KR102403566B1 - Method for preparing novel benzofuro[2,3-c]isoquinoline derivatives and anticancer composition containing the same - Google Patents

Abstract

The present invention relates to a novel benzofuro[2,3-c] isoquinoline derivative having a preventive or therapeutic effect on cancer and uses thereof. The novel benzofuro[2,3-c]isoquinoline derivative or a pharmaceutically acceptable salt thereof according to the present invention is expected to be able to more effectively treat prostate cancer and breast cancer.

Description

A novel method for preparing benzofuro[2,3-c]isoquinoline derivatives and an anticancer composition containing the same

The present invention relates to a novel method for preparing a benzofuro[2,3-c]isoquinoline derivative and an anticancer composition comprising the same.

Hormone-dependent cancers, including prostate cancer and breast cancer, contribute to the incidence of the majority of cancers in the United States and worldwide [Non-Patent Document 0001]. In 2018 alone, more than 400,000 men and women in the United States were affected by hormonal cancer, and more than 100,000 died from this cancer [Non-Patent Document 0001]. Over the past decade, the understanding of these cancers has increased at the molecular level, and the number of therapeutic agents to treat these two cancers has increased significantly [Non-Patent Document 0002-0003].

Both prostate cancer and breast cancer depend on male and female hormones for sustained growth [Non-Patent Document 0003-0004]. Estrogen receptor (ER) and androgen receptor (Androgen receptor, AR) are growth promoters of these two cancers, and therapeutic agents regulating these receptors are often used to inhibit the growth of cancer [Non-Patent Document 0005-0006] ]. Although this new treatment effectively prevents cancer progression and improves patient survival, anticancer treatment becomes difficult due to the development of drug resistance of cancer cells to existing drugs [Non-Patent Document 0001, 0007-0009].

For example, androgen deprivation therapy (ADT), including enzalutamide and abiraterone, is used to treat prostate cancer, but if refractory to treatment, about 20% of prostate cancers are castration-resistant. resistant prostate cancer, CRPC) [Non-Patent Document 0010-0011].

Drugs targeting estrogen signaling have shown therapeutic effects in the treatment of breast cancer affected by ER and progesterone receptors (PR) [Non-Patent Document 0012-0014]. However, 10-20% of breast cancers are triple-negative breast cancer (TNBC), unaffected by ER and PR, and there is no standard treatment. Currently, anthracycline-based chemotherapy is used for the treatment of TNBC, but the optimal chemotherapy approach is still controversial [Non-Patent Documents 0001, 0015]. Therefore, in the treatment of prostate cancer and breast cancer, the development of anticancer agents with novel molecular scaffolds is required.

[Non-Patent Document 0001] CA Cancer J Clin., 68 (2018) 7-30. [Non-patent document 0002] EMBO Mol. Med., 10 (2018). [Non-Patent Document 0003] Endocr. Connect., 8 (2019) R10-r26 [Non-Patent Document 0004] Urology., 57 (2001) 31-38. [Non-patent document 0005] Nat. Rev. Cancer., 10 (2010) 205-212. [Non-Patent Document 0006] Breast Cancer., 8 (2014) 15-38. [Non-patent document 0007] Ther. Adv. Med. Oncol., 8 (2016) 267-275. [Non-Patent Document 0008] Clin. Cancer Res., 21 (2015) 795-807. [Non-Patent Document 0009] Oncogene., 34 (2015) 1745-1757. [Non-Patent Document 0010] Nat. Rev. Urol., 15 (2018) 271-286. [Non-Patent Document 0011] Curr. Drug Targets., 13 (2012) 1308-1323. [Non-Patent Document 0012] Nat. Rev. Drug Discov., 2 (2003) 205-213. [Non-Patent Document 0013] Clin. Interv. Aging., 9 (2014) 1437-1452. [Non-Patent Document 0014] Clin. Breast Cancer., 14 (2014) 1-9. [Non-Patent Document 0015] Breast Care., 12 (2017) 102-107.

The present invention has been devised to solve the above problems, and the present inventors have studied intensively to find a novel substance that inhibits anticancer, in particular, PC-3 cells, which are prostate cancer cells, and MDA-MB-231 cells, which are breast cancer cells. , PC-3, and MDA-MB-231 Identified novel benzofuro[2,3-c]isoquinoline derivatives that inhibit cell growth and migration and cause apoptosis, and based on this, the present invention was completed.

Accordingly, an object of the present invention is to provide a novel benzofuro[2,3-c]isoquinoline derivative or a pharmaceutically acceptable salt thereof that inhibits the growth and migration of cancer cells and causes apoptosis will be.

Another object of the present invention is to provide a method for preparing the novel benzofuro[2,3-c]isoquinoline derivative.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the benzofuro[2,3-c]isoquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. .

Another object of the present invention, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer comprising the benzofuro[2,3-c]isoquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient , colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, Multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer , astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, kidney cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant , malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, triple negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, Gestational chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease , tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer and thymus cancer at least one type selected from the group consisting of prevention or treatment To provide a pharmaceutical composition for

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the object of the present invention as described above, the present invention provides a compound of Formula 2 or a pharmaceutically acceptable salt thereof.

[Formula 2]

In Formula 2,

R ₁ is benzodioxole, phenyl or furanyl unsubstituted or substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₂ and R ₃ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl unsubstituted or substituted with one or more non-hydrogen substituents;

R ₂ and R ₃ are joined together with the carbon atom to which they are attached to form a 6 membered hydrocarbon compound,

The non-hydrogen substituent in R ₂ and R ₃ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound of Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, Oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic Myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, non-sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma , childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer , urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, triple negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, chorionic gestational disease, cervical cancer, endometrial cancer, uterus Sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, It provides a pharmaceutical composition for preventing or treating at least one selected from the group consisting of lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer and thymus cancer.

In one embodiment of the present invention, the composition can inhibit the growth and migration of cancer cells and cause apoptosis.

The novel benzofuro[2,3-c]isoquinoline derivative or a pharmaceutically acceptable salt thereof according to the present invention inhibits the growth and migration of cancer cells and exhibits an activity causing apoptosis. It is expected that the pharmaceutical composition comprising the composition can be usefully used for the prevention and treatment of cancer.

