CN101899011B - Dithiocarbamates compound, preparation method and application thereof - Google Patents

Abstract

The invention discloses a dithiocarbamates compound with a structure shown as the general formula (I) as well as a medical salt, a preparation method and application thereof in the preparation of antitumor drugs, wherein definitions of all groups are specified in the specification. The compound of the invention is a new kind of tyrosine kinase inhibitors, and is used as an antitumor drug, preferably as a drug for treating breast cancer, non-small cell lung cancer, gastric cancer or pancreatic cancer.

Description

Carbamate compound, its preparation method and application

technical field

The invention relates to a carbamate compound, its preparation method and application. The compound of the invention is a novel tyrosine kinase inhibitor and can be used as an antitumor drug.

Background technique

The epidermal growth factor receptor (ErbB) family belongs to the type I receptor tyrosine kinase family, which has four members: ErbB-1 (EGFR), ErbB-2 (HER-2), ErbB-3 and ErbB-4 . Studies have shown that EGFR and HER-2 are highly expressed in bladder cancer, breast cancer, colon cancer, lung cancer and other tumor cells, and there is a strong correlation between solid tumors and their high expression. Therefore, in recent years, research on targeted anti-tumor drugs using EGFR and HER-2 as targets has been highly valued.

At present, the main structural types of EGFR and HER-2 inhibitors that have been discovered include the following five types, namely 4-aminoquinazolines (4-Aminoquinazolines, A), 4-amino-3-cyanoquinolines (4- Aminoquinoline-3-carbonitriles, B), benzylidenemalononitriles (C), salicylamides (Salicylanilides, D) and pyrrolotriazines (Pyrrolotrazines, E). Among these five structures, 4-aminoquinazolines (A) and 4-amino-3-cyanoquinolines (B) are the most studied, such as Chinese patent application CN200610023526.7 and international application publications WO2008/0033748 and Compounds disclosed in WO2008/0033749. And some compounds with good anti-tumor activity have been found, some of which have entered clinical practice.

Carbamate compounds are another class of compounds with anti-tumor activity. Li Runtao and others disclosed such compounds in Chinese invention patent applications CN01118399.3 and CN200410054686.9, wherein the disclosed compound 990208 (Hyd) and 990227 are two compounds with better activity.

Based on the research results of the prior art on carbamate compounds and the research progress of epidermal growth factor receptor inhibitors (EGFR inhibitor), the inventors have discovered a class of new structure, strong activity, and selectivity through a large number of experiments. An epidermal growth factor receptor inhibitor with high toxicity and low toxicity.

Contents of the invention

The object of the present invention is to provide a class of compounds with following general formula (I) structure or pharmaceutically acceptable salts thereof:

in:

A is a nitrogen atom or -CCN;

D is -(CH ₂ ) _m -, -(CH ₂ ) _m -O-, -(CH ₂ ) _m -NH- or -CH ₂ CH ₂ CONH-, wherein m is independently an integer of 1-3;

E is a sulfur atom or NR ³ , wherein R ³ is H, methyl, ethyl or phenyl;

R is R ⁴ R ⁵ N- or R ⁶ S-, wherein R ⁴ and R ⁵ are each independently H, alkyl or aryl, or R ⁴ and R ⁵ together with the attached nitrogen atom represent substituted or unsubstituted In addition, a saturated heterocyclic ring containing 1 nitrogen atom, oxygen atom or sulfur atom, wherein the substituent is a C _1-4 alkyl group, and the C _1-4 alkyl group can be replaced by phenyl or Halogenated phenyl monosubstituted or multi-substituted; or wherein R ⁶ represents the following groups:

Wherein R ⁷ and R ⁸ are each independently hydrogen, methyl, ethyl, phenyl or benzyl; q is an integer of 1-3;

^R is selected from the following groups: halogen, phenyl, phenoxy, benzyl, benzyloxy, pyridylmethyl or pyridylmethoxy, wherein on the phenyl, benzyl or pyridyl Can have 1-3 substituents selected from the following groups: halogen, hydroxyl, amino, C _1-4 alkyl or C _1-4 alkoxy;

n is an integer from 1 to 3; and

R ² is H, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy or halogen substituted C _1-4 alkoxy.

The pharmaceutically acceptable salt of the compound of general formula (I) of the present invention refers to the acid addition salt of the compound of the present invention, including inorganic acid addition salt or organic acid addition salt, and described inorganic acid is sulfuric acid, hydrochloric acid, Sulfuric acid, boric acid, phosphoric acid, sulfonic acid, hydrobromic acid or hydrofluoric acid etc.; Described organic acid is for example acetic acid, valeric acid, acetic acid, maleic acid, fumaric acid, oxalic acid, oleic acid, lactic acid, palmitic acid, Lauric acid, stearic acid, citric acid, succinic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, gluconic acid, lactobionic acid or laurylsulfonic acid, etc; Metal or alkaline earth metal cations, such as lithium, sodium, potassium, calcium, magnesium, etc., and various organic ammonium cations, such as tetramethylamine, tetraethylamine, methylamine, dimethylamine, ethylamine, etc. Ammonium salt cation.

The above-mentioned compound of the present invention is an epidermal growth factor receptor inhibitor (EGFR inhibitor), which can be used to treat tumors, and is especially suitable for treating diseases mediated by protein tyrosine kinases, such as breast cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, etc. cancer etc.

Preferably, the group D in the compound of general formula (I) of the present invention is -CH ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₃ -O-, -(CH ₂ ) ₃ -NH- or -CH ₂ CH ₂ CONH-; wherein the group E is a sulfur atom or -NH-; more preferably, the -ED- group is: -NH-CH ₂ -, -NH-(CH ₂ ) ₃ - , -S-(CH ₂ ) ₃ -O- or -S-CH ₂ CH ₂ CONH-.

When the R group in the general formula is R ⁴ R ⁵ N-, and R ⁴ and R ⁵ represent substituted or unsubstituted together with the connected nitrogen atom, and also contain 1 nitrogen atom, oxygen atom or sulfur atom, wherein the saturated heterocycle is a saturated six-membered or seven-membered heterocycle. Preferably, the saturated six-membered or seven-membered heterocycle is:

More preferred saturated heterocycles are substituted or unsubstituted piperazine or morpholine rings. When the saturated six-membered or seven-membered heterocycle has a substituent, preferably the substituent is methyl, halophenylmethyl or bis(fluorophenyl)methyl. Most preferred is 4-methylpiperazinyl.

When R described in the general formula is R ⁶ S-, R ⁶ therein preferably represents the following groups:

Preferred ^R group is selected from: halogen, benzyloxy or benzyloxy with 1-3 halogen substituents, more preferably the group connected to quinoline ring or quinazoline ring 4-position amino is:

Preferred ^R2 groups are H, _C1-4 alkoxy or halogen substituted _C1-4 alkoxy; more preferably H or methoxy.

In the above definition of the compounds of the present invention, the term "alkyl" used therein refers to a saturated hydrocarbon group, preferably a linear or branched chain alkyl group having 1-6 carbon atoms, more preferably having 1-3 carbon atoms straight-chain or branched-chain alkyl groups, such as methyl, ethyl, propyl, isopropyl, etc.

The term "aryl" used in the present invention refers to phenyl, naphthyl and other aromatic groups with 6-10 carbon atoms, preferably phenyl or naphthyl.

The term "halogen" used in the present invention refers to fluorine, chlorine, bromine and iodine atoms, preferably fluorine, chlorine or bromine atoms.

In the term "substituted or unsubstituted" used in the definition of the compounds of the present invention, the "substituted" refers to a group that is mono-substituted or multi-substituted by the substituent at any substitutable position.

Preferred compounds of the present invention are:

4-methylpiperazine-1-dithiocarboxylic acid-[3-[4-(3-bromoanilino)quinazoline-6-oxygen]]propyl ester (compound 1);

4-methylpiperazine-1-dithiocarboxylic acid-[3-[4-(3-chloro-4-fluoroanilino)quinazoline-6-oxygen]]propyl ester (compound 2);

4-Methylpiperazine-1-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline-6-oxo]propyl ester (compound 3);

4-methylpiperazine-1-dithiocarboxylic acid-{3-[4-(3-bromoanilino)-7-methoxyquinazoline-6-oxygen]}propyl ester (compound 4);

4-methylpiperazine-1-dithiocarboxylic acid-{3-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline-6-oxygen]}propyl ester (compound 5);

4-methylpiperazine-1-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6- Oxy]]propyl ester (compound 6);

Piperazine-4-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxygen]]propane Esters (Compound 7);

Homopiperazine-4-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxo]] Propyl ester (compound 8);

Morpholine-4-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxygen]]propane Esters (Compound 9);

Thiomorpholine-4-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxo] ] Propyl ester (compound 10);

4-[bis(4-fluorophenyl)methyl]piperazine-1-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7 -Methoxyquinazoline-6-oxo]]propyl ester (compound 11);

4-methylpiperazine-1-dithiocarboxylic acid-[2-[4-(3-chloro-4-fluoroanilino)quinazoline-6-carbamoyl]]ethyl ester (compound 12);

4-Methylpiperazine-1-dithioformic acid-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline-6-carbamoyl]]ethyl ester (compound 13);

{4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylaminodithiocarbamate-2-[2-(1,3-dioxolane base)] ethyl ester (compound 14);

[4-(3-Chloro-4-fluoroanilino)quinazolinyl]-6-methylaminodithiocarbamate-2-[2-(1,3-dioxolane)]ethyl ester (compound 15);

[4-(3-bromoanilino)quinazolinyl]-2-[2-(1,3-dioxolopentyl)]ethyl-6-methylaminodithiocarboxylate (compound 16);

{4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylaminodithiocarbamate-2-cyanoethyl ester (compound 17);

{4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylaminodithiocarbamate-2-methoxyformyl ethyl ester (compound 18);

{4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-2-benzylsulfone ethyl 6-methylaminodithiocarbamate (compound 19);

{4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]-3-cyano-7-methoxyquinolinyl}-6-methylaminodithioformic acid-2-[2 -(1,3-Dioxolane)] ethyl ester (compound 20)

[4-(3-Chloro-4-fluoroanilino)-3-cyano-7-methoxyquinolinyl]-6-methylaminodithioformic acid-2-[2-(1,3-di Oxycyclopentyl)] ethyl ester (compound 21);

[4-(3-Bromoanilino)-3-cyano-7-methoxyquinolinyl]-6-methylaminodithioformic acid-2-[2-(1,3-dioxolyl )] ethyl ester (compound 22); and

[4-(3-Bromoanilino)quinazolinyl]-2-benzylsulfonylethyl ester of 6-methylaminodithiocarbamate (Compound 23).

