WO2008113255A1 - Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof - Google Patents

Abstract

Novel benzamide derivatives of formula I, wherein the definition of substituents Het, G1, G2, G3, Y, X1, X2, X3 and X4 see also in the description. Preparation processes for these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds as active ingredients in medicament for the treatment of diseases associated with proliferation, such as leukaemia and solid tumor.

Description

 Benzamide derivatives having antiproliferative activity and pharmaceutical preparations thereof

Technical field

 The present invention relates to a compound for treating a disease associated with proliferation, and more particularly to a novel benzoquinone derivative and a process for the preparation thereof, a salt of the derivative and the compound or a salt thereof A drug that is an active ingredient.

Background technique

 Malignant tumors are a serious threat to human life and health. According to the World Health Organization, about 6.3 million people die of malignant tumors every year in the world. About 1.5 million people die of cancer every year in China. At present, there are more than 1.8 million new cancer patients in China every year. Due to environmental pollution, lifestyle changes and other factors, the number of malignant tumor deaths in China is increasing year by year, and the task of cancer prevention and treatment is very large. Medications play an important role in the three major treatments for malignant tumors, and they are developing rapidly. In recent years, cancer chemotherapy has made considerable progress, and the survival time of cancer patients has been significantly prolonged, but the treatment of most malignant tumors that are most harmful to human life and health remains

Failed to achieve satisfactory results.

 In the traditional sense, chemotherapeutic drugs often produce more serious toxic and side effects because of the lack of selectivity of the target, which greatly restricts the clinical effects. In recent years, advances in pharmacogenomics, proteomics, and molecular pharmacology have led to the clarification of the pathogenesis of tumors; the application of large-scale virtual screening, combinatorial chemistry, and genetic engineering has accelerated the process of drug development, research on anticancer drugs and Development has entered a new era. Pharmacists and oncologists are increasingly aware that to improve the efficacy of cancer treatment, we must start with the mechanism of tumor development, in order to achieve breakthrough progress, and fundamentally prevent and treat cancer. Therefore, anti-tumor drugs are developing from traditional cytotoxic drugs to novel anti-tumor drugs that target molecular targets at multiple targets. For example, Gefitinib, a newly marketed anti-non-small cell lung cancer drug, is a specific protein kinase targeting tumor cell signaling systems, showing good efficacy and low toxic side effects. Discovery and clinical use are transforming oncology treatment from palliative care to #^'.

 Proteins associated with the occurrence and metastasis of tumors, and proteins with universal biological significance for the regulation of tumor cell growth factors, are most likely to be targets for broad-spectrum, low-toxicity anti-tumor drugs. Histone deacetylase (HDAC) is one such protein that is one of the new targets for anti-tumor effects. Because of its unique mechanism of gene level, it has attracted great attention from researchers at home and abroad.

Chromatin is composed of DNA, histones, and non-histones. The nucleosome is the basic repeat unit of chromatin, an octamer composed of histones H3, H4, H2A, H2B, and a histone HI located outside the nucleosome and a DNA containing 146 city-pairs entangled outside it. Composition. The acetylation state of histones plays an important role in the regulation of gene transcription. Studies have shown that the ε-lysine of histones in the nucleosomes is highly acetylated at sites with high transcriptional activity, while the histones that are transcriptionally at a relatively static site are It is in a low acetylation state. The acetylation status of histones is regulated by two types of enzymes, histone acetyltransferases (HAT) and histone deacetylases (histone). Deacetylase, HDAC), HAT can specifically catalyze the acetylation of several histone components H1, H2A, H2B, H3, H4 amino terminal lysine residues, HDAC catalyzes the deacetylation of histones, causing the corresponding genes The expression is decreased, and under normal physiological conditions, the regulation of histone acetylation by these two types of enzymes is in equilibrium. When the cells are transformed, the activity of HDAC is significantly enhanced. The original gene expression equilibrium state is broken, leading to an imbalance in the expression of molecules that affect cell proliferation and regulate the cell cycle, which leads to cell malignant transformation.

 Current studies have confirmed that histones are mostly hypoacetylated in tumor cells, and the imbalance of histone acetylation status is closely related to tumorigenesis. The best illustration of the relationship between histone hypoacetylation and tumorigenesis is the study of acute promyelocytic leukemia. The retinoic acid receptor (RAR) is an important transcriptional regulator of myeloid differentiation. RARa forms a heterodimer with RAR and binds to the retinoic acid response element on DNA. In the absence of retinoic acid, SIN3/HDAC3 can be recruited by nuclear co-repressors and retinoic acid scorpion receptor silencing regulators to inhibit transcription.

HAT is widely present in cells ranging from yeast to mammalian organisms, and a variety of protein molecules of HAT activity have been discovered, and various classification methods are available depending on structure and function. Mammalian HDAC, at the molecular level, can be divided into three types: I / Π type HDAC is Zn ²⁺ dependent, and type III HDAC is nicotinamide adenine dinucleotide (NAD) dependent type. Type I includes HDAC1, 2, 3, 8, and 11, all located in the core, and has a relative molecular weight of 42,000 55,000.

 Type II includes HDAC4, 5, 6, 7, and 9, which are relatively large molecular weight proteins with a relative molecular weight of 120,000 to 130,000. It is mainly located in the cytoplasm but can shuttle between the nucleus and the cytoplasm. Type III HDAC has homology with the yeast Sir2 family and has not been extensively studied in mammalian systems (Liu Bing, Liu Aijun, Liao Chenzhong, et al. "Three-dimensional quantitative structure-activity relationship of sulfonamide hydroxamic acid HDAC inhibitors". 》 2005, 21(3): 333-337 ).

Studies have shown that histone deacetylase (HDAC) inhibitors can inhibit tumor cell growth, promote differentiation, and induce apoptosis. Compared with traditional anti-tumor drugs, the therapeutic advantages of HDAC inhibitors will be mainly reflected in two aspects: (1) It can directly act on the key link of abnormal expression of genes, thereby inhibiting and correcting excessive proliferation and escape of tumor cells. The ability to differentiate is different, which is different from the traditional anti-tumor drugs only for the single phenotype of excessive cell proliferation, and has weaker effects on other phenotypes caused by abnormal gene expression; in vitro experiments have confirmed that HDAC inhibitors have a wide range of Anti-tumor effect, showing good killing effect on tumor cells from a variety of swollen sources, including bladder, bone, breast, uterus, central nervous system, esophagus, lung, ovary, pancreas, prostate, etc. After treatment with HDAC inhibitors, these The cells showed obvious apoptosis, inhibition of proliferation, and cell cycle arrest. Animal experiments showed that HDAC inhibitors can effectively inhibit and kill tumor cells of tumor-bearing animals without obvious adverse reactions. These drugs have changed the way traditional chemotherapeutic drugs fight against all rapidly dividing cells. The treatment of abnormal gene mutations or gene expression of tumor cells has little effect on normal cells. (2) HDAC inhibitors can not only increase the selectivity of anti-tumor drugs, but also can be combined with drugs with different mechanisms of action to combat tumor resistance and ultimately improve tumor patients. Survival is of great significance. HDAC inhibitors are also used in combination with a variety of chemotherapeutic drugs to demonstrate good synergistic therapeutic effects. For example, the application of TSA or SAHA at the beginning of treatment can increase the sensitivity of tumor cells to the target drug or topoisomerase chemotherapeutic drug etoposide. The combination of SAHA and Gleevec can re-susceptibility to Gleevec-resistant chronic myeloid leukemia cells. VEGF inhibitors used together with the HDAC inhibitor LAQ824 to inhibit 51% of cultured endothelial cells (twice the effect when using both drugs alone). In a mouse model, this association can be controlled 60% of new blood vessels are formed, compared to 50% when used alone. The inhibition rates of tumor growth in mice with prostate cancer were 35% and 75%, respectively. When combined, the inhibition rate was 85%. The tumor inhibition rates of these two inhibitors in breast cancer mice were 54% and 60%, respectively, and the combined tumor growth was reduced by 80%.

 HDAC inhibitors are known to be: (1) short-chain fatty acids such as butyric acid, phenylbutyric acid; (2) hydroxamic acids such as SAHA, Scriptaid; (3) cyclotetraquinone structures containing an epoxyketone group, such as TrapoxinB, HC-Toxin, etc.; (4) a cyclotetrapeptide structure free of epoxy ketone groups, such as FK228; (5) benzoquinones, such as MS-275 (EP0847992A1, US2002/0103192A1, WO02/26696A1, WO01/ 18171A2). These compounds all show potential anti-tumor activity; valproic acid (July 2005) and SAHA (October 2006) have been approved for marketing by the US FDA.

However, these drugs have the following disadvantages: (1) low efficacy, short-chain fatty acids, such as butyric acid, etc.; (2) large side effects, hydroxamic acid compounds are Zn ²⁺ as a binding target, known in vivo There are many Zn ²⁺ containing proteins, so the side effects of hydroxamic acid compounds are large; (3) high cost, cyclotetraquinone structure containing epoxy ketone group, and cyclotetrapeptide structure containing no epoxy ketone group The preparation method is separated and purified by high performance liquid chromatography, which is not suitable for scale production. The production cost is high; if it is prepared by chemical method, the cost is higher. (4) Poor stability, clumsy amides have physicochemical properties due to their phenylenediamine structure. MS-275 is the first histone deacetylase inhibitor that has been shown to have oral anticancer activity in animals. Currently, MS-275 is undergoing clinical studies of leukemia and solid tumors in the United States. However, some new compounds with better performance have yet to be developed in order to obtain HDAC inhibitors with high anticancer activity, small side effects and more stability.

Summary of the invention

 It is an object of the present invention to provide novel buckwheat amide derivatives having the following structure:

Or a salt of a pharmaceutically acceptable acid, wherein the definition of each substituent in the formula is as detailed below.

 Another object of the present invention is to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable acid salt.

 Another object of the present invention is to provide a process for the preparation of the above compound or a pharmaceutically acceptable acid salt thereof.

 Another object of the invention is to provide the use of a compound as described above or a pharmaceutically acceptable acid salt thereof.

 The present invention provides novel benzoquinone derivatives having the structure of formula (I):

x ₂ Or a pharmaceutically acceptable acid salt thereof,

 among them:

 Het is an aryl group, a heterocyclic aryl group, a cycloalkyl group or a heterocyclic group, and these groups may be optionally substituted, and each group may be arbitrarily fused with one or more aryl or heterocyclic aryl groups, or Or a plurality of saturated or partially unsaturated cycloalkyl or heterocyclic rings, each ring may be optionally substituted;

 G, selected from a chemical bond, T, L-T, T-L or T-L-T;

 Wherein in the presence of L, 1^ is 8, 0, C=0 or N(R!), wherein 1] is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and tert-butoxycarbonyl;

T is dC ₄ alkylene in the presence of;

G ₂ is an arylene group or a heterocyclic arylene group, and each group may be optionally substituted;

G ₃ is a vinylidene group or is absent (ie, the G ₂ group is directly attached to -C=0 in formula I);

Y is NH ₂ or OH;

XX ₂ , X ₃ , each independently selected from hydrogen, halogen (which may preferably be fluorine, chlorine, bromine or iodine), dC ₄ alkyl or ^- alkoxy, and defines x!, x ₂ , x ₃ , At least one of them is not hydrogen.

Preferred compounds of formula I according to the invention, wherein are selected from the group consisting of fluorine, dC ₄ alkoxy, X, X ₃ , each independently selected from hydrogen, fluoro, chloro, bromo, iodo, dC ₄ alkyl or dC ₄ alkoxy .

Preferred compounds of formula I according to the invention, wherein X ₂ is fluoro, dC ₄ alkoxy, Xi, x ₃ , are all hydrogen. Preferred compounds of the invention of formula I, wherein G ₃ is absent.

Preferred compounds of formula I, wherein G ₂ is phenylene, and

 Het- Gi is

 Preferred compounds of formula (I) of the invention have the structure of formula (IA):

R ₂ is hydrogen or -C 4 alkyl;

Y is -NH ₂ or -OH;

X _{2 is} selected from fluorine or -C 4 alkoxy;

Het is selected from a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, a benzothiazolyl group, a benzimidazolyl group or a benzotriazole group, and each group may be optionally substituted. A preferred compound of formula (IA) of the invention having the structure of formula (I A-1):

Where: L is NH or S;

 P, Q, M, G, and U are each independently CH or N and M, Q, and U cannot be N at the same time, as long as no more than two of P, Q, M, G, and U are N, including P and Q. In the rings of M, G, and U, the S or O of one ring is not adjacent to S or O on the other ring;

R ₂ is hydrogen or C _r C ₄ alkyl;

X _{2 is} selected from fluorine or. ₁ -. ₄ methoxy group;

The groups A and B may be the same or different and independently selected from hydrogen, halogen, dC ₄ alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy, heteroarylalkoxy, alkoxyalkyl , haloalkyl, amino, nitro, alkylthio, amido, carbamide or

, o > , -c -



Preferred compounds of formula (IA) of the invention having the structure of formula (IA-2):

among them:

 L is S or NH;

R ₂ is hydrogen or -alkyl;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

 A, B is as defined in the compound of formula (I A-1 ).

 Preferred compounds of formula (IA) according to the invention have the structure of formula (IA-3):

among them:

 Is S or NH;

X _{2 is} selected from fluorine or C _r C ₄ alkoxy;

 A, B are as defined in the compound of formula (I A-1 ).

 Preferred compounds of formula (IA) of the invention have the structure of formula (IA-4):

among them:

 L is S or NH;

 D is N-R3 or S;

 E is N or C-A;

R ₂ and R ₃ are each independently hydrogen or C _r C ₄ alkyl; x _{2 is} selected from fluorine or C!-alkoxy;

 A, B is as defined in the compound of formula (IA-1).

 Preferred compounds of formula (IA) of the invention have the structure of formula (IA-5):

( I A-5)

among them:

 L is NH;

X _{2 is} selected from fluorine or C,-C ₄ alkoxy;

 A, B is as defined in the compound of formula (I A-1 ).

 Preferred compounds of formula (I) of the invention have the structure of formula (IA-6):

, I A-0

among them:

A is hydrogen or C _r C ₄ alkyl;

 B is as defined in the formula (I A-I );

X _{2 is} selected from fluorine or dC ₄ alkoxy;

Preferred compounds of formula (I) of the invention have the structure of formula (IA-7):

among them:

 P is CH, N;

 B is as defined in the compound of formula (I A-1 );

X _{2 is} selected from fluorine or Ci-C ₄ alkoxy;

 Preferred compounds of formula (I) of the invention have the structure of formula (IB):

( IB)

among them:

0 ₁ is 1\ LT or TL, where 1^ is 8, 0 or NH T is -CH ₂ -;

Ζι is 0, S, NH or CH ₂ ;

Z ₂ is N or CH;

X _{2 is} selected from fluorine or dC ₄ alkoxy; Het is selected from phenyl, pyridyl, pyrimidinyl or benzothiazolyl, and may be substituted by A and 1 or B; A, B is as defined in the compound (I A-1 ); Het may also be 1, 2 The or three groups are optionally substituted, and these groups are independently selected from alkoxy, haloalkoxy, acyl, morphinolinyl or alkoxy optionally substituted phenyl.

Preferred compounds of formula (I) of the invention have the structure shown by formula (IC):

among them:

0 ₁ is 1\ LT or TL;

 L A S, O or NH;

T is -CH ₂ -;

Z ₂ is N or CH;

 ∑, is 0, S, NH or C3⁄4;

X _{2 is} selected from fluorine or -C ₄ alkoxy;

 Het is selected from a strepyl, pyridyl, pyrimidinyl or benzothiazolyl group, which may be substituted by A and/or B, and A, B is as defined in the compound of formula (I A-1); Het may also be substituted by one, Two or three groups are optionally substituted, and these groups are independently selected from alkoxy, haloalkoxy, acyl, morphinolinyl or alkoxy optionally substituted phenyl.

Preferred compounds of formula (I) of the invention have the structure of formula (ID):

among them

 Het is:

X _{2 is} selected from fluorine or -C ₄ alkoxy. Preferred compounds of formula (I) of the invention have the structure shown by formula (IE):

Y is -OH or -NH ₂ ;

X _{2 is} selected from fluorine or ^- alkoxy;

Het is a heterocyclic or heteroaryl group, each ring containing at least one nitrogen atom as part of the ring and optionally substituted. In a preferred compound of the formula (IE) according to the invention, Y is -NH ₂ ; X ₂ is fluoro or dC ₄ alkoxy;

 Het is a heterocyclic or heteroaryl group, each ring containing at least one nitrogen atom as part of a ring, and optionally substituted by 1 or 2 substituents selected from A or B, A, B such as formula (IA) -1 ) as defined in the compound.

