KR101789934B1 - Novel compound having tumor diagnosis or tumor growth inhibitory activity on EGFR mutant and medical uses comprising the same - Google Patents

Abstract

The present invention relates to a novel compound or a salt thereof having tumor growth and growth inhibitory activity with epithelial cell growth factor receptor mutants, a contrast agent containing the same, and a pharmaceutical composition for treating or preventing EGFR-related cancer diseases containing the same as an active ingredient The novel compound or its salt according to the present invention can selectively inhibit the EGFR mutant without inhibiting the wild-type EGFR, and thus can treat and prevent lung cancer, colon cancer or breast cancer which is an EGFR-related cancer disease. Especially, Can effectively treat and prevent non-small cell lung cancer.
In addition, the novel compounds or salts thereof according to the present invention target tumor response to EGFR mutation-inducing cancer cells or EGFR T790M mutation-inducing cancer cells through EGFR mutation rather than wild-type EGFR-overexpressing cancer cells, And can be used as a contrast agent that can be distinguished.

Description

TECHNICAL FIELD [0001] The present invention relates to novel compounds having epithelial cell growth factor receptor mutants having tumor diagnostic and tumor growth inhibitory activity and medicinal applications comprising the same,

The present invention relates to a novel compound or a salt thereof having tumor growth and growth inhibitory activity with epithelial cell growth factor receptor mutants, a contrast agent containing the same, and a pharmaceutical composition for treating or preventing EGFR-related cancer diseases containing the same as an active ingredient will be.

The epithelial growth factor receptor (EGFR) regulates cell proliferation, survival, migration, differentiation, and plays an important role in the growth of cancer cells. The EGFR inhibitors gefitinib (Iressa) and erlotinib (Tarceva) are currently in clinical use for the treatment of non-small cell lung cancer (NSCLC).

However, gefitinib and elotinib show a good effect on EGFR with a mutant (L858R) that activates wild-type EGFR or kinase domain but has a weak effect on EGFR-T790M.

The T790M mutant is a single point mutation at the gatekeeper of the ATP binding pocket, resulting in a change of Threonine ⁷⁹⁰ to Methionine ⁷⁹⁰ . When this mutation occurs, the affinity of EGFR for gefitinib and elothinib is almost unchanged, but affinity for ATP is increased. Thus, gefitinib and elotinib do not show good effects on T790M. This EGFR T790M mutation is a major obstacle to the treatment of non-small cell lung cancer, accounting for approximately 50% of clinically occurring adaptive tolerance.

Many researchers are currently working on overcoming the T790M. Currently known EGFR T790M inhibitors are ATP competitive irreversible inhibitors that covalently bind to Cystein ⁷⁹⁷ at the ATP binding site. However, first-generation inhibitors with quinazoline structures such as HKI-272, PF00299804, and BIBW-2992 have had less than expected clinical trials.

Therefore, it is necessary to develop a novel EGFR T790M inhibitor that can effectively treat EGFR-related cancer diseases such as non-small cell lung cancer.

It is also clear that EGFR-related cancer diseases such as non-small cell lung cancer are wild-type EGFR-overexpressing cancer cells, cancerous cells (ΔE746-A750, L858R) with EGFR mutation, or cancer cells showing EGFR T790M mutation , It is necessary to develop a technology that can clearly diagnose the characteristics of EGFR-related cancer cells because it is more effective in treating cancer diseases.

Korean Patent No. 0524701

It is an object of the present invention to develop an EGFR inhibitor that selectively inhibits EGFR mutant without inhibiting wild-type EGFR.

It is also an object of the present invention to develop a contrast agent comprising a wild-type EGFR-overexpressing cancer cell, a cancer cell having Zephyr's sensitivity through an EGFR mutation or a cancer cell target compound capable of clearly distinguishing a cancer cell showing an EGFR T790M mutation have.

In order to achieve the above object, the present invention provides a compound represented by the following formula (1) or a salt thereof:

[Chemical Formula 1]

In the above formula (1), R may be selected from propionamido or acrylamido.

The present invention also provides a pharmaceutical composition for the treatment or prevention of cancer diseases related to epithelial growth factor receptor (EGFR), which comprises a compound represented by the following formula (1) or a salt thereof as an active ingredient:

[Chemical Formula 1]

In the above formula (1), R may be selected from propionamido or acrylamido.

The present invention also provides a contrast agent comprising a compound represented by the following formula (2) or a salt thereof:

(2)

In Formula 2, R may be selected from propionamido or acrylamido.

The novel compound or its salt according to the present invention can selectively inhibit the EGFR mutant without inhibiting the wild-type EGFR, and thus can treat and prevent lung cancer, colon cancer or breast cancer, which is an EGFR-related cancer disease. Especially, Can effectively treat and prevent non-small cell lung cancer.

In addition, the novel compounds or salts thereof according to the present invention target tumor response to EGFR mutation-inducing cancer cells or EGFR T790M mutation-inducing cancer cells through EGFR mutation rather than wild-type EGFR-overexpressing cancer cells, And can be used as a contrast agent that can be distinguished.

Figures 1 and 2 show the ¹⁸ F labeling reaction conditions, the course of the reaction, and the final compound labeled ¹⁸ F.
FIGS. 3 and 4 show the result of analyzing the peak of the final compound labeled with ¹⁸ F by conducting an experiment with CONDITION B. FIG.

 The terms, techniques, and the like described in the present invention are used in the meaning commonly used in the technical field to which the present invention belongs, unless otherwise specified. In addition, all documents referred to in this specification are included in the present specification as a document for explaining the present invention.

Hereinafter, the present invention will be described in more detail.

The present invention provides a compound represented by the following formula (1) or a salt thereof:

[Chemical Formula 1]

In the above formula (1), R may be selected from propionamido or acrylamido.

The compound was prepared from N- (4- (3-chloro-4-fluorophenylamino) -7- (1- (4- fluorobenzyl) -1H- (4- (3-chloro-4-fluorophenylamino) -7- ((1- (4-fluorobenzyl) -1H-1,2 , 3-triazol-4-yl) methoxy) quinazolin-6-yl) acrylamide.

The compounds according to the present invention can be prepared into corresponding salts by known methods. Such salts are preferably water-soluble without toxicity. Preferred salts include salts of alkali metals such as potassium, sodium and the like; Salts of alkaline earth metals such as calcium, magnesium and the like; And amines such as tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, And salts of pharmaceutically acceptable amines such as N-methyl-D-glucamine and the like.

In addition, the compounds according to the present invention can be prepared by the known methods with the corresponding acid addition salts. These acid addition salts are preferably water-soluble without toxicity. Preferred acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate, or organic acid salts such as acetate, lactate, tartrate, oxalate, fumarate, maleate, citrate, benzoate, methane Organic acid salts such as sulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate and gluconate.

The compound or its salt according to the present invention can be prepared as a hydrate by a known method.

In particular, the compounds or salts thereof according to the present invention can selectively inhibit EGFR mutants without inhibiting wild-type EGFR.