1 is a graph showing the experimental results of the effect of the 2n compound of the present invention on cell viability and migration in PC-3 and MDA-MB-231 cells (A: PC-3 cells were treated with 2n at the indicated concentration for 72 hours). Incubated with, BC: scratch migration assay performed on PC-3 cells, D: MDA-MB-231 cells incubated at 2n at the indicated concentrations for 72 h, EF: scratch migration assay performed on MDA-MB-231 cells , Scratch migration assay, in which cells were treated with 0.3, 0.5 and 1 μM of 2n, representative images were taken at 0 and 18 hours post-scratch, wound closure was measured for 24 hours (mean ± SE, n = 3- 4)).
Figure 2 is a graph showing the experimental results of the effect of the 2n compound of the present invention on Caspase-3 activity and PARP cleavage in PC-3 and MDA-MB-231 cells (AB: cells were treated with 1 μM of 2n for 24 hours After incubation, treated with 2 μM Caspase-3 substrate and 1 μM Hoechst 33342 for 20 min, white bars are 200 μm, CD: cells were incubated with 2n at the indicated concentrations for 24 h, followed by 1 μM Caspase-3 Substrate treatment for 30 min, Caspase-3 activity was inhibited by 10 μM Ac-DEVD-CHO (mean ± SE, n = 3-4), EF: Cells were incubated with 2n for 24 h Western blotting ( western blotting) was used to detect PARP, cleaved PARP and β-actin, **P<0.01, ***P<0.001).
3 is a graph showing the experimental results of the effect of compound 2o of the present invention on cell viability and migration in PC-3 and MDA-MB-231 cells (A: PC-3 cells were treated with 2o at the indicated concentration for 72 hours). Incubated with, BC: scratch migration assay performed on PC-3 cells, D: MDA-MB-231 cells incubated at 2o at the indicated concentrations for 72 h, EF: scratch migration assay performed on MDA-MB-231 cells , Scratch migration assay, in which cells were treated with 0.1, 0.3 and 1 μM of 2n, and representative images were taken at 0 and 18 h post-scratch, wound closure was measured for 24 h (mean ± SE, n = 3- 4)).
4 is a graph showing the experimental results of the effect of compound 2o of the present invention on Caspase-3 activity and PARP cleavage in PC-3 and MDA-MB-231 cells (AB: cells were treated with 1 μM 2o for 24 hours After incubation, treated with 2 μM Caspase-3 substrate and 1 μM Hoechst 33342 for 20 min, white bars are 200 μm, CD: cells were incubated at the indicated concentrations of 2o for 24 h, followed by 1 μM Caspase-3 Substrate treatment for 30 min, Caspase-3 activity was inhibited by 10 μM Ac-DEVD-CHO (mean ± SE, n = 3-4), EF: cells were incubated at 2o for 24 h Western blotting ( western blotting) was used to detect PARP, cleaved PARP and β-actin, **P<0.01, ***P<0.001).

Hereinafter, the present invention will be described in detail.

The present invention provides a compound of Formula 2 or a pharmaceutically acceptable salt thereof.

[Formula 2]

In Formula 2,

R ₁ is benzodioxole, phenyl or furanyl unsubstituted or substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₂ and R ₃ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl unsubstituted or substituted with one or more non-hydrogen substituents;

R ₂ and R ₃ are joined together with the carbon atom to which they are attached to form a 6 membered hydrocarbon compound,

The non-hydrogen substituent in R ₂ and R ₃ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.

"Phenyl" is a functional group consisting of carbon and hydrogen, and is a substituent derived by removing one hydrogen from benzene. It is the simplest among the aryl groups, and can be expressed as -Ph as an abbreviation. It is very stable and is found in many organic compounds. The simplest compound is phenol (C ₆ H ₅ OH).

"Alkyl" refers generally to linear and branched saturated hydrocarbon groups having the specified number of carbon atoms (eg, from 1 to 12 carbon atoms). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and n-heptyl, and the like. Alkyl may be attached to a parent group or substrate at any ring atom provided that attachment does not violate valence requirements. Likewise, an alkyl or alkenyl group may contain one or more non-hydrogen substituents provided that attachment does not violate valence requirements.

"Alkoxy" is an alkyl group bonded to oxygen. The range of (R-O)alkoxy groups is very large and includes methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy.

"Halogen" is an element belonging to group 17 of the periodic table, and since there are 7 electrons in the outermost electron shell, it is easy to obtain electrons from other elements and become negative ions. It exists mainly in the form of other elements and compounds because of its high non-metallic properties and high reactivity in each cycle. These include fluorine, chlorine, bromine, and iodine.

"Hydroxy" is a functional group whose structural formula is represented by -OH.

In one embodiment of the present invention, in Formula 2,

R ₁ is benzodioxole, phenyl or furanyl unsubstituted or substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₂ and R ₃ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl unsubstituted or substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₂ and R ₃ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.

In one embodiment of the present invention, in Formula 2,

R ₁ is benzodioxole, phenyl or furanyl unsubstituted or substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₂ and R ₃ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₂ and R ₃ is halogen,

R ₄ , R ₅ and R ₆ are each independently hydrogen or C ₁ -C ₄ alkoxy.

In another embodiment of the present invention, according to claim 1,

The compound of Formula 2 may be a compound having a structure of Formula 2a below.

[Formula 2a]

In Formula 2a,

R ₁ is phenyl unsubstituted or substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.

In another embodiment of the present invention, in Formula 2a,

R ₁ is phenyl unsubstituted or substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₁ is halogen or C ₁ -C ₄ alkoxy;

R ₄ , R ₅ and R ₆ are C ₁ -C ₄ alkoxy.

In another embodiment of the present invention, R ₁ is

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

또는

일 수 있다.

or

can be

In another embodiment of the present invention, the 6-membered hydrocarbon compound may be benzene.

In another embodiment of the present invention, R ₁ is

;

또는

일 수 있다.