Another object of the present invention is to provide the preparation method of above-mentioned general formula (I) compound or pharmaceutically acceptable salt thereof, this method comprises at first synthesizing quinoline ring or quinazoline ring according to conventional synthetic method, then according to conventional method with arbitrary The sequence of introducing the desired amino substituent at its 4-position followed by the desired group at its 6-position.

For example, when the compound of general formula (I) is a quinazoline derivative and is connected to an oxygen atom at the 6-position, the method for synthesizing the quinazoline ring and introducing the desired amino substituent at its 4-position can refer to WO2008 The reaction scheme 1, 2, 6 or 15 disclosed in /0033749 is carried out; according to the above various synthetic methods, the intermediate compound in which the 6-position of the quinazoline ring is a hydroxyl or a protected hydroxyl can be obtained:

Then, it is deprotected, and the 6-position of the quinazoline ring is a hydroxyl intermediate compound and the compound of general formula (III): X(CH ₂ ) _m Br is reacted to obtain the compound of general formula (IV):

wherein m is as defined above, and X is a halogen;

The target compound whose R group is R ⁴ R ⁵ N- can be obtained by reacting the above compound (IV) with carbon disulfide and R ⁴ R ⁵ NH under conventional reaction conditions.

When the compound of general formula (I) is a quinazoline derivative, when the nitrogen atom is connected to the 6-position, the method for synthesizing the quinazoline ring and introducing the desired amino substituent at its 4-position can refer to WO2008/0033749 The disclosed reaction scheme 3 is carried out; According to the above various synthetic methods, the 6-position of the quinazoline ring is the intermediate compound of the amino group, and then the 6-position of the quinazoline ring is the intermediate compound of the amino group and R ⁶ X and CS ₂ are reacted under conventional reaction conditions to obtain the target compound whose R group is R ⁶ S-.

When the compound of general formula (I) is a quinazoline derivative, and what is connected to the 6-position of the quinazoline ring is C _1-3 alkylaminodithiocarbamate, the preparation method of the object compound comprises First prepare the protected intermediate of the alkylamino group at the 6-position of the quinazoline ring, wherein the protecting group is phthaloyl as an example:

Then the obtained intermediate compound is deprotected, and the intermediate compound is reacted with R ⁶ X and CS ₂ under conventional reaction conditions to obtain quinazoline-6-C _1-3 alkylamino di Thioformic esters of interest.

When the compound of general formula (I) is a quinoline derivative, that is, when the 6-position of the quinoline ring is connected to a carbamate compound of C _1-3 alkylamino, the corresponding quinoline Derivatives are used as raw materials, and the corresponding target compounds are prepared in a manner similar to the above reaction scheme.

When the intermediate in which the 6-position amino of the quinoline ring is protected is an aminomethyl intermediate, another method for obtaining the aminomethylation intermediate in which the amino group is protected at the 6-position of the quinoline ring can be, for example:

Then, the above-mentioned intermediate compound is deprotected and reacted with R ⁶ X and CS ₂ under conventional reaction conditions to obtain quinoline-6-methylaminodithiocarbamate compounds.

In this reaction process, the position corresponding to the 6-position of the above-mentioned intermediate compound in the starting material compound raw material is a methyl group, it can be understood that, according to the number of carbon atoms required by the target compound, the methyl group can be C _1-3 alkyl groups.

The preparation of the pharmaceutically acceptable salt of the compound of general formula (I) of the present invention can be completed in the process of preparing the compound, or after the compound is prepared, the compound is reacted with the corresponding acid according to the conventional method for preparing an addition salt. The response is obtained.

The various raw materials used in the above methods are available in the market or prepared by known methods.

Another object of the present invention is to provide a pharmaceutical composition, which is a tyrosine kinase inhibitor, which can be used to treat diseases mediated by protein tyrosine kinases, for example, to treat tumors, especially It is suitable for the treatment of breast cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, etc. The composition uses the compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and may optionally contain a pharmaceutically acceptable carrier.

Specifically, the composition contains a therapeutically effective amount of the compound of general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. Preferably, the content of the active ingredient in the composition of the present invention is 0.5%-99%, and the content of the pharmaceutical carrier is 1%-99.5%.

The composition of the present invention can be made into various conventional pharmaceutical dosage forms, such as oral and parenteral administration forms, such as various injection administration, topical administration, inhalation administration, etc. drug, rectal or implanted form.

Pharmaceutically suitable oral administration preparations are, for example, tablets, capsules, granules, or other pharmaceutically suitable liquid forms such as solutions, emulsions, suspensions and the like. The preferred oral formulation is a tablet, and the tablet can be made into a coated, enteric-coated, sustained-release or quantitative-release form.

In order to prepare a suitable dosage form, one or more pharmaceutical carriers can be added to the active ingredient as required, and the pharmaceutical carrier includes various conventional pharmaceutical adjuvants, such as excipients, fillers, diluents, Disintegrants, surfactants, wetting agents, preservatives, sweeteners, coloring agents, etc.

According to the type of disease, the degree of severity and the condition of the patient, such as gender, age, body weight, etc., the appropriate dosage form and dosage are selected. Usually, the dosage for adults is 1-200 mg/kg body weight/day, preferably 1-50 mg/kg body weight / between days.

The pharmaceutical composition of the present invention and various formulations of the composition can be prepared according to conventional methods known in the field of pharmacy.

Another object of the present invention is to provide the pharmaceutical use of the compound of general formula (I) or its acceptable salt, and the present invention discloses the compound of general formula (I) or its acceptable salt, and the pharmaceutical combination containing the above compound The application of the compound in the preparation of tyrosine kinase inhibitors, especially the application in the preparation of antitumor drugs. The antitumor drug is especially suitable for treating breast cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer and other tumors.

By screening the activity of the compounds of the present invention, including the results of protein tyrosine kinase inhibitory activity screening tests and in vitro antitumor activity tests, it can be seen that the compounds of the general formula (I) of the present invention or their pharmaceutically acceptable salts have excellent The protein tyrosine kinase inhibitory activity and anticancer activity are expected to be developed into a new type of antitumor drug with a new structure.

Another object of the present invention is to provide a method for treating tumors, which comprises administering a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

Detailed ways

The technical solutions of the present invention will be further described through specific implementation methods below, wherein the illustrated embodiments are descriptions of the present invention, and do not limit its protection scope in any way.

Preparation Example 1 6-hydroxyl-3H-quinazolin-4-ketone

Add 2-amino-5-hydroxybenzoic acid (1.53g, 10mmol) into 10mL of formamide, react at 150°C for 0.5h, cool the reaction solution to room temperature, add 30mL of water to the reaction solution, a large amount of solid is precipitated, and suction filtered. After drying, 1.44 g of brown solid product was obtained, the yield was 88%, and mp>300°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=7.25(s, 1H), 7.40(s, 1H), 7.52(s, 1H), 7.90(s, 1H), 10.07(s, 1H), 12.03 (s, 1H).

Preparation Example 2 6-Acetoxyl group-3H-quinazolin-4-ketone

Add 6-hydroxy-3H-quinazolin-4-one (0.81g, 5mmol) to 8mL of acetic anhydride, add 1mL of pyridine, reflux for 2h, cool the reaction solution to room temperature, add 30mL of ice water to the reaction solution, and a large amount of The solid was suction filtered and dried to obtain 0.66 g of off-white solid product, the yield was 64%, and mp>300°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.32(s, 3H), 7.60(dd, J=2.7, 8.7Hz, 1H), 7.73(d, J=2.7Hz, 1H), 7.83(d , J=2.4Hz, 1H), 8.11(s, 1H), 12.35(s, 1H).

Preparation Example 3 4-(3-bromoanilino)-6-acetoxyquinazoline

Add 6-acetoxy-3H-quinazolin-4-one (1.03g, 5mmol) into 10mL of thionyl chloride, drop into N,N-dimethylformamide (DMF) (0.5mL), Refluxing for 6 hours, distilling off excess thionyl chloride under reduced pressure to obtain the intermediate 4-chloro-6-acetoxyquinazoline, which was directly dissolved in 15 mL of isopropanol without purification, and m-bromoaniline (0.86 g, 5mmol), 1mL triethylamine, reflux reaction for 4h, the reaction solution was cooled to room temperature, suction filtered, the filter cake was washed with isopropanol, water, ether, and dried to obtain 1.24g light yellow solid product, yield 69 %, mp238-239°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.40(s, 3H), 7.44-7.54(m, 2H), 7.78(d, J=7.5Hz, 1H), 7.93-8.09(m, 3H) , 8.67(s, 1H), 8.99(s, 1H), 11.39(s, 1H).

Preparation Example 4 4-(3-chloro-4-fluoroanilino)-6-acetoxyquinazoline

According to the method described in Preparation Example 3, except that m-bromoaniline was changed to 3-chloro-4-fluoroaniline, the yield was 74%, m.p.>300°C.

Preparation Example 5 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-acetoxyquinazoline

According to the method described in Preparation Example 3, except that m-bromoaniline was changed to 3-chloro-4-(3-fluorobenzyloxy)aniline, the yield was 73%, m.p.290-292°C.

Preparation Example 6 4-(3-bromoanilino)-6-hydroxyquinazoline

Dissolve 4-(3-bromoanilino)-6-acetoxyquinazoline (0.72g, 2mmol) in 15mL of methanol, add 4mL of ammonia water, react at room temperature for 3h, filter with suction, and dry to obtain 0.31g off-white The solid was concentrated and the filtrate was separated and purified by silica gel column (eluent, petroleum ether: ethyl acetate = 1:2, v:v) to obtain 0.28 g of off-white solid 0.59 g, yield 93%, mp > 300°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=7.28-7.37(m, 1H), 7.46(d, J=9.0Hz, 1H), 7.71(d, J=9.0Hz, 1H), 7.80(s , 1H), 8.27(s, 1H), 8.52(s, 1H), 9.60(s, 1H), 10.11(s, 1H).

Preparation Example 7 4-(3-chloro-4-fluoroanilino)-6-hydroxyquinazoline

According to the method described in Preparation Example 6, except that 4-(3-bromoanilino)-6-acetoxyquinazoline was changed to 4-(3-chloro-4-fluoroanilino)-6-acetoxyquinazoline Quinazoline, yield 91%, mp>300°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=7.56(t, J=9.0Hz, 1H), 7.72-7.74(m, 2H), 7.92(d, J=8.7Hz, 1H), 8.04-8.07 (m, 2H), 8.87 (s, 1H), 10.98 (s, 1H), 11.38 (s, 1H).

Preparation Example 8 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-hydroxyquinazoline

According to the method described in Preparation Example 6, except that 4-(3-bromoanilino)-6-acetoxyquinazoline was changed to 4-[3-chloro-4-(3-fluorobenzyloxy)benzene Amino]-6-acetoxyquinazoline, yield 94%, mp>300°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=5.25(s, 1H), 7.16-7.34(m, 4H), 7.40-7.51(m, 2H), 7.67(d, J=8.7Hz, 1H) , 7.74-7.78 (m, 2H), 8.07 (d, J=2.7Hz, 1H), 8.44 (s, 1H), 9.50 (s, 1H), 10.09 (s, 1H).

