 1H, H-4'), 4.05-4.09 (1H, m, H-3'), 4.00 (dd, J = 12.0, 2.0 Hz, 1H, H-6'a), 3.95 (dd, J =12.0, 2.0 Hz, 1H, H-6'b), 3.82-3.85 (1H, m, H-5'), 2.88 (s, 3H, N-CH ₃ ), 2.39-2.44 (m, 1H, H -2'a), 2.27-2.30 (m, 1H, H-2'b), 1.69 (s, 9H, (C H ₃ ) ₃ CO-), 1.05-1.11 (m, 3H, ((CH ₃ ) ₂ C H ) ₃ Si-), 1.02 (d, J = 6.0 Hz, 18H, ((C H ₃ ) ₂ CH) ₃ Si-). ¹³ C NMR (125 MHz, CDCl ₃ ) δ 171.1, 171.0, 158.5 , 149.2, 137.7, 135.8, 135.2, 130.6, 129.0, 128.6, 128.4 × 2, 127.7 × 2, 127.6 × 2, 126.6, 125.8, 124.6, 123.2, 122.5, 122.2, 121.8, 121.6, 115.1, 110.6, 110.5, 107.1, 84.6, 79.5, 78.4, 71.7, 67.4, 67.1, 63.0, 55.8, 29.6, 29.4, 28.2 × 3, 17.9 × 3,11.9×6; ESIMS m/z 889.6[M+H] ⁺

191g: [α] _D ²⁰ +9.3° (c 0.40, CH ₂ Cl ₂ ); ¹ H NMR (500MHz, CDCl ₃ ) δ 8.15 (d, J = 7.2 Hz, 1H, ArH), 8.13 (s, 1H) , ArH), 7.64 (s, 1H, ArH), 7.39-7.42 (m, 3H, ArH), 7.28-7.33 (m, 3H, ArH), 7.22-7.25 (m, 1H, ArH), 7.15-7.20 ( m, 2H, ArH), 6.95 (t, J = 7.0 Hz, 1H, ArH), 6.78 (t, J = 8.0 Hz, 1H, ArH), 6.72 (d, J = 8.0 Hz, 1H, ArH), 6.10 (dd, J = 10.0, 6.0 Hz, 1H, H-1'), 5.23 (s, 2H, PhCH ₂ OC H ₂ N), 4.76 (t, J = 7.8 Hz, 1H, H-4'), 4.72 (s, 2H, PhC H ₂ OCH ₂ N), 3.99-4.04 (m, 1H, H-3'), 3.85-3.94 (m, 2H, H-6'), 3.80-3.83 (m, 1H, H -5'), 2.87 (s, 3H, N-CH ₃ ), 2.39-2.45 (m, 1H, H-2'a), 2.05-2.13 (m, 1H, H-2'b), 1.69 (s , 9H, (C H ₃ ) ₃ CO-), 1.05-1.10 (m, 3H, ((CH ₃ ) ₂ CH) ₃ Si-), 1.02 (d, J = 6.0 Hz, 18H, ((C H _{3 2} CH) ₃ Si-). ¹³ C NMR (125MHz, CDCl ₃ ) δ 171.0, 170.9, 157.2, 149.2, 137.8, 136.0, 135.4, 130.8, 129.3, 128.4 × 3, 127.7, 127.6 × 2, 127.3, 126.7, 126.0, 124.6, 123.2, 122.4 × 2, 121.9, 121.6, 115.3 110.5,110.3,107.1,84.7,78.6,72.4,71.8,68.8,67.4,63.5,53.6,29.7,29.2,28.2 × 3,17.9 × 3,11.9 × 6; ESIMS m / z 889.6 [M + H] +.

Vii) Preparation of compounds 191i and 194b

Compound 191f (226 mg, 0.254 mmol) was dissolved in 40 mL of toluene. After bringing back to room temperature, filtered over silica gel, eluting with ethyl acetate to give 200mg 191h compound, yield 100%; ESIMS m / z 787.4 [M + H] +. The compound 194a (201 mg, yield 100%) was obtained from the compound 191 g (226 mg), ESIMS m/z 787.5 [M+H] ⁺ . Compound 191h (200mg, 0.253mmol) was dissolved in 30mL of tetrahydrofuran, reduced to 0 ° C, added tetrabutylammonium fluoride (1.0mL, 1.0mmol, 1.0M in THF), reacted at room temperature for 1h, diluted with ethyl acetate and washed with water The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated, and then purified,363363363363363363363363363363363363363 Using 194a (201 mg) as a starting material, 152 mg of Compound 194b was obtained in the same manner, yield 94%.

191i: [α] _D ²⁰ +11.6° (c 0.55, CH ₂ Cl ₂ ); ¹ H NMR (500MHz, CDCl ₃ ) δ 8.82 (brs, 1H, NH), 7.69 (d, J = 3.0 Hz, 1H) , ArH), 7.62 (s, 1H, ArH), 7.37-7.38 (m, 2H, ArH), 7.28-7.33 (m, 4H, ArH), 7.23-7.26 (m, 1H, ArH), 7.15-7.19 ( m, 1H, ArH), 7.14 (d, J = 7.5 Hz, 1H, ArH), 7.07-7.10 (m, 1H, ArH), 6.-6.92 (m, 2H, ArH), 6.77-6.80 (m, 1H, ArH), 5.71 (dd, J = 10.5, 2.0 Hz, 1H, H-1'), 5.17 (s, 2H, PhCH ₂ O CH ₂ N), 4.68 (s, 2H, Ph CH ₂ OCH ₂ N ), 4.46 (1H, dd, J = 9.0, 7.0 Hz, H-4'), 3.92-3.95 (m, 1H, H-3'), 3.85-3.87 (m, 1H, H-6'a), 3.76-3.79 (m, 1H, H-5'), 3.66-3.69 (m, 1H, H-6'b), 2.82 (s, 3H, N-CH ₃ ), 2.30-2.36 (m, 1H, H -2'a), 2.20-2.23 (m, 1H, H-2'b). ¹³ C NMR (125MHz, CDCl ₃ ) δ 171.6, 171.5, 158.4, 137.7, 136.1, 136.0, 129.2, 129.0, 128.4 × 2,127.8,127.7×2,127.6,126.8,126.5,124.8,123.2,122.8,122.7,122.2,121.4,120.4,111.5,109.8,107.6,106.7,78.8,77.6,71.6,67.2,62.1,60.5,55.7 , 29.5, 28.9; ESIMS m/z 631.3 [MH] ⁺ .

194b: [α] _D ²⁰ +19.3° (c 0.25, CH ₂ Cl ₂ ); ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.90 (s, 1H, NH), 7.83 (d, J = 3.0 Hz, 1H) , ArH), 7.47 (s, 1H, ArH), 7.45 (d, J = 7.5 Hz, 1H, ArH), 7.38-7.41 (m, 3H, ArH), 7.36 (d, J = 8.0 Hz, 1H, ArH ), 7.29-7.32 (m, 2H, ArH), 7.20-7.25 (m, 2H, ArH), 7.08-7.11 (m, 1H, ArH), 7.00-7.03 (t, J = 7.2 Hz, 1H, ArH) , 6.73-6.76 (m, 2H, ArH), 6.06 (dd, J = 10.0, 5.0 Hz, 1H, H-1'), 5.20-5.25 (m, 2H, PhCH ₂ O CH ₂ N), 4.72 (s , 2H, Ph CH ₂ OCH ₂ N), 4.62 (t, J = 9.5 Hz, 1H, H-4'), 3.94 - 3.99 (m, 1H, H-3'), 3.71-3.73 (m, 1H, H-6'a), 3.61-3.63 (m, 1H, H-6'b), 3.54-3.57 (m, 1H, H-5'), 2.81 (s, 3H, N-CH ₃ ), 2.42- 2.47 (m, 1H, H-2'a), 2.01-2.08 (m, 1H, H-2'b); ¹³ C NMR (125MHz, CDCl ₃ ) δ 171.5 × ₂ , 157.0, 137.8, 136.2, 135.8 , 129.3, 129.0, 128.4 × 2, 127.7 × 3, 127.4, 127.2, 126.8, 124.3, 123.2, 122.8, 122.7, 122.2, 121.5, 120.4, 111.6, 109.8, 107.7, 106.7, 78.3, 71.7, 71.3, 68.6, 67.3 , 62.1 53.2,29.7,28.9; ESIMS m / z: 631.3 [MH] -.

Viii) Preparation of Compounds 191j and 194c

10 mg of compound 191i (0.016 mmol) was dissolved in 1000 mL of acetone, and 1 mg of iodine was added thereto, and the reaction was irradiated by a 125-W high-pressure mercury lamp for 12 hours. The solution was changed from red to green fluorescence, concentrated, and then saturated with sodium thiosulfate solution and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated and evaporated tolululululululululululululululu Take Compound 194b (10 mg) was used as a starting material, and 5.3 mg of Compound 194c was obtained in the same manner, yield 53%.

191j: [α] _D ²⁰ -51.7° (c 0.07, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ): δ 11.0 (s, 1H, NH), 9.06 (d, J = 7.8 Hz, 1H, ArH), 8.64 (d, J = 7.8 Hz, 1H, ArH), 7.47 (t, J = 7.7 Hz, 1H, ArH), 7.39 (d, J = 7.5 Hz, 2H, ArH), 7.38 (d , J = 7.7 Hz, 1H, ArH), 7.31 (t, J = 7.8 Hz, 2H, ArH), 7.23 - 7.26 (m, 3H, ArH), 7.19 (t, J = 7.8 Hz, 1H, ArH), 6.85 (t, J = 8.4 Hz, 1H, ArH), 6.11 (d, J = 11.0 Hz, 1H, H-1'), 5.15 (t, J = 7.8 Hz, 1H, H-4'), 4.95 ( s, 2H, PhCH ₂ O CH ₂ N), 4.70 (s, 2H, Ph CH ₂ OCH ₂ N), 4.28 (d, J = 10.8 Hz, 1H, H-3'), 4.04-4.08 (m, 3H) , H-5', H-6'), 2.88 (s, 3H, N-CH ₃ ), 2.21-2.26 (m, 1H, H-2'a), 1.97-2.00 (m, 1H, H-2 'b); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 169.2, 168.9, 158.8, 140.7, 139.6, 137.5, 129.6, 128.5 × 2, 128.1, 127.9 × 3, 127.4, 126.9, 125.9, 124.7, 122.4, 121.5, 121.4, 120.4, 120.2, 119.2, 118.1, 117.8, 111.3, 108.6, 79.1, 78.3, 71.6, 66.5, 66.3, 60.5, 56.1, 29.6, 28.9; ESIMS m/z 629.3 [MH] ^- .

194c: [α] _D ²⁰ +32.6° (c 0.11, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ): δ 9.78 (s, 1H, NH), 8.91 - 8.94 (m, 2H, ArH ), 7.47 (d, J = 8.2 Hz, 1H, ArH), 7.39-7.41 (m, 3H, ArH), 7.34 (t, J = 7.5 Hz, 1H, ArH), 7.31 (t, J = 7.8 Hz, 2H, ArH), 7.27 (d, J = 8.2 Hz, 1H, ArH), 7.23 - 7.26 (m, 1H, ArH), 7.21 (t, J = 7.8 Hz, 1H, ArH), 7.16 (t, J = 7.8 Hz, 1H, ArH), 6.62-6.64 (m, 1H, H-1'), 5.00-5.08 (m, 2H, PhCH ₂ O. CH ₂ N), 4.70 (s, 2H, Ph CH ₂ OCH ₂ N), 4.68 (brs, 1H, H-4'), 4.49-4.50 (m, 1H, H-3'), 4.31-4.33 (m, 1H, H-5'), 4.04-4.09 (m, 2H) , H-6 '), 2.59 (s, 3H, N-CH 3), 2.07-2.11 (m, 1H, H-2'a), 1.97-2.03 (m, 1H, H-2'b); 13 C NMR (150MHz, CDCl ₃ ) δ 169.2, 169.0, 157.0, 140.6, 139.7, 137.6, 129.1, 128.6 × 2, 128.1 × 2, 128.0 × 2, 127.7, 127.1, 125.8, 124.9, 122.2, 121.6 × 2, 121.0, 123.1, 118.7, 118.3, 118.1, 111.9, 109.0, 77.6, 75.3, 70.9, 66.8, 64.6, 60.5, 54.6, 29.8, 28.8; ESIMS m/z 629.2 [MH] ^- .