The present invention also provides a pharmaceutical composition for the treatment or prevention of cancer diseases related to epithelial growth factor receptor (EGFR), which comprises a compound represented by the following formula (1) or a salt thereof as an active ingredient:

[Chemical Formula 1]

In the above formula (1), R may be selected from propionamido or acrylamido.

The compound was prepared from N- (4- (3-chloro-4-fluorophenylamino) -7- (1- (4- fluorobenzyl) -1H- (4- (3-chloro-4-fluorophenylamino) -7- ((1- (4-fluorobenzyl) -1H-1,2 , 3-triazol-4-yl) methoxy) quinazolin-6-yl) acrylamide.

The epithelial growth factor receptor (EGFR) -related cancer disease may be a cancer disease selected from the group consisting of lung cancer, colon cancer and breast cancer, preferably non-small cell lung cancer.

The pharmaceutical compositions may further comprise suitable carriers, excipients or diluents conventionally used in the manufacture of pharmaceutical compositions.

Examples of the carrier, excipient or diluent which can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .

In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.

In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The compound or its salt according to the present invention may be contained in an amount of 0.01 to 30.0 parts by weight based on 100 parts by weight of the total amount of the pharmaceutical composition. If the content is less than 0.01% by weight, the effect of inhibiting the mutant EGFR T790M is insignificant. If the content is more than 30.0% by weight, the effect of the amount may be insignificant.

The amount of the compound of the present invention which is an active ingredient of the above pharmaceutical composition or its salt may vary depending on the age, sex, body weight and disease of the patient, but it is 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg It can be administered once to several times a day.

In addition, the dose of the compound or its salt according to the present invention may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intratracheal, intrauterine or intracerebroventricular injections.

The compound or its salt according to the present invention has a stability of not less than 2 g / kg of 50% lethal dose (LC ₅₀ ) and can be used in the pharmaceutical composition of the present invention.

The present invention also provides a contrast agent comprising a compound represented by the following formula (2) or a salt thereof:

(2)

In Formula 2, R may be selected from propionamido or acrylamido.

Such a compound can be very useful for diagnosing whether to target any one of tumor cells selected from wild-type EGFR-overexpressing cells, zetitinib-sensitive EGFR mutant cells or T790M mutant cells.

The contrast agent may further comprise optional additives such as a pH adjusting agent such as an acid, a base, a buffer, a stabilizing agent such as ascorbic acid, or an isotonic agent such as sodium chloride.

The compound used as the contrast agent is introduced into a tissue or patient in a detectable amount, and can be administered to a tissue or patient by methods known to those skilled in the art. For example, the compounds may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, topically (by powders, ointments or drops) Or as an intranasal spray. Administration of the labeled compound to a patient can be by a systemic or topical route of administration. For example, the labeled compound may be administered to a patient to be delivered throughout the body. Alternatively, the labeled compound can be administered to the desired specific organ or tissue.

Those skilled in the art are well aware of the various ways to detect labeled compounds. For example, radioactive labeled compounds can be detected using magnetic resonance imaging (MRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT). The label that is introduced into the compound will be determined according to the desired detection method.

Hereinafter, the present invention will be described in detail with reference to the following Production Examples, Examples and Experimental Examples. However, the following Production Examples, Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Production Examples, Examples and Experimental Examples.

< Reference Example  1> Preparation of the synthesis of the compound

TLC silica gel (DC Kiesegel 60 F254, Merck) was used for thin layer chromatography (TLC) and 1 mm silica gel (PLC Kiesegel 60 F254, Merck) was used for fractional silica gel column chromatography (PTLC). Column chromatography used silica gel (Kiesegel 60 F254, 230-40 mesh, Merck). The microwave reactor used was Anton Paar's Monowave ^TM 300. ¹ H NMR (nuclear magnetic resonance) spectra were measured using Gemini 2000 (300 MHz) and VNS (600 MHz, Varian). TMS (tetramethylsilane) was used as an internal standard, chemical shifts were expressed in ppm (parts per million), and coupling constants in Hz.

Example 1 Synthesis of Compounds 6a to 10f

[Reaction Scheme 1]

1. Synthesis of 6-iodoquinazolin-4-ol (1)

5-Iodoanthranilic acid methyl ester (1 g, 3.61 mmol) and formamide (2 ml) were placed in a microwave reactor vial and used as a reaction material and solvent. For 1 hour. After the completion of the reaction, the resulting solid compound was washed with water, and then the water was removed from the oven at 100 ° C for 1 hour to obtain Compound 1 (784 mg, 2.88 mmol, 80%).

^{1 H NMR (300 MHz, acetone} -d 6): δ 8.50 (d, 1H, J = 2.1 Hz), 8.17 (s, 1H), 8.11 (dd, 1H, J = 8.7Hz, 2.1 Hz), 7.50 ( d, 1 H, J = 8.7 Hz)

2. 4-Chloro-6-iodoquinazoline (2) Synthesis

Compound 1 (784 mg, 2.88 mmol) was dissolved in 10 ml of tetrahydrofuran (THF), and oxalyl chloride (731 mg, 5.76 mmol) was added. Two droplets of DMF were immediately added as a reaction catalyst. And the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was completely concentrated to obtain Compound 2 (828 mg, 2.85 mmol, 99%).

^{1 H NMR (300 MHz, acetone} -d 6): δ 8.42 (s, 1H), 8.40 (d, 1H, J = 2.1 Hz), 8.15 (dd, 1H, J = 8.7 Hz, 2.1 Hz), 7.52 ( d, 1 H, J = 8.7 Hz)

3. Synthesis of N- (3-chloro-4-fluorophenyl) -6-iodoquinazolin-4-amine (3)

Compound 2 (828 mg, 2.85 mmol) was dissolved in 10 ml of THF. 3-Chloro-4-fluoroaniline (498 mg, 3.42 mmol) was dissolved in 5 ml of THF and the mixture was refluxed for 1 hour. The resulting solid was washed with cold THF and dried to obtain Compound 3 (819 mg, 2.05 mmol, 60%).

^{1 H NMR (300 MHz, acetone} -d 6): δ 8.83 (d, 1H, J = 1.8 Hz), 8.71 (s, 1H), 8.32 (dd, 1H, J = 6.6 Hz, 2.4 Hz), 8.16 ( (d, 1H, J = 8.7 Hz, 1.8 Hz), 7.89-7.92 (m, 1H), 7.62

4. Synthesis of N- (3-chloro-4-fluorophenyl) -6 - ((trimethylsilyl) ethynyl) quinazolin-

Tetramethylsilylacetylene (402 mg, 4.1 mmol) was iodinated during stirring at room temperature after compound 3 (819 mg, 2.05 mmol) and tetrakistriphenylphosphine palladium (0) (473 mg, 0.41 mmol) After dissolving in copper (192 mg, 0.41 mmol) and 10 ml of THF, TEA (418 mg, 4.1 mmol) was added and the solution color changed from yellow to fluorescent orange. The acetylene mixture was added dropwise to the reaction solution flask of compound 3, Respectively. When the reaction was complete, the residue was diluted with CH ₂ Cl ₂ and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography under the conditions of ethyl acetate (EA): hexane (HEX) = 1: 20 to give compound 4 (758 mg, 2.05 mmol, 50% .