 In a more preferred compound of the formula (IE) of the present invention, Het may be optionally substituted by 1 or 2 substituents, and these groups are independently selected from:

-CN , , , ο ,. - -,

.

In a preferred compound of formula (I), G ₃ is absent; G ₂ is phenylene, fluorenyl or indanyl, each of which may be optionally substituted, is a chemical bond, -C3⁄4-, -0-CH ₂ -, -S-CH ₂ -, -S-CH(CH ₃ )- or -NiR -CH^ In a more preferred compound of formula (I), G ₂ is a fluorenyl or indane group; is -03⁄4 -or-N^ -CHr;

Het is:

In a preferred compound of formula (I), G ₃ is absent;

G ₂ is a phenylene;

Gi is -S-C3⁄4- or -SC(CH ₃ )(H)-;

 Het is:

X»- or

among them: J is selected from the following groups:

Preferred compounds of formula (I) of the invention have the structure shown by formula (IF):

among them:

 Y is -OH or -N3⁄4;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

 Het is a heterocyclic or heteroaryl group in which each group may be optionally substituted, and each ring contains at least one nitrogen atom. In a preferred compound of formula (IF) of the invention, Het is:

 A preferred formula (IF) of the invention:

Y is -NH ₂ ;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

 A is as defined by the structure (I A-1).

 Preferred compounds of formula (I) of the invention have the structure of formula (IG):

among them: "

Het, G, and Y are as defined in the structure of formula (I), and X _{2 is} selected from fluorine or alkoxy.

 Preferred compounds of formula (I) of the invention have the structure represented by formula (IH):

 L is S, ◦ or -NH-;

X _{2 is} selected from fluorine or C, -C 4 alkoxy;

 A, B are as defined in the structure (I A-1 ).

 In a preferred compound of formula (IH), A is optionally substituted pyridine or optionally substituted phenyl; B is hydrogen or halogen. Preferred compounds of formula (I) of the invention have the structure of formula (I-I):

! ^ is , 0 or -NH;

X _{2 is} selected from fluorine or Ci-C 4 alkoxy;

R4 is hydrogen or C _r C ₆ alkyl.

 The invention also provides novel benzoquinone derivatives having the structure of formula II:

 Or a salt of a pharmaceutically acceptable acid.

 Hetl is an aryl or heteroaryl group which may be optionally substituted, each group may be arbitrarily combined with one or more aryl or heterocyclic groups, or with one or more saturated or partially unsaturated cycloalkyl or hetero Ring, each ring can be arbitrarily substituted;

Xi X ₂ , X ₃ , , Y are as defined by formula (I); d is a covalent bond C ₀ -C ₄ hydrocarbyl group, C ₀ -C ₄ -hydrocarbyl-(CO)-C0-C4-hydrocarbyl group, C ₀ -C ₄ -hydrocarbyl-(NR5)-C ₀ -C ₄ -hydrocarbyl group, C. -C ₄ -hydrocarbyl-(S)-C. -C ₄ -hydrocarbyl, C. -C ₄ -hydrocarbyl-(〇)-C. -C ₄ -transcarbyl, CQ-C ₄ -hydrocarbyl-(SO)- -C ₄ -hydrocarbyl, C _Q -C4-hydrocarbyl-(SO)-CQ-C ₄ -hydrocarbyl, CG-C4-hydrocarbyl-(NH )-(CO)-CQ-C ₄ -hydrocarbyl, Co-C ₄ -hydrocarbyl-(CO)-(NH)-C ₀ -C ₄ -hydrocarbyl, -NH-CO-NH-, -NH-CS-NH - , -O-CO-O-, -O-CS-O-, -NH-C(NH)-NH-, -S(0) ₂ -N(R ₅ )-, -N(R ₅ )- S(0) ₂ -, -NH-C(0)-0-, or - O- C(O)- NH -, wherein R5 may be hydrogen, dC ₅ alkyl, aryl, aralkyl, heterocyclic Base, heterocyclic aryl, S0 ₂ -alkyl, S0 ₂ -aryl, CO-alkyl, CO-aryl, CO-NH-alkyl, CO-NH-aryl, CO-0-alkyl or CO-0-aryl;

 n may be 0, 1, 2, 3 or 4;

 Z is N or CH;

Y is NH ₂ or OH.

 The compound of the present invention contains a basic group which can form a salt with an acid, and a salt of the derivative can be formed by an ordinary means.

 Common salts include organic acid salts, inorganic acid salts, and the like. Commonly used organic acid salts are citrate, fumarate, oxalate, malate, lactate, camphorsulfonate, p-toluenesulfonate, sulfonate, etc.; There are hydrohalides, sulfates, phosphates, nitrates, and the like.

 For example, a lower alkylsulfonic acid such as sulfonic acid, trifluorosulfonium sulfonic acid or the like may form an oxime sulfonate or a trifluorosulfonium sulfonate; and an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid. Forming p-toluenesulfonate and besylate; forming a corresponding salt with an organic carboxylic acid such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; Amino acids, such as glutamic acid or aspartic acid, can form glutamate or aspartate. Corresponding salts may also be formed with inorganic acids such as hydrohalic acids (e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid.

 The solvate of the benzamide derivative of the present invention is also within the scope of the present invention, and the solvent is preferably water, ethanol or decyl alcohol.

 The present invention also provides a process for the preparation of the benzamide derivatives of the present invention.

 The preparation of the compound of the formula I of the present invention comprises reacting a compound of the formula III with a compound of the formula IV in a solvent to obtain a product having the following reaction formula:

(I) wherein, in the compound of formula III, the definitions of Het, G ₂ , G ₃ are the same as those of the compound of formula I, wherein Y is -NH 2 , or OH, Χ, . X ₂ , X ₃ , each independently selected from the group consisting of Hydrogen, halogen (which may preferably be fluorine, chlorine, bromine or iodine), dC ₄ alkyl or -Ct alkoxy, and stipulate that at least one of Χ, X ₂ , X ₃ is not hydrogen.

Starting Materials The compounds of formula III are prepared according to or as disclosed in reference to WO2005092899. Compound IV can be purchased from the market or synthesized by conventional methods.

 The solvent used in the above preparation method may be selected from various options such as chloroform, dichlorodecane, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, xylene, toluene, dimethyl sulfoxide. , triethylamine, and other organic solvents; the reaction temperature is -30 - +80 ° C; if necessary, a base such as sodium hydroxide, triethylamine, pyridine, etc. may be added, such as hydrochloric acid, acetic acid, trifluoroacetic acid and the like.

The amino group (if any) of the compound of formula III, Het, G _{1 3⁄4} G ₂ , G ₃ or the compound of formula IV, if any, may be protected with the corresponding protecting group to give a compound of formula I containing a protecting group. , then deprotected to give a compound of formula I. These protecting groups and methods for their introduction or removal are well known to those skilled in the art.

 The compound of the formula I can be purified by a common separation method such as column chromatography, recrystallization or the like. Similarly, according to the method of synthesizing amide, the compound of formula (II) can be prepared:

Wherein, Hetl, G, Z, n, Χ, X ₂ , X ₃ , , or Y have the same definitions as the compound of formula (II). The present invention also provides a pharmaceutical composition comprising the cucurbitamide compound of the present invention or a salt or solvate thereof. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, including conventional diluents in the pharmaceutical field, excipients, fillers, binders, wetting agents, disintegrating agents, An absorption enhancer, a surfactant, an adsorption carrier, a lubricant, etc., if necessary, a flavoring agent, a sweetener or the like may be added. The medicament of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral liquids and injectable preparations, and the medicaments of the above respective dosage forms can be prepared according to a conventional method in the pharmaceutical field. Among them, oral administration is the best in clinical practice. The dosage is 0.0001 to 200 mg/kg body weight per day.

 The present invention also provides the use of the benzoquinone compound of the present invention or a salt or solvate thereof as a therapeutic and proliferation-related disease such as blood cancer and solid tumor.

 The inventors of the present invention confirmed by experiments that the compound disclosed by the present invention exhibits a positive inhibitory effect on tumor cell proliferation, and the tumor suppressing activity is significantly better than the positive control drug MS-275, and the compound of the present invention is less toxic to normal cells than MS-275. .

 Further, the compounds disclosed in the present invention are more stable in physical and chemical properties than the compounds disclosed in the positive control drugs MS-275 and WO2005092899.

BEST MODE FOR CARRYING OUT THE INVENTION The embodiments of the present invention are described below by way of examples, and those skilled in the art should understand that modifications or substitutions of the corresponding technical features are still within the scope of the present invention.

EXAMPLES 1. Synthesis of N-(2- -5-fluorophenyl)-4((4-(pyridin-3-yl)pyrimidin-2-Jmethyl)benzene Sfcamine (Compound 1)

 Step 1. Synthesis of 3,3-dimethylamino-1-pyridin-3-yl-propenone

 2 g of 3-acetylpyridine was dissolved in 5 ml of anhydrous N,N-didecylamide, and 5 ml of hydrazine, hydrazine-dimethylformamide diacetal was added to the solution, and the reaction was heated to 110 ° C. After 3 hours, thin layer chromatography showed the end of the reaction. The hydrazine and hydrazine-dimethyl phthalamide were recovered under reduced pressure. The residue was placed in a refrigerator overnight, and a yellow solid was precipitated, filtered, and washed with ethyl acetate/petroleum 1:1. A yellow solid was obtained in 2.05 g.

 The product has a melting point of m.p. 82-83. C ;

Step 2. Synthesis of 4-mercaptopurinyl-benzoic acid 2 g of methyl isothiourea sulfate was dissolved in 10 ml of a 1 mol/L sodium hydroxide aqueous solution, and 2.15 g of 4-aminomethylbenzoic acid was slowly added dropwise in an ice bath, and the reaction was stirred overnight at room temperature to precipitate a white solid. , filtered, dried, white solid

2.56g.

 Step 3. Synthesis of 4-[(4-pyridin-3-yl-pyrimidin-2-yl-amino)-methyl]cyanic acid

 1.57 g of the product of step 1 and 1.88 g of the product of step 2 were dissolved in 10 ml of isopropanol, while 1.26 g of potassium carbonate was added thereto, and the mixture was added thereto, and the mixture was heated under reflux for 12 hours. The thin layer chromatography showed the reaction was finished, cooled, filtered, dried and evaporated. The solid was 1.87 g.

 The melting point of the product is m.p.219.5-221;

 Step 4. Synthesis of N-(2-amino-5-fluorophenyl)-4((4-(pyridine-3-yl)pyrimidin-2-yl)indolyl)benzamide (Compound 1)

 The product of lg step 3, 0.54 g of N,N-carbonyldiimidazole was dissolved in 8 ml of anhydrous tetrahydrofuran, reacted at 45 ° C for 1.5 h, cooled, and set aside. Take another dry 100 ml three-necked flask, dissolve 0.52 g of 4-fluoro-1,2-phenylenediamine in 7 ml of anhydrous tetrahydrofuran under nitrogen, add 0.38 g of trifluoroacetic acid dropwise, and add the alternate reaction solution. Stirring at room temperature overnight, thin layer chromatography showed the end of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel, ethyl acetate / petroleum ether / ethanol 2:1:2, and the eluent was concentrated and crystallised to give white solid. 0.28g.

 The melting point of the product is m.p. 180-181.5 °C;

1H NMR (DMSO-d ₆ ) (5 ppm): 4.640-4.654 (d, 2H), 5.212 (s, 2H), 6.338-6.354 (m, lH), 6.506-6.54 l (dd, lH), 7.069-7.107 ( t,lH) , 7.262-7.274(d,lH) , 7.492-7.53 l(m,3H) , 7.910-8.044(m,3H), 8.407-8.420(d,2H), 8.680-8.690(d,lH) , 9.246 (s, lH), 9.515-9.532 (d, lH). The following compounds 2~4, 9-17, 51~55, 125~126 were synthesized as in Example 1 (Compound 1)

N-(2-i^-5-|L-phenyl)-4((4-(pyridin-2-yl)pyrimidin-2-yl)methyl)benzene S*J& (Compound 2)

The melting point of the product is m.p. 206-207 °C;

'HNMR (DMSO-d ₆ ) (5 ppm): 4.653-4.667 (d, 2H), 5.208 (s, 2H), 6.337-6.344 (m, lH), 6.503-6.539 (dd, lH), 7.066-7.104 ( t,lH), 7.494-7.520(m,4H), 7.908-7.997(m,4H), 8.317-8.337(d,lH), 8.442-8.455(d,lH), 8.692-8.703(d,lH), 9.525 (s, lH).

 N-(2-^-5-fluorophenyl)-4((4-(pyridin-4-yl)pyrimidin-2-yl)benzene (Compound 3)

The melting point of the product is m.p. 206-207 ° C;

 'HNMR(DMSO-d6) (δρριη): 4.647-4.662(d,2H), 5.192(s,2H), 6.324-6.367(m,lH), 6.508-6.543(dd,lH), 7.073-7.1 ll( m,lH), 7.284-7.297(d,lH), 7.486-7.494(d,2H), 0.89(t,3H), 7.909-8.074(m,5H), 8.460-8.472(d,lH), 8.720- 8.734(d, 2H) 9.510(s, lH). The product has a melting point of m.p. 209-209.5 °C;

'HNMR (DMSO-d ₆ ) (5 ppm): 3.831 (s, 3H), 4.676 (s, 2H), 6.349-6.392 (m, lH), 6.528-6.563 (dd, lH), 7.049-7.220 (m, 4H), 7.484-7.503(d,2H), 7.916-7.936(d,2H), 8.081-8.110(dd,2H), 8.318-8.331(d,lH), 9.539(s,lH). N-(2-J^-5-fluorophenyl)-4((4-(4-bromophenyl)sulfon-2-11^)methyl)benzene S!t^ (Compound 9)

lHNMR (DMSO-d ₆ ) (6 ppm): 4.632-4.645 (d, 2H), 5.223 (s, 2H), 6.330-6.367 (m, lH), 6.514-6.549 (dd, lH), 7.075-7.112 (t , lH), 7.186-7.200(d,lH), 7.481(s,2H), 7.698-7.717(d,2H), 7.912-8.050(m,5H), 8.372-8.384(d,lH), 9.540(s , lH).

N-(2-J^-5-fluorophenyl)-4((4-(3, 4-difluorophenyl)pyrimidin-2-yl)methyl)benzene gfcamine (Compound 10)

 'HNMRC DMSO-de) (6 ppm): 4.631-4.654 (d, 2H), 5.189 (s, 2H), 6.337-6.344 (m, lH), 6.507-6.542 (dd, lH), 7.071-7.108 (t, lH ), 7.218-7.230(d,lH), 7.487-7.579(m,3H), 7.904-7.974(m,4H), 8.120-(s,lH), 8.381-8.393(d,lH), 9.509(s, lH).

 N-(2-IL^-5-fluorophenyl)-4((4-(2,4-dimethylthiazol-5-yl)sulfan-2-11^)methyl)benzene compound 11) ' HNMRC DMSO-de) (6 ppm): 2.614 (s, 6H), 4.558-4.574 (d, 2H), 5.192 (s, 2H), 6.326-6.36 l (m, lH), 6.509-6.544 (dd, lH), 6.826-6.839(d,lH), 7.075-7.112(t,lH), 7.440-7.459(d,2H), 7.899-7.919(d,3H), 8.317-8.329(d,lH), 9.507(s,lH ).

 N-(2-^-5-fluorophenyl)-4((4-((2-(piperidinyl))ethyl Hgphenyl)pyrimidin-2-()methyl)benzene SUfe (Compound 12)

'HNMR (DMSO-d ₆ ) (5 ppm): 1.525-1.759 (m, 6H), 3.155-3.601 (m, 6H), 4.359-4.372 (t, 2H), 4.626-4.614 (d, 2H), 5.188 ( s, 2H), 6.340-6.368 (m, lH), 6.511-6.540 (dd, lH), 7.072-7.129 (m, 4H), 7.464-7.483 (d, 2H), 7.802 (t, lH), 7.903- 7.923 (d, 2H), 8.068-8.090 (d, 2H), 8.300-8.321 (d, lH), 9.512 (s, lH).

N-(2-^-5-fluorophenyl)-4((4-(3-fluoro-4-(methyl)phenyl)pyrimidiniummethyl)benzene Sfeamine (Compound 13)

(6ppm): 2.505(s,3H), 4.625-4.640(d,2H), 5.188(s,2H), 6.337-6.366(m,lH), 6.507-6.542(dd,lH) , 7.072-7.110(q , lH), 7.199-7.212 (d, lH), 7.423-7.485 (m, 3H), 7.904-7.966 (m, 5H), 8.354-8.366 (d, lH), 9.508 (s, lH).

