KR20220008474A - Method for preparing novel quinone-indolizine hybrid derivatives and anticancer composition containing the same - Google Patents

Abstract

The present invention relates to a novel quinone-indolizine hybrid derivative having a preventive or therapeutic effect on prostate cancer and oral cancer, and uses thereof. The novel quinone-indolizine hybrid derivative or a pharmaceutically acceptable salt thereof according to the present invention is expected to more effectively treat these intractable cancers in the prevention or treatment of prostate and oral cancers.

Description

Novel quinone-indolizine hybrid derivative preparation method and anticancer composition comprising the same

The present invention relates to a novel quinone-indolizine hybrid derivative preparation method and an anticancer agent composition comprising the same.

Quinone and indolizine are the two basic chemical backbones frequently included in many biologically active natural and synthetic products. Indeed, individual cores have been widely used as substructures of many materials with therapeutic potential. Moreover, hybrid compounds composed of these two pharmacokinetics are known to possess a variety of interesting pharmacological activities, including antibacterial and anticancer activities. [Non-patent document 0001-0003]

Therefore, many synthetic approaches to these hybrid motifs have been reported. For example, pyrido[1,2-a]indole-1,4-dione derivatives were accessed by three-component coupling of quinone, pyridine and acetylene dicarboxylate, followed by pyrido[2,1-a]iso Indole-7,10-dione (2) [Non-Patent Document 0004-0007] was synthesized by 1,3-dipolar cycloaddition of quinone with pyridine-derived azomethines. In both cases, the central pyrrole ring is formed through the ring. In an ongoing effort to create new hybrid structures, the present inventors deduced that a novel quinone-indolizine molecular hybrid structure would be constructed via a ring of N-substituted pyrrole-2-carboxaldehyde and quinone. Mechanistically, we expected that the central pyridine ring would be formed by a domino Michael addition-molecular aldol-dehydration-aromatic procedure. Indeed, this idea was realized under mild conditions, and biological studies of these compounds and their derivatives showed anticancer effects on prostate cancer and oral squamous cell carcinoma, the subject of this paper.

Prostate cancer, which accounts for about 6.6% of all cancer-related deaths in men, is the fifth leading cause of cancer-related deaths in men [Non-Patent Document 0008]. Metastasis is found in about 5% of patients at the time of diagnosis of prostate cancer [Non-Patent Document 0009], and early hormone therapy that depletes testosterone and inhibits androgen receptor signaling is effective for most prostate cancer patients. However, ~20% of patients still develop castration-resistant prostate cancer (CRPC) within 5 years [Non-Patent Documents 0010, 0011]. Oral cancer is one of the most common malignancies worldwide, and 90% of them are oral squamous cell carcinoma (OSCC) [Non-Patent Documents 0012, 0013]. Although significant progress has been made in diagnosis and treatment strategies, the 5-year survival rate of OSCC patients remains low, mainly due to insufficient efficacy and high metastasis rates [Non-Patent Documents 0014, 0015]. Therefore, there is an urgent need to develop new therapeutic agents for prostate cancer and oral squamous cell carcinoma.

[Non-patent document 0001] Eur. J. Med. Chem., 127 (2017) 166-173. [Non-patent document 0002] Bioorg. Med. Chem., 26 (2018) 4886-4897. [Non-patent document 0003] Eur. J. Med. Chem., 152 (2018) 195-207. [Non-Patent Document 0004] Angew. Chem. Int. Ed., 52 (2013) 1003-1007. [Non-Patent Document 0005] Chem. Sci., 6 (2015) 436-441. [Non-Patent Document 0006] Synthesis, 2010 (2010) 4007-4014. [Non-patent document 0007] Org. Biomol. Chem., 8 (2010) 4921-4926. [Non-Patent Document 0008] Ca-Cancer J. Clin., 68 (2018) 394-424. [Non-Patent Document 0009] Ca-Cancer J. Clin., 68 (2018) 7-30. [Non-patent document 0010] Clin. Cancer Res., 15 (2009) 4792-4798. [Non-patent document 0011] Int. J. Clin. Pract., 65 (2011) 1180-1192. [Non-Patent Document 0012] J Oral Biol Craniofac Res., 6 (2016) S51-S54. [Non-Patent Document 0013] OncoTargets Ther., 11 (2018) 3989-4000. [Non-Patent Document 0014] Arch. Oral Biol., 95 (2018) 141-148. [Non-Patent Document 0015] Cancer Chemother. Pharmacol., 81 (2018) 549-554.

The present invention was devised to solve the above problems, and the present inventors studied intensively to find new substances that inhibit PC-3 cells, which are prostate cancer cells, and CAL-27 cells, which are oral squamous cell carcinoma cells, for the purpose of anticancer. As a result, a novel quinone-indolizine hybrid derivative that inhibits the growth and migration of PC-3 and CAL-27 cells and causes apoptosis was identified, and based on this, the present invention was completed.

Accordingly, an object of the present invention is to provide a novel quinone-indolizine hybrid derivative or a pharmaceutically acceptable salt thereof that inhibits the growth and migration of prostate and oral cancer cells and causes apoptosis.

Another object of the present invention is to provide a method for producing a novel quinone-indolizine hybrid derivative that inhibits the growth and migration of prostate and oral cancer cells and causes apoptosis.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the quinone-indolizine hybrid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating prostate cancer and oral cancer, comprising the quinone-indolizine hybrid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

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 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ₁ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl ester, or nitrile,

R ₂ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₃ -C ₆ heterocyclic compound,

R ₃ and R ₄ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or phenyl;

R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, aryl, phenoxy, or morpholinyl;

R ₅ and R ₆ are joined together with the carbon atom to which they are attached to form a 6 membered ring with or without one or two nitrogen atoms,

R ₇ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy;

)으로 표현된 결합선은, 단일 탄소-탄소 결합, 또는 2중 탄소-탄소 결합을 나타낸다.In Formula 1, the double line of the solid line and the dotted line (

) represents a single carbon-carbon bond or a double carbon-carbon bond.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing or treating prostate cancer or oral cancer, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

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

The novel quinone-indolizine hybrid derivative according to the present invention or a pharmaceutically acceptable salt thereof inhibits the growth and migration of cancer cells and exhibits activity causing apoptosis. , for example, is expected to be usefully used in the prevention and treatment of prostate cancer, oral cancer, and the like.