Ix) Preparation of Compounds 191l and 194e

242 mg of triphenylphosphine (0.92 mmol) and imidazole (126 mg, 1.85 mmol) were dissolved in 20 mL of dichloromethane, and then reduced to 0 ° C, iodine (234 mg, 1.85 mmol) was added and stirred for 1 h. Compound 191j (97 mg, 0.15 mmol) was dissolved in 20 mL of dichloromethane, and then slowly added to the reaction mixture, and the mixture was allowed to react at room temperature for 6 h. After being reduced to 0 ° C, it was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography, eluting with petroleum ether: ethyl acetate=2:1 (v/v) 191k, yield 77%; ESIMS m / z 741.3 [m + H] +. Compound 194d (90 mg, yield: 95%) was obtained from compound 194c (yield: 80 mg), ESIMS m/z 741.2 [M+H] ⁺ . Compound 191k (105 mg, 0.14 mmol) was dissolved in 10 mL of tetrahydrofuran, then reduced to 0 ° C, DBU (0.4 mL, 2.67 mmol) was added and reacted at 0 ° C for 1 h, and then allowed to react at 40 ° C for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and evaporated. Compound 194e (67 mg, yield 90%) was obtained in the same manner from Compound 194d (90 mg).

191l: [α] _D ²⁰ -96.0° (c 0.55, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 12.2 (s, 1H, NH), 9.22 (d, J = 7.8 Hz) , 1H, ArH), 9.08 (d, J = 8.4 Hz, 1H, ArH), 7.88 (d, J = 8.4 Hz, 1H, ArH), 7.75 (d, J = 8.4 Hz, 1H, ArH), 7.64 ( m, 2H, ArH), 7.49 (d, J = 7.2 Hz, 1H, ArH), 7.34 - 7.43 (m, 5H, ArH), 7.29 (m, 1H, ArH), 7.24 (m, 1H, H-1) '), 5.46 (d, J = 8.5 Hz, 1H, H-4'), 5.13 (s, 2H, PhCH ₂ O CH ₂ N), 5.10 (m, 2H, H-6'), 4.67 (s, 2H,Ph CH ₂ OCH ₂ N), 4.40 (m, 1H, H-3'), 2.77 (3H, s, N-CH ₃ ), 2.53 (m, 1H, H-2'a), 2.18 (m) , 1H, H-2'b); ¹³ C NMR (150MHz, DMSO-d ₆ ) δ169.4,169.3,157.1,152.9,142.1,140.5,138.3,129.6,129.2,128.8×2,128.2,128.1×3 , 127.9, 125.5, 124.8, 123.6, 122.4, 121.7, 121.4, 120.3, 119.2, 118.6, 118.4, 113.6, 112.8, 101.2, 81.0, 71.4, 70.9, 67.0, 53.0, 28.8, 28.1; ESIMS m/z 611.1 [MH ] ^- .

194e: [α] _D ²⁰ +12.4° (c 0.20, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.62 (s, 1H, NH), 9.28 (d, J = 8.2 Hz, 1H) , ArH), 9.10 (d, J = 8.2 Hz, 1H, ArH), 7.66 (d, J = 8.2 Hz, 1H, ArH), 7.55 - 7.59 (m, 2H, ArH), 7.42 - 7.47 (m, 4H) , ArH), 7.36-7.41 (m, 3H, ArH), 7.30 (t, J = 7.8 Hz, 1H, ArH), 6.30 (dd, J = 11.4, 2.4 Hz, 1H, H-1'), 5.52 ( d, J = 2.0 Hz, 1H, H-6'a), 5.36 (d, J = 2.0 Hz, 1H, H-6'b), 5.11 (d, 1H, J = 7.2 Hz, H-4') , 5.08-5.18 (m, 2H, PhCH ₂ O CH ₂ ), 4.67 (s, 2H, Ph CH ₂ OCH ₂ N), 4.18-4.21 (m, 1H, H-3'), 2.83 (s, 3H, N-CH ₃ ), 2.51-2.57 (m, 1H, H-2'a), 2.43-2.47 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.3, 169.2 , 156.7, 151.1, 140.9, 139.9, 138.0, 129.4, 128.6 × 2, 128.3, 128.1 × 2, 128.0, 127.9, 127.7, 126.4, 125.4, 122.7, 122.4, 121.9, 121.7, 121.0, 119.5, 119.3, 118.9, 112.0 , 108.9, 100.2, 82.0, 71.7, 70.3, 66.9, 54.6, 33.0, 29.3; ESIMS m/z 611.4 [MH] ^- .

x) Preparation of compounds 191m and 194f

The compound 191 l (80 mg, 0.13 mmol) was dissolved in tetrahydrofuran / methanol 10 mL / 1 mL, then cooled to 0 ° C, then potassium t-butoxide (59 mg, 0.2 mmol) was added, the solution was changed from yellow to red, slowly warmed to room temperature and stirred for 2 h. Iodine (133 mg, 0.15 mmol), the solution darkened and reacted overnight. The mixture was cooled to 0 ° C, poured into saturated sodium thiosulfate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography, petroleum ether: ethyl acetate = 1:2 (v/v) The product was eluted to yield 60 mg of product 191 m, yield 62%. Compound 194f (25 mg, yield 52%) was obtained in the same manner from Compound 194e (40 mg).

191m: [α] _D ²⁰ -40.2° (c 0.06, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.22 (d, J = 7.8 Hz, 1H, ArH), 9.00 (d) , J = 7.8 Hz, 1H, ArH), 8.10 (d, J = 8.4 Hz, 1H, ArH), 8.05 (d, J = 8.4 Hz, 1H, ArH), 7.63 - 7.67 (m, 2H, ArH), 7.49-7.54 (m, 1H, ArH), 7.43 (t, J = 7.2 Hz, 1H, ArH), 7.37-7.38 (m, 2H, ArH), 7.29-7.32 (m, 2H, ArH), 7.23 (t , J = 7.2 Hz, 1H, ArH), 7.09 (dd, J = 9.6, 7.2 Hz, 1H, H-1'), 5.92 (d, J = 12.0 Hz, 1H, H-4'), 5.20 (s , 2H, PhCH ₂ O CH ₂ ), 4.69 (s, 2H, Ph CH ₂ OCH ₂ ), 4.61 (1H, d, J = 12.6 Hz, H-6'a), 4.51-4.53 (m, 1H, H -3'), 3.80 (1H, d, J = 12.6 Hz, H-6'b), 3.01 (s, 3H, N-CH ₃ ), 2.86-2.90 (m, 1H, H-2'a), 2.51-2.55 (m, 1H, H-2'b); ¹³ C NMR (150MHz, DMSO-d ₆ ) δ 169.4, 169.1, 156.8, 139.8, 138.5, 138.2, 137.4, 132.0, 129.1, 128.6 × 2, 128.1, 127.9 × 3, 125.5, 125.0, 124.4, 122.3, 121.5, 121.2, 120.5, 119.2, 117.5, 116.8, 113.0, 110.6, 93.3, 78.2, 70.8, 70.3, 65.4, 52.7, 29.3, 28.4, 1 1.6; ESIMS m/z 761.1 [M+Na] ⁺ .

194f: [α] _D ²⁰ +51.3° (c 0.12, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, DMSO-d ₆ ) δ 9.25 (d, J = 8.2 Hz, 1H, ArH), 9.03 (d , J = 8.2 Hz, 1H, ArH), 8.17 (d, J = 8.2 Hz, 1H, ArH), 7.90 (d, J = 8.2 Hz, 1H, ArH), 7.66 (m, 1H, ArH), 7.65- 7.68 (m, 1H, ArH), 7.60-7.63 (m, 1H, ArH), 7.44 - 7.50 (m, 2H, ArH), 7.36 (d, J = 8.2 Hz, 2H, ArH), 7.30 (t, J) = 7.2 Hz, 2H, ArH), 7.23 (t, J = 7.2 Hz, 1H, ArH), 7.04-7.07 (m, 1H, H-1'), 5.49 (d, J = 9.0 Hz, 1H, H- 4'), 5.13-5.18 (m, 2H, PhCH ₂ O CH ₂ ), 4.93 (d, J = 11.4 Hz, 1H, H-6'a), 4.67 (s, 2H, Ph CH ₂ OCH ₂ ), 4.34-4.38(m,1H,H-3'), 3.96 (1H,d,J=11.4Hz, H-6'b), 2.99-3.03(m,1H,H-2'a),2.65(s , 3H, N-CH ₃ ), 2.51-2.55 (m, 1H, H-2'b); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 169.6, 169.3, 155.9, 141.6, 138.4, 138.3, 132.2 ×2,132.1,128.9,128.8×2,128.1×4,125.4,125.1,124.4,122.3,121.8,121.5,120.5,119.2,118.2,116.7,116.1,110.2,92.6,80.1,73.6,71.0,65.6,53.1 , 30 .6, 29.0, 14.2; ESIMS m/z 761.1 [M+Na] ⁺ .

Xi) Preparation of Compounds 191n and 194g

The compound 191 m (60 mg, 0.08 mmol) was dissolved in EtOAc (EtOAc)EtOAc. After being cooled to room temperature, it was concentrated, and purified by column chromatography, eluting with petroleum ether: ethyl acetate========================================== Using the compound 194f (25 mg) as a starting material, 194 g (20 mg, yield: 96%) of compound was obtained.

191n: [α] _D ²⁰ -63.5° (c 0.09, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.30 (d, J = 7.2 Hz, 1H, ArH), 9.10 (d, J) = 7.8 Hz, 1H, ArH), 7.68-7.61 (m, 3H, ArH), 7.51-7.43 (m, 4H, ArH), 7.37 (t, J = 7.2 Hz, 3H, ArH), 7.30 (t, J = 7.8 Hz, 1H, ArH), 6.55 (dd, J = 9.6, 7.2 Hz, 1H, H-1'), 5.71 (d, J = 9.6 Hz, 1H, H-4'), 5.20-5.31 (m , 2H, PhCH ₂ O CH ₂ ), 4.81 (s, 2H, Ph CH ₂ OCH ₂ ), 4.44 - 4.46 (m, 1H, H-3'), 3.18 (s, 3H, N-CH ₃ ), 2.76 -2.81 (m, 1H, H-2'a), 2.46-2.51 (m, 1H, H-2'b), 1.99 (s, 3H, 6'-CH ₃ ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ169.3,169.1,157.3,140.1,138.1,137.7,130.1,128.9,128.5×2,127.9×2,127.8,127.6,127.4,126.5,126.2,124.6,122.1,122.0,121.4,120.9,119.4,118.4 , 117.4, 112.3, 107.8, 94.0, 77.2, 71.7, 71.4, 66.8, 52.7, 29.6, 26.2, 24.6; ESIMS m/z 613.5 [M+H] ⁺ .

194g: [α] _D ²⁰ +33.1° (c 0.13, CH ₂ Cl ₂ ); ¹ H NMR (600MHz, CDCl ₃ ) δ 9.38 (d, J = 8.0 Hz, 1H, ArH), 9.21 (d, J) = 7.9 Hz, 1H, ArH), 8.08 (d, J = 8.6 Hz, 1H, ArH), 7.57-5.60 (m, 2H, ArH), 7.41 - 7.46 (m, 5H, ArH), 7.31 (t, J = 7.6 Hz, 2H, ArH), 7.23 (t, J = 7.4 Hz, 1H, ArH), 6.58 (dd, J = 10.3, 6.4 Hz, 1H, H-1'), 5.30-5.35 (m, 2H, PhCH ₂ O CH ₂ ), 5.09 (d, J = 8.9 Hz, 1H, H-4'), 4.76 (s, 2H, Ph CH ₂ OCH ₂ ), 4.24 - 4.28 (m, 1H, H-3') , 2.80-2.84 (m, 1H, H-2'a), 2.76 (s, 3H, 3'-NCH ₃ ), 2.41-2.47 (m, 1H, H-2'b), 2.07 (s, 3H, 6'-CH ₃ ); ¹³ C NMR (150MHz, CDCl ₃ ) δ169.5,169.3,155.9,142.2,137.9,137.8,130.7,128.7,128.5×2,128.0×2,127.8,127.6,127.5,126.5, 125.8, 124.6, 122.3, 122.2, 121.6, 120.9, 119.7, 119.5, 117.3, 116.4, 107.6, 93.3, 79.1, 76.2, 71.6, 67.0, 53.1, 30.1, 29.8, 29.7; ESIMS m/z 613.6 [M+H] ⁺ .

