KR20220089328A - Novel heterocyclic compounds and medical use thereof - Google Patents

Abstract

The present invention relates to a novel heterocycle compound and its use as an anticancer agent, wherein the novel heterocycle compound exhibited a tumor cell killing effect at a very small dose, and it was confirmed that it exhibits excellent cancer metastasis and tumor growth inhibitory effects. Accordingly, the composition containing the heterocyclic compound as an active ingredient may be provided as an anticancer agent for the prevention and treatment of cancer diseases.

Description

Novel heterocyclic compounds and medical use thereof

The present invention relates to a novel heterocyclic compound and its use as an anticancer agent.

Cancer is a disease in which cells do not differentiate normally due to an abnormality in the cell cycle constituting human tissue and continue to divide. Cancer occurs through three stages: initiation, promotion, and progression. . It is known that the cause of cancer is mutation in the gene or cancer suppressor gene of normal cells by carcinogens contained in the environment or food, and these cells proliferate abnormally while receiving continuous stimulation from carcinogens to form cancerous tissue. The cause of cancer has not yet been clearly elucidated.

Cancer is divided into benign tumors and malignant tumors. Benign tumors grow relatively slowly and do not metastasize from the original site of the tumor to other tissues, whereas malignant tumors. Tumors leave the primary part and invade other tissues and rapidly grow, so they are life-threatening and a very important cause of death.

Cancer is one of the incurable diseases that mankind needs to solve, and despite huge capital investment worldwide and innovative medical technology, the incidence of cancer and deaths due to cancer continue to increase. is in trend According to the latest statistical data of the World Health Organization, it is known that more than 10 million new cancer patients occur every year worldwide. dying of cancer

Surgical therapy, radiation therapy, and chemotherapy are used to treat cancer, but it is reported that more than 50% of all cancer patients eventually die without being cured, despite many studies. The reason for this is that even after surgical resection, the cancer recurs because the microscopically metastasized cancer cells cannot be removed, or when cancer treatment using anticancer drugs is used despite the development of various anticancer drugs, the death of cancer cells is not induced or early stage. This is because the cancer cells that have developed resistance to chemotherapy rapidly proliferate during or after treatment, although the tumor appears to be shrinking due to the response to chemotherapy.

As such, if cancer is not detected at an early stage, it is almost impossible to cure it, and as the disease progresses, the pain and economic loss for patients and families is enormous, and it causes great social costs such as financial exhaustion of medical insurance. The importance of prevention and early treatment is being emphasized more and more.

Republic of Korea Patent Publication No. 10-2020-0048510 (published on May 8, 2020)

The present invention provides a novel heterocyclic compound, and an object of the present invention is to provide a composition containing the heterocyclic compound as an active ingredient as a cancer metastasis inhibitor and anticancer agent.

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

[Formula 1]

In Formula 1,

W is (CR ¹ R ² ) _m -(C=O) _n -(NR ³ ) _p -(C=O) _r -Y,

m, n, p or r are each an integer from 0 to 2,

R ¹ to R ³ may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo, trifluoromethyl or trifluoromethoxy,

Y is selected from aryl, (5- to 6-ring) heteroaryl including nitrogen, (C3 to C8) cycloalkyl, or hetero (C3 to C8) cycloalkyl including nitrogen, oxygen or sulfur, each of which is allowed by the valence optionally substituted with one or more substituents independently selected from methyl, (C3-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy.

The present invention provides a pharmaceutical composition for treating or preventing cancer disease, comprising the compound or a pharmaceutically acceptable salt thereof.

The present invention provides a health functional food composition for improving or preventing cancer disease comprising the compound or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical composition for inhibiting cancer metastasis comprising the compound or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of cancer disease comprising a compound or a pharmaceutically acceptable salt thereof, and an immuno-cancer agent.

According to the present invention, the novel heterocyclic compound exhibited a tumor cell killing effect at a very small dose, and as it was confirmed that it exhibited excellent cancer metastasis and tumor growth inhibitory effects, a composition containing the heterocyclic compound as an active ingredient may be provided as an anticancer therapeutic agent for the prevention and treatment of cancer diseases.

1 is a result of confirming the cancer metastasis inhibitory effect of Compound 30, and is a result of confirming the tumor level present in metastasized lung tissue.
2 is a result confirming the tumor growth inhibitory effect of compound 30 in an animal model of lung cancer by the A549 non-small cell lung cancer (NSCLC) cell line.

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

The present invention may provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

W is (CR ¹ R ² ) _m -(C=O) _n -(NR ³ ) _p -(C=O) _r -Y,

m, n, p or r are each an integer from 0 to 2,

R ¹ to R ³ may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo, trifluoromethyl or trifluoromethoxy,

Y is selected from aryl, (5- to 6-ring) heteroaryl including nitrogen, (C3 to C8) cycloalkyl, or hetero (C3 to C8) cycloalkyl including nitrogen, oxygen or sulfur, each of which is allowed by the valence optionally substituted with one or more substituents independently selected from methyl, (C3-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy.

wherein W is (CR ¹ R ² ) _m -(C=O) _n -(NH) _p -(C=O) _r -Y, m and p are 1, and one of n and r is 1 and the other is 0, one of R ¹ to R ² is (C1 to C4)alkyl, and the other is hydrogen, (C1 to C4)alkyl, (C1 to C4)alkoxy, halo, trifluoromethyl or triple is selected from loromethoxy, and Y is substituted or substituted with one or more substituents selected from (C3-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy It may be a compound characterized in that it is an unsubstituted aryl or a pharmaceutically acceptable salt thereof.

The compound may be a compound characterized in that it is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

[Formula 2]

In Formula 2,

R ⁴ and R ⁵ may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo, trifluoromethyl or trifluoromethoxy.

The present invention may provide a pharmaceutical composition for the treatment or prevention of cancer diseases comprising the compound or a pharmaceutically acceptable salt thereof.

The cancer disease is breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colorectal cancer, fallopian tube cancer, endometrial cancer , cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, may be one selected from the group consisting of bronchial cancer and bone marrow cancer.

The present invention may provide a health functional food composition for improving or preventing cancer diseases, including a compound or a pharmaceutically acceptable salt thereof.

The present invention may provide a pharmaceutical composition for inhibiting cancer metastasis comprising a compound or a pharmaceutically acceptable salt thereof.