1 is a chemical formula of quinone and indolizine having physiological activity.
2 is a crystal structure of the 4s compound of the present invention.
3 is a graph showing the experimental results of the effect of the compound 4o of the present invention on cell viability and migration in PC-3 and CAL-27 cells (A: PC-3 cells were cultured at the indicated concentration at 4o for 72 hours) , BC: scratch migration assay performed on PC-3 cells, D: CAL-27 cells incubated at 4o at the indicated concentrations for 72 h, EF: scratch migration assay performed on CAL-27 cells, scratch migration assay is, Cells were treated with 0.1, 0.3 and 1 μM of 4o and representative images were taken at 0 and 18 hours post-scratch, wound closure was measured for 24 hours (mean ± SE, n = 3-4)).
4 is a graph showing the experimental results of the effect of the compound 4o of the present invention on Caspase-3 activity and PARP cleavage in PC-3 and CAL-27 cells (AB: cells were incubated with 1 μM 4o for 24 hours Then, 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 at 4o for 24 hours, 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 4o for 24 h Western blotting ) to detect PARP, cleaved PARP and β-actin, **P<0.01, ***P<0.001).
5 is a graph showing the experimental results of the effect of the 4s compound of the present invention on cell viability and migration in PC-3 and CAL-27 cells in the same manner as in FIG. 3 .
6 is a graph showing the experimental results of the effect of the 4s compound of the present invention on Caspase-3 activity and PARP cleavage in PC-3 and CAL-27 cells in the same manner as in FIG. 4 .
7 is a graph showing the experimental results of the effect of the 4p compound of the present invention on cell viability and migration in PC-3 and CAL-27 cells in the same manner as in FIG. 3 .
8 is a graph showing the experimental results of the effect of the 4p compound of the present invention on Caspase-3 activity and PARP cleavage in PC-3 and CAL-27 cells in the same manner as in FIG. 4 .

Hereinafter, the present invention will be described in detail.

The present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ₁ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl ester, or nitrile,

R ₂ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₃ -C ₆ heterocyclic compound,

R ₃ and R ₄ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or phenyl;

R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, aryl, phenoxy, or morpholinyl;

R ₅ and R ₆ are joined together with the carbon atom to which they are attached to form a 6 membered ring with or without one or two nitrogen atoms,

R ₇ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy;

)으로 표현된 결합선은, 단일 탄소-탄소 결합, 또는 2중 탄소-탄소 결합을 나타낸다.In Formula 1, the double line of the solid line and the dotted line (

) represents a single carbon-carbon bond or a double carbon-carbon bond.

"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.

"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).

"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.

"Alkyl esters" have the general formula -COOR, wherein R represents C ₁ -C ₄ alkyl. The alkyl ester may be, for example, an ethyl ester.

A "heterocyclic compound" is a compound in which two or more elements constituting a ring among ring compounds.

In one embodiment of the present invention, in Formula 1,

R ₁ is hydrogen, halogen, or C ₁ -C ₄ alkyl ester,

R ₂ is C ₁ -C ₄ alkyl, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₅ heterocyclic compound,

R ₃ and R ₄ are each independently hydrogen, halogen, C ₁ -C ₄ alkoxy, or phenyl;

R ₅ and R ₆ are each independently hydrogen, C ₁ -C ₄ alkoxy, phenoxy, or morpholinyl;

R ₅ and R ₆ are joined together with the carbon atom to which they are attached to form a 6-membered hydrocarbon compound, or an aromatic heterocyclic compound,

R ₇ is hydrogen, or C ₁ -C ₄ alkyl.

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

The compound of Formula 1 may be a compound having a structure of Formula 2 below.

[Formula 2]

In Formula 2,

R ₁ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl ester, or nitrile,

R ₂ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₃ -C ₆ heterocyclic compound,

R ₇ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl, or halogen,

R ₈ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy;

R ₉ and R ₁₀ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy;

wherein X and Y are each independently nitrogen or carbon.

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

R ₁ is hydrogen, halogen, or C ₁ -C ₄ alkyl ester,

R ₂ is C ₁ -C ₄ alkyl, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₅ heterocyclic compound,

R ₃ and R ₄ are each independently hydrogen, halogen, C ₁ -C ₄ alkoxy, phenyl, or halogen,

R ₇ is C ₁ -C ₄ alkyl, or hydrogen,

R ₈ is C ₁ -C ₄ alkoxy, hydroxy, or hydrogen,

R ₉ and R ₁₀ are each independently C ₁ -C ₄ alkyl, or hydrogen,

wherein X and Y are each independently nitrogen or carbon.

In another embodiment of the present invention, in Formula 1,

R ₁ is hydrogen, halogen, or C ₁ -C ₄ alkyl ester,

R ₂ is C ₁ -C ₄ alkyl, phenyl substituted with one or more non-hydrogen substituents, or naphthalenyl;

R ₃ and R ₄ are each independently hydrogen, halogen, C ₁ -C ₄ alkoxy, or phenyl;

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

R ₇ is hydrogen.

In another embodiment of the present invention, R ₂ is

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

;

; 또는

일 수 있다.

; or

can be

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

In another embodiment of the present invention, the aromatic heterocyclic compound may be pyridine or pyrimidine.

In another embodiment of the present invention, R ₂ is

;

;

;

;

;

;

; 또는

일 수 있다.