Xii) Preparation of Compounds 191 and 194

Compound 191n (40 mg, 0.065 mmol) was dissolved in ethyl acetate/methanol (10 mL / 10 mL) in 20 mL. After argon gas, 20 mg of 20% palladium hydroxide carbon was added, followed by hydrogen replacement and overnight reaction. Filtration over silica gel, concentration, semi- preparative HPLC separation, eluting with MeOH:H ₂ O=7:3 (v/v) affords 28 mg of 4'-O-des-methyl-(4'-O,3'-N)carbonyl -7-Oxoin-1',5'-bis-sporosporine (191), yield 89%. Using 194 g (20 mg) of the compound as a starting material, 15 mg of 4'-O-desmethyl-(4'-O,3'-N)carbonyl-7-oxyalkylpyrazine (194) was obtained in the same manner. The yield was 96%.

191: [α] _D ²⁰ -69.5° (c 2.0, CH ₂ Cl ₂ ); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.2 (s, 1H, NH), 9.21. (d, J = 7.8 Hz , 1H, ArH), 8.98 (d, J = 7.8 Hz, 1H, ArH), 8.07 (d, J = 7.8 Hz, 1H, ArH), 7.94 (d, J = 8.4 Hz, 1H, ArH), 7.61 7.67 (m, 2H, ArH), 7.48 (t, J = 7.8 Hz, 1H, ArH), 7.41 (t, J = 7.8 Hz, 1H, ArH), 6.98-7.01 (m, 1H, H-1') , 5.76 (d, J = 10.4 Hz, 1H, H-4'), 4.44 - 4.46 (m, 1H, H-3'), 2.99 (s, 3H, N-CH ₃ ), 2.81 (ddd, J = 9.6, 6.0, 2.4 Hz, 1H, H-2'a), 2.18 (ddd, J = 9.6, 6.0, 2.4 Hz, 1H, H-2'b), 1.80 (s, 3H, 6'-CH ₃ ) ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.5, 171.2, 157.4, 140.5, 138.6, 130.2, 129.1, 127.8, 127.7, 125.8, 125.3, 124.3, 122.1, 122.0, 121.5, 121.4, 120.7, 117.6, 116.5, 114.3, 110.7, 94.1, 77.9, 71.4, 52.4, 29.5, 25.4, 24.9; ESIMS m/z 491.3 [MH] ^- .

194: [α] _D ²⁰ +112.9° (c 0.1, CH ₂ Cl ₂ ); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.2 (s, 1H, NH), 9.23 (d, J = 9.0 Hz) , 1H, ArH), 9.04 (d, J = 9.0 Hz, 1H, ArH), 8.09 (d, J = 9.5 Hz, 1H, ArH), 7.88 (d, J = 9.5 Hz, 1H, ArH), 7.65 ( t, J = 9.0 Hz, 1H, ArH), 7.58 (t, J = 9.5 Hz, 1H, ArH), 7.43 (t, J = 9.0 Hz, 2H, ArH), 7.01 (dd, J = 10.0, 8.5 Hz) , 1H, H-1'), 5.33 (d, J = 8.5 Hz, 1H, H-4'), 4.31-4.36 (m, 1H, H-3'), 2.93-2.98 (m, 1H, H- 2'a), 2.57 (s, 3H, N-CH ₃ ), 2.04-2.11 (m, 1H, H-2'b), 2.05 (3H, s, 6'-CH ₃ ); ¹³ C NMR (125 MHz , DMSO-d ₆ ) δ 170.8, 170.5, 155.5, 141.3, 137.6, 129.8, 128.0, 127.0, 126.5, 124.8, 124.5, 123.5, 121.2, 121.0 × 2, 120.8, 119.8, 117.4, 116.5, 115.7, 109.3, 92.6, 79.0, 75.3, 52.0, 29.6, 28.2 × 2; ESIMS m/z 491.1 [MH] ^- .

Preparation of Compounds 192, 193, 195 and 196

The compound 191 (10 mg, 0.020 mmol) was dissolved in 10 mL of methanol, and then reduced to 0 ° C, sodium borohydride (7.6 mg, 0.2 mmol) was added, and the mixture was allowed to react at room temperature for two hours, and the solution was changed from yellow to colorless with ethyl acetate. After dilution, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated. The crude product was dissolved in 5 mL of glacial acetic acid, zinc powder (15 mg, 0.23 mmol) was added, and the mixture was heated to 40 ° C for 1.5 hours. After being cooled to room temperature, diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution, anhydrous sulfuric acid. The sodium is dried and concentrated. Semi-preparative HPLC separation, elution with acetonitrile:water = 7:13 (v/v) afforded 4'-O-desmethyl-(4'-O,3'-N)carbonyl-1',5'-double Staurosporine (192) (3.2 mg, yield 35%), 5-deoxy-7-oxophenyl-4'-O-desmethyl-(4'-O,3'-N)carbonyl-1 ', 5'-Bisphine (193) (3.2 mg, yield 35%). Starting from compound 194 (10 mg), 5-deoxy-7-oxyphenyl-4'-O-desmethyl-(4'-O,3'-N)carbonylsporin was obtained in the same manner. 195) (2.7 mg, yield 28%) and 2.7 mg of 4'-O-desmethyl-(4'-O,3'-N)carbonylsporin (ACT-007, 196) in 28%.

192: [α] _D ²⁰ -78.2 ° (c 0.05, MeOH); ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.19 (d, J = 7.8 Hz, 1H, ArH), 8.65 (s, 1H, NH), 8.10 (d, J = 7.6 Hz, 1H, ArH), 7.97 (d, J = 8.3 Hz, 1H, ArH), 7.91 (d, J = 8.3 Hz, 1H, ArH), 7.57 (t, J = 7.8 Hz, 1H, ArH), 7.48-7.51 (m, 1H, ArH), 7.43 (t, J = 7.5 Hz, 1H, ArH), 7.29 (t, J = 7.5 Hz, 1H, ArH), 6.92 ( Dd, J = 9.8, 6.8 Hz, 1H, H-1'), 5.72 (d, J = 9.7 Hz, 1H, H-4'), 4.94 - 5.03 (m, 2H, H-7), 4.41-4.44 (m, 1H, H-3'), 2.98 (s, 3H, N-CH ₃ ), 2.71-2.76 (m, 1H, H-2'a), 2.07-2.12 (m, 1H, H-2' b), 1.79 (s, 3H, 6'-CH ₃ ). ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ 171.6, 156.9, 138.8, 136.9, 133.2, 128.4, 125.6 × 2, 125.5, 124.9, 124.8 , 122.3, 122.0, 121.2, 120.6, 119.6, 116.1, 115.2, 113.6, 109.4, 93.3, 77.4, 71.1, 52.0, 45.5, 28.9, 25.0, 24.4; HR-ESIMS m/z 479.1710 [M+H] ⁺ (calcd For C ₂₈ H ₂₃ N ₄ O ₄ ⁺ 479.1719).

193: [α] _D ²⁰ -76.5 ° (c 0.05, MeOH); ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.49 (d, J = 7.8 Hz, 1H, ArH), 8.61 (s, 1H, NH), 8.09 (d, J = 7.8 Hz, 1H, ArH), 8.03 (d, J = 8.2 Hz, 1H, ArH), 7.84 (d, J = 8.4 Hz, 1H, ArH), 7.52-7.55 (m) , 2H, ArH), 7.36 (t, J = 7.5 Hz, 2H, ArH), 6.93 (dd, J = 9.7, 7.0 Hz, 1H, H-1'), 5.76 (d, J = 9.5 Hz, 1H, H-4'), 4.94-5.02 (m, 2H, H-5), 4.44-4.46 (m, 1H, H-3'), 2.99 (s, 3H, N-CH ₃ ), 2.78 (ddd, J =10.1, 6.9, 2.4 Hz, 1H, H-2'a), 2.14-2.18 (m, 1H, H-2'b), 1.75 (s, 3H, 6'-CH ₃ ). ¹³ C NMR (150 MHz , DMSO-d ₆ ) δ 171.9, 156.9, 138.9, 137.0, 134.5, 127.3, 126.4 × 2, 126.2, 125.7, 125.5, 125.2, 122.0, 120.5, 120.4, 119.6, 117.2, 114.5, 113.0, 109.9, 93.3, 77.4, 71.1, 52.0, 45.1, 28.9, 25.1, 24.1; HR-ESIMS m/z 479.1711 [M+H] ⁺ (calcd for C ₂₈ H ₂₃ N ₄ O ₄ ⁺ 479.1719).

195: [α] _D ²⁰ + 66° (c 0.05, MeOH); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.51 (d, J = 7.9 Hz, 1H, ArH), 8.61 (s, 1H, NH), 8.10 (d, J = 7.7 Hz, 1H, ArH), 8.01 (d, J = 8.5 Hz, 1H, ArH), 7.85 (d, J = 8.2 Hz, 1H, ArH), 7.56 (t, J = 7.6 Hz, 1H, ArH), 7.46 (t, J = 7.6 Hz, 1H, ArH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.4 Hz, 1H, ArH) , 6.96 (dd, J = 9.6, 6.2 Hz, 1H, H-1'), 5.30 (d, J = 8.7 Hz, 1H, H-4'), 4.94 - 5.02 (m, 2H, H-5), 4.32-4.37 (m, 1H, H-3'), 2.92-2.96 (m, 1H, H-2'a), 2.59 (s, 3H, N-CH ₃ ), 2.05-2.10 (m, 1H, H -2'b), 1.99 (s, 3H, 6'-CH ₃ ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.8, 155.6, 140.3, 136.5, 134.2, 126.9, 126.5, 125.6, 125.4, 125.0×2, 122.0, 121.7, 120.4, 119.9, 119.3, 117.6, 115.9, 114.1, 109.2, 92.4, 79.1, 75.4, 52.0, 44.9, 29.4, 28.7, 28.2; HR-ESIMS m/z 479.1727 [M+H] ⁺ (calcd for C ₂₈ H ₂₃ N ₄ O ₄ ⁺ 479.1719).

196: [α] _D ²⁰ +73.2° (c 0.05, MeOH); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.23 (d, J = 7.9 Hz, 1H, ArH), 8.66 (s, 1H, NH), 8.06 (d, J = 8.5 Hz, 1H, ArH), 8.03 (d, J = 7.7 Hz, 1H, ArH), 7.79 (d, J = 8.3 Hz, 1H, ArH), 7.51 (t, J = 8.3 Hz, 1H, ArH), 7.53 (t, J = 7.7 Hz, 1H, ArH), 7.38 (t, J = 7.4 Hz, 1H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH) , 6.96 (dd, J=9.7, 6.3 Hz, 1H, H-1'), 5.31 (d, J = 8.7 Hz, 1H, H-4'), 4.95-5.03 (m, 2H, H-7), 4.33-4.36 (m, 1H, H-3'), 2.89-2.94 (m, 1H, H-2'a), 2.59 (s, 3H, N-CH ₃ ), 2.03 (s, 3H, 6'- CH ₃ ), 1.97-2.03 (m, 1H, H-2'b); ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 171.5, 155.6, 140.3, 136.4, 132.9, 128.6, 125.7, 125.4, 124.9, 124.6×2,122.4,121.1,120.9,120.2,119.5,116.5,115.8,115.4,108.6,92.4,79.1,75.4,52.0,45.4,29.5,28.6,28.2;HR-ESIMS m/z 479.1725[M+H] ⁺ (calcd for C ₂₈ H ₂₃ N ₄ O ₄ 479.1719).

