KR100584157B1 - Quinazoline derivatives - Google Patents

Abstract

The present invention is a novel compound useful for the treatment of diseases caused by abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc. due to its excellent inhibitory activity against tyrosine kinase, C-6 and C- of quinazoline It relates to a quinazoline derivative having a tricyclic structure linked to position 1 by a 1,4-dioxane group, a preparation method thereof, and a medicinal use thereof.

Tyrosine kinases, quinazoline derivatives, 1,4-dioxane

Description

Quinazolin derivatives             

1 is a graph showing a comparison of the cell growth inhibitory activity of the compound according to the invention and the control compound (Iressa ™).

The present invention is a novel compound useful for the treatment of diseases caused by abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc. due to its excellent inhibitory activity against tyrosine kinase, and C-6 and C- of quinazoline It relates to a quinazoline derivative having a tricyclic structure linked to position 1 by a 1,4-dioxane group, a preparation method thereof, and a medicinal use thereof.

Various types of tyrosine kinase inhibitors have been developed and are being studied for the purpose of treating cancer-related diseases. These tyrosine kinase inhibitors competitively bind around the ATP binding site of epidermal growth factor receptor (EGFR) tyrosine kinase and interfere with signaling pathways by interfering with autophosphorylation of kinase tyrosine, thus inhibiting tumor growth and eventually disappearing. Will cause.

Receptor tyrosine kinases that bind to growth factors are the most important proteins in intracellular signaling. The signaling system of protein tyrosine kinases regulates a variety of intracellular actions, typically cell growth, differentiation, migration, and metabolism. However, abnormally activated signaling systems result in the generation, growth, and spread of cancer. Receptor tyrosine kinases consist of extracellular ligand binding domains linked to tyrosine kinase domains of cells. Epidermal growth factor receptor (EGFR) comprises a number of subfamily, representatively known as EGFR, HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). When epidermal growth factor (EGF) binds to the receptor of the ligand binding domain (EGFR), the receptor kinase forms a dimer (homo- or hetero-dimerization). At the same time, phosphorylation of tyrosine residues by ATP results in the activation of the kinase signaling system. The formed biological signaling passes through multiple stages of signal, eventually controlling the growth and differentiation of cells.

Quinazoline-based compounds that inhibit the signaling system of epidermal growth factor (EGF) that is currently being developed or are under development include PD-153035, Iressa ™ (ZD-1839), OSI-774, PKI166, GW572016, CI-1033. And the like, most of which show excellent selectivity to epidermal growth factor (EGF). Iresa was first released in Japan in 2002 as a non-small cell lung cancer drug, and was subsequently released in the US in 2003. Iresa (Iressa ™) has excellent therapeutic effects in special cases, but has a number of side effects and has the disadvantage of being used in a limited group of terminal non-small cell lung cancer patients. In addition, most of the above-described developing quinazoline compounds exhibit low bioavailability due to low solubility when administered orally, and thus development has been progressed toward increasing pharmacokinetic properties. PD-153035, which is known to exhibit the best tyrosine kinase activity, has not been further developed due to low bioavailability due to low solubility. In an effort to increase solubility, much research has been made on the introduction of amine groups at the C-6 position of quinazoline. As an example, Iressa ™ has significantly increased the stability of compounds in vivo as well as bioavailability by introducing morpholinyl propoxy groups into C-6. Research on increasing solubility, absorption and bioavailability using Yeresa's successful synthesis strategy is still active. The present invention is also a result of a study to increase the water solubility by changing the C-6 or C-7 position of quinazoline.

The present inventors can be used as an inhibitor that inhibits the signaling system of a number of receptor tyrosine kinases associated with various cancers, and have been researching for many years to develop new compounds having high solubility and excellent bioavailability. As a result, C-6 and C-7 of quinazoline are combined with each other by a 1,4-dioxane group to synthesize a quinazoline derivative having a novel structure, and the synthesized new compound is epithelial cell. The present invention has been completed by confirming that the growth factor receptor (EGFR) tyrosine kinase shows excellent activity, and at the same time, the 1,4-dioxane group is bound to increase the solubility of the compound to increase the bioavailability.

Accordingly, an object of the present invention is to provide a novel quinazoline derivative having a tricyclic structure in which C-6 and C-7 of quinazoline are connected to each other by a 1,4-dioxane group.

It is another object of the present invention to provide a method for preparing the novel compound.

The present invention also provides a use for use as a therapeutic agent for various diseases caused by abnormal tyrosine kinase activity because the novel compounds exhibit superior activity to epidermal growth factor receptor (EGFR) compared to the control drug. There is a purpose.

The present invention is characterized by a quinazoline derivative having a tricyclic structure represented by the following formula (1) showing inhibitory activity against tyrosine kinase, a preparation method thereof, and a medicinal use thereof.

In Chemical Formula 1,

m is an integer from 1 to 5; R ¹ is a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 haloalkyl group, a cyano group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a methylthio group, a nitro group, or —NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are the same as or different from each other, each is a hydrogen atom or an alkyl group of C _1-6 ); R ² and R ³ are the same as or different from each other, and each hydrogen atom, an alkyl group of C _1-6 , a hydroxyalkyl group of C _2-3 , or a substituted benzyl group (wherein the substituent is a hydrogen atom, a halogen atom, or a hydroxy group). , C _1-6 alkyl group or C _1-6 alkoxy group); Or R ² and R ³ are 5 to 7 membered heterocyclic groups linked together with N to which they are attached or with another heteroatom selected from O, S, and NR ⁶ , wherein R ⁶ is hydrogen Atom, C _1-6 alkyl group or C _3-7 cycloalkyl group).

Referring to the present invention in more detail as follows.

The compound represented by Chemical Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid , Gluturonic acid, embon acid, glutamic acid, or aspartic acid, and the like can be used.

In addition, the compound represented by Chemical Formula 1 according to the present invention may also exist in the form of a solvate (for example, a hydrate).

In addition, the compound represented by Formula 1 according to the present invention may have one or more asymmetric centers, and in the case of such compounds, enantiomers or diastereomers may be present. Accordingly, the present invention includes each isomer or a mixture of these isomers.

In the compound represented by Formula 1 according to the present invention, preferably m is an integer of 1 to 5; R ¹ is a hydrogen atom, a halogen atom, a C _1-6 haloalkyl group, a C _1-6 alkyl group, or an alkoxy group of C _1-6, and; R ² and R ³ are the same as or different from each other, and are each an alkyl group of C _1-6 , or a hydroxyalkyl group of C _2-3 , or R ² and R ³ together with N to which they are attached or O and NR ⁶ A compound which forms a 5 to 7 membered heterocyclic group linked to each other with another hetero atom selected from R ³ , wherein R ⁶ is a hydrogen atom, an alkyl group of C _1-6 or a cycloalkyl group of C _3-7 Is the case.

In the compound represented by Formula 1 according to the present invention, more preferably, m is an integer of 1 to 5; R ¹ is a hydrogen atom, a halogen atom, a trifluoromethyl group, a methyl group, an ethyl group, a propyl group, or a methoxy group; R ² and R ³ are the same or different from each other and are an ethyl group or a hydroxyethyl group, or R ² and R ³ are linked to each other to form a piperidine, pyrrolidine, morpholine, or N-methylpiperazine group This is the case of the compound.

In the compound represented by Formula 1 according to the present invention, particularly preferred compounds are as follows:

(3-chlorophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4- General] -amine,

(3-chlorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [2,3-g] Quinazolin-4-yl} -amine,

(3-chlorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine,

(3-chlorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine,

(3-chlorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]- Amine,

2-[{2- [4- (3-chlorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethyl}- (2-hydroxyethyl) -amino] -ethanol,

(3-bromophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine,

(3-bromophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl} -amine,

(3-bromophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin- 4-yl] -amine,

(3-bromophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin- 4-yl] -amine,

(3-bromophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl] Amines,

2-[{2- [4- (3-bromophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethyl} -(2-hydroxyethyl) -amino] -ethanol,

(3-chloro-4-fluorophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] Quinazolin-4-yl] -amine,

(3-chloro-4-fluorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [2 , 3-g] quinazolin-4-yl} -amine,

(3-chloro-4-fluorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine,

(3-chloro-4-fluorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine,

(3-chloro-4-fluorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazoline- 4-yl] -amine,

2-[{2- [4- (3-chloro-4-fluorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl ] -Ethyl}-(2-hydroxyethyl) -amino] -ethanol,

(4-bromo-2-fluorophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine,

(4-bromo-2-fluorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [ 2,3-g] quinazolin-4-yl} -amine,

(4-bromo-2-fluorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3- g] quinazolin-4-yl] -amine,

(4-bromo-2-fluorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3- g] quinazolin-4-yl] -amine,

(4-bromo-2-fluorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazoline -4-yl] -amine,

[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-tri Fluoromethylphenyl) -amine,

[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(4-propyl Phenyl) -amine,

(4-bromophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine,

(3-chloro-4-trifluoromethylphenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine,

And pharmaceutically acceptable salts, solvates (eg hydrates), isomers thereof, and the like of the compounds.