; or

can be

In another embodiment of the present invention, the compound of formula 1 is

5-benzoylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4a);

5-(3-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4b);

5-(4-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4c);

5-(2,5-dimethoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4d);

5-(4-methylbenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4e);

5-(2-naphthoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4f);

5-([1,1'-biphenyl]-4-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4g);

5-(4-fluorobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4h);

5-(4-chlorobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4i);

5-(4-bromobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4j);

5-(furan-2-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4k);

5-acetylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (41);

5-benzoyl-7-hydroxybenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4m);

5-benzoyl-7-methoxybenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4n);

5-benzoylpyrrolo[1,2-b]isoquinoline-6,9-dione (4o);

5-(4-chlorobenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione (4p);

5-benzoyl-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4q);

5-benzoyl-7-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4q');

5-(4-fluorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4r);

5-(4-chlorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4s);

8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione (4t);

5-(2-naphthoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4u);

5-benzoyl-7,8-dimethoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4v);

11-benzoylindolizino[7,6-g]quinoline-5,12-dione (4w);

6-benzoylindolizino[6,7-g]quinazoline-5,12-dione (4x);

5-benzoyl-8-phenoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4y);

5-benzoyl-8-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione (4z);

5-benzoyl-7-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione (4z');

2-bromo-5- (4-methoxybenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4aa);

2-bromo-8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione (4ab);

ethyl 5- (4-methoxybenzoyl)-6,11-dioxo-6,11-dihydrobenzo [g] pyrrolo [1,2-b] isoquinoline-2-carboxylate (4ac);

ethyl8-methoxy-5-(4-methoxybenzoyl)-6,9-dioxo-6,9-dihydropyrrolo[1,2-b]isoquinoline-2-carboxylate (4ad);

5-(4-methoxybenzoyl)-12-methylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (5);

5-benzoyl-8,9-dimethyl-6a,7,10,10a-tetrahydrobenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (7); or

5-benzoyl-8,9-dimethylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (9);

In addition, as shown in Scheme 1 below, the compound in the present invention can prepare the quinone-indolizine hybrid derivative of claim 1, which is compound 4, using naphthoquinone and compound 3, but is limited to this example. no.

[Scheme 1]

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 alkandioates. 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, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, 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 with 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.

As can be seen in the Examples below, the compound of Formula 1 may be used for the purpose of inhibiting the growth and migration of prostate and oral cancer cells and inducing apoptosis.

The present invention provides a pharmaceutical composition for the prevention or treatment of prostate cancer and oral cancer, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, the compound of Formula 1 or a pharmaceutical thereof for treatment of the disease Provided are the use of a therapeutically acceptable salt, and a method of treating the disease, comprising administering to a subject a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

As used herein, the term “prevention” refers to any action that suppresses or delays the onset of prostate and oral cancers 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 oral 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 topically) 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 1> Basic method for synthesizing the compound

To EtOH (2.5 mL) containing a mixture of naphthoquinone (27 mg, 0.17 mmol, 1.2 equiv) and 3a (30 mg, 0.14 mmol, 1 equiv) was added dropwise TEA (1 equiv) at room temperature. After stirring at 80° C. for 6 hours using a heating mantle, the reaction mixture was cooled to room temperature. The precipitate was filtered off with suction, washed with hexanes and dried to give a red solid. to obtain the product remaining in the EtOH filtrate; The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (EtOAc/hexanes=1:5) to give additional product 4a. The yield was 86% (red solid, 42 mg).

It was synthesized by scaling up as follows.

A mixture of EtOH (20 mL) containing 3a (1 g, 4.695 mmol), naphthoquinone (1.2 equiv), and EtN (1 equiv) was stirred at 80 °C for 10 h, and then the reaction mixture was cooled to 0 °C. made it The precipitate was filtered off with suction, washed with hexanes (20 mL) and dried to give a red solid (75%). The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (hexane/EtOAc/CH ₂ Cl ₂ =10: 1: 2) to give additional product 4a (10%). The combined yield was 85% (red solid, 1.4 g).

The compounds of Examples below were obtained by the method of Example 1.

<Example 2> 5-benzoylbenzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4a)

Red solid (42 mg, 86%); mp: 233-234 °C; R _f = 0.3 in 33% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.1 Hz) , 2H), 7.79 (t, J = 7.5 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H) ), 7.29 (d, J = 2.1 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 7.05 - 7.00 (m, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.3, 182.0, 181.0, 137.2, 134.9, 134.8, 134.7, 134.6, 134.1, 134.0, 133.2, 129.5, 128.7, 127.6 , 121.6, 121.0, 119.8, 117.5 , 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₃ H ₁₄ NO ₃ 352.0968, found 352.0970.

<Example 3> 5-(3-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4b)

Red solid (39 mg, 73%); mp: 284-285 °C; R _f = 0.3 in 35% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.4 Hz) , 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.64 (s, 1H), 7.34-7.27 (m, 3H), 7.18 (d, J = 7.3 Hz, 1H), 7.07 (s, 1H) , 7.02 (d, J = 2.2 Hz, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.0, 182.0, 180.9, 160.5, 137.1, 136.1, 134.8, 134.6, 134.1, 134.0, 133.1, 130.5, 127.6, 121.6, 121.5, 121.4, 120.9, 119.8 , 117.4, 115.5, 112.3, 109.6, 55.6; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₄ H ₁₆ NO ₄ 382.1074, found 382.1076.

<Example 4> 5-(4-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4c)

Yellow solid (47 mg, 88%); mp: 203-205 °C; R _f = 0.3 in 35% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.1 Hz) , 2H), 7.79 (t, J = 7.4 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J = 3.6 Hz, 1H), 7.02 (d) , J = 2.7 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.8, 182.0, 181.2, 165.0, 137.6, 134.8, 134.5, 134.3, 134.0, 133.1, 131.2, 128.0, 127.6, 121.5, 121.1, 119.7, 117.6, 115.2 , 114.8, 109.6, 55.8; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₄ H ₁₆ NO ₄ 382.1074, found 382.1072.