[Example 2] Antitumor activity test

1 test method

Preparation of test sample solution: The test sample was the monomer compound 1 to 196 synthesized in the above Example 1. Accurately weigh the appropriate amount of the sample, and prepare a solution of the desired concentration in DMSO for activity testing.

Subculture of cell lines and cells: Activity tests using human HL-60, A549, HepG2, MCF-7, Jurkat, MV-4-11, H1975, K562 cell lines and doxorubicin resistant strain K562/A02. Various cells were subcultured with RPMI-1640 medium containing 10% FBS and incubated at 37 ° C in a 5% carbon dioxide incubator.

In this experiment, the MTT assay was used to evaluate the inhibitory activity of the tested samples on the proliferation of human HL-60, Jurkat, A549, H1975, HepG2 and MCF-7 cancer cells. The cell proliferation inhibitory activity of the tested samples against human MV-4-11, K562 and its doxorubicin-resistant strain K562/A02 was evaluated by CCK8 assay.

MTT method: succinate dehydrogenase in living cell mitochondria can metabolize yellow 3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide in blue-purple water-insoluble The amount of formazan, formazan can be determined by measuring the absorbance by a microplate reader. Since the amount of formazan is proportional to the number of living cells, the number of living cells can be determined from the absorbance to understand the ability of the drug to inhibit or kill tumor cells. For the activity test, the cells in the logarithmic growth phase were prepared into a cell suspension with a density of 5 × 10 ⁴ cells per ml using fresh RPMI-1640 medium, and seeded in a 96-well plate at 100 ul per well. After incubating for 12 hours at ° C, the medium in the wells was aspirated, and different concentrations of the samples diluted with 200 μL of the corresponding medium were added to each well, and the cultivation was continued for 72 hours. Then, 12 μL of LTTT solution (5 mg/L) was added and cultured for further 4 hours. After removing the culture solution, 150 μL of DMSO was added to dissolve formazan, and the absorbance was measured at 570 nm or 490 nm. Growth inhibition rate (IR%) of the cells in accordance with the following equation for each concentration: IR% = (OD _sample -OD _{blank control)} / OD _blank × 100%.

CCK-8 method: succinate dehydrogenase in living cell mitochondria can metabolize 3-(2-methoxy-4-nitrophenyl)-2-(4-nitrophenyl)-5-(2, The 4-disulfobenzene)-2H-tetrazole monosodium salt is a highly water-soluble yellow formazan product (Formazan), and the amount of formazan produced is proportional to the number of living cells. The absorbance of the light at 450 nm is measured by an enzyme-linked immunosorbent assay, which indirectly reflects the number of viable cells. Since the amount of formazan is proportional to the number of living cells, the number of living cells can be determined from the absorbance to understand the ability of the drug to inhibit or kill tumor cells. For the activity test, the cells in the logarithmic growth phase were prepared into a cell suspension with a density of 5×10 ⁴ cells per ml using fresh RPMI-1640 medium, and seeded in a 96-well plate at 100 μL per well. After incubating for 12 hours at ° C, the medium in the wells was aspirated, and different concentrations of the samples diluted with 100 μL of the corresponding medium were added to each well, and the culture was continued for 72 hours. Then, 10 μL of CCK-8 solution was added, and further cultured for 6 hours, and the absorbance was measured at 450 nm. The cell proliferation inhibition rate (IR%) at each concentration was calculated according to the formula "IR% = (OD blank control - OD sample) / OD blank control x 100%".

Doxorubicin (ADM) and gefitinib were positive controls.

The results are shown in Table 1 to Table to Table 9.

Table 1 Inhibitory activity against human acute promyelocytic leukemia HL-60 (IC ₅₀ , μM)

Compound	IC 50	Compound	IC 50
46	0.99	74	0.60
48	0.05	84	0.37
55	0.46	85	0.34
57	0.87	97	0.87
ADM	0.02

Table 2 Inhibitory activity against human chronic myeloid leukemia K562 (IC ₅₀ , μM)

Compound	IC 50	Compound	IC 50
55	0.053	79	0.94
73	0.72	84	0.25
74	0.24	85	0.36
78	0.43	ADM	0.30

Table 3 Inhibitory activity against human T lymphocytic leukemia Jurkat (IC ₅₀ , μM)

Compound	IC 50	Compound	IC 50
105	0.26	126	0.81
115	2.13	120	0.20
107	0.54	122	0.39
124	0.44	ADM	0.44

Table 4 Inhibitory activity against human breast invasive ductal carcinoma MCF-7 (IC ₅₀ , μM)

Compound	IC 50
7	0.9
55	0.3
84	0.85
ADM	1.00

Table 5 Inhibitory activity against human lung adenocarcinoma A549 (IC ₅₀ , μM)

Compound	IC 50	Compound	IC 50
8	0.64	175	0.16
31	0.51	176	0.15

74	0.91	177	0.42
167	0.02	178	0.12
168	0.3	179	0.49
169	0.71	180	0.03
170	0.41	181	0.06
171	0.32	183	0.02
172	0.36	188	0.21
174	0.68	ADM	0.90

Table 6 Inhibitory activity against human hepatoma cell HepG2 (IC ₅₀ , μM)

Compound	IC 50	Compound	IC 50
2	2.80	83	1.80
8	2.50	84	1.20
12	2.30	73	2.30
twenty three	3.40	75	0.43
28	0.35	120	1.16
43	2.10	122	0.84
44	2.54	105	1.34
47	1.60	107	2.36
56	1.90	124	2.25
59	1.70	ADM	0.60

Table 7 Inhibitory activity (IC ₅₀ , μM) of human acute double phenotype (B, mononuclear) myeloid leukemia MV-4-11 with FLT3-ITD mutation

Table 8 Inhibitory activity against doxorubicin-resistant leukemia K562/A02 (IC ₅₀ , μM)

Compound	IC 50	Compound	IC 50
1	1.25	84	1.10
2	0.75	66	4.40
3	1.00	73	2.10
8	0.42	130	1.38
45	4.50	133	2.00
55	3.38	135	3.91
ADM	19.20

Table 9 Inhibitory activity of gefitinib or erlotinib-acquired EGFR-T790M/L858R lung adenocarcinoma resistant mutant H1975 (IC ₅₀ , μM)

Compound	IC 50	Compound	IC 50
103	6.91	113	1.32
104	1.11	114	5.20
105	0.89	115	4.71
106	1.80	119	5.60
107	2.32	120	2.40
108	2.10	121	4.80
110	4.78	122	3.30
111	2.60	124	5.20
112	2.92	127	5.61
Gefitinib	16.82

Conclusion: The results showed that the above compounds have good inhibitory activity against human cancer cell lines HL-60, A549, Jurkat, MV-4-11, H1975, HepG2, MCF-7, K562 and K562/A02, which can be used as A drug for preventing and treating the above tumors.

In particular, the therapeutic effects of the above compounds on drug-resistant tumors enable precise treatment of specific drug-resistant tumors. For example, the use of the epidermal growth factor receptor (EGFR) inhibitor gefitinib or erlotinib in the treatment of non-small cell lung cancer (NSCLC), patients with good efficacy at the initial stage of treatment, but eventually relapse due to drug resistance. H1975 is a EGFR-T790M/L858R lung adenocarcinoma resistant mutant acquired from gefitinib or erlotinib. The compound having the inhibitory effect of H1975 has a therapeutic effect on the EGFR-T790M/L858R acquired drug-resistant mutant lung adenocarcinoma, and can be used for precise treatment of such lung cancer patients.

[Example 3]

1, α-glucosidase inhibitory activity test

(1) Test method

The α-glucosidase inhibitory activity of some compounds was tested using p-nitrophenyl-α-D-glucopyranoside (PNPG) as a substrate. PNPG is an analog of maltose, which can produce yellow p-nitrophenol after α-glucosidase treatment, and can be directly used for the detection of spectrophotometer. Specifically: first, the sample was dissolved in PBS sodium phosphate buffer solution (pH 6.8) to prepare 5 concentrations; then 10 μL of sample solution, 20 μL of PBS solution, and 20 μL of 2.5 mM glucoside were added to each well of a 96-well plate. The solution (dissolved in a phosphate buffer solution) was incubated for 5 minutes in a 37 ° C incubator. The α-glucosidase was diluted to 0.2 U/mL with 0.01 M PBS solution, and 10 μL per well was added to the above test solution, and cultured in a 37 ° C incubator for 15 min, and then the 405 nm per well was measured by a microplate reader. The absorbance value (OD value) was calculated by the following formula (%): [1-(OD _sample /OD _control )] × 100%, and IC ₅₀ (μM) was determined. The blank control was phosphate buffered saline and the positive controls were acarbose and rutamycin.

(2) Experimental results

Table 10 α-Glucosidase inhibitory activity (IC ₅₀ , μM)

Compound	IC 50	Compound	IC 50
8	11.5	15	28.8
28	2.31	33	100
34	114.8	35	100
36	19.3	38	78.0
39	7.79	40	14.8
49	42.9	52	111.3
58	38.6	61	100
62	124.3	63	86.3
75	201.5	76	92.7
79	5.09	88	45.7
89	86.6	91	168.7
92	77.1	93	98.3
97	34.3	100	109.8
107	22.0	108	8.61
128	2.11	135	125.4
153	59.67	184	1.58
187	226.2	188	162.6
190	246.1	196	253.6
Acarbose	101.5	Nojimycin	78.6

The results showed that the above compounds have strong inhibitory activity against α-glucosidase.

2. In vivo anti-diabetic nephropathy (DKD) experiment

In vivo anti-diabetic nephropathy (DKD) activity of Compound 49 was evaluated using a classical db/db diabetic nephropathy animal model.

Animal experiments were divided into 6 groups, 12 mice in each group, and the positive drug was selected losartan. Each group was administered by subcutaneous injection. After continuous administration for 4 weeks, the control group was given the same volume of physiological saline. The results showed that lower injection doses of Compound 49 (1.0 mg/kg/day and 2.0 mg/kg/day) significantly reduced 24-hour urine protein (24UPE) in the absence of significant changes in fasting blood glucose (FBG). And blood urea nitrogen (BUN) levels; especially at the dose of 1.0 mg / kg / day, the inhibition of 24UPE was as high as 48.3%, better than the positive drug Losartan (35.2%). The results are shown in Table 11.

Table 11. Anti-diabetic nephropathy (DKD) activity in mice of compound 49

^{. * P <0.05, ** p} <0.01vs normal control ^{group; # p <0.05, ## p} <0.01vs.STZ control group p;. ^C p <0.05vs losartan group; ^A left relative kidney index = Kidney weight (g) / body weight (g). The value is the mean ± SD (n = 12).

H&E staining of renal tissue sections showed that the glomerular mesangial area of diabetic nephropathy db/db mice was significantly dilated, extracellular matrix increased, diffuse mesangial sclerosis, glomerular basement membrane thickening; compound 49 treatment After showing good therapeutic effect, especially at doses of 1.0mg/kg/day and 2.0mg/kg/day, it can significantly inhibit the pathological changes of renal tissue, reduce mesangial expansion, inhibit diffuse mesangial sclerosis; therapeutic effect Better than the positive drug losartan (Figure 1).