On the other hand, the present invention includes a method for producing a quinazoline derivative of the tricyclic structure represented by the formula (1).

Method for producing a compound represented by Formula 1 according to the present invention, as shown in the following Scheme 1,

1) a process of preparing a compound represented by the following Chemical Formula 4 by combining the dioxyno quinazoline compound represented by the following Chemical Formula 2 with the aniline compound represented by the following Chemical Formula 3;

2) preparing a compound represented by the following Chemical Formula 5 by deprotecting the compound represented by Chemical Formula 4, and

3) After converting the hydroxy group of the compound represented by the formula (4) to a leaving group, by coupling with the amine compound represented by HNR ² R ³ to produce a quinazoline derivative or isomer thereof of the tricyclic structure represented by the following formula (1) Including the process.

In Reaction Scheme 1, R ¹ , R ² , R ³ , and m are as defined in Formula 1, respectively.

The manufacturing method according to the present invention will be described in more detail by dividing each manufacturing process as follows.

The coupling reaction between the compound represented by Formula 2 and the aniline compound including various substituents represented by Formula 3 may be various organic amines, such as pyridine, triethylamine, 2,6-lutidine, diisopropylethylamine, and the like. Optionally at 10 ° C. to 150 ° C. in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane in the presence of an organic base or an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide.

The deprotection reaction of the benzyl protecting group of Formula 4 may be carried out by a method well known in the literature (Protective Groups in Organic Synthesis, T. W. Green and R. G. M. Wuts, 3rd Ed. Wiely). Specifically, a hydrogenation reaction using palladium complex call (Pd / C), platinum oxide, or solvent-free in the presence of an organic acid (for example trifluoroacetic acid or methanesulfonic acid), dichloromethane, chloroform, benzene and Optionally at 20 ° C. to 120 ° C. in a solvent such as toluene or in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane in the presence of Lewis acid (eg tribromoborane or trichloroborane) Optionally at -20 ° C to 50 ° C.

In order to introduce an amine group into the hydroxy group of the compound represented by Formula 5, the hydroxy group is first converted into a leaving group and then reacted with an appropriate amine compound. Compounds in which the leaving group is a sulfonyloxy group can be obtained by carrying out a reaction with methanesulfonylchloride or p-toluenesulfonylchloride in the presence of an organic base (for example, triethylamine, pyridine, diisopropylethylamine) , Compounds having a leaving group of halogen (Cl, Br) may be reacted with thionyl chloride (SOCl ₂ ), phosphorus chloride (PCl ₃ ), or triphenylphosphine with tetrachloromethane or tetrabromethane You can get each one. The introduction reaction of the various R ² and R ³ substituted amine compounds to the compound substituted with leaving group was carried out in the presence of inorganic or organic base (eg sodium carbonate, calcium hydroxide, triethylamine, pyridine, diisopropylethylamine). Any variety of amine compounds are used in the presence of conventional organic solvents (e.g. dichloromethane, dioxane, N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone) at temperatures between < RTI ID = 0.0 > 100 C < / RTI > The reaction may be performed using only an amine compound in which R ² and R ³ are substituted without using a solvent or a base. At this time, catalytic amounts of potassium iodine and sodium iodine can be used.

Compound represented by the formula (2) used as a starting material in the preparation method according to Scheme 1 has an optical activity, by using the isomer represented by the formula (2) optically pure to the compound represented by the formula (1) It can also be prepared as pure optical isomers.

On the other hand, the compound represented by the formula (2) used as a starting material in the preparation method according to Scheme 1, can be synthesized by performing the preparation method according to the following scheme 2.

The benzyloxyethyl oxirane compound represented by the formula (6) used in Scheme 2 is already well known method ( J. Org. Chem . 1988 , 53, 1026; Tetrahedron Lett . 1987 , 28, 3597; J. Med. Chem 1990, can be synthesized by 33, 2476). Benzyloxyethyl oxirane compound represented by the formula (6) is 100 ℃ to in the presence of a compound represented by the formula (7) and inorganic bases (for example, sodium fluoride, potassium fluoride, cesium fluoride) purchased commercially At 150 ° C., a cyclization reaction may be performed under a solvent such as dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidine to obtain a compound represented by Chemical Formula 8. The compound represented by Chemical Formula 8 is a benzodioxin compound represented by Chemical Formula 9 by performing a Mitsunobu reaction using diisopropylazodicarboxylate (DIAD) and triphenylphosphine (PPh ₃ ). Can be obtained. A compound represented by Chemical Formula 2 may be obtained by introducing a nitro group into the compound represented by Chemical Formula 9, reducing the nitro group, and performing a cyclization reaction and a halogenation reaction. Each procedure for the synthesis of the compound represented by the formula (2) is generally well known known methods ( J. Med. Chem . 1977 , 20, 146; J. Med. Chem . 2002 , 45, 3865; J. Med. Chem 1996 , 30, 267; Bioorg. Med. Chem. Lett . 1997 , 7, 2723; Bioorg. Med. Chem. Lett . 2001 , 11, 1911; US patent 5,770,599.

In the present invention, the compound represented by the formula (9) was added to the mixture of nitric acid and acetic acid or sulfuric acid and stirred at 0 to 100 ℃ to obtain the nitro compound represented by the formula (10). Reduction of the nitro group was hydrogenated in the presence of palladium complex call (Pd / C) or platinum, or heated to 50 ℃ to 100 ℃ in the presence of iron powder and ammonium chloride to obtain the amine compound represented by the formula (11) . The cyclization reaction of the compound represented by Formula 11 was carried out by heating to 150 ℃ in the presence of ammonium carbonate and formamide. The halogenation reaction of the compound represented by Chemical Formula 12 was carried out by heating under reflux in the presence of thionyl chloride or phosphorus oxychloride, and the solvent was concentrated under reduced pressure to obtain a quinazoline compound represented by Chemical Formula 2.

The reaction intermediate compound obtained in the above-mentioned preparation method or the target compound represented by Chemical Formula 1 may be separated and purified by conventional methods such as chromatography and recrystallization.

On the other hand, the compounds according to the present invention can be formulated into a conventional formulation in the pharmaceutical field by the addition of conventional non-toxic pharmaceutically acceptable carriers, adjuvant and excipients. Conventional formulations include, for example, oral (tablets, capsules, powders), oral cavity, sublingual, intrarectal, intravaginal, intranasal, topical or parenteral (intravenous, cavernous, intramuscular, subcutaneous). And dosage forms). For example, the compounds according to the invention may be in the form of tablets containing starch or lactose, in the form of capsules alone or in the form of excipients, or in the form of elixirs or suspensions containing chemicals which flavor or color. It can be administered orally, orally or sublingually. Liquid formulations may be suspending agents (eg, methyl cellulose, semisynthetic glycerides such as witepsol or mixtures of apricot kernel oil with PEG-6 esters or PEG-8 with caprylic / capric glycerol). Pharmaceutically acceptable additives such as glyceride mixtures such as mixtures of lides). It may also be parenterally injected, for example, intravenously, intracavernosally, intramuscularly, subcutaneously and intratracheally. For parenteral administration, it is most preferred to use it in the form of a sterile aqueous solution, in which the solution contains other substances (e.g. salts or monosaccharides such as mannitol, glucose) to have isotonicity with the blood. You may.