;

or

can be

In another embodiment of the present invention, the compound of formula 2 is

2,3,9,10-tetramethoxy-5-(2-methoxyphenyl)benzofuro[2,3-c]isoquinoline (2a);

2,3,9,10-tetramethoxy-5-(p-tolyl)benzofuro[2,3-c]isoquinoline (2b);

5-(benzo[d][1,3]dioxol-5-yl)-2,3,9,10-tetramethoxybenzofuro[2,3-c]isoquinoline (2c);

10-chloro-2,3-dimethoxy-8-methyl-5-phenylbenzofuro[2,3-c]isoquinoline (2d);

10-(4-bromophenyl)-2,3-dimethoxy-5-phenylbenzofuro[2,3-c]isoquinoline (2e);

2,3,9,10,11-pentamethoxy-5-phenylbenzofuro[2,3-c]isoquinoline (2f);

2,3,4,9,10-pentamethoxy-5-phenylbenzofuro[2,3-c]isoquinoline (2g);

5-(4-chlorophenyl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline (2h);

2,3,4-trimethoxy-5-phenylnaphtho[1',2':4,5]furo[2,3-c]isoquinoline (2i);

5-(3,4-dimethoxyphenyl)-2,3,4-trimethoxynaphtho[1',2':4,5]furo[2,3-c]isoquinoline (2j);

5-(4-chlorophenyl)-2,3,4-trimethoxynaphtho[1',2':4,5]furo[2,3-c]isoquinoline (2k);

2,3,4,10-tetramethoxy-5-phenylbenzofuro[2,3-c]isoquinoline (21);

5-(4-chlorophenyl)-2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinoline (2m);

5-(3,4-dimethoxyphenyl)-2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinoline (2n);

5-(5-chlorofuran-2-yl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline (2o);

5-(3,4-dimethoxyphenyl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline (2p);

5-(furan-2-yl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline (2q);

5-(5-bromofuran-2-yl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline (2r);

2-methoxy-5-(2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinolin-5-yl)phenol (2s);

2-methoxy-4-(2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinolin-5-yl)phenol (2t); or

5-(5-chlorofuran-2-yl)-2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinoline (2u);

Also, the present invention provides a method for preparing a compound of Formula 2, comprising reacting a compound of Formula 1 with a compound of Formula 3 to obtain a compound of Formula 2.

[Formula 1]

[Formula 2]

[Formula 3]

In the above formula,

R ₁ is benzodioxole, phenyl or furanyl unsubstituted or substituted with one or more non-hydrogen substituents,

The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₂ and R ₃ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl unsubstituted or substituted with one or more non-hydrogen substituents;

R ₂ and R ₃ are joined together with the carbon atom to which they are attached to form a 6 membered hydrocarbon compound,

The non-hydrogen substituent in R ₂ and R ₃ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.

Meanwhile, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.

As used herein, the term "salt" is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanoates. It is obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methylbenzoate Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol late, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the invention is prepared by a conventional method, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile. can be manufactured. It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).

In addition, the compound of the present invention includes all salts, isomers, hydrates and solvates that can be prepared by conventional methods as well as pharmaceutically acceptable salts.

The present invention provides a pharmaceutical composition for the prevention or treatment of cancer, comprising the compound of Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient, the compound of Formula 2 or a pharmaceutically acceptable salt thereof for the treatment of the disease Provided are possible uses of salts, and methods of treating the above diseases comprising administering to a subject a therapeutically effective amount of the compound of Formula 2 or a pharmaceutically acceptable salt thereof.

The cancer is applied without limitation as long as it is a known cancer, for example, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungus Sarcoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, Retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, Meningiomas, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, unknown primary site Cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, triple-negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer , metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid cancer, vaginal cancer, spinal cord cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma , may be at least one selected from the group consisting of skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymus cancer.

As can be seen in the Examples below, the compound of Formula 2 may be used for the purpose of inhibiting the growth and migration of prostate and breast cancer cells, and inducing apoptosis.

As used herein, the term “prevention” refers to any action that suppresses or delays the onset of prostate cancer and breast cancer by administration of the pharmaceutical composition according to the present invention.

As used herein, the term “treatment” refers to any action in which symptoms for prostate cancer and breast cancer are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. In this case, pharmaceutically acceptable carriers are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose. , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. may be additionally included in addition to the above components.

The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or locally applied) according to a desired method, and the dosage may vary depending on the condition and weight of the patient, and the disease. Although it varies depending on the degree, drug form, administration route and time, it may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and type of the patient's disease; Sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well known in the medical field may be determined. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient into the body, inactivation rate and excretion rate, disease type, and drugs used in combination, in general 0.0001 to 1000 mg, preferably 0.001 to 500 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, the severity of obesity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.

In the present invention, "individual" refers to a subject in need of treatment for a disease, and more specifically, refers to mammals such as humans or non-human primates, mice, dogs, cats, horses and cattle. .

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

<Example> Basic method for synthesizing compounds

DCE with 3-(3,4-dimethoxyphenyl)-5,6-dimethoxybenzofuran-2-amine (50 mg, 0.15 mmol) and 2-methoxy benzaldehyde (0.3 mmol, 2.0 equiv) To the (2mL) solution was added Yb(OTf) ₃ (0.03 mmol, 0.2 equiv) at room temperature. After stirring at 130° C. for 27 h, the reaction mixture was diluted with CH ₂ Cl ₂ (10 mL) and washed with aqueous NaHCO ₃ (5 mL×2) solution. The organic layer was dried over MgSO ₄ and concentrated in vacuo to give the crude product. Purification by flash chromatography on silica gel (hexane/EtOAc) gave 2a.

The compounds of the following examples were obtained by the method of the above examples.

<Example 1> 2,3,9,10-tetramethoxy-5-(2-methoxyphenyl)benzofuro[2,3-c]isoquinoline (2a)

Brown solid (62 mg, 91%); mp: 229-231 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (s, 1H), 7.53 - 7.30 (m, 5H), 7.19 (s, 1H), 7.04 (d, J = 6.9 Hz, 1H), 4.12 (s, 3H), 4.01 (s, 3H), 3.99 (s, 3H), 3.88 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.8, 158.7, 154.3, 153.2, 149.7, 149.4, 148.2, 146.4, 141.0, 129.8, 129.4, 122.6, 119.9, 115.3, 115.1, 114.9, 107.7, 107.5, 104.2, 101.5 , 96.2, 57.1, 56.3, 56.1, 55.9, 55.5; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₄ NO ₆ 446.1598, found 446.1594.