In general, cancer is divided into primary cancer existing at the site of occurrence and metastatic cancer that has spread from the site of occurrence to other parts of the body. In other words, “cancer metastasis” refers to a state in which a malignant tumor has spread to other tissues away from the diseased organ, and cancer cells are formed by spreading through blood or lymphatic circulation, usually moving through blood circulation to other organs. It is a new tumor that grows after the liver, or is formed by cancer cells moving directly to neighboring tissues. In the present invention, cancer metastasis refers to the spread of cancer cells by invasion, in which cancer cells directly move and infiltrate into neighboring tissues, and metastasis in which cancer cells move through the bloodstream to form a new tumor in an organ that is not physically adjacent to the primary cancer. (metastasis) is included.

In addition, the present invention may provide a pharmaceutical composition for treating or preventing cancer disease, comprising a compound or a pharmaceutically acceptable salt thereof, and an immuno-cancer agent.

The immuno-cancer agent is anti-PD1, anti-PDL1, anti-CTLA4, anti-LAG3, anti-VISTA, anti-BTLA, anti-TIM3, anti-HVEM, anti-CD27, anti-CD137, anti-OX40, anti- selected from the group consisting of CD28, anti-PDL2, anti-GITR, anti-ICOS, anti-SIRPα, anti-ILT2, anti-ILT3, anti-ILT4, anti-ILT5, anti-EGFR, anti-CD19 and anti-TIGIT It may be one or more types of immuno-cancer drugs, but is not limited thereto.

In one embodiment of the present invention, the pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof is prepared according to a conventional method for injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, and emulsions. , any one formulation selected from the group consisting of drops or liquids may be used.

In another embodiment of the present invention, the pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof is a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant commonly used in the preparation of pharmaceutical compositions. , flavoring agents, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders and lubricants may further include one or more additives selected from the group consisting of.

Specifically, carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil can be used, and solid preparations for oral administration include tablets, pills, powders, granules, and capsules. agent, and the like, and the solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like in the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid preparations for oral use include suspensions, solutions, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included in addition to commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base material for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

According to an embodiment of the present invention, the pharmaceutical composition is administered in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal routes. can be administered to the subject.

A preferred dosage of the compound or a pharmaceutically acceptable salt thereof may vary depending on the condition and weight of the subject, the type and extent of the disease, the drug form, the route and duration of administration, and may be appropriately selected by those skilled in the art. According to an embodiment of the present invention, although not limited thereto, the daily dose may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or may be administered in several divided doses, thereby not limiting the scope of the present invention.

In the present invention, the 'subject' may be a mammal including a human, but is not limited to these examples.

In addition, the health food of the present invention is used together with other foods or food additives other than the compound or a pharmaceutically acceptable salt thereof, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be suitably determined according to the purpose of its use, for example, prophylactic, health or therapeutic treatment.

The effective dose of the compound contained in the health food may be used according to the effective dose of the therapeutic agent, but in the case of long-term intake for health and hygiene or health control, it may be less than or equal to the above range, It is clear that the ingredient can be used in an amount beyond the above range because there is no problem in terms of safety.

The type of health food is not particularly limited, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes.

Hereinafter, examples will be described in detail to help the understanding of the present invention. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

<Example> Synthesis of compounds

Example 1. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N- (4-ethylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-( 4-ethylphenyl)acetamide (Compound 1)]

Step 1) 6,7-dimethoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [6,7-dimethoxy-2H-benzo[d][1,3] oxazine-2,4(1H)-dione (intermediate 1)

[Scheme 1]

To a solution of 2-amino-4,5-dimethoxybenzoic acid (1.00 eq.) dissolved in dry THF (Tetrahydrofuran), bis(trichloromethyl)carbonate (0.34 eq. ) dissolved in dry THF solution was added at room temperature for 2 hours. The mixture was poured into ice water to form a suspension, filtered and washed with ether to obtain a solid (Intermediate 1) without further purification.

Step 2) 2-Mercapto-6,7-dimethoxy-3-(4-(trifluoromethyl)phenethyl)quinazolin-4(3H)-one[2-mercapto-6,7-dimethoxy-3 -(4-(trifluoromethyl)phenethyl)quinazolin-4(3H)-one (intermediate 3)]

[Scheme 2]

2-(4-(trifluoromethyl)phenyl)ethan-1-amine [2-(4-(trifluoromethyl)phenyl)ethan-1-amine (1.50 eq.) in DMF solution in which Intermediate 1 (1.00 eq.) was dissolved .)] was added at room temperature for 2 hours until the reaction was complete.

The solvent was removed in vacuo without further purification. after 2.20 eq. Potassium hydroxide water/ethanol solution was added and then carbon disulfide (4.00 eq.) was added.

The reaction mixture was heated to 60° C. for 5 h and cooled with 1M HCl to give a white solid (Intermediate 3).

Step 3) 2-bromo-N-(4-ethylphenyl)acetamide [2-bromo-N-(4-ethylphenyl)acetamide (Intermediate 4)]

[Scheme 3]

TEA (1.20 eq.) was added to a dry DCM solution in which 4-ethylaniline (4-ethylaniline, 1.00 eq.) was dissolved at 0° C., stirred for 5 minutes, and then 2-bromoacetyl bromide [2-bromoacetyl bromide, 1.20 eq.] at 0 °C It was added dropwise and stirred for 1 hour, followed by stirring at 25° C. for 1 hour. The reaction mixture was cooled with ice water and filtered to give a white solid (Intermediate 4).

Step 4) 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N -(4-ethylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N- (4-ethylphenyl)acetamide (Compound 1)]

[Scheme 4]

Intermediate 3 and Intermediate 4 were dissolved in acetone and potassium carbonate (2.00 eq.) was added. The mixture was heated to reflux for 5 hours, poured into ice water, and filtered to obtain a white suspension. The product was loaded on silica gel and purified by flash column chromatography to obtain compound 1.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.72 (s, 1 H), 7.57 (m, 3 H), 7.42 (d, 2 H, J = 8.0 Hz), 7.34 (d, 2 H, J = 8.4 Hz), 7.09 (d, 2 H, J = 8.4 Hz), 7.01 (s, 1 H), 4.32 (t, 2 H, J = 8.0 Hz), 4.00 (s, 8 H), 3.12 (t, 2 H, J = 8.0 Hz), 2.56 (m, 2 H), 1.16 (t, 3 H, J = 7.6 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.4, 160.5, 155.7, 155.1, 149.0, 142.9, 141.5, 140.5, 135.6, 129.3, 128.5, 125.7, 119.4, 112.6, 106.2, 105.8, 56.6, 56.4, 46.1, 35.9, 34.0, 28.3, 15.7; MS m/z (M+H) ⁺ : 572.18.