Claims (15)

1. A compound of formula A, a pharmaceutically acceptable salt or prodrug thereof:

   

   among them,

   The dotted line indicates that there is no chemical bond or a single bond;

   R ₁ and R ₂ are each independently selected from: -H; alkyl, optionally substituted by amino, cyano, hydroxy, carboxy, alkoxy, heteroheterocyclyl, aryl, heteroaryl, - COA substituted; alkenyl group, optionally substituted by amino group, cyano group, hydroxyl group, carboxyl group, alkoxy group, aliphatic heterocyclic group, aryl group, heteroaryl group, -COA; monosaccharide group, said monosaccharide The hydroxy group of the group is optionally substituted by an alkyl group; wherein A is selected from the group consisting of hydrogen, -NR ₁₃ R ₁₄ , aryl, arylamino, alkyl optionally substituted by hydroxy, halo, alkoxy optionally substituted by hydroxy, halo base;

   Alternatively, R ₁ and R ₂ together form _{- (CH 2) m1 -O- (} CH 2) m2 -, wherein the H is optionally substituted with - (CH ₂₎ substituted with _{0 ~ 8 -NR 13 R 14,} m1 and m2 are each Independently an integer from 1 to 6;

   Alternatively, R ₁ and R ₂ together form the following groups:

   

   Wherein R ₉ and R _{10 are} independently -H or alkyl; or R ₉ together with R ₁₀ constitute -C(=O)-;

   R _{8 is} selected from the group consisting of: -H; hydroxy; alkyl, optionally substituted by alkoxy; alkenyl; alkynyl; aryl, optionally substituted by amino, hydroxy, halo, alkoxy , alkyl, haloalkyl substituted; aliphatic heterocyclic group, optionally substituted by amino, hydroxy, halogen, alkoxy, alkyl, haloalkyl; heteroaryl, optionally substituted Substituted by amino, hydroxy, halogen, alkoxy, alkyl, haloalkyl; -C(=Y ₁ )-Y ₂ ;-S(=O) ₂ -Y ₃ ;

   Y _{1 is} selected from the group consisting of: =O; =S; = NH;

   Y _{2 is} selected from the group consisting of: alkyl; alkoxy; hydroxylamine; -NR ₁₃ R ₁₄ ; aryl, optionally substituted by amino, hydroxy, halogen, alkoxy, alkyl, haloalkyl; a heteroaryl group optionally substituted by an amino group, a hydroxyl group, a halogen, an alkoxy group, an alkyl group or a halogenated alkyl group; an aliphatic heterocyclic group optionally substituted with an amino group, a hydroxyl group, a halogen or an alkane An oxy group, an alkyl group, a halogenated alkyl group; an aliphatic heterocyclic group-substituted alkyl-substituted aliphatic heterocyclic group, which is optionally an amino group, a hydroxyl group, a halogen group, an alkoxy group, an alkyl group or an alkyl halide. Substituted; an alkylamino group substituted by at least one of an oxygen group, a hydroxyl group, a heteroaryl group, and an aryl group, optionally substituted with an amino group, a hydroxyl group, a halogen group, an alkoxy group, or an alkyl group. Halogenated alkyl substituted;

   Y ₃ is an aryl group optionally substituted by halogen or haloalkyl;

   R _{3 is} selected from -H; hydroxy; halogen; -NR ₁₃ R ₁₄ ; -(C=O)NR ₁₁ R ₁₂ ; -(C=O)R ₁₅ ; -O(C=O)R ₁₆ ;-NR ₁₇ -(C=O)R ₁₈ ;-NR ₁₉ -(COO)R ₂₀ ;-NR ₂₁ -(SO ₂ )R ₂₂ ;-O(C=O)NR ₂₃ R ₂₄ ;-SR ₂₅ ;-(S= O) R ₂₆ ; -(SO ₂ )R ₂₇ ; -(SO ₂ )NR ₃₂ R ₃₃ ; alkyl group, optionally substituted by hydroxyl group, cyano group, carboxyl group, monosaccharide group, alkoxy group, aryl group , heteroaryl, alicyclic, -NH-CO-alkylene (NH ₂ )(A ₁ ), -NR ₁₃ R ₁₄ substituted, the aryl, heteroaryl, heteroheterocyclic group optionally Alkenyl, hydroxy, halogen, alkyl, haloalkyl; alkenyl, optionally substituted by hydroxy, cyano, carboxy, monosaccharide, alkoxy, aryl, heteroaryl, heteroheterocyclyl, -NH-CO-alkylene (NH ₂ ) (A ₁ ), -NR ₁₃ R ₁₄ substituted; alkynyl, optionally substituted by hydroxy, cyano, carboxy, monosaccharide, alkoxy, aryl a heteroaryl group, an aliphatic heterocyclic group, a -NH-CO-alkylene (NH ₂ ) (A ₁ ), a -NR ₁₃ R ₁₄ substituent;

   A _{1 is} selected from -H, an alkyl group optionally substituted by a heteroaryl group;

   R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

   When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each is independently selected from -H; hydroxy; -NR ₁₃ R ₁₄ ; -(C=O)R ₁₅ ; -NR ₁₇ -(C= O) R ₁₈ ; -SR ₂₅ ; aryl, which is optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _{0- 2} R ₃₄ substituted; heteroaryl, which is optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; alkoxy, optionally substituted by halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ An aryloxy group optionally substituted by halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ;

   G ₁ to G ₈ are each independently selected from -H; halogen; hydroxy; cyano; nitro; carboxy; -NR ₁₃ R ₁₄ ; -(C=O)NR ₁₁ R ₁₂ ;-(C=O)R ₁₅ ;-O(C=O)R ₁₆ ;-NR ₁₇ -(C=O)R ₁₈ ;-NR ₁₉ -(COO)R ₂₀ ;-NR ₂₁ -(SO ₂ )R ₂₂ ;-O(C=O NR ₂₃ R ₂₄ ; -SR ₂₅ ; -(S=O)R ₂₆ ; -(SO ₂ )R ₂₇ ; -CH=NOR ₂₈ ; -CH=NR ₂₉ ;-CH=NNR ₃₀ R ₃₁ ;-(SO ₂ ) NR ₃₂ R ₃₃ ; alkyl group, the alkyl group optionally being selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxyl, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; alkenyl, optionally substituted by halogen, hydroxy, cyano, nitro, carboxy, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; alkyne Any one selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; aryl, The aryl group is optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; heteroaryl, said heteroaryl Optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; alkoxy, which is optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _{0- 2} R ₃₄ substituted; aryloxy, optionally selected from halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ replaced;

   R ₁₃ and R ₁₄ are each independently selected from -H; amino; monosaccharide group, the hydroxy hydrogen of said monosaccharide group optionally substituted by an alkyl group; alkyl group optionally selected from halogen, hydroxy group, Cyano, nitro, carboxy, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; aryl, which is optionally substituted by amino, hydroxy, halo, alkyl, The alkyl group is optionally substituted with a halogen, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an azide group, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; an aliphatic heterocyclic group, The aliphatic heterocyclic group is optionally substituted by an amino group, a hydroxyl group, a halogen, an alkyl group, which is optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxyl, azide, -NR ₁₃ R ₁₄ , -S (O) _0-2 R ₃₄ substitution;

   R ₁₁ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ are each independently selected from: -H; alkyl; aryl;

   The heteroheterocyclyl and heteroaryl each independently contain from 1 to 4 heteroatoms selected from the group consisting of N, O, and S.
2. A compound of the formula A according to claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein the alkyl group and the alkyl group in the haloalkyl group, the alkoxy group or the alkylamino group are a C ₁ - C ₂₀ alkyl group. Or a C ₁ -C ₁₈ alkyl group, or a C ₁ -C ₆ alkyl group, or a C ₁ -C ₄ alkyl group; the alkenyl group is a C ₂ -C ₂₀ alkenyl group, or a C ₂ -C ₁₈ alkenyl, either C ₂ -C ₆ alkenyl or C ₂ -C ₄ alkenyl; the alkynyl group is a C ₂ -C ₂₀ alkynyl group, or a C ₂ -C ₁₈ alkynyl group, or C _{a 2} to C ₆ alkynyl group, or a C ₂ -C ₄ alkynyl group; the aliphatic heterocyclic group is a 4 to 14 membered monocyclic or polycyclic heterocyclic group, and the number of hetero atoms on the ring is 1 to 3, or a ring The number of heteroatoms is 1 to 2; the aryl group in the aryl group and the aryloxy group is a C ₆ -C ₁₄ monocyclic or polycyclic aryl group; the heteroaryl group is a 5 to 14 membered monocyclic or polycyclic ring The heteroaryl group has 1 to 3 hetero atoms in the ring or 1 to 2 in the ring.
3. A compound of formula A according to claim 1 or 2, a pharmaceutically acceptable salt or prodrug thereof, wherein:

   R ₁ and R ₂ are each independently selected from: -H; C ₁ ~ C ₆ alkyl group, a C ₁ ~ C ₆ alkyl group optionally substituted by amino, cyano, hydroxy, carboxy, C ₁ ~ C ₆ alkoxy a 5-, 6- or 6-membered alicyclic, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, -COA substituted; C ₂ -C ₆ alkenyl, optionally C ₂ -C ₆ alkenyl Substituted by amino group, cyano group, hydroxyl group, carboxyl group, C ₁ -C ₆ alkoxy group, 5- or 6-membered aliphatic heterocyclic group, C ₆ -C ₁₀ aryl group, 5- to 10-membered heteroaryl group, -COA; a hydroxyl group of the monosaccharide group optionally substituted by a C ₁ -C ₆ alkyl group; wherein A is selected from the group consisting of hydrogen, -NR ₁₃ R ₁₄ , a C ₆ -C ₁₀ aryl group, a C ₆ -C ₁₀ arylamino group, a C ₁ -C ₆ alkyl group optionally substituted by a hydroxy group or a halogen, a C ₁ -C ₆ alkoxy group optionally substituted by a hydroxy group or a halogen;

   Alternatively, R ₁ and R ₂ together form the following groups:

   

   Wherein R ₉ and R _{10 are} independently -H or C ₁ -C ₆ alkyl; or R ₉ and R ₁₀ together form -C(=O)-;

   R _{8 is} selected from the group consisting of: -H; hydroxy; C ₁ -C ₁₈ alkyl, said C ₁ -C ₁₈ alkyl optionally substituted by C ₁ -C ₆ alkoxy; C ₂ -C ₁₈ alkenyl; C ₂ ~ C ₁₈ alkynyl group; C ₆ ~ C ₁₀ aryl group, a C ₆ ~ C ₁₀ aryl group optionally substituted by amino, hydroxy, halo, C ₁ ~ C ₆ alkoxy group, C ₁ ~ C ₆ alkyl, C _{a 1-} to C ₆ haloalkyl group; a 5 or 6 membered alicyclic group optionally substituted with an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, or a C ₁ to C ₆ haloalkyl substituted; 5 to 10 membered heteroaryl, the heteroaryl optionally being amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl substituted; -C(=Y ₁ )-Y ₂ ; -S(=O) ₂ -Y ₃ ;

   Y _{1 is} selected from the group consisting of: =O; =S; = NH;

   Y _{2 is} selected from the group consisting of: C ₁ -C ₁₈ alkyl; C ₁ -C ₁₈ alkoxy; hydroxylamine; -NR ₁₃ R ₁₄ ; C ₆ -C ₁₀ aryl, optionally C ₆ -C ₁₀ aryl Substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; 5-10 membered heteroaryl, optionally substituted by amino a hydroxyl group, a halogen, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group; a 5 or 6-membered aliphatic heterocyclic group, said aliphatic heterocyclic group optionally being Amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl substituted; 5 or 6-membered aliphatic heterocyclyl substituted C ₁ -C ₆ alkyl substituted a 5- or 6-membered alicyclic group, optionally substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane substituents; C ₁ ~ C ₆ alkylamino group, a C ₁ ~ C ₆ alkylamino group is oxo, hydroxy, 5-10 membered heteroaryl, C ₆ ~ C ₁₀ aryl group substituted with at least one of the 5 ~ membered heteroaryl group, C ₆ ~ C ₁₀ aryl group optionally substituted by amino, hydroxy, halo, C ₁ ~ C ₆ alkoxy group, C ₁ ~ C ₆ alkyl group, C ₁ ~ C ₆ halogen Substituted alkyl;

   Y ₃ is a C ₆ -C ₁₀ aryl group optionally substituted by halogen, halogenated C ₁ -C ₆ alkyl;