 N-(2-J-5-fluorophenyl)-4((4-(3-氡-4-(methyl H3⁄4J phenyl)pyrimidine-2-^)methyl)benzene (Compound 1)

¹ H NMR (DMSO-d ₆ ) (5 ppm): 3.904 (s, 3H), 4.621-4.635 (d, 2H), 5.213 (s, 2H), 6.326-6.369 (m, lH), 6.508-6.543 (dd, lH) , 7.070-7.107(t,lH) , 7.161-7.173(d,lH) , 7.254-7.296(t,lH), 7.483(s,2H), 7.908-7.928(m,5H), 8.316-8.329( d, lH), 9.534 (s, lH). N-(2-J>-5-fluorophenyl)-4((4-0*fc ~2-yl)pyrimidinylmethyl)benzene SUFT (Compound 15)

'HNMR^DMSO-ds) (6ppm): 4.673(d,2H), 5.215(s,2H), 6.338-6.35(m,lH), 6.503-6.538(dd,lH), 7.065-7.101 (t,lH ), 7.451-7.53 l(m,3H), 7.915-7.935(dd,2H), 8.159(s,lH), 8.503-8.515(d,lH), 8.785(s,2H), 9.451 (s,lH) , 9.539 (s, lH).

N-(2-^-5-fluorophenyl)-4((4-(4-(carbin-3-yl))pyrimidin-2-()methyl)benzene) (Compound 16) 'ΗΝΜΚ( ΟΜ8Ο-ά ₆ )(δρριη): 4.602-4.618(ά,2Η), 5.190(s,2H), 6.337-6.366(m,lH),

6.514-6.542(dd,lH), 7.045-7.094(t,2H), 7.498(d,2H), 7.639-7.918(m,5H),

8.287-8.306(d, 2H), 9.503(s, lH).

N-(2-J-5-fluorophenyl)-4((4-(4-methyl!3⁄4^yl)pyrimidinemethyl)benzil Bfc fe (compound 17)

'HNMRC DMSO-de) (5 ppm): 2.51 l (s, 3H), 4.627-4.642 (d, 2H), 5.192 (s, 2H), 6.325-6.367 (m, lH), 6.518-6.546(dd,lH) , 7.090-7.149(m,2H), 7.344-7.488 (q,4H) , 7.832-8.040(m,5H) , 8.320-8.333(d,lH), 9.508(s,lH ).

 N-(2-IL^-5- Lphenyl)-4((4-(4-(2-)-Phenylphenyl)pyrimidinemethyl)benzene StJfe (Compound 51)

MS (FAB): 543 (M+l)

N-(2-tJ-5-fluorophenyl)-4((4-(4-ethyl)pyridin-2-|1^)methyl)benzene SUfe (Compound 52)

 'HNMR (DMSO-d6) (5 ppm): 1.33-1.36 (m, 3H), 4.07-4.10 (q, 2H), 4.63-4.64 (d, 2H), 5.19 (s, 2H), 6.33-6.37 (q , lH), 6.51-6.55 (dd, lH), 7.01-7.1 l(q,4H), 7.47-7.49(d,2H), 7.76-7.79(m,lH), 7.90-7.92(d,2H), 8.03-8.05 (d, 2H), 8.28-8.29 (d, lH), 9.51 (s, lH).

N-(2-J^-5-fluorophenyl)-4((4-(4-butylphenyl)pyrimidinemethyl)benzene"·^(compound 53)

 'HNMR (DMSO-d6) (5 ppm): 0.92-0.96 (m, 3H), 1.43-1.45 (q, 2H), 1.70-1.71 (q, 2H), 4.02-4.05 (m, 2H), 4.62-4.63 (d,2H), 5.21(s,2H), 6.34-6.35(q,lH), 6.50-6.54(dd,lH), 7.02-7.1 l(q,4H), 7.46-7.48(q,2H) , 7.80-7.83 (m, lH), 7.90-7.92 (d, 2H), 8.03-8.05 (d, 2H), 8.28-8.29 (d, lH), 9.53 (s, lH).

N-(2-J^-5-|Lphenyl)-4((4-phenyl)pyrimidine-2-.ΙΙδ·)methyl)benzene SJfe (Compound 54)

 'HNMR (DMSO-d6) (6 ppm): 4.64-4.65 (d, 2H), 5.2 l (s, 2H), 6.33-6.36 (q, lH), 6.51-6.54 (dd, lH), 7.07-7.1 l (m,lH), 7.17-7.19(d,lH), 7.50(s,5H), 7.91-7.93(m,3H), 8.08-8.09(d,2H), 8.35-8.37(d,lH), 9.53 (s, lH).

 N-(2-J 5-fluorophenyl)-4((4-cyclo-SJ)-pyridin-2-()methyl)benzene SU^ (Compound 55)

'HNMRi DMSO-de) (6 ppm): 1.59-1.71 (q, 6H), 1.94-1.99 (q, 2H), 4.62-4.63 (d, 2H), 4.88-4.91 (m, lH), 5.21 (s, 2H) ), 6.34-6.37(q,lH), 6.51-6.53(dd,lH), 6.98-7.10(q,4H), 7.46-7.48(d,2H), 7.79-7.82(q,lH), 7.90-7.92 (d, 2H), 8.02-8.04 (d, 2H), 8.28-8.29 (d, lH), 9.53 (s, lH).

N-(2-tJ^5-fluorophenyl)-4((4-(3-methylphenyl)pyrimidin-2-)methyl)phenylhydrazine SUfe (Compound 125)

'HNMR (DMSO-d6) (5 ppm): 3.814 (s, 3H), 4.623-4.638 (d, 2H), 5.187 (s, 2H), 6.322-6.343 (m, lH), 6.512-6.54 l (dd, lH), 7.059-7.179 (m, 3H), 7.382-7.647 (m, 5H), 7.877-7.92 l (t, 3H), 8.345-8.358 (d, lH), 9.504 (s, lH).

 N-(2-H^-5-fluorophenyl)-4((4-(3,4-methylenediphenyl)pyrimidinemethyl)benzene SUfe (Compound 126)

¹ H NMR (DMSO-d6) (5 ppm): 4.615-4.630 (d, 2H), 5.190 (s, 2H), 6.096 (s, 2H), 6.336-6.344 (m, lH), 6.506-6.541 (dd, lH ), 7.077-7. lll(m,3H), 7.457-7.477(d,2H), 7.625-7.620(m,5H), 8.282-8.295(d,lH), 9.507(s,lH).

R!=HR ₂ =OCH ₃ R ₃ =HR ₄ =HR ₅ =H Compound 5

RfH R ₂ =OCH ₃ R ₃ =OCH ₃ R ₄ =HR ₅ =H Compound 6

R,=OCH ₃ R ₂ =OCH ₃ R ₃ =OCH ₃ R ₄ =HR ₅ =H Compound 7

R!=HR ₂ =OCF ₃ R ₃ =HR ₄ =HR ₅ =H Compound 18

 0,

^R 1, ^R 2= < R ₃ =HR ₄ =HR ₅ =H Compound 19

 O

R ₂ =HR ₃ =HR ₄ =HR ₅ =H Compound 82

Ri=HR ₂ =HR ₃ =H R4=HR ₅ =H Compound 83

R,=HR ₂ =CH ₃ R ₃ =HR ₄ =HR ₅ =H Compound 84

R!=HR ₂ =OC ₂ H ₅ R ₃ =HR ₄ =HR ₅ =H Compound 85

R ₄ =HR ₅ =H Compound 86

R,=HR ₂ =Br R ₃ =H R4=HR ₅ =H Compound 87

Rj=HR ₂ =H R3-CF3 R4=HR ₅ =H Compound 88

R]=HR ₂ =HR ₃ =H R4 ⁼ CH3 R ₅ =H Compound 89

Rj=HR ₂ =HR ₃ =H R4=Cl R ₅ =CH ₃ compound 90

 ^式 2

Example 2. Synthesis of N-(2-4L^-5-fluorophenyl)-4-((4-methylphenolyl)methyl)benzamide (Compound 5) Step 1. Synthesis of p-Benzylbenzene Ethyl formate

 2.0 g of the aldehyde benzoic acid was dissolved in 20 ml of methanol, and 1.81 ml of thionyl chloride was slowly added dropwise in a water bath. After the addition was completed, the mixture was heated to reflux for 3 hours, and the reaction was completed by thin layer chromatography. Cooled and filtered to give abr.

 The product has a melting point of m.p. 59-61 °C;

Step 2. Synthesis of 4-((4-methoxyphenylamino)methyl)benzoic acid methyl ester hydrochloride

1.59 g of p-aminoanisole and 2.13 g of the product of Step 1 were dissolved in 15 ml of decyl alcohol, 3.07 g of NaBH4 was added in portions under ice bath, and glacial acetic acid was added dropwise to keep the reaction solution pH 5-6, and the reaction was completed by thin layer chromatography. The solvent was evaporated under reduced pressure. EtOAc EtOAc m. Step 33: Combine into 44--(((44--methoxymethoxyphenylphenylaminoamino))methylmethyl))benzoic acid

 The product of step 22..6677gg step 11 will be suspended and suspended in 88mmll tetrahydrofuranfuran//88mmll water, and added to 00..5533 gg lithium lithium oxyhydroxide, The room temperature is stirred at room temperature and stirred overnight. The thin layer chromatography indicates that the reaction is completed at the end of the reaction, and the reduced solvent is returned to the recovered solvent. The residual residue is added to the 2200mmll. The water is dissolved in water, and the PPHH is adjusted to about 55 left and right with 11NN hydrochloric acid, and is allowed to stand still. After filtration, the white-white solid solid body 22..1177gg is obtained. .

 55 melting point of product product melting point mm..pp..117788--118800..55 °°CC ;;

 Step 44: Combine synthesis into NN--((22--aminoamino--55--fluorofluorophenylphenyl))--44--(((44--decyloxy) Phenylphenylaminoaminoamino))methylmethyl)) benzoylcarboxamide ((Chemical Complex 55))

 The product of step 23.33177g,, hydrazine, hydrazine-carboyl bis-imidazolidinium 11..3399gg will be dissolved and dissolved in 1100mmll anhydrous water without tetrahydrofurfurfuran. In the middle of the middle, 4455 ° ° CC reaction should be 11..55hh, cold cooling, but ready for use. . Take another one of the three or three neck bottle bottles, under the nitrogen and nitrogen gas protection protection, will be 11..3344gg 44--fluorofluoro--11,22-phenylbenzenediamine The amine solution is dissolved in tetrahydrofurfurfuran without anhydrous water, and 00..9988gg trifluorofluoroacetic acid is added dropwise, and then added dropwise for additional reaction. Liquid and liquid, room temperature stir stirring reaction should be overnight, thin layer chromatography analysis 1100 shows that the reaction should end the bundle, reduce the pressure back to recover the solvent, The residual residue is passed through a silica gel column, and ethyl acetate ethyl acetate//petroleum oleic acid 11::22 is washed, and the eluted liquid is concentrated and concentrated, and the crystal is precipitated. Crystal, which gives a white-white solid solid body 11..0055gg. .

 Melting point of product product melting point mm..pp.. 220055..55--220066 °°CC ;

((δδρρρριιηη)):: 33..660033((ss,,33HH)),, 44..228844--44..229999((dd,,22HH)),, 55..221144((ss,, 22HH)),, 55..993399--55..996699((tt,,llHH)),, 66..332299--66..337722((mm,,llHH)) ,, 66..449966- -66..553399((mm,,33HH)) ,, 66..666600--66..668833((dd,,22HH)) ,, 77..007733--77..11 ll ll((qq ,,,,,,,, .552299((ss,,llHH)). .

 The following steps are carried out in the following steps: (Compound compound 55) ) ..

 NN--((22-- ^^--55--fluorofluorophenylphenyl))--44--(((33,,44--didimethylformyl HH^^)JJ>> Methyl group)) benzophenone BBfefeiifefe ((Chemical Complex 66))

 Melting point of product product melting point mm..pp.. 113355..55--113366..55°°CC ;

2200 ''HH MMRR((DDMMSSOO--dd66)) ((66ppppmm)):: 33..558899((ss,,33HH)),, 33..665599((ss,,33HH)),, 44. .229922--44..330066((dd,,22HH)),, 55..119922 ((ss,,22HH)),, 55..996688--66..000099((mm,,22HH)) ,, 66..332244--66..335522((mm,,22HH)) ,, 66..551177--66..666655((mm,,22HH)) ,, 77..008811--77. .111188((tt,,llHH)) ,, 77..446600--77..448800((dd,,22HH)),, 77..009977--77..779900((dd,,22HH)) ,, 99..552211((ss,,llHH)). .

 NN--((22-- JJ--55--fluorofluorophenylphenyl))--44--(((33,,44,,55--三三甲甲HH^^SS^^ Methyl group)) benzophenone SStt amine amine ((Chemical Compound 77))

 Melting point of product product melting point mm..pp.. 116666--116677°°CC ;

2255 ''HHNNMMRR((DDMMSSOO--dd66)) ((55ppppmm)):: 33..449955((ss,,33HH)),, 33..662244((ss,,33HH)),, 33.. 664433((ss,,33HH)),, 44..331133--44..332288((dd,,22HH)),, 55..222299((ss,,22HH)) ,, 55..888822( (ss,,22HH)) , , 66..333322--66..337755((mm,,22HH)) ,, 66..551122--66..554488((dddd,,llHH)) ,, 77 ..007755--77..009977((qq,,llHH)) ,, 77..447799--77..449999((dd,,22HH)),, 77..991199--77..993399( (dd,,22HH)),, 99..555511((ss,,llHH)). .

 NN--((22-- ^^--55--iiLL Phenylphenyl)) --44--((((44--tritrifluorofluoromethyl ttJJ^^::基基^^甲Methyl)) phenylbenzene SSUUfefe ((Chemical Complex 1188))

 ' 'HHNNMMRRCCDDMMSSOO--ddee)) ((55ppppmm)):: 44..440088--44..442233((dd,,22HH)),, 55..223344((ss,,22HH)),, 66 ..333333--66..337755((mm,,llHH)),, 3300 66..551144--66..554422((dddd,,llHH)),, 66..779977--66..889944 ((mm,, 44HH)),, 77..007766--77..226666((mm,,22HH)),, 77..446655--77..448866((dd,,22HH)),, 77..993311 --77..9955 ll((dd,,22HH)),, 99..556622((ss,,llHH)). .

 ΝΝ--((22--··^^--55--fluorofluorophenylphenyl))--44--(((33,,44--Ya Methylene-2)HHJJ^^gg Base)) methylmethyl)) benzophenone SStt amine ((Chemical Complex 1199))

1H1HNNMMRR((DDMMSSOO--dd ₆₆ ))((SSppppmm))::44..227777--44..229922((dd,,22HH)),,55..223300((ss,,22HH)), , 55..880044((ss,,22HH)),,55..995566--55..997799((dddd,,llHH)) ,, 66..001166--66..113377((tt,, llHH)) , , 66..225577--66..226622((dd,,llHH)) ,, 66..333366--66..337744((mm,,llHH)) ,, 66..551122- -66..662277((mm,,22HH)) ,, 3355 77..009900--77..111122((qq,,llHH)),, 77..444455--77..446655((dd, , 22HH)),, 77..990077--77..992288 ((dd,, 22HH)),, 99..554433 ((ss,, llHH)). .

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^Formula 3 Example 3. Synthesis of 4-(((phenethyl)(2-hydroxyethyl)methyl)-N-(2-^-5-fluorophenyl)benzamide (Compound 8)

Step 1. Synthesis of 4-((phenylethylamino)indolyl) phthalate hydrochloride

 1.43 ml of phenylethylamine, 1.46 g of decyl aldehyde benzoate, dissolved in 10 ml of decyl alcohol, 2.5 g of sodium borohydride was added in portions under ice bath, and glacial acetic acid was added dropwise to keep the reaction solution PH 5 ~ 6, The reaction was completed by thin-layer chromatography. The solvent was evaporated under reduced pressure, and the residue was partitioned from ethyl acetate/water, and acidified with 2N hydrochloric acid to give a white solid, which was filtered and dried to give a white solid.

