CN103755647B - C2-position derivatives of 4(3H)-quinazolinones and their preparation methods and uses - Google Patents

Abstract

The invention discloses the C2 bit derivant of 4 (3H)-quinazolinones shown in general formula (I), wherein, R ¹-R ⁵definition refer to specification sheets.In addition, the preparation method of above-claimed cpd, its medicinal compositions is also disclosed.The propagation of compound shown in this general formula (I) to people's lung cancer (A-549), human breast carcinoma (MFC-7), human colon carcinoma (HT29, HCT-116) and human cervical carcinoma (HeLa) cell is inhibited, can be used as antitumor drug.

Description

C2-position derivatives of 4(3H)-quinazolinones and their preparation methods and uses

technical field

The invention relates to the field of medicinal chemistry, more specifically to C2 derivatives of 4(3H)-quinazolinones, their preparation methods and their application in antitumor drugs.

Background technique

Quinazoline derivatives with different side chains at C5 or C6 exhibit antitumor activity by inhibiting folate-dependent enzymes, such as ZD1694 (structural formula 1) [Cunningham, D., Zalcberg, J., Maroun, J. , James, R., Clarke, S., Maughan T.S., Vincent M., Schulz J., Baron, M.G., Facchini, T. Efficacy, tolerance and management of raltitrexed monotherapy patients with advanced colorectal cancer: a review of phase II/III trials. Eur. J. Cancer 2002, 38, 478], 3AG （结构式1）[S.Webber,C.A.Bartlett,T.J.Boritzki,J.A.Hilliard,E.F.Howland,A.L.Johnston,M.Kosa,S.A.Margosiak,C.A.Morse,B.V.Shetty,AG337,anovellipophilicthymidylatesynthaseinhibitor:invitroandinvivopreclinicalstudies,CancerChemother.Pharmacol.1996,37,509 -517] (structural formula 1). The inventor once introduced aminodithioformate as a side chain into the C6 position of 4(3H)-quinazolone, and synthesized 4(3H)-quinazolone as the aminodithiocarbamate of ester component. Substituted formate derivatives (structural formula 2), have a significant inhibitory effect on the proliferation of human leukemia K562 cells (Cao Shengli, 4-quinazolinone derivatives and their application in antitumor drugs, Chinese patent number: ZL200510053618 .5). And 4(3H)-quinazolinone is connected with amino group, and the formed 4-quinazolinone-6-methylaminodithiocarbamate compound (structural formula 3) is effective against human lung cancer A549 and human breast cancer MCF -7. Proliferation of colon cancer HT29 and cervical cancer HeLa cells has significant inhibitory effect (Cao Shengli, Xu Xingzhi, Liao Ji, Wang Yao, Han Ying, Zhao Baoli, Liu Hongqin, Chen Linlin, Li Xiaorong, 4-quinazolone-6- Methylcarbamate and its medicinal composition and use, Chinese Patent No.: ZL201010034364.3).

Structural formula 1. The structure of ZD1694 and AG337

Structural formula 2.4 (3H)-quinazolone as carbamate derivative of ester group component

Structural formula 3.4 (3H)-quinazolone as the carbamate derivative of amino component

Contents of the invention

The present inventor has been through a large number of research tests, and carbamate side chain is introduced into the C2 position of 4 (3H)-quinazolone, has synthesized 4 (3H)-quinazolone derivative, and this derivative is to It can inhibit the proliferation of human lung cancer A549, breast cancer cell MCF-7, cervical cancer HeLa, colon cancer HT-29 and HCT-116 cells.

The object of the present invention is to provide a C2 derivative of 4(3H)-quinazolinone.

Another object of the present invention is to provide a preparation method for the C2-position derivative of the above-mentioned 4(3H)-quinazolinone.

Another object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned C2-position derivative of 4(3H)-quinazolinone.

Another object of the present invention is to provide the use of the above-mentioned C2-position derivatives of 4(3H)-quinazolinone in the preparation of anticancer drugs.

Specifically, the present invention provides a C2 derivative of 4(3H)-quinazolinone, as shown in general formula (I):

Among them, in formula (I)

R ² , R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, or hydroxyl; here, the C1-C4 alkyl is selected from From methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the C1-C4 alkoxy group is selected from methoxy, ethoxy, n-propoxy , isopropoxy, n-butoxy, isobutoxy or tert-butoxy; the halogen is selected from fluorine, chlorine, bromine or iodine;

Preferably, R ² , R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, or hydroxyl; more preferably, R ³ is methyl base, methoxy, fluorine, chlorine, bromine, iodine, nitro, or hydroxyl, and R ² , R ⁴ and R ⁵ are each independently hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, Nitro, or hydroxyl; or, R ⁴ is methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, or hydroxyl, and R ² , R ³ and R ⁵ are each independently hydrogen, methyl, Methoxy, fluoro, chloro, bromo, iodo, nitro, or hydroxy; or, R ⁵ is methyl, methoxy, fluoro, chloro, bromo, iodo, nitro, or hydroxy, and R ² , R ³ and R ^are each independently hydrogen, methyl, methoxy, fluoro, chloro, bromo, iodo, nitro, or hydroxy;

R ¹ is C1-C4 alkyl or substituted C1-C4 alkyl, here, the C1-C4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or Tert-butyl; the substituted C1-C4 alkyl refers to a C1-C4 alkyl substituted by one or two or more aromatic hydrocarbon groups or substituted aromatic hydrocarbon groups, or heterocyclic or substituted heterocyclic rings; preferably, R ¹ is a substituted C1-C4 alkyl group, more preferably a substituted methyl group; the aromatic hydrocarbon group is a phenyl group or a substituted phenyl group, wherein the substituted phenyl group means that the phenyl ring is replaced by one or two More than one C1-4 alkyl, any halogenated C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl, hydroxyl, halogen (such as fluorine, chlorine, bromine, or iodine), nitro or The cyano group is substituted, and the position of substitution on the benzene ring is not limited, and optionally the substituents on the benzene ring are connected to each other, more preferably, the substituted phenyl is selected from 4-methylphenyl, 4-methyl Oxyphenyl, 2-methoxyphenyl, 4-nitrophenyl, 4-cyanophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 2- Fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, or 3 ,4-methylenedioxyphenyl;

The heterocycle is selected from furan, tetrahydrofuran, pyran, tetrahydropyran, thiophene, tetrahydrothiophene, thiazole, imidazole, pyridine, or pyrimidine; the substituted heterocycle means that the heterocycle is replaced by one or more C1-4 alkyl, any halogenated C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl, hydroxyl, halogen (such as fluorine, chlorine, bromine, or iodine), nitro or cyano Substitution, and the substitution position on the heterocycle is not limited; preferably, the heterocycle is selected from thiophene, furan, or pyridine, more preferably thiophen-2-yl, furan-2-yl, pyridine-2- Base, pyridin-3-yl, or pyridin-4-yl; said substituted heterocycle is preferably 6-trifluoromethyl-pyridin-3yl.

As a preferred embodiment, the compound of formula (I) provided by the present invention is the compound of formula (II):

Wherein, the definition of R ¹ in formula (II) is as in the compound of formula (I).

As a preferred embodiment, the compound of formula (I) provided by the present invention is the compound of formula (III):

Wherein, the definitions of R ² , R ³ , R ⁴ and R ⁵ in formula (III) are as in the compound of formula (I).