In addition, the dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is based on an adult patient having a weight of 70 kg. Generally, it is 0.01-400 mg / day, and can be dividedly administered once a day to several times at regular time intervals according to the judgment of a doctor or a pharmacist.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1. 4- (4-benzyloxy-2-hydroxybutoxy) -3-hydroxybenzoic acid ethyl ester

3,4-dihydroxybenzoic acid ethyl ester (7.5 g, 41 mmol) and cesium fluoride (0.14 g, 0.9 mmol) were dissolved in dimethylformamide (100 mL) and stirred at 130 ° C. with 2- (2-benzyloxy Ethyl) -oxirane (8.0 g, 44.9 mmol) was added slowly and stirred at the same temperature for 14 hours. After the reaction, ethyl acetate (200 mL) was added to the reaction mixture, diluted, washed with brine, dried over anhydrous magnesium sulfate (MgSO ₄ ), and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 3: 1) to give 4- (4-benzyloxy-2-hydroxy-butoxy) -3-hydroxybenzoic acid ethyl ester (6.2 g, 42%). Got.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.59 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.3, 2.1 Hz, 1H), 7.25-7.37 (m, 5H), 6.82 (d , J = 8.3 Hz, 1H), 4.54 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 4.08-3.92 (m, 3H), 3.76-3.69 (m, 2H), 1.90-1.76 ( m, 2H), 1.37 (t, J = 7.2 Hz, 3H); MS-ESI 360 (M ⁺ , 1), 179 (5), 137 (6), 91 (100).

Example 2. 3- (2-benzyloxyethyl) -2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester

4- (4-benzyloxy-2-hydroxybutoxy) -3-hydroxybenzoic acid ethyl ester (8.5 g, 23.5 mmol) was dissolved in anhydrous benzene (200 mL) and diisopropylazodicarboxyl at 0 ° C. Eight (DIAD; 4.1 mL, 25.9 mmol) and triphenylphosphine (PPh ₃ ) were added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and then purified by column chromatography (hexane / ethyl acetate = 5: 1) to obtain 3- (2-benzyloxyethyl) -2,3-dihydrobenzo [1,4] dioxine-6. -Carboxylic acid ethyl ester (7.9 g, 98%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.57-7.54 (m, 2H), 7.34-7.25 (m, 5H), 6.87 (d, J = 9.0 Hz, 1H), 4.53 (s, 2H), 4.31 (q, J = 6.9 Hz, 2H), 3.97 (dd, J = 11.6, 7.8 Hz, 1H), 3.72-3.64 (m, 2H), 1.98 (m, 2H), 1.37 (t, J = 6.9 Hz, 3H); MS-ESI 342 (M ⁺ , 6), 161 (4), 91 (100).

Example 3. 3- (2-benzyloxyethyl) -7-nitro-2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester

 3- (2-benzyloxyethyl) -2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester (4.2 g, 11.7 mmol) was added to acetic acid (30 mL), followed by 65% Nitric acid (10 mL) was added slowly. Then, the mixture was stirred for 3 hours at 50-60 ° C. and then the reaction mixture was added to the cooling water. Extract twice with dichloromethane (100 mL), wash twice with water, wash with saturated aqueous sodium bicarbonate solution, dry the organic layer over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain 3- (2-benzyloxyethyl) -7-nitro-. 2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester (1.9 g, 45%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ7.50 (s, 1H), 7.37 (m, 5H), 7.14 (s, 1H), 5.20 (s, 2H), 4.71 (m, 1H), 4.38 (q , J = 7.1 Hz, 2H), 4.06 (m, 1H), 2.85 (dd, J = 16.2, 6.4 Hz, 1H), 2.70 (dd, J = 16.2, 6.4 Hz, 1H), 1.32 (t, J = 7.1 Hz, 1H).

Example 4. 7-Amino-3- (2-benzyloxyethyl) -2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester

Iron (2.5 g) and ammonium chloride (4 g) were added to a mixed solution of methanol and water (2: 1, 60 mL) and heated to reflux for 15 minutes. 3- (2-benzyloxyethyl) -7-nitro-2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester (6.2 g, 16.0 mmol) was added and heated to reflux for 3 hours. It was. After cooling the reaction solution to room temperature, the solid material was filtered, and the solid was washed several times with dichloromethane, the filtrate and the washing solution were combined, washed with saturated aqueous sodium bicarbonate solution, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 7-amino. 3- (2-benzyloxyethyl) -2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester (4.7 g, 82%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.4-7.25 (m, 6H), 6.13 (s, 1H), 4.52 (s, 2H), 4.40-4.1 (m, 5H), 3.89-3.71 (m, 2H), 1.97-1.86 (m, 2H), 1.39-1.3 (m, 3H); MS-ESI 357 (M ⁺ , 52), 196 (32), 167 (13), 91 (100).

Example 5. 7- (2-benzyloxyethyl) -7,8-dihydro-3H- [1,4] dioxino [2,3-g] quinazolin-4-one

7-amino-3- (2-benzyloxyethyl) -2,3-dihydrobenzo [1,4] dioxine-6-carboxylic acid ethyl ester (2.2 g, 6.2 mmol) was added to formamide (25 mL). And ammonium carbonate (0.99 g, 9.9 mmol) and heated to reflux for 3 hours. After the reaction, the reaction mixture was cooled to room temperature and stirred with a small amount of water. The solid formed was filtered and dried to afford a white solid 7- (2-benzyloxyethyl) -7,8-dihydro-3H- [1,4]. Dioxyno [2,3-g] quinazolin-4-one (1.5 g, 72%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.83 (b, 1 H), 7.95 (t, J = 22.5 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.35-7.26 (m) , 4H), 7.0 (d, J = 10.8 Hz, 1H), 4.51-4.37 (m, 4H), 4.11-4.04 (m, 1H), 3.68-3.62 (m, 2H), 1.97-1.91 (m, 2H ); MS-ESI 338 (M ⁺ , 6), 229 (3), 202 (2), 174 (1), 91 (100).

Example 6. 7- (2-benzyloxyethyl) -4-chloro-7,8-dihydro- [1,4] dioxino [2,3-g] quinazoline

7- (2-benzyloxyethyl) -7,8-dihydro-3H- [1,4] dioxino [2,3-g] quinazolin-4-one (0.9 g, 2.7 mmol) is thionyl Dissolved in chloride (SOCl ₂ , 10 mL), dimethylformamide (2 drops) was added, and then heated to reflux for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove thionyl chloride. Dichloromethane (15 mL) was added to the residue to dissolve it, washed several times with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (30% EtOAc / Hexane) to give 7- (2 -Benzyloxyethyl) -4-chloro-7,8-dihydro- [1,4] dioxino [2,3-g] quinazoline (0.7 g, 74%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 7.51 (d, J = 11.5 Hz, 1H), 7.34-7.26 (m, 6H), 4.54-4.41 (m, 4H) 4.14 (q, J = 18.9 Hz, 1H), 3.68-3.6 (m, 2H), 1.99-1.90 (m, 2H); MS-ESI 356 (M ⁺ , 2), 338 (15), 174 (11), 91 (100).

Example 7 [7- (2-benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-chlorophenyl ) -Amine

7- (2-benzyloxyethyl) -4-chloro-7,8-dihydro- [1,4] dioxino [2,3-g] quinazoline (0.40 g, 1.12 mmol) wasopropyl alcohol ( 5 mL), 3-chloroaniline (0.21 g, 1.36 mmol) was added thereto, heated to reflux for 2 hours, cooled to room temperature, and then the formed solid was filtered to [7- (2-benzyloxyethyl) -7 , 8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-chlorophenyl) -amine (0.34 g, 67%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ11.0 (b, 1H), 8.88 (s, 1H), 8.39 (d, J = 12.3 Hz, 1H), 7.95 (t, J = 4.8 Hz, 1H ), 7.74 (d, J = 9.9 Hz, 1H), 7.52 (t, J = 16.2 Hz, 1H), 7.39-7.28 (m, 7H), 4.59 (m, 4H), 4.20 (dd, J = 16.2, 6.4 Hz, 1H), 3.7 (t, J = 13.5 Hz, 2H), 2.09-1.96 (m, 2H); MS-ESI 447 (M ⁺ , 9), 354 (1), 257 (2), 222 (1), 104 (4), 91 (100).