Step 2. Synthesis of 4-((2-(tert-butyldimethylsilyloxy)ethyl)(phenethyl)amino)indolyl)benzoate

 Take 100ml dry three-necked flask, under the protection of dry nitrogen, 2.06g of 4-((phenylethylamino)indolyl) benzoic acid methyl ester hydrochloride dissolved in 20ml anhydrous dimercaptosulfoxide, stir at room temperature, and 2.87 ml of anhydrous triethylamine free hydrochloride was added, and the solid was dissolved. Then, 3.91 g of (2-bromoethoxy)(tert-butyl)dimercaptosilane was added, and the temperature was raised to 60 ° C, and the reaction was kept at a constant temperature for 24 hours. The layer chromatography indicated the end of the reaction. The reaction mixture was partitioned between ethyl acetate/water, and the ethyl acetate layer was collected. The solvent was evaporated under reduced pressure. The concentrate was applied to silica gel column eluted with ethyl acetate/petroleum ether 1: 6 Concentrated to a pale yellow oil, 1.53 g.

Step 3. Synthesis of 4-(((2-(tert-butyldimethylsilyloxy)ethyl)(phenethyl)amino)indolyl)benzoic acid (IV)

1.53 g of the product of step 2 was dissolved in 6 ml of THF / 6 ml of water, 0.32 g of lithium hydroxide was added, and the mixture was stirred overnight. The thin layer chromatography showed the end of the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in water, and carefully adjusted to pH 6.5 with 1N hydrochloric acid. , filtered, dried to give a white solid, 1.02 g. The product has a melting point of mp246-248.5 °C;

Step 4. Synthesis of 4-(((2-(tert-butyldimethoxysilyloxy)ethyl)(phenethyl)amino)methyl)-N-(2-amino-5-fluorophenyl) Indoleamide (compound 8)

 1.02 g of the product of Step 3, 0.44 g of hydrazine, hydrazino-carbodiimidazole was dissolved in 7 ml of anhydrous tetrahydrofuran, reacted at 45 ° C for 1.5 h, cooled, and set aside. Take another 100 ml dry three-necked flask, dissolve 0.35 g of 4-fluoro-1,2-phenylenediamine in 5 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, add 0.26 g of trifluoroacetic acid dropwise, and then add the alternate reaction solution. Stirring at room temperature overnight, the reaction was completed by thin layer chromatography, and the solvent was evaporated under reduced pressure. The residue was applied to silica gel column, ethyl acetate: petroleum ether 1 : 2 washed, eluent concentrated, crystallized to give white solid 0.34 g

Step 5. Synthesis of 4-(((phenethyl)(2-hydroxyethyl)amino)indolyl)-N-(2-amino-5-fluorophenyl)benzamide (Compound 8) Take a 100 ml dry A three-necked flask was purged with dry nitrogen. At -20 ° C, 0.34 g of the product of step 4 was added, and 5 ml of anhydrous tetrahydrofuran was dissolved. Then, 0.17 g of tetrabutylammonium fluoride was slowly added dropwise, and the temperature was slowly raised to room temperature. The reaction was stirred overnight, and the mixture was evaporated to dryness. EtOAc was evaporated.

 The melting point of the product is m.p. 100.0-101.5 °C;

'HNMRC DMSO-cU) (6 ppm): 2.593-2.746 (m, 6H), 3.611-3.750 (q, 4H), 5.182 (s, 2H),

6.317-6.359(m,lH) , 6.502-6.537(dd,lH) , 7.063-7.391(m,8H) , 7.873-7.893(d,2H) ,

9.521 (s, lH).

The following compounds 20-21 were synthesized in the same manner as in Example 3 (Compound 8).

4-(((4-methylmethyl)(2-hydroxyethyl)methyl)-N-(2- -5-L-phenyl)benzyl SUfe (Compound 20) ⁿ HNMR (DMSO-d ₆ ) ( 5ppm): 2.498-2.508(t,2H), 3.487-3.523(d,4H), 3.601-3.634(t,2H), 3.730(s,3H), 5.234(s,2H), 6.333-6.376(m, lH), 6.513-6.548(dd,lH), 6.879-6.90 l(d,2H), 7.077-7.115(q,lH), 7.263-7.285(d,2H), 7.469-7.490(m,2H) , 7.922 -7.943 (d, 2H), 9.563 (s, lH).

4-(((3,4-difluorobenzyl)(2-hydroxyethyl)methyl)-N-(2-|^-5- Lphenyl)benzene SUfe (Compound 21) ⁿ HNMR( DMSO-d ₆ ) (Sppm): 2.500-2.509 (t, 2H), 3.387-3.423 (d, 4H), 3.594-3.603 (t, 2H), 5.235 (s, 2H), 6.333-6.379 (m, lH) ), 6.520-6.552(dd,lH), 7.095-7.108(q,lH), 7.231-7.233(d,lH), 7.368-7.395(d,lH), 7.487-7.539(m,3H), 7.930-7.95 l(d, 2H), 9.569(s, lH).

27 28 29 30 31 60 61 62

Formula 4 Example 4. Synthesis of 4-(2-fluorobenzyl 3⁄4J-N-(2-^-5-fluorophenyl)benzoquinone «Jfe (Compound 22)

 Step 1. Synthesis of 4-(2-fluorobenzylamino)benzoic acid

 1.59 g of 2-fluorobenzaldehyde and 2.13 g of 4-aminobenzoic acid were dissolved in 15 ml of decyl alcohol, and 3.07 g of NaBH4 was added in portions under ice-cooling, and glacial acetic acid was added dropwise to keep the reaction liquid PH 5 - 6, and the reaction was carried out by thin layer chromatography. After completion, the solvent was evaporated under reduced pressure, and the residue was evaporated.

 Product melting point m.p.178-180.5 'C ;

Step 2. Synthesis of N-(2-amino-5-fluorophenyl)-4-((4-methoxyphenylamino)indolyl benzene amide (Compound 22)

2.17 g of the product of step 1 and 1.39 g of hydrazine, hydrazine-carbamoimidazole were dissolved in 10 ml of anhydrous tetrahydrofuran, reacted at 45 ° C for 1.5 h, cooled, and set aside. Take another three-necked flask and dissolve 1.34 g of 4-fluoro-1,2-phenylenediamine in anhydrous tetrahydrofuran under nitrogen atmosphere, add 0.98 g of trifluoroacetic acid dropwise, then add the alternate reaction solution, stir at room temperature. The reaction was carried out overnight, and the reaction was completed by thin layer chromatography. The solvent was evaporated under reduced pressure, and the residue was applied to silica gel column, ethyl acetate / petroleum ether 1 : 2 •(Hl's)Zi 6 XllZ^iS LM L

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 Compound 36 Compound 37 Compound 38 Compound 63 Compound 67

 Compound 68

 Compound 69

Example 5. Synthesis of N-(2-IL^-5-fluorophenyl)-4((4-(3,4-difluorophenyl)pyrimidin-2-)methyl)benzene BU3⁄4 (Compound 32)

Step 1. Synthesis of 3,3-didecylamino small (3,4-difluorophenyl)-propenone

 2 g of 3,4-difluoroacetophenone was dissolved in 5 ml of anhydrous DMF, and 2.56 ml of DMAPDMA was added to the solution, and the mixture was heated to 110 for 3 hours. TCL showed the reaction was completed, and DMF was recovered under reduced pressure. The mixture was placed in a refrigerator overnight, and a yellow solid was precipitated, which was filtered, and ethyl acetate / pet.

 Product melting point m.p.79-8rC;

Step 2. Synthesis of 4-(3,4-difluorophenyl)pyrimidine-2-thiol

 0.17g of sodium is dissolved in 20ml of absolute ethanol, and then 0.58g of thiourea is added, 1.60g of the product of step 1, after the addition, the temperature is refluxed for 4h, TCL shows the reaction is finished, the solvent is recovered under reduced pressure, and the residue is dissolved in an appropriate amount of water. 1N hydrochloric acid adjusts the pH to be weakly acidic, and a large amount of yellow solid precipitates, which is filtered and dried to obtain.

Step 3. Synthesis of 4-((4-(3,4-difluorophenyl)pyrimidin-2-yl)-indenyl) benzoate 0.22 g of sodium hydride was suspended in 20 ml of anhydrous DMF, and 1.40 g of the product of step 1 was added. After half an hour, 1.16 g of decyl 4-chloromercaptobenzoate was added and reacted at room temperature for 6 h. TCL showed the end of the reaction. A proper amount of water was added to the bottle to precipitate a large amount of solid, which was filtered and dried to give 1.76 g of a color solid.

 The melting point of the product is m.p.l02.5-104 °C;

Step 4. Synthesis of 4-((4-(3,4-difluorophenyl)pyrimidin-2-yl)-indenyl)benzoic acid

 1.5 g of the product of step 3 was suspended in 15 ml of decyl alcohol 15/ml of water, 0.52 g of lithium hydroxide was added, and the mixture was stirred at room temperature overnight, and the reaction was completed by thin layer chromatography. The solvent was evaporated under reduced pressure, and the residue was dissolved in 20 ml of water, using 1N hydrochloric acid. Adjust the pH to about 5, let stand, and filter to obtain 1.29 g of solid.

Step 5. Synthesis of N-(2-amino-5-fluorophenyl)-4((4-(3,4-difluorophenyl)pyrimidin-2-yl)methyl)benzamide (Compound 32)

 The product of lg step 4, 0.46 g of N,N-carbonyldiimidazole was dissolved in 8 ml of anhydrous tetrahydrofuran, reacted at 45 ° C for 1.5 h, cooled, and set aside. Take another dry 100 ml three-necked flask, dissolve 0.42 g of 4-fluoro-1,2-phenylenediamine in 7 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, add 0.32 g of trifluoroacetic acid dropwise, and add the alternate reaction solution. After stirring at room temperature overnight, TCL showed the reaction was completed, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel, ethyl acetate / pet.

 'HNMRCDMSO-c^Xappm) : 4.573-4.587(d,2H) , 5.221(s,2H) , 6.324-6.367(m,lH) , 6.508-6.536(dd,lH) , 7.071-7.093(q,lH) , 7.849-7.929 (m, 3H), 8.104-8.291 (m, 2H), 8.737-8.750 (d, lH), 9.530 (s, lH). The following synthesis of the compound 33-38, 63-69 was carried out as in Example 5 (Compound 32).

 N-(2-J^-5-fluorophenyl)-4((4-(3-fluoro-4-methoxyphenyl)pyrimidin-2-«^)methyl)benzene (Compound 33)

'HNMR (DMSO-d6) (6 ppm): 3.934 (s, 3H), 4.575 (s, 2H), 5.205 (s, 2H), 6.495-6.515 (m, lH), 6.712-6.741 (dd, lH), 7.152-7.189(q,lH) , 7.317-7.361(t,lH) , 7.600-7.62 l(d,2H) , 7.774-8.076(m,5H), 8.654-8.668(d,lH), 9.528 (s, lH).

N-(2-J^-5-fluorophenyl)-4((4-(4-methyl13⁄4^yl)pyrimidine-2-3⁄4^)methyl)benzene (Compound 34)

¹ H NMR (DMSO-d ₆ ) (6 ppm): 2.550 (s, 3H), 4.571-4.954 (s, 2H), 5.202 (s, 2H), 6.335-6.363 (m, lH), 6.504-6.532 (dd, lH) , 7.069-7.090(q,lH) , 7.406-7.428(d,2H) , 7.587-7.608(d,2H) , 7.766-7.923(m,3H), 8.140-8.162(d,2H), 8.659- 8.672 (d,lH), 9.522 (s,lH)„

N-(2-^-5-fluorophenyl)-4((4-(phen-3-yl)pyrimidin-2-)methyl)benzene SUfe (Compound 35)

'HNMR (DMSO-d ₆ ) (5 ppm): 4.557 (S, 2H), 5.232 (s, 2H), 6.321-6.364 (m, lH), 6.499-6.535 (dd, lH), 7.061-7.099 (q, lH), 7.593-7.614(d,2H), 7.672-7.686(d,lH), 7.735-7.755(q,lH), 7.841 -7.920(m,3H), 8.552-8.560(m,lH), 8.647- 8.660(d,lH), 9.548(s,lH). N-(2-iJ 5-fluorophenyl)-4((4-(4-bromophenyl)pyrimidin-2-)methyl)benzene BtJfe (Compound 36)

1H NMR (DMSO-d ₆ ) (5 ppm): 4.574 (s, 2H), 5.168 (s, 2H), 6.361-6.395 (m, lH), 6.531-6.566 (dd, lH), 7.086-7.102 (d, lH ), 7.602-7.62 l(d,2H) , 7.772-7.792(d,3H) , 7.898-7.914(d,2H), 8.129-8.145(d,2H), 8.710-8.723 (d,lH), 9.580 ( s, lH). 6Z

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R ₂ =OCH ₃ R ₃ =H Compound 39

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R ₃ =OCH ₃

R ₁ =OCH ₃ R ₂ =OCH ₃ compound 41

R ₂ =HR ₃ =H

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R!=HR ₂ =FR ₃ =H Compound 71

R!=HR ₂ =C1 R ₃ =H Compound 72

R!=HR ₂ =HR ₃ =CH ₃ compound 73

R!=HR ₂ =CF ₃ R ₃ =H Compound 74

Rj=HR ₂ =OCF ₃ R ₃ =H Compound 75

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Example 6. Synthesis of N-(2-^-5- L-phenyl)-3-(4-((4-methyl LJ^^)methyl)phenylpropanium (Compound 39)

Step 1. Synthesis of decyl 3-(4-((4-methoxyphenylamino)indolyl) phenyl) acrylate

 2 g of p-aminoanisole and 3.09 g of decyl aldehyde aldehyde acrylate were dissolved in 15 ml of decyl alcohol, and 3.07 g of NaBH4 was added in portions under ice bath, and glacial acetic acid was added dropwise to keep the reaction liquid PH 5-6. After the completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was partitioned from ethyl acetate/water, and acidified with 2N hydrochloric acid to give a white solid, which was filtered and dried to give a white solid.

Step 2. Synthesis of 3-(4-((4-methoxyphenyl)amino)indolyl)acrylic acid

 3.10 g of the product of step 2 was suspended in 8 ml of THF / 8 ml of water, 0.66 g of lithium oxychloride was added, and the mixture was stirred at room temperature overnight. The reaction was completed by thin layer chromatography, and the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of water and adjusted to pH with 1N hydrochloric acid. 5 or so, let stand, filter, and get a white solid 2.99g.

 The product has a melting point of m.p. 176.5-178.5 °C;

Step 3. Synthesis of N-(2-amino-5-fluorophenyl)-3-(4-((4-decyloxyphenylamino)methyl)phenyl acrylamide (Compound 39). 1.44g of N,N-carbonyldiimidazole was dissolved in 10ml of anhydrous tetrahydrofuran, reacted at 45 ° C for 1.5h, cooled, and set aside. Take another three-necked flask, under the protection of nitrogen, 1.33g of 4-fluoro-1, 2-Phenylenediamine is dissolved in anhydrous tetrahydrofuran, l.Olg trifluoroacetic acid is added dropwise, and the reaction mixture is added dropwise. The reaction mixture is stirred at room temperature overnight, and the reaction is completed by thin layer chromatography. The solvent is recovered under reduced pressure. Column, ethyl acetate/petroleum ether 1:2 wash, eluent concentration, analysis '(H£' ^b )6S -0 B 'im^iYL-WL '(ΐΙ ^ 6Ζ'ί-ςΖ'ί '(H 'P^OHO'A '(ΗΓΡ)ς8·9·ΐ8·9 '( H b)£9'9-0S9 '(ΗΓ&) ·9·εε·9 '(HZ^LZ^ '(ΗΓΡ)ΐε "0£ (9p-OSWa)3⁄4iMNH _l £

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 Equation 7

Example 7. Synthesis of 6-(4-methyl 1⁄2 benzyl)-N-(2-J-5-fluorophenyl)-smoke (Compound 42)

Step 1. Synthesis of 6-(4-decyloxybenzylamine)nic acid

Lg 6-chloronic acid, 1.26 g of p-oxobenzylamine, 1.3 g of K ₂ C0 ₃ , 20 ml of anhydrous DMF was added to the reaction flask, and the temperature was raised to 150 ° C for 6 h, and thin layer chromatography showed the end of the reaction. An appropriate amount of water was added to the reaction flask, and the mixture was extracted once with ethyl acetate. The aqueous layer was adjusted to pH 6 - 7 with 1N hydrochloric acid to precipitate a large white solid, which was filtered and dried to give 1.67 g.