In one embodiment of the present invention, the present invention provides a compound of the above general formula (I), which is selected from the following compounds:

Benzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 1);

Benzhydrylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 2);

4-methylbenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 3);

4-methoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 4);

2-methoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 5);

2,4-dimethoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 6);

3,4,5-trimethoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 7);

3,4-methyleneoxydioxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 8);

4-bromobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 9);

4-chlorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 10);

2,4-dichlorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 11);

4-fluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 12);

2-fluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 13);

2,4-difluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 14);

4-cyanobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 15);

4-nitrobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 16);

(thiophen-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 17);

(furan-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 18);

(Pyridin-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 19);

(Pyridin-3-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 20);

(6-(trifluoromethyl)pyridin-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 21);

(Pyridin-4-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 22);

(6-methyl-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 23);

(8-methyl-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 24);

(6-hydroxy-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 25);

(6-fluoro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 26);

(6-chloro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 27);

(6-bromo-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 28);

(6-iodo-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 29);

(6-nitro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 30);

(7-nitro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 31);

(6,8-dichloro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 32); or

(6,7-dimethoxy-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (Compound 33).

In another aspect, the present invention provides a method for preparing a C2-position derivative of 4(3H)-quinazolinone as shown in general formula (I), comprising the following steps:

The compound of formula (IV) reacts with the compound of formula (V) in the presence of CS ₂ and potassium phosphate to obtain the compound of formula (I)

The substituent X in the compound of formula (IV) is halogen, selected from bromine or chlorine;

The substituents R ² , R ³ , R ⁴ and R ⁵ in the compound of formula (IV) are as defined in the compound of formula (I);

R ¹ in the compound of formula (V) is as defined in the compound of formula (I).

The preparation method of the C2-position derivative of 4(3H)-quinazolinone as shown in general formula (I) provided by the present invention, wherein the compound of formula (I) is the compound of formula (II), and when the formula (IV ) When X in the compound is bromine, it can be prepared by the following process:

As shown in Scheme 1, anthranilic acid (VI) and acetic anhydride are heated and refluxed to obtain benzoxazinone (VII). The product is directly used in the next step without separation and purification. After VII reacts with ammonia water, 2-methyl-4(3H)-quinazolinone (VIII) is obtained. Using anhydrous DMF as a solvent, the intermediate VIII was reacted with NBS at 40°C to obtain 2-bromomethyl-4(3H)-quinazolinone (IX). Reaction of IX with carbon disulfide, variously substituted amines R ¹ NH ₂ in the presence of anhydrous K ₃ PO ₄ affords compounds 1-22.

Route 1. The synthetic route of compound 1-22

Reagents and reaction conditions: a. (AcO) ₂ O, reflux, 2h; b. NH ₃ ·H ₂ O, EtOH (ethanol), room temperature, 48h; c. NBS (N-bromosuccinimide), DMF (N,N-dimethylformamide), 40℃, 24h; dR ¹ NH ₂ , CS ₂ , K ₃ PO ₄ , DMF (N,N-dimethylformamide), room temperature, 1-3h;

Here, the substituents in the compound of formula (II) and R ¹ NH ₂ are as defined above.

The preparation method of the C2-position derivative of 4(3H)-quinazolinone as shown in general formula (I) provided by the present invention, wherein the compound of formula (I) is the compound of formula (III), and when the compound of formula (IV ) When X in the compound is chlorine, the compound of formula (III) can be prepared by the following process:

As shown in route 2, anthranilic acid (X) with different substituents is dissolved in absolute ethanol, and dry HCl gas is passed through, heated to reflux for 6 hours to obtain anthranilic acid with different substituents ethyl ester (XI). Carlo, AA; Carty, MD; Danley, DE; Hageman, DL; Karam, GA; Levy, CB; Mansour, MN; Mathiowetz, AM; McClure, LD; Nestor, NB; McPherson ,RK;Pandit,J.;Pustilnik,LR;Schulte,GK;Soeller,WC;Treadway,JL;Wang,IK;Bauer,PHJMed.Chem.2002,45(18),3865–3877.] In chloroacetonitrile, pass through dry HCl gas, and react at room temperature for 16 hours to obtain 2-chloromethyl-4(3H)-quinazolinone (XIIa-k) with different substituents (R ² ). Reaction of XIIa-k with carbon disulfide, ₄ -methoxybenzylamine in the presence of anhydrous _K3PO4 affords compounds 23-33.

Route 2. The synthetic route of compound 23-33.

Reagents and reaction conditions: a. EtOH, HCl (g); b. ClCH ₂ CN, HCl (g), room temperature, 16h; c. 4-CH ₃ OC ₆ H ₄ CH ₂ NH ₂ , CS ₂ , K ₃ PO ₄ , DMF, room temperature, 3h.

In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned C2-position derivative of 4(3H)-quinazolinone. The pharmaceutical composition includes a pharmacologically effective amount of the compound of formula (I) and pharmaceutically acceptable auxiliary materials. These excipients are known to those skilled in the art, for example, physiological saline, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, modified starch, cellulose, modified cellulose, sodium glycolate , calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc. In addition, these compositions may further contain: stabilizers, wetting agents, emulsifiers, sweeteners, flavoring agents, buffering agents and the like.

The pharmaceutical composition comprising the C2 derivatives of the above-mentioned 4(3H)-quinazolinones provided by the present invention can be formulated into solid or liquid forms for oral administration, such as tablets, pills, oral solutions, etc.; sterile solutions, suspensions or emulsions for parenteral administration, sprays, etc.

For example, a tablet formulation:

The preparation method is as follows: pass the raw and auxiliary materials through a 100-mesh sieve, and then mix evenly; use 90% ethanol to make soft materials, granulate, granulate, add magnesium stearate, mix evenly, and tablet to obtain.

Injection formulation:

Preparation:

Add mannitol to 1600mL water for injection, stir to dissolve; add the compound of the present invention to the above solution, stir to dissolve; adjust the pH value of 4% disodium hydrogen phosphate solution to 4.15; add water for injection to 2000mL, add activated carbon, and heat at 50°C Insulate and stir for 20 minutes, filter and decarbonize; filter with a 0.22 μm microporous membrane, and potting. 121 ℃, 15min high temperature and humid heat sterilization.

In another aspect, the present invention provides the use of the compound of formula (I) in the preparation of antitumor drugs. The compound of the present invention can be used to treat lung cancer, breast cancer, colon cancer, liver cancer, gastric cancer, ovarian cancer, cervical cancer, oral cancer, leukemia and the like.

Experiments have proved that the compound of formula (I) of the present invention has anti-tumor activity, and is effective against human lung cancer (A-549), breast cancer (MCF-7), colon cancer (HT29, HCT-116) and cervical cancer (HeLa) cells The proliferation of the compound has inhibitory effect, and can be used as an anti-tumor drug or an anti-tumor active ingredient in an anti-tumor pharmaceutical composition. The reference dose of the drug is 0.1-10 mg/kg body weight, and the method of use is oral or intravenous injection.

Detailed ways

The following examples illustrate the implementation of the present invention. For those of ordinary skill in the art, under the teaching of the present invention, according to the prior art, improvements to the implementation of the present invention still belong to the protection of the present invention. within range.

The sources of the compound raw materials used in the examples are: anthranilic acid, substituted anthranilic acid, benzylamine, substituted benzylamine, benzhydrylamine, thiophene, furan or picolylamine, and other raw materials are Commercially available chemical reagents.

The human lung cancer (A-549), breast cancer (MCF-7), colon cancer (HT29, HCT-116) and cervical cancer (HeLa) cells used in the examples were from Beijing Key Laboratory of DNA Damage Response, Capital Normal University.

Preparation Example 1

Synthesis of 2-methyl-4(3H)-quinazolinone (VIII)

Add anthranilic acid (IIa) (1.37g, 10mmol) and 10mL of acetic anhydride to a reaction flask equipped with a reflux condenser (connected to anhydrous CaCl ₂ drying tube), and heat to reflux for 2h. After cooling to room temperature, most of the acetic anhydride was removed by rotary evaporation. After cooling, the precipitated solid was collected by filtration and dried to obtain 1.47 g of intermediate III with a yield of 91%, which was directly used in the next reaction.