<Example 2> 2,3,9,10-tetramethoxy-5- ( p -Tolyl) benzofuro [2,3- c ]Isoquinoline (2b)

Brown solid (34 mg, 52%); mp: 221-223 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (d, J = 7.8 Hz, 2H), 7.59 (s, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 7.35 (d, J = 7.7 Hz, 2H), 7.21 (s, 1H), 4.14 (s, 3H), 4.02 (s, 3H), 4.00 (s, 3H), 3.89 (s, 3H), 2.47 (s, 3H); ¹³ C[7] NMR (100 MHz, CDCl ₃ ) δ 158.9, 154.8, 153.2, 149.6, 149.4, 148.2, 146.4, 138.5, 136.9, 130.1, 130.1, 129.8, 129.2, 129.2, 120.0, 115.2, 107.7, 107.4, 104.2, 101.5, 96.2, 57.1, 56.4, 56.1, 55.9, 21.5; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₄ NO ₅ 430.1649, found 430.1641.

<Example 3> 5- (benzo [ d ][1,3]dioxol-5-yl)-2,3,9,10-tetramethoxybenzofuro[2,3- c ]Isoquinoline (2c)

Brown solid (21 mg, 30%); mp: 229-231 °C; R _f = 0.2 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.29 (d, J = 3.8 Hz, 1H), 7.26 (s, 1H) , 7.24 (s, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.07 (s, 2H), 4.17 (s, 3H), 4.05 (s, 3H), 4.02 (s, 3H), 3.92 ( s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.9, 154.1, 153.3, 149.8, 149.5, 148.3, 148.1, 148.0, 146.5, 133.8, 129.9, 124.2, 120.0, 115.2, 110.7, 108.3, 107.6, 107.5, 104.4, 101.7 , 101.5, 96.3, 57.2, 56.4, 56.2, 56.0; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₂ NO ₇ 460.1391, found 460.1391.

<Example 4> 10-chloro-2,3-dimethoxy-8-methyl-5-phenylbenzofuro [2,3- c ]Isoquinoline (2d)

light yellow solid (36 mg, 56%); mp: 208-210 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.81 - 7.76 (m, 2H), 7.58 - 7.48 (m, 5H), 7.27 (s, 1H), 4.17 (s, 3H), 3.87 (s, 3H), 2.60 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.4, 157.3, 153.9, 151.3, 148.6, 139.5, 130.6, 130.2, 130.2, 128.9, 128.6, 128.6, 128.5, 127.5, 124.3, 124.1, 120.1, 118.6, 107.8, 106.6 , 101.6, 56.4, 55.9, 15.4; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₄ H ₁₉ ClNO ₃ 404.1048, found 404.1047.

<Example 5> 10- (4-bromophenyl) -2,3-dimethoxy-5-phenylbenzofuro [2,3-c] isoquinoline (2e)

Brown crystal (52.4 mg, 65%); mp: 104-105.2 °C; R _f = 0.2 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J = 1.5 Hz, 1H), 8.12 (d, J = 7.2 Hz, 2H), 7.81 (d, J = 6.7 Hz, 2H), 7.72 (s) , 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.60 (s, 1H), 7.57 (s, 2H), 7.55 (d, J = 1.6 Hz, 1H), 7.48 (t, J = 7.7 Hz) , 2H), 4.18 (s, 3H), 3.89 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.9, 159.6, 157.1, 153.9, 153.8, 148.5, 140.6, 139.6, 135.9, 133.9, 132.1, 130.7, 130.3, 130.2, 129.3, 129.0, 128.6, 125.9, 124.4, 121.6 , 120.2, 120.0, 112.6, 107.8, 106.8, 101.8, 77.48, 56.3, 56.0; HRMS (ESI-QTOF) m/z [M + H] ⁺ calcd for C ₂₉ H ₂₁ BrNO ₃ 510.0699, found 510.0699.

<Example 6> 2,3,9,10,11-pentamethoxy-5-phenylbenzofuro[2,3- c ]Isoquinoline (2f)

White solid (44 mg, 71%); mp: 163-165 °C; R _f = 0.2 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (s, 1H), 7.79 (d, J = 7.0 Hz, 2H), 7.60-7.44 (m, 4H), 7.04 (s, 1H), 4.20 (s, 3H), 4.19 (s, 3H), 3.98 (s, 6H), 3.87 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.5, 155.0, 153.9, 152.9, 151.0, 148.3, 147.7, 139.9, 138.9, 130.2, 130.1, 130.1, 128.6, 128.5, 128.5, 120.3, 110.8, 108.3, 107.0, 105.6 , 92.2, 62.5, 61.5, 56.5, 56.2, 55.9; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₄ NO ₆ 446.1598, found 446.1598.

<Example 7> 2,3,4,9,10-pentamethoxy-5-phenylbenzofuro[2,3- c ]Isoquinoline (2g)

White solid (32 mg, 87%); mp: 211-213 °C; R _f = 0.2 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (s, 1H), 7.58 - 7.53 (m, 2H), 7.50 (s, 1H), 7.47-7.39 (m, 3H), 7.26 (s, 1H), 4.17 (s, 3H), 4.07 (s, 3H), 4.02 (s, 3H), 3.93 (s, 3H), 3.37 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.9, 157.3, 155.0, 151.6, 149.8, 149.5, 146.6, 143.4, 141.1, 131.9, 128.9, 128.9, 127.4, 127.2, 127.2, 115.9, 115.2, 107.3, 104.5, 98.0 , 96.4, 61.4, 61.1, 57.2, 56.4, 56.1; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₄ NO ₆ 446.1598, found 446.1604.