 The product has a melting point of m.p. 221-223. C ;

Step 2. Synthesis of 6-(4-methoxybenzylamino)-N-(2-amino-5-fluorophenyl)-nicotinamide (Compound 42)

 The product of lg step 1, 0.64 g of N,N-carbonyldiimidazole was dissolved in 8 ml of anhydrous tetrahydrofuran, reacted at 45 ° C for 1.5 h, cooled, and set aside. Take another dry 100 ml three-necked flask, dissolve 0.6 g of 4-fluoro-1,2-phenylenediamine in 7 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, add 0.44 g of trifluoroacetic acid dropwise, and add the alternate reaction solution. The mixture was stirred at room temperature overnight. EtOAc (EtOAc)EtOAc.

 'HNMRC DMSO-de) (6 ppm): 3.715 (S, 3H), 4.529-4.543 (d, 2H), 5.266 (s, 2H), 6.302-6.345 (m, lH), 6.487-6.522 (dd, lH), 6.623-6.654(q,lH) , 6.862-6.883(d,2H), 7.011-7.049(q,lH), 7.248-7.269(d,2H), 8.191-8.207(m,2H), 8.516(t,lH ), 9.554(s,lH). The following compound 43-44, 76 was synthesized as in Example 7 (Compound 42)

 N-(2- -5-|L-phenyl)-6-((3,4-methylenedihydrocarbyl)methyl)SJ-smoke SUfe (Compound 43)

1H NMR (DMSO-d ₆ ) (5ppm): 4.512-4.526 (d, 2H), 5.253 (s, 2H), 5.961 (s, 2H), 6.305-6.348 (m, lH), 6.491-6.656 (m, 2H) ), 6.814-7.059 (m, 4H), 8.187-8.203 (m, 2H), 8.491-8.519 (t, lH), 9.543 (s, lH).

N-(2-iJ>-5-|Lphenyl)-6-(2-(1Η-吲哚-3-yl)ethyl J ^Smoke StJfe (Compound 44 )

'HNMRC DMSO-deXappm): 2.964-2.983 (t, 2H), 3.690-3.704 (q, 2H), 5.222 (s, 2H), 6.316-6.359 (m, lH), 6.498-6.620 (m, 2H), 6.964 -7.172(m,4H) , 7.313-7.333(d,lH) , 7.573-7.593(d,lH), 8.114-8.288(m,3H), 9.486(s,lH), 10.796(s,lH).

6-(2-benzyl)ethyl^-N-(2-^-5-fluorophenyl)-smoke Sfe fe (compound 76)

 'HNMR (DMSO-d6) (8 ppm): 2.853-2.871 (m, 2H), 3.633-3.648 (t, 2H), 5.28 (s, 2H), 6.331-6.334 (q, lH), 6.599-6.630 (q) , 2H), 7.253-7.285 (q, 6H), 8.213-8.225 (q, 3H), 9.499 (s, lH).

^Cl 3⁄4 ^cl

 Compound 79

 Compound 77

 o? Compound 80

 , Compound 78

 Compound 81

 ^式8

Example 8. Synthesis of Ν-(2-|^-5-fluorophenyl)-5-((3,4-methylenediphenyl)methyl· Ι^)-benzofuran-2-A Sodium (Compound 45)

Step 1. Synthesis of 5-nitrobenzofuran-2-ethyl decanoate

Dissolve 1.0 g of 2-hydroxy-5-nitrobenzaldehyde and 1.65 g of K ₂ CO ₃ in 20 ml of N,N-dimethylformamide, stir at room temperature for 1 h, then slowly add 0.67 bromoacetate B. The ester was heated to 80 ° C for 3 h, and thin layer chromatography showed the reaction was completed, cooled, and the mixture was diluted with water and filtered to give a yellow-yellow solid.

Step 2. Synthesis of 5-amino benzofuran-2-carboxylate

1.40 g of iron powder and 0.51 g of NaCl were added to a 100 ml three-necked flask, and 6.63 ml of H ₂ 0 and 0.15 ml of 30% HCl were added thereto, and the mixture was heated to 100 ° C and refluxed for 1 h. 1.5 lg of ethyl 5-nitrobenzofuran-2-furic acid (step 1 product) was added at this temperature, and refluxing was continued for 3 h. TLC showed the reaction was finished, cooled, filtered, washed with water, ethyl acetate. The ethyl acetate layer was collected, dried over anhydrous MgS0 _4, filtered, and ethyl acetate recovered under reduced pressure to give a pale yellow oil 1.16g step 3. synthesis of 5 - ((3,4-dioxo Yue phenyl) amino Yue ) benzofuran-2-furic acid ethyl ester hydrochloride

1.10 g of 3,4-decylene dioxetaldehyde and 1.50 g of the product of step 2 were dissolved in 15 ml of methanol, and added in portions under ice bath. 3.07g of NaB was added, and glacial acetic acid was added dropwise to maintain the pH of the reaction mixture. The reaction was completed by thin layer chromatography. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate/water and acidified with 5N hydrochloric acid. White solid, filtered, dried, white solid 1.96g

 Step 4. Synthesis of 5-((3,4-methylenedioxyphenyl)methylamino)benzofuran-2-decanoic acid

 1.56 g of the product of step 3 was suspended in 8 ml of tetrahydrofuran / 8 ml of water, 0.53 g of lithium hydroxide was added, and the mixture was stirred at room temperature overnight, and the reaction was completed by thin layer chromatography. The solvent was evaporated under reduced pressure, and the residue was dissolved in 20 ml of water and adjusted to pH with 1 N hydrochloric acid. It is about 5, left to stand, and filtered to obtain 1.30 g of a white solid.

Step 5. Synthesis of N-(2-amino-5-fluorophenyl)-5-((3,4-ytylenedioxyphenyl)decylamino)-benzofuran-2-indoleamide (Compound 45)

 0.68 g of the product of Step 4, 0.358 g of N,N-carbonyldiimidazole was dissolved in 10 ml of anhydrous tetrahydrofuran, and reacted at 45 ° C for 1.5 h, cooled, and set aside. Take another three-necked flask, dissolve 0.33 lg of 4-fluoro-1,2-phenylenediamine in anhydrous tetrahydrofuran under nitrogen, add 0.36 g of trifluoroacetic acid dropwise, then add the alternate reaction solution, stir at room temperature. The reaction was carried out overnight, and the reaction was completed by a thin layer chromatography. The solvent was evaporated under reduced pressure, and the residue was applied to silica gel column eluted with ethyl acetate/ petroleum ether 1:2, and the eluent was concentrated and crystallised to give white solid 0.38 g

 The melting point of the product is m.p. 205.5-206 °C;

'HNMR (DMSO-d ₆ ) (Sppm): 4.195-4.210 (d, 2H), 5.253 (s, 2H), 5.971 (s, 2H), 6.150-6.180 (t, lH), 6.338-6.381 (m, lH), 6.520-6.556(dd,lH), 6.727-6.733(d,lH), 6.848-6.874(m,3H), 6.953-6.955(d,lH) , 7.099-7.137(q,lH), 7.376- 7.398(d,lH), 7.422(s,lH), 9.656(s,lH). The following synthetic procedures for compounds 46-50, 77-81 are as in Example 8 (Compound 45)

Ν-(2- -5-fluorophenyl)-5-(4-(dimethylbenzylbenzofurazan-2-methyl SUfe (Compound 46)

nHNMR (DMSO-d6) (Sppm): 2.854 (s, 6H), 4.145-4.159 (d, 2H), 5.250 (s, 2H), 6.007-6.035 (t, lH), 6.338-6.373 (m, lH) , 6.521-6.549(dd,lH), 6.686-6.738(q,3H), 6.855-6.883(dd,lH), 7.101-7.224(m,3H), 7.362-7.384(d,lH), 7.439(s, lH), 9.649 (s, lH).

N-(2-J^-5-fluorophenyl)-5-(4- gas benzoyl-benzofuran-2-yl (compound 47)

HNMR (DMSO-d ₆ ) (Sppm): 4.280-4.294 (d, 2H), 5.253 (s, 2H), 6.221 -6.25 l (t, lH), 6.338-6.380 (m, lH), 6.521-6.556 ( Dd, lH), 6.726-6.731 (d, lH), 6.856-6.885 (dd, lH), 7.099-7.175 (m, 3H), 7.382-7.448 (m, 4H), 9.657 (s, lH).

N-(2-g^-5-fluorophenyl)-5-(2-fluorobenzyl)-benzofuran-2-carboxamide (Compound 48)

1H NMR (DMSO-d ₆ ) (δρριη): 4.34-4.35 (d, 2H), 5.25 (s, 2H), 6.17-6.20 (t, lH), 6.35-6.38 (m, lH), 6.52-6.55 (dd , lH), 6.75-6.76 (d, lH), 6.88-6.90 (dd, lH), 7.11-7.45 (m, 7H), 9.66 (s, lH).

 Ν-(2- -5-fluorophenyl)-5-(2-chlorobenzoylbenzofurazan-2-methyl SUfe (Compound 49)

1H NMR (DMSO-d ₆ ) (Sppm): 4.37-4.38 (d, 2H), 5.25 (s, 2H), 6.29-6.36 (m, 2H), 6.52-6.55 (dd, iH), 6.67-6.20 (d , lH), 6.87-6.89 (dd, lH), 7.1 l-7.13 (q, lH), 7.28-7.48 (m, 6H), 9.66 (s, lH).

 N-(2- -5-fluorophenyl)-5-(2,4-dichlorobenzoylbenzofuran-2-methyl StJfe (Compound 50)

'HNMR (DMSO-d ₆ ) (5 ppm): 4.35-4.36 (d, 2H), 5.25 (s, 2H), 6.33-6.38 (m, 2H), 6.52-6.67 (m, 2H), 6.86-6.88 ( Dd,lH), 7.10-7.14(q,lH), 7.41-7.45(m,4H), 7.63-7.64(d,lH), 9.67(s,lH).

 Ν-(2- -5-fluorophenyl)-5-(3,4-difluorobenzoic benzofuran-2-methyl SUfe (compound 77)

 'HNMRC DMSO-de) (8 ppm): 4.292-4.306 (d, 2H), 5.271 (s, 2H), 6.317-6.377 (q, 2H), 6.513-6.548 (dd, lH), 6.714-6.720 (d, lH) ), 6.847-6.875 (dd, lH), 7.086-7.123 (t, lH), 7.248 (s, lH), 7.378-7.450 (q, 4H), 9.688 (s, lH).

N-(2-J^-5-fluorophenyl)-5-(2-methylbenzophenone J-benzofuren-2-yl (compound 78)

 • HNMRC DMSO-de) (6 ppm): 3.853 (s, 3H), 4.246-4.261 (d, 2H), 5.250 (s, 2H), 6.024-6.054 (m, lH), 6.339-6.381 (q, lH), 6.522-6.557(dd,lH) , 6.687-6.692(d,lH) , 6.859-6.902(q,2H) , 7.002-7.022(d,lH) , 7.100-7.138(t,lH) , 7.212-7.296(q , 2H), 7.379-7.44 l(q, 2H), 9.658(s, lH).

N-(2-J>-5-fluorophenyl)-5-(4-methyl 1^methyl^)-benzofurazan-2-methyl SUfe (compound 79)

1H NMR (DMSO-d ₆ ) (5ppm): 3.724 (s, 3H), 4.207-4.222 (d, 2H), 5.275 (s, 2H), 6.150-6.179 (m, lH), 6.338-6.381 (q, lH) ), 6.518-6.553(dd,lH), 6.723-6.728(d,lH), 6.855-6.909(q,3H), 7.092-7.130(t,lH), 7.307-7.443(q,4H), 9.686(s , lH).

N-(2-i -5-like phenyl)-5-(3,4-dimethyl L^Lmethyl-benzofuren-2-曱 SUfe (compound 80)

'HNMR (DMSO-d ₆ ) (5 ppm): 3.737 (s, 6H), 4.201 - 4.215 (d, 2H), 5.276 (s, 2H), 6.156-6.157 (m, lH), 6.352-6.359 (q, lH), 6.515-6.550 (dd, lH), 6.740-6.745 (d, lH), 6.885-6.91 l(q,3H), 7.015-7.016(d,lH), 7.090-7.128(t,lH), 7.379 -7.45 l(q, 2H), 9.687(s, lH).

 N-(2-J-5-fluorophenyl)-5-(pyridin-3-yl-methyl^)-benzofuran-2-methyl SUfe (compound 81)

'HNMRC DMSO-d^ (5 ppm): 4.332-4.347 (d, 2H), 5.276 (s, 2H), 6.309-6.358 (q, 2H), 6.513-6.549 (dd, lH), 6.764-6.770 (d, lH ), 6.868-6.898(dd,lH), 7.087-7.125(t,lH), 7.356-7.45 l(q,3H), 7.780-7.800(q,lH), 8.443-8.455(dd,lH), 8.622- 8.627(d,lH), 9.694(s,lH).

Compound 97 compound 98 compound 100 compound 102

 ^式 9

EXAMPLE 9. Synthesis Ν-(2-·|^-5-Methoxyphenyl)-4 (4-(pyridinyl)pyridin-2-yl)methyl)benzamide (Compound 97)

 Step 1. Synthesis of 3,3-didecylamino-1-pyridin-3-yl-propenone

2 g of 3-acetylpyrazole ¹ 3⁄4: was dissolved in 5 ml of anhydrous DMF, and 5 ml of DMAPDMA was added to the solution, and the reaction was carried out, and the mixture was heated to 110 ° C for 3 hours. The thin layer chromatography showed the end of the reaction, and the DMF was recovered under reduced pressure. The liquid was placed in a refrigerator overnight, and a yellow solid was separated.

 Product melting point m.p. 82-83 ° C MS (FAB);

 Step 2. Synthesis of 4-mercaptomethyl-benzoic acid

 2 g of mercaptoisothiourea sulfate was dissolved in 10 ml of 1 mol/L NaOH aqueous solution, and 2.15 g of 4-aminomercaptobenzoic acid was slowly added dropwise in an ice bath, and the reaction was stirred overnight at room temperature to precipitate a white solid, which was filtered. Drying gave 2.56 g of a white solid.

 Step 3. Synthesis of 4-[(4-pyridin-3-yl-pyrimidin-2-yl-amino)-indenyl]benzoic acid

 1.57 g of the product of step 1 and 1.88 g of the product of step 2 were dissolved in 10 ml of isopropanol, and 1.26 g of K 2 C03 was added thereto. After the addition, the temperature was refluxed for 12 h, and the reaction was completed by thin layer chromatography, cooled, filtered and dried to give a white solid. 1.87g.

 The product has a melting point of m.p. 219.5-221 °C;

 Step 4. Synthesis of N-(2-amino-5-fluorophenyl)-4((4-(pyridin-3-yl)pyrimidin-2-amino)indolyl)benzoyl compound 1) lg Step 3 product, 0.54 gN, N-carbonyldiimidazole was dissolved in 8 ml of anhydrous tetrahydrofuran, reacted at 45 ° C for 1.5 h, cooled, and set aside. Take another dry 100 ml three-necked flask, dissolve 0.52 g of 4-fluoro-1,2-phenylenediamine in 7 ml of anhydrous tetrahydrofuran under nitrogen, add 0.38 g of trifluoroacetic acid dropwise, and then add the alternate reaction solution. After stirring at room temperature overnight, the reaction was completed by thin-layer chromatography. The solvent was evaporated under reduced pressure. The residue was purified by silica gel, ethyl acetate / petroleum hexane / ethanol 2:1:2, and the eluent was concentrated and crystallised to give white solid. 0.28g.

 The melting point of the product is m.p. 165-167 ° C;

lHNMR(DMSO-d6) (ppm): 3.641-3.670 (d,3H), 4.636-4.649 (d,2H), 5.212(s,2H), 6.150 -6.178 (dd,lH), 6.330 -6.337 (d, lH), δ 6.969-6.991 (d,lH), 7.262-7.274(d,lH), 7.492-7.531(m,3H), 7.901-8.045(m,3H), 8.407-8.420(d,2H), 8.680 -8.690(d,lH), 9.246 (s,lH), 9.475 (d,lH) The compounds of Examples 98-102 were synthesized as in Example 9.

 Ν-(2-·^-5-methylphenyl)-4((4-(4-ethyl)pyrimidinyl)benzene (Compound 98)

 The product has a melting point of m.p. 215-217 ° C;

'HNMR (DMSO-d ₆ ) (5 ppm): 1.328-1.363 (m, 3H), 3.670 (s, 3H), 4.066-4.101 (dd, 2H), 4.620-4.634 (d, 2H), 4.877 (s, 2H), 6.159-6.180(dd,lH), 6.334-6.340(d,lH),

6.997-7.104 (m, 4H), 7.453-7.473 (d, 2H), 7.751-8.048 (m, 5H), 8.277-8.289 (d, lH), 9.443 (s, lH).