To a mixture of 2-methylbenzoxazinone (VII) (1.47g, 9.1mmol) and absolute ethanol (20mL), 36.8mL of 25% ammonia water was added, and stirred at room temperature for 48h. Most of the solvent was removed by rotary evaporation, cooled, and the precipitated solid was collected by filtration, dried, and recrystallized from ethanol to obtain 1.12 g of white solid (IV), with a yield of 76%, mp233.2-236.3°C (document mp237-239°C). ¹ HNMR(600MHz,DMSO-d ₆ )δ:2.61(s,2H,CH ₃ ),7.65(t,J=7.8Hz,1H,quin6-H),7.83(d,J=7.8Hz,1H,quin8 -H),7.96(t,J=7.8Hz,1H,quin7-H),8.16(d,J=7.8Hz,1H,quin5-H).ESI-HRMSm/z:C ₉ H ₉ N ₂ O( [M+H] ⁺ ) calculated value: 161.0715; measured value: 161.0709.

Synthesis of 2-bromomethyl-4(3H)-quinazolinone (IX)

2-Methyl-4(3H)-quinazolinone (VIII) (6.40g, 40mmol) was dissolved in N,N-dimethylformamide (35mL), and N-bromosuccinimide ( NBS) (7.12g, 40mmol), reacted at 40°C for 24h. Cool to room temperature, collect the precipitated solid by filtration, wash with ether, and dry to obtain 7.37g of white solid, yield 77%, mp227.3-230.2°C (literature mp>300°C). ¹ HNMR (600MHz, DMSO-d ₆ )δ:4.41(s,2H,CH ₂ Br),7.55(t,J=7.8Hz,1H,quin6-H),7.67(d,J=7.8Hz,1H,quin8-H),7.84(t, J=7.8Hz,1H,quin7-H),8.12(d,J=7.8Hz,1H,quin5-H),12.57(brs,1H,NH).ESI-HRMSm/z:C ₉ H ₈ BrN ₂ O ([M+H] ⁺ ) calculated value: 238.9820,240.9800; measured value: 238.9813,240.9790.

Synthetic general method of compound 1-22 of the present invention

Dissolve benzylamine or heterocyclic methylamine (1.5mmol) in N,N-dimethylformamide (20mL), add finely ground anhydrous potassium phosphate (0.40g, 1.89mmol), carbon disulfide (0.6mL, 9.98mmol), stirred at room temperature for 0.5h, added 2-bromomethyl-4(3H)quinazolinone (IX) (0.36g, 1.5mmol), and continued to stir for 1-3h. The reaction solution was poured into 150 mL of distilled water, the precipitated solid was collected by filtration, dried in the air, and purified by silica gel column chromatography to obtain compound 1-22.

Example 1

Benzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 1)

Yield: 63%, pale yellow solid, mp171.9-174.2℃ (eluent: CH ₂ Cl ₂ ). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.45(s, 2H, SCH ₂ ), 4.85 (d,J=5.4Hz,2H,CH ₂ NH),7.29(m,1H,ph4'-H),7.33(m,4H,ph2'-H,3'-H,5'-H,6' -H),7.42(d,J=7.8Hz,1H,quin8-H),7.49(t,J=7.8Hz,1H,quin6-H),7.77(t,J=7.8Hz,1H,quin7-H ),8.09(d,J=7.8Hz,1H,quin5-H),10.70(t,J=5.4Hz,1H,CH ₂ NH),12.41(s,1H,NH).ESI-MSm/z:342 [M+H] ⁺ .Elemental analysis (C ₁₇ H ₁₅ N ₃ OS ₂ ·0.7H ₂ O) Calculated: C,57.67; H,4.67; N,11.87. Found: C,57.61;H,4.45; N, 11.67.

Example 2

Benzhydrylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 2)

Yield 70%, yellow solid, mp97.2-99.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.17(s, 1H ,Ph ₂ CH),4.48(s,2H,SCH ₂ ),6.93(d,J=8.4Hz,1H,quin8-H),7.29-7.34(m,10H,ph-H),7.49(t,J =7.8Hz,1H,quin6-H),7.74(t,J=8.4Hz,1H,quin7-H),8.09(d,J=7.8Hz,1H,quin5-H),11.12(d,J=8.4 Hz,1H,CHNH),12.43(s,1H,NH).Elemental analysis (C ₂₃ H ₁₉ N ₃ OS ₂ ·0.3H ₂ O)Calculated value: C,65.31;H,4.67;N,9.93.Measured value : C, 65.32; H, 4.84; N, 9.84.

Example 3

4-Methylbenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 3)

Yield 51%, off-white solid, mp186.3-187.2℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=95:5). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 2.29(s, 3H,CH ₃ ),4.44(s,2H,SCH ₂ ),4.80(d,J=5.4Hz,2H,CH ₂ NH),7.14(d,J=7.8Hz,2H,ph-H),7.22( d,J=7.8Hz,2H,ph-H),7.38(d,J=8.4Hz,1H,quin8-H),7.49(t,J=7.8Hz,1H,quin6-H),7.76(t, J=8.4Hz,1H,quin7-H),8.09(d,J=7.8Hz,1H,quin5-H),10.66(t,J=5.4Hz,1H,CH ₂ NH),12.40(s,1H, NH).Elemental analysis (C ₁₈ H ₁₇ N ₃ OS ₂ ) calculated value: C,60.82;H,4.82;N,11.82. Found value:C,60.81;H,4.92;N,11.82.

Example 4

4-Methoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 4)

Yield: 61%, light yellow solid, mp178.1-179.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.74(s ,3H,OCH ₃ ),4.43(s,2H,SCH ₂ ),4.77(d,J=5.4Hz,2H,CH ₂ NH),6.89(d,J=8.4Hz,2H,ph3'-H,5 '-H),7.27(d,J=8.4Hz,2H,ph2'-H,6-H),7.39(d,J=7.8Hz,1H,quin8-H),7.49(t,J=7.8Hz ,1H,quin6-H),7.76(t,J=7.8Hz,1H,quin7-H),8.08(d,J=7.8Hz,1H,quin5-H),10.63(t,J=5.4Hz,1H , CH ₂ NH), 12.40 (s, 1H, NH). Elemental analysis (C ₁₈ H ₁₇ N ₃ O ₂ S ₂ ) calculated: C, 58.20; H, 4.61; N, 11.31. Found: C, 58.16 ;H,4.75;N,11.11.

Example 5

2-Methoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 5)

Yield: 49%, pale yellow solid, mp157.0-158.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.80(s ,3H,OCH ₃ ),4.42(s,2H,SCH ₂ ),4.77(d,J=5.4Hz,2H,CH ₂ NH),6.90(t,J=7.8Hz,1H,ph5'-H), 7.03(d, J=7.8Hz, 1H, ph3'-H), 7.21(d, J=7.8Hz, 1H, ph6'-H), 7.30(t, J=7.8Hz, 1H, ph6'-H) ,7.38(d,J=8.4Hz,1H,quin8-H),7.50(t,J=8.4Hz,1H,quin6-H),7.77(t,J=8.4Hz,1H,quin7-H),8.09 (d,J=8.4Hz,1H,quin5-H),10.55(t,J=5.4Hz,1H,CH ₂ NH),12.41(s,1H,NH).ESI-HRMSm/z:C ₁₈ H ₁₈ Calculated for N ₃ O ₂ S ₂ ([M+H] ⁺ ): 372.0840; Found: 372.0833.