<Example 5> 5- (2,5-dimethoxybenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4d)

Red solid (36 mg, 62%); mp: 237-239 °C; R _f = 0.3 in 35% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 (s, 1H), 8.36 (d, J = 7.4 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.86 (s, 1H), 7.77 (t, J = 7.1 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.28 (s, 1H), 7.19 - 7.11 (m, 1H), 7.00 (d, J = 12.8 Hz, 2H) , 6.81 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 3.19 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 188.8, 182.3, 181.4, 154.9, 154.4, 141.4, 134.9, 134.4, 134.3, 133.9, 133.0, 127.5, 124.9, 123.9, 121.4, 120.4, 119.2, 116.8 , 114.5, 113.4, 113.2, 109.1, 56.71, 56.02; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₅ H ₁₈ NO ₅ 412.1179, found 412.1183.

<Example 6> 5- (4-methylbenzoyl) benzo [ g ]pyrrolo[1,2- b ]Isoquinoline-6,11-dione (4e)

Dark solid (48 mg, 94%); mp: 239-241 °C; R _f = 0.4 in 33% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.8 Hz) , 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.29 - 7.26 (m, 3H), 7.06 (d, J = 3.9 Hz, 1H), 7.01 - 6.99 (m, 1H), 2.41 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.9, 182.0, 181.1, 146.0, 137.4, 134.8, 134.5, 134.2, 134.0, 133.1, 132.4, 130.2, 130.2, 128.9, 127.6, 121.5, 121.0, 119.7 , 117.5, 115.3, 109.6, 22.0; HRMS (ESI-QTOF) m/z [M+Na] ⁺ calcd for C ₂₄ H ₁₅ NNaO ₃ 388.0944, found 388.0947.

<Example 7> 5-(2-naphthoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4f)

Red solid (51 mg, 90%); mp: 242-243 °C; R _f = 0.4 in 35% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.21-8.04 (m, 2H), 7.99 (d, J = 6.67 Hz, 1H), 7.88 (d, J = 5.7 Hz, 1H), 7.85-7.70 (m, 2H), 7.67 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.33 (s, 1H) ), 7.08 (s, 1H), 7.01 (s, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.2, 181.9, 181.0, 137.3, 136.5, 134.7, 134.5, 134.1, 133.9, 133.2, 132.7, 132.4, 130.8, 129.8, 129.6, 129.3, 128.0, 127.5 , 127.1, 123.6, 121.6, 121.0, 119.8, 117.5, 115.6, 109.6; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₇ H ₁₆ NO _3, 402.1125, found 402.1124.

<Example 8> 5-([1,1'-biphenyl]-4-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4g)

Red solid (57 mg, 97%); mp: 260-262 °C; R _f = 0.4 in 35% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 8.38 (d, J = 7.0 Hz, 1H), 8.17 (d, J = 7.0 Hz, 1H), 8.00 (d, J = 7.2 Hz) , 2H), 7.79 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 7.3 Hz, 3H), 7.59 (d, J = 6.5 Hz, 2H), 7.44 (d, J = 6.7 Hz, 2H) ), 7.40 (d, J = 6.5 Hz, 1H), 7.34 (s, 1H), 7.09 (s, 1H), 7.04 (s, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.9, 182.1, 181.0, 147.5, 139.7, 137.2, 134.8, 134.6, 134.1, 134.0, 133.6, 133.2, 129.3, 129.1, 128.6, 128.2, 127.6, 127.4 , 121.7, 121.0, 119.8, 117.5, 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₉ H ₁₈ NO ₃ 428.1281, found 428.1283.

<Example 9> 5- (4-fluorobenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4h)

Red solid (50 mg, 96%); mp: 229-231 °C; R _f = 0.4 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.97 - 7.90 (m, 2H) , 7.78 (t, J = 7.4 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.26 (s, 1H), 7.15 (t, J = 8.2 Hz, 2H), 7.07 (d, J = 3.8 Hz, 1H), 7.02 (s, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.7, 182.0, 180.9, 168.0, 165.4, 136.6, 134.7, 134.6, 134.0, 133.2, 131.5, 131.4, 127.6, 127.5, 121.7, 120.9, 119.9, 117.3 , 116.9, 116.7, 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₃ H ₁₃ FNO ₃ 370.0874, found 370.0873.

<Example 10> 5- (4-chlorobenzoyl) benzo [ g ]pyrrolo[1,2- b ]Isoquinoline-6,11-dione (4i)

Red solid (34 mg, 63%); mp: 262-264 °C; R _f = 0.4 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 8.5 Hz) , 2H), 7.81 (td, J = 7.5, 1.2 Hz, 1H), 7.73 (td, J = 7.6, 1.1 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 3.7 Hz, 1H), 7.06 - 7.01 (m, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.1, 182.1, 180.9, 141.3, 136.5, 134.8, 134.7, 134.1, 134.0, 133.4, 133.2, 130.0, 129.9, 127.7, 127.6, 121.8, 121.0, 120.0 , 117.3, 115.7, 109.8; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₃ H ₁₃ ClNO ₃ 386.0578, found 386.0576.

<Example 11> 5- (4-bromobenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4j)

Yellowish red solid (54 mg, 90%); mp: 274-275 °C; R _f = 0.4 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.2 Hz) , 3H), 7.71 (t, J = 7.5 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.26 (s, 1H), 7.08 (d, J = 3.9 Hz, 1H), 7.05 - 6.99 (m, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.3, 182.1, 180.8, 136.4, 134.8, 134.7, 134.1, 134.0, 133.7, 133.2, 132.8, 130.1, 130.0, 127.7, 127.6, 121.8, 120.9, 119.9 , 117.3, 115.7, 109.8; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₃ H ₁₃ BrNO ₃ 430.0073, found 430.0072.