Example 8 [7- (2-benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-bromo Phenyl) -amine

Yield 71%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.98 (b, 1H), 8.87 (s, 1H), 8.37 (d, J = 12.3 Hz, 1H), 8.06 (d, J = 5.0 Hz, 1H ), 7.77 (t, J = 7.8 Hz, 1H), 7.50-7.26 (m, 8H) 4.63-4.52 (m, 4H), 4.23 (dd, J = 16.1, 6.4 Hz, 1H), 3.69 (t, J = 12.9 Hz, 2H), 2.08-1.95 (m, 2H); MS-ESI 492 (M ⁺ , 1), 384 (1), 340 (2), 291 (12), 220 (10), 164 (100).

Example 9 [7- (2-benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-chloro- 4-fluorophenyl) -amine

Yield 97%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ11.1 (b, 1H), 8.83 (s, 1H), 8.34 (s, 1H), 8.02 (m, 1H), 7.70 (m, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.32-7.28 (m, 6H), 7.72 (m, 1H), 4.53-4.69 (m, 2H), 4.49 (s, 2H), 4.24 (dd, J = 16.2, 6.4 Hz, 1H), 3.7 (m, 2H), 2.09-1.96 (m, 2H); MS-ESI 465 (M ⁺ , 6), 274 (1), 157 (2), 91 (100).

Example 10. [7- (2-Benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(4-bromo -3-chlorophenyl) -amine

Yield 67%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.32 (b, 1H), 8.79 (s, 1H), 8.32 (d, J = 12.6 Hz, 1H), 7.77 (d, J = 9.9 Hz, 1H ), 7.58-7.26 (m, 8H), 4.57 (m, 2H), 4.52 (s, 2H), 4.23 (dd, J = 16.1, 6.3 Hz, 1H), 3.67 (m, 2H), 2.05-1.95 ( m, 2H); MS-ESI 510 (M ⁺ , 3), 490 (2), 430 (5), 269 (7), 131 (4), 91 (100).

Example 11. [7- (2-benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-trifluoro Romethylphenyl) -amine

Yield 84%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.64 (s, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.18-8.09 (m, 2H), 7.74-7.38 (m, 8H), 4.56 (m, 2H), 4.52 (s, 2H), 4.23 (dd, J = 16.1, 6.2 Hz, 1H), 3.66 (m, 2H), 2.04-1.94 (m, 2H); MS-ESI 481 (M ⁺ , 5), 314 (4), 302 (4), 222 (3), 91 (100), 145 (79), 921 (100).

Example 12. [7- (2-Benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(4-propylphenyl ) -Amine

Yield 90%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.04 (s, 1H), 8.72 (s, 1H), 8.32 (s, 1H), 7.54-7.26 (m, 10H), 4.56 (m, 2H) , 4.52 (s, 2H), 4.23 (dd, J = 16.1, 6.2 Hz, 1H), 3.66 (m, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.04-1.94 (m, 2H), 1.57 (m, 2H), 0.86 (t, J = 7.5 Hz, 3H).

Example 13. [7- (2-benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(4-fluoro -3-trifluoromethylphenyl) amine

Yield 91%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.01 (brs, 1 H), 8.80 (s, 1 H), 8.35 (s, 1 H), 8.23-8.15 (m, 2H), 7.72-7.4 (m, 6H), 7.33 (s, 1H), 4.56 (m, 2H), 4.53 (s, 2H), 4.24 (dd, J = 16.0, 6.1 Hz, 1H), 3.65 (m, 2H), 2.04-1.94 (m , 2H).

Example 14 [7- (2-benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-methoxy Phenyl) -amine

Yield 89%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.19 (s, 1H), 8.83 (s, 1H), 8.46 (s, 1H), 7.57-7.3 (m, 9H), 6.93-6.9 (m, 1H), 4.57 (m, 2H), 4.54 (s, 2H), 4.24 (dd, J = 16.1, 6.1 Hz, 1H), 3.77 (s, 3H), 3.64 (m, 2H), 2.04-1.93 (m , 2H).

Example 15. [7- (2-Benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(4-bromo Phenyl) -amine

Yield 94%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.1 (brs, 1H), 8.86 (s, 1H), 8.36 (s, 1H), 8.05 (m, 1H), 7.73 (m, 1H), 7.6 -7.04 (m, 6H), 7.31 (s, 1H), 4.57 (m, 2H), 4.54 (s, 2H), 4.24 (dd, J = 16.0, 6.1 Hz, 1H), 3.63 (m, 2H), 2.04-1.93 (m, 2 H).

Example 16. [7- (2-Benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-chloro- 4-trifluoromethylphenyl) -amine

Yield 72%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.69 (s, 1 H), 9.47 (s, 1 H), 8.48 (s, 1 H), 8.23-8.2 (m, 1 H), 7.86-7.21 (m, 6H), 4.56 (m, 2H), 4.55 (s, 2H), 4.24 (dd, J = 16.2, 6.2 Hz, 1H), 3.64 (m, 2H), 2.01-1.92 (m, 2H).

Example 17. 2- [4- (3-Chloro-4-fluorophenylamino) -7,8-dihydro- [1,4] dioxino [2.3-g] quinazolin-7-yl]- ethanol

[7- (2-benzyloxyethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-chloro-4-fluoro Phenyl) -amine (0.3 g, 0.64 mmol) was dissolved in dried dichloromethane (20 mL) and 1N-BBr ₃ (0.97 mL, 0.97 mmol) was slowly added at -30 ° C and stirred for 2 hours. Methanol was slowly added to the reaction mixture, followed by concentration under reduced pressure. Dichloromethane was added to the residue to dissolve it, washed with 2N-NaOH aqueous solution, washed with a small amount of brine, dried over Na ₂ SO ₄ and concentrated to 2- [4- (3-chloro-4-fluorophenylamino)- 7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethanol (0.16 g, 67%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.62 (b, 1H), 8.54 (s, 1H), 8.3 (m, 1H), 8.12 (s, 1H), 7.91 (m, 1H), 7.48 (t, J = 18.2 Hz, 1H), 7.27 (s, 1H), 4.80 (t, J = 5.0 Hz, 1H), 4.77-4.49 (m, 2H), 4.17 (dd, J = 11.4, 7.7 Hz, 1H), 3.70 (m, 2 H), 1.88 (m, 2 H); MS-ESI 375 (M ⁺ , 99), 374 (100), 44 (34).

Example 18. 2- [4- (3-chlorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethanol

¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.50 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.87 (d, J = 7.3Hz, 1H ), 7.3 (t, J = 12.4 Hz, 1H), 7.17 (m, 2H), 4.75 (d, J = 3.5 Hz, 1H), 4.49 (s, 2H), 3.34 (s, 2H), 1.83 (d , J = 6.2 Hz, 2H); MS-ESI 357 (M ⁺ , 2), 356 (100), 286 (23), 127 (14), 9 (21).

Example 19. 2- [4- (3-Bromophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethanol

Yield 94%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.60 (b, 1H), 8.56 (s, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 7.99 (d, J = 9.0Hz , 1H), 7.55-7.25 (m, 3H), 4.59-4.47 (m, 2H), 4.19 (dd, J = 11.7, 7.8 Hz, 1H), 3.77-3.46 (m, 2H), 1.97-1.86 (m , 2H); MS-ESI 402 (M ⁺ , 100), 275 (38), 251 (47), 193 (42), 114 (29), 43 (4).

Example 20. 2- [4- (4-Bromo-2-fluorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7- Japanese] -ethanol

Yield 75%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.57 (brs, 1H), 8.33 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 11.2 Hz, 1H), 7.54-7.43 (m, 2H), 7.18 (s, 1H), 4.71 (m, 1H), 4.53-4.41 (m, 2H), 4.12 (dd, J = 11.7, 7.8 Hz, 1H), 3.64 (m, 2H), 1.9-1.77 (m, 2 H); MS-ESI 420 (M ⁺ , 55), 403 (46), 269 (88), 103 (39), 91 (76), 71 (81), 43 (100).