Example 6

2,4-Dimethoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 6)

Yield: 51%, pale yellow solid, mp162.0-163.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.76(s ,3H,OCH ₃ ),3.77(s,3H,OCH ₃ ),4.38(s,2H,SCH ₂ ),4.67(d,J=5.4Hz,2H,CH ₂ NH),6.48(dd,J=8.4 ,2.4Hz,1H,ph5'-H),6.59(d,J=2.4Hz,1H,ph3'-H),7.15(d,J=8.4Hz,1H,ph6'-H),7.33(d, J=7.8Hz,1H,quin8-H),7.50(t,J=7.8Hz,1H,quin6-H),7.76(t,J=7.8Hz,1H,quin7-H),8.09(d,J= 7.8Hz,1H,quin5-H),10.64(t,J=5.4Hz,1H,CH ₂ NH),12.40(s,1H,NH).ESI-HRMSm/z:C ₁₉ H ₂₀ N ₃ O ₃ S ₂ ([M+H] ⁺ ) calculated value: 402.0946; measured value: 402.0933.

Example 7

3,4,5-Trimethoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 7)

Yield: 48%, pale yellow solid, mp168.0-170.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.64(s ,3H,OCH ₃ ),3.70(s,6H,2OCH ₃ ),4.44(s,2H,SCH ₂ ),4.76(d,J=4.8Hz,2H,CH ₂ NH),6.68(s,2H,ph2 '-H,6'-H),7.34(d,J=7.8Hz,1H,quin8-H),7.49(t,J=7.8Hz,1H,quin6-H),7.74(t,J=7.8Hz ,1H,quin7-H),8.09(d,J=7.8Hz,1H,quin5-H),10.64(t,J=4.8Hz,1H,CH ₂ NH),12.42(s,1H,NH).ESI -HRMSm/z: Calcd. for C ₂₀ H ₂₂ N ₃ O ₄ S ₂ ([M+H] ⁺ ): 432.1052; Found: 432.1038.

Example 8

3,4-Methyleneoxydioxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 8)

Yield: 47%, pale yellow solid, mp176.0-177.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.43(s ,2H,SCH ₂ ),4.74(d,J=4.8Hz,2H,CH ₂ NH),6.0(s,2H,OCH ₂ O),6.82(d,J=7.8Hz,1H,ph6'-H) ,6.86(d,J=7.8Hz,1H,ph5'-H),6.90(s,1H,ph2'-H),7.42(d,J=7.8Hz,1H,quin8-H),7.49(t, J=7.8Hz,1H,quin6-H),7.77(t,J=7.8Hz,1H,quin7-H),8.08(d,J=7.8Hz,1H,quin5-H),10.62(t,J= 4.8Hz, 1H, CH ₂ NH), 12.41(s, 1H, NH). ESI-HRMSm/z: Calcd. for C ₁₈ H ₁₆ N ₃ O ₃ S ₂ ([M+H] ⁺ ): 386.0633; found :386.0622.

Example 9

4-Bromobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 9)

Yield: 71%, pale yellow solid, mp192.1-193.2℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=95:5). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.43(s ,2H,SCH ₂ ),4.80(d,J=5.4Hz,2H,CH ₂ NH),7.26(d,J=8.4Hz,2H,ph2'-H,6'-H),7.43(d,J =7.8Hz,1H,quin8-H),7.47(t,J=7.8Hz,quin6-H),7.50(d,J=8.4Hz,2H,ph3'-H,5'-H),7.76(t ,J=7.8Hz,1H,quin7-H),8.07(d,J=7.8Hz,1H,quin5-H),10.67(t,J=5.4,1H,CH ₂ NH),12.40(brs,1H, NH).Elemental analysis (C ₁₇ H ₁₄ BrN ₃ OS ₂ ) calculated value: C,48.57;H,3.36;N,10.00. Found value:C,48.79;H,3.37;N,9.59.

Example 10

4-Chlorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 10)

Yield: 50%, pink solid, mp188.3-190.1℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=95:5). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.45(s ,2H,SCH ₂ ),4.84(d,J=5.4Hz,2H,CH ₂ NH),7.33(d,J=8.4Hz,2H,ph2'-H,6'-H),7.38(d,J =8.4Hz,2H,ph3'-H,5'-H),7.45(d,J=7.8Hz,1H,quin8-H),7.50(t,J=7.8Hz,1H,quin6-H),7.78 (t,J=7.8Hz,1H,quin7-H),8.09(d,J=7.8Hz,1H,quin5-H),10.69(t,J=5.4Hz,1H,CH ₂ NH),12.41(s ,1H,NH).Elemental analysis (C ₁₇ H ₁₄ ClN ₃ OS ₂ ) calculated: C,54.32; H,3.75;N,11.18. Found: C,54.48;H,3.91;N,11.04.

Example 11

2,4-Dichlorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 11)

Yield: 57%, brown solid, mp179.8-180.1℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.46(s, 2H,SCH ₂ ),4.86(d,J=4.8Hz,2H,CH ₂ NH),7.35(d,J=8.4Hz,1H,ph6'-H),7.39(dd,J=8.4,1.8Hz, 1H, ph5'-H), 7.49(d, J=7.8Hz, 1H, quin8-H), 7.51(t, J=7.8Hz, 1H, quin6-H), 7.63(d, J=1.8Hz, 1H ,ph3'-H),7.79(t,J=7.8Hz,1H,quin7-H),8.10(d,J=7.8Hz,1H,quin5-H),10.66(t,J=4.8Hz,1H, CH ₂ NH), 12.43(s,1H,NH).ESI-HRMSm/z: Calcd. for C ₁₇ H ₁₄ Cl ₂ N ₃ OS ₂ ([M+H] ⁺ ): 409.9955, 411.9926; Found: 409.9944, 411.9911.

Example 12

4-Fluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 12)

Yield: 64.9%, white solid, mp167.6-169.2℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.45(s, 2H,SCH ₂ ),4.83(d,J=5.4Hz,2H,CH ₂ NH),7.16(t,J=8.4Hz,2H,ph3'-H,5'-H),7.37(dd,J= 8.4,5.4Hz,2H,ph2'-H,6'-H),7.45(d,J=7.8Hz,1H,quin8-H),7.50(t,J=7.8Hz,1H,quin6-H), 7.78(td, J=7.8,1.2Hz,1H,quin7-H),8.09(dd,J=7.8,1.2Hz,1H,quin5-H),10.68(t,J=5.4Hz,1H,CH ₂ NH ),12.41(s,1H,NH).Elemental analysis (C ₁₇ H ₁₄ FN ₃ OS ₂ ·0.7H ₂ O)Calculated value: C,54.88;H,4.17;N,11.29.Measured value:C,55.04; H, 4.19; N, 11.07.

Example 13

2-Fluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 13)

Yield: 69%, light yellow solid, mp159.2-160.4℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.45(s ,2H,SCH ₂ ),4.86(d,J=4.8Hz,2H,CH ₂ NH),7.15(t,J=7.2Hz,1H,ph3'-H),7.21(t,J=9.0Hz,1H ,ph5'-H),7.36(m,2H,ph4'-H,6'-H),7.46(d,J=7.8Hz,1H,quin8-H),7.50(t,J=7.8Hz,1H ,quin6-H),7.78(td,J=7.8,1.2Hz,1H,quin7-H),8.09(dd,J=7.8,1.2Hz,1H,quin5-H),10.66(t,J=4.8Hz ,1H,CH ₂ NH),12.41(s,1H,NH).Elemental analysis (C ₁₇ H ₁₄ FN ₃ OS ₂ ) Calcd.: C,56.81; H,3.93;N,11.69. Found: C,56.83 ;H,3.97;N,11.60.