<Example 12> 5-(furan-2-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4k)

Red solid (43 mg, 91%); mp: 249-251 °C; R _f = 0.4 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 8.33 (d, J = 7.0 Hz, 1H), 8.16 (d, J = 7.0 Hz, 1H), 7.83-7.66 (m, 2H) , 7.60 (s, 1H), 7.41 (s, 1H), 7.26 (s, 1H), 7.11-6.98 (m, 2H), 6.58 (s, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 182.1, 180.9, 178.5, 151.7, 148.1, 135.5, 134.7, 134.6, 134.1, 134.0, 133.2, 127.6, 122.0, 120.9, 119.7, 119.6, 117.3, 115.8 , 113.1, 109.7; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₁ H ₁₂ NO ₄ 342.0761, found 342.0761.

<Example 13> 5-acetylbenzo [ g ]pyrrolo[1,2- b ]Isoquinoline-6,11-dione (4l)

Brown solid (28 mg, 70%); mp: 203-205 °C; R _f = 0.4 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.35 (d, J = 6.6 Hz, 1H), 8.27 (d, J = 6.8 Hz, 1H), 7.85 - 7.74 (m, 2H) , 7.40 (s, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 2.75 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 198.5, 182.6, 180.9, 138.8, 134.9, 134.7, 134.1, 133.2, 127.7, 127.5, 121.5, 120.9, 119.9, 116.5, 113.6, 109.8, 30.1; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₁₈ H ₁₂ NO ₃ 290.0812, found 290.0814.

<Example 14> 5-benzoyl-7-hydroxybenzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4m)

Red solid (27 mg, 53%, brsm 69%); mp: 245-247 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.06 (s, 1H), 8.64 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 1.2 Hz, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.33-7.27 (m, 2H), 7.12 (d, J = 4.1 Hz, 1H), 7.06-7.03 (m, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.0, 186.5, 181.4, 163.1, 137.4, 136.6, 134.9, 134.8, 134.1, 133.1, 129.5, 128.7, 124.5, 121.8, 120.5, 120.1, 119.6, 118.1 , 117.4, 115.2, 110.5; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₃ H ₁₄ NO ₄ 368.0917, found 368.0918.

<Example 15> 5-benzoyl-7-methoxybenzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4n)

Red solid (52 mg, 97%); mp: 236-238 °C; R _f = 0.2 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 8.1 Hz) , 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.32-7.19 (m, 2H), 7.04 (d, J = 3.7 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.4, 181.3, 181.2, 161.0, 137.0, 136.7, 135.5, 135.0, 134.4, 133.1, 129.3, 129.3, 128.9, 122.1, 121.0, 120.6, 120.1, 119.5 , 117.8, 117.4, 117.3, 109.2, 56.7; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₄ H ₁₆ NO ₄ 382.1074, found 382.1074.

<Example 16> 5-benzoylpyrrolo[1,2-b]isoquinoline-6,9-dione (4o)

_{To a mixture of CH 3} CN (7 mL) containing 3a (30 mg, 0.14 mmol) and 1,4-benzoquinone (2.5 equiv) was added dropwise Et3N (1 equiv) at room temperature. After stirring at room temperature for 20 h, the reaction mixture was concentrated under reduced pressure and the crude residue was filtered through a plug of silica gel with a _{mixed solvent (hexane: EtOAc: CH 2} Cl _{2 =3: 1: 2) as eluent.} to remove polar impurities. The filtrate was concentrated in vacuo to give a crude residue, which was purified by column chromatography (hexane : EtOAc : CH ₂ Cl ₂ = 6 : 1 : 2) to give 4o as a red solid (28 mg, 67 %). ). mp: 238-239 °C; R _f = 0.4 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.64 (t, J = 7.0 Hz, 1H), 7.48 (t, J = 7.5 Hz) , 2H), 7.12 - 6.93 (m, 4H), 6.83 (d, J = 10.4 Hz, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.9, 183.3, 182.4, 141.1, 139.7, 136.9, 134.9, 134.7, 132.8, 129.4, 128.8, 128.7, 121.2, 120.0, 119.7, 117.9, 114.5, 110.4 ; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₁₉ H ₁₂ NO ₃ 302.0812, found 302.0812.

<Example 17> 5- (4-chlorobenzoyl) pyrrolo [1,2-b] isoquinoline-6,9-dione (4p)

Red Solid (19 mg, 46%); mp: 239-241 °C; R _f = 0.3 in 25% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.80 (d, J = 7.1 Hz, 2H), 7.46 (d, J = 7.1 Hz, 2H), 7.26 (s, 1H), 7.08 (d, J = 3.5 Hz, 1H), 7.07-7.01 (m, 2H), 6.85 (dd, J = 10.4, 1.8 Hz, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.8, 183.4, 182.3, 141.5, 141.3, 139.7, 136.2, 133.2, 132.8, 130.0, 129.9, 121.4, 120.0, 119.9, 117.8, 114.7, 110.6; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₁₉ H ₁₁ ClNO ₃ 336.0422, found 336.0421.

<Example 18> 5-benzoyl-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4q) and 5-benzoyl-7-methoxypyrrolo[1,2-b]iso Quinoline-6,9-dione (4q')

After heating a solution of 4o (0.14 mmol) in MeOH (2 mL) with TEA (2 eq) at 80 °C for 12 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by column chromatography eluting with a hexane solvent containing 30% EtOAc to obtain 4q' and 4q as red solids (42 mg, total 91%) in a 3:1 ratio ( ¹ H NMR). determined by the integral value of ). Spectral data for 4q' was recorded from the mixture.