 Ν-(2-·3⁄4^-5-methoxyphenyl)-4(4-(4-methylphenyl)pyrimidin-2-Jmethyl)benzene SUfe (Compound 99) Product melting point mpl83-186°C ;

'HNMRC DMSO-de) (δρριη) : 3.562-3.670(m,3H), 3.818(s,3H) , 4.620-4.632(d,2H), 4.899(s,2H) , 6.158-6.180(dd,lH) , 6.333-6.339(d,lH) , 7.028-7.117(m,4H) , 7.460-7.475(d,2H), 7.815-7.917(m,3H), 8.046-8.067(d,2H), 8.283-8.296(d , 2H), 9.469 (s, lH).

 N-(2-J^-5-methylphenyl)-4((4-(4-methylfluorophenyl)pyrimidin-2-yl)methyl)benzene SUfe (Compound 100) Product melting point mp219- 222 ° C;

¹ H NMR (DMSO-d ₆ ) (δρριη) : 4.361-3.670(s,3H), 3.903(s,3H), 4.616-4.63 l(d,2H), 4.901 (s,2H), 6.151-6.180(dd , 1 H), 6.330-6.337 (d, 1 H), 6.968-6.990 (d, 1 H),

7.162-7.277(m,2H), 7.474(m,2H), 7.898-7.944(m,5H), 8.315-8.328(d,lH),

N-(2-IL^-5-methoxyphenyl)-4((4-(4,5-difluorophenyl)pyrimidine-2-^)methyl)benzene SUfe (Compound 101)

¹ H NMR (DMSO-d ₆ ) (5 ppm): 3.63-3.672 (s, 3H), 4.629-4.644 (d, 2H), 4.879 (s, 2H), 6.154-6.182 (dd, lH), 6.334-6.341 ( d,lH), 6.974-6.996(d,lH), 7.217-7.230(d,lH), 7.457-7.580(m,3H), 7.900-7.967(m,4H), 8.121(m,lH), 8.381- 8.393(d,lH),

N-(2-J^-5-methoxyphenyl)-4((4-(4-bromophenyl)pyrimidinemethyl)benzene SU^ (Compound 102)

The product has a melting point of m.p. 212-215 ° C;

'HNMR (DMSO-d ₆ ) (Sppm): 3.565-3.673 (s, 3H), 4.629-4.644 (d, 2H), 4.833 (s, 2H), 6.156-6.184 (dd, lH), 6.339-6.345 ( d,lH), 6.980-7.00 l(dd,lH), 7.177-7.191 (d,lH), 7.460-7.77(d,2H), 7.69-7.714(d,2H), 7.900-7.942(m,3H) , 8.024-8.045 (d, 2H), 8.369-8.382 (d, lH), 9.451 (s, lH).

Compound 96 Ar = X ₂ = FA = CH ₃ Compound 103 Ar = X ₂ = FA = H Compound 104 Ar = X ₂ = FA = H Compound 105 X ₂ = FA = H

Compound 106 Ar = X ₂ = FA = H

Compound 107 Ar = X ₂ = FA = H Compound 108 Ar = X ₂ = FA = H

 MeO'^OMe

Compound 109 Ar= Or X ₂ =OCH ₃ A=CH ₃

Compound 110 Ar = X ₂ = OCH ₃ A = CH ₃

 OMe

Compound 111 Ar = X ₂ = FA = CH ₃ Compound 112 Ar = X ₂ = FA = CH ₃ Compound 113 Ar = X ₂ = OCH ₃ A = CH ₃

Compound 114 Ar = X ₂ = FA = CH ₃

Compound 115 Ar = X ₂ = FA = CH ₃

Compound 116 Ar = X ₂ = FA = CH ₃

MeO ^A ^OMe

Compound 123 Ar= X ₂ =OCH ₃ A=H

 MeO^^OMe

 Equation 10

Example 10. Synthesis of N-(2-IL^-5-methylphenyl)-4((6-phenylpyrimidin-4-Jmethyl)benzone SUfe (Compound 91) Step 1. Synthesis of p-aminomethylbenzoic acid methyl ester hydrochloride

 Weigh 2g of ampicillin acid in 100ml of sterol, slowly add 2ml of thionyl chloride under ice bath, add, continue stirring at room temperature for 3 hours, then 5 (TC reflux reaction for 3 hours, The reaction of the plate was almost complete, extracted with ethyl acetate, washed with saturated sodium sulfate, dried over magnesium sulfate, and concentrated to give a white solid.

Step 2. Synthesis of 4-((6-chloropyrimidin-4-amino)indolyl) benzoate

 9.5 g of hydrazinyl benzoic acid decanoate hydrochloride was dissolved in a mixed solution of 250 ml of THF/DMF (=5:1), 20 ml of triethylamine was added dropwise, and after being suspended, 7 g of 4, 6 was added. The dichloropyrimidine was stirred and refluxed at 70 ° C for 15 hours, and a white solid precipitated, which was filtered, washed with water and dried to give a white solid (13.8 g).

Step 3. Synthesis of 4-((6-phenylpyrimidin-4-amino)methyl)benzoic acid

 Weigh 0.2836g of tris-p-phosphorus and 0.1214g of palladium acetate in 10ml, 4-dioxane, react at 80 ° C for 1 hour under nitrogen protection, and add 50ml of B1/water (= a mixed solvent of 3: 2), and 1.5 g of methyl 4-((6-chloropyrimidin-4-amino)indolyl benzoate, 1.12 g of potassium carbonate and 0.1 g of sodium bromide were added and reacted at 90 ° C After half an hour, 0.79 g of phenylboronic acid was added, and the reaction was completed overnight. The reaction was completed, and the mixture was allowed to cool to 60 ° C, filtered, suspended, and adjusted to pH = 5-6 with hydrochloric acid to give a large amount of solid, which was obtained by suction filtration.

Step 4. Synthesis of N-(2-amino-5-nonyloxyphenyl)-4((6-phenylpyrimidin-4-amino)indolyl)benzamide

 0.3 g of 4-((6-phenylpyrimidin-4-Jindolyl)benzoic acid and 0.16 g of N,N-carbonyldiimidazole were dissolved in 8 ml of anhydrous tetrahydrofuran, refluxed at 50 ° C for 1.5 h, and cooled. Take another dry 100ml three-necked flask, dissolve 0.14g of 4-decyloxy-1,2-diamine in 7ml of anhydrous tetrahydrofuran under nitrogen, add 0.12g of trifluoroacetic acid, add dropwise The reaction mixture was stirred at room temperature overnight. EtOAc was evaporated. EtOAc EtOAc.

'HNMR (DMSO-d ₆ ) (6 ppm): 3.650-3.677 (s, 3H), 4.633-4.675 (d, 2H), 4.895 (s, 2H), 6.168-6.189 (dd, lH), 6.344-6.350 ( d, lH), 6.989-7.026 (d, 2H), 7.050-7.502 (m, 6H), 7.926-8.060 (m, 6H), 8.515 (s, lH), 9.477 (s, lH). The following compounds 92-96, 103-119, 123-124 were synthesized as in Example 10 (Compound 91).

 N-(2-J-5-methylphenyl)-4((6-(3-methyl)pyrimidin-4-^)methyl)benzene SUfe (compound 92)

'HNMRC DMSO-d^) (5 ppm): 3.647-3.674 (s, 3H), 3.821 (s, 3H), 4.655-4.669 (d, 2H), 4.892 (s, 2H), 6.165-6.186 (dd, lH) , 6.339 -6.346(d,lH) , 6.984-7.038(m,3H) , 7.388-7.564(m,5H), 7.919-8.032(m,3H), 8.506(s,lH), 9.471(s,lH) .

N-(2-J^-5-methoxyphenyl)-4((6-(4-methyl)pyrimidin-4-HJmethyl)benzene SUfe (Compound 93)

'HNMRC DMSO-de) (5 ppm): 3.674 (s, 3H), 3.815 (s, 3H), 4.644-4.656 (d, 2H), 4.892 (s, 2H), 6.165-6.186 (dd, lH), 6.339- 6.346(d,lH), 6.983-7.052 (m,4H), 7.39-7.59(d,2H), 7.917-7.980(dd,5H), 8.460(s,lH), 9.496(s,lH).

Ν-(2-·^-5-methoxyphenyl)-4((6-(3-pyridinyl)-4-)methyl)benzene StJ^ (Compound 94)

1H NMR (DMSO-d ₆ ) (6 ppm): 3.647-3.674 (s, 3H), 4.667-4.68 l (d, 2H), 4.892 (s, 2H), 6.165-6.187 (dd, lH), 6.339 -6.346 ( d,lH), 6.984-7.096 (m,2H), 7.449-7.527 (m,3H), 7.922-7.943(d,2H), 8.130-8.162(t,lH), 8.334-8.353(d,lH), 8.544-8.678(m,2H), 9.196 (s,lH), 9.473 (s,lH).

 N-(2-J^-5-methylphenyl)-4((6-(3,4-methylenephenyl)pyrimidin-4-)methyl)benzene "Compound 95"

'HNMRC DMSO-de) (5 ppm): 3.647-3.674 (s, 3H), 4.641-4.653 (d, 2H), 4.890 (s, 2H), 6.092 (s, 2H), 6.164-6.186 (dd, lH), 6.338-6.345 (s,lH), 7.004-7.03 l(m,3H) , 7.435-7.541(m,4H), 7.915-7.935(m,3H), 8.450 (s,lH) , 9.468(s,lH) .

N-(2-H^-5- Lphenyl)-4((6-phenylpyrimidin-4-methyl)benzoquinone BUfe (Compound 103)

1H NMR (DMSO-de) (6 ppm): 4.665-4.667 (s, 2H), 5.205 (s, 2H), 6.330-6.373 (m, lH), 6.516-6.55 l (dd, lH), 7.026 (s, lH) ), 7.085-7.122(t,lH), 7.478-7.502(m,6H), 7.930-8.066(m,6H), 8.514(s,lH), 9.535(s,lH).

 N-(2-J>-5-fluorophenyl)-4((6-(3-methyl! 3⁄4 J^yl)pyrimidine-4-J methyl)benzene SUfe (Compound 104)

'HNMR (DMSO-d ₆ ) (5 ppm): 3.821 (s, 3H), 4.661-4.673 (s, 2H), 5.226 (s, 2H), 6.330-6.373 (m, lH), 6.517-6.546 (dd, lH) , 7.041 -7.097(m,3H) , 7.392-7.469(m,3H) , 7.548-7.567(s,2H), 7.928-7.949(d,2H), 8,057-8.088(t,lH) , 8.506 ( s,lH), 9.556 (s,lH). N-(2- -5-fluorophenyl)-4((6-(4-methyl)pyrimidin-4-Jmethyl)benzene BS^ (Compound 105)

'HNMR (DMSO-d ₆ ) (5 ppm): 3.815 (s, 3H), 4.646-4.660 (s, 2H), 5.203 (s, 2H), 6.328-6.371 (m, lH), 6.513-6.548 (dd, lH), 6.942-7.119 (m, 4H), 7.448-7.468 (d, 2H), 7.924-7.98 l (m, 5H), 8.458-8.3460 (s, lH), 9.531 (s, lH).

 N-(2- J-5- Lphenyl) -4((6-(3-pyridyl)pyrimidinylmethyl)benzene Sfcamine (Compound 106)

1H NMR (DMSO-d ₆ ) (5 ppm): 4.669-4.682 (s, 2H), 5.202 (s, 2H), 6.342-6.349 (m, lH), 6.511-6.547 (dd, lH), 7.079-7.117 (t , 2H), 7.454-7.535 (m, 3H), 7.927-7.948 (d, 2H), 8.135-8.165 (t, lH), 8.334-8.354 (d, lH), 8.544-8.674 (m, 2H), 9.170 (s,lH), 9.532 (s,lH).

 N-(2-|^-5-fluorophenyl)-4((6-(3,4-methylenedi)pyrimidin-4-Jmethyl)benzoic acid as (Compound 107) 1HNMR (DMSO -d6) (6ppm): 4.643-4.825(d,2H), 5.201 (s,2H), 6.093(s,2H), 6.328-6.371(m,lH) , 6.512-6.547(dd,lH) , 6.924- 7.118 (m, 3H), 7.446-7.586 (m, 5H), 7.921-7.974 (m, 4H), 8.450 (s, lH), 9.527 (s, lH).

N-(2-^-5-fluorophenyl)-4((6-(2,4-dimethoxyphenyl)pyrimidinylmethyl)benzylamine (Compound 108) 'H MR(DMSO-d ₆ (6ppm): 3.818-.083(d,6H), 4.607(s,2H) , 5.201 ( s,2H ) , 6.330-6.373(m,lH) , 6.514-6.655(m,3H) , 7.084-7.12 l(q,2H), 7.436-7.457(d,2H), 7.913-7.964(m,4H), 8.432(s,lH), 9.533 (s,lH).

 N-(2- -5-methylphenyl ((2-methyl-6-phenylpyrimidin-4-41^)methyl)benzoquinone «Jfe (Compound 109)

¹ H NMR (DMSO-d ₆ ) (5 ppm): 2.416-2.505 (s, 3H), 3.674 (s, 3H), 4.658 (s, 2H), 4.892 (s, 2H), 6.158-6.186 (dd, lH) , 6.339-6.346(d,lH), 6.822(s,lH), 6.984-7.005(d,lH), 7.463-7.474(m,5H), 7.923-7.993 (m,5H), 9.473 (s,lH) „

N-(2-SJ-5-methyl H ^ group) -4((6-(3-methylphenyl)-2-methylpyrimidin-4-methyl)benzene SUfe (compound 110 )

 ^MRCDMSO-de) (5ppm): 2.412(s,3H), 3.674 (s,3H), 3.815 (s,3H), 4.645-4.655(s,2H), 4.890(s,2H), 6.158-6.186 ( Dd,lH), 6.339-6.345(d,lH), 6.813(d,lH), 6.982-7.046(m,2H), 7.388-7.548 (m,5H),. 7.883-7.941(t,3H), 9.472(s,lH).

N-(2-Amino-5-methoxyphenyl)-4((2-methyl-6-(3,4-methylenedioxyphenyl)pyrimidine-4-amino)methyl)benzene St amine (compound 113)

 ^MRCDMSO-de) (6ppm): 2.401(s,3H), 3.674 (s,3H) , 4.638 ( s,2H ) , 4.890(s,2H) ,

6.082- 6.185(m,3H) , 6.338-6.345(d,lH) , 6.729(s,lH) , 6.982-7.010(q,2H) , 7.445-7.576(m,4H), 7.810-7.936(t,3H ), 9.467 (s, lH).

N-(2-lL^-5-fluorophenyl)-4-((2-methyl-6-phenylpyrimidin-4-Jmethyl)benzamide (Compound 96)

 ^MRCDMSO-de) (6ppm): 2.415(s,3H), 4.652(s,2H), 5.201(s,2H), 6.349(m,lH), 6.511-6.546(dd,lH) , 6.781-6.822( s,lH), 7.079-7.117(t,lH), 7.413-7.480(d,6H), 7.905-7.992(m,5H), 9.532(s,lH).

 N-(2-Amino-5-fluorophenyl)-4-((6-(3-methoxyphenyl)-2-methylpyrimidin-4-amino)methyl)benzamide (Compound 111)

¹ H NMR (DMSO-d ₆ ) (δρρπι): 2.496 (s, 3H), 3.815 (s, 3H), 4.646-4.658 (s, 2H), 5.202 (s, 2H), 6.328-6.371 (m, lH) , 6.511-6.546(dd,lH) , 6.824-6.835(s,lH), 7.019-7.100(m,2H), 7.369-7.548(m,5H), 7.888-7.947 (ds,3H), 9.532(s, lH).

 N-(2-Amino-5-fluorophenyl)-4-((6-(4-methoxyphenyl)-2-mercaptopyrimidine-4-amino)indolyl)benzamide (Compound 112)

, (5ppm): 2.497(s,3H), 3.808(s,3H), 4.632(d,2H), 5.200(s,2H), 6.328-6.370(m,lH), 6.511-6.546(dd,lH) , 6.742 (s, lH), 7.010-7.166 (m, 3H), 7.4-32-7.476 (m, 2H), 7.924-7.962 (t, 5H), 9.529 (s, lH).