Example 14

2,4-Difluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 14)

Yield: 78%, pale yellow solid, mp161.9-162.8℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=95:5). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.45(s ,2H,SCH ₂ ),4.82(d,J=4.8Hz,2H,CH ₂ NH),7.05(td,J=8.4,1.8Hz,1H,ph3'-H),7.25(td,J=9.9, 1.8Hz,1H,ph5'-H),7.43(m,1H,ph6'-H),7.50(m,2H,quin8-H,6-H),7.79(t,J=7.8Hz,1H,quin7 -H),8.09(d,J=7.8Hz,1H,quin5-H),10.63(t,J=4.8Hz,1H,CH ₂ NH),12.41(s,1H,NH).ESI-HRMSm/z : Calculated for C ₁₇ H ₁₄ F ₂ N ₃ OS ₂ ([M+H] ⁺ ): 378.0546; Found: 378.0539.

Example 15

4-cyanobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 15)

Yield: 52%, pale yellow solid, mp164.0-166.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=95:5). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.47(s ,2H,SCH ₂ ),4.94(d,J=5.4Hz,2H,CH ₂ NH),7.48(d,J=7.8Hz,2H,ph2'-H,6'-H),7.51(m,2H ,quin6-H,8-H),7.79(m,3H,ph3'-H,5'-H,quin7-H),8.09(d,J=7.8Hz,1H,quin5-H),10.75(t ,J=5.4Hz,1H,CH ₂ NH),12.42(s,1H,NH).ESI-HRMSm/z:C ₁₈ H ₁₅ N ₄ OS ₂ ([M+H] ⁺ ) calculated value: 367.0687; measured Value: 367.0678.

Example 16

4-Nitrobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 16)

Yield: 41%, pale yellow solid, mp178.6-180.2℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.48(s ,2H,SCH ₂ ),4.99(d,J=5.4Hz,2H,CH ₂ NH),7.49(m,2H,quin8-H,6-H),7.52(d,J=8.4Hz,2H,ph3 '-H,5'-H),7.78(t,J=7.8Hz,1H,quin7-H),8.09(d,J=7.8Hz,1H,quin5-H),8.18(d,J=8.4Hz ,2H,ph2'-H,6'-H),10.79(t,J=5.4Hz,1H,CH ₂ NH),12.43(s,1H,NH).Elemental analysis (C ₁₇ H ₁₄ N ₄ O ₃ S ₂ ) Calculated: C, 52.84; H, 3.65; N, 14.50. Found: C, 53.05; H, 3.81; N, 14.24.

Example 17

(Thien-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 17)

Yield: 46%, pale yellow solid, mp176.0-178.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.44(s ,2H,SCH ₂ ),5.02(d,J=3.0Hz,2H,CH ₂ NH),6.99(t,J=4.2Hz,1H,thiophene4'-H),7.10(d,J=2.4Hz,1H ,thiophene3'-H),7.44(d,J=4.8Hz,1H,thiophene5'-H),7.48(d,J=7.8Hz,1H,quin8-H),7.49(t,J=7.8Hz,1H ,quin6-H),7.77(t,J=7.8Hz,1H,quin7-H),8.09(d,J=7.8Hz,1H,quin5-H),10.75(brs,1H,CH ₂ NH),12.41 (s,1H,NH).ESI-HRMSm/z: Calcd. for C ₁₅ H ₁₄ N ₃ OS ₃ ([M+H] ⁺ ): 348.0299; Found: 348.0293.

Example 18

(Furan-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 18)

Yield: 48%, light yellow solid, mp166.0-168.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.40(s ,2H,SCH ₂ ),4.80(d,J=5.4Hz,2H,NHCH ₂ ),6.36(d,J=3.0Hz,1H,furan3'-H),6.40(m,1H,furan4'-H) ,7.47(m,2H,quin6-H,8-H),7.60(m,1H,furan5'-H),7.76(td,J=7.8,1.8Hz,1H,quin7-H),8.06(dd, J=7.8,1.8Hz,1H,quin5-H),10.64(t,J=5.4Hz,1H,CH ₂ NH),12.38(s,1H,NH).ESI-HRMSm/z:C ₁₅ H ₁₄ N Calculated for ₃ O ₂ S ₂ ([M+H] ⁺ ): 332.0527; Found: 332.0519.

Example 19

(Pyridin-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 19)

Yield: 48%, pale yellow solid, mp147.0-149.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.46(s ,2H,SCH ₂ ),4.93(d,J=3.0Hz,2H,CH ₂ NH),7.30(m,2H,pyridine3'-H,5'-H),7.49(d,J=7.8Hz,1H ,quin8-H),7.53(t,J=7.8Hz,1H,quin6-H),7.74(d,J=7.8Hz,1H,pyridine4'-H),7.79(t,J=7.8Hz,1H, quin7-H),8.09(d,J=7.8Hz,1H,quin5-H),8.52(d,J=4.2Hz,1H,pyridine6'-H),10.80(brs,1H,CH ₂ NH),12.42 (s,1H,NH).ESI-HRMSm/z: Calcd. for C ₁₆ H ₁₅ N ₄ OS ₂ ([M+H] ⁺ ): 343.0687; Found: 343.0681.

Example 20

(Pyridin-3-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 20)

Yield: 52%, pale yellow solid, mp180.0-182.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.46(s ,2H,SCH ₂ ),4.87(d,J=5.4Hz,2H,CH ₂ NH),7.35(m,1H,pyridine5'-H),7.48(d,J=7.8Hz,1H,quin8-H) ,7.50(t,J=7.8Hz,1H,quin6-H),7.72(d,J=7.8Hz,1H,pyridin4'-H),7.78(t,J=7.8Hz,1H,quin7-H), 8.09(d,J=7.8Hz,1H,quin5-H),8.49(d,J=7.8Hz,1H,pyridine6'-H),8.56(s,1H,pyridine2'-H),10.71(t,J =5.4Hz,1H,CH ₂ NH),12.42(s,1H,NH).ESI-HRMSm/z:C ₁₆ H ₁₅ N ₄ OS ₂ ([M+H] ⁺ )calculated: 343.0687; found: 343.0682.

Example 21

(6-(trifluoromethyl)pyridin-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 21)

Yield: 50%, light yellow solid, mp164.0-166.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.48(s ,2H,SCH ₂ ),4.97(s,2H,CH ₂ NH),7.50(m,2H,quin8-H,6-H),7.77(t,J=7.8Hz,1H,quin7-H),7.87 (d,J=7.8Hz,1H,pyridine5'-H,7.97(d,J=7.8Hz,1H,pyridine4'-H),8.09(d,J=7.8Hz,1H,quin5-H),8.73( s,1H,pyridine2'-H),10.79(s,1H,CH ₂ NH),12.42(s,1H,NH).ESI-HRMSm/z: C ₁₇ H ₁₄ F ₃ N ₄ OS ₂ ([M+ H] ⁺ ) calculated value: 411.0561; measured value: 411.0552.

Example 22

(Pyridin-4-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (compound 22)

Yield: 50%, light yellow solid, mp148.0-150.0℃ (eluent: CH ₂ Cl ₂ /CH ₃ OH=98:2). ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.48(s ,2H,SCH ₂ ),4.88(d,J=4.8Hz,2H,CH ₂ NH),7.27(d,J=4.8Hz,2H,pyridine3'-H,5'-H),7.52(m,2H ,quin8-H,6-H),7.80(t,J=7.8Hz,1H,quin7-H),8.10(d,J=7.8Hz,1H,quin5-H),8.73(d,J=4.8Hz ,2H,pyridine2'-H,6'-H),10.75(s,1H,CH ₂ NH),12.43(s,1H,NH).ESI-HRMSm/z: C ₁₆ H ₁₅ N ₄ OS ₂ ([ M+H] ⁺ ) calculated value: 343.0687; measured value: 343.0681.