Example 2. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(o-tolyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N- (o-tolyl)acetamide (Compound 2)]

In step 3 of Example 1, o-toluidine was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain Compound 2.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.78 (s, 1 H), 7.57 (d, 3 H, J = 6.4 Hz), 7.43 (d, 2 H, J = 7.6 Hz), 7.32 (s, 1 H), 7.16 (m, 2 H), 7.02 (s, 1 H), 6.88 (d, 1 H, J = 7.6 Hz), 4.32 (t, 2 H, J = 8.4 Hz), 4.01 (s, 8 H), 3.12 (t, 2 H, J = 8.4 Hz), 2.27 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.6, 160.5, 155.7, 155.2, 149.1, 142.9, 141.5, 139.1, 137.9, 129.6, 129.3, 129.0, 125.8, 125.7, 125.2, 120.0, 116.4, 112.7, 106.3, 105.8, 56.5, 56.4, 46.2, 36.0, 34.0, 21.6; MS m/z (M+H) ⁺ : 558.16.

Example 3. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(m-tolyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N- (m-tolyl)acetamide (Compound 3)]

In Step 3 of Example 1, m-toluidine was used instead of 4-ethylaniline, and Step 4 of Example 1 was repeated to obtain Compound 3.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 8.72 (s, 1 H), 7.83 (d, 1 H, J = 8.0 Hz), 7.57 (m, 3 H), 7.44 (d, 2 H, J = 8.0 Hz), 7.12 (m, 3 H), 6.96 (s, 1 H), 4.34 (t, 2 H, J = 8.4 Hz), 4.12 (s, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.13 (t, 2 H, J = 8.4 Hz), 2.02 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.6, 155.5, 154.3, 149.0, 143.1, 141.5, 135.6, 130.5, 129.3, 128.6, 126.9, 125.8, 125.3, 122.9, 112.6, 106.4, 106.1, 56.5, 56.4, 46.0, 35.6, 34.1, 18.0; MS m/z (M+H) ⁺ : 558.16.

Example 4. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(p-tolyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N- (p-tolyl)acetamide (Compound 4)]

In step 3 of Example 1, p-toluidine was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 4.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.71 (s, 1 H), 7.57 (m, 3 H), 7.42 (d, 2 H, J = 8.0 Hz), 7.31 (d, 2 H, J = 8.0 Hz) 8.8 Hz), 7.06 (d, 2 H, J = 8.0 Hz), 7.01 (s, 1 H), 4.32 (t, 2 H, J = 8.0 Hz), 4.00 (m, 8 H), 3.12 (t, 2 H, J = 8.0 Hz), 2.27 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.4, 160.5, 155.7, 155.1, 149.1, 142.9, 141.5, 135.5, 134.0, 129.6, 129.3, 125.8, 125.7, 119.3, 112.7, 106.3, 105.8, 56.6, 56.4, 46.1, 35.9, 34.0, 20.9; MS m/z (M+H) ⁺ : 558.16.

Example 5. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2,4-dimethylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio) -N-(2,4-dimethylphenyl)acetamide (Compound 5)]

In step 3 of Example 1, 2,4-dimethylaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 5.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 8.64 (s, 1 H), 7.60 (m, 4 H), 7.43 (d, 2 H, J = 8.0 Hz), 6.95 (s, 3 H), 4.34 (t, 2 H, J = 8.4 Hz), 4.11 (s, 2 H), 3.99 (s, 3 H), 3.96 (s, 3 H), 3.12 (t, 2 H, J = 8.4 Hz), 2.24 (s, 3 H), 1.99 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.6, 155.5, 154.3, 149.0, 143.2, 141.5, 135.2, 132.9, 131.2, 129.3, 129.0, 127.4, 125.7, 123.2, 112.6, 106.4, 106.0, 56.5, 56.4, 46.0, 35.5, 34.1, 20.9, 17.9; MS m/z (M+H) ⁺ : 572.18.

Example 6. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2,5-dimethylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio) -N-(2,5-dimethylphenyl)acetamide (Compound 6)]

In step 3 of Example 1, 2,5-dimethylaniline (2,5-dimethylaniline) was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 6.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 8.63 (s, 1 H), 7.55 (m, 6 H), 6.97 (m, 2 H), 6.85 (d, 2 H, J = 8.4 Hz), 4.34 (t, 2 H, J = 8.0 Hz), 4.12 (s, 2 H), 3.99 (s, 3 H), 3.96 (s, 3 H), 3.13 (t, 2 H, J = 8.0 Hz), 2.29 (s, 3 H), 1.99 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.8, 155.5, 154.3, 149.0, 143.1, 141.5, 136.7, 135.3, 130.3, 129.3, 126.1, 125.8, 125.5, 123.5, 112.6, 106.4, 106.0, 56.49, 56.43, 46.0, 35.6, 34.1, 21.2, 17.6; MS m/z (M+H) ⁺ : 572.18.

Example 7. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(3,4-dimethylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio) -N-(3,4-dimethylphenyl)acetamide (Compound 7)]

In step 3 of Example 1, 3,4-dimethylaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 7.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.67 (s, 1 H), 7.58 (m, 3 H), 7.43 (d, 2 H, J = 7.6 Hz), 7.14 (dd, 1 H, J = 8.0, 2.0 Hz), 7.01 (m, 2 H), 4.32 (t, 2 H, J = 8.4 Hz), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.99 (s, 2 H) , 3.12 (t, 2 H, J = 8.4 Hz), 2.17 (s, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.3, 160.5, 155.7, 155.1, 149.0, 142.9, 141.5, 137.4, 135.7, 132.8, 130.1, 129.3, 125.8, 125.7, 120.7, 116.8, 112.7, 106.2, 105.8, 56.5, 56.4, 46.1, 35.9, 34.0, 20.0, 19.2; MS m/z (M+H) ⁺ : 572.18.

Example 8. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(3,5-dimethylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio) -N-(3,5-dimethylphenyl)acetamide (Compound 8)]

In step 3 of Example 1, 3,5-dimethylaniline (3,5-dimethylaniline) was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 8.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.71 (s, 1 H), 7.58 (m, 3 H), 7.43 (d, 2 H, J = 8.4 Hz), 7.08 (s, 2 H), 7.03 (s, 1 H), 6.71 (s, 1 H), 4.32 (t, 2 H, J = 8.4 Hz), 4.01 (s, 6 H), 3.99 (s, 2 H), 3.12 (t, 2 H) , J = 8.4 Hz), 2.23 (s, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.5, 160.5, 155.6, 155.1, 149.0, 142.9, 141.5, 138.9, 137.9, 129.3, 126.1, 125.8, 125.7, 117.4, 112.7, 106.3, 105.8, 56.5, 56.4, 46.1, 36.0, 34.0, 21.4; MS m/z (M+H) ⁺ : 572.18.