Preparation Example 9 4-(3-bromoanilino)-6-(3-chloropropoxy)quinazoline

4-(3-bromoanilino)-6-hydroxyquinazoline (0.32g, 1mmol) was dissolved in 20mL of acetonitrile, potassium carbonate (0.56g, 4mmol) and catalytic amount of tetrabutylammonium bromide were added, heated Reflux for 20min, add 1,3-bromochloropropane (0.32g, 2mmol), reflux for 2h, cool the reaction solution to room temperature, filter, wash the filter cake with acetonitrile, concentrate the filtrate, and separate and purify on a silica gel column (eluent, petroleum Ether:ethyl acetate=2:1, v:v), 0.27g off-white solid was obtained, yield 68%, mp 175-176°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.29(t, J=6.0Hz, 2H), 3.88(t, J=6.0Hz, 2H), 4.30(t, J=6.0Hz, 2H), 7.30-7.41(m, 2H), 7.54-7.57(m, 2H), 7.77(d, J=9.0Hz, 1H), 7.90-7.96(m, 2H), 8.19(s, 1H), 8.57(s, 1H), 9.70 (s, 1H).

Preparation Example 10 4-(3-chloro-4-fluoroanilino)-6-(3-chloropropoxy)quinazoline

According to the method described in Preparation Example 9, just change 4-(3-bromoanilino)-6-hydroxyquinazoline to 4-(3-chloro-4-fluoroanilino)-6-hydroxyquinazoline , yield 60%, mp 140-141°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.29(t, J=6.3Hz, 2H), 3.88(t, J=5.7Hz, 2H), 4.30(t, J=6.0Hz, 2H), 7.44-7.57 (m, 2H), 7.75-7.82 (m, 2H), 7.93 (s, 1H), 8.16-8.18 (m, 1H), 8.55 (s, 1H), 9.74 (s, 1H).

Preparation Example 11 4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]-6-(3-chloropropoxy)quinazoline

Follow the method described in Preparative Example 9, except that 4-(3-bromoanilino)-6-hydroxyquinazoline is changed to 4-[3-chloro-4-(3-fluorobenzyloxy)anilino] -6-Hydroxyquinazoline, yield 67%, mp144-146°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.28(t, J=6.6Hz, 2H), 3.87(t, J=6.0Hz, 2H), 4.28(t, J=5.7Hz, 2H), 5.26(s, 2H), 7.19(m, 1H), 7.27-7.35(m, 3H), 7.47-7.54(m, 2H), 7.72-7.75(m, 2H), 7.91(m, 1H), 7.99( d, J=2.4Hz, 1H), 8.49(s, 1H), 9.61(s, 1H).

Example 1 4-methylpiperazine-1-dithioformic acid-[3-[4-(3-bromoanilino)quinazoline-6-oxygen]]propyl ester

Dissolve N-methylpiperazine (0.10g, 1mmol) in 15mL DMF, add anhydrous potassium phosphate (0.43g, 2mmol), add carbon disulfide (0.19g, 2.5mmol) dropwise under stirring at room temperature, react for 30min, add 4-(3-Bromoanilino)-6-(3-chloropropoxy)quinazoline (0.40 g, 1 mmol) was stirred at room temperature and detected by TLC until the reaction was completed. Add 15 mL of water to the reaction system, extract with ethyl acetate (15 mL×3), combine the organic layers, wash with water (15 mL×2), dry over anhydrous sodium sulfate, concentrate, and recrystallize the residue with acetonitrile to obtain 0.38 g of solid, Yield 71%, mp 152-153°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.20-2.24(m, 5H), 2.38(t, J=5.1Hz, 4H), 3.47(t, J=7.2Hz, 2H), 3.91 (m, 2H), 4.24(t, J=5.4Hz, 4H), 7.30-7.40(m, 2H), 7.54(dd, J=2.7, 9.3Hz, 1H), 7.76(d, J=9.0Hz , 1H), 7.91-7.93 (m, 2H), 8.19-8.20 (m, 1H), 8.57 (s, 1H), 9.67 (s, 1H). Elemental analysis C ₂₃ H ₂₆ BrN ₅ OS ₂ : Theoretical: C, 51.88; H, 4.92; N, 13.15. Found: C, 51.81; H, 4.92; N, 13.03.

Example 2 4-methylpiperazine-1-dithioformic acid-[3-[4-(3-chloro-4-fluoroanilino)quinazoline-6-oxygen]]propyl ester

According to the method described in Example 1, just change the raw material 4-(3-bromoanilino)-6-(3-chloropropoxy)quinazoline into 4-(3-chloro-4-fluoroanilino) -6-(3-chloropropoxy)quinazoline, yield 63%, mp 154-155°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.20-2.24(m, 5H), 2.39(t, J=5.1Hz, 4H), 3.46(t, J=7.2Hz, 2H), 3.92 (m, 2H), 4.25(t, J=5.7Hz, 4H), 7.47(t, J=9.0Hz, 1H), 7.54(dd, J=2.4, 9.0Hz, 1H), 7.76(d, J=9.0Hz, 1H), 7.81-7.87(m, 1H), 7.91(d, J=2.1Hz, 1H), 8.17(dd, J=2.7, 6.9Hz, 1H), 8.55(s, 1H), 9.70 (s, 1H). Elemental analysis C ₂₃ H ₂₅ ClFN ₅ OS ₂ : Theoretical: C, 54.59; H, 4.98; N, 13.84. Found: C, 54.65; H, 5.00; N, 13.75.

Example 3 4-methylpiperazine-1-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline-6-oxygen]propane ester

According to the method described in Example 1, just change the raw material 4-(3-bromoanilino)-6-(3-chloropropoxy)quinazoline into 4-[3-chloro-4-(3-fluoro Benzyloxy)anilino]-6-(3-chloropropoxy)quinazoline, yield 57%, mp128-130°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.19(m, 5H), 2.39(t, J=4.8Hz, 4H), 3.46(t, J=6.6Hz, 2H), 3.92(m, 2H), 4.24(s, 4H), 5.26(s, 2H), 7.19(t, J=8.7Hz, 1H), 7.27-7.35(m, 3H), 7.44-7.53(m, 2H), 7.71- 7.74 (m, 2H), 7.90 (s, 1H), 7.99 (d, J=2.4Hz, 1H), 8.49 (s, 1H), 9.59 (s, 1H). HRMS: C ₃₀ H ₃₁ ClFN ₅ O ₂ S ₂ +H, calc. 612.16700; found (ESI-FTMS, (M+H) ⁺¹ ), 612.16556.

Preparation Example 12 3-Hydroxy-4-methoxybenzoic acid methyl ester

Dissolve 3-hydroxy-4-methoxybenzoic acid (1.68g, 10mmol) in 15mL of methanol, slowly add thionyl chloride (1.1mL) dropwise under ice-cooling, after the dropwise completion, react at room temperature for 24h, evaporate the excess Add 15mL of water, extract with ethyl acetate (15mL×3), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, separate and purify on a silica gel column, eluent (petroleum ether:ethyl acetate=5:1, v:v) to obtain 1.56 g of white solid product, yield 85%, mp61-63°C. ¹ H NMR (300MHz, CDCl ₃ ): δ=3.88(s, 1H), 3.95(s, 1H), 5, 67(s, 1H), 6.87(d, J=8.1Hz, 1H), 7.60(s , 1H), 7.63 (d, J=1.5Hz, 1H).

Preparation Example 13 3-(3-chloropropoxy)-4-methoxybenzoic acid methyl ester

Dissolve the product of Preparation Example 12 (1.82g, 10mmol) in 20mL of acetonitrile, add potassium carbonate (2.76g, 20mmol) and a catalytic amount of tetrabutylammonium bromide, heat to reflux for 20min, add 1,3-bromochloropropane ( 0.32g, 2mmol), reflux reaction for 4h, the reaction solution was cooled to room temperature, acetonitrile was distilled off, 15mL water was added to the reaction system, extracted with ethyl acetate (15mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated , silica gel column separation and purification (eluent, petroleum ether: ethyl acetate = 5: 1, v: v), to obtain 2.41 g of white solid, yield 93%, mp51-52 ° C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.14-2.23(m, 2H), 3.77-3.85(m, 8H), 4.12(t, J=6.0Hz, 2H), 7.09(d, J= 8.7Hz, 1H), 7.47 (d, J=1.8Hz, 1H), 7.60 (dd, J=1.8, 8.4Hz, 1H).

Preparation Example 14 2-nitro-4-methoxy-5-(3-chloropropoxy) methyl benzoate

The product of Preparation Example 13 (6.46g, 25mmol) was dissolved in 50mL of chloroform, and a mixed acid composed of concentrated nitric acid (4.5mL) and concentrated sulfuric acid (5mL) was added dropwise at 10°C, and the reaction was carried out at 20°C for 4h. Add 50mL ice water to dilute the reaction solution, separate the water layer, wash the chloroform layer with 20mL saturated aqueous sodium bicarbonate solution, wash to neutral, dry over anhydrous sodium sulfate, evaporate the solvent, separate and purify on a silica gel column (eluent, petroleum ether : ethyl acetate=5:1, v:v), 6.84g of yellow solid was obtained, yield 90%, mp68-70°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.21(t, J=6.0Hz, 2H), 3.78(t, J=6.3Hz, 2H), 3.82(s, 3H), 3.92(s, 3H ), 4.25(t, J=6.0Hz, 2H), 7.37(s, 1H), 7.65(s, 1H).

Preparation Example 15 2-Amino-4-methoxy-5-(3-chloropropoxy)methyl benzoate

Add the product of Preparation Example 14 (1.83g, 6mmol), ammonium chloride (1.61g, 30mmol), and reduced iron powder (1.11g, 19.8mmol) into 30mL of methanol and 15mL of water, reflux for 2h, and cool the reaction solution to room temperature , the reaction solution was adjusted to neutral with saturated aqueous sodium bicarbonate solution, suction filtered, and the insoluble matter was filtered off, the filtrate was extracted with dichloromethane (15mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the silica gel Column separation and purification (eluent, petroleum ether: ethyl acetate = 4: 1, v: v) gave 6.84 g of white solid, yield 65%, mp 97-99°C. ¹ H NMR (400MHz, CDCl ₃ ): δ=2.20-2.26(m, 2H), 3.76(t, J=4.8Hz, 2H), 3.84(s, 3H), 3.84(s, 3H), 4.08(t , J=4.5Hz, 2H), 5.51(s, 2H), 6.15(s, 1H), 7.36(s, 1H).