Preparation example 2

General Synthesis of 2-Chloromethyl-4(3H)-Quinazolinone (XIIa-k)

Anthranilic acid (X) (10 mmol) with different substituents was dissolved in absolute ethanol (15 mL), passed through with dry HCl gas, stirred overnight at room temperature, and then heated to reflux for 6 h. Add sodium carbonate to adjust pH=8-9, extract with dichloromethane (15mLv3), combine the organic phases, wash with saturated NaCl solution (15mLv2), dry _over anhydrous _Na2SO4 , and remove the solvent by rotary evaporation to obtain the substituted ortho Ethyl aminobenzoate (XIa-k) was used directly in the next reaction.

In the mixed solution of intermediate XIa-k (10mmol) and chloroacetonitrile (15mL, 0.25mmol), dry HCl gas was introduced, and the reaction solution gradually became turbid, and then became gelatinous. Continue to inject HCl gas until it dissolved. , stop ventilation, and stir at room temperature for 16h. The reaction solution was poured into 50 mL of water, cooled in an ice-water bath, adjusted to pH = 7 with concentrated ammonia water, the precipitated solid was collected by filtration, dried in the air, and recrystallized with acetic acid to obtain intermediates XIIa-k.

2-Chloromethyl-6-methyl-4(3H)-quinazolinone (XIIa)

Yield: 93%, white solid, mp242-243℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.56(s, 2H, ClCH ₂ ), 7.44(t, J=7.2Hz, 1H, quin8-H ),7.70(d,J=7.2Hz,1H,quin7-H),7.97(d,J=7.2Hz,1H,quin5-H),12.56(brs,1H,NH).EI-MSm/z:208 [M ⁺ ].

2-Chloromethyl-8-methyl-4(3H)-quinazolinone (XIIb)

Yield: 91%, white solid, mp238-240℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 2.54(s, 3H, CH ₃ ), 4.56(s, 2H, ClCH ₂ ), 7.43(t, J=7.8Hz,1H,quin6-H),7.70(d,J=7.8Hz,1H,quin7-H),7.97(d,J=7.8Hz,1H,quin5-H),12.56(s,1H, NH).EI-MSm/z:208[M ⁺ ].

2-Chloromethyl-6-hydroxy-4(3H)-quinazolinone (XIIc)

Yield: 95%, white solid, mp258-260℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.51(s, 2H, ClCH ₂ ), 7.43(d, J=7.8Hz, 1H, quin7-H ),7.41(s,1H,quin5-H),7.55(d,J=7.8Hz,1H,quin8-H),10.17(s,1H,OH),12.38(s,1H,NH).EI-MSm /z:210[M ⁺ ].

2-Chloromethyl-6-fluoro-4(3H)-quinazolinone (XIId)

Yield: 86%, white solid, mp235-237℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.53 (s, 2H, ClCH ₂ ), 7.69-7.76 (m, 2H, quin7-H, 8- H),8.01(dd,J=8.4,2.4Hz,1H,quin5-H),12.70(s,1H,NH).EI-MSm/z:212[M ⁺ ].

2-Chloromethyl-6-chloro-4(3H)-quinazolinone (XIIe)

Yield: 96%, white solid, mp231-232℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.56(s, 2H, ClCH ₂ ), 7.72(d, J=8.4Hz, 1H, quin8-H ),7.87(d,J=8.4Hz,1H,quin7-H),8.01(s,1H,quin5-H),12.78(s,1H,NH).EI-MSm/z:228[M ⁺ ].

2-Chloromethyl-6-bromo-4(3H)-quinazolinone (XIIf)

Yield: 88%, white solid, mp254-256℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.55(s, 2H, ClCH ₂ ), 7.64(d, J=8.4Hz, 1H, quin8-H ),7.99(dd,J=8.4,2.4Hz,1H,quin7-H),8.20(d,J=2.4Hz,1H,quin5-H),12.78(s,1H,NH).EI-MSm/z :272[M ⁺ ].

2-Chloromethyl-6-iodo-4(3H)-quinazolinone (XIIg)

Yield: 86%, white solid, mp258-260℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.54(s, 2H, ClCH ₂ ), 7.46(d, J=8.4Hz, 1H, quin8-H ),8.10(d,J=8.4Hz,1H,quin7-H),8.38(s,1H,quin5-H),12.73(s,1H,NH).EI-MSm/z:320[M ⁺ ].

2-Chloromethyl-6-nitro-4(3H)-quinazolinone (XIIh)

Yield: 83%, white solid, mp262-265℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.61 (s, 2H, ClCH ₂ ), 7.88 (d, J=9.0Hz, 1H, quin8-H ),8.56(d,J=9.0Hz,1H,quin7-H),8.80(s,1H,quin5-H),13.09(s,1H,NH).EI-MSm/z:239[M ⁺ ].

2-Chloromethyl-7-nitro-4(3H)-quinazolinone (XIIIi)

Yield: 84%, white solid, mp251-252℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.59(s, 2H, ClCH ₂ ), 8.26(d, J=8.4Hz, 1H, quin5-H ),8.34(d,J=9.0Hz,1H,quin6-H),8.38(s,1H,quin8-H),13.0(s,1H,NH).EI-MSm/z:239[M ⁺ ].

2-Chloromethyl-6,8-dichloro-4(3H)-quinazolinone (XIIj)

Yield: 75%, white solid, mp227-230℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 4.58(s, 2H, ClCH ₂ ), 8.02(s, 1H, quin7-H), 8.15(s ,1H,quin5-H),13.01(s,1H,NH).EI-MSm/z:239[M ⁺ ].

2-Chloromethyl-6,7-dimethoxy-4(3H)-quinazolinone (XIIk)

Yield: 94%, white solid, mp216-218℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.88(s, 3H, OCH ₃ ), 3.91(s, 3H, OCH ₃ ), 4.52(s, 2H,ClCH ₂ ),7.17(s,1H,quin8-H),7.44(s,1H,quin5-H),12.43(s,1H,NH).EI-MSm/z:239[M ⁺ ].

Synthetic general method of compound 23-33 of the present invention

Dissolve 4-methoxybenzylamine (1.0mmol) in N,N-dimethylformamide (10mL), add finely ground anhydrous potassium phosphate (0.26g, 1.0mmol), carbon disulfide (0.4mL, 6.65mmol), stirred at room temperature for 0.5h, added 2-chloromethyl-4(3H)quinazolinone (XIIa-k) (1.0mmol) with different substituents, and continued to stir for 1-3h. The reaction solution was poured into 100 mL of water, the precipitated solid was collected by filtration, dried in the air, and purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ /CH ₃ OH=95:5) to obtain compound 23-33.

Example 23

(6-Methyl-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (Compound 23)

Yield: 46%, white solid, mp203-204℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 2.43(s, 3H, CH ₃ ), 3.74(s, 3H, OCH ₃ ), 4.40(s, 2H,SCH ₂ ),4.77(d,J=5.4Hz,2H,NHCH ₂ ),6.89(d,J=8.4Hz,2H,ph3'-H,5'-H),7.27(d,J=8.4 Hz,2H,ph2'-H,6'-H),7.28(d,J=8.4Hz,1H,quin8-H),7.58(d,J=8.4Hz,1H,quin7-H),7.88(s ,1H,quin5-H),10.63(t,J=5.4Hz,1H,CH ₂ NH),12.30(s,1H,NH).ESI-HRMSm/z:C ₁₉ H ₂₀ N ₃ O ₂ S ₂ ( [M+H] ⁺ ) calculated value: 386.0997; measured value: 386.0988.