Example 9. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-mesitylacetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-mesitylacetamide (compound 9)]

In step 3 of Example 1, 2,4,6-trimethylaniline (2,4,6-trimethylaniline) was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 9.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 8.38 (s, 1 H), 7.59 (d, 2 H, J = 8.4 Hz), 7.54 (s, 1 H), 7.44 (d, 2 H, J = 7.6 Hz), 6.92 (s, 1 H), 6.84 (s, 2 H), 4.35 (t, 2 H, J = 8.0 Hz), 4.11 (s, 2 H), 3.98 (s, 3 H), 3.96 (s, 3 H), 3.13 (t, 2 H, J = 8.0 Hz), 2.22 (s, 3 H), 2.11 (s, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.6, 155.5, 154.0, 149.0, 143.2, 141.6, 137.3, 134.8, 130.7, 129.4, 129.0, 125.8, 112.6, 106.3, 106.0, 56.4, 46.0, 34.9, 34.1, 20.9, 18.3; MS m/z (M+H) ⁺ : 586.20.

Example 10. N-(4-Butylphenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquina Zolin-2-yl)thio)acetamide [N-(4-butylphenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin- 2-yl)thio)acetamide (Compound 10)]

In step 3 of Example 1, 4-pentylaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 10.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.71 (s, 1 H), 7.57 (m, 3 H), 7.42 (d, 2 H, J = 8.0 Hz), 7.33 (d, 2 H, J = 8.4 Hz), 7.07 (d, 2 H, J = 8.0 Hz), 7.01 (s, 1 H), 6.32 (m, 2 H, J = 8.0 Hz), 4.00 (s, 8 H), 3.12 (t, 2 H, J = 8.0 Hz), 2.52 (t, 2 H, J = 7.6 Hz), 1.51 (m, 2 H), 1.29 (m, 2 H), 0.87 (t, 3 H, J = 7.6 Hz) , 2.11 (s, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.4, 160.5, 155.7, 155.1, 149.0, 142.9, 141.5, 139.2, 135.6, 129.3, 129.0, 125.7, 119.3, 112.7, 106.3, 105.8, 56.6, 56.4, 46.1, 35.9, 35.0, 34.0, 33.7, 22.2, 13.9; MS m/z (M+H) ⁺ : 600.21.

Example 11. N-(4-(tert-butyl)phenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4 -dihydroquinazolin-2-yl)thio)acetamide [N-(4-(tert-butyl)phenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl) phenethyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (compound 11)]

In step 3 of Example 1, 4-(tert-butyl)aniline [4-(tert-butyl)aniline] was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 11.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.71 (s, 1 H), 7.57 (s, 1 H), 7.57 (d, 2 H, J = 7.6 Hz), 7.42 (d, 2 H, J = 8.4 Hz), 7.36 (m, 2 H), 7.28 (s, 2 H), 7.01 (s, 1 H), 4.31 (t, 2 H, J = 8.0 Hz), 4.01 (s, 5 H), 4.00 (s, 3 H), 3.11 (t, 2 H, J = 8.0 Hz), 1.25 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.5, 160.5, 155.7, 155.1, 149.0, 147.4, 142.9, 141.5, 135.4, 129.3, 126.0, 125.8, 125.7, 119.1, 112.6, 106.2, 105.8, 56.6, 56.4, 46.1, 35.8, 34.4, 34.0, 31.3. MS m/z (M+H) ⁺ : 600.21

Example 12. 2-((6,7-dimethoxy-2-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-isopropylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-isopropylphenyl)acetamide (Compound 12)]

In step 3 of Example 1, 2-isopropylaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 12.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 8.68 (s, 1 H), 7.75 (d, 1 H, J = 8.4 Hz), 7.59 (d, 2 H, J = 8.0 Hz), 7.57 (s, 1 H), 7.44 (d, 2 H, J = 8.0 Hz), 7.15 (m, 3 H), 6.96 (s, 1 H), 4.35 (t, 2 H, J = 8.4 Hz), 4.15 (s, 2 H), 3.99 (s, 3 H), 3.96 (s, 3 H), 3.11 (t, 2 H, J = 8.4 Hz), 2.75 (m, 1 H), 0.89 (d, 6 H, J = 6.8 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 167.0, 160.6, 154.1, 149.0, 143.2, 139.7, 134.0, 129.3, 126.5, 126.1, 125.8, 125.5, 124.3, 112.6, 106.4, 106.0, 56.5, 56.4, 46.0, 35.4, 34.1, 28.0, 22.7. MS m/z (M+H) ⁺ : 586.19

Example 13. 2-((6,7-dimethoxy-4-oxo-3-(4-trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N -(3-isopropylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N -(3-isopropylphenyl)acetamide (compound 13)]

In step 3 of Example 1, 3-isopropylaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 13.

¹ H NMR (400 MHz, CDCl _3, ) δ 9.79 (s, 1 H), 7.58 (s, 1 H), 7.57 (d, 2 H, J = 8.0 Hz), 7.42 (d, 2 H, J = 8.0 Hz), 7.31 (t, 1 H, J = 1.2 Hz), 7.26 (m, 1 H), 7.18 (t, 1 H, J = 8.0 Hz), 7.03 (s, 1 H), 6.94 (d, 1 H, J = 8.0 Hz), 4.32 (t, 2 H, J = 8.4 Hz), 4.00 (m, 8 H), 3.12 (t, 2 H, J = 8.4 Hz), 2.80 (m, 1 H) , 1.16 (d, 6 H, J = 6.8 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.5, 160.5, 155.7, 155.2, 150.2, 149.0, 142.9, 141.5, 138.0, 129.3, 129.1, 125.8, 125.7, 122.5, 117.5, 116.8, 112.7, 106.3, 105.7, 56.5, 56.4, 46.2, 36.0, 34.2, 34.0, 23.9. MS m/z (M+H) ⁺ : 586.19

Example 14. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-methoxyphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-methoxyphenyl)acetamide (Compound 14)]

In step 3 of Example 1, 2-methoxyaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 14.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.88 (s, 1 H), 7.57 (s, 1 H), 7.57 (d, 2 H, J = 7.6 Hz), 7.42 (d, 2 H, J = 8.4 Hz), 7.24 (m, 1 H), 7.14 (t, 1 H, J = 8.4 Hz), 7.02 (s, 1 H), 6.86 (m, 1 H), 6.61 (m, 1 H), 4.32 (t, 2 H, J = 8.4 Hz), 4.00 (m, 8 H), 3.73 (m, 3 H), 3.12 (t, 3 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.6, 160.4, 160.3, 1557, 155.2, 149.1, 142.8, 141.5, 139.2, 129.8, 129.3, 125.7, 112.7, 111.4, 109.8, 106.3, 105.7, 105.4, 56.6, 56.4, 55.3, 46.2, 36.0, 34.0; MS m/z (M+H) ⁺ : 574.16.