   R _{3 is} selected from -H; hydroxy; halogen; -NR ₁₃ R ₁₄ ; -(C=O)NR ₁₁ R ₁₂ ; -(C=O)R ₁₅ ; -O(C=O)R ₁₆ ;-NR ₁₇ -(C=O)R ₁₈ ;-NR ₁₉ -(COO)R ₂₀ ;-NR ₂₁ -(SO ₂ )R ₂₂ ;-O(C=O)NR ₂₃ R ₂₄ ;-SR ₂₅ ;-(S= O) R ₂₆ ; -(SO ₂ )R ₂₇ ; -(SO ₂ )NR ₃₂ R ₃₃ ; C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group optionally being a hydroxyl group, a cyano group, a carboxyl group, Monosaccharide group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryl group, 5- to 10-membered heteroaryl group, 5- or 6-membered aliphatic heterocyclic group, -NH-CO-C ₁ -C ₆ -alkylene Substituted by a group of (NH ₂ )(A ₁ ), —NR ₁₃ R ₁₄ , the C ₆ —C ₁₀ aryl group, a 5- to 10-membered heteroaryl group, a 5- or 6-membered aliphatic heterocyclic group, optionally an amino group, a hydroxyl group, Halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; C ₂ -C ₆ alkenyl, the C ₂ -C ₆ alkenyl optionally being hydroxy, cyano, carboxy, monosaccharide, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, 5- or 6-membered alicyclic, -NH-CO-C ₁ -C ₆ -alkylene (NH _{2 ) (A 1), - NR} 13 R 14 substituents; C ₂ ~ C ₆ alkynyl group, a C ₂ ~ C ₆ alkynyl group optionally substituted by hydroxy, cyano, carboxy, a monosaccharide group, C ₁ ~ C ₆ alkyl alkoxy, C ₆ C ₁₀ aryl, 5- to 10-membered heteroaryl, 5 or 6-membered aliphatic heterocyclic _{group, -NH-CO-C 1 ~} C 6 alkylene group _{(NH 2) (A 1)} , - NR 13 R 14 substituents ;

   A _{1 is} selected from -H, C ₁ -C ₆ alkyl optionally substituted by 5 to 10 membered heteroaryl;

   R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

   When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each is independently selected from -H; hydroxy; -NR ₁₃ R ₁₄ ; -(C=O)R ₁₅ ; -NR ₁₇ -(C= _{O) R 18; -SR 25;} C 6 ~ C 10 aryl group, a C ₆ ~ C ₁₀ aryl group optionally substituted selected from halogen, hydroxy, cyano, nitro, carboxyl, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; 5 to 10 membered heteroaryl optionally selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, - NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₁ -C ₆ alkoxy group, the C ₁ -C ₆ alkoxy group optionally being selected from the group consisting of halogen, hydroxy, cyano, nitro , carboxy, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₆ -C ₁₀ aryloxy, said C ₆ -C ₁₀ aryloxy group optionally being selected from halogen , hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted;

   G ₁ to G ₈ are each independently selected from -H; halogen; hydroxy; cyano; nitro; carboxy; -NR ₁₃ R ₁₄ ; -(C=O)NR ₁₁ R ₁₂ ;-(C=O)R ₁₅ ;-O(C=O)R ₁₆ ;-NR ₁₇ -(C=O)R ₁₈ ;-NR ₁₉ -(COO)R ₂₀ ;-NR ₂₁ -(SO ₂ )R ₂₂ ;-O(C=O NR ₂₃ R ₂₄ ; -SR ₂₅ ; -(S=O)R ₂₆ ; -(SO ₂ )R ₂₇ ; -CH=NOR ₂₈ ; -CH=NR ₂₉ ;-CH=NNR ₃₀ R ₃₁ ;-(SO ₂ ) NR ₃₂ R ₃₃ ; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group optionally being selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxyl, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₂ -C ₆ alkenyl, the C ₂ -C ₆ alkenyl optionally selected from halogen, hydroxy, cyano, nitro, carboxy, azide , -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₂ -C ₆ alkynyl, optionally C ₂ -C ₆ alkynyl selected from halogen, hydroxy, cyano, nitro , carboxy, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; C ₆ -C ₁₀ aryl, the C ₆ -C ₁₀ aryl optionally being selected from halogen, hydroxy , cyano, nitro, carboxyl, _{azido, -NR 13 R 14, -S (} O) 0-2 R 34 substituents; 5 to 10-membered heteroaryl, said heteroaryl Selected from the group selected from halogen, hydroxy, cyano, nitro, carboxyl, _{azido, -NR 13 R 14, -S (} O) 0-2 R 34 substituents; C ₁ ~ C ₆ alkoxy group, a C _{The 1} -C ₆ alkoxy group is optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; C ₆ -C ₁₀ aryloxy, said C ₆ -C ₁₀ aryloxy group optionally being selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ replacement;

   R ₁₃ and R ₁₄ are each independently selected from -H; amino; monosaccharide group, the hydroxy hydrogen of said monosaccharide group is optionally substituted by C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl, said C _{The 1} -C ₆ alkyl group is optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, azide, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ ; C ₆ - C ₁₀ an aryl group, a C ₆ ~ C ₁₀ aryl group optionally substituted by amino, hydroxy, halo, C ₁ ~ C ₆ alkyl group, a C ₁ ~ C ₆ alkyl group optionally substituted selected from halogen, hydroxy, cyano , nitro, carboxyl, azido, -NR ₁₃ R ₁₄ , -S(O) _0-2 R ₃₄ substituted; 5 or 6-membered alicyclic group, optionally substituted with amino group, hydroxyl group, halogen, C ₁ ~ C ₆ alkyl group, a C ₁ ~ C ₆ alkyl group optionally substituted selected from halogen, hydroxy, cyano, nitro, carboxyl, azido, -NR ₁₃ R _14, -S ( O) _0-2 R ₃₄ substitution;

   R ₁₁ , R ₁₂ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ are each independently selected from: -H; C ₁ -C ₆ alkyl; C ₆ -C ₁₀ aryl;

   The heteroheterocyclyl and heteroaryl each independently contain from 1 to 4 heteroatoms selected from the group consisting of N, O, and S.
4. A compound of formula A according to any one of claims 1 to 3, a pharmaceutically acceptable salt or prodrug thereof, which is a compound of formula I, a compound of formula II or a pharmaceutically acceptable salt or prodrug thereof,

   

   Where, in formula I,

   The dotted line indicates that there is no chemical bond or a single bond;

   G ₁ to G ₈ are each independently selected from -H; halogen; C ₁ -C ₆ alkyl; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl;

   R _{3 is} selected from -H; -NR ₁₃ R ₁₄ ; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group optionally being hydroxy, cyano, carboxyl, monosaccharide, C ₁ -C ₆ alkane An oxy group, a C ₆ -C ₁₀ aryl group, a 5- to 10-membered heteroaryl group, a 5- or 6-membered aliphatic heterocyclic group, -NH-CO-C ₁ -C ₆ alkylene group (NH ₂ )(A ₁ ), Substituting -NR ₁₃ R ₁₄ , the 5- or 6-membered alicyclic group, 5- to 10-membered heteroaryl group, C ₆ -C ₁₀ aryl group optionally being amino group, hydroxy group, halogen, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl substituted;

   Wherein A _{1 is} selected from the group consisting of: -H; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group is optionally substituted by a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is optionally Amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; R ₁₃ , R ₁₄ are each independently selected from: -H; C ₁ -C ₆ alkyl;

   R ₁ and R ₂ are each independently selected from: -H; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl optionally being cyano, hydroxy, carboxy, C ₆ -C ₁₀ aryl, 5 ～10-membered heteroaryl substituted, the C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl optionally substituted by amino, hydroxy, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl ;

   In formula II,

   G ₁ to G ₈ are each independently selected from -H; halogen;

   R _{3 is} selected from -H; C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group is optionally a hydroxyl group, a cyano group, a carboxyl group, a monosaccharide group, a C ₁ -C ₆ alkoxy group, or a C ₆ - C ₁₀ aryl, 5- to 10-membered heteroaryl, 5- or 6-membered aliphatic heterocyclic group, -NH-CO-C ₁ -C ₆ alkylene (NH ₂ )(A ₁ ), -NR ₁₃ R ₁₄ substituted The 5- or 6-membered alicyclic group, 5- to 10-membered heteroaryl group, and C ₆ -C ₁₀ aryl group are optionally amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane Base substitution

   Wherein A _{1 is} selected from the group consisting of: -H; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group is optionally substituted by a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is optionally Amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; R ₁₃ , R ₁₄ are each independently selected from: -H; C ₁ -C ₆ alkyl;

   R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

   When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each is independently selected from -H or -OR ₃₅ , and R ₃₅ is -H or C ₁ -C ₆ alkyl;

   R ₉ and R _{10 are} independently -H or C ₁ -C ₆ alkyl; R _{8 is} selected from -C(=Y ₁ )-Y ₂ , -S(=O) ₂ -Y ₃ ;

   Wherein Y _{1 is} selected from the group consisting of =O; =S; = NH;

   Y _{2 is} selected from the group consisting of hydroxylamine groups; C ₆ -C ₁₀ aryl groups, and the C ₆ -C ₁₀ aryl group is optionally an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl substituted; 5-10 membered heteroaryl, the 5-10 membered heteroaryl optionally being amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkane a C ₁ -C ₆ haloalkyl group; a 5 or 6 membered alicyclic group, optionally substituted by amino, hydroxy, halo, C ₁ -C ₆ alkoxy, C ₁ ～C ₆ alkyl, C ₁ -C ₆ haloalkyl substituted; 5 or 6-membered alicyclic substituted C ₁ -C ₆ alkyl substituted 5 or 6-membered alicyclic group, said 5 or 6-membered lipid The heterocyclic group is optionally substituted by amino group, hydroxyl group, halogen, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group; C ₁ -C ₆ alkylamino group, said C _{The 1-} to C ₆ alkylamino group is substituted with at least one of oxygen, a hydroxyl group, a 5- to 10-membered heteroaryl group, and a C ₆ -C ₁₀ aryl group, and the 5- to 10-membered heteroaryl group and the C ₆ -C ₁₀ aryl group are Selected by amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

   Y ₃ is a C ₆ -C ₁₀ aryl group optionally substituted by halogen, halogenated C ₁ -C ₆ alkyl;

   Alternatively, R ₉ and R ₁₀ together form -C(=O)-, R _{8 is} selected from -H; C ₁ -C ₁₈ alkyl; C ₁ -C ₆ alkoxy substituted C ₁ -C ₁₈ alkyl.
5. A compound of formula A according to claim 4, a pharmaceutically acceptable salt or prodrug thereof, wherein:

   In formula I,

   The dotted line indicates that there is no chemical bond or a single bond;

   G ₁ to G _{8 are} as defined in the compound of formula I as claimed in claim 4;

   R _{3 is} selected from -H; -NR ₁₃ R ₁₄ ; C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl group optionally being hydroxy, cyano, carboxyl, monosaccharide, C ₁ -C ₆ alkane Oxyl, morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl or -NH-CO-C ₁ -C ₆ alkylene (NH ₂ )(A ₁ ), -NR ₁₃ R ₁₄ substituted, The morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl is optionally substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

   Wherein A _{1 is} selected from the group consisting of: -H; a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl group is optionally substituted with an imidazolyl group, a fluorenyl group, optionally an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group; R ₁₃ and R ₁₄ are each independently selected from: -H; a C ₁ -C ₆ alkyl group;

   R ₁ and R ₂ are each independently selected from -H; C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group is optionally substituted by cyano, hydroxy, carboxy, phenyl, naphthyl, pyridyl, The phenyl, naphthyl, pyridyl group is optionally substituted with an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group;

   In formula II,

   G ₁ to G _{8 are} as defined in the compound of formula II as claimed in claim 4;

   R _{3 is} selected from -H; C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group is optionally substituted with amino, hydroxy, phenyl, morpholinyl, piperidinyl, piperazinyl, said benzene The group, morpholinyl, piperidinyl, piperazinyl is optionally substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

   R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

   When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each independently selected from -H or -OH;

   R ₉ and R ₁₀ are a methyl group;

   R _{8 is} selected from -C(=Y ₁ )-Y ₂ ; -S(=O) ₂ -Y ₃ ;