Example 24

(8-Methyl-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (Compound 24)

Yield: 52%, white solid, mp189-190℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 2.43(s, 3H, CH ₃ ), 3.72(s, 3H, OCH ₃ ), 4.46(s, 2H,SCH ₂ ),4.78(d,J=5.4Hz,2H,NHCH ₂ ),6.85(d,J=9.0Hz,2H,ph3'-H,5'-H),7.22(d,J=9.0 Hz,2H,ph2'-H,6'-H),7.38(t,J=7.8Hz,1H,quin6-H),7.64(d,J=7.2Hz,1H,quin7-H),7.93(d ,J=7.8Hz,1H,quin5-H),10.53(t,J=5.4Hz,1H,CH ₂ NH),12.36(s,1H,NH).ESI-HRMSm/z:C ₁₉ H ₂₀ N ₃ Calculated for O ₂ S ₂ ([M+H] ⁺ ): 386.0997; Found: 386.0990.

Example 25

(6-Hydroxy-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (Compound 25)

Yield: 49%, white solid, mp175-176℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.74(s, 3H, OCH ₃ ), 4.36(s, 2H, SCH ₂ ), 4.77(d, J=5.4Hz,2H,NHCH ₂ ),6.89(d,J=8.4Hz,2H,ph3'-H,5'-H),7.19(dd,J=8.4,1.2Hz,1H,quin7-H) ,7.21(d,J=8.4Hz,1H,quin8-H),7.27(d,J=8.4Hz,2H,ph2'-H,6'-H),7.36(d,J=1.2Hz,1H, quin5-H),10.07(s,1H,OH),10.63(t,J=5.4Hz,1H,CH ₂ NH),12.19(s,1H,NH).ESI-HRMSm/z:C ₁₈ H ₁₈ N Calculated for ₃ O ₃ S ₂ ([M+H] ⁺ ): 388.0790; Found: 388.0783.

Example 26

(6-fluoro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (Compound 26)

Yield: 56%, pale yellow solid, mp195-196℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.74(s, 3H, OCH ₃ ), 4.44(s, 2H, SCH ₂ ), 4.76(d ,J=5.4Hz,2H,NHCH ₂ ),6.89(d,J=8.4Hz,2H,ph3'-H,5'-H),7.26(d,J=8.4Hz,2H,ph2'-H, 6'-H),7.50(dd,J=9.0,4.8Hz,1H,quin8-H),7.65(td,J=9.0,3.0Hz,1H,quin7-H),7.76(dd,J=8.4, 3.0Hz,1H,quin5-H),10.58(t,J=5.4Hz,1H,CH ₂ NH),12.54(s,1H,NH).ESI-HRMSm/z:C ₁₈ H ₁₇ FN ₃ O ₂ S ₂ ([M+H] ⁺ ) Calculated value: 390.0746; Measured value: 390.0734.

Example 27

(6-Chloro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (Compound 27)

Yield: 46%, pale yellow solid, mp174-175℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.74(s, 3H, OCH ₃ ), 4.44(s, 2H, SCH ₂ ), 4.76(d ,J=5.4Hz,2H,NHCH ₂ ),6.89(d,J=8.4Hz,2H,ph3'-H,5'-H),7.25(d,J=8.4Hz,2H,ph2'-H, 6'-H),7.46(d,J=8.4Hz,1H,quin8-H),7.80(d,J=8.4Hz,1H,quin7-H),8.02(s,1H,quin5-H),10.57 (t,J=5.4Hz,1H,CH ₂ NH),12.60(s,1H,NH).ESI-HRMSm/z: Calculated for C ₁₈ H ₁₇ ClN ₃ O ₂ S ₂ ([M+H] ⁺ ) :406.0451,408.0421; Measured value: 406.0438,408.0405.

Example 28

(6-Bromo-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 28)

Yield: 47%, pale yellow solid, mp217-218℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.73(s, 3H, OCH ₃ ), 4.44(s, 2H, SCH ₂ ), 4.76(d ,J=4.2Hz,2H,NHCH ₂ ),6.88(d,J=7.8Hz,2H,ph3'-H,5'-H),7.25(d,J=7.8Hz,2H,ph2'-H, 6'-H),7.38(d,J=8.4Hz,1H,quin8-H),7.90(d,J=8.4Hz,1H,quin7-H),8.15(s,1H,quin5-H),10.57 (t,J=4.2Hz,1H,CH ₂ NH),12.59(s,1H,NH).ESI-HRMSm/z: Calculated for C ₁₈ H ₁₇ BrN ₃ O ₂ S ₂ ([M+H] ⁺ ) :449.9946,451.9925; measured value: 449.9933,451.9909.

Example 29

4-Methoxybenzylcarbamate (6-iodo-3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester (Compound 29)

Yield: 59%, pale yellow solid, mp206-207℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.74(s, 3H, OCH ₃ ), 4.42(s, 2H, SCH ₂ ), 4.76(d ,J=4.2Hz,2H,NHCH ₂ ),6.88(d,J=8.4Hz,2H,ph3'-H,5'-H),7.21(d,J=8.4Hz,1H,quin8-H), 7.25(d,J=8.4Hz,2H,ph2'-H,6'-H),8.04(d,J=8.4Hz,1H,quin7-H),8.34(s,1H,quin5-H),10.57 (t,J=4.2Hz,1H,CH ₂ NH),12.56(s,1H,NH).ESI-HRMSm/z: Calculated for C ₁₈ H ₁₇ IN ₃ O ₂ S ₂ ([M+H] ⁺ ) :497.9807; Measured value: 497.9794.

Example 30

(6-nitro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 30)

Yield: 42%, pale yellow solid, mp167-168℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.73(s, 3H, OCH ₃ ), 4.52(s, 2H, SCH ₂ ), 4.76(d ,J=4.8Hz,2H,NHCH ₂ ),6.89(d,J=8.4Hz,2H,ph3'-H,5'-H),7.25(d,J=8.4Hz,2H,ph2'-H, 6'-H),7.66(d,J=9.0Hz,1H,quin8-H),8.50(dd,J=9.0,2.4Hz,1H,quin7-H),8.78(d,J=2.4Hz,1H ,quin5-H),10.57(t,J=4.8Hz,1H,CH ₂ NH),12.92(s,1H,NH).ESI-HRMSm/z:C ₁₈ H ₁₇ N ₄ O ₄ S ₂ ([M +H] ⁺ ) calculated value: 417.0691; measured value: 417.0679.

Example 31

(7-nitro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 31)

Yield: 56%, light yellow solid, mp142-143℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.72(s, 3H, OCH ₃ ), 4.48(s, 2H, SCH ₂ ), 4.77(d ,J=5.4Hz,2H,NHCH ₂ ),6.87(d,J=8.4Hz,2H,ph3'-H,5'-H),7.25(d,J=8.4Hz,2H,ph2'-H, 6'-H),8.11(d,J=2.4Hz,1H,quin8-H),8.21(dd,J=8.4,2.4Hz,1H,quin6-H),8.30(d,J=8.4Hz,1H ,quin5-H),10.54(t,J=5.4Hz,1H,CH ₂ NH),12.83(s,1H,NH).ESI-HRMSm/z:C ₁₈ H ₁₇ N ₄ O ₄ S ₂ ([M +H] ⁺ ) calculated value: 417.0691; measured value: 417.0679.

Example 32

(6,8-dichloro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 32)

Yield: 69%, pale yellow solid, mp206-207℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.73(s, 3H, OCH ₃ ), 4.48(s, 2H, SCH ₂ ), 4.78(s ,2H,NCH ₂ ),6.87(brs,2H,ph3'-H,5'-H),7.23(brs,ph2'-H,6'-H),7.99(s,1H,quin7-H), 8.10(s,1H,quin5-H),10.61(s,1H,CH ₂ NH),12.83(s,1H,NH).ESI-HRMSm/z: C ₁₈ H ₁₆ Cl ₂ N ₃ O ₂ S ₂ ( [M+H] ⁺ ) calculated value: 440.0061,442.0031; measured value: 440.0051,442.0018.