^{1 H NMR (300 MHz, CDCl} 3): δ 8.58 (s, 1H), 8.56 (d, 1H, J = 1.2 Hz), 8.09 (dd, 1H, J = 6.6 Hz, 2.4 Hz), 7.86 (dd, 1H, J = 8.4 Hz, 1.5 Hz), 7.69-7.76 (m, 3H), 7.27

5. Synthesis of N- (3-chloro-4-fluorophenyl) -6-ethynylquinazolin-4-amine (5)

To a flask containing Compound 4 (758 mg, 2.05 mmol), THF (4.1 mmol, 4.1 ml) was added to 1M of Compound 4, stirred at room temperature for 10 minutes, and the reaction was terminated by TLC. The solution was concentrated under reduced pressure to remove THF, the residue was diluted with CH ₂ Cl ₂ , and washed with water and brine. The filtrate was dried over anhydrous MgSO ₄ , concentrated under reduced pressure, and subjected to column chromatography under conditions of EA: HEX = 1: 2 to obtain Compound 5 (428 mg, 1.44 mmol, 70%).

^{1 H NMR (300 MHz, CDCl} 3): δ 8.70 (s, 1H), 8.60 (d, 1H, J = 1.2 Hz), 8.34 (dd, 1H, J = 6.6 Hz, 2.4 Hz), 7.81-7.93 ( m, 3H), 7.39 (t, IH, J = 9 Hz), 3.90

6. Synthesis of compounds 6a to 10f

After dissolving Compound 5 (20 mg, 0.067 mmol) in H ₂ O: i-PrOH, various azide compounds (0.1 mmol) were added and sodium ascorbate (1.4 mg, 0.007 mmol) (II) 5 hydrate (0.2 mg, 0.0007 mmol) dissolved in dichloromethane (100 μl) were added in this order. And the mixture was stirred at room temperature for 10 minutes. The resulting solid was filtered, dissolved in THF, and separated by CH ₂ Cl ₂ : MeOH = 20: 1 using PTLC to obtain compounds 6a to 10f.

1) 6- (l-Benzyl-lH-1,2,3-triazol-4-yl) -N- (3-chloro-4- fluorophenyl) quinazolin-

Yield 4.8 mg, 0.011 mmol, 16%

^{1 H NMR (300 MHz, acetone} -d 6): δ 9.53 (s, 1H), 8.84 (d, 1H, J = 1.2 Hz), 8.66 (s, 1H), 8.49 (s, 1H), 8.33-8.35 (m, 1H), 8.30 (dd, 1H, J = 8.4 Hz, 1.8 Hz), 7.89-7.92 (m, 1H), 7.87 (d, 1H, J = 9 Hz), 7.31-7.44

2) N- (3-Chloro-4-fluorophenyl) -6- (1- (4-fluorobenzyl) -1H-1,2,3- triazol- 4-yl) quinazolin- (6b)

Yield: 5 mg, 0.011 mmol, 16%

¹ H NMR (600 MHz, CD ₃ OD):? 8.21 (d, 1H, J = 1.8 Hz), 8.57 (s, 1H), 8.42 1H, J = 9Hz), 7.71-7.74 (m, 1H,), 7.46-7.48 (m, 2H), 8.07 (dd, 1H, J = 6.6Hz, 2.4Hz) 7.28 (t, 1 H, J = 9 Hz), 7.14-7.18 (m, 2H), 5.69

3) Synthesis of N- (3-chloro-4-fluorophenyl) -6- (1- (4-methoxybenzyl) -1H-1,2,3- triazol-4-yl) quinazolin- (6c)

Yield: 4 mg, 0.008 mmol, 13%

^{1 H NMR (600 MHz, acetone} -d 6): δ 9.52 (s, 1H), 8.81 (d, 1H, J = 1.8 Hz), 8.66 (s, 1H), 8.41 (s, 1H), 8.32-8.35 (m, 1H), 8.28 (dd, 1H, J = 9 Hz, 1.8 Hz), 7.88-7.92 (m, 1H), 7.38-7.41 ), 6.96-6.98 (m, 2H), 5.65 (s, 2H), 3.80 (s, 3H)

4) Synthesis of N- (3-chloro-4-fluorophenyl) -6- (1- (3-methoxybenzyl) -1H-1,2,3- triazol-4-yl) quinazolin- (6d)

Yield: 6 mg, 0.013 mmol, 19%

¹ H NMR (600 MHz, CD ₃ OD):? 8.77 (dd, 1H, J = 1.8 Hz, 0.6 Hz), 8.55 (s, 1H), 8.38 (D, 1H, J = 9 Hz), 7.69-7.22 (m, 1H), 7.32 2H), 6.94 (dd, 1H, J = 8.4 Hz, 1.2 Hz), 5.65 (s, 2H), 3.79 s, 3H)

5) Synthesis of N- (3-chloro-4-fluorophenyl) -6- (1- (4-methylbenzyl) -1H-1,2,3- triazol-4-yl) quinazolin- 6e)

Yield: 7 mg, 0.015 mmol, 23%

^{1 H NMR (300 MHz, acetone} -d 6): δ 9.54 (s, 1H), 8.82 (d, 1H, J = 2.1 Hz), 8.66 (s, 1H), 8.44 (s, 1H), 8.28-8.35 (m, 2H), 7.85-7.93 (m, 2H), 7.22-7.36 (m, 4H), 6.79 (s,

6) N- (3-Chloro-4-fluorophenyl) -6- (1- (4-chlorophenethyl) -1H-1,2,3- triazol-4-yl) quinazolin- (7)

Yield: 8 mg, 0.016 mmol, 24%

^{1 H NMR (600 MHz, acetone} -d 6): δ 10.12 (s, 1H), 9.03 (d, 1H, J = 1.8 Hz), 8.63 (d, 2H, J = 2.4 Hz), 8.24 (dd, 1H 2H), 7.47 (t, 1H, J = 9 Hz), 7.25-7.27 (m, 2H), 4.73 (t, 2H, J = 9 Hz), 3.26 (t, 2H, J = 7.2 Hz)

7) N- (3-Chloro-4-fluorophenyl) -6- (1- (3-phenylpropyl) -lH-1,2,3- triazol-4-yl) quinazolin- 8)

Yield: 7 mg, 0.015 mmol, 22%

^{1 H NMR (600 MHz, acetone} -d 6): δ 9.57 (s, 1H), 8.85 (d, 1H, J = 1.8 Hz), 8.67 (d, 2H, J = 1.2 Hz), 8.35-8.38 (m J = 6.6 Hz, 2.4 Hz), 7.91-7.94 (m, IH), 7.88 (d, IH, J = 2H, J = 7.2 Hz), 7.26-7.35 (m, 5H), 7.19-7.22 (m, 2H)

8) Synthesis of (E) -N- (3-chloro-4-fluorophenyl) -6- (1-cinnamyl-1H-1,2,3- triazol-4-yl) quinazolin- 9)