Preparation Example 16 4-hydroxyl-6-(3-chloropropoxy)-7-methoxyquinazoline

Add the product of Preparation Example 15 (0.55 g, 2 mmol) into 5 mL of formamide, heat in an oil bath, stir to completely dissolve the solid, slowly add 1 mL of phosphorus oxychloride dropwise, control the temperature between 85-95 °C, and complete the dropwise addition , react at this temperature for 2 hours, after the reaction is complete, add an appropriate amount of ice water to the obtained reddish-brown viscous substance, stir at room temperature, adjust the pH to 6-7 with 1N aqueous sodium hydroxide solution, and obtain an orange-red turbid solution. After suction filtration, 0.35 g of purple-brown solid was obtained, yield 65%, mp 213-215°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.23(t, J=6.3Hz, 2H), 3.81(t, J=6.3Hz, 2H), 3.92(s, 3H), 4.19(t, J =6.3Hz, 2H), 7.15(s, 1H), 7.47(s, 1H), 7.99(s, 1H), 12.09(s, 1H).

Preparation Example 17 4-(3-bromoanilino)-6-(3-chloropropoxy)-7-methoxyquinazoline

The product of Preparation Example 16 (1.08 g, 4 mmol) was added to 10 mL of thionyl chloride, 0.5 mL of DMF was added dropwise, refluxed for 3 hours, and excess thionyl chloride was evaporated under reduced pressure to obtain the intermediate 4-chloro-6-( 3-chloropropoxy)-7-methoxyquinazoline, without separation, the intermediate was dissolved in 15mL of isopropanol, m-bromoaniline (0.69g, 4mmol), 1mL of triethylamine were added, and the reaction was refluxed for 3h , the reaction solution was cooled to room temperature, filtered with suction, washed with cold isopropanol, and dried to obtain 1.52 g of light yellow solid, yield 89%, mp 198-200°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=2.27-2.34(m, 2H), 3.86(t, J=4.8Hz, 2H), 3.96(s, 3H), 4.29(t, J=4.5Hz , 2H), 7.23(s, 1H), 7.27-7.30(m, 1H), 7.36(t, J=6.0Hz, 1H), 7.84-7.89(m, 1H), 7.96(s, 1H), 8.15( t, J=1.5Hz, 1H), 8.53(s, 1H), 9.53(s, 1H).

Preparation Example 18 4-(3-chloro-4-fluoroanilino)-6-(3-chloropropoxy)-7-methoxyquinazoline

According to the method described in Preparation Example 17, except that the raw material m-bromoaniline was changed to 3-chloro-4-fluoroaniline, the yield was 82%, mp 224-226°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.29(t, J=6.0Hz, 2H), 3.85(t, J=5.4Hz, 2H), 4.02(s, 3H), 4.34(t, J =5.7Hz, 2H), 7.31(s, 1H), 7.57(t, J=8.7Hz, 1H), 7.70(s, 1H), 8.01(d, J=7.2Hz, 1H), 8.23(s, 1H ), 8.87(s, 1H), 11.21(s, 1H).

Preparation Example 19 4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]-6-(3-chloropropoxy)-7-methoxyquinazoline

According to the method described in Preparation Example 17, except that the raw material m-bromoaniline was changed to 3-chloro-4-(3-fluorobenzyloxy)aniline, the yield was 72%, mp 194-196°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.31(t, J=4.8Hz, 2H), 3.85(t, J=4.8Hz, 2H), 4.01(s, 3H), 4.34(t, J =4.5Hz, 2H), 5.31(s, 2H), 7.17-7.22(m, 1H), 7.32-7.36(m, 4H), 7.46-7.51(m, 1H), 7.61(dd, J=1.8, 6.6 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 8.26 (s, 1H), 8.84 (s, 1H), 11.25 (s, 1H).

Example 4 4-methylpiperazine-1-dithioformic acid-{3-[4-(3-bromoanilino)-7-methoxyquinazoline-6-oxygen]}propyl ester

Dissolve N-methylpiperazine (0.10g, 1mmol) in 15mL DMF, add anhydrous potassium phosphate (0.43g, 2mmol), add carbon disulfide (0.19g, 2.5mmol) dropwise under stirring at room temperature, react for 30min, add 4 -(3-Bromoanilino)-6-(3-chloropropoxy)-7-methoxyquinazoline (0.43g, 1mmol), continue to stir at room temperature, and detect by TLC until the reaction is complete. Add 15 mL of water to the reaction system, extract with ethyl acetate (15 mL×3), combine the organic layers, wash with water (15 mL×2), dry over anhydrous sodium sulfate, concentrate, and recrystallize the residue with acetonitrile to obtain 0.42 g of solid, Yield 74%, mp 166-168°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.20-2.25(m, 5H), 2.39(t, J=4.5Hz, 4H), 3.44(t, J=6.6Hz, 2H), 3.95(s , 5H), 4.25(t, J=5.7Hz, 4H), 7.23(s, 1H), 7.27-7.39(m, 2H), 7.86-7.90(m, 2H), 8.15(s, 1H), 8.53( s, 1H), 9.52 (s, 1H). Elemental analysis C ₂₄ H ₂₈ BrN ₅ O ₂ S ₂ : Theoretical: C, 51.24; H, 5.02; N, 12.45. Found: C, 51.29; H, 5.06; N, 12.61.

Example 5 4-methylpiperazine-1-dithioformic acid-{3-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline-6-oxygen]}propane ester

According to the method described in Example 4, just change the raw material 4-(3-bromoanilino)-6-(3-chloropropoxy)-7-methoxyquinazoline into 4-(3-chloro- 4-fluoroanilino)-6-(3-chloropropoxy)-7-methoxyquinazoline, yield 69%, mp86-87℃. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.20-2.25(m, 5H), 2.38(t, J=5.1Hz, 4H), 3.44(t, J=7.2Hz, 2H), 3.95(s , 5H), 4.22(t, J=5.7Hz, 4H), 7.22(s, 1H), 7.46(t, J=9.0Hz, 4H), 7.79-7.84(m, 2H), 8.12(dd, J= 2.4, 6.9Hz, 1H), 8.51(s, 1H), 9.55(s, 1H). Elemental analysis C ₂₄ H ₂₇ ClFN ₅ O ₂ S ₂ : Theoretical: C, 53.77; H, 5.08; N, 13.06. Determined: C, 53.69; H, 5.06; N, 12.97.

Example 6 4-methylpiperazine-1-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline -6-Oxo]]propyl ester

According to the method described in Example 4, just change the raw material 4-(3-bromoanilino)-6-(3-chloropropoxy)-7-methoxyquinazoline into 4-[3-chloro- 4-(3-fluorobenzyloxy)anilino]-6-(3-chloropropoxy)-7-methoxyquinazoline, yield 62%, mp84-85℃. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.19-2.23(m, 5H), 2.37(t, J=4.5Hz, 4H), 3.42(t, J=7.2Hz, 2H), 3.92(s , 5H), 4.21(s, 4H), 5.24(s, 2H), 7.15-7.33(m, 6H), 7.42-7.50(m, 1H), 7.69(dd, J=2.4, 8.7Hz, 1H), 7.81 (s, 1H), 7.94 (d, J=2.4Hz, 1H), 8.44 (s, 1H). Elemental analysis C ₃₁ H ₃₃ ClFN ₅ O ₃ S ₂ .CH ₃ CN: Theoretical: C, 58.01; H, 5.31; N, 12.30. Found: C, 57.90; H, 5.42; N, 12.23.

Example 7 Piperazine-4-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxo ]] Propyl ester

Dissolve piperazine monohydrochloride (0.1mmol) in 10mL DMF, slowly drop into carbon disulfide (0.1mmol), stir at room temperature for 0.5h, add anhydrous potassium phosphate (0.2mmol) and 4-[3-chloro-4 -(3-fluorobenzyloxy)anilino]-6-(3-chloropropoxy)-7-methoxyquinazoline (0.1 mmol), continue to stir the reaction at room temperature, and monitor the reaction by TLC until the reaction is complete. Add 15 mL of water to the reaction system, extract with ethyl acetate (15 mL×3), combine the organic layers, wash with water (15 mL×2), dry over anhydrous sodium sulfate, concentrate, and recrystallize the residue with acetonitrile to obtain 35 mg of solid, Rate 55%, mp124-126°C. HRMS: C ₃₀ H ₃₁ ClFN ₅ O ₃ S ₂ +H, calc. 628.16191; found (ESI-FTMS, (M+H) ⁺¹ ), 628.16196.

Example 8 Homopiperazine-4-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6- Oxy]]propyl ester

According to the method described in Example 7, except that the raw material piperazine monohydrochloride was changed to homopiperazine monohydrochloride, the yield was 47%, mp 179-180°C. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=1.21 (s, 1H), 2.03-2.20 (m, 5H), 3.92-4.55 (m, 14H), 5.24 (s, 2H), 7.15-7.20 ( m, 2H), 7.24-7.34(m, 3H), 7.44-7.49(m, 1H), 7.69(dd, J=1.8, 6.9Hz, 1H), 7.81(s, 1H), 7.94(d, J= 1.5Hz, 1H), 8.45(s, 1H), 9.42(s, 1H).

Example 9 Morpholine-4-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxo ]] Propyl ester

According to the method described in Example 6, except that the raw material N-methylpiperazine was changed to morpholine, the yield was 66%, mp80-82°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=2.20-2.27(m, 2H), 3.46(t, J=5.4Hz, 2H), 3.66((t, J=3.3Hz, 4H), 3.94( s, 5H), 4.23(t, J=4.5Hz, 4H), 5.25(s, 2H), 7.16-2.21(m, 2H), 7.26-7.35(m, 3H), 7.45-7.50(m, 1H) , 7.69 (dd, J = 1.8, 6.6Hz, 1H), 7.83 (s, 1H), 7.95 (d, J = 1.8Hz, 1H), 8.46 (s, 1H), 9.42 (s, 1H). Elemental analysis C ₃₀ H ₃₀ ClFN ₄ O ₄ S ₂ : Cal.: C, 57.27; H, 4.81; N, 8.90. Found: C, 57.69; H, 4.91; N, 8.70.

Example 10 Thiomorpholine-4-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6 -oxy]]propyl ester

According to the method described in Example 6, except that the raw material N-methylpiperazine was changed to thiomorpholine, the yield was 80%, and the mp was 176-177°C. ¹ HNMR (400MHz, DMSO-d ₆ ): δ=2.20-2.27(m, 2H), 2.71-2.74(m, 4H), 3.46(t, J=5.4Hz, 2H), 3.94(s, 3H), 4.22-4.52(m, 6H), 5.25(s, 2H), 7.16-7.21(m, 2H), 7.26-7.35(m, 3H), 7.45-7.50(m, 1H), 7.69(dd, J=2.1 , 6.9Hz, 1H), 7.82(s, 1H), 7.95(d, J=1.8Hz, 1H), 8.46(s, 1H), 9.42(s, 1H). Elemental analysis C ₃₀ H ₃₀ ClFN ₄ O ₃ S ₃ : Theoretical: C, 55.84; H, 4.69; N, 8.68. Found: C, 55.86; H, 4.91; N, 8.67.