Example 33

(6,7-dimethoxy-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate (compound 33)

Yield: 58%, pale yellow solid, mp193-195℃. ¹ HNMR (600MHz, DMSO-d ₆ ) δ: 3.72(s, 3H, OCH ₃ ), 3.84(s, 3H, OCH ₃ ), 3.86(s ,3H,OCH ₃ ),4.40(s,2H,SCH ₂ ),4.77(d,J=4.8Hz,2H,NHCH ₂ ),6.88(s,1H,quin8-H),6.89(d,J=8.4 Hz,2H,ph3'-H,5'-H),7.28(d,J=8.4Hz,2H,ph2'-H,6'-H),7.41(s,1H,quin5-H),10.63( t,J=4.8Hz,1H,CH ₂ NH),12.24(s,1H,NH).ESI-HRMSm/z: Calculated for C ₂₀ H ₂₂ N ₃ O ₄ S ₂ ([M+H] ⁺ ): 432.1052; Found: 432.1041.

Test case

antiproliferative activity

The following MTT method was used to measure the half-inhibitory concentration (IC ₅₀ ) of the compound of formula I to human lung cancer A549, breast cancer MCF-7, cervical cancer HeLa, colon cancer HT-29 and HCT-116 cell proliferation, using 5-fluorouracil ( 5-FU) as a positive control.

Adherent tumor cells in the exponential growth phase were selected, digested with trypsin, and prepared a cell suspension of 5×10 ⁴ to 10×10 ⁴ cells/mL with RPMI1640 culture medium containing 10% calf serum, and inoculated at 96 Add 90PL to each well in the experimental wells of the well culture plate, and set the background well at the same time (that is, add 90PL culture solution). Incubate for 24 hours at 37°C, 5% CO ₂ environment. When preparing the sample solution, each compound was prepared into solutions with different concentrations in the culture solution, and the control group was the culture solution containing 2% DMSO. Add 10 PL sample solution to the sample well, add 10 PL culture solution containing 2% DMSO to the control well, add 10 PL culture solution to the background well, set 3 duplicate wells in each well, and incubate at 37°C, 5% CO ₂ for 72 hours . Add 20PLMTT solution (CellTiter of Promega Company) to each well AQ _ueous Single Solution Cell Proliferation Detection Kit), continue to culture at 37°C for 2h. The optical density (OD) value of each well at a wavelength of 492 nm was measured with an enzyme-linked immunosorbent assay. The cell proliferation inhibition rate (InhibitionRate, IR%) was calculated according to the following formula, and then the half inhibitory concentration ( _IC50 value) was calculated by SPSS mathematical statistics software. The results are shown in Table 1 and Table 2. The IC ₅₀ value of 5-fluorouracil was obtained by the same method, and the values are listed in Table 1 and Table 2.

IR%=[1－(OD _{sample group} －OD _{background group} )/(OD _{control group－} OD _{background group} )]×100%

Table 1. Antiproliferative activity of compounds 1-22 (compounds of formula II) on A549, MCF-7, HeLa, HT-29 and HCT-116 cells

Table 2. Antiproliferative activity of compounds 23-33 (compounds of formula III) on A549, MCF-7, HeLa, HT-29 and HCT-116 cells

In addition, the results of tubulin polymerization assay (Tublinpolymerization assay, Cat.#BK006P, Versinon1.2, 1/7/2011, www.cytoskeleton.com) showed that compounds of the present invention such as compound 4 can significantly promote tubulin Therefore, the compound of the present invention not only has anti-proliferation activity on A549, MCF-7, HeLa, HT-29 and HCT-116 cells, but also has anti-proliferation activity on drug-resistant tumor cell lines.

In summary, the above are only preferred embodiments of the present invention, and are not intended to limit the protection scope of the present invention. Therefore, any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention, All should be included within the protection scope of the present invention.

Claims (11)

1. a C2 position derivative of 4(3H)-quinazolinone shown in general formula (I): in: R ² , R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, or hydroxyl; R ¹ is a substituted methyl group; here, the substituted methyl group refers to a methyl group substituted by one or more phenyl groups or substituted phenyl groups, or heterocycles or substituted heterocycles; wherein, the The above-mentioned substituted phenyl means that the phenyl ring is replaced by one or more C1-4 alkyl, halogenated C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl, hydroxyl, halogen, nitro or The cyano group is substituted, and the substituted position on the benzene ring is not limited, or the substituted phenyl is 3,4-methylenedioxyphenyl; the heterocycle is selected from furan, thiophene, or pyridine; the The substituted heterocycle refers to pyridine substituted by halogenated C1-4 alkyl. 2. The derivative according to claim 1, wherein, in formula (I), R ² , R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, or hydroxyl. 3. The derivative according to claim 1, wherein the substituted phenyl group is selected from 4-methylphenyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-nitrobenzene Base, 4-cyanophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2,4 -difluorophenyl, 2,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, or 3,4-methylenedioxyphenyl. 4. The derivative according to claim 1, wherein the heterocycle is thiophen-2-yl, furan-2-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl . 5. The derivative according to claim 1, wherein the substituted heterocycle is 6-trifluoromethyl-pyridin-3yl. 6. derivatives according to claim 1, wherein, formula (I) is following formula (II) compound: Wherein, the definition of R in formula (II) is as defined in the compound of formula (I) in claim ¹ . 7. derivatives according to claim 1, wherein, formula (I) is following formula (III) compound: Wherein, the definitions of R ² , R ³ , R ⁴ and R ⁵ in formula (III) are as defined in the compound of formula (I) in claim 1. 8. Derivatives as claimed in claim 1, selected from the following compounds: Benzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; Benzhydrylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 4-Methylbenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 4-methoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 2-Methoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 2,4-Dimethoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 3,4,5-trimethoxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 3,4-Methylenedioxybenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 4-Bromobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 4-chlorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 2,4-Dichlorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 4-fluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 2-fluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 2,4-Difluorobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 4-cyanobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; 4-nitrobenzylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; (Thien-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; (furan-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; (Pyridin-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; (Pyridin-3-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; (6-(trifluoromethyl)pyridin-2-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; (Pyridin-4-yl)methylaminodithio(3,4-dihydro-4-oxoquinazolin-2-yl)methyl ester; (6-methyl-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (8-Methyl-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (6-Hydroxy-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (6-fluoro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (6-Chloro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (6-bromo-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (6-iodo-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (6-nitro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (7-nitro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; (6,8-dichloro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate; or (6,7-dimethoxy-3,4-dihydro-4-oxoquinazolin-2-yl)methyl 4-methoxybenzylcarbamate. 9. the preparation method of derivative described in claim 1, comprises the steps: The compound of formula (IV) reacts with the compound of formula (V) in the presence of CS ₂ and potassium phosphate to obtain the compound of formula (I) The substituent X in the compound of formula (IV) is halogen, selected from bromine or chlorine; The definitions of the substituents R ² , R ³ , R ⁴ and R ⁵ in the compound of formula (IV) are as defined in the compound of formula (I) according to claim 1; The definition of R ¹ in the compound of formula (V) is as defined in the compound of formula (I) in claim 1. 10. A pharmaceutical composition comprising a derivative according to any one of claims 1 to 8. 11. Use of the derivative according to any one of claims 1 to 8 in the preparation of medicines for treating human lung cancer, human breast cancer, human colon cancer, or human cervical cancer.