Yield: 6 mg, 0.013 mmol, 19%

¹ H NMR (600 MHz, acetone-d ₆ ):? 8.77 (d, 1H, J = 1.8 Hz), 8.54 (s, 1H), 8.44 (M, 2H), 7.31 (d, 1H, J = 9 Hz), 8.05 (dd, 1H, J = 6.6Hz, 3Hz), 7.81 2H), 7.23-7.28 (m, 2H), 6.81 (d, 1H, J = 16.2 Hz), 6.50-6.55

9) Preparation of N- (3-chloro-4-fluorophenyl) -6- (1- (2-ethoxyethyl) -1H-1,2,3- triazol-4-yl) quinazolin- (10a)

Yield: 6 mg, 0.014 mmol, 21%

^{1 H NMR (600 MHz, DMSO} -d 6): δ 10.12 (s, 1H), 9.06 (d, 1H, J = 1.8 Hz), 8.63 (d, 2H, J = 1.2 Hz), 8.31 (dd, 1H 2H), 7.47 (t, 1H, J = 9Hz), 4.64 (t, 2H, J = 8.4Hz, 1.8Hz), 8.20 (dd, 1H, J = 7.2Hz, 3Hz), 7.86-7.89 2H, J = 5.4 Hz), 3.85 (t, 2H, J = 5.4 Hz), 5.27

10) N- (3-Chloro-4-fluorophenyl) -6- (1- (2-propoxyethyl) -1H-1,2,3- triazol- 4- yl) quinazolin- (10b)

Yield: 5 mg, 0.011 mmol, 17%

^{1 H NMR (300 MHz, acetone} -d 6): δ 9.60 (s, 1H), 8.85 (d, 1H, J = 4.2 Hz), 8.68 (s, 1H), 8.48 (s, 1H), 8.37-8.40 J = 18 Hz), 4.69 (t, 2H, &lt; RTI ID = 0.0 &gt; J = 3H, J = 14.2 Hz), 3.92 (t, 2H, J = 10.2 Hz)

11) Synthesis of N- (3-chloro-4-fluorophenyl) -6- (1- (2-methoxyethyl) -1H-1,2,3- triazol- (10c)

Yield: 8 mg, 0.02 mmol, 30%

^{1 H NMR (600 MHz, acetone} -d 6): δ 9.56 (s, 1H), 8.84 (d, 1H, J = 1.2 Hz), 8.67 (s, 1H), 8.45 (s, 1H), 8.35-8.38 (m, 1H), 8.33 (dd, 1H, J = 8.4 Hz, 1.8 Hz), 7.91-7.94 J = 4.8 Hz), 3.36 (s, 3H), 4.68 (t, 2H, J =

12) Synthesis of N- (3-chloro-4-fluorophenyl) -6- (1- (3-methoxypropyl) -1H-1,2,3- triazol- (10d)

Yield: 6 mg, 0.014 mmol, 21%

¹ H NMR (600 MHz, acetone-d ₆ ):? 9.56 (s, IH), 8.67 (s, IH), 8.47 (s, IH), 8.35-8.38 J = 9Hz), 7.91-7.94 (m, 1H), 7.89 (d, 1H, J = 9 Hz), 7.34 6 Hz), 3.44 (t, 2H, J = 6 Hz), 3.32 (s, 3H), 2.20-2.24

13) Synthesis of 4- (4- (4- (3-chloro-4-fluorophenylamino) quinazolin-6-yl) -1H-1,2,3- triazol- (10e)

Yield: 4 mg, 0.009 mmol, 13%

^{1 H NMR (600 MHz, DMSO} -d 6): δ 10.13 (s, 1H), 9.07 (d, 1H, J = 3 Hz), 8.70 (s, 1H), 8.64 (s, 1H), 8.29 (dd 1H, J = 17.4 Hz, 1.8 Hz), 8.21 (dd, 1H, J = 13.8 Hz, 5.4 Hz), 7.88-7.92 (m, 2H), 7.47 2H, J = 13.8 Hz), 3.41 (t, 2H, J = 13.8 Hz), 1.92-2.03 (m, 2H), 1.52-1.62

14) N- (3-Chloro-4-fluorophenyl) -6- (1-pentyl-1 H-1,2,3- triazol-4-yl) quinazolin-

Yield: 8 mg, 0.019 mmol, 29%

^{1 H NMR (600 MHz, DMSO} -d 6): δ 10.10 (s, 1H), 9.04 (d, 1H, J = 2.1 Hz), 8.66 (s, 1H), 8.62 (s, 1H), 8.26 (dd 1H, J = 8 Hz), 8.19 (dd, 1H, J = 6.6 Hz, 2.4 Hz), 7.85-7.88 (m, 2H), 7.45 2H, J = 7.2 Hz), 1.84-1.90 (m, 2H), 1.27-1.34

Example 2 Synthesis of Compounds 16a to 17 and Compounds 18a to 22c

[Reaction Scheme 2]

1. Synthesis of 7-chloro-N- (3-chloro-4-fluorophenyl) -6-nitroquinazolin-4-amine (12)

10 ml of phosphorous oxychloride, 7-chloro-6-nitroquinazolin-4 (3H) -one 11 (5 g, 22.16 mmol) dissolved in 30 ml of CH ₃ CN was added And the mixture was stirred at 80 ° C for 5 hours. After 5 hours, 3-chloro-4-fluoroaniline (3.871 g, 26.59 mmol) dissolved in 10 ml of dioxane was added dropwise thereto, followed by stirring for 1 hour. After the completion of the reaction was confirmed by TLC, the pH of the solution was adjusted to 8-10 with 2N KOH solution in the reaction solution, and the resulting solid was filtered. The solid compound was washed with water and ethanol, and then Compound 12 (6.574 g, 18.61 mmol , 70%).

¹ H NMR (300 MHz, acetone-d ₆ ):? 9.15 (s, IH), 8.79 (s, IH), 8.45 (dd, IH, J = 6.3 Hz, 2.1 Hz), 8.07 , 7.80-7.85 (m, IH), 7.37 (t, IH, J = 9 Hz)

2. Synthesis of N- (3-chloro-4-fluorophenyl) -6-nitro-7-phenylsulfonyl) quinazolin-

Compound 12 (6.574 g, 18.61 mmol) and benzenesulfinic acid sodium salt (3.667 g, 22.34 mmol) were dissolved in 30 ml of DMF and stirred at 90 ° C for 6 hours. After confirming that the reaction was completed by TLC, the resulting solid compound was filtered, washed with water and ethanol, and dried in an oven at 100 ° C for 8 hours to obtain Compound 13 (6.833 g, 14.89 mmol, 80%).

¹ H NMR (300 MHz, acetone-d ₆ ):? 9.07 (s, IH), 8.91 (s, IH), 8.74 (M, 2H), 7.97 (s, 1H), 7.72-7.70 (m 6H), 7.38

3. Synthesis of N- (3-chloro-4-fluorophenyl) -6-nitro-7- (prop-2-yloxy) quinazolin-

To a solution of compound 13 (6.833 g, 14.89 mmol) in 20 ml of t-BuOH was added propargyl alcohol (1.669 g, 29.78 mmol) and 1M potassium t-butoxide mmol) was added dropwise. After stirring at room temperature for 10 hours, the temperature was raised to 80 ° C and stirred overnight. After confirming that the reaction was terminated, the reaction residue was concentrated under reduced pressure to remove the solvent, diluted with CHCl ₃ : i-PrOH = 3: 1, neutralized with 2N HCl, and washed with water and brine. The residue was dried over anhydrous MgSO ₄ , concentrated under reduced pressure, and subjected to column chromatography under conditions of EA: HEX = 1: 5 to obtain Compound 14 (2.220 g, 5.95 mmol, 40%).