   Wherein Y _{1 is} selected from the group consisting of =O; =S; = NH;

   Y _{2 is} selected from the group consisting of: hydroxylamine; phenyl, which is optionally substituted by amino, hydroxy, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; Imidazolyl; piperazinyl, said piperazinyl optionally substituted by morpholinyl; alkylamino, said alkylamino substituted by at least one of oxygen, hydroxy, thiol, phenyl;

   Y ₃ is phenyl optionally substituted by halogen, C ₁ -C ₆ haloalkyl;

   Alternatively, R ₉ and R ₁₀ together form -C(=O)-, R _{8 is} selected from -H; C ₁ -C ₁₈ alkyl; C ₁ -C ₆ alkoxy substituted C ₁ -C ₁₈ alkyl.
6. A compound of formula A according to claim 4 or 5, a pharmaceutically acceptable salt or prodrug thereof, wherein:

   In formula I,

   The dotted line indicates that there is no chemical bond or a single bond;

   G ₁ to G _{8 are} as defined in the compound of formula I as claimed in claim 4;

   R _{3 is} selected from the group consisting of C ₁ -C ₆ alkyl groups, which are morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl or -NH-CO-C ₁ -C ₆ alkylene ( At least one of NH ₂ )(A ₁ ), the morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl optionally being amino, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ to C ₆ haloalkyl substituted; C ₂ -C ₆ alkyl, the C ₂ -C ₆ alkyl group is substituted by a hydroxy group; C ₃ -C ₆ alkyl group, the C ₃ -C ₆ alkyl group is -NR ₁₃ R ₁₄ substitution;

   Wherein A _{1 is} selected from the group consisting of: -H; a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl group is optionally substituted with an imidazolyl group, a fluorenyl group, optionally an amino group, a hydroxyl group, a halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group; R ₁₃ and R ₁₄ are each independently selected from: -H; a C ₁ -C ₆ alkyl group;

   R ₁ and R ₂ are each independently selected from a C ₁ -C ₆ alkyl group, and the C ₁ -C ₆ alkyl group is substituted with at least one of a phenyl group, a naphthyl group, and a pyridyl group;

   Optionally,

   In formula I,

   The dotted line indicates that there is no chemical bond or a single bond;

   G ₁ to G ₈ are each independently selected from -H, halogen, allyl, isopentenyl;

   R _{3 is} selected from -H; -Me; -(CH ₂ ) _{1 to 6} OH; -(CH ₂ ) _{0 to 6} NH ₂ ; -(CH ₂ ) _{1 to 4} NMe ₂ ; -(CH ₂ ) _{1 to 4} CN; -(CH ₂ ) _{1 to 4} CO ₂ H; -(CH ₂ ) _{1 to 4} C ₆ H ₅ OH; -(CH ₂ ) _{1 to 4} C ₆ H ₅ OMe; -(CH ₂ ) _{1 to 4} C ₆ H ₅ NH ₂ ; -(CH ₂ ) _{1 to 4} M; morpholine ethyl; piperidinyl ethyl; piperazinyl ethyl; methyl piperazinyl ethyl; pyridylethyl; halophenylethyl; (CH ₂ ) _{1 to 6} -NH-CO-CH(NH ₂ )(A ₁ ); wherein A ₁ , R ₁₃ and R _{14 are} as defined in claim 4, and M is a monosaccharide group;

   Alternatively, the R _{3 is} selected from the group consisting of morpholine ethyl; piperidinyl ethyl; piperazinyl ethyl; methyl piperazinyl ethyl; pyridylethyl; aminobenzyl; aminophenethyl; hydroxybenzyl; Benzene ethyl; -(CH ₂ ) _1~6 -NH-CO-CH(NH ₂ )(A ₁ ); -(CH ₂ ) _{2 to 4} OH; -(CH ₂ ) _{3 to 6} NH ₂ ;- (CH ₂ ) _{1 to 4} NMe ₂ ; wherein A _{1 is} selected from -H; imidazole methyl;

   Alternatively, said R _{3 is} selected from the group consisting of 2-(4-morpholinyl)ethyl; 2-(piperidin-1-yl)ethyl; 2-(piperazin-1-yl)ethyl; 2-(4 -methylpiperazin-1-yl)ethyl; 2-(pyridin-2-yl)ethyl; p-aminobenzyl; p-aminophenethyl; p-hydroxybenzyl; 2-(2-chloro- 6-fluorophenyl)ethyl; -(CH ₂ ) _{1 to 6} -NH-CO-CH(NH ₂ )(A ₁ ); -(CH ₂ ) _{2 to 4} OH; -(CH ₂ ) _{3 to 6} NH ₂ ; -(CH ₂ ) _{1 to 4} NMe ₂ ; wherein A _{1 is} selected from -H; (imidazol-4-yl)methyl; (indol-3-yl)methyl;

   R ₁ and R ₂ are each independently selected from -H; -Et; -(CH ₂ ) _{1 to 4} CN; -(CH ₂ ) _{1 to 4} CO ₂ H; -(CH ₂ ) _{1 to 4} OH; Naphthylethyl; pyridylethyl;

   Or, each of R ₁ and R _{2 is} independently selected from phenethyl; naphthylethyl; pyridylethyl;

   In formula II,

   G ₁ to G ₈ are each independently selected from -H; halogen;

   R ₃ is -H;

   R ₄ together with R ₅ constitutes =0, and/or R ₆ together with R ₇ constitutes =0;

   When R ₄ and R ₅ or R ₆ and R ₇ do not constitute =0, each is independently selected from -H or -OR ₃₅ , and R ₃₅ is -H or C ₁ -C ₆ alkyl;

   R ₉ and R ₁₀ are both methyl;

   R _{8 is} selected from -C(=Y ₁ )-Y ₂ ; -S(=O) ₂ -Y ₃ ;

   Wherein Y _{1 is} selected from the group consisting of =O; =S; = NH;

   Y _{2 is} selected from the group consisting of: hydroxylamine; phenyl, which is optionally substituted by halogen, C ₁ -C ₆ haloalkyl; imidazolyl; oxoindenylamino; oxyphenylethylamino; (morpholine) Ethyl)piperazinyl; (halophenyl)methylamino; (halophenyl)ethylamino; (halomethylphenyl)ethylamino; phenylmethylamino; (methoxyphenyl)methylamino ; hydroxypropylamino; 4-(N,N-bis(2-chloroethyl)amino)phenylpropyl;

   Alternatively, Y _{2 is} selected from the group consisting of: hydroxylamine; phenyl; halophenyl; trifluoromethyl substituted phenyl; 2-oxophenyl-2-(1H-indol-3-yl)-1-ethylamino ; imidazol-1-yl; 2-oxophenyl-2-phenyl-1-ethylamino; 4-(2(morpholin-1-yl)ethyl)piperazin-1-yl; (2,6- Difluorophenyl)methylamino; (3-chloro-4-fluorophenyl)methylamino; 2-(2-chloro-6-fluorophenyl)-1-ethylamino; 2-(4-trifluoromethyl Phenyl)-1-ethylamino; phenylmethylamino; (4-methoxyphenyl)methylamino; (S)-2-hydroxy-1-propylamino; 4-(N,N-bis(2) -chloroethyl)amino)phenylpropyl;

   Y ₃ is phenyl optionally substituted by halogen, C ₁ -C ₆ haloalkyl;

   Alternatively, Y _{3 is} selected from halophenyl; trifluoromethyl substituted phenyl;

   or,

   R ₉ together with R ₁₀ constitutes -C(=O)-;

   R _{8 is} selected from -H; C ₁ -C ₁₈ alkyl; C ₁ -C ₆ alkoxy-substituted C ₁ -C ₁₈ alkyl; or R ₈ is methyl.
7. A compound of formula A according to any one of claims 1 to 6, a pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of the following compounds, pharmaceutically acceptable salts or prodrugs thereof:

   

   

   

   
8. A compound of formula A according to any one of claims 1 to 7, a pharmaceutically acceptable salt or prodrug thereof, wherein:

   The pharmaceutically acceptable salt includes a salt of an organic or inorganic acid;

   Optionally, the pharmaceutically acceptable salt is selected from the group consisting of a salt of the compound of formula A with the following compound: hydrochloric acid; sulfuric acid; phosphoric acid; formic acid; acetic acid; propionic acid; lactic acid; citric acid; tartaric acid; succinic acid; Horse acid; maleic acid; mandelic acid; malic acid; camphorsulfonic acid;

   The pharmaceutically acceptable prodrug comprises a phosphate prodrug or a carbamate prodrug of the compound of formula A.
9. A process for the preparation of a compound of the formula A according to any one of claims 1-8, a pharmaceutically acceptable salt or prodrug thereof, which comprises a compound of the formula I-1, a compound of the formula I-2, I-3 a preparation step of a compound, a compound of II-1, or a compound of II-2,

   In the compound of the formula I-1, G ₁ to G ₈ , R ₁ , R _{2 are} as described in any one of claims 1 to 8, and the preparation steps of the compound of the formula I-1 include:

   1) a preparation step of the compound of the formula a3, which is selected from the following method (1) or method (2),

   Process (1): a compound of the formula a1 and a compound of the formula a2 are obtained by a Perkin condensation reaction to obtain a compound of the formula a3;

   Process (2): a compound of the formula a2, a compound of the formula a6 and a compound of the formula a7 are reacted by Grignard and reacted with ethyl iodide to prepare a compound of the formula a8, and then the compound of the formula a8 is obtained by hydrolysis under basic conditions and then acidification. a compound of formula a3;

   And 2) a preparation step of the compound of the formula I-1,

   Preparing a compound of formula I-1 from a compound of formula a3;

   In the compound of the formula I-2, G ₁ to G ₈ , R ₁ , R ₂ and R _{3 are} as defined in any one of claims 1 to 8, but R _{3 is} not H, and the compound of the formula I-2 The preparation step comprises: preparing a compound of formula 1-2 from a compound of formula I-1;

   The compound of the formula I-3, wherein G ₁ to G ₈ , R ₁ , R ₂ , R _{3 are} as defined in any one of claims 1 to 8, the preparation step of the compound of the formula I-3 comprises:

   1): a compound of the formula I-1 is obtained by a cyclization reaction or an oxidative cyclization reaction of dichlorodiacyanyl p-benzoquinone (DDQ), and a compound of the formula I-3 is obtained from a compound of the formula a5, wherein In the compound of formula I-3, R ₃ is H;

   Or 2): a compound of the formula 1-2 is obtained by a photo-cyclization reaction or an oxidative cyclization reaction of dichlorodicyan-p-benzoquinone (DDQ), wherein the compound of the formula I-3 is not R ₃ H;

   Wherein, when R ₁ and R ₂ are a reactive group, the protecting group is optionally protected;

   

   In the compound of the formula II-1, R ₉ and R ₁₀ are -H or an alkyl group; and G ₁ to G ₈ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R _{8 are} as defined in claims 1-8. In any one of the above, the preparation step of the compound of the formula II-1 comprises: a compound of the group II-1-A, a compound of the group II-1-B, a compound of the group II-1-C, a compound of the group II-1-D Or the preparation steps of the II-1-E compound,

   

   The compound of the formula II-1-A is a compound of the formula II-1 as defined below: in the compound of the formula II-1, R ₈ is -C(=Y ₁ )-Y ₂ , and Y _{1 is} selected from =O or =S; ₂ is an aryl group, which is optionally substituted by an amino group, a hydroxyl group, a halogen, an alkoxy group, an alkyl group, or a halogenated alkyl group;

   The preparation step of the II-1-A compound comprises: preparing the compound of the formula b1 by an acylation reaction with an arylformyl reagent or an arylsulfonyl reagent, in the arylformyl reagent or the arylsulfonyl reagent The substituent on the aryl group is the same as the substituent on the Y ₂ aryl group; in the compound of the formula b1, G ₁ to G ₈ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ as described in the class II-1-A compound;