Example 21. 2- [4- (3-trifluoromethylphenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethanol

Yield 88%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.63 (s, 1H), 8.56 (s, 1H) 8.32 (s, 1H), 7.89 (d, J = 10.9Hz, 1H), 7.75-7.38 ( m, 3H), 7.19 (s, 1H), 4.56 (m, 2H), 4.52 (s, 2H), 4.23 (dd, J = 11.1, 6.2 Hz, 1H), 3.66 (m, 2H), 2.04-1.94 (m, 2 H).

Example 22. 2- [4- (4-propylphenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethanol

Yield 90%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.58 (s, 1H), 9.27 (s, 1H), 8.38 (s, 1H), 7.78 (s, 1H), 7.71 (d, J = 8.4Hz , 2H), 7.16 (m, 2H), 4.56 (m, 2H), 4.52 (s, 2H), 4.23 (dd, J = 11.1, 6.2 Hz, 1H), 3.66 (m, 2H), 2.54 (t, J = 7.3 Hz, 2H), 2.04-1.94 (m, 2H), 1.60 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

Example 23. 2- [4- (4-bromophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethanol

Yield 69%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.68 (s, 1H), 9.44 (s, 1H), 8.46 (s, 1H), 7.88 (m, 2H), 7.8 (m, 2H), 7.21 (s, 1H), 4.59-4.47 (m, 2H), 4.21 (dd, J = 11.7, 7.8 Hz, 1H), 3.77-3.46 (m, 2H), 1.97-1.86 (m, 2H)

Example 24. 2- [4- (3-Chloro-4-trifluoromethylphenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7- Japanese] -ethanol

Yield 72%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 9.47 (s, 1H), 8.48 (s, 1H), 8.23-8.2 (m, 1H), 7.83 (m, 2H) , 4.56 (m, 2H), 4.24 (dd, J = 11.2, 6.2 Hz, 1H), 3.64 (m, 2H), 2.01-1.92 (m, 2H).

Example 25. Methanesulfonic Acid 2- [4- (3-Chloro-4-fluorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7 -Yl] -ethyl est

2- [4- (3-Chloro-4-fluoro) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethanol (0.15 g , 0.40 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (0.22 mL, 1.60 mmol) and methanesulfonyl chloride (0.07 mL, 0.8 mmol) were added at 0 ° C. After stirring for 5 hours at room temperature, the mixture was concentrated under reduced pressure, and then dissolved in dichloromethane (15 mL). The residue was washed several times with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated to methanesulfonic acid 2- [4- (3-Chloro-4-fluorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethyl ester (0.27 g) Got it. Used for the next reaction without further purification.

Example 26. (3-Chloro-4-fluorophenyl)-[7- (2-morpholin-4-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2, 3-g] quinazolin-4-yl] -amine

Methanesulfonic acid 2- [4- (3-chloro-4-fluorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl]- Ethyl ester (94 mg, 0.21 mmol) and a small amount of potassium iodine (KI, 3 mg) were added to morpholine (2 mL) and stirred at 80 ° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, separated by column chromatography (2% MeOH / MC) to give (3-chloro-4-fluorophenyl)-[7- (2-morpholin-4-yl-ethyl ) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl] -amine (48 mg, 57%) was obtained.

¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.61 (b, 1H), 8.54 (s, 1H), 8.31 (dd, J = 7.1, 2.5Hz, 1H), 8.13 (s, 1H) 7.95- 7.90 (m, 1H), 7.48 (t, J = 9.1 Hz, 1H), 7.27 (s, 1H), 4.57 (d, J = 10.1 Hz, 1H), 4.46 (m, 1H), 4.18 (dd, J = 11.5, 8.1 Hz, 1H), 3.65 (m, 2H), 3.39 (m, 4H), 2.46 (m, 4H), 1.96-1.85 (m, 2H); MS-ESI 444 (M ⁺ , 2), 433 (30), 84 (66), 66 (100).

Example 27. (3-Chloro-4-fluorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] di Oxino [2,3-g] quinazolin-4-yl} -amine

Yield 42%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.58 (b, 1H), 8.49 (s, 1H), 8.26 (dd, J = 7.0, 2.4 Hz, 1H), 8.08 (s, 1H), 7.89 -7.84 (m, 1H), 7.45 (t, J = 9.1 Hz, 1H), 7.21 (s, 1H), 4.52 (d, J = 10.2 Hz, 1H), 4.4 (m, 1H), 4.13 (dd, J = 11.3, 8.0 Hz, 1H), 3.33 (m, 6H), 2.33-2.21 (m, 7H), 1.9-1.83 (m, 2H); MS-ESI 457 (M ⁺ , 18), 152 (19), 113 (89), 70 (52), 55 (38), 39 (100).

Example 28. (3-Chloro-4-fluorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2 , 3-g] quinazolin-4-yl] -amine

Yield 58%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.61 (brs, 1H), 8.49 (s, 1H), 8.25 (dd, J = 7.1, 2.4 Hz, 1H), 8.09 (s, 1H), 7.88 -7.83 (m, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.23 (s, 1H), 4.51 (d, J = 11.0 Hz, 2H), 4.30 (m, 1H), 4.01 (dd, J = 11.2, 8.0 Hz, 1H), 2.51 (m, 2H), 2.41 (m, 4H), 1.89 (m, 2H), 1.49 (m, 4H), 1.37 (m, 2H); MS-ESI 442 (M ⁺ , 4), 410 (100), 307 (16), 98 (76).

Example 29. (3-Chloro-4-fluorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2 , 3-g] quinazolin-4-yl] -amine

Yield 51%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.60 (brs, 1H), 8.50 (s, 1H), 8.24 (dd, J = 7.2, 2.4 Hz, 1H), 8.09 (s, 1H), 7.87 -7.84 (m, 1H), 7.43 (t, J = 9.1 Hz, 1H), 7.23 (s, 1H), 4.45 (d, J = 10.9 Hz, 1H), 4.31 (m, 1H), 4.01 (dd, J = 11.2, 8.0 Hz, 1H), 2.52 (m, 2H), 2.41 (m, 4H), 1.77 (m, 2H), 1.02 (m, 6H).

Example 30. 2-[{2- [4- (3-chloro-4-fluorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazoline -7-yl] -ethyl}-(2-hydroxyethyl) -amino] -ethanol

Yield 22%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.60 (brs, 1H), 8.50 (s, 1H), 8.24 (dd, J = 7.2, 2.4 Hz, 1H), 8.09 (s, 1H), 7.87 -7.84 (m, 1H), 7.43 (t, J = 9.1 Hz, 1H), 7.23 (s, 1H), 4.45 (d, J = 10.9 Hz, 1H), 4.31 (m, 1H), 4.01 (dd, J = 11.2, 8.0 Hz, 1H), 3.71 (m, 4H), 2.51 (m, 2H), 2.41 (m, 4H).

Example 31. (3-Chloro-4-fluorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine

Yield 51%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.60 (b, 1H), 8.50 (s, 1H), 8.24 (dd, J = 7.2, 2.4Hz, 1H), 8.09 (s, 1H), 7.87 -7.84 (m, 1H), 7.43 (t, J = 9.1 Hz, 1H), 7.23 (s, 1H), 4.45 (d, J = 10.9 Hz, 1H), 4.31 (m, 1H), 4.01 (dd, J = 11.2, 8.0 Hz, 1H), 2.52 (m, 2H), 2.36 (m, 4H), 1.91 (m, 2H), 1.59 (m, 6H).

Example 32. (4-Bromo-2-fluorophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2 , 3-g] quinazolin-4-yl] -amine

¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.66 (b, 1H), 8.34 (s, 1H), 7.72 (s, 1H), 7.65 (d, J = 9.9Hz, 1H), 7.45-7.56 (m, 2H), 7.23 (s, 1H), 4.55 (d, J = 10.1 Hz, 1H), 4.45 (m, 1H), 4.19 (dd, J = 11.3, 8.0 Hz, 1H), 3.64 (m, 2H), 3.40 (m, 4H), 2.42 (m, 4H), 1.96-1.85 (m, 2H); MS-ESI 489 (M ⁺ , 2), 401 (9), 395 (100), 84 (12).