<Example 8> 5- (4-chlorophenyl) -2,3,4,9,10-pentamethoxybenzofuro [2,3- c ]Isoquinoline (2h)

White solid (16.1 mg, 54%); mp: 259-260 °C; R _f = 0.2 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (s, 1H), 7.51 (d, J = 7.2 Hz, 3H), 7.41 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 4.18 (s, 3H), 4.07 (s, 3H), 4.03 (s, 3H), 3.95 (s, 3H), 3.40 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.8, 157.4, 153.4, 151.3, 150.0, 149.6, 146.7, 141.8, 141.2, 133.4, 131.9, 130.5, 130.5, 127.3, 127.3, 115.8, 115.1, 107.6, 104.5, 98.1 , 96.4, 61.4, 61.1, 57.3, 56.5, 56.1; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₆ H ₂₃ ClNO ₆ 480.1208, found 480.1203.

<Example 9> 2,3,4-trimethoxy-5-phenylnaphtho [1 ', 2': 4,5] puro [2,3- c ]Isoquinoline (2i)

White solid (21.6 mg, 87%); mp: 202-204 °C; R _f = 0.3 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.06 (d, J = 8.3 Hz, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.00 (dd, J = 8.8, 1.7 Hz, 1H), 7.87 (dd, J = 8.8, 2.2 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.65 - 7.56 (m, 3H), 7.52-7.40 (m, 3H), 4.19 (s, 3H), 3.98 (s, 3H), 3.39 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.7, 156.6, 156.3, 152.8, 151.6, 143.4, 141.1, 132.2, 131.4, 130.1, 128.9, 128.9, 128.9, 128.5, 127.5, 127.2, 127.2, 126.2, 125.1, 124.7 , 118.3, 116.4, 113.2, 108.8, 101.1, 61.4, 61.1, 56.3; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₈ H ₂₂ NO ₄ 436.1543, found 436.1545.

<Example 10> 5- (3,4-dimethoxyphenyl) -2,3,4-trimethoxynaphtho [1 ', 2': 4,5] puro [2,3- c ]Isoquinoline (2j)

White solid (28 mg, 66%); mp: 212-214 °C; R _f = 0.3 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.03 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.9 Hz) , 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 1.7 Hz, 1H) ), 7.21 (dd, J = 8.2, 1.8 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 4.17 (s, 3H), 4.00 (s, 3H), 3.98 (s, 3H), 3.95 (s, 3H), 3.45 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.4, 156.4, 155.7, 152.5, 151.5, 148.7, 147.7, 141.0, 135.8, 132.2, 131.2, 129.9, 128.7, 128.3, 126.0, 124.9, 124.5, 121.8, 118.1, 116.1 , 112.9, 112.6, 109.9, 108.4, 101.0, 61.3, 61.3, 56.2, 56.0, 55.9; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₃₀ H ₂₆ NO ₆ 496.1755, found 496.1752.

<Example 11> 5- (4-chlorophenyl) -2,3,4-trimethoxynaphtho [1 ', 2': 4,5] puro [2,3- c ]Isoquinoline (2k)

White solid (16 mg, 40%); mp: 221-223 °C; R _f = 0.3 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05 (d, J = 8.6 Hz, 1H), 8.27 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.6 Hz) , 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.60- 7.54 (m, 2H), 7.47-7.42 ( m, 2H), 4.19 (s, 3H), 4.00 (s, 3H), 3.42 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.6, 156.7, 154.7, 152.9, 151.3, 141.7, 141.2, 133.6, 132.2, 131.4, 130.5, 130.5, 130.2, 129.1, 128.5, 127.4, 127.4, 126.3, 125.1, 124.7 , 118.2, 116.3, 113.2, 109.1, 101.2, 61.4, 61.1, 56.4; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₈ H ₂₁ ClNO ₄ 470.1154, found 470.1149.

<Example 12> 2,3,4,10-tetramethoxy-5-phenylbenzofuro[2,3- c ]Isoquinoline (2l)

White solid (17.2 mg, 86%); mp: 180-181 °C; R _f = 0.3 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.60-7.56 (m, 1H), 7.55 (s, 2H), 7.47-7.40 (m, 2H), 7.29 (s, 1H), 7.11 (dd, J = 8.9, 2.4 Hz, 1H), 4.18 (s, 3H), 3.98 (s, 3H), 3.94 (s, 3H), 3.37 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.7, 157.8, 157.2, 156.2, 154.4, 151.8, 149.0, 143.4, 140.6, 132.7, 129.1, 128.8, 127.2, 126.2, 124.4, 122.0, 115.8, 112.7, 106.8, 102.9 , 98.1, 61.4, 61.1, 56.3, 56.2; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₅ H ₂₂ NO ₅ 416.1492, found 416.1501.

<Example 13> 5- (4-chlorophenyl) -2,3,4,10-tetramethoxybenzofuro [2,3- c ]Isoquinoline (2m)

White solid (16 mg, 73%); mp: 189-191 °C; R _f = 0.3 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.25-7.12 (m, 1H), 7.12 (dd, J = 8.9, 2.4 Hz, 1H), 4.17 (s, 3H), 3.98 (s, 3H), 3.95 (s, 3H), 3.40 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.7, 157.9, 157.7, 156.2, 155.6, 154.3, 151.4, 149.0, 141.7, 139.1, 133.6, 132.7, 130.4, 128.6, 127.4, 124.3, 115.7, 112.9, 106.9, 102.8 , 98.2, 61.4, 61.1, 56.3, 56.1; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₅ H ₂₁ ClNO ₅ 450.1103, found 450.1101.

<Example 14> 5- (3,4-dimethoxyphenyl) -2,3,4,10-tetramethoxybenzofuro [2,3- c ]Isoquinoline (2n)

White solid (14.7 mg, 64%); mp: 190-192 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.54 (s, 1H), 7.18 (d, J = 1.6 Hz) , 1H), 7.14 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (dd, J = 8.9, 2.4 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 4.16 (s, 3H) , 3.98 (s, 3H), 3.96 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.44 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.7, 157.7, 156.8, 156.2, 151.8, 149.0, 148.8, 147.8, 141.2, 136.0, 132.8, 124.4, 121.9, 115.7, 112.7, 112.6, 112.6, 110.1, 106.8, 106.5, 98.1, 61.4, 61.4, 56.4, 56.2 , 56.1, 56.1; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₇ H ₂₆ NO ₇ 476.1704, found 476.1703.