^{1 H NMR (300 MHz, CD} 3 OD): δ 9.54 (s, 1H), 8.96 (s, 1H), 8.71 (s, 1H), 8.25-2.28 (m, 1H), 7.70-7.90 (m, 1H 1H), 7.61 (s, 1H), 7.35 (t, 1H, J = 9 Hz), 5.19

4. N ⁴ - (3-chloro-4-fluorophenyl) -7- (prop-2-ynyloxy) quinazoline-4,6-diamine (15)

Fe (1.667 g, 29.77 mmol) was added to the reaction flask, and 10 ml of 50% EtOH was added. Two or three drops of concentrated HCl were added and the mixture was refluxed for 30 minutes. Compound 14 (2.220 g, 5.95 mmol) dissolved in 10 ml of 50% EtOH was added dropwise and refluxed for 3 hours. After the reaction was completed by TLC, the reaction residue was filtered with celite to remove Fe, and the filtrate was concentrated under reduced pressure. The residue was diluted with CHCl ₃ : i-PrOH = 3: 1 and a saturated aqueous solution of sodium hydrogencarbonate And then washed with water and brine. The residue was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain Compound 15 (1.886 g, 5.35 mmol, 90%).

¹ H NMR (600 MHz, DMSO-d ₆ ):? 9.59 (s, IH), 8.42 (s, IH), 8.16 (dd, IH, J = 6.6 Hz, 1.8 Hz), 7.77-7.80 ), 7.40-7.43 (m, 2H), 7.22 (s, IH), 5.45 (s, IH), 5.04 (d,

5. Synthesis of compounds 16a to 17

Compound 15 (200 mg, 0.58 mmol) was dissolved in THF (5 ml), and various acyl chloride derivatives (1.16 mmol, 2 eq) dissolved in 1 ml of THF were added dropwise at 0 ° C, trimethylamine (0.58 mmol, 1 eq) Lt; / RTI &gt; After confirming that the reaction was completed, the reaction residue was concentrated and separated by EA: HEX = 1: 2 using PTLC to obtain compounds 16a to 17 at various yields.

1) Synthesis of N- (4- (3-chloro-4-fluorophenylamino) -7- (prop-2-ynyloxy) quinazolin-

Yield: 46 mg, 0.116 mmol, 20%

^{1 H NMR (300 MHz, DMSO} -d 6): δ 8.93 (s, 1H), 8.48 (s, 1H), 8.02 (dd, 1H, J = 7.8 Hz, 2.7 Hz), 7.65-7.71 (m, 1H ), 7.4 (s, 1H), 7.25 (t, 1H, J = 9 Hz), 6.63-6.73 (m, 1H), 6.47 (dd, 1H, J = 16.8 Hz, 1H, J = 10.2Hz, 1.8Hz), 5.07 (d, 1H, J = 2.4Hz)

2) Synthesis of N- (4- (3-chloro-4-fluorophenylamino) -7- (prop-2-ynyloxy) quinazolin-

Yield: 94 mg, 0.232 mmol, 40%

¹ H NMR (300 MHz, CDCl ₃ ):? 9.81 (s, IH), 9.45 (s, IH), 8.82 2H, J = 7.2 Hz), 7.79-7.82 (m, 1H), 7.42 (t, ), 1.70-1.76 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz)

3) Synthesis of N- (4- (3-chloro-4-fluorophenylamino) -7- (prop- 2-ynyloxy) quinazolin-

Yield: 55.7 mg, 0.13 mmol, 45%

¹ H NMR (300 MHz, CDCl ₃ ):? 9.81 (s, IH), 9.45 (s, IH), 8.82 2H, J = 7.8 Hz), 7.79-7.82 (m, 1H), 7.42 (t, ), 1.65-1.70 (m, 2H), 1.35-1.42 (m, 2H), 0.92 (t, 3H,

4) To a solution of N- (4- (3-chloro-4-fluorophenylamino) -7- (prop-2-ynyloxy) quinazolin-

Yield: 53 mg, 0.12 mmol, 43%

¹ H NMR (300 MHz, CDCl ₃ ):? 9.81 (s, IH), 9.45 (s, IH), 8.82 2H, J = 7.2 Hz), 7.79-7.82 (m, 1H), 7.42 (t, ), 2.14-2.21 (m, IH), 1.00 (s, 3H), 0.99 (s, 3H)

5) N- (4- (3-Chloro-4-fluorophenylamino) -7- (prop-2-ynyloxy) quinazolin-

Yield: 854 mg, 2.14 mmol, 40%

¹ H-NMR (600 MHz, DMSO-d ₆ ):? 9.81 (s, IH), 9.45 (s, IH), 8.82 2H, J = 6.6 Hz, 2.4 Hz), 7.79-7.82 (m, 1H), 7.42 (t, 15 Hz, 7.2 Hz), 1.13 (t, 3H, J = 7.2 Hz)

6. Synthesis of compounds 18a to 22c

After dissolving compound 17 (20 mg, 0.05 mmol) in H2O: i-PrOH, various azide compounds (0.75 mmol) were added and sodium ascorbate (1 mg, 0.005 mmol, 0.1 eq) dissolved in water The copper sulfate (II) pentahydrate (0.14 mg, 0.0007 mmol, 0.01 eq) dissolved in water (100 μl) was added in this order, and the mixture was stirred at room temperature for 10 minutes. The resulting solid was collected by filtration, dissolved in THF, and separated by CH ₂ Cl ₂ : MeOH = 20: 1 using PTLC to obtain compounds 18a to 22c.