Example 33. (4-Bromo-2-fluorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] Dioxyno [2,3-g] quinazolin-4-yl} -amine

Yield 40%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.66 (b, 1H), 8.33 (s, 1H), 7.72 (s, 1H), 7.65 (d, J = 9.9Hz, 1H), 7.45-7.56 (m, 2H), 7.23 (s, 1H), 4.51 (d, J = 10.1 Hz, 1H), 4.4 (m, 1H), 4.12 (dd, J = 11.2, 8.0 Hz, 1H), 3.32 (m, 6H), 2.33-2.21 (m, 7H), 1.90-1.83 (m, 2H); MS-ESI 502 (M ⁺ , 2), 342 (41), 246 (30), 230 (28), 84 (73), 66 (10).

Example 34. (4-Bromo-2-fluorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [ 2,3-g] quinazolin-4-yl] -amine

Yield 35%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.66 (brs, 1H), 8.33 (s, 1H), 7.72 (s, 1H), 7.65 (d, J = 9.9 Hz, 1H), 7.45-7.56 (m, 2H), 7.23 (s, 1H), 4.50 (d, J = 10.9 Hz, 2H), 4.30 (m, 1H), 4.02 (dd, J = 11.2, 8.0 Hz, 1H), 2.51 (m, 2H), 2.41 (m, 4H), 1.88 (m, 2H), 1.47 (m, 4H), 1.36 (m, 2H); MS-ESI 487 (M ⁺ , 1), 440 (1), 399 (2), 110 (1), 84 (57), 66 (100).

Example 35. (4-Bromo-2-fluorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [ 2,3-g] quinazolin-4-yl] -amine

Yield 55%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.65 (b, 1H), 8.34 (s, 1H), 7.72 (s, 1H), 7.64 (d, J = 10.0 Hz, 1H), 7.54-7.46 (m, 2H), 7.23 (s, 1H), 4.46 (d, J = 11.0 Hz, 1H), 4.31 (m, 1H), 4.02 (dd, J = 11.1, 8.0 Hz, 1H), 2.52 (m, 2H), 2.41 (m, 4H), 1.77 (m, 2H), 1.02 (m, 6H).

Example 36. (4-Bromo-2-fluorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3- g] quinazolin-4-yl] -amine

Yield 40%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.65 (b, 1H), 8.34 (s, 1H), 7.72 (s, 1H), 7.64 (d, J = 10.0 Hz, 1H), 7.54-7.46 (m, 2H), 7.23 (s, 1H), 4.44 (d, J = 10.9 Hz, 1H), 4.32 (m, 1H), 4.02 (dd, J = 11.1, 8.0 Hz, 1H), 2.53 (m, 2H), 2.36 (m, 4H), 1.90 (m, 2H), 1.60 (m, 6H); MS-ESI 489 (M ⁺ , 1), 467 (12), 463 (16), 460 (100), 395 (8), 271 (9), 78 (12).

Example 37. (3-Chlorophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quina Zolin-4-yl] -amine

Yield 45%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.60 (b, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.92 (d, J = 8.2Hz , 1H), 7.43 (t, J = 8.2Hz, 1H), 7.35 (m, 1H), 7.15 (d, J = 7.9Hz, 1H), 4.56 (d, J = 11.5Hz, 1H), 4.45 (m , 1H), 4.16 (dd, J = 11.5, 8.0 Hz, 1H), 3.64 (m, 2H), 3.40 (m, 4H), 2.43 (m, 4H), 1.96-1.84 (m, 2H).

Example 38. (3-Chlorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [2, 3-g] quinazolin-4-yl} -amine

Yield 32%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.61 (brs, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.93 (d, J = 8.1 Hz , 1H), 7.43 (t, J = 8.1Hz, 1H), 7.35 (m, 1H), 7.14 (d, J = 7.9Hz, 1H), 4.52 (d, J = 10.1Hz, 1H), 4.40 (m , 1H), 4.11 (dd, J = 11.2, 8.0 Hz, 1H), 3.33 (m, 6H), 2.33-2.24 (m, 7H), 1.90-1.80 (m, 2H).

Example 39. (3-Chlorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] Quinazolin-4-yl] -amine

Yield 33%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.60 (brs, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.92 (d, J = 8.0 Hz , 1H), 7.42 (t, J = 8.0Hz, 1H), 7.35 (m, 1H), 7.13 (d, J = 7.9Hz, 1H), 4.51 (d, J = 11.0Hz, 2H), 4.31 (m , 1H), 4.01 (dd, J = 11.0, 8.0 Hz, 1H), 2.51 (m, 2H), 2.40 (m, 4H), 1.89 (m, 2H), 1.47 (m, 4H), 1.35 (m, 2H).

Example 40. (3-Chlorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] Quinazolin-4-yl] -amine

Yield 43%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.61 (brs, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.91 (d, J = 8.0 Hz , 1H), 7.42 (t, J = 8.0Hz, 1H), 7.35 (m, 1H), 7.13 (d, J = 7.9Hz, 1H), 4.45 (d, J = 11.1Hz, 1H), 4.30 (m , 1H), 4.02 (dd, J = 11.1, 8.0 Hz, 1H), 2.51 (m, 2H), 2.40 (m, 4H), 1.79 (m, 2H), 1.01 (m, 6H).

Example 41. (3-Chlorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine

Yield 54%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.60 (b, 1H), 8.54 (s, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.90 (d, J = 8.0Hz , 1H), 7.42 (t, J = 8.0Hz, 1H), 7.34 (m, 1H), 7.13 (d, J = 7.9Hz, 1H), 4.42 (d, J = 11.0Hz, 1H), 4.32 (m , 1H), 4.02 (dd, J = 11.1, 8.0 Hz, 1H), 2.52 (m, 2H), 2.35 (m, 4H), 1.91 (m, 2H), 1.62 (m, 6H).

Example 42. 2-[{2- [4- (3-chlorophenylamino) -7,8-dihydro- [1,4-dioxino [2,3-g] quinazolin-7-yl] -Ethyl}-(2-hydroxyethyl) -amino] -ethanol

Yield 29%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.62 (b, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.91 (d, J = 8.0Hz , 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.33 (m, 1H), 7.13 (d, J = 7.9 Hz, 1H), 4.44 (d, J = 10.9 Hz, 1H), 4.30 (m , 1H), 4.03 (dd, J = 11.1, 8.1 Hz, 1H), 3.70 (m, 4H), 2.51 (m, 2H), 2.42 (m, 4H).

Example 43. (3-Bromophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] Quinazolin-4-yl] -amine

Yield 41%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.50 (b, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.91 (d, J = 7.1Hz , 1H), 7.34-7.17 (m, 3H), 4.50 (d, J = 10.5 Hz, 1H), 4.39 (m, 1H), 4.10 (dd, J = 11.4, 7.9 Hz, 1H), 3.58-3.55 ( m, 4H), 3.31 (m, 2H), 2.39-2.37 (m, 4H), 1.86-1.75 (m, 2H); MS-ESI 471 (M ⁺ , 1), 230 (100), 156 (78), 129 (32), 40 (74).

Example 44. (3-Bromophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [2 , 3-g] quinazolin-4-yl} -amine

Yield 44%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.50 (brs, 1H), 8.47 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 7.1 Hz , 1H), 7.34-7.16 (m, 3H), 4.48 (d, J = 10.1 Hz, 1H), 4.38 (m, 1H), 4.08 (dd, J = 11.1, 8.0 Hz, 1H), 3.30 (m, 6H), 2.30-2.22 (m, 7H), 1.88-1.78 (m, 2H); MS-ESI 484 (M ⁺ , 3), 113 (100), 84 (72), 70 (99), 66 (77).

Example 45. (3-Bromophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine

Yield 47%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.58 (b, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.91 (d, J = 7.1Hz , 1H), 7.38-7.20 (m, 3H), 4.53 (d, J = 11.0Hz, 2H), 4.35 (m, 1H), 4.15 (dd, J = 11.0, 8.0Hz, 1H), 2.51 (m, 2H), 2.40 (m, 4H), 1.89 (m, 2H), 1.47 (m, 4H), 1.36 (m, 2H); MS-ESI 469 (M ⁺ , 1), 320 (5), 267 (4), 193 (5), 95 (8), 44 (100).