<Example 15> 5- (5-chlorofuran-2-yl) -2,3,4,9,10-pentamethoxybenzofuro [2,3- c ]Isoquinoline (2o)

Yellow solid (24 mg, 62%); mp: 184-186 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (s, 1H), 7.36 (s, 1H), 7.21 (s, 1H), 6.74 (d, J = 3.3 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H), 4.13 (s, 3H), 4.04 (s, 3H), 4.01 (s, 3H), 3.95 (s, 3H), 3.84 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.5, 157.5, 154.5, 151.0, 150.2, 149.9, 146.7, 141.9, 141.3, 136.0, 131.6, 116.6, 114.8, 111.1, 108.9, 107.7, 104.3, 97.6, 96.2, 61.8 , 61.2, 57.1, 56.4, 56.1; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₄ H ₂₁ ClNO ₇ 470.1001, found 470.1015.

<Example 16> 5- (3,4-dimethoxyphenyl) -2,3,4,9,10-pentamethoxybenzofuro [2,3- c ]Isoquinoline (2p)

Off-white solid (26 mg, 37%); mp: 222-224 °C; R _f = 0.3 in 35% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (s, 1H), 7.63 (s, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 7.03 (s, 2H), 4.19 (s, 3H), 4.07 (s, 3H), 4.02 (s, 3H), 3.95 (s, 3H), 3.93 (s, 6H), 3.92 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.8, 154.4, 153.4, 153.3, 153.3, 149.9, 149.6, 148.4, 146.6, 138.5, 135.3, 129.9, 119.9, 115.2, 107.7, 107.6, 107.5, 107.5, 104.5, 101.7 , 96.4, 61.1, 57.2, 56.4, 56.4, 56.4, 56.2, 56.0; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₈ H ₂₈ NO ₈ 506.1809, found 506.1809.

<Example 17> 5-(furan-2-yl)-2,3,4,9,10-pentamethoxybenzofuro[2,3- c ]Isoquinoline (2q)

White solid (19 mg, 52%); mp: 201-202 °C, R _f = 0.3 in 35% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (s, 1H), 7.53 (d, J = 4.0 Hz, 1H), 7.40 (d, J = 4.2 Hz, 1H), 7.24 - 7.20 (m, 1H) , 6.76 (d, J = 0.9 Hz, 1H), 6.59 - 6.56 (m, 1H), 4.13 (s, 3H), 4.04 (s, 3H), 4.01 (s, 3H), 3.95 (s, 3H), 3.70 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.6, 157.4, 154.7, 151.2, 150.1, 149.8, 146.7, 143.4, 142.4, 141.4, 131.7, 116.6, 115.0, 111.1, 109.3, 108.5, 104.3, 97.7, 96.2, 61.9 , 61.3, 57.2, 56.5, 56.1; HRMS (ESI-QTOF) m/z [M+Na] ⁺ calcd for C ₂₄ H ₂₁ NNaO ₇ 458.1210, found 458.1219.

<Example 18> 5-(5-bromofuran-2-yl)-2,3,4,9,10-pentamethoxybenzofuro[2,3- c ]Isoquinoline (2r)

White solid (13 mg, 31%); mp: 199-200 °C, R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (s, 1H), 7.43 (s, 1H), 7.25 (s, 1H), 6.72 (d, J = 3.3 Hz, 1H), 6.50 (d, J = 3.3 Hz, 1H), 4.16 (s, 3H), 4.06 (s, 3H), 4.02 (s, 3H), 3.95 (s, 3H), 3.85 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.5, 157.6, 156.9, 151.1, 150.4, 146.8, 142.0, 141.3, 131.7, 128.9, 121.6, 116.7, 114.9, 112.9, 111.4, 109.0, 104.5, 97.7, 96.3, 62.0 , 61.3, 57.2, 56.5, 56.17; HRMS (ESI-QTOF) m/z [M+Na] ⁺ calcd for C ₂₄ H ₂₀ BrNNaO ₇ 536.0315, found 536.0314.

<Example 19> 2-methoxy-5- (2,3,4,10-tetramethoxybenzofuro [2,3- c ]Isoquinolin-5-yl)phenol (2s)

Yellow solid (17 mg, 40%); mp: 174-175 °C, R _f = 0.2 in 35% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.52 (s, 1H), 7.16 (s, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 5.68 (s, 1H), 4.17 (s, 3H), 3.97 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.46 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.7, 157.7, 156.7, 156.1, 151.9, 149.0, 146.4, 144.5, 141.2, 136.8, 132.7, 124.4, 121.1, 115.8, 115.7, 112.6, 112.5, 109.6, 106.7, 106.5 , 98.1, 61.4, 61.3, 56.3, 56.2, 56.1; HRMS (ESI-QTOF) m/z [M+Na] ⁺ calcd for C ₂₆ H ₂₃ NNaO ₇ 484.1367, found 484.1369.

<Example 20> 2-methoxy-4- (2,3,4,10-tetramethoxybenzofuro [2,3- c ]Isoquinolin-5-yl)phenol (2t)

White solid (22 mg, 50%); mp: 211-212 °C, R _f = 0.2 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 7.10 (d, J = 6.0 Hz, 2H), 6.98 (d, J = 7.9 Hz, 1H), 5.79 (s, 1H), 4.16 (s, 3H), 3.97 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.44 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.7, 157.7, 156.8, 156.1, 151.8, 149.0, 145.5, 141.2, 135.4, 132.8, 124.4, 122.7, 115.7, 113.3, 112.6, 112.1, 106.8, 106.7, 106.4, 98.1 , 98.1, 61.4, 61.3, 56.3, 56.2, 56.1; HRMS (ESI-QTOF) m/z [M+Na] ⁺ calcd for C ₂₆ H ₂₃ NNaO ₇ 484.1367, found 484.1364.

<Example 21> 5- (5-chlorofuran-2-yl) -2,3,4,10-tetramethoxybenzofuro [2,3- c ]Isoquinoline (2u)

Yellow solid (32 mg, 78%); mp: 179-180 °C, R _f = 0.2 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (d, J = 7.8 Hz, 2H), 7.42 (s, 1H), 7.14 - 7.06 (m, 1H), 6.78 (d, J = 2.9 Hz, 1H) , 6.37 (d, J = 2.8 Hz, 1H), 4.14 (s, 3H), 3.95 (s, 6H), 3.85 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.2, 157.8, 156.1, 154.2, 151.0, 149.1, 144.0, 141.1, 136.2, 132.3, 123.9, 116.2, 113.4, 112.5, 111.3, 108.0, 107.7, 106.6, 97.6, 61.8 , 61.1, 56.2, 56.1; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₃ H ₁₉ ClNO ₆ 440.0895, found 440.0895.