1) N- (7 - ((1 -Benzyl-1H-1,2,3-triazol-4-yl) methoxy) -4- (3-chloro-4-fluorophenylamino) quinazolin- -Yl) propionamide &lt; / RTI &gt; (18a)

Yield: 9 mg, 0.016 mmol, 32%

¹ H NMR (600 MHz, DMSO-d ₆ ):? 9.78 (s, IH), 9.31 (s, IH), 8.77 (d, 1H, J = 7.2 Hz, 2.4 Hz), 7.78-7.81 (m, 1H), 7.51 (s, 1H), 7.30-7.43 (m, 6H), 7.45 2H, J = 7.8 Hz), 5.64 (s, 2H), 5.42

2) N- (4- (3-Chloro-4-fluorophenylamino) -7 - ((1- (4-chlorobenzyl) -1H-1,2,3-triazol- ) Quinazolin-6-yl) propionamide (18b)

Yield: 7 mg, 0.012 mmol, 24%

¹ H NMR (600 MHz, MeOD): [delta] 8.74 (s, IH), 8.45 (s, IH), 8.16 (s, IH), 7.99 (dd, IH, J = 6.6 Hz, 3 Hz), 7.62-7.65 2H, J = 7.8 (m, 1H), 7.29-7.36 (m, 5H), 7.22 Hz), 1.19 (t, 3H, J = 7.2 Hz)

3) Synthesis of N- (4- (3-chloro-4-fluorophenylamino) -7- (1- (4-fluorobenzyl) -1H-1,2,3-triazol- 6-yl) propionamide (18c) &lt; RTI ID = 0.0 &gt;

Yield: 10 mg, 0.018 mmol, 36%

¹ H NMR (600 MHz, DMSO-d ₆ ):? 9.78 (s, IH), 9.31 (s, IH), 8.77 (m, 3H), 7.18-7.22 (m, 2H), 5.63 (d, 1H, J = 7.2 Hz, 2.4 Hz), 7.78-7.81 (s, 2H), 5.42 (s, 2H), 2.40 (q, 2H, J = 7.8 Hz), 1.07

4) Synthesis of N- (4- (3-chloro-4-fluorophenylamino) -7- (1- (3-fluorobenzyl) -1H-1,2,3-triazol- Ethoxy) quinazolin-6-yl) propionamide (18d)

Yield: 8 mg, 0.014 mmol, 28%

^{1 H NMR (600 MHz, DMSO} -d 6): δ 9.78 (s, 1H), 9.32 (s, 1H), 8.77 (s, 1H), 8.53 (s, 1H), 8.38 (s, 1H), 8.13 (d, 1H, J = 7.2 Hz, 1.5 Hz), 7.78-7.81 (m, 1H), 7.51 (s, 1H), 7.40-7.43 (m, 2H), 7.14-7.20 (s, 2H), 5.43 (s, 2H), 2.40 (q, 2H, J = 7.8 Hz), 1.07

5) Synthesis of N- (4- (3-chloro-4-fluorophenylamino) -7- (1- (2-fluorobenzyl) -1H-1,2,3-triazol- 6-yl) &lt; / RTI &gt; propionamide (18e)

Yield: 6 mg, 0.01 mmol, 20%

¹ H NMR (600 MHz, DMSO-d ₆ ):? 9.78 (s, IH), 8.32 (s, IH) (d, 1H, J = 7.2 Hz, 2.4 Hz), 7.78-7.81 (m, IH), 7.51 (s, IH), 7.40-7.45 2H, J = 7.8 Hz), 7.20-7.27 (m, 2H), 5.70 (s, 2H), 5.42

6) N- (4- (3-Chloro-4-fluorophenylamino) -7 - ((1- (4-methylbenzyl) -1H- ) Quinazolin-6-yl) propionamide (18f)

Yield: 4 mg, 0.007 mmol, 14%

¹ H NMR (600 MHz, DMSO-d ₆ ):? 9.78 (s, IH), 9.31 (s, IH), 8.77 (d, 1H, J = 6.6 Hz, 2.4 Hz), 7.78-7.81 (m, IH), 7.50 (s, IH), 7.42 2H), 2.39 (q, 2H, J = 7.8 Hz), 2.27 (s, 1H), 1.07 (s, t, 3H, J = 7.8 Hz)

7) N- (4- (3-Chloro-4-fluorophenylamino) -7 - ((19- ) Quinazolin-6-yl) propionamide (18 g)

Yield: 5 mg, 0.008 mmol, 16%

¹ H NMR (600 MHz, DMSO-d ₆ ):? 9.78 (s, IH), 9.31 (s, IH), 8.77 2H), 7.28-7.31 (m, 2H), 7.50 (d, 1H, J = 6.6Hz, 2.4Hz), 7.78-7.81 2H, J = 7.8 Hz), 6.90 (s, 3H), 6.90 (s, = 7.8 Hz)

8) N- (4- (3-Chloro-4-fluorophenylamino) -7 - ((1- (2-methoxyethyl) -1H-1,2,3-triazol- 6-yl) &lt; / RTI &gt; propionamide (19a)

Yield: 6 mg, 0.012 mmol, 24%

¹ H NMR (600 MHz, DMSO-d ₆ ):? 9.81 (s, IH), 9.45 (s, IH), 8.82 2H, J = 9 Hz), 7.79-7.82 (m, 1H), 7.42 (t, , 7.2 Hz), 1.13 (t, 3H, J = 7.2 Hz)

9) Synthesis of N- (7 - ((1-butyl-1H-1,2,3-triazol-4-yl) methoxy) -4- (3-chloro-4-fluorophenylamino) quinazolin- Yl) propionamide (19b)

Yield: 4 mg, 0.008 mmol, 16%

^{1 H NMR (600MHz, DMSO-} d 6): δ 9.36 (s, 1H), 8.95 (s, 1H), 8.82 (s, 1H), 8.54 (s, 1H), 8.25 (d, 1H, J = 6.6 2H), 4.45 (t, 1H, J = 9 Hz), 8.19 (s, 1H), 7.82-7.85 2H, J = 7.2 Hz), 2.47-2.51 (m, 2H), 1.87-1.91 (m, 2H), 1.30-1.37 3H, J = 7.2 Hz)

10) N- (4- (3-Chloro-4-fluorophenylamino) -7- (1- (4-fluorobenzyl) -1H-1,2,3-triazol- 6-yl) &lt; / RTI &gt; acrylamide (20)

Yield: 3 mg, 0.005 mmol, 10%

¹ H NMR (600 MHz, DMSO-d ₆ ):? 9.81 (s, IH), 9.69 (s, IH), 8.88 (d, 1H, J = 6.6 Hz, 2.4 Hz), 7.79 ~ 7.81 (m, 1H), 7.53 (s, 1H), 7.38-7.44 (D, 1H, J = 10.8 Hz), 5.62 (s, 2H), 5.44 (s, sH)

11) N- (4- (3-Chloro-4-fluorophenylamino) -7 - ((1- (4-fluorophenyl) -1H- Yl) propionamide (21a) &lt; RTI ID = 0.0 &gt;

Yield: 4 mg, 0.007 mmol, 14%

¹ H NMR (300 MHz, CDCl ₃ ):? 9.04 (s, IH), 8.64 (s, IH), 8.17 2H), 7.21-7.28 (m, 2H), 7.12 (t, 1H, J = 8.7Hz), 7.81-7.76 (m, 3H), 7.43-7.53 , 5.48 (s, 2H), 2.49 (q, 2H, J = 7.5 Hz), 1.26 (t,

12) N- (4- (3-Chloro-4-fluorophenylamino) -7 - ((1- (4-fluorophenyl) -1H-1,2,3-triazol- Yl) acrylamide (21b) &lt; RTI ID = 0.0 &gt;

Yield: 3 mg, 0.005 mmol, 10%

^{1 H NMR (300 MHz, CDCl} 3): δ 9.16 (s, 1H), 8.69 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.93-7.97 (m, 1H), 7.71 2H), 5.83 (d, 2H, J = 17.1 Hz), 7.69-7.76 (m, 3H), 7.51-7.56 , 2H, J = 11.1 Hz), 5.51 (s, 2H)