Red solid (44 mg, 94%); mp: 210-213 °C; R _f = 0.2 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.62 (t, J = 7.1 Hz, 1H), 7.46 (t, J = 7.5 Hz) , 2H), 7.26 (s, 1H), 7.05 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.06 (s, 1H), 3.86 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.0, 183.1, 177.4, 162.6, 135.8, 134.9, 134.6, 132.8, 129.3, 129.3, 128.6, 128.6, 122.0, 119.5, 119.2, 118.3, 114.4, 111.3 , 110.8, 56.7; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₀ H ₁₄ NO ₄ 332.0917, found 332.0922.

Red solid (31.5 mg, 68%); R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 7.3 Hz) , 2H), 7.26 (s, 1H), 7.01 (d, J = 3.9 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.25 (s, 1H), 3.83 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.8, 182.6, 178.3, 161.3, 134.8, 134.7, 132.8, 129.4, 128.7, 122.0, 120.3, 120.3, 119.7, 117.5, 112.6, 112.5, 110.8, 109.8 , 56.6; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₀ H ₁₄ NO ₄ 332.0917, found 332.0911.

<Example 19> 5- (4-fluorobenzoyl) -8-methoxypyrrolo [1,2- b ]Isoquinoline-6,9-dione (4r)

Red solid (45 mg, 93%); mp: 260-262 °C; R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 7.94 - 7.82 (m, 2H), 7.25 (s, 1H), 7.14 (t, J = 8.1 Hz, 2H), 7.06 (d, J = 3.2 Hz, 1H), 6.98 (s, 1H), 6.06 (s, 1H), 3.87 (s, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.5, 183.1, 177.3, 167.9, 165.4, 162.7, 135.3, 132.8, 131.5, 122.1, 119.6, 119.2, 118.2, 116.8, 116.6, 114.4, 111.3, 110.9 , 56.8; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₀ H ₁₃ FNO ₄ 350.0823, found 350.0827.

<Example 20> 5-(4-chlorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4s)

Red solid (38 mg, 74%); mp: 267-269°C; R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.07 (s, 1H), 6.98 (s, 1H), 6.06 (s, 1H), 3.88 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.9, 183.1, 177.3, 162.7, 141.2, 135.1, 133.4, 132.9, 129.9, 129.8, 122.1, 119.6, 119.2, 118.1, 114.6, 111.2, 110.9, 56.8 ; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₀ H ₁₃ ClNO ₄ 366.0528, found 366.0530.

<Example 21> 8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione (4t)

Red solid (47 mg, 92%); mp: 227-228 °C; R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J = 3.9 Hz, 1H), 6.98 -6.90 (m, 3H), 6.07 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.5, 183.0, 177.5, 164.9, 162.5, 136.1, 132.7, 131.2, 128.0, 121.9, 119.4, 118.4, 114.7, 114.0, 111.5, 110.7, 56.7, 55.7 ; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₁ H ₁₆ NO ₅ 362.1023, found 362.1027.

<Example 22> 5-(2-naphthoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4u)

Red solid (51 mg, 95%); mp: 278-279°C; R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.16 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.31 (s) , 1H), 7.08 (d, J = 3.9 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.05 (s, 1H), 3.86 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.1, 183.1, 177.5, 162.6, 136.5, 135.9, 132.9, 132.7, 132.5, 130.7, 129.8, 129.6, 129.3, 128.1, 127.2, 123.6, 122.1, 119.5 , 119.4, 118.4, 114.5, 111.4, 110.8, 56.7; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₄ H ₁₆ NO ₄ 382.1074, found 382.1073.

<Example 23> 5-benzoyl-7,8-dimethoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4v)

Red solid (20 mg, 40%, brsm 82%); mp: 191-193°C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz) , 2H), 7.21 (d, J = 2.7 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 6.99 - 6.87 (m, 1H), 4.14 (s, 3H), 3.96 (s, 3H) ; ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.9, 180.1, 179.3, 150.6, 148.6, 136.5, 134.8, 132.8, 129.4, 128.8, 120.8, 119.3, 119.0, 117.8, 113.4, 110.2, 61.5; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₁ H ₁₆ NO ₅ 362.1023, found 362.1025.

<Example 24> 11-benzoyl indolizino [7,6-g] quinoline-5,12-dione (4w)

Red solid (37 mg, 76%); mp: 299-301 °C; R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.10 (s, 1H), 8.73 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 6.7 Hz, 2H), 7.65 (s, 2H), 7.50 (d, J = 6.8 Hz, 2H), 7.31 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 190.9, 181.5, 179.4, 155.5, 150.2, 137.5, 135.9, 135.0, 134.6, 133.2, 131.3, 129.6, 129.3, 128.7, 128.1, 127.7, 120.6, 120.3 , 118.0, 114.7, 110.5; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₂ H ₁₃ N ₂ O ₃ 353.0921, found 353.0928.

<Example 25> 6-benzoyl indolizino [6,7-g] quinazoline-5,12-dione (4x)

Red solid (15 mg, 30%, brsm 78%); mp: 334-335 °C; R _f = 0.2 in 50% EtOAc in hexane; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 9.45 (s, 1H), 8.69 (s, 1H), 7.93 (d, J = 6.9 Hz, 2H), 7.79-7.69 ( m, 1H), 7.61-7.53 (m, 2H), 7.50 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H); ¹³ C{ ¹ H} NMR (100 MHz, DMSO-d ₆ ) δ 190.4, 180.8, 178.9, 162.3, 157.7, 155.2, 136.1, 135.0, 134.1, 132.6, 129.5, 128.7, 126.6, 121.7, 121.1, 120.5, 118.2 , 114.7, 110.9; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₁ H ₁₂ N ₃ O ₃ 354.0873, found 354.0879.