Experimental Example 1. Biological evaluation method and conditions

Cell viability assay

CellTiter 96® AQueous One Solution Cell Proliferation Assay Kit (Promega) was used for cell viability analysis. PC-3 and MDA-MB-231 cells were seeded in a 96-well cell culture plate at a density of 1.0*10 ³ together with a culture medium containing 2% FBS. Compounds were treated every 24 hours for 72 hours. MTS solution was applied to each well and incubated for 1 hour. Absorbance at 490 nm was measured using an Infinite M200 microplate reader (Tecan). The procedure was repeated 3 times and all data are presented as mean ± standard error.

In vitro scratch wound assay

PC-3 and MDA-MB-231 cells were cultured in 96-well plates to reach 100% confluence. A 96-well wound machine (MI: Essen BioScience) was used to make the wound site. After wounding, each well was washed twice with serum-free medium and incubated with culture medium supplemented with 2% FBS. Images of wounds were taken using an IncuCyte ZOOM (Essen BioScience, MI), and the percentage of wound healing was analyzed with IncuCyte software.

Caspase-3 activity assay

PC-3 and MDA-MB-231 were cultured in 96-well plates to reach approximately 30% confluency. The test compound was then treated for 24 hours. The culture medium was replaced with phosphate buffered saline (PBS) containing 2 μM of caspase-3 substrate, NucView 488 or Caspase-3 inhibitor and incubated at room temperature for 40 min. After staining the cells with 1 μM Hoechst 33342, the fluorescence intensity of NucView 488 and Hoechst 33342 was measured with a FLUOstar Omega microplate reader (BMG Labtech), and fluorescence images were taken with a Lionheart FX automated live cell microscope (BioTek).

Western blot analysis

Sample preparation for Western blot was performed by known methods [PLoS One, 11 (2016) e0155771.]. The obtained protein sample was separated by a 4-12 % Tris-Glycine precast gel (KOMA BIOTECH) and transferred to a PVDF membrane. Then, the PVDF membrane was blotted with Tris-buffered saline (TBST) containing 5% skim milk and 0.1% Tween 20 for 1 hour. The membrane was then incubated with primary antibodies including anti-ANO1 antibody (Abcam), anti-cleavage PARP antibody (BD Biosciences) and anti-beta-actin antibody (Santa Cruz Biotechnology), followed by HRP-conjugated anti secondary It was cultured with an IgG antibody (Enzo life science). Finally, chemiluminescent protein detection was performed using an ECL plus Western blotting detection system (GE Healthcare).

Experimental Example 2. Cytotoxicity and IC of the compound according to the present invention ₅₀ value

The inhibitory effect (IC ₅₀ (μM)) of PC-3 and MDAMB-231 by treatment with the benzofuran-isoquinoline derivative of Table 1 below according to the present invention was measured.

Example substance name PC-3 MDA-MB-231 Example substance name PC-3 MDA-MB-231 One 2a 27.9 37.5 12 2l 1.81 1.83 2 2b 35.3 21.0 13 2m 37.6 79.0 3 2c 43.0 87.0 14 2n 1.01 0.88 4 2d 18.5 49.4 15 2o 0.93 0.82 5 2e 21.8 52.8 16 2p 9.59 8.12 6 2f 21.3 41.4 17 2q 31.0 30.7 7 2g 5.35 5.71 18 2r 36.3 33.5 8 2h 84.1 42.4 19 2s 21.5 21.1 9 2i 15.1 17.2 20 2t 62.4 61.7 10 2j 3.27 3.63 21 2u 9.9 9.5 11 2k 20.3 43.1 psoralen 9.1 9.8

Experimental Example 3. PC-3 and MDA-MB-231 Effects of benzofuro[2,3c]isoquinoline derivatives on cell viability, cell migration and apoptosis in cells

The anticancer effect of 2n was investigated in PC-3 and MDA-MB-231 cells. As shown in Figure 1, 2n strongly inhibited the cell viability of PC-3 and MDA-MB-231 with IC ₅₀ values of 0.57 ± 0.24 μM and 0.46 ± 0.2 μM, respectively. In addition, 2n significantly inhibited the migration of PC-3 and MDA-MB-231 cells in a dose-dependent manner. To investigate whether 2n induces apoptosis in PC-3 and MDAMB-231 cells, the effect of 2n on caspase-3 activity and PARP cleavage was investigated. Caspase-3 activity was assessed by staining cells with a fluorogenic caspase-3 substrate ( FIGS. 2A and 2B ). 2n significantly increased caspase-3 activity in PC-3 and MDA-MB-231 cells in a dose-dependent manner. In particular, 1 μM of 2n increased caspase-3 activity ~6-fold, and the 2n-induced activation of caspase-3 was completely blocked by Ac-DEVD-CHO, a specific inhibitor of caspase-3 (Fig. 2C and 2D). To observe the effect of 2n on PARP cleavage, PC-3 and MDA-MB-231 cells were treated with 1 μM of 2n for 24 h. The level of cleaved PARP was significantly increased by 2n treatment in PC-3 and MDA-MB-231 cells ( FIGS. 2E and 2F ).

In addition, the anticancer effect of 2o on PC-3 and MDA-MB-231 cells was investigated. As shown in FIG. 3 , 2o significantly inhibited the cell viability of PC-3 and MDA-MB-231 cells with IC ₅₀ values of 0.38 ± 0.19 μM and 0.37 ± 0.20 μM, respectively. In addition, 2o strongly inhibited the migration of PC-3 and MDA-MB-231 cells in a dose-dependent manner. To investigate whether 2o induces apoptosis in PC-3 and MDA-MB-231 cells, the effect of 2o on caspase-3 activity and PARP cleavage was investigated. 2o significantly increased caspase-3 activity in PC-3 and MDA-MB-231 cells, and the activation of caspase-3 induced by 2o was completely blocked by Ac-DEVD-CHO ( FIGS. 4A-4D ). . In addition, the level of cleaved PARP was significantly increased by 2o treatment in PC-3 and MDA-MB-231 cells ( FIGS. 4E and 4F ).