 N-(2-^-5-fluorophenyl)-4-((2-methyl-6-(3-pyranyl)pyrimidine-4-^)methyl)benzamide (Compound 114) taMRCDMSO-dg (5ppm): 2.497(s,3H), 4.664(s,2H), 5.601 (s,2H), 6.328-6.370(m,lH), 6.511-6.546(dd,lH) , 6.903(s,lH) , 7.080-7.166(t,3H), 7.466-7.513(m,3H), 7.929-8.005(sd,3H), 8.314-8.33(d,lH), 8.643-8.655(dd,lH), 9.144(s, lH), 9.534 (s, lH).

N-(2-^-5-fluorophenyl)-4-((6-(3,4-methylenedi-l-phenyl)-2-methylpyrimidin-4-indolemethyl)benzamide ( Compound 115)

^MRCDMSO-de) (5ppm): 2.492(s,3H) , 4.629-4.639(s,2H) , 5.200(s,2H),

6.083- 6.097(s,2H), 6.321 -6.370 (m,lH), 6.511-6.546 (dd,lH), 6.728 (s,lH) ,6.990-7.116 (td,2H), 7.453-7.576(td,4H ), 7.818 -7.942 (ds, 3H), 9.526 (s, lH).

 N-(2-J^-5-fluorophenyl)-4-((6-(2,4-dimethylphenyl)-2-methylpyrimidin-4-J^methyl)benzamide (Compound 116 )

^MRCDMSO-de) (5ppm): 2.365(s,3H), 3.810(s,6H), 4.592 (s,2H), 5.201(s,2H), 6.331-6.374(m,lH) , 6.515-6.551( Dd,lH) , 6.601 -6.633(q,2H) , 7.084-7.121 (q,2H) , 7.444-7.465 (d, 2H), 7.766-7.780 (t, lH), 7.919-7.952 (m, 3H), 9.537 (s, lH).

N-(2-J^-5-methylphenyl)-4-((6-(2,4-dimethyl H >phenyl)pyrimidin-4-ylmethyl)) Amazon SU^ (Compound 123)

 ^MRCDMSO-de) (8ppm): 3.674(s,3H), 3.818-3.856(s,6H), 4.628(s,2H), 4.923(s,2H), 6.158-6.186(dd,lH), 6.337- 6.344(d,lH), 6.625-6.658(m,2H), 6.979-7.00 l(d,lH), 7.229(s,lH), 7.427-7.447(d,2H), 7.924-7.970(m,4H) , 8.434(s,lH), 9.510(s,lH).

 Equation 11

 N-(2-H^-5-fluorophenyl)-4-((6-(4-methyl HJ^) 2-11^) fluorenyl)benzyl Stife (compound 117 )

'HNMR (DMSO-d ₆ ) (5 ppm): 3.799 (s, 3H), 4.648-4.663 (d, 2H), 5.196 (s, 2H), 6.325-6.361 (m, lH), 6.511-6.539 (dd, lH) , 7.011-7.097(td,3H) , 7.503-7.523(d,2H) , 7.727-7.756(t,lH), 7.899-7.968 (m,5H), 8.246(s,lH), 9.521 (s, lH).

N-(2-^-5-methoxyphenyl)-4-((6-(4-methyl)3⁄4b^2-^)methyl)benzene StJfe (compound 118) 'HNMRCDMSO-de) (δρρηι ): 3.670-3.677(s,3H) , 3.799(s,3H) , 4.642-4.657 (d,2H), 4.882(s,2H) , 6.159-6.188(dd,lH) , 6.334-6.34 l(d, lH), 6.975-7.023(t,3H), 7.491-7.51 l(d,2H), 7.718-7.748(t,lH), 7.894-7.966(m,5H), 8.242(s,lH), 9.457(s , lH).

N-(2-Amino-5-fluorophenyl)-4-((6-(3,4-methylenediphenyl)pyridazin-2-yl)methyl)benzamide (Compound 119)

 • HNMRC DMSO-de) (5 ppm): 4.638-4.653 (d, 2H), 5.193 (s, 2H), 6.066 (s, 2H), 6.323-6.365 (m, lH), 6.507-6.535 (dd, lH), 6.978-7.110(m,2H), 7.491-7.535(m,4H), 7.746-7.775(t,lH), 7.909-7.94 l(t,3H), 8.239(s,lH), 9.519(s,lH) .

N-(2-tJ-5-fluorophenyl)-4-((6-phenylfc 2-Jmethyl)benzene SUft (Compound 124)

'HNMRi DMSO-de) (6 ppm): 4.662-4.676 (d, 2H), 5.224 (s, 2H), 6.324-6.366 (m, lH), 6.503-6.53 l (dd, lH), 7.080-70102 (q, lH), 7.436-7.529 (m, 5H), 7.928-8.018 (m, 6H), 8.315 (s, lH), 9.550 (s, lH).

 SOC1,

 COOH CH3OH H HCC11 ^COOMe R R 1

 I N

COOMe HN LiOH

SOCl ₂ COOMe

DMF NEt, /DMF THF / H ₂ 0

Compound 120 X ₂ =OCH ₃ R!=R ₂ =OCH ₃ compound 121 ₂ =FR!=R ₂ =OCH ₃ ^Formula 12

Example 12. Synthesis of N-(2-H^-5-methyl HJJ^)-4-(6,7-dimethyl quinonemethyl)benzene (Compound 120)

Step 1. Synthesis of p-aminomethyl benzoate decyl ester hydrochloride

 The synthesis method is the same as step 1 of the embodiment 10.

Step 2. Synthesis of 2-amino-4,5-didecyloxy decanoate

 15 g of 4,5-dimethoxy-2-nitrobenzoic acid decyl ester, 0.86 g of ferric chloride, 3 g of dry activated carbon were added

In 150 ml of ethanol, heated to 80 ° C under nitrogen for 0.5 h, the temperature was lowered to 60 ° C, 10 ml of hydrazine hydrate (85%) was slowly added dropwise to the reaction solution, and the mixture was further refluxed for 3 h, thin layer chromatography. After the completion of the reaction, the reaction mixture was filtered while hot, and the filtrate was concentrated under reduced pressure to remove most of the ethanol. The residue was evaporated to give a pale yellow solid, which was filtered and dried to yield 8.6 g.

Step 3. Synthesis of 6,7-dimethoxy-3H quinazolin-4-one

 7.2 g of the product of step 2, 7.2 g of methyl acetate was added to 100 ml of ethanol, and the mixture was heated under reflux for 4 hours. The thin layer chromatography showed the end of the reaction, and the reaction mixture was cooled and filtered to give a white solid.

Step 4. Synthesis of 6, 7-dimethoxy-4-chloroquinazoline

5.4 g of the product of step 3, a mixed solution of thionyl chloride (30 ml) and DMF (2.5 ml) was stirred and heated to 50 ° C for 5 h, thin layer chromatography showed the end of the reaction, and the thionyl chloride was removed under reduced pressure. The solid is washed with ethanol and dried. Step 5. Synthesis of 4-((6,2-dimethoxyquinoline-4-amino)indolyl) benzoate

5.0 g of the product of step 4, 4.4 g of the product of step 1, 8.6 ml of triethylamine was added to 50 ml of DMF, and the mixture was refluxed at 80 ° C for 18 h under nitrogen atmosphere. The thin layer chromatography showed the end of the reaction, and the reaction solution was poured into 100 ml of water. , ph=7 with hydrochloric acid (2N), precipitated solid, filtered, and dried. Step 6. Synthesis of 4-((6,7-dimethoxyquinazolin-4-amino)indolyl)benzoic acid

 A mixed solution of 6.4 g of the product of Step 5, 2.3 g of lithium hydroxide, 40 ml of THF and 20 ml of water was stirred at 30 ° C for 4 h, and thin layer chromatography showed the end of the reaction. The THF was concentrated under reduced pressure and the residual solution was adjusted with hydrochloric acid (2N) Ph=3, a white solid precipitated, filtered and dried.

Step 7. Synthesis of (2-amino-5-nonyloxyphenyl)-4-(6,6-dimethoxyquinazolin-4-amino)decyl)benzoylamine,

 0.4 step 6 product, 0.19 g of N,N-carbonyldiimidazole was dissolved in 10 ml of anhydrous DMF, and was allowed to stand at 45 ° C for 1.5 h, cooled, and set aside. Take another dry 100 ml three-necked flask, dissolve 0.19 g of 4-decyloxy-1,2-phenylenediamine in 7 ml of anhydrous tetrahydrofuran under nitrogen, add 0.44 g of trifluoroacetic acid dropwise, and add dropwise reaction. The mixture was stirred at room temperature overnight. EtOAc (EtOAc)EtOAc. ~

^MRCDMSO-de) (5ppm): 3.672 (s,3H), 3.902(s,6H), 4.834-4.848(d,2H), 4.915 (s,2H), 6.163-6.178(m,lH), 6.335- 6.342(dd,lH) , 6.999-7.115(m,2H) , 7.448-7.469(d,2H) , 7.674(s,lH), 7.908-7.929(t,2H), 8.320(s,lH), 8.557- 8.589(t,lH), 9.497(s,lH).

N-(2-IL^-5-fluorophenyl)-4-((6,7-dioxin)-quinazolinemethyl)benzamide (Compound 121)

^MRCDMSO-de) (Sppm) : : 3.902(s,6H) , .835-4.850(d,2H) , 5.195 (s,2H), 6.343-6.350(m,lH) , 6.512-6.547(dd,lH ), 7.082-7.112(m,2H), 7.458-7.478(d,2H), 7.684(s,lH), 7.912-7.952(t,2H), 8.317(s,lH), 8.536-8.566(t ₅ lH ), 9.520(s,lH).

Compound 122 R= H ^X 2 ^=F

l ₃ C. _N ~,

 Compound 127 R= Compound 128 R=

 ^式13

Example 13. Synthesis of N-(2-^-5-fluorophenyl)-4-((2,4-dioxo-1,2-dihydroquino#~3(4H)-yl)methyl) Benzene StJfe (Compound 122)

Step 1. Synthesis of 4-((2-nitrobendoylamino)methyl)benzoate

 1.6 g of o-nitrobenzoic acid was suspended in 15 ml of re-distilled dichloromethane, and 1.28 g of N,N,-dicyclohexylcarbodiimide was added portionwise in an ice bath, followed by addition of 0.66 g of N- Hydroxysuccinimide, catalytic amount of 4-dimethylaminopyridine, stirred at room temperature, ready for use; take another reaction flask, add 2 g of hydrazinyl phthalate hydrochloride, 1.47 ml of triethylamine, 10 ml of steamed After half an hour, the reaction mixture was slowly added dropwise, and after stirring at room temperature for two hours, TLC showed the reaction was complete, the reaction was stopped, and the filtrate was collected, washed with acid water three times, and then washed with saturated sodium carbonate. After 3 times, the organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a white solid 1.46 g.

Step 2. Synthesis of 4-((2-nitrobenzoylamino)methyl) succinic acid

 U5g step 1 product, 0.67g sodium hydroxide was suspended in 10ml tetrahydrofuran/10ml water mixture, stirred at room temperature overnight, the solvent was removed under reduced pressure, the appropriate amount of water was added to the residue, and the pH was adjusted to 5-6 with dilute hydrochloric acid, and filtered. Drying gave a white solid of 0.94 g.

Step 3. Synthesis of 4-((2-aminobenzoylamino)indolyl)benzoic acid

 0.8 g of the product of step 2, 0.13 g of ferric chloride, 0.24 g of dry activated carbon, suspended in 20 ml of absolute ethanol, heated to reflux for half an hour, the heating was stopped, 0.4 ml of hydrazine hydrate was slowly added dropwise, and reflux was continued for 2 h, TLC The reaction is complete, filtered while hot, the filtrate is collected, the solvent is removed under reduced pressure, and an appropriate amount of water is added to the residue to adjust the pH to about 7, filtered, and dried to give a white solid, 0.68 g.

Step 4. Synthesis of 4-((2-(ethoxycarbonyl))]amino)methyl)benzoic acid

 0.62 g of the product of Step 3 was dissolved in 15 ml of pyridine, and 0.24 ml of ethyl chlorofurate was slowly added dropwise in an ice bath. After stirring for 2 hours, the reaction was completed by TLC, and an appropriate amount of acid water was added to the reaction solution to make the pH acidic. The mixture was extracted with chloroform. EtOAc (EtOAc m.).

Step 5. Synthesis of 4-((2,4-dioxo-1,2-dihydroquinoline-3( 4H ) -yl) fluorenyl)benzoic acid

 0.50 g of the product of step 3 was suspended in 10 ml of a mixture of decyl alcohol / 10 ml of water, and then added with 0.074 g of NaOH. After heating under reflux for 12 h, TLC showed the reaction was complete, and the filtrate was collected, the solvent was removed under reduced pressure, and an appropriate amount of water was added to the residue. The pH was adjusted to about 5-6, filtered and dried to give a white solid of 0.46 g.

Step 6. Synthesis of N-(2-amino-5-fluorophenyl)-4-((2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) fluorenyl) Benzoylamide

0.43 g of the product of Step 5 and 0.24 g of N,N-carbonyldiimidazole were dissolved in 8 ml of anhydrous tetrahydrofuran, refluxed at 50 ° C for 1.5 h, cooled and taken up. Take another dry 100ml three-necked flask, under the protection of nitrogen, 0.23g 4-fluoro-1,2- The stearic diamine was dissolved in 7 ml of anhydrous tetrahydrofuran, 0.165 g of trifluoroacetic acid was added dropwise, and the reaction mixture was added dropwise thereto, and the mixture was stirred at room temperature overnight. TCL showed the reaction was completed, and the solvent was evaporated under reduced pressure. The ethanol was eluted at 10:1, the eluent was concentrated, and crystallized to give a white solid 0.25 g.

¹ H NMR (DMSO-d ₆ ) (5 ppm): 5.131 (s, 2H), 5.295 (s, 2H), 6.942-7.112 (m, 3H),

7.215-7.348(m,4H), 7.669-7.706(t,lH), 7.845-7.964(m,3H), 9.520(s,lH), 11.425(s,lH). The synthesis of the following compound 127,128 was as in Example 13 (Compound 122).

 N-(2-J^-5-fluorophenyl)-4-((1-(2-(dimethyl)ethyl)-2,4-dioxo-1,2-dihydrotransazole 3 ( 4H)-yl)methyl)benzazole Sfcamine (Compound 127)

'HNMR (DMSO-d ₆ ) (5 ppm): 2.271 (s, 6H), 5.134 (s, 2H), 5.301 (s, 2H), 6.944-7.113 (m, 3H), 7.216-7.350 (m, 4H) , 7.670-7.706(t,lH), 7.853-7.969(m,3H), 9.532(s,lH)„

N-(2-tJ 5-fluorophenyl)-4-((l-(2-morpholinethyl)-2,4-di-hydrogen-1,2-dihydroquinazoline (4H)-yl) Methyl) Benzene Bfe^ (Compound 128)

'HNMR (DMSO-d ₆ ) (5 ppm): 2.389-2.401 (t, 4H), 3.671-3.680 (t, 4H), 5.131 (s, 2H), 5.295 (s, 2H), 6.942-7.112 (m, 3H), 7.215-7.348 (m, 4H), 7.669-7.706 (t, lH), 7.845-7.964 (m, 3H), 9.522 (s, lH).

Example 9. Inhibition of the growth of the compound of the present invention on the sputum

The MTT assay detects that the cells to be cultured are in good condition. The cells were prepared as a homogeneous suspension and inoculated into 96-well plates at a certain density. ΙΟΟμί cell suspension was added to each well so that the number of cells per well was 10,000 to 50,000 per well. Set 0~500μΜ different drug concentration groups, and set blank control group and solvent control group. Three replicate wells per concentration, each dose of ΙΟμΙ^ drug, the drug is added in order of low to high concentration, the drug must be mixed when adding. The 96-well plate is sealed, leaving a small convective slit to reduce errors due to evaporation of the cell culture fluid. After 48 hours of drug stimulation, cell proliferation was detected by MTT assay. The absorbance value was measured at a wavelength of 570 nm, and mathematical statistics were performed to obtain GI ₅ . Value (concentration of compound that inhibits cell growth by 50%).