Example 11 4-[bis(4-fluorophenyl)methyl]piperazine-1-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)phenylamino ]-7-methoxyquinazoline-6-oxy]]propyl ester

According to the method described in Example 6, except that the raw material N-methylpiperazine was changed to 1-[bis(4-fluorophenyl)methyl]piperazine, the yield was 45%, and the mp was 151-153°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ=2.09(s, 1H), 2.21(t, J=5.1Hz, 2H), 2.36(t, J=3.3Hz, 4H), 3.42(t, J =5.4Hz, 2H), 3.93(s, 4H), 4.21(t, J=4.5Hz, 4H), 4.46(s, 1H), 5.26(s, 2H), 7.12-7.21(m, 6H), 7.26 -7.35(m, 3H), 7.42-7.50(m, 5H), 7.70(dd, J=1.8, 6.6Hz, 1H), 7.81(s, 1H), 7.94(d, J=1.8Hz, 1H), 8.46(s, 1H), 9.41(s, 1H). Elemental analysis C ₄₃ H ₃₉ ClF ₃ N ₅ O ₃ S ₂ : Theoretical: C, 62.20; H, 4.73; N, 8.43. Found: C, 62.41; H, 4.97; N, 8.29.

Preparation Example 20 5-Nitroisatin

Dissolve isatin (5.88g, 40mmol) in 25.2mL concentrated sulfuric acid, stir under ice bath, slowly add 1.88mL fuming nitric acid dropwise, and react at 0°C for 45min. After the reaction is complete, pour the reaction solution into crushed ice to precipitate The orange-red solid was suction-filtered, washed with water until neutral, and dried to obtain 6.3 g of orange-red solid, yield 81%, m.p.253-254°C.

Preparation Example 21 2-amino-5-nitrobenzoic acid

Dissolve 5-nitroisatin (1.92g, 10mmol) in 50mL of 1N aqueous sodium hydroxide solution, add 3.2mL of hydrogen peroxide dropwise, and react at 10-15°C for 30min. Insoluble matter was removed, and the filtrate was adjusted to pH=5-6 with 3N hydrochloric acid solution, a large amount of yellow solid was precipitated, filtered by suction, and dried to obtain 1.24 g of yellow solid, yield 68%, mp275-276°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=6.87(d, J=9.3Hz, 1H), 7.88(s, 2H), 8.08(dd, J=3.0, 9.3Hz, 1H), 8.59(d , J=2.7Hz, 1H), 13.29 (br s, 1H).

Preparation Example 22 4-hydroxyl-6-nitroquinazoline

Add 2-amino-5-nitrobenzoic acid (0.91g, 5mmol) into 5mL formamide, react at 150°C for 6h, cool the reaction solution to room temperature, add 30mL ethyl acetate to the reaction flask, suction filter, remove Insoluble matter, the filtrate was extracted with ethyl acetate-water mixed system, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was recrystallized with methanol-water to obtain 0.60g of yellow solid, yield 62%, mp284-286℃ . ¹ H NMR (300MHz, DMSO-d ₆ ): δ=7.87(d, J=9.0Hz, 1H), 8.32(s, 1H), 8.56(dd, J=2.7, 9.0Hz, 1H), 8.81(d , J=2.7Hz, 1H), 12.77(s, 1H).

Preparation Example 23 4-(3-chloro-4-fluoroanilino)-6-nitroquinazoline

4-Hydroxy-6-nitroquinazoline (0.96g, 5mmol) was added in 10mL of thionyl chloride, dripped into 0.5mL of DMF, refluxed for 6h, and the excess thionyl chloride was evaporated under reduced pressure to obtain intermediate 4 -Chloro-6-nitro-quinazoline, without separation, the intermediate was dissolved in 15 mL of isopropanol, added 3-chloro-4-fluoroaniline (0.73 g, 5 mmol), 1 mL of triethylamine, and refluxed for 4 h , the reaction solution was cooled to room temperature, filtered with suction, and the filter cake was washed with isopropanol, water, and ether in sequence, and dried to obtain 1.24 g of light yellow solid, the total yield of two steps was 87%, m.p.244-246°C.

Preparation Example 24 4-(3-chloro-4-fluoroanilino)-6-aminoquinazoline

Dissolve 4-(3-chloro-4-fluoroanilino)-6-nitroquinazoline (0.64g, 2mmol) in 30mL of absolute ethanol, add tin powder (1.19g, 10mmol), stir at room temperature, Add 10mL of concentrated hydrochloric acid, continue to react at room temperature for 12h, add 50ml of ethyl acetate and 50mL of water to the reaction solution, stir vigorously, adjust the pH of the mixture to 8-9 with 1N aqueous sodium hydroxide solution, and filter with suction to remove insoluble matter , separated, the aqueous layer was extracted with ethyl acetate (15mL×2), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent, petroleum ether: ethyl acetate=1:2, v:v), 0.38 g of yellow solid was obtained, the yield was 65%, m.p.260-262°C.

Preparation Example 25 4-(3-chloro-4-fluoroanilino)-6-(3-bromopropionamido)quinazoline

4-(3-Chloro-4-fluoroanilino)-6-aminoquinazoline (0.58g, 2mmol) was dissolved in 20mL of tetrahydrofuran, 1mL of triethylamine was added, and 3-bromopropionyl chloride ( 0.69g, 4mmol), dropwise, reacted at room temperature for 2h, added 15mL water to the reaction system, extracted with ethyl acetate (15mL×3), combined organic layers, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography ( Eluent, petroleum ether: ethyl acetate = 1:1, v:v), to obtain 0.45 g of yellow solid, yield 53%.

Example 12 4-methylpiperazine-1-dithioformic acid-[2-[4-(3-chloro-4-fluoroanilino)quinazoline-6-carbamoyl]]ethyl ester

Dissolve N-methylpiperazine (0.10g, 1mmol) in 15mL DMF, add anhydrous potassium phosphate (0.43g, 2mmol), add carbon disulfide (0.19g, 2.5mmol) dropwise under stirring at room temperature, react for 30min, add 4-(3-Chloro-4-fluoroanilino)-6-(3-bromopropionamido)quinazoline (0.43 g, 1 mmol) was stirred at room temperature, and detected by TLC until the reaction was completed. Add 15 mL of water to the reaction system, extract with ethyl acetate (15 mL × 3), combine the organic layers, wash with water (15 mL × 2), dry over anhydrous sodium sulfate, concentrate, and separate by silica gel column chromatography (eluent, ethyl acetate Ester:methanol=15:1, v:v), 0.25 g of solid was obtained, yield 48%, mp 236-237°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.19(s, 3H), 2.37(s, 4H), 2.87(t, J=6.0Hz, 2H), 3.57(t, J=5.4Hz, 2H ), 3.88(s, 2H), 4.23(s, 2H), 7.39-7.46(m, 1H), 7.78-7.79(m, 3H), 8.12(d, J=6.9Hz, 1H), 8.54(d, J=1.8Hz, 1H), 8.74(s, 1H), 9.93(s, 1H), 10.36(s, 1H). Elemental analysis C ₂₃ H ₂₄ ClFN ₆ OS ₂ : Theoretical: C, 53.22; H, 4.66; N, 16.19. Found: C, 53.20; H, 4.68; N, 16.16.

Preparation Example 26 4-hydroxyl-7-chloroquinazoline

Add 4-chloro-2-aminobenzoic acid (1.72g, 10mmol) into 10mL formamide, react at 150°C for 5h, cool the reaction solution to room temperature, and a large amount of solid precipitates, add 10mL water to the reaction solution, suction filter, and dry After drying, 1.65 g of off-white solid was obtained, yield 91%, mp 248-250°C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=7.56 (d, J=7.8 Hz, 1H), 7.73 (s, 1H), 8.10-8.15 (m, 2H), 12.40 (s, 1H).

Preparation Example 27 4-hydroxyl-6-nitro-7-chloroquinazoline

4-Hydroxy-7-chloroquinazoline (1.60g, 8.86mmol) was slowly added to the mixed acid composed of concentrated sulfuric acid (4mL) and fuming nitric acid (4mL) in an ice bath. After the reaction was completed, cool to room temperature, pour the reaction solution into 100 mL of ice water, a large amount of light yellow solid was precipitated, filtered by suction, and dried to obtain 1.80 g of light yellow solid, yield 90%, mp>300°C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=8.05 (s, 1H), 8.33 (s, 1H), 8.69 (s, 1H), 12.80 (s, 1H).

Preparation Example 28 4-Hydroxy-6-nitro-7-methoxyquinazoline

Under ice-bath conditions, metal sodium (0.41g, 17.64mmol) was added to 20mL of anhydrous methanol, stirred until the sodium was completely dissolved, and 4-(3-chloro-4-fluorophenylamino)-6-nitroquine The DMF (20ml) solution of oxazoline (1.26g, 5,58ml) was added to the reaction system, and then 0.98g (5.58mmol) potassium iodide was added, and the reaction solution was reacted at 90°C for 24h. After the reaction was completed, the pH of the reaction solution was adjusted with acetic acid Adjust to about 7, add 20mL of water into the reaction solution, stir, a large amount of yellow precipitate appears, filter with suction, and dry to obtain 0.91g of yellow solid, yield 73%, m.p.240-242°C.

Preparation Example 29 4-(3-chloro-4-fluoroanilino)-6-nitro-7-methoxyquinazoline

According to the method described in Preparation Example 23, the raw material 4-hydroxyl-6-nitroquinazoline was changed to 4-hydroxyl-6-nitro-7-methoxyquinazoline, the yield was 45%, mp234- 236°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=4.11(s, 1H), 7.53-7.59(m, 1H), 7.62-7.64(m, 1H), 7.75-7.76(m, 1H), 8.06- 8.08 (m, 1H), 8.95 (s, 1H), 9.58-9.63 (m, 1H), 11.71 (s, 1H).

Preparation Example 30 4-(3-chloro-4-fluoroanilino)-6-amino-7-methoxyquinazoline

According to the method described in Preparation Example 24, except that the starting material 4-(3-chloro-4-fluorophenylamino)-6-nitroquinazoline was changed to 4-(3-chloro-4-fluorophenylamino)- 6-nitro-7-methoxyquinazoline, yield 61%, m.p.260-262°C.

Preparation Example 31 4-(3-chloro-4-fluoroanilino)-6-(3-bromopropionamido)-7-methoxyquinazoline

According to the method described in Preparation Example 25, except that the starting material 4-(3-chloro-4-fluoroanilino)-6-aminoquinazoline was changed to 4-(3-chloro-4-fluorophenylamino)-6 -Amino-7-methoxyquinazoline, yield 47%.