<Example 26> 5-benzoyl-8-phenoxypyrrolo [1,2-b] isoquinoline-6,9-dione (4y)

Red solid (39 mg, 70%); mp: 213-214 °C; R _f = 0.2 in 20% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 (s, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.61 (t, J = 7.0 Hz, 1H), 7.49 - 7.37 (m, 4H) , 7.31-7.26 (m, 2H), 7.14-7.06 (m, 3H), 7.01 - 6.98 (m, 1H), 5.84 (s, 1H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.0, 183.1, 177.2, 162.7, 152.8, 136.0, 134.9, 134.7, 132.9, 130.5, 130.5, 129.4, 128.6, 126.8, 122.1, 121.2, 119.6, 119.4 , 118.5, 114.8, 114.4, 111.0; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₅ H ₁₆ NO ₄ 394.1074, found 394.1076.

<Example 27> 5-benzoyl-8-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione (4z) and 5-benzoyl-7-morpholinopyrrolo[1,2-b ]Isoquinoline-6,9-dione (4z')

To a solution of 4o (0.14 mmol) in CH ₃ CN (2 mL) was added dropwise morpholine (0.28 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure and purified by column chromatography eluting with a hexane solvent containing 40% EtOAc to separate 4z' and 4z (6:1 ratio, 49 mg). , an overall yield of 91%) was obtained. 4z' is more polar than 4z in TLC.

Red solid (36 mg, 67%); mp: 194-196 °C; R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.2 Hz) , 2H), 7.24 (s, 1H), 7.02 (d, J = 3.9 Hz, 1H), 6.94 (dd, J = 2.6, 1.5 Hz, 1H), 5.91 (s, 1H), 3.85 (t, J = 4.2 Hz, 4H), 3.54 (d, J = 4.8 Hz, 4H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.4, 181.7, 180.0, 155.1, 135.3, 134.5, 134.4, 132.9, 129.3, 128.6, 121.9, 121.1, 119.0, 117.8, 114.9, 113.5, 110.0, 66.6 , 49.3; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₃ H ₁₉ N ₂ O ₄ 387.1339, found 387.1339.

Red solid (46 mg, 86%); mp: 181-182 °C; R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.64 (d, J = 5.9 Hz, 1H), 7.50 (d, J = 6.8 Hz) , 2H), 7.16 (s, 1H), 6.94 (d, J = 4.3 Hz, 2H), 6.12 (s, 1H), 3.79-3.65 (m, 4H), 3.47-3.20 (m, 4H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.2, 181.7, 181.1, 154.3, 137.5, 134.8, 132.9, 129.5, 128.9, 120.4, 119.3, 119.2, 116.9, 116.1, 115.2, 108.9, 66.4, 49.2 ; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₃ H ₁₉ N ₂ O ₄ 387.1339, found 387.1339.

<Example 28> 2-bromo-5- (4-methoxybenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4aa)

Red solid (56 mg, 87%); mp: 234-235 °C; R _f = 0.3 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.7 Hz) , 2H), 7.80 (t, J = 7.5 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.06 (s, 1H), 6.97 (d, J = 8.4 Hz) , 2H), 3.87 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.2, 181.7, 180.9, 165.2, 138.8, 136.5, 134.7, 134.6, 134.3, 134.2, 133.3, 131.3, 127.7, 122.2, 119.9, 116.9, 115.4, 115.0 , 111.0, 109.9, 55.8; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₄ H ₁₅ BrNO ₄ 460.0179, found 460.0181.

<Example 29> 2-bromo-8-methoxy-5- (4-methoxybenzoyl) pyrrolo [1,2-b] isoquinoline-6,9-dione (4ab)

Red solid (52 mg, 85%); mp: 253-255 °C; R _f = 0.2 in 40% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.05 (s, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.08 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 188.9, 182.7, 177.4, 165.1, 162.3, 135.2, 133.0, 131.2, 127.8, 120.4, 120.2, 117.7, 114.9, 114.8, 111.9, 111.7, 109.4, 56.8 , 55.8; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₁ H ₁₅ BrNO ₅ 440.0128, found 440.0132.

<Example 30> Ethyl 5- (4-methoxybenzoyl) -6,11-dioxo-6,11-dihydrobenzo [g] pyrrolo [1,2-b] isoquinoline-2-carboxylate ( 4ac)

Red solid (49 mg, 78%); mp: 313-315 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.6 Hz) , 2H), 7.87 - 7.78 (m, 1H), 7.76 (s, 2H), 7.44 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H), 4.38-4.26 (m, 2H), 3.87 ( s, 3H), 1.35 (t, J = 6.4 Hz, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.1, 181.7, 180.8, 165.2, 163.4, 137.9, 134.9, 134.6, 134.4, 134.2, 133.1, 131.3, 127.8, 125.6, 122.8, 122.4, 119.8, 117.0 , 116.5, 115.0, 109.8, 61.2, 55.8, 14.5; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₇ H ₂₀ NO ₆ 454.1285, found 454.1289.

<Example 31> Ethyl 8-methoxy-5-(4-methoxybenzoyl)-6,9-dioxo-6,9-dihydropyrrolo[1,2-b]isoquinoline-2-carboxylate (4ad)

Red solid (44 mg, 73%); mp: 319-321 °C; R _f = 0.2 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.41 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.10 (s, 1H), 4.35-4.26 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 188.8, 182.5, 177.2, 165.1, 163.3, 162.4, 136.5, 132.7, 131.3, 127.9, 125.4, 123.0, 120.6, 120.5, 115.3, 114.8, 111.8, 110.8, 61.2, 56.8, 55.8, 14.5; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₄ H ₂₀ NO ₇ 434.1234, found 434.1234.