Example 15. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(3-methoxyphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(3-methoxyphenyl)acetamide (Compound 15)]

In step 3 of Example 1, 3-methoxyaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 15.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.49 (s, 1 H), 8.37 (dd, 1 H, J = 8.0, 1.6 Hz), 7.56 (s, 1 H), 7.56 (d, 2 H = 8.0 Hz), 7.42 (d, 2 H, J = 7.6 Hz), 7.06 (s, 1 H), 7.00 (td, 1 H = 8.0, 1.6 Hz), 6.94 ((td, 1 H = 8.0, 1.6 Hz) ), 6.75 (dd, 1 H = 8.0, 1.6 Hz), 4.32 (t, 2 H, J = 8.0 Hz), 4.12 (s, 2 H), 4.00 (s, 3 H), 3.98 (s, 3 H) ), 3.30 (s, 3 H), 3.13 (t, 2 H, J = 8.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.8, 155.3, 154.1, 148.1, 148.0, 143.4, 141.6 , 129.3, 127.7, 125.8, 125.7, 124.0, 121.2, 120.1, 112.5, 110.0, 107.0, 105.8, 56.5, 56.4, 55.4, 45.9, 35.9, 34.1 MS m/z (M+H) ⁺ : 574.16.

Example 16. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-(trifluoromethyl)phenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl )thio)-N-(2-(trifluoromethyl)phenyl)acetamide (compound 16)]

In step 3 of Example 1, 2-(trifluoromethyl)aniline [2-(trifluoromethyl)aniline] was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 16.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 8.89 (s, 1 H), 8.06 (d, 1 H, J = 8.8 Hz), 7.57 (m, 5 H), 7.45 (d, 2 H = 8.4 Hz) ), 7.23 (t, 1 H, J = 7.6 Hz), 6.97 (s, 1 H), 4.34 (t, 2 H, J = 8.4 Hz), 4.15 (s, 2 H), 3.98 (s, 3 H) ), 3.96 (s, 3 H), 3.14 (t, 2 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 167.1, 160.8, 155.3, 153.2, 148.9, 143.4, 141.6, 134.8, 132.9, 129.3, 126.2, 125.8, 125.7, 125.6, 125.2, 121.3, 121.0, 112.5, 112.2, 106.8, 105.8, 56.3, 46.0, 35.5, 34.1. MS m/z (M+H) ⁺ : 612.13

Example 17. N-(2,5-bis(trifluoromethyl)phenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl) -3,4-dihydroquinazolin-2-yl)thio)acetamide [N-(2,5-bis(trifluoromethyl)phenyl)-2-((6,7-dimethoxy-4-oxo-3-( 4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (compound 17)]

Compound 17 was obtained by using 2,5-bis(trifluoromethyl)aniline [2,5-bis(trifluoromethyl)aniline] instead of 4-ethylaniline in step 3 of Example 1 and repeating step 4 of Example 1 got it

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.02 (s, 1 H), 8.49 (s, 1 H), 7.67 (d, 1 H, J = 8.4 Hz), 7.58 (d, 2 H, J = 7.6 Hz), 7.54 (s, 1 H), 7.45 (m, 3 H), 6.95 (s, 1 H), 4.34 (t, 2 H, J = 8.4 Hz), 4.17 (s, 2 H), 3.98 (s, 3 H), 3.96 (s, 3 H), 3.13 (t, 2 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 167.2, 160.7, 155.3, 153.1, 149.0, 143.3, 141.5, 135.8, 129.3, 126.9, 125.8, 125.7, 122.2, 121.6, 112.5, 106.7, 105.8, 56.3, 46.1, 35.5, 34.1. MS m/z (M+H) ⁺ : 680.12

Example 18. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(4-ethynylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(4-ethynylphenyl)acetamide (compound 18)]

In step 3 of Example 1, 4-ethynylaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 18.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 10.08 (s, 1 H), 7.58 (s, 1 H), 7.57 (d, 2 H, J = 8.0 Hz), 7.41 (m, 5 H), 6.99 (s, 1 H), 4.32 (t, 2 H, J = 8.4 Hz), 4.01 (s, 5 H), 3.99 (s, 3 H), 3.12 (t, 2 H, J = 8.4 Hz), 3.02 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.7, 160.4, 155.8, 155.3, 149.1, 142.7, 141.4, 138.5, 133.1, 129.3, 125.84, 125.80, 118.9, 117.7, 112.7, 106.3, 105.5, 83.2, 56.6, 56.5, 46.2, 36.0, 34.0. MS m/z (M+H) ⁺ : 568.14

Example 19. N-(4-(cyanomethyl)phenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4 -dihydroquinazolin-2-yl)thio)acetamide [N-(4-(cyanomethyl)phenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl) -3,4-dihydroquinazolin-2-yl)thio)acetamide (compound 19)]

In step 3 of Example 1, 2-(4-aminophenyl)acetonitrile [2-(4-aminophenyl)acetonitrile] was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 19.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.98 (s, 1 H), 7.59 (s, 1 H), 7.57 (d, 2 H, J = 8.0 Hz), 7.43 (m, 4 H), 7.22 (d, 2 H, J = 8.0 Hz), 7.00 (s, 1 H), 4.32 (t, 2 H, J = 8.4 Hz), 4.01 (s, 5 H), 4.00 (s, 3 H), 3.67 (s, 2 H), 3.12 (t, 2 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.4, 155.8, 155.3, 149.2, 142.8, 141.5, 137.9, 129.3, 128.8, 125.8, 125.6, 119.8, 117.8, 112.7, 106.3, 105.6, 56.6, 56.5, 46.2, 35.9, 34.0, 23.1. MS m/z (M+H) ⁺ : 582.15

Example 20. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-fluoro-4-methylphenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl) thio)-N-(2-fluoro-4-methylphenyl)acetamide (compound 20)]

In step 3 of Example 1, 2-fluoro-4-methylaniline [2-fluoro-4-methylaniline] was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 20.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.69 (s, 1 H), 8.18 (t, 1 H, J = 8.4 Hz), 7.56 (m, 3 H), 7.42 (d, 2 H, J = 8.4 Hz), 7.11 (d, 1 H, J = 2.8 Hz), 6.90 (d, 1 H, J = 8.8 Hz), 6.81 (dd, 1 H, J = 8.4, 1.2 Hz), 4.31 (t, 2) H, J = 8.4 Hz), 4.04 (s, 2 H), 4.02 (s, 3 H), 3.99 (s, 3 H), 3.11 (t, 2 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.6, 155.4, 154.6, 153.5, 151.1, 148.9, 143.2, 141.6, 134.99, 134.92, 129.3, 125.8, 125.7, 125.1, 121.5, 115.4, 115.2, 112.5, 106.8, 106.7, 105.8, 56.46, 56.42, 46.1, 35.9, 34.0, 20.9. MS m/z (M+H) ⁺ : 576.15