Example 13 4-methylpiperazine-1-dithioformic acid-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline-6-carbamoyl] ] ethyl ester

According to the method described in Example 12, just change the raw material 4-(3-chloro-4-fluoroanilino)-6-(3-bromopropionamido)quinazoline into 4-(3-chloro-4- Fluoroanilino)-6-(3-bromopropionamido)-7-methoxyquinazoline, yield 43%, mp242-244°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ=2.21(s, 3H), 2.40(s, 4H), 2.93(s, 2H), 3.56(t, J=7.2Hz, 2H), 3.90-4.00 (m, 5H), 4.24(s, 2H), 7.28(s 1H), 7.42(t, J=8.7Hz, 1H), 7.78-7.79(m, 1H), 8.12(d, J=5.1Hz, 1H ), 8.53(s, 1H), 8.53(s, 1H), 9.63(s, 1H), 9.82(s, 1H). HRMS: C ₂₄ H ₂₆ ClFN ₆ O ₂ S ₂ +H, calc. 549.13095; found (ESI-FTMS, (M+H) ⁺¹ ), 549.12920.

Preparation Example 32 4-hydroxyl-6-methylquinazoline

Mix 2-amino-5-methylbenzoic acid (7.20g, 48mmol) and formamide (7.6mL, 192mmol), heat to 130-135°C, and reflux for 4h. After the reaction was completed, 1 mL of water was added dropwise to destroy the reaction, and when the temperature dropped to 60°C, 20 mL of water was added, cooled to room temperature, and continued to stir for 30 min. Suction filtration and washing with water gave off-white solid. Methanol was recrystallized to obtain 5.50 g of white flocculent solid, yield 77%, mp 266-267°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.44(s, 3H), 7.57(d, J=8.4Hz, 1H), 7.64(dd, J=8.25Hz, 1.2Hz, 1H), 7.92( d, J = 0.9 Hz, 1H), 8.03 (s, 1H), 12.17 (br, 1H).

Preparation Example 33 4-chloro-6-methylquinazoline

4-Hydroxy-6-methylquinazoline (3.12g, 21mmol) was added into thionyl chloride (52mL), a catalytic amount of DMF (1mL) was added dropwise, and heated under reflux for 3h. After the reaction, thionyl chloride was distilled off under reduced pressure, and the residue was separated and purified by silica gel column (eluent, petroleum ether: ethyl acetate = 3:1, v:v) to obtain 1.36 g of yellow solid compound, the yield 36%, mp 107-108°C. ¹ H NMR (300MHz, CDCl ₃ ): δ2.62(s, 3H), 7.81(dd, J=8.5Hz, 1.5Hz, 1H), 7.98(d, J=8.7Hz, 1H), 8.04(s, 1H), 8.99 (s, 1H).

Preparation Example 34 6-bromomethyl-4-chloro-quinazoline

4-Chloro-6-methylquinazoline (0.89 g, 5 mmol) and N-bromosuccinimide (NBS) (0.89 g, 5 mmol) were dissolved in CCl ₄ (10 mL), and a catalytic amount of Benzoyl oxide was heated to reflux for 0.5h. After the reaction was detected by TLC, it was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated and purified by silica gel column (eluent, petroleum ether:ethyl acetate=15:1, v:v) to obtain a white solid 0.60 g, yield 45%, mp118-120°C. ¹ H NMR (300MHz, CDCl ₃ ): δ4.69(s, 2H), 8.01(d, J=8.7Hz, 2.1Hz, 1H), 8.09(d, J=8.4Hz, 1H), 8.26(d, J=1.5Hz, 1H), 9.07(s, 1H).

Preparation Example 35 4-Chloro-6-(phthalimide methyl) quinazoline

The potassium salt of phthalimide (0.74g, 4mmol) was dissolved in acetone (10mL), heated to reflux, and 6-bromomethyl-4-chloro-quinazoline (1.03g, 4mmol) was added dropwise acetone solution, continue to reflux for 1h. TLC detects that the raw material disappears, stop the reaction, cool to room temperature, filter, the filter cake is the target compound, and the filtrate is concentrated and purified by silica gel column separation and purification (eluent, petroleum ether:ethyl acetate=1:1, v:v), to obtain White solid 1.20g, yield 92%, mp212-214°C. ¹ H NMR (300MHz, CDCl ₃ ): δ5.09(s, 2H), 7.74-7.77(m, 2H), 7.88-7.91(m, 2H), 8.06(s, 2H), 8.34(s, 1H) , 9.04(s, 1H). EI-MS: [M+]＝323.1. (Molecular formula: C ₁₇ H ₁₀ ClN ₃ O ₂ , molecular weight: 323.733)

Preparation Example 36 4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]-6-(phthalimidemethyl)quinazoline

Mix the product of Preparation Example 35 (1mmol) and 3-chloro-4-(3-fluorobenzyloxy)aniline (1mmol) into isopropanol (2mL), heat to reflux, a solid precipitates out, stop the reaction, and cool , filtered and dried to obtain a yellow solid product with a yield of 77%, mp259-262°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ5.01(s, 2H), 5.30(s, 2H), 7.17-7.22(m, 1H), 7.30-7.35(m, 3H), 7.44-7.57( m, 2H), 7.82(d, J=5.7Hz, 1H), 7.87-7.97(m, 5H), 8.07-8.10(d, J=8.7Hz, 1H), 8.64(s, 1H), 8.90(s , 1H), 11.49 (br, 1H).

Preparation Example 37 2-[4-(3-Chloro-4-fluoroanilino)-6-(phthalimidemethyl)quinazoline

Following the method described in Preparation Example 36, except that the starting material 3-chloro-4-(3-fluorobenzyloxy)aniline was changed to 3-chloro-4-fluoroaniline, the yield was 81%, mp 267-268°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ4.98(s, 2H), 7.45(t, J=9.0Hz, 1H), 7.74-7.95(m, 7H), 8.13(d, J=6.0Hz , 1H), 8.44 (s, 1H), 8.61 (s, 1H), 9.98 (br, 1H).

Preparation Example 38 2-[4-(3-bromoanilino) 6-(phthalimide methyl) quinazoline

Following the method described in Preparation Example 36, except that the starting material 3-chloro-4-(3-fluorobenzyloxy)aniline was changed to m-bromoaniline, the yield was 92%, mp 236-237°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ5.02(s, 2H), 7.43-7.56(m, 2H), 7.68(d, J=8.1Hz, 1H), 7.87-7.98(m, 6H) , 8.10 (d, J=8.7Hz, 1H), 8.70 (s, 1H), 8.96 (s, 1H), 11.57 (br, 1H).

Example 14 {4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylaminodithioformic acid-2-[2-(1,3-di Oxycyclopentyl)] ethyl ester

The product of Preparation Example 36 (0.20 g) was dissolved in methanol (2 mL), stirred evenly, and added dropwise into methylamino alcohol solution (10 mL), stirred for 10 min, methanol was added until the reaction solution was clear, and stirred overnight at room temperature. After the reaction, the solvent was evaporated under reduced pressure, and the residue was acidified with 3N hydrochloric acid (5mL) solution, and a solid precipitated, and water was added until the solid was completely dissolved, extracted with ethyl acetate (20mL×2), and the aqueous phase was alkalinized with 1N sodium hydroxide solution. The mixture was adjusted to pH 7-8, extracted with ethyl acetate (20 mL×3), combined and basified ethyl acetate layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a solid. The solid (1mmol) was dissolved in DMF (2mL), Et ₃ N (2mmol) was added dropwise, after stirring for 10min, CS ₂ (4mmol) was added dropwise, after stirring for 15min, 2-(2-bromoethyl)-1 , 3-dioxolane (1.2 mmol), stirred overnight at room temperature. After the reaction was completed, excess water (50 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column separation and purification ( Eluent, petroleum ether: ethyl acetate = 1:1.5, v:v), the title product was obtained, yield 35%, mp 158-160°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.95-2.04(m, 2H), 3.31(t, J=7.5Hz, 2H), 3.80-3.97(m, 4H), 4.92(t, J= 7.5Hz, 1H), 5.05(d, J=5.1Hz, 2H), 5.31(s, 2H), 7.20-7.39(m, 4H), 7.48-7.56(m, 1H), 7.77-7.82(m, 3H ), 8.07 (d, J=2.1 Hz, 1H), 8.50 (s, 1H), 8.63 (s, 1H), 9.88 (br, 1H), 10.57 (br, 1H). Elemental analysis C ₂₈ H ₂₆ ClFN ₄ O ₃ S ₂ : Theoretical: C, 57.48; H, 4.48; N, 9.58. Found: C, 57.32; H, 4.75; N, 9.43.

Example 15 [4-(3-chloro-4-fluorophenylamino)quinazolinyl]-6-methylaminodithioformic acid-2-[2-(1,3-dioxolyl)]B ester

According to the method described in Example 14, only the product of Example 36 was changed from the raw material to the product of Example 37, the yield was 40%, mp 162-163°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.90-1.97(m, 2H), 3.26(t, J=7.5Hz, 2H), 3.75-3.92(m, 4H), 4.88(t, J= 7.5Hz, 1H), 5.01(d, J=5.4Hz, 2H), 7.47(t, J=9.0Hz, 1H), 7.80(s, 3H), 8.19-8.21(m, 1H), 8.47(s, 1H), 8.64 (s, 1H), 9.96 (br, 1H), 10.54 (br, 1H). Elemental analysis C ₂₁ H ₂₀ ClFN ₄ O ₂ S ₂ : Theoretical: C, 52.66; H, 7.21; N, 11.70. Found: C, 52.51; H, 4.233; N, 11.36.

Example 16 [4-(3-bromoanilino)quinazolinyl]-6-methylaminodithioformic acid-2-[2-(1,3-dioxolyl)]ethyl ester

According to the method described in Example 14, except that the raw material was changed from the product of Example 36 to the product of Example 38, the yield was 36%, and mp90-92°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.90-1.99(m, 2H), 3.26(t, J=7.5Hz, 2H), 3.75-3.92(m, 4H), 4.88(t, J= 7.5Hz, 1H), 5.02(d, J=5.4Hz, 2H), 7.30-7.40(m, 2H), 7.80(s, 2H), 7.93(t, J=6.9Hz, 1H), 8.23(s, 1H), 8.51 (s, 1H), 8.67 (s, 1H), 9.92 (br, 1H), 10.54 (br, 1H). HRMS: C ₂₁ H ₂₁ BrN ₄ O ₂ S ₂ +H, calc. 505.03621; found (ESI-FTMS, (M+H) ⁺¹ ), 505.03601.