13) N- (4- (3-Chloro-4-fluorophenylamino) -7 - ((1- (4-fluorobenzyl) -1H-1,2,3-triazol- 6-yl) &lt; / RTI &gt; butylamide (22a)

Yield: 9 mg, 0.016 mmol, 32%

¹ H NMR (300 MHz, CDCl ₃ ):? 8.98 (s, IH), 8.57 (s, IH), 8.08 2H), 5.53 (s, 2H), 5.31 (s, 2H), 7.63 (s, 2H), 2.38 (t, 2H, J = 7.2 Hz), 1.70-1.76 (m,

14) N- (4- (3-Chloro-4-fluorophenylamino) -7 - ((1- (4-fluorobenzyl) -1H-1,2,3-triazol- 6-yl) &lt; / RTI &gt; pentanamide (22b)

Yield: 8 mg, 0.014 mmol, 28%

¹ H NMR (300 MHz, CDCl ₃ ):? 9.00 (s, IH), 8.58 (s, IH), 8.05 (S, 2H), 5.32 (s, 2H), 7.63 (s, 2H), 2.40 (t, 2H, J = 7.8 Hz), 1.65-1.70 (m, 2H), 1.35-1.42

15) Synthesis of N- (4- (3-chloro-4-fluorophenylamino) -7- (1- (4-fluorobenzyl) -1H-1,2,3-triazol- 6-yl) -3-methylbutanamide (22c) &lt; / RTI &gt;

Yield: 7 mg, 0.012 mmol, 24%

¹ H NMR (300 MHz, CDCl ₃ ):? 9.00 (s, IH), 8.58 (s, IH), 8.00 (s, IH), 7.90 (S, 2H), 5.31 (s, 2H), 7.66 (s, 1H), 7.38-7.41 (m, 1H), 7.28-7.31 2H), 2.27 (d, 2H, J = 7.2 Hz), 2.14-2.21 (m,

< Example  3> ¹⁸ F Labeling (labeling)

As shown in FIG. 1 and FIG. 2, labeling was performed with ¹⁸ F having a half-life of 110 minutes, and the reaction conditions were 10 to 30 minutes at 100 DEG C with TBAB / DMF. Direct comparison was made between the CAU condition and only the high temperature coupling. CONDITION A consisted of compound c dissolved in 1.0 mL of water / iPrOH (2/1), sodium ascorbate (trace amount) dissolved in 1.0 mL of water, and copper (II) Sulfate hydrate (Copper (II) Sulfate hydrate) (trace amount) was reacted at room temperature for 10 minutes, and Compound B dissolved in DMF was reacted at 90 ° C for 10 minutes. The final compound labeled with &lt; RTI ID = 0.0 &gt; ¹⁸ F &lt; / RTI &gt;

The results of the experiment with CONDITION B are shown in FIG. 3 and FIG. The experiment showed a clear solution and no Cu catalyst. The HPLC RT pattern showed a similar pattern to the LC containing the reagent, and the peaks were sharper (Fig. 3). On the other hand, HPLC in which RI and UV are overlapped is shown in Fig. The final labeling conditions and separation conditions were confirmed as shown in FIG.

&Lt; Experimental Example 1 >

1.Kineise Assay

The experimental procedure of the Kinase Profiler Screening (Millipore) is as follows. EGFR (WT), EGFR (L858R) and EGFR (T790M) were incubated with 8 mM MOPS [3- (N-morpholino) propanesulfonic acid] (pH 7.0), 0.2 mM ethylenediaminetetraacetic acid, 0.1 mg / MgATP mix (mixed solution of MgCl ₂ and ATP) was added to the buffer solution composed of Tyr (Glu = 4, Tyr = 1), 10 mM magnesium acetate and γ- ³³ P-ATP and reacted at room temperature for 40 minutes. / Tyr was used as a kinase substrate, and the reaction was stopped by adding a 3% aqueous solution of phosphoric acid (by volume) to the reaction solution, adding 10 μL of the compound per each test group to the filter mat A, After rinsing 3 times with 75 mM phosphoric acid solution at intervals, the remaining phosphoric acid solution was removed by gently washing with methanol. The filter mat was dried and then scintillation index was measured with a luminometer. -Triazolylquinazoline &lt; / RTI &gt; derivatives of the present invention are shown in Table 2 as 7-triazolylmethoxyquinazoline Respectively. &Lt; tb &gt;&lt; TABLE &gt;

[Table 1]

As shown in Table 1, the compounds 6a to 6f are compounds having a benzyl structure at the N-th position of the triazole linker, and the compound 6a having a benzyl group has a similar inhibitory activity of wtEGFR compared to the reference drug gefitinib Respectively. Compound 6b with EWG incorporated into the benzyl structure of R1 and compounds 6c, 6d and 6e with EDG showed similar inhibitory effects on wtEGFR as Compound 6a and showed a slight decrease in T790M inhibitory activity. Compounds 7, 8, and 9, in which phenetyl, phenylpropyl, and cinnamyl were respectively introduced at the N position of triazole, showed inhibitory effects of wtEGFR similar to that of zetitib and lower inhibitory effect than that of zetitib at T790M.

Compounds 10a to 10f in which various carbon chains and ether chains were introduced at the nitrogen position of triazole showed similar inhibitory activities of wtEGFR as compared with those of compounds 6a and zetitipine, No results showing activity were obtained.

Thus, 6-triazole derivatives substituted with various groups by linking 1,2,3-triazole at position 6 showed a good inhibitory activity against wtEGFR, but the expected inhibitory activity against T790M mutation was not obtained .

[Table 2]

As shown in Table 2, Compound 17 exhibited similar activities to zetitifib in terms of wtEGFR and lower IC ₅₀ values with respect to EGFR mutant enzyme T790M, indicating that the inhibitory activity was increased. Compound 17, which was a click reacted with benzyl azide for acetylenic compound 17, exhibited similar activity to both wtEGFR and T790M as compared to zetifinib. Compounds 18b, in which EWG chloride (Cl) was introduced into the benzyl group of compound 18a, exhibited a similar inhibitory activity against EGFR T790M, as compared to zetifinib, with respect to wtEGFR. Compound 18c in which the benzyl group of Compound 18a was substituted with EWG phosphoryl (F) showed an increase in the inhibitory activity against both EGFR and EGFR T790M mutations. Compounds 18d and 18e were converted to the 3-fluoro and 2-fluoro positions of the benzyl group of compound 18c, and showed similar activity to compound 18c for wtEGFR and T790M. Compounds 18f and 18g changed the 4-fluoro substituent to the methyl and methoxy groups, EDG, for compound 18c, both compounds showed a lower inhibitory effect on wtEGFR compared to compound 18c and compound 18f for compound 18f Compound 18g showed similar inhibitory effect as compound 18c.