Example 21. N-(2,6-dibromo-4-methylphenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)- 3,4-dihydroquinazolin-2-yl)thio)acetamide [N-(2,6-dibromo-4-methylphenyl)-2-((6,7-dimethoxy-4-oxo-3-(4) -(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (compound 21)]

Compound 21 was obtained by using 2,6-dibromo-4-methylaniline (2,6-dibromo-4-methylaniline) instead of 4-ethylaniline in step 3 of Example 1 and repeating step 4 of Example 1 got it

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.22 (s, 1 H), 7.59 (d, 2 H, J = 7.6 Hz), 7.53 (s, 1 H), 7.44 (d, 2 H, J = 8.0 Hz), 7.36 (s, 2 H), 7.07 (s, 1 H), 4.35 (t, 2 H, J = 8.0 Hz), 4.11 (s, 2 H), 3.97 (s, 6 H), 3.13 (t, 2 H, J = 8.0 Hz), 2.27 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.6, 155.5, 154.6, 148.9, 143.2, 141.6, 140.5, 133.0, 131.6, 129.4, 125.8, 125.7, 123.0, 112.5, 106.5, 106.0, 56.6, 56.4, 46.1, 35.0, 34.1, 20.5. MS m/z (M+H) ⁺ : 713.98

Example 22. N-(4-Bromo-2-fluorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3 ,4-dihydroquinazolin-2-yl)thio)acetamide [N-(4-bromo-2-fluorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl) )phenethyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (Compound 22)]

In step 3 of Example 1, 4-bromo-2-fluoroaniline (4-bromo-2-fluoroaniline) was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 22.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.89 (s, 1 H), 8.28 (t, 1 H, J = 8.4 Hz), 7.56 (m, 3 H), 7.42 (d, 2 H, J = 7.6 Hz), 7.25 (m, 1 H), 7.17 (dd, 1 H, J = 10.4, 2.4 Hz), 7.07 (d, 1 H, J = 2.8 Hz), 4.31 (t, 2 H, J = 8.4) Hz), 4.04 (s, 2 H), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.11 (t, 2 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 167.1, 160.5, 155.4, 154.7, 153.2, 149.0, 143.0, 141.5, 129.3, 127.9, 125.9, 125.8, 125.7, 122.8, 122.6, 118.5, 118.3, 115.9, 115.8, 112.5, 106.67, 106.62, 105.9, 56.48, 56.45, 46.2, 35.9, 34.0. MS m/z (M+H) ⁺ : 639.05

Example 23. N-(2-Bromo-4-methylphenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4 -dihydroquinazolin-2-yl)thio)acetamide [N-(2-bromo-4-methylphenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl) )-3,4-dihydroquinazolin-2-yl)thio)acetamide (compound 23)]

In step 3 of Example 1, 2-bromo-4-methylaniline (2-bromo-4-methylaniline) was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 23.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 8.94 (s, 1 H), 8.10 (d, 1 H, J = 8.4 Hz), 7.57 (d, 2 H, J = 8.0 Hz), 7.53 (s, 1 H), 7.44 (d, 2 H, J = 8.0 Hz), 7.27 (d, 1 H, J = 1.6 Hz), 7.10 (dd, 1 H, J = 8.4, 1.6 Hz), 7.04 (s, 1) H), 4.34 (t, 2 H, J = 8.4 Hz), 4.14 (s, 2 H), 3.98 (s, 3 H), 3.97 (s, 3 H), 3.14 (t, 2 H, J = 8.4) Hz), 2.26 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.7, 160.8, 155.3, 153.4, 148.8, 143.4, 141.6, 135.9, 132.6, 129.4, 129.0, 125.7, 122.6, 113.7, 112.6, 107.1, 105.8, 56.5, 56.4, 46.0, 35.8, 34.1, 20.6. MS m/z (M+H) ⁺ : 636.07

Example 24. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4- dihydroquinazolin-2-yl)thio)-N-(2-fluoro-4-(trifluoromethyl)phenyl)acetamide (Compound 24)]

In step 3 of Example 1, using 2-fluoro-4-(trifluoromethyl)aniline [2-fluoro-4-(trifluoromethyl)aniline] instead of 4-ethylaniline and repeating step 4 of Example 1 Compound 24 was obtained.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 10.08 (d, 1 H, J = 1.6 Hz), 8.54 (t, 1 H, J = 8.4 Hz), 7.57 (m, 3 H), 7.40 (m, 3 H), 7.26 (m, 1 H), 7.09 (d, 1 H, J = 3.2 Hz), 4.32 (t, 2 H, J = 8.0 Hz), 4.06 (s, 2 H), 4.03 (s, 3 H), 4.00 (s, 3 H), 3.12 (t, 2 H, J = 8.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 167.4, 160.5, 155.5, 154.7, 149.1, 143.0, 141.5, 129.3, 125.7, 122.1, 121.5, 112.6, 106.6, 105.9, 56.5, 56.4, 46.2, 35.9, 34.0. MS m/z (M+H) ⁺ : 630.12

Example 25. N-(2-Chlorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquina Zolin-2-yl)thio)acetamide [N-(2-chlorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin- 2-yl)thio)acetamide (compound 25)]

In step 3 of Example 1, 2-chloroaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 25.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.23 (s, 1 H), 8.34 (d, 1 H, J = 8.4 Hz), 7.56 (d, 2 H, J = 8.4 Hz), 7.53 (s, 1 H), 7.42 (d, 2 H, J = 8.0 Hz), 7.27 (m, 2 H), 7.05 (s, 1 H), 7.01 (td, 1 H, J = 8.0, 1.6 Hz), 4.33 ( t, 2 H, J = 8.4 Hz), 4.14 (s, 2 H), 3.985 (s, 3 H), 3.983 (s, 3 H), 3.13 (t, 2 H, J = 8.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 167.0, 160.7, 155.3, 153.7, 148.9, 143.4, 141.6, 134.7, 129.4, 129.1, 127.8, 125.8, 125.7, 125.1, 123.0, 122.2, 112.6, 107.0, 105.8, 56.5, 56.4, 46.0, 35.9, 34.1. MS m/z (M+H) ⁺ : 578.10

Example 26. N- (3-chlorophenyl) -2- ((6,7-dimethoxy-4-oxo-3- (4- (trifluoromethyl) phenethyl) -3,4-dihydroquina Zolin-2-yl)thio)acetamide [N-(3-chlorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin- 2-yl)thio)acetamide (compound 26)]