Example 17 {4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylaminodithiocarbamate-2-cyanoethyl ester

According to the method described in Example 14, except that the raw material 2-(2-bromoethyl)-1,3-dioxolane was changed to β-bromopropylcyanide, the yield was 45%, and the mp was 173-177°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.93(t, J=6.3Hz, 2H), 3.50(t, J=6.9Hz, 2H), 5.02(s, 2H), 5.27(s, 2H ), 7.17-7.49(m, 5H), 7.72-7.79(m, 3H), 8.03(s, 1H), 8.47(s, 1H), 8.59(s, 1H), 9.84(br, 1H), 10.75( br, 1H). HRMS: C ₂₆ H ₂₁ ClFN ₅ OS ₂ +H, calc. 538.09328; found (ESI-FTMS, (M+H) ⁺¹ ), 538.09230.

Example 18 {4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylcarbamodithioate-2-methoxyformyl ethyl ester

According to the method described in Example 14, except that the raw material 2-(2-bromoethyl)-1,3-dioxolane was changed to methyl acrylate, the yield was 38%, mp 169-171°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.74(t, J=6.3Hz, 2H), 3.50(t, J=6.9Hz, 2H), 3.61(s, 3H), 5.00(d, J =4.5Hz, 2H), 5.26(s, 2H), 7.16-7.52(m, 5H), 7.12-7.78(m, 3H), 8.03(s, 1H), 8.45(s, 1H), 8.58(s, 1H), 9.84 (br, 1H), 10.59 (br, 1H). Elemental analysis C ₂₇ H ₂₄ ClFN ₄ O ₃ S ₂ : Theoretical: C, 56.78; H, 4.24; N, 9.81. Found: C, 56.85; H, 4.255; N, 9.757.

Example 19 {4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylcarbamodithioate-2-benzylsulfone ethyl ester

According to the method described in Example 14, just change the raw material 2-(2-bromoethyl)-1,3-dioxolane into (2-bromoethylsulfone)methylbenzene, the yield is 24%, mp168-170°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ3.40-3.44(m, 2H), 3.57-3.61(t, J=8.4, 2.4Hz, 2H), 4.57(s, 2H), 5.00-5.01( d, J=5.2Hz, 2H), 5.26(s, 2H), 7.16-7.21(m, 1H), 7.29-7.35(m, 3H), 7.38-7.50(m, 6H), 7.73(dd, J= 8.8, 2.8Hz, 1H), 7.78(s, 1H), 8.02(d, J=2.8Hz, 1H), 8.46(s, 1H), 8.59(s, 1H), 9.85(br, 1H), 10.70( br, 1H). Elemental analysis C ₃₂ H ₂₈ ClFN ₄ O ₃ S ₃ : Theoretical: C, 57.60; H, 4.23; N, 8.40. Found: C, 57.15; H, 4.23; N, 8.38.

Preparation Example 39 2-cyano-3-(3-methoxy-4-methylanilino) ethyl acrylate

Dissolve 3-methoxy-4-methylaniline (10.96g, 80mmol) and ethyl 2-cyano-3-ethoxyacrylate (13.54g, 80mmol) in toluene (32mL), heat to reflux for 5h, After standing and cooling, a large amount of yellow solid precipitated, filtered, washed with ether, and dried to obtain 18.6 g of yellow solid, yield 94%, mp 152-156°C. ¹ H NMR (300MHz, CDCl ₃ ): δ1.37(t, J=7.2Hz, 3H), 2.19(s, 3H), 3.85(s, 3H), 4.26-4.33(m, 1H), 6.51(d , J=1.8Hz, 1H), 6.60(dd, J=7.8, 2.1Hz, 1H), 7.12(d, J=8.1Hz, 1H), 7.83(d, J=13.5Hz, 1H), 10.72(br , 1H).

Preparation Example 40 3-cyano-4-hydroxyl-6-methyl-7-methoxyquinoline

The product of Preparation Example 39 (5.00g, 19mmol) was dissolved in diphenyl ether and biphenyl mixture (200mL, v:v, 3:1), heated to 258°C and refluxed for 24h, cooled, and poured into 100mL cyclohexane , and filtered to obtain 2.14 g of black solid compound, yield 53%, mp>300°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.25(s, 3H), 3.91(s, 3H), 6.99(s, 1H), 7.88(s, 1H), 8.63(s, 1H), 12.58 (br, 1H).

Preparation Example 41 3-cyano-4-chloro-6-methyl-7-methoxyquinoline

The product of Preparation Example 40 (0.39 g, 2 mmol) was added to phosphorus oxychloride (2 mL), and a catalytic amount of DMF (3 drops) was added dropwise, and heated to reflux at 110° C. for 2 h. Cool, drop the reaction solution into ice water, add 10N sodium hydroxide until the solution pH = 7, filter, and separate and purify the filter cake through a silica gel column (eluent, petroleum ether: ethyl acetate = 1:1, v:v) , to obtain 0.37 g of light yellow solid compound, yield 84%, mp 196-197°C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.42 (s, 3H), 4.04 (s, 3H), 7.53 (s, 1H), 8.08 (s, 1H), 9.06 (s, 1H).

Preparation Example 42 3-cyano-4-chloro-6-bromomethyl-7-methoxyquinoline

The product of Preparation Example 41 (0.37 g, 1.7 mmol) and N-bromosuccinimide (NBS) (0.36 g, 2 mmol) were dissolved in CCl ₄ (5 mL), and a catalytic amount of benzoyl peroxide was added, Heat to reflux for 0.5h. After the reaction was detected by TLC, the heating was stopped, cooled to room temperature, filtered, the filtrate was concentrated, and the crude product was separated and purified on a silica gel column (eluent, petroleum ether:ethyl acetate=4:1, v:v) to obtain a white solid 0.43 g, yield 85%, mp 178-182°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ4.10(s, 3H), 4.14(s, 3H), 4.90(s, 2H), 7.58(s, 1H), 7.63(s, 1H), 7.69 (s, 1H), 8.45 (s, 1H), 8.60 (s, 1H), 9.13 (s, 1H), 9.17 (s, 1H).

Preparation Example 43 3-cyano-4-chloro-6-phthalimidemethyl-7-methoxyquinoline

Dissolve the potassium salt of phthalimide (0.55g, 3mmol) in acetone (20mL), heat to reflux, drop into the acetone solution of the product of Preparation Example 42 (0.43g, 1.5mmol), and continue to reflux for 1h . TLC detects that the raw material disappears, stop the reaction, cool to room temperature, filter, the filter cake is compound c-7, and the filtrate is concentrated and purified by silica gel column separation and purification (eluent, petroleum ether: ethyl acetate = 2: 1, v: v) , to obtain 0.23 g of white solid compound, yield 45%, mp 240-244°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ4.06(s, 3H), 4.96(s, 2H), 7.63(s, 1H), 7.88-7.97(m, 5H), 9.11(s, 1H) .

Preparation Example 44 3-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-phthalimidemethyl-7-methoxyquinoline

Mix the compound of Preparation Example 43 (1mmol) and 3-chloro-4-(3-fluorobenzyloxy)aniline (1mmol) into isopropanol (2mL), heat to reflux, a solid precipitates out, stop the reaction, and cool , filtered, dried, yield 80%, mp278-282°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ4.01(s, 3H), 4.84(s, 3H), 5.24(s, 2H), 7.15-7.46(m, 8H), 7.83-7.94(m, 4H), 8.05 (s, 1H), 8.50 (s, 1H), 9.61 (br, 1H).

Preparation Example 45 3-cyano-4-(3-chloro-4-fluoroanilino)-6-phthalimidemethyl-7-methoxyquinoline

Following the method described in Preparation Example 44, except that the starting material 3-chloro-4-(3-fluorobenzyloxy)aniline was changed to 3-chloro-4-fluoroaniline, the yield was 83%, mp 310-313°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ4.05(s, 3H), 4.85(s, 2H), 7.37-7.47(m, 3H), 7.64(d, J=1.8Hz, 1H), 7.90 (d, J=8.4Hz, 4H), 8.15(s, 1H), 8.83(s, 1H), 10.44(br, 1H).

Preparation Example 46 3-cyano-4-(3-bromoanilino)-6-phthalimidemethyl-7-methoxyquinoline

Following the method described in Preparation Example 44, except that the starting material 3-chloro-4-(3-fluorobenzyloxy)aniline was changed to 3-bromoaniline, the yield was 99%, mp 310-312°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ4.05(s, 3H), 4.85(s, 2H), 7.31-7.60(m, 5H), 7.86-7.94(m, 5H), 8.25(s, 1H), 8.95 (s, 1H), 10.91 (br, 1H).

Example 20 {4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-3-cyano-7-methoxyquinolinyl}-6-methylaminodithioformic acid-2 -[2-(1,3-dioxolopentyl)]ethyl ester

The product of Preparation Example 44 (0.20 g) was dissolved in methanol (2 mL), stirred evenly, and added dropwise into methylamino alcohol solution (10 mL), stirred for 10 min, methanol was added until the reaction solution was clear, and stirred overnight at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and the residue was acidified with 3N hydrochloric acid solution (5mL), and a solid precipitated, and water was added until the solid was completely dissolved, extracted with ethyl acetate (20mL×2), and the aqueous phase was alkalized with 1N sodium hydroxide solution. The mixture was adjusted to pH 7-8, extracted with ethyl acetate (20 mL×3), combined and basified ethyl acetate layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a solid compound. The above compound (1mmol) was dissolved in DMF (2mL), Et ₃ N (2mmol) was added dropwise, after stirring for 10min, CS ₂ (4mmol) was added dropwise, after stirring for 15min, 2-(2-bromoethyl) was added dropwise -1,3-dioxolane, stirred overnight at room temperature. After the reaction was completed, excess water (50 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column separation and purification ( Eluent, petroleum ether: ethyl acetate=1:1.5, v:v), the target compound was obtained with a yield of 24%, mp174-177°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.86-1.93(m, 2H), 3.20(t, J=7.5Hz, 2H), 3.72-3.89(m, 4H), 3.97(s, 3H) , 4.83 (t, J=4.5Hz, 3H), 5.25 (s, 2H), 7.17-7.47 (m, 8H), 8.27 (s, 1H), 8.51 (s, 1H). HRMS: C ₃₁ H ₂₈ ClFN ₄ O ₄ S ₂ +H, calc. 639.12973; found (ESI-FTMS, (M+H) ⁺¹ ), 639.12921.

Example 21 [4-(3-chloro-4-fluoroanilino)-3-cyano-7-methoxyquinolinyl]-6-methylaminodithioformic acid-2-[2-(1, 3-Dioxocyclopentyl)] ethyl ester

According to the method described in Example 20, except that the raw materials used to prepare the product of Example 44 were changed to the product of Example 45, the yield was 53%, and mp 190-192°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.88-1.90(m, 2H), 3.21(t, J=7.5Hz, 2H), 3.77-3.99(m, 9H), 4.86(s, 3H) , 7.25-7.47 (m, 4H), 8.21 (s, 1H), 8.61 (s, 1H), 9.78 (br, 1H), 10.19 (br, 1H). HRMS: C ₂₄ H ₂₂ ClFN ₄ O ₃ S ₂ +H, calc. 533.08786; found (ESI-FTMS, (M+H) ⁺¹ ), 533.08724.