 Table 2 compounds inhibit proliferation of tumor cells

Compounds of each tumor cell of GI ₅ o(M) normal cells. Ι ₅₀ (μΜ)

HL60 Jurkat HepG2 SMMC-7721 MCF-7 MDA-MB-231 CCD-1059SK

MS-275 0.1556 1.9819 21.1000 16.4364 3.4298 4.2304 68.4250 Compound 0.0434 0.7135 10.7112 2.9744 0.2493 0.1435 107.3823 6

Compound 0.3524 1.6457 50.3113 11.9981 2.2350 1.4480 91.5674 4

Compound 0.123 1.460 3.1500 12.7655 1.4068 0.4817 115.670 11 Compound 0.197 1.6671 16.4080 8.9738 0.3684 1.7916 120.580

9

Compound 0.086 0.8934 5.4012 5.4495 0.9460 2.8503 86.085 32

Compound 0.075 0.7695 2.9837 10.8659 0.7108 1.2895 140.780 37

Compound 0.094 0.9782 16.1249 9.7845 1.8548 3.4760 102.357 33

Compound 0.056 0.9587 8.0233 6.1566 0.9561 1.5624 99.123 93

Compound 0.112 0.7892 12.3654 7.2655 0.8648 1.5772 101.255 96

Compound 0.078 0.7548 16.1255 5.2613 0.9875 1.0488 82.165 103

Compound 0.1253 0.9884 11.2565 8.4658 1.2564 1.2548 90.254 104

Compound 0.1879 0.9724 8.2654 9.2645 1.8012 2.0566 100.987 105

Compound 0.0955 0.8542 9.2156 8.1256 1.5648 3.4698 120.546 107

Compound 0.0925 0.7785 9.5656 5.0255 0.7854 2.4869 100.748 110

Compound 0.0665 1.2563 5.1662 7.0235 0.4568 0.4561 87.012

111

Compound 0.0523 0.5524 8.2021 6.4556 1.2554 2.4556 85.021

1 12

Compound 0.0874 0.6458 8.868 8.1665 1.0455 1.5554 130.254 116

Compound 0.0789 0.8742 6.663 5.1742 0.8756 0.1514 110.223 1 17

 * Positive 0.1823 2.4500 25.3750 20.1547 4.2903 3.7900 57.6937 Reference drug

Object (YX)

 * Positive control drug: N-(2-aminophenyl)-4-((3,4-dimethoxyphenyl)aminoindolyl)benzamide (a compound disclosed in WO2005092899, which we disclose as disclosed Method was synthesized)

Cell source: SMMC-7721: Human liver cancer cell HepG2: human liver cancer cell

 MCF-7: Human Breast Cancer Cell MDA-MB-231: Human Breast Cancer Cell

 HL-60: Human myeloid leukemia cells Jurkat: human T lymphocyte leukemia

 CCD-1059SK: normal fibroblast

 The results show that the compounds disclosed in the present invention have significant anticancer activity, especially for human breast cancer cells MDA-MB-231, MCF-7, and compound 6 are 29 and 13 times higher than MS-275, respectively; for leukemia cells HL60, Jurkat, Compound 6 was 3 and 2 times higher than MS-275, respectively. For human liver cancer cells SMMC-7721 and HepG2, compound 6 was 5 and 1 times higher than MS-275, respectively. The proliferation inhibitory activity of Compound 4 on tumor cells was comparable to that of MS-275. The compounds disclosed in the present invention are less toxic to normal cells than MS-275 or the positive control drug (YX).

 3 preliminary stability test

 A. High temperature test

 Take 2 samples of the pre-test compound samples, place them in a weighing bottle, and lay them into a thin layer of 5mm. Place them in a 60 °C incubator for 10 days, and sample them at 5 and 10 days respectively to examine the appearance, related substances and content. Change, the results are shown in Table 3.

 Table 3. Table of results of high temperature stability test of compounds

 Conclusion: After 10 days of high temperature, MS-275 has a white appearance and becomes a red powder. The content and related substances change significantly, indicating that the product is unstable to high temperature. After 6-10 days of strong light irradiation, the appearance, content and related substances have no obvious change. , indicating that the product is stable to high temperatures.

 B. Strong light irradiation test

 Take appropriate amount of pre-test compound, lay it into a thin layer of 5mm thickness, and illuminate for 10 days under the condition of illumination of 4500Lx ± 500Lx, sample at 5 and 10 days respectively, and examine the appearance, related substances and content changes of the sample. The results are shown in Table 4. .

 Table 4. Results of test results of pre-test compound strong light irradiation

 Time, eve, view, related substances (%), content (%)

 (Day) Reference substance * Compound 6 Reference substance * Compound 6 Reference substance * Compound 6

 White powder white powder 0.20 99.75

0 0.46 99.58

 End

 Light red powder white powder 0.31 99.48

5 2.30 97.24

End Red powder white powder 0.43 99.35

10 5.73 94.10

 End

 Conclusion: After 10 days of strong light irradiation, the appearance of white became red powder, and the content and related substances changed significantly, indicating that the reference substance was unstable to light. After 10 days of strong light irradiation, there was no significant change in appearance, content and related substances. , indicating that the product is more stable to light than the control (the compound disclosed in WO2005092899).

 *N-(2-Aminophenyl)-4-((3,4,5-trimethoxyphenylamino)methyl)benzamide (control) is a compound disclosed in WO2005092899, which we disclose The method was synthesized: melting point mp164.5-165 °C; lHNMR (DMSO-d6) (5 ppm): 3.646 (s, 6H), 3.500 (s, 3H), 4.313-4.327 (d, 2H), 5.186-5.206 (d, 2H), 5.887(s, 2H), 6.138-6.169(t,lH), 6.331 -6.374(m,lH), 6.515-6.550(dd,lH) , 7.082-7.103(dd,lH) , 7.477 -7.498 (d, 2H), 7.917-7.938 (d, 2H), 9.529 (s, lH).

Industrial applicability

 The inventors of the present invention confirmed by experiments that the compound disclosed by the present invention exhibits a positive inhibitory effect on tumor cell proliferation, and the tumor suppressing activity is significantly better than the positive control drug MS-275, and the compound of the present invention is less toxic to normal cells than MS-275. . Further, the compounds disclosed in the present invention are more stable in physical and chemical properties than the compounds disclosed in the positive control drugs MS-275 and WO2005092899.

Claims

Claim

 1. A compound of formula (I):

Or a pharmaceutically acceptable acid salt thereof,

among them:

 Het is an aryl group, a heterocyclic aryl group, a cycloalkyl group or a heterocyclic group, and these groups may be optionally substituted, and each group may be arbitrarily fused with one or more aryl or heterocyclic aryl groups, or Or a plurality of saturated or partially unsaturated cycloalkyl or heterocyclic rings, each ring may be optionally substituted;

 Gi is selected from a chemical bond, T, L-T, T-L or T-L-T;

 Wherein in the presence of L, 1^ is 8, 0, C=0 or N(R!), which is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and tert-butoxycarbonyl;

T is dC ₄ alkylene in the presence of;

G ₂ is an arylene group or a heterocyclic arylene group, and each group may be optionally substituted;

G ₃ is a vinylidene group, or absent (ie, the G ₂ group is directly attached to -C=0 in formula I);

Y is NH ₂ or OH;

X, X ₂ and X ₃ are each independently selected from hydrogen, halogen, C _r C ₄ alkyl or dC ₄ alkoxy, and it is specified that at least one of Χι, x ₂ and x ₃ is not hydrogen.

2. The compound according to claim 1, wherein X _{2 is} selected from fluorine or -C4 alkoxy, Xi, X ₃ , each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, dC ₄ alkyl or dC ₄ alkoxy.

3. A compound according to claim 2, wherein X ₂ is fluorine, Yue group, X! X _3, are both hydrogen.

4. A compound according to claim 1, wherein G ₃ is absent.

5. The compound according to claim 1, wherein G ₂ is phenylene, and

 Het-d is

6. The compound according to claim 1, wherein the compound has a structure represented by the formula (IA):

among them:

L is S, O or N (R1) wherein is hydrogen or -C ₄ alkyl;

R ₂ is hydrogen or C _r C ₄ alkyl;

Y is -NH ₂ or -OH;

X _{2 is} selected from the group consisting of fluoro C C 4 alkoxy;

 Het is selected from a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, a benzothiazolyl group, a benzimidazolyl group or a benzotriazole group, and each group may be optionally substituted.

 The compound according to claim 6, wherein the compound has the structure of the formula (IA-1):

among them:

 L is NH or S;

 P, Q, M, G, and U are each independently CH or >^ and 1^1, Q, U cannot be N at the same time, as long as no more than two of P, Q, M, G, and U are N, inclusive In the rings of P, Q, M, G, and U, the S or O of one ring is not adjacent to S or O on the other ring;

R ₂ is hydrogen or dC ₄ alkyl;

X _{2 is} selected from fluorine or -C ₄ alkoxy;

The groups A and B may be the same or different and independently selected from hydrogen, halogen, d-C4 alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxy, heteroarylalkoxy, alkoxylated Base, haloalkyl, amino, nitro, alkylthio, amido, aminodecanoyl or Z

00S000/800ZN3/X3d ss capsule OAV

The compound according to claim 6, wherein the compound has the structure of the formula (IA-2):

 L is S or NH;

R ₂ is hydrogen or C _r C ₄ alkyl;

X _{2 is} selected from fluorine or -C 4 alkoxy;

 A, B are as defined in claim 7.

 The compound according to claim 6, wherein the compound has a structure represented by the formula (IA-3):

 L is S or NH;

X _{2 is} selected from fluorine or -01 alkoxy;

 A, B are as defined in claim 7.

 10. The compound according to claim 6, wherein the compound has the structure represented by the formula (IA-4):

 among them:

 L is S or NH;

 D is ^^- or S;

 E is N or C-A;

R ₂ and R ₃ are each independently hydrogen or dC ₄ alkyl;

X _{2 is} selected from fluorine or C,-C ₄ alkoxy;

A, B are as defined in claim 7.

The compound according to claim 7, wherein the compound has a structure represented by the formula (I A-5 ):

among them

 t is NH;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

 A, B are as defined in claim 7.

 12. The compound according to claim 7: wherein the compound has the structure represented by formula (I A-6):

A is hydrogen or C _r C ₄ alkyl;

 B is as defined in claim 7;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

 The compound according to claim 7, wherein the compound has a structure represented by the formula (I A-7):

among them

 P is CH, N;

 B is as defined in claim 7;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

 The compound according to claim 1, wherein the compound has a structure represented by the formula (IB):

among them:

0 ₁ is 1\ LT or TL, where 1^ is 8, 0 or NH; T is -CH ₂ -; Z] is 0, S, NH or CH ₂ ;

Z ₂ is N or CH;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

Het is selected from phenyl, pyridyl, pyrimidinyl or ¹ ¾ stupid group and thiazolyl group, and is optionally substituted with 1 or A and B; A, B are as defined in claim 7; or Het optionally substituted with a further Any one, two or three groups are optionally substituted, and these groups are independently selected from alkoxy, haloalkoxy, acyl, morphinolinyl or alkoxy optionally substituted phenyl.

 The compound according to claim 1, wherein the compound has a structure represented by the formula (IC):

among them:

0 ₁ is 1\ LT or TL;

 1^ is 8, 0 or NH;

 T is -C3⁄4-;

Z ₂ is N or CH;

Ζ^ Ο, S, NH or CH ₂ ;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

 Het is selected from phenyl, pyridyl, pyrimidinyl or benzothiazolyl, and is optionally substituted by A and/or B, A, B is as defined in claim 7; or Het is further optionally 1 The three or three groups are optionally substituted, and these groups are independently selected from alkoxy, haloalkoxy, acyl, morphinolinyl or phenyl optionally substituted by alkane.

 The compound according to claim 1, wherein the compound has a structure represented by the formula (Id):

among them:

Het is:

X _{2 is} selected from fluorine or Ci-alkoxy.

 17. The compound of claim 1, wherein the compound has the structure shown by formula (IE):

Y is -OH or -NH ₂ ;

X _{2 is} selected from fluorine or - alkoxy;

 Het is a heterocyclic or heteroaryl group, each ring containing at least one nitrogen atom as part of the ring and optionally substituted.

The compound according to claim 15, wherein Y is -NH ₂ ; X ₂ is fluorine; Het is a heterocyclic or heteroaryl group, Each ring contains at least one nitrogen atom as part of the ring and may be optionally substituted by 1 or 2 substituents selected from A or B, and A, B are as defined in claim 7. .

 The compound according to claim 15, wherein Het is optionally optionally substituted by 1 or 2 substituents, and these groups are independently selected from:

The compound according to claim 1, wherein G ₂ is a phenylene, an anthracenyl or an indanyl group, each of which may be optionally substituted, and G is a chemical bond, -CH ₂ -, -0-CH ₂ -, -S-CH ₂ -, -S-CH(C3⁄4)- or -N(Ri)-CH ₂ -.

21. The compound according to claim 18, wherein G ₂ is indolyl or indolinyl group;

G, is -CH ₂ - or -N^-CHr;

 Het is:

MeO- or

MeO,

22. The compound according to claim 18, wherein G ₃ is absent;

G ₂ is a phenylene;

G, is -S-CH ₂ - or -SC(CH ₃ )(H)-;

Het is:

 among them:

 J is selected from the following groups:

,

23. The compound of claim 1 wherein the compound has the structure of formula (IF):

among them:

Y is -OH or -NH ₂ ;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

 Het is a heterocyclic or heteroaryl group in which each group may be optionally substituted, and each ring contains at least one nitrogen atom.

24. The compound of claim 21, wherein Het is:

 The compound according to claim 1, wherein the compound has a structure represented by the formula (I F-1 ):

among them:

Y is -NH ₂ ;

X _{2 is} selected from fluorine or C!-Ct alkoxy;

 A is as defined in claim 7.

 The compound according to claim 1, wherein the compound has a structure represented by the formula (IG):

among them:

Het, G, Y are as defined in claim 1, and X _{2 is} selected from fluorine or C _r C ₄ alkoxy.

27. The compound according to claim 1, wherein the compound has the structure represented by the formula (IH):

among them:

 L is 8, O or -NH-;

X _{2 is} selected from fluorine or C _r C 4 alkoxy;

 A, B are as defined in claim 7.

 28. The compound of claim 25, wherein A is an optionally substituted pyridine or an optionally substituted phenyl; B is hydrogen or halogen.

 The compound according to claim 1, wherein the compound has a structure represented by the formula (I-I):

among them:

 L A S. O or -NH;

X _{2 is} selected from fluorine or dC ₄ alkoxy;

R4 is hydrogen or dC ₆ alkyl.

 30. Compound of formula II:

Or a salt of a pharmaceutically acceptable acid.

 Het, which is aryl or heteroaryl, may be optionally substituted, each group may be arbitrarily combined with one or more aryl or heterocyclic groups, or with one or more saturated or partially unsaturated cycloalkyl groups or a heterocyclic ring, each ring may be optionally substituted;

X, X ₂ , X ₃ , , Y are as defined in claim 1;

G, is a covalent bond, Co-C ₄ -hydrocarbyl, Co-C ₄ -hydrocarbyl-(CO)-Co-C ₄ -hydrocarbyl, Co-C ₄ -hydrocarbyl-(NR ₅ )-Co-C ₄ -hydrocarbyl , Co-C ₄ -hydrocarbyl-(S)-C ₀ -C ₄ -hydrocarbyl, Co-C ₄ -hydrocarbyl-(0)-C. -C ₄ -hydrocarbyl, C. -C ₄ -hydrocarbyl-(SO)-C ₀ -C ₄ -hydrocarbyl, C ₀ -C ₄ -hydrocarbyl-(SO)-Co-C ₄ -hydrocarbyl, Co-C ₄ -hydrocarbyl-(NH)-(CO )-Co-C ₄ -hydrocarbyl, C ₀ -C ₄ -hydrocarbyl-(CO)-(NH)-C ₀ -C ₄ -hydrocarbyl, -NH-CO-NH- , -NH-CS-NH- , 0-CO-O- , -0-CS-O- , -NH-C(NH)-NH-, -S(0) ₂ -N(R ₅ )-, -N(R ₅ )- S(0 ) ₂ -, -NH-C(0)-0-, or - O- C(O)- NH-, where R ₅ may be hydrogen, dC ₅ alkyl, aryl, aralkyl, heterocyclic, heterocyclic aryl, S0 ₂ -alkyl, S0 ₂ -aryl, CO-alkyl, CO-aryl, CO -NH-alkyl, CO-NH-aryl, CO-0-alkyl or CO-0-aryl;

 n is 0, 1, 2, 3 or 4;

 Z is N or CH;

 Y is N3⁄4 or OH.

 31. A process for the preparation of a compound according to any one of claims 1 to 28 which comprises the following reaction:

Wherein each group is as defined in the claims.

 32. A pharmaceutical composition comprising one or more compounds of any one of claims 1-28, and a pharmaceutically acceptable carrier.

 33. Use of a compound according to any one of claims 1-28 for the manufacture of a medicament for the treatment of proliferative-related psoriasis, blood cancer or solid tumors in human or animal cells.