In step 3 of Example 1, 3-chloroaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 26.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 10.10 (s, 1 H), 7.55 (m, 4 H), 7.42 (d, 2 H, J = 8.0 Hz), 7.32 (m, 1 H), 7.18 (t, 1 H, J = 8.0 Hz), 7.03 (dt, 1 H, J = 6.8, 1.2 Hz), 7.00 (s, 1 H), 4.32 (t, 1 H, J = 8.0 Hz), 4.02 ( s, 3 H), 4.01 (s, 3 H), 3.99 (s, 2 H), 3.12 (t, 2 H, J = 8.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.4, 155.8, 155.3, 149.2, 142.7, 141.4, 139.2, 134.8, 130.2, 129.3, 125.8, 124.3, 119.4, 117.2, 112.7, 106.4, 105.5, 56.6, 56.5, 46.2, 35.9, 34.0. MS m/z (M+H) ⁺ : 578.10

Example 27. N-(2,5-dichlorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-di hydroquinazolin-2-yl)thio)acetamide [N-(2,5-dichlorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3, 4-dihydroquinazolin-2-yl)thio)acetamide (Compound 27)]

In step 3 of Example 1, 2,5-dichloroaniline (2,5-dichloroaniline) was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 27.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.28 (s, 1 H), 8.45 (d, 1 H, J = 2.0 Hz), 7.56 (d, 2 H, J = 8.0 Hz), 7.53 (s, 1 H), 7.42 (d, 2 H, J = 7.6 Hz), 7.18 (d, 1 H, J = 8.8 Hz), 7.03 (s, 1 H), 6.99 (dd, 1 H, J = 8.8, 2.8) Hz), 4.32 (t, 2 H, J = 8.0 Hz), 4.14 (s, 2 H), 3.986 (s, 3 H), 3.982 (s, 3 H), 3.12 (t, 2 H, J = 8.0) Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 167.1, 160.6, 155.3, 153.8, 148.9, 143.3, 141.5, 135.6, 133.6, 129.7, 129.4, 125.8, 124.9, 121.9, 120.9, 112.6, 107.0, 105.9, 56.5, 56.4, 46.1, 35.9, 34.1. MS m/z (M+H) ⁺ : 612.07

Example 28. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-fluorophenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(2-fluorophenyl)acetamide (compound 28)]

In step 3 of Example 1, 2-fluoroaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 28.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.78 (s, 1 H), 8.35 (d, 1 H, J = 8.0 Hz), 7.57 (m, 5 H), 7.05 (m, 4 H), 4.31 (t, 2 H, J = 8.0 Hz), 4.05 (s, 2 H), 4.03 (s, 3 H), 3.99 (s, 3 H), 3.12 (t, 2 H, J = 8.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 167.0, 160.6, 155.4, 154.6, 149.0, 143.2, 141.6, 129.3, 126.6, 126.5, 125.8, 125.7, 124.8, 124.5, 124.4, 121.7, 114.9, 114.7, 112.5, 166.8, 106.7, 105.8, 56.47, 56.42, 46.1, 35.9, 34.0. MS m/z (M+H) ⁺ : 562.13

Example 29. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(3-fluorophenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(3-fluorophenyl)acetamide (Compound 29)]

In step 3 of Example 1, 3-fluoroaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 29.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 10.07 (s, 1 H), 7.50 (m, 6 H,), 7.19 (m, 1 H), 7.02 (m, 2 H), 6.76 (m, 1 H), 4.32 (t, 2 H, J = 8.4 Hz), 4.01 (s, 8 H), 3.12 (t, 2 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 161.9, 160.4, 155.8, 155.3, 149.2, 142.7, 141.4, 139.6, 139.5, 130.3, 130.2, 129.3, 125.8, 125.7, 114.5, 112.7, 111.1, 110.9, 107.1, 106.8, 106.4, 105.6, 56.6, 56.5, 46.2, 35.9, 34.0. MS m/z (M+H) ⁺ : 562.13

Example 30. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(4-fluorophenyl)acetamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(4-fluorophenyl)acetamide (compound 30)

In step 3 of Example 1, 4-fluoroaniline was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 30.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 9.85 (s, 1 H), 7.50 (m, 7 H,), 6.95 (m, 3 H), 4.32 (t, 2 H, J = 8.4 Hz), 4.01 (s, 2 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 3.12 (t, 2 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.6, 160.4, 158.1, 155.8, 155.2, 149.1, 142.8, 141.5, 134.1, 129.3, 125.8, 125.7, 121.0, 120.9, 115.9, 115.7, 112.7, 106.3, 105.6, 56.6, 56.5, 46.2, 35.8, 34.0. MS m/z (M+H) ⁺ : 562.13

Example 31. N-(3-Bromophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydro Quinazolin-2-yl)thio)acetamide [N-(3-bromophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin -2-yl)thio)acetamide (compound 31)

In step 3 of Example 1, 3-bromoaniline (3-bromoaniline) was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 31.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 10.11 (s, 1 H), 7.53 (m, 7 H,), 7.15 (m, 2 H), 7.00 (s, 1 H), 4.32 (t, 2 H, J = 8.4 Hz), 4.03 (s, 3 H), 4.01 (s, 3 H), 3.99 (s, 2 H), 3.12 (t, 2 H, J = 8.4 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.4, 155.8, 155.3, 149.2, 142.7, 141.4, 139.3, 130.5, 129.3, 127.2, 125.84, 125.80, 122.7, 122.2, 117.7, 112.7, 106.4, 105.5, 56.6, 56.5, 46.2, 36.0, 34.0. MS m/z (M+H) ⁺ : 622.05

Example 32. N-(3,4-dichlorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-di hydroquinazolin-2-yl)thio)acetamide [N-(3,4-dichlorophenyl)-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3, 4-dihydroquinazolin-2-yl)thio)acetamide (compound 32)

In step 3 of Example 1, 3,4-dichloroaniline (3,4-dichloroaniline) was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 32.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 10.21 (s, 1 H), 7.62 (t, 1 H, J = 1.6 Hz), 7.58 (m, 3 H), 7.42 (d, 2 H, J = 8.0 Hz), 7.30 (d, 2 H, J = 1.6 Hz), 6.98 (s, 1 H), 4.32 (m, 2 H), 4.019 (s, 3 H), 4.013 (s, 3 H), 3.98 (s, 2 H), 3.12 (t, 2 H, J = 8.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 166.8, 160.3, 155.9, 155.4, 149.2, 142.7, 141.4, 137.5, 132.9, 130.7, 129.3, 127.4, 125.84, 125.80, 120.9, 118.5, 112.7, 106.4, 105.4, 56.6, 56.5, 46.3, 35.9, 34.0. MS m/z (M+H) ⁺ : 612.07

Example 33. N-allyl-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl )thio)acetamide [N-allyl-2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)acetamide (compound 33)

In step 3 of Example 1, prop-2-en-1-amine was used instead of 4-ethylaniline, and step 4 of Example 1 was repeated to obtain compound 33.