   The compound of the formula II-1-B is a compound of the formula II-1 as defined below: wherein R ₈ is -C(=Y ₁ )-Y ₂ , and Y _{1 is} selected from =O or =S; Y; ₂ is an imidazolyl group; the preparation step of the II-1-B compound comprises: reacting a compound of the formula b1 with 1,1'-thiocarbonyldiimidazole or triphosgene with imidazole to obtain a compound of the formula b2; wherein the compound of the formula b2 Where Y ₁ is =O or =S;

   The compound of the formula II-1-C is a compound of the formula II-1 as defined below: in the compound of the formula II-1, R ₈ is -C(=Y ₁ )-Y ₂ , and Y _{1 is} selected from =O or =S; _{2 is} selected from the group consisting of hydroxylamine groups; -NR ₁₃ R ₁₄ ; an aliphatic heterocyclic group-substituted alkyl-substituted aliphatic heterocyclic group, which is optionally an amino group, a hydroxyl group, a halogen group, an alkoxy group, or an alkyl group. a haloalkyl group; an alkylamino group substituted with at least one of an oxygen group, a hydroxyl group, a heteroaryl group, and an aryl group, optionally substituted with an amino group, a hydroxyl group, a halogen group, an alkoxy group, An alkyl group, a haloalkyl group; wherein R ₁₃ and R _{14 are} as defined in claim 1; and the step of preparing the II-1-C compound comprises: reacting a compound of formula b2 with methyl iodide to form a compound of formula b3, formula b3 The compound is obtained by reacting with a compound R; wherein the compound R is selected from an aliphatic heterocyclic group-substituted alkyl-substituted aliphatic heterocyclic ring, and the aliphatic heterocyclic group and the aliphatic heterocyclic ring are optionally an amino group, a hydroxyl group, or a halogen. Alkoxy, alkyl, haloalkyl substituted; alkylamine substituted by at least one of oxygen, hydroxy, heteroaryl, aryl, said heteroaryl, aryl Optionally substituted amino, hydroxy, halo, alkoxy, alkyl, haloalkyl;

   The II-1-D compound is a compound of the formula II-1 as defined below: in the compound of the formula II-1, R ₈ is -C(=NH)-NHOH; the preparation steps of the II-1-D compound include The compound of the formula b4 is obtained from the compound of the formula b1, and the compound of the formula b4 is reacted with hydroxylamine hydrochloride;

   The II-1-E compound is a compound of the formula II-1 as defined below: in the compound of the formula II-1, R ₈ is -C(=Y ₁ )-Y ₂ , Y ₁ is =O, and Y ₂ is 4- (N,N-bis(2-chloroethyl)amino)phenylpropyl; the preparation step of the II-1-E compound comprises: reacting a compound of the formula b1 with chlorambucil;

   In the compound of the formula II-2, R ₉ and R ₁₀ together form -C(=O)-; G ₁ to G ₈ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R _{8 are} as claimed. 1-8, wherein the preparation of the compound of the formula II-2 comprises: reacting a compound of the formula c1 with a compound of the formula c2 to obtain a compound of the formula c3, which is then reacted to obtain a compound of the formula c4, which is then obtained by a reaction. The compound of the formula c5 is further reacted to obtain the compound of the formula c6, and the compound of the formula c7 is obtained by the reaction, and the compound of the formula c8 is obtained by the reaction, and the compound of the formula c9 is obtained by the reaction, and the compound of the formula II-2 is obtained by the reaction. ;

   When R ₃ is a reactive group, it is optionally protected with a protecting group;

   

   

   Optionally, the Perkin condensation reaction is carried out in the presence of oxalyl chloride, triethylamine (Et ₃ N), dichloromethane;

   Optionally, the aminolysis reaction is carried out in the presence of hexamethyldisilazide (HMDS), N,N-dimethylformamide and methanol;

   Optionally, the photo-cyclization reaction uses acetone as a solvent, using iodine as a catalyst, and performing under high-pressure mercury lamp illumination;

   Optionally, the oxidative cyclization reaction of dichlorodicyanoquinone (DDQ) is oxidatively ring-closing with DDQ in a benzene solvent under the catalysis of p-toluenesulfonic acid;

   Optionally, the compound of the formula a6 is obtained by reacting dibromomaleimide with methyl iodide;

   Alternatively, the compound of the formula a8 is obtained by hydrolysis under basic conditions to obtain a compound of the formula a3;

   Optionally, when R ₁ , R ₂ or R ₃ is a reactive group, the protecting group is selected from (Boc) ₂ O;

   Optionally, in the II-1-A compound, R ₃ is -H; R ₆ and R ₇ together form =0; R ₈ is a methyl group, and the preparation steps of the II-1-A compound include: 1 acylation reaction, dissolving the cruciferine in dichloromethane, adding triethylamine, and acylation reaction with the halogenated benzoylating reagent; 2 halogenating reaction, the product obtained in step 1 in methanol and halogenated The diimide undergoes a halogenation reaction at room temperature; 3 oxidation, the product obtained in step 2 is oxidized with an oxidizing agent to obtain R ₄ , R _{5 is} independently selected from -H; -OH; or R ₄ and R ₅ together constitute =0. a compound; the acylation reaction, a halogenation reaction, an oxidation reaction are carried out in an optional order; alternatively, the oxidation reaction is carried out using the following reagents: O ₂ , DMSO, t-BuOK;

   Optionally, in the II-1-B compound, R ₃ in the compound of formula b2 is -H; R ₄ and R _{5 are} independently selected from -H; R ₆ together with R ₇ constitutes =0; R ₈ is Methyl; the preparation of the II-1-B compound is carried out by the following method: Method 1: Dissolving cruciferine in dichloromethane, then adding triethylamine, and reacting with 1,1'-thiocarbonyldiimidazole Or method 2: dissolving cruciferine in tetrahydrofuran, then adding diisopropylethylamine and triphosgene to react, dissolving the crude product in tetrahydrofuran, adding diisopropylethylamine, imidazole and p-dimethylamino Made from pyridine;

   Optionally, in the II-1-C compound, R ₃ is -H; R ₄ and R ₅ are both -H; R ₆ together with R ₇ constitutes =0; R ₈ is methyl; The preparation step of the 1-C compound comprises: forming a salt of the compound of the formula b2 with iodomethane in an acetonitrile solvent, then dissolving in dichloromethane, adding triethylamine and compound R to carry out a reaction to replace the imidazole salt;

   Optionally, in the II-1-D compound, R ₃ is -H; R ₄ and R ₅ are both -H; R ₆ together with R ₇ constitutes =0; R ₈ is methyl; 4) The preparation method of the compound comprises the following steps: preparing a reaction of Fradcarbazole C with hydroxylamine hydrochloride;

   Optionally, in the II-1-E compound, R ₃ is -H, R ₄ and R ₅ are both -H; R ₆ together with R ₇ constitutes =0; R ₈ is methyl; The preparation step of the 1-E compound comprises: reacting staurosporine with chlorambucil;

   Alternatively, in the compound of the formula II-2, R ₃ is -H; R ₄ together with R ₅ constitutes =0; R ₆ together with R ₇ constitutes =0; R ₈ is methyl; 2 The preparation steps of the compound include: 1 using glucose as a raw material, undergoing peracetylation, 1-position bromination, 1,2-position olefination reaction, deacetylation, 6-position hydroxyl group TIPS protection, 3,4-position Constructing oxazolone, methylation, reduction of sodium hydroxymercury hydride to introduce hydroxyl group at 1-position to obtain sugar donor; 2 using 2,3-dibromomaleimide as raw material, protected by BOM, and The 吲哚 氏 reagent reacts to introduce one molecule of hydrazine, and then protects the hydrazine nitrogen hydrogen with Boc, and then reacts with the 吲哚 氏 reagent to obtain a mother nucleus; 3 the sugar donor described in step 1 and step 2 The mother nucleus, using the Mitsunobu reaction for glycosidation to form the first glycosidic bond, the isomer of the glycosidic bond is separated by silica gel column chromatography, and then the Boc and TIPS protecting groups are removed, and the high pressure mercury lamp is irradiated to carry out the ring, and then The 6-position hydroxyl group is substituted with iodine, the 5,6-position deiodination is double bond, and then the second glycosidic bond is formed under iodine catalysis, and the iodine is deiodated with tetrabutyltin hydride, 20% of hydrogen and oxygen. Palladium-carbon removal of BOM;

   Alternatively, in the compound of the formula II-2, R ₃ is -H; R ₈ is a methyl group; R ₄ together with R ₅ constitutes =0, R ₆ and R ₇ are both -H; or, R ₄ , R ₅ is -H, and R ₆ and R ₇ together constitute =0; the preparation step of the compound of the formula II-2 includes: the R ₃ is -H, and R ₄ and R ₅ together constitute =0, R ₆ The compound of the formula II-2 which together with R _{7 is} =0, and R ₈ is a methyl group is obtained by reduction of sodium borohydride and reduction of zinc powder by acetic acid;

   Alternatively, the compound of the formula II-2 is prepared by using a D-glucose or an L-glucose to carry out a glycosidic bond and an isomer of a different configuration of the oxazolidine.
10. An antitumor pharmaceutical composition comprising at least one of a compound of formula A according to any one of claims 1 to 8, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient; optionally The anti-tumor drug is an anti-drug resistant drug; optionally, the anti-tumor drug is an anti-leukemia drug, an anti-breast cancer drug, an anti-lung cancer drug or an anti-liver cancer drug; alternatively, the anti-tumor drug is Anti-mutagenic leukemia drug or anti-mutation lung cancer drug; optionally, the anti-tumor drug is anti-acute promyelocytic drug, anti-chronic myeloid leukemia drug, anti-T lymphocytic leukemia drug, anti-FLT3-ITD mutation Human acute double phenotype (B, mononuclear) myeloid leukemia drug, anti-adriamycin-resistant leukemia drug, anti-breast invasive ductal carcinoma drug, anti-lung adenocarcinoma drug, anti-K-ras mutant lung adenocarcinoma drug, Or anti-gefitinib or erlotinib to obtain EGFR-T790M/L858R mutant lung adenocarcinoma drugs.
11. A biological probe for inhibiting cell proliferation, comprising at least one of the compound of formula A according to any one of claims 1 to 8, a pharmaceutically acceptable salt or prodrug thereof, and an optional solvent. Alternatively, the solvent is water, methanol, dimethyl sulfoxide or a mixed solvent of two or more thereof.
12. The use of a compound of formula A according to any one of claims 1-8, a pharmaceutically acceptable salt or prodrug thereof for the preparation of an antitumor drug, optionally, the antitumor drug is an anti-drug resistant drug; Optionally, the anti-tumor drug is an anti-leukemia drug, an anti-breast cancer drug, an anti-lung cancer drug or an anti-liver cancer drug; optionally, the anti-tumor drug is an anti-mutagenic leukemia drug or an anti-mutation lung cancer drug; Optionally, the anti-tumor drug is an acute double-phenotype (B, mononuclear) myeloid cell against acute promyelocytic leukemia drug, anti-chronic myeloid leukemia drug, anti-T lymphocytic leukemia drug, anti-FLT3-ITD mutation Leukemia drugs, anti-adriamycin-resistant leukemia drugs, anti-breast invasive ductal carcinoma drugs, anti-lung adenocarcinoma drugs, anti-K-ras mutant lung adenocarcinoma drugs, or anti-gefitinib or erlotinib EGFR-T790M/L858R mutant lung adenocarcinoma drug.
13. Use of a compound of formula A according to any one of claims 1-8, a pharmaceutically acceptable salt thereof or a prodrug thereof as a biological probe for inhibiting cell proliferation.
14. A composition for inhibiting alpha-glucosidase, anti-diabetic, or anti-diabetic complications, comprising at least one of a compound of formula A according to any one of claims 1-8, a pharmaceutically acceptable salt or prodrug thereof And a pharmaceutically acceptable excipient; optionally, the diabetes is alpha-glucosidase mediated diabetes; optionally, the diabetic complication is diabetic nephropathy.
15. Use of a compound of formula A according to any one of claims 1-8, a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of an a-glucosidase inhibitor, an anti-diabetic, or an anti-diabetic complication drug; The diabetes is alpha-glucosidase mediated diabetes; optionally, the diabetic complication is diabetic nephropathy.

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