Example 22 [4-(3-bromoanilino)-3-cyano-7-methoxyquinolinyl]-6-methylaminodithioformic acid-2-[2-(1,3-dioxo Cyclopentyl)] ethyl ester

According to the method described in Example 20, except that the product of Preparation Example 44 was changed to the product of Preparation Example 46, the yield was 41%, mp 155-157°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.88-1.99(m, 2H), 3.21(t, J=7.5Hz, 2H), 3.74-4.05(m, 7H), 4.85(t, J= 4.5Hz, 3H), 7.16-7.41(m, 5H), 8.22(s, 1H), 8.66(s, 1H), 9.80(br, 1H), 10.19(br, 1H). Elemental analysis C ₂₄ H ₂₃ BrN ₄ O ₃ S ₂ : Theoretical: C, 51.52; H, 4.14; N, 10.01. Found: C, 51.26; H, 4.15; N, 9.94.

Example 23 [4-(3-bromoanilino)quinazolinyl]-2-benzylsulfonyl ethyl ester of 6-methylaminodithiocarbamate

According to the method described in embodiment 14, just change the product of raw material preparation embodiment 36 into the product of preparation embodiment 38, change raw material 2-(2-bromoethyl)-1,3-dioxolane into ( 2-Bromoethylsulfone) methylbenzene, yield 39%, mp180-182°C. ¹ H NMR (300MHz, DMSO-d ₆ ): δ3.38-3.43(m, 2H), 3.55-3.60(m, 2H), 4.57(s, 2H), 4.55(s, 2H), 4.50(s, 2H), 7.29-7.39(m, 8H), 7.80(s, 2H), 7.91(d, J=8.1Hz, 1H), 8.22(s, 1H), 8.50(s, 1H), 8.65(s, 1H ). HRMS: C ₂₅ H ₂₃ BrN ₄ O ₂ S ₃ +H, calc. 587.02393; found (ESI-FTMS, (M+H) ⁺¹ ), 587.02408.

Biological Activity Evaluation of Compounds of Test Example 1 - Protein Tyrosine Kinase Inhibitory Activity Screening

Screening method: enzyme-linked immunosorbent assay (ELISA)

This example adopts the conventional method of screening test for protein tyrosine kinase inhibitory activity in the field of pharmacy, such as the method described in Chinese patent publication CN1944398A. The test results are shown in Table 1 below.

The inhibitory rate (%) of table 1 tyrosine kinase activity

Compound No. EGFR average inhibition rate (%) activity evaluation Example 2 88.4 efficient Example 3 92.1 efficient Example 4 95.6 efficient Example 6 98.6 efficient Example 14 98.2 efficient Example 15 88.2 efficient Example 20 88.1 efficient Example 22 77.8 efficient Example 23 100 efficient lapatinib 98.3 efficient

Among them, lapatinib (Lapatinib) is a known anti-tumor drug and a new EGFR-targeted therapy drug for advanced breast cancer. It was used as a positive control drug in the above-mentioned test.

In the above test, EGFR concentration: 10 μM; action time: 1 h; result evaluation: invalid: 10 μM<50%; effective: 10 μM≥50%.

Biological Activity Evaluation of Test Example 2 Compound - In Vitro Antitumor Activity Test

The test method used in this example is a conventional anti-tumor activity test method in the pharmaceutical field, for example, refer to the following literature: (J. Immunol Method, 1983, 65, 55). In the test, compound 23 was used as a representative example of the compound of the present invention, and the known drug gefitinib was used as a positive control drug. The test results are shown in Table 2 below.

The cell activity test result of table 2 embodiment compound 23

*Screening method and test model: A: MTT method (HL-60 human leukemia); B: SRB method (BGC-823 human gastric cancer); C: SRB method (Bel-7402 human liver cancer); D: SRB method (KB human nasopharyngeal carcinoma).

From the above test results, it can be clearly seen that the compound of general formula (I) for which patent protection is claimed in the present invention has excellent protein tyrosine kinase inhibitory activity and anticancer activity. It is expected to be developed into a new anti-tumor drug with a new structure type.

Now having described the embodiment of the present invention in detail, it is obvious to those skilled in the art that many improvements and changes can be made without departing from the basic spirit of the present invention, and all these changes and improvements are within the scope of the present invention. Its characteristics are determined by the above description.

Claims (17)

1. A carbamate compound or a pharmaceutically acceptable salt thereof having a structure of general formula (I): in: A is a nitrogen atom or a carbon atom, and the carbon atom is substituted by -CN; D is -(CH ₂ ) _m -, -(CH ₂ ) _m -O-, -(CH ₂ ) _m -NH- or -CH ₂ CH ₂ CONH-, wherein m is each independently an integer of 1-3; E is a sulfur atom or NR ³ , wherein R ³ is H, methyl, ethyl or phenyl; R is R ⁴ R ⁵ N- or R ⁶ S-, when the R group is R ⁴ R ⁵ N-, wherein R ⁴ and R ⁵ represent substituted or unsubstituted together with the connected nitrogen atom, and also contain A saturated six-membered or seven-membered heterocyclic ring with 1 nitrogen atom, oxygen atom or sulfur atom, wherein the substituent is methyl, halophenylmethyl or bis(fluorophenyl)methyl; or when said When R is R ⁶ S-, R ⁶ represents the following groups:

Wherein R ⁷ and R ⁸ are each independently hydrogen, methyl or benzyl; q is an integer of 1-3; ^R is selected from the following groups: halogen or benzyloxy, wherein there may be 1-3 halogens on the benzyl; n is an integer from 1 to 3; and R ² is H, C _1-4 alkyl, halogen substituted C _1-4 alkyl, C _1-4 alkoxy or halogen substituted C _1-4 alkoxy. 2. The compound according to claim 1, wherein said group D is -CH ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₃ -O-, -(CH ₂ ) ₃ -NH - or _{-CH2CH2CONH- .} 3. The compound according to claim 1, wherein said group E is a sulfur atom or -NH-. 4. The compound according to claim 2 or 3, wherein said -ED- group is: -NH-CH ₂ -, -NH-(CH ₂ ) ₃ -, -S-(CH ₂ ) ₃ - O- or -S _{- CH2CH2CONH-} . 5. The compound according to claim 1, wherein the saturated six-membered or seven-membered heterocyclic ring is: 6. The compound according to claim 1, when the R group is R ⁶ S-, wherein R ⁶ represents the following groups:

7. The compound according to claim 1, wherein the group connected to quinoline ring or quinazoline ring 4-position amino is:

8. The compound of claim 1, wherein said ^R2 group is H or methoxy. 9. The compound of claim 1, wherein said compound is: 4-Methylpiperazine-1-dithiocarboxylate-[3-[4-(3-bromoanilino)quinazoline-6-oxy]]propyl ester; 4-Methylpiperazine-1-dithiocarboxylate-[3-[4-(3-chloro-4-fluoroanilino)quinazoline-6-oxo]]propyl ester; 4-Methylpiperazine-1-dithiocarboxylate-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline-6-oxo]propyl ester; 4-Methylpiperazine-1-dithiocarboxylate-{3-[4-(3-bromoanilino)-7-methoxyquinazoline-6-oxo]}propyl ester; 4-methylpiperazine-1-dithiocarboxylic acid-{3-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline-6-oxy]}propyl ester; 4-methylpiperazine-1-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6- Oxy]] propyl ester; Piperazine-4-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxygen]]propane ester; Homopiperazine-4-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxo]] Propyl ester; Morpholine-4-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxygen]]propane ester; Thiomorpholine-4-dithioformic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7-methoxyquinazoline-6-oxo] ] propyl ester; 4-[bis(4-fluorophenyl)methyl]piperazine-1-dithiocarboxylic acid-[3-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-7 -Methoxyquinazoline-6-oxo]]propyl ester; 4-Methylpiperazine-1-dithiocarboxylic acid-[2-[4-(3-chloro-4-fluoroanilino)quinazoline-6-carbamoyl]]ethyl ester; 4-Methylpiperazine-1-dithioformic acid-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline-6-carbamoyl]]ethyl ester ; {4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylaminodithiocarbamate-2-[2-(1,3-dioxolane base)] ethyl ester; [4-(3-Chloro-4-fluoroanilino)quinazolinyl]-6-methylaminodithiocarboxylate-2-[2-(1,3-dioxolyl)]ethyl ester; [4-(3-Bromoanilino)quinazolinyl]-6-methylaminodithiocarboxylate-2-[2-(1,3-dioxolyl)]ethyl ester; {4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-6-methylaminodithiocarbamate-2-cyanoethyl ester; {4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-2-methoxyformyl ethyl 6-methylaminodithiocarbamate; {4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]quinazolinyl}-2-benzylsulfonylethyl 6-methylaminodithiocarbamate; {4-[3-Chloro-4-(3-fluorobenzyloxy)anilino]-3-cyano-7-methoxyquinolinyl}-6-methylaminodithioformic acid-2-[2 -(1,3-dioxolyl)]ethyl ester; [4-(3-Chloro-4-fluoroanilino)-3-cyano-7-methoxyquinolinyl]-6-methylaminodithioformic acid-2-[2-(1,3-di Oxycyclopentyl)] ethyl ester; [4-(3-Bromoanilino)-3-cyano-7-methoxyquinolinyl]-6-methylaminodithioformic acid-2-[2-(1,3-dioxolyl )] ethyl ester; and [4-(3-Bromoanilino)quinazolinyl]-2-benzylsulfonylethyl ester of 6-methylaminodithiocarbamate. 10. A pharmaceutical composition, which contains a therapeutically effective amount of the compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9 as an active ingredient, and optionally contains one or more pharmaceutically acceptable carrier. 11. The pharmaceutical composition according to claim 10, wherein the content of the active ingredient is 0.5%-99%, and the content of the pharmaceutical carrier is 1%-99.5%. 12. The pharmaceutical composition according to claim 11, wherein the composition is made into a form of oral or parenteral administration, and the form of parenteral administration includes injection administration, topical administration, inhalation administration drug, rectal or implanted form. 13. The pharmaceutical composition according to claim 12, wherein the dosage form for oral administration is a preparation in tablet, capsule, granule or liquid form suitable for pharmaceutical use. 14. The pharmaceutical composition according to claim 13, wherein the tablet is in the form of coating, enteric coating, sustained release or quantitative release. 15. Use of the compound according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 10-14 in the preparation of tyrosine kinase inhibitors. 16. The use according to claim 15, wherein said tyrosine kinase inhibitor is an antineoplastic drug. 17. The use according to claim 16, wherein the antitumor drug is a drug for treating breast cancer, non-small cell lung cancer, gastric cancer or pancreatic cancer.