Compounds 19a and 19b had a structure in which a carbon chain was introduced instead of the benzyl group at the N-th position of the triazole, and showed a good inhibitory activity against wtEGFR but a similar inhibitory activity with respect to T790M. Compound 20 was obtained by modifying the ethylamide structure to acrylamide at position 6 of quinazoline with respect to compound 18c and expected to exhibit an irreversible inhibitory effect. Compound 20 exhibited activity similar to that of zetitifib with respect to wtEGFR In the T790M mutation, the inhibitory activity was highly improved, suggesting that the inhibitory activity was increased by forming a covalent bond in the kinase receptor structure of T790M mutation.

Compounds 17 to 20 in which triazolylmethoxy was introduced at position 7 of the quinazoline whose inhibitory activity was improved than that of the triazolyl derivatives of quinazoline at position 6 were tested for inhibitory activity against the EGFR mutant enzyme L858R, Gt; IC50 &lt; _{/ RTI} &gt; values were obtained.

Thus, compounds 17-20 did not exhibit the expected inhibitory activity with respect to the T790M mutant receptor that was initially targeted, but may be similar to zetti-nip-like compounds in patients with the EGFR L858R mutation in the zetifinib-sensitive patients.

Compound 18c was selected as the lead drug based on the data obtained from these kinase assays and compound 21a and 21b were synthesized by modifying the R1 structure of compound 18c from a benzyl group to a phenyl group to synthesize the present compounds 21a and 21b. Compounds 22a, 22b and 22c were synthesized by further increasing the chain length of the carbon chain.

2. Cell culture

(ATCC, Manassas, Va., USA), PC9 (professor at Yonsei University College of Medicine professor Byung Chul Cho), PC9-GR (Yonsei University College of Medicine, The cells were cultured in RPMI-1640 (Welgene) culture medium containing 10% FBS (Welgene) and 1% penicillin / streptomycin (Gibco) in a humidified 37 ° C incubator maintained at 5% CO ₂ .

3. Cell viability analysis

2000, A949, PC9 and PC9-GR cell lines were plated on 96-well plates under the condition of 3000 cells / 100 μl / well for H1975 and HCC827 cell lines. At this time, RPMI-1640 culture medium containing 5% and 1% penicillin in FBS was used. The cells were placed in a cell incubator for 24 hours to allow them to adhere completely to the bottom of the culture dish, and then the compound diluted with DMSO was treated at the concentration to be tested. After 72 hours of compound treatment, 10 μl of EZ-CYTOX (DOGEN, Daejeon, Korea) was added and incubated for 2 hours (A549, PC9, PC9- HCC827). Absorbance was measured at a wavelength of 450 nm in a plate reader. The IC ₅₀ (half maximal inhibitory concentration) values were calculated by the GraphPad Prism program, and the results are shown in Table 3 below.

[Table 3]

(EGFR wild type lung cancer cell line), HCC827 and PC9 (? E746-A750, Gefitinib sensitive), PC9-GR (? E746-A750, T790M mutation), and 17-22c, which are 7-triazolylmethoxyquinazoline derivatives, As a result of measuring the inhibitory activity in H1975 (L858R, T790M mutation), Compound 18c showed an inhibitory activity higher than that of zetitib in A549, but the IC ₅₀ value was 2 mM, ₅₀ values of 43 nM and 25 nM showed better inhibitory effects on the zetitifib sensitive cell line than the wtEGFR cell line. As a result, NSCLC EGFR mutation is expected to be a good medicine as an inhibitor of tyrosine kinase receptor.

Compound 20, which was predicted to exhibit irreversible inhibitory activity by introducing acrylamide at position 6 of the quinazoline of compound 18c, exhibited an inhibitory activity as compared to compound 18c as expected in PC9GR, H1975. On the other hand, it was confirmed that the selectivity to T790M was increased due to an increase in the IC ₅₀ value compared with the compound 18c, although the activity was better than that of zetitib in A549.

&Lt; Experimental Example 2 >

Compound 18c was suspended in 0.5% methylcellulose solution in male Balb / c mice, and single oral doses of 0.5g / kg, 1g / kg and 2g / kg were administered once, and the survival rate and body weight of mice were examined for 7 days.

After this administration, we observed the mortality of the animal, clinical symptoms, weight change, hematologic test and blood biochemical test, and autopsied the visceral organs and thoracic organs were observed.

As a result, no clinical symptoms or dead animals were found in all animals, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings.

As a result, the compounds of the present invention did not show toxic changes up to 2 g / kg in mice, and thus, it was judged that the oral LD50 was 2 g / kg or more.

Hereinafter, formulation examples of the composition containing the compound 18c according to the present invention will be described, but the present invention is not intended to be limited thereto but is specifically described.

&Lt; Formulation Example 1 > Preparation of powders

5 mg of Compound 18c, 100 mg of lactose, and 10 mg of talc were mixed and filled in airtight bags to prepare powders.

&Lt; Formulation Example 2 > Preparation of tablet

5 mg of Compound 18c, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed and tableted according to a conventional preparation method.

&Lt; Formulation Example 3 > Preparation of capsule agent

5 mg of Compound 18c, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed, and the above components were mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

&Lt; Formulation Example 4 > Preparation of injection

2 mg of Compound 18c, sterile distilled water suitable amount for injection, and pH adjuster were mixed, and the contents were adjusted to the above contents in the amount of 2 ml per ampoule according to the usual preparation method of injections.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (8)

A compound represented by the following formula (1) or a salt thereof:
[Chemical Formula 1]

In Formula 1, R is selected from propionamido or acrylamido. The compound according to claim 1, wherein the compound is N- (4- (3-chloro-4-fluorophenylamino) -7 - ((1- (4-fluorobenzyl) -1H-1,2,3-triazole Yl) methoxy) quinazolin-6-yl) propionamide or N- (4- (3-chloro-4-fluorophenylamino) 1H-1,2,3-triazol-4-yl) methoxy) quinazolin-6-yl) acrylamide. A pharmaceutical composition for the treatment or prevention of cancer diseases related to epithelial growth factor receptor (EGFR) comprising a compound represented by the following formula (1) or a salt thereof as an active ingredient:
[Chemical Formula 1]

In Formula 1, R is selected from propionamido or acrylamido. 4. The compound of claim 3 wherein said compound is selected from the group consisting of N- (4- (3-chloro-4-fluorophenylamino) -7- (1- (4-fluorobenzyl) Yl) methoxy) quinazolin-6-yl) propionamide or N- (4- (3-chloro-4-fluorophenylamino) 1H-1,2,3-triazol-4-yl) methoxy) quinazolin-6-yl) acrylamide. [Claim 4] The pharmaceutical composition according to claim 3, wherein the epithelial growth factor receptor (EGFR) -related cancer disease is cancer disease selected from the group consisting of lung cancer, colon cancer and breast cancer. [Claim 4] The pharmaceutical composition according to claim 3, wherein the epithelial growth factor receptor (EGFR) -related cancer disease is non-small cell lung cancer. A contrast agent comprising a compound represented by the following formula (2) or a salt thereof:
(2)

In Formula 2, R is selected from propionamido or acrylamido. [Claim 7] The contrast agent according to claim 7, wherein the compound is used to diagnose whether to target any one of tumor cells selected from wild-type EGFR-overexpressing cells, zetotinib-sensitive EGFR mutant cells or T790M mutant cells.

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