Example 46. (3-Bromophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine

Yield 41%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.51 (b, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.93 (d, J = 8.5Hz , 1H), 7.36-7.19 (m, 3H), 4.50 (d, J = 11.3Hz, 1H), 4.42 (m, 1H), 4.11 (dd, J = 11.3, 8.0Hz, 1H), 2.61 (m, 2H), 2.47 (m, 4H), 1.89 (m, 2H), 1.71 (m, 4H); MS-ESI 455 (M ⁺ , 2), 362 (71), 178 (30), 84 (55), 66 (100).

Example 47. (3-Bromophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin- 4-yl] -amine

Yield 41%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.51 (b, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.91 (d, J = 8.5Hz , 1H), 7.37-7.18 (m, 3H), 4.40 (d, J = 11.0Hz, 1H), 4.31 (m, 1H), 4.04 (dd, J = 11.0, 8.0Hz, 1H), 2.52 (m, 2H), 2.34 (m, 4H), 1.90 (m, 2H), 1.62 (m, 6H).

Example 48. 2-[{2- [4- (3-bromophenylamino) -7,8-dihydro- [1,4-dioxino [2,3-g] quinazolin-7-yl ] -Ethyl}-(2-hydroxyethyl) -amino] -ethanol

Yield 29%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.53 (b, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.0Hz , 1H), 7.37-7.19 (m, 3H), 4.44 (d, J = 10.9 Hz, 1H), 4.30 (m, 1H), 4.03 (dd, J = 11.1, 8.1 Hz, 1H), 3.70 (m, 4H), 2.51 (m, 2H), 2.42 (m, 4H); MS-ESI 489 (M ⁺ , 1), 457 (20), 129 (15), 118 (26), 88 (100), 65 (49).

Example 49. [7- (2-Morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]- (3-trifluoromethylphenyl) -amine

Yield 38%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.53 (s, 1 H), 8.52 (s, 1 H) 8.30 (s, 1 H), 7.87 (d, J = 10.9 Hz, 1 H), 7.75-7.38 ( m, 3H), 7.19 (s, 1H), 4.51 (d, J = 10.5 Hz, 1H), 4.38 (m, 1H), 4.11 (dd, J = 11.2, 7.9 Hz, 1H), 3.58-3.53 (m , 4H), 3.31 (m, 2H), 2.39-2.37 (m, 4H), 1.86-1.74 (m, 2H).

Example 50. [7- (2-Morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]- (4-propylphenyl) -amine

Yield 40%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.50 (s, 1H), 9.27 (s, 1H), 8.38 (s, 1H), 7.77 (s, 1H), 7.72 (d, J = 8.4Hz , 2H), 7.15 (m, 2H), 4.51 (d, J = 11.1Hz, 1H), 4.36 (m, 1H), 4.10 (dd, J = 11.1, 8.0Hz, 1H), 3.58-3.53 (m, 4H), 3.31 (m, 2H), 2.54 (t, J = 7.3 Hz, 2H), 2.39-2.37 (m, 4H), 2.04-1.94 (m, 2H), 1.86-1.74 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

Example 51. (4-Bromophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro [2,3-g] quinazolin-4-yl] amine.

Yield 42%; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ9.52 (s, 1H), 9.28 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.80 (m, 2H), 7.21 (s, 1H), 4.50 ( d, J = 11.0Hz, 1H), 4.37 (m, 1H), 4.10 (dd, J = 11.0, 8.0Hz, 1H), 3.58-3.53 (m, 4H), 3.32 ( m, 2H), 2.40-2.36 (m, 4H), 1.85-1.72 (m, 2H).

Example 52. (3-Chloro-4-trifluoromethylphenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro [2,3-g] quinazolin-4 -Yl] amine.

Yield 22%; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ9.52 (s, 1H), 9.46 (s, 1H), 8.45 (s, 1H), 8.23-8.20 (m, 1H), 7.82 (m, 2H) , 4.51 (d, J = 10.9 Hz, 1H), 4.35 (m, 1H), 4.11 (dd, J = 11.0, 7.9 Hz, 1H), 3.58-3.52 (m, 4H), 3.33 (m, 2H), 2.41-2.35 (m, 4H), 1.87-1.73 (m, 2H).

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1: tablet (direct pressure)

After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

Formulation 2: Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3: Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture should be solid no. Filled in 5 gelatin capsules.

Formulation 4: Injection

Injectables were prepared by containing 100 mg of the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

In addition, in order to determine the activity of the receptor tyrosine kinase of the compounds according to the present invention, the experiment to confirm the inhibition rate of the activity of epidermal growth factor receptor (EGFR) was carried out in the following manner.

Experimental Example 1.Effect of EGFR tyrosine kinase

The activity of EGFR tyrosine kinase was measured using an Alpha Screen ™ P-Tyr-100 screening device (Packard BioScience). Alpha Screen means Amplified Luminescent Proximity Homogenous Assay, and is an immunoassay using Luminescent Oxygen Radical Channel. In this experiment, biotinylated poly [Glu: Tyr] (4: 1) (Packard BioScience) was used as a substrate for the enzyme, and a streptavidin-coated donor could bind to these substrates. Receptor beads combined with an antibody (P-Tyr-100) capable of recognizing and reacting beads and phosphorylated substrates were used for the enzymatic reaction. EGFR tyrosine kinase was isolated from Sf21 insect cells by inducing large expression of the enzyme by infecting EFGR with pBacPAK8 insect expression vector (Clontech).

The analysis was carried out through the following three steps using a white and opaque 384-well plate (Greiner Bio-One) so that the total reaction volume of each well was 25 μL. First, add 5 μL of EGFR and VEGFR enzyme (5 ng) to each well of a 384-well plate with 5 μL of known standard inhibitor Tyrphostin A51 (Upstate Biotech) or the compound to be tested and react at room temperature for 15 minutes. It was. Second, after 15 minutes of reaction, 5 μL of biotinylated poly [Glu: Tyr] (4: 1) and ATP were added to each well so that the final concentrations were 5 nM and 100 μM, respectively. Proceeded. The composition of the buffer used for the enzyme reaction was 50 mM Tris-HCl (pH 7.5), 5 mM MgCl ₂ , 5 mM MnCl ₂ , 2 mM DTT and 0.01% Tween-20. Third, after 1 hour of enzymatic reaction, 10 μL of capture buffer containing donor and receptor beads was added thereto, and the enzyme reaction was further performed at room temperature for 1 hour. This process captures a streptavidin donor with a final concentration of 20 μg / mL, a P-Tyr-100 bead receptor, and EDTA to stop the ongoing enzymatic reaction and recognize the degree of phosphorylation of the substrate. buffer) was used. The composition (2.5-fold concentration) of the capture buffer was 62.5 mM HEPES (pH 7.4), 250 mM NaCl, 100 mM EDTA and BSA 0.25%. After the reaction, the activity of the enzyme can be determined by measuring the AlphaScreen signal using a Fusion ™ microplate analyzer (PerkinElmer).

In order to compare the activity of the compounds according to the present invention on epidermal growth factor receptor (EGFR), AstraZeneca's ZD-1839 (Iressa ™) compound and PD-150307 compound were used as control compounds. The results of the activity comparison are shown in Table 1 below.

Was Example 26, 37, 38, 39, 40, 41, 43, 44, 45 and 46 compounds appeared to have inhibitory activity against EGFR similar or superior as compared to the ZD-1839 according to the disease, in vitro The compounds of Examples 37, 39 and 46 were found to show a higher inhibitory effect of at least 90% even when compared to the PD-150305 compound known as the compound having the highest drug efficacy in.

Test Example 2: MTT efficacy search (Growth-inhibitory assay)

The growth inhibitory effect of compounds on various types of human cancer cells was measured using (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT). First, the compound was added to each well of the 96-well plate, and 100 μL of the cell culture solution containing the cells to be confirmed was added thereto, and the compound and the culture solution were shaken to mix well. Start incubation with ⁴ cells / 100 μL cell culture (RPMI-1640 [Gibco]; 10% FBS [Gibco], 100 μg / mL streptomycin, and 100 U / mL penicillin) at 37 ° C., 5% CO ₂ Incubate for 48 hours in an incubator After 48 hours incubation, add 20 μL of MTT (Sigma) dissolved in 5 mg / mL in PBS to each well for 1 hour and 30 minutes in a 37 ° C, 5% CO ₂ incubator. The reaction was induced by incubation, after which the supernatant was removed and 100 μL of di Butyl sulfoxide: adding (DMSO Sigma Co.) using the following standard, ELISA reader to mix on a shaker (shaker plate) was measured at 570 nm.