The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (12)

A compound of Formula 2 or a pharmaceutically acceptable salt thereof:
[Formula 2]

In Formula 2,
R ₁ is benzodioxole, phenyl unsubstituted or substituted with one or more non-hydrogen substituents, or furanyl unsubstituted or substituted with one or more non-hydrogen substituents;
The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;
R ₂ and R ₃ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl unsubstituted or substituted with one or more non-hydrogen substituents;
R ₂ and R ₃ are joined together with the carbon atom to which they are attached to form a 6 membered hydrocarbon compound,
The non-hydrogen substituent in R ₂ and R ₃ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;
R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.
However, compounds in which R ₁ is phenyl substituted with halogen and R ₂ to R ₆ are hydrogen are excluded. The method of claim 1,
In Formula 2,
R ₁ is benzodioxole, phenyl unsubstituted or substituted with one or more non-hydrogen substituents, or furanyl unsubstituted or substituted with one or more non-hydrogen substituents,
The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;
R ₂ and R ₃ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl unsubstituted or substituted with one or more non-hydrogen substituents,
The non-hydrogen substituent in R ₂ and R ₃ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;
R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.
However, compounds in which R ₁ is phenyl substituted with halogen and R ₂ to R ₆ are hydrogen are excluded. The method of claim 1,
In Formula 2,
R ₁ is benzodioxole, phenyl unsubstituted or substituted with one or more non-hydrogen substituents, or furanyl unsubstituted or substituted with one or more non-hydrogen substituents;
The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;
R ₂ and R ₃ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl substituted with one or more non-hydrogen substituents,
The non-hydrogen substituent in R ₂ and R ₃ is halogen,
R ₄ , R ₅ and R ₆ are each independently hydrogen or C ₁ -C ₄ alkoxy.
However, compounds in which R ₁ is phenyl substituted with halogen and R ₂ to R ₆ are hydrogen are excluded. The method of claim 1,
The compound of Formula 2 is a compound having the structure of Formula 2a:
[Formula 2a]

In Formula 2a,
R ₁ is phenyl unsubstituted or substituted with one or more non-hydrogen substituents,
The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;
R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy. 5. The method of claim 4,
In Formula 2a,
R ₁ is phenyl unsubstituted or substituted with one or more non-hydrogen substituents,
The non-hydrogen substituent in R ₁ is halogen or C ₁ -C ₄ alkoxy;
R ₄ , R ₅ and R ₆ are C ₁ -C ₄ alkoxy. The method of claim 1,
R ₁ is

;

;

;

;

;

;

;

;

or

phosphorus compound. The method of claim 1,
The 6-membered hydrocarbon compound is benzene. 5. The method of claim 4,
R ₁ is

;

or

phosphorus compound. The method of claim 1,
The compound of Formula 2 is,
2,3,9,10-tetramethoxy-5-(2-methoxyphenyl)benzofuro[2,3-c]isoquinoline;
2,3,9,10-tetramethoxy-5-(p-tolyl)benzofuro[2,3-c]isoquinoline;
5-(benzo[d][1,3]dioxol-5-yl)-2,3,9,10-tetramethoxybenzofuro[2,3-c]isoquinoline;
10-chloro-2,3-dimethoxy-8-methyl-5-phenylbenzofuro[2,3-c]isoquinoline;
10-(4-bromophenyl)-2,3-dimethoxy-5-phenylbenzofuro[2,3-c]isoquinoline;
2,3,9,10,11-pentamethoxy-5-phenylbenzofuro[2,3-c]isoquinoline;
2,3,4,9,10-pentamethoxy-5-phenylbenzofuro[2,3-c]isoquinoline;
5-(4-chlorophenyl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline;
2,3,4-trimethoxy-5-phenylnaphtho[1',2':4,5]furo[2,3-c]isoquinoline;
5-(3,4-dimethoxyphenyl)-2,3,4-trimethoxynaphtho[1',2':4,5]furo[2,3-c]isoquinoline;
5-(4-chlorophenyl)-2,3,4-trimethoxynaphtho[1',2':4,5]furo[2,3-c]isoquinoline;
2,3,4,10-tetramethoxy-5-phenylbenzofuro[2,3-c]isoquinoline;
5-(4-chlorophenyl)-2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinoline;
5-(3,4-dimethoxyphenyl)-2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinoline;
5-(5-chlorofuran-2-yl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline;
5-(3,4-dimethoxyphenyl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline;
5-(furan-2-yl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline;
5-(5-bromofuran-2-yl)-2,3,4,9,10-pentamethoxybenzofuro[2,3-c]isoquinoline;
2-methoxy-5-(2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinolin-5-yl)phenol;
2-methoxy-4-(2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinolin-5-yl)phenol; or
5-(5-chlorofuran-2-yl)-2,3,4,10-tetramethoxybenzofuro[2,3-c]isoquinoline; A pharmaceutical composition for the prevention or treatment of cancer comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. 11. The method of claim 10
The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer ; Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant, melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Breast cancer, breast cancer, triple negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord Cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood At least one selected from the group consisting of cancer and thymus cancer, the pharmaceutical composition. A method for preparing a compound of formula (2) comprising reacting a compound of formula (1) with a compound of formula (3) to obtain a compound of formula (2):
[Formula 1]

[Formula 2]

[Formula 3]

In the above formula,
R ₁ is benzodioxole, phenyl unsubstituted or substituted with one or more non-hydrogen substituents, or furanyl unsubstituted or substituted with one or more non-hydrogen substituents;
The non-hydrogen substituent in R ₁ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;
R ₂ and R ₃ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or phenyl unsubstituted or substituted with one or more non-hydrogen substituents;
R ₂ and R ₃ are joined together with the carbon atom to which they are attached to form a 6 membered hydrocarbon compound,
The non-hydrogen substituent in R ₂ and R ₃ is halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;
R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.

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