¹ H NMR (400 MHz, CDCl ₃ ,) δ 7.57 (d, 2 H, J = 8.0 Hz), 7.53 (s, 1 H), 7.41 (d, 1 H, J = 8.4 Hz), 7.26 (t, 1 H, J = 4.8 Hz), 6.87 (s, 1 H), 5.80 (m, 1 H), 5.09 (m, 2 H), 4.31 (m, 2 H), 3.978 (s, 3 H), 3.971 (s, 3 H), 3.91 (s, 2 H), 3.88 (td, 2 H, J = 5.6, 1.2 Hz), 3.11 (t, 2 H, J = 8.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ,) δ 168.1, 160.7, 155.4, 154.0, 148.9, 143.2, 141.7, 134.0, 129.4, 125.79, 125.75, 116.3, 112.6, 106.3, 105.9, 56.45, 56.42, 46.0, 42.1, 34.9, 34.1. MS m/z (M+H) ⁺ : 508.14

<Experimental Example 1> Inhibition of proliferation of cancer cells

In order to confirm the cell activity of the previously synthesized compounds using lung cancer cell lines A549 and NCI-H460, cell viability was checked and the concentration IC ₅₀ value indicating 50% inhibition of cell activity was confirmed.

Each cell was seeded in an appropriate number of cells in a 96-well plate (3,000 cells each for A549 and NCI-H460), and after treatment with each compound at each concentration, the cells were further cultured for 48 hours, followed by EZ-cytox (EZ-1000, DOGEN) was treated to calculate cell viability to obtain an IC ₅₀ value.

As a result, as shown in Table 1, the anticancer effect was confirmed by selecting Compound 30 among compounds having a low IC ₅₀ value of 10 μM or less for lung cancer cells.

compound A549
(IC ₅₀ , μM) NCI-H460
((IC ₅₀ , μM)) compound A549
(IC ₅₀ , μM) NCI-H460
(IC ₅₀ , μM) One >100 - 18 7.5 27 2 >100 >100 19 >100 >100 3 >100 >100 20 >100 >100 4 44 43 21 87 >100 5 >100 >100 22 >100 >100 6 >100 >100 23 84 >100 7 >100 >100 24 6.6 19 8 >100 >100 25 6.7 49 9 >100 >100 26 13 45 10 >100 >100 27 19 32 11 2.8 3 28 34 >100 12 8.5 12 29 6 8.2 13 6.8 9.2 30 5.7 6.5 14 7.3 6.6 31 12 21 15 41 >100 32 8.8 16 16 >100 >100 33 >100 >100 17 >100 >100

<Experimental Example 2> Confirmation of in vivo anticancer effect

1. Confirmation of metastasis inhibition effect in lung cancer metastasis model

In order to confirm the cancer metastasis inhibitory effect of compound 30, which showed an excellent IC ₅₀ value among previously synthesized compounds, a mouse lung cancer (LLC, Lewis lung carcinoma) metastasis model was used. After injecting Lewis lung carcinoma cells into ICR mice with 4 × 10 ⁵ cells, Compound 30 was administered intravenously (IV) twice a week at concentrations of 0.1 and 0.5 mg/kg for 4 weeks.

As a result, as shown in FIG. 1 , it was confirmed that lung tumors were significantly reduced in the mouse experimental group administered with Compound 30 compared to the control group.

2. Confirmation of anticancer effect in lung cancer model by A549 non-small cell lung cancer (NSCLC) cell line

In the same manner as in the previous experiment, the anticancer effect of compound 30 was confirmed in a lung cancer mouse model in which tumors were formed by transplanting the A549 non-small cell lung cancer (NSCLC) cell line into nude mice.

As a result, as shown in FIG. 2 , it was confirmed that the weight of the lung tumor was significantly reduced in the mouse experimental group administered with Compound 30 as compared to the control group.

As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, it is clear that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (9)

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

In Formula 1,
W is (CR ¹ R ² ) _m -(C=O) _n -(NR ³ ) _p -(C=O) _r -Y,
m, n, p or r are each an integer from 0 to 2,
R ¹ to R ³ may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo, trifluoromethyl or trifluoromethoxy,
Y is selected from aryl, (5- to 6-ring) heteroaryl including nitrogen, (C3 to C8) cycloalkyl, or hetero (C3 to C8) cycloalkyl including nitrogen, oxygen or sulfur, each of which is allowed by the valence optionally substituted with one or more substituents independently selected from methyl, (C3-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy. The method according to claim 1, wherein W is (CR ¹ R ² ) _m -(C=O) _n -(NH) _p -(C=O) _r -Y, m and p are 1, and n and r one of silver is 1, the other is 0, one of R ¹ to R ² is (C1-C4)alkyl, the other is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo, is selected from trifluoromethyl or trifluoromethoxy, and Y is a substituent selected from (C3 to C4)alkyl, (C1 to C4)alkoxy, (C3 to C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy One or more substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof. The method according to claim 2, wherein the compound is a compound represented by the following formula (2), or a pharmaceutically acceptable salt thereof, characterized in that:
[Formula 2]

In Formula 2,
R ⁴ and R ⁵ may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo, trifluoromethyl or trifluoromethoxy. A pharmaceutical composition for treating or preventing cancer, comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. The method according to claim 4, wherein the cancer disease is breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube cancer Cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer and bone marrow cancer, characterized in that selected from the group consisting of cancer treatment or prevention pharmaceutical composition for use. A health functional food composition for improving or preventing cancer disease, comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for inhibiting cancer metastasis, comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing cancer, comprising the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and an immuno-cancer agent. The method according to claim 8, wherein the immunotherapy is anti-PD1, anti-PDL1, anti-CTLA4, anti-LAG3, anti-VISTA, anti-BTLA, anti-TIM3, anti-HVEM, anti-CD27, anti-CD137, anti -OX40, anti-CD28, anti-PDL2, anti-GITR, anti-ICOS, anti-SIRPα, anti-ILT2, anti-ILT3, anti-ILT4, anti-ILT5, anti-EGFR, anti-CD19 and anti-TIGIT A pharmaceutical composition for treating or preventing cancer, characterized in that it is one or more immuno-cancer agents selected from the group consisting of.

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