In order to compare the activity for the compounds according to the invention, AstraZeneca's ZD-1839 (Iressa ™) compound was used as a control compound. The results of the activity comparison for the synthesized example compound and the control compound are shown in FIG. 1. According to Figure 1, the compounds of Examples 37, 38 and 48 shows a cell growth inhibitory effect similar to Iressa ™, but Example 46 shows a better effect than Iressa.

Test Example 3 Oral Toxicity Test

Some compounds according to the invention were subjected to acute toxicity testing in rats. As a result, up to 10 mg / kg oral dose showed no serious toxicity symptoms, and up to 100 mg / kg oral dose did not cause any death.

As described in detail above, the novel quinazoline derivative represented by Chemical Formula 1 according to the present invention is a substance having a 1,4-dioxane group having a tricyclic structure connected to the C-6 and C-7 positions of quinazoline. The effect of increasing the solubility of the compound can be expected by the introduction of the, 4-dioxane group, and since the inhibitory activity of tyrosine kinase is excellent, it can be usefully used as a therapeutic agent for diseases caused by abnormal kinase activity, particularly lung cancer and breast cancer.

Claims (11)

A quinazoline derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof: [Formula 1]

In Chemical Formula 1, m is an integer from 1 to 5; R ¹ is a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 haloalkyl group, a cyano group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a methylthio group, a nitro group, or —NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are the same as or different from each other, each is a hydrogen atom or an alkyl group of C _1-6 ); R ² and R ³ are the same as or different from each other, and each hydrogen atom, an alkyl group of C _1-6 , a hydroxyalkyl group of C _2-3 , or a substituted benzyl group (wherein the substituent is a hydrogen atom, a halogen atom, or a hydroxy group). , C _1-6 alkyl group or C _1-6 alkoxy group); Or R ² and R ³ are piperidine, pyrrolidine, morpholine, or piperazine groups linked together with N to which they are attached or with another heteroatom selected from O, S, and NR ⁶ . In this case, R ⁶ represents a hydrogen atom, a C _1-6 alkyl group or a C _3-7 cycloalkyl group. The compound of claim 1, wherein m is an integer of 1 to 5; R ¹ is a hydrogen atom, a halogen atom, a C _1-6 haloalkyl group, a C _1-6 alkyl group, or an alkoxy group of C _1-6, and; R ² and R ³ are the same as or different from each other, and are each an alkyl group of C _1-6 , or a hydroxyalkyl group of C _2-3 ; Or R ² and R ³ are piperidine, pyrrolidine, morpholine, or piperazine groups linked together with N to which they are attached or with another heteroatom selected from O, and NR ⁶ , wherein R ⁶ is a hydrogen atom, an alkyl group of C _1-6 or a cycloalkyl group of C _3-7 ). The compound of claim 1, wherein m is an integer of 1 to 5; R ¹ is a hydrogen atom, a halogen atom, a trifluoromethyl group, a methyl group, an ethyl group, a propyl group, or a methoxy group; R ² and R ³ are the same or different from each other and are an ethyl group or a hydroxyethyl group, or R ² and R ³ are linked to each other to form a piperidine, pyrrolidine, morpholine, or N-methylpiperazine group Compounds characterized in that. According to claim 1, wherein the quinazoline derivative represented by Formula 1 is (3-chlorophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4- General] -amine; (3-chlorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [2,3-g] Quinazolin-4-yl} -amine; (3-chlorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine; (3-chlorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine; (3-chlorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]- Amines; 2-[{2- [4- (3-chlorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethyl}- (2-hydroxyethyl) -amino] -ethanol; (3-bromophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine; (3-bromophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl} -amine; (3-bromophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin- 4-yl] -amine; (3-bromophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin- 4-yl] -amine; (3-bromophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl] Amines; 2-[{2- [4- (3-bromophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl] -ethyl} -(2-hydroxyethyl) -amino] -ethanol; (3-chloro-4-fluorophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] Quinazolin-4-yl] -amine; (3-chloro-4-fluorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [2 , 3-g] quinazolin-4-yl} -amine; (3-chloro-4-fluorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine; (3-chloro-4-fluorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine; (3-chloro-4-fluorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxyno [2,3-g] quinazoline- 4-yl] -amine; 2-[{2- [4- (3-chloro-4-fluorophenylamino) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-7-yl ] -Ethyl}-(2-hydroxyethyl) -amino] -ethanol; (4-bromo-2-fluorophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine; (4-bromo-2-fluorophenyl)-{7- [2- (4-methylpiperazin-1-yl) -ethyl] -7,8-dihydro- [1,4] dioxino [ 2,3-g] quinazolin-4-yl} -amine; (4-bromo-2-fluorophenyl)-[7- (2-piperidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3- g] quinazolin-4-yl] -amine; (4-bromo-2-fluorophenyl)-[7- (2-pyrrolidin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3- g] quinazolin-4-yl] -amine; (4-bromo-2-fluorophenyl)-[7- (2-diethylamino-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazoline -4-yl] -amine; [7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(3-tri Fluoromethylphenyl) -amine; [7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4-yl]-(4-propyl Phenyl) -amine; (4-bromophenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g] quinazolin-4 -Yl] -amine; And (3-chloro-4-trifluoromethylphenyl)-[7- (2-morpholin-1-yl-ethyl) -7,8-dihydro- [1,4] dioxino [2,3-g ] Quinazolin-4-yl] -amine The compound characterized in that it is selected from. 2. A compound according to claim 1, wherein said pharmaceutically acceptable salt is in the form of an acid addition salt formed by free acid. The method of claim 5, wherein the free acid is citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, gluturonic acid, embonic acid, glutamic acid and An organic acid selected from partic acid, or an inorganic acid selected from bromic acid, sulfuric acid and phosphoric acid. A process of preparing a compound represented by the following Chemical Formula 4 by combining the dioxyno quinazoline compound represented by the following Chemical Formula 2 with the aniline compound represented by the following Chemical Formula 3, Deprotecting the compound represented by Chemical Formula 4 to prepare a compound represented by the following Chemical Formula 5, and After converting the hydroxy group of the compound represented by Formula 5 to a leaving group selected from sulfonyloxy group and halogen, it is combined with an amine compound represented by HNR ² R ³ to form a quinazoline derivative represented by the following Formula 1 Or a process for preparing the isomers thereof Manufacturing method characterized in that consisting of:

In the above, R ¹ , R ² , R ³ , and m are as defined in claim 1, respectively. The method according to claim 7, wherein the dioxyno quinazoline compound represented by Formula 2 is a racemate or an optical isomer. Quinazolin derivatives represented by the following formula (1), pharmaceutically acceptable salts thereof, solvates thereof, or isomers for the treatment of tumor diseases, characterized in that it contains: [Formula 1]

In Chemical Formula 1, m is an integer from 1 to 5; R ¹ is a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 haloalkyl group, a cyano group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a methylthio group, a nitro group, or —NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are the same as or different from each other, each is a hydrogen atom or an alkyl group of C _1-6 ); R ² and R ³ are the same as or different from each other, and each hydrogen atom, an alkyl group of C _1-6 , a hydroxyalkyl group of C _2-3 , or a substituted benzyl group (wherein the substituent is a hydrogen atom, a halogen atom, or a hydroxy group). , C _1-6 alkyl group or C _1-6 alkoxy group); Or R ² and R ³ are 5 to 7 membered heterocyclic groups linked together with N to which they are attached or with another heteroatom selected from O, S, and NR ⁶ , wherein R ⁶ is hydrogen Atom, C _1-6 alkyl group or C _3-7 cycloalkyl group). The pharmaceutical composition for treating tumor disease according to claim 9, wherein the composition is formulated as an oral administration or injection. The pharmaceutical composition for treating tumor disease according to claim 10, wherein the oral dosage form is selected from tablets, capsules and powders.

Images