<Example 32> 5-(4-methoxybenzoyl)-12-methylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (5)

Red solid (34 mg, 61%); mp: 196-197 °C; R _f = 0.4 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.78 (t) , J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.26 (s, 1H), 7.14 (d, J = 4.1 Hz, 1H), 7.00 - 6.89 (m, 3H), 3.85 (s, 3H), 3.11 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 189.9, 183.4, 182.7, 164.7, 137.3, 136.7, 136.3, 134.7, 134.6, 133.4, 133.3, 131.1, 128.2, 127.5, 127.1, 118.7, 118.0, 117.6 , 116.4, 114.8, 108.8, 55.7, 18.0; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₅ H ₁₈ NO ₄ 396.1230, found 396.1229.

<Example 33> 5-benzoyl-8,9-dimethyl-6a,7,10,10a-tetrahydrobenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (7)

A solution of 4o (0.14 mmol) and 2,3-dimethyl-1,3-butadiene (2 equiv, 0.28 mmol) in EtOH (2 mL) was stirred at 60 °C for 18 hours, and then cooled to room temperature. The precipitate was filtered and washed with hexanes to give 7 as a yellow solid (51 mg, 96%).

Yellow solid (51 mg, 96%); mp: 200-201 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.5 Hz) , 2H), 7.26 (s, 1H), 7.01 (s, 2H), 3.32-3.35 (m, 2H), 2.58 - 2.32 (m, 2H), 2.21 - 1.94 (m, 2H), 1.62 (s, 3H) ), 1.58 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.4, 135.7, 134.9, 134.7, 133.2, 129.4, 128.6, 123.5, 121.2, 120.6, 119.5, 116.8, 108.5, 47.2, 46.6, 30.7, 30.3, 19.1 , 19.0; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₅ H ₂₂ NO ₃ 384.1594, found 384.1591.

<Example 34> 5-benzoyl-8,9-dimethylbenzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (9)

A solution of 3a (0.14 mmol), 8 (1.2 equiv) and triethylamine (2 equiv) in EtOH (2 mL) was stirred at 70 °C for 5 h, then the reaction mixture was concentrated, containing 20% EtOAc Purification by column chromatography using elution using a hexane solvent to give 9 as a red solid (50 mg, 94 %).

Yellow solid (50 mg, 94%); mp: 299-300 °C; R _f = 0.3 in 30% EtOAc in hexane; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 8.07 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.88 (s, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.5 Hz, 3H), 7.03 (d, J = 3.8 Hz, 1H), 7.01 - 6.96 (m, 1H), 2.40 (s, 3H), 2.33 (s, 3H); ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 191.4, 182.1, 181.2, 144.7, 144.0, 136.9, 135.0, 134.6, 133.1, 132.7, 132.0, 129.4, 128.6, 128.5, 121.3, 119.5, 117.2, 115.8 , 109.3, 20.4, 20.3; HRMS (ESI-QTOF) m/z [M+H] ⁺ calcd for C ₂₅ H ₁₈ NO ₃ 380.1281, found 380.1280.

Experimental Example 1. Biological evaluation method and conditions

Cytotoxicity assay

CellTiter 96® AQueous One Solution Cell Proliferation Assay Kit (Promega) was used for MTS analysis. PC-3 and CAL-27 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±SEM.

In vitro scratch wound assay

PC-3 and CAL-27 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 CAL-27 were seeded into 96-well culture plates to reach approximately 30% confluence. Test compounds were treated for 24 hours. The culture medium was replaced with phosphate buffered saline (PBS) containing 1 μM of caspase 3 substrate, NucView 488 or Caspase-3 inhibitor and incubated for 30 min at room temperature. After staining with 1 μM Hoechst 33342, the fluorescence intensities of NucView 488 and Hoechst 33342 were 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 4-12% Tris-Glycine precast gel (KOMA BIOTECH) and transferred to PVDF membrane. The membrane was then blocked with Tris-buffered saline supplemented with 0.1% Tween 20 (TBST) with 5% bovine serum albumin (BSA) for 1 h. The membrane was then incubated with primary antibodies comprising anti-ANO1 antibody (Abcam), anti-cleavage PARP (BD Biosciences) and beta-actin (Santa Cruz Biotechnology) followed by HRP-conjugated anti-secondary IgG antibody (Enzo). life science) and incubated. Finally, chemiluminescent protein detection was performed using an ECL plus Western blotting detection system (GE Healthcare).

Experimental Example 2. Cytotoxicity and IC50 value of the compound according to the present invention

The inhibitory effect of PC-3 and CAL-27 by treatment with the quinone-indolizine hybrid derivative of Table 1 below according to the present invention was measured.

Example substance name PC-3 CAL-27 Example substance name PC-3 CAL-27 2 4a 0.42 1.26 21 4t 0.12 0.35 3 4b 0.26 0.78 22 4u 0.35 1.08 4 4c 0.39 1.21 23 4v 0.14 0.42 5 4d 0.48 1.43 24 4w 0.11 0.32 6 4e 2.17 2.89 25 4x 0.11 0.30 7 4f 0.42 1.30 26 4y 0.22 0.66 8 4g 2.06 2.73 27 4z 0.37 0.86 9 4h 0.27 0.80 28 4aa 2.74 2.55 10 4i 0.38 1.22 29 4ab 0.24 0.64 11 4j 0.38 1.14 30 4ac 4.10 3.88 12 4k 0.48 1.39 31 4ad 6.51 11.1 13 4l 0.38 1.07 32 5 0.18 0.53 14 4m 0.31 0.95 18 4q' 0.20 1.21 15 4n 0.20 0.59 27 4z' 0.27 1.37 16 4o 0.11 0.12 33 7 0.20 0.60 17 4p 0.024 0.027 34 9 0.38 1.06 18 4q 0.21 0.62 mitoxantrone 1.10 1.32 19 4r 0.23 0.11

Experimental Example 3. Effect of quinone-indolizine hybrid derivatives on cell viability, cell migration and apoptosis in PC-3 and CAL-27 cells

The anticancer effect of 4o was investigated in PC-3 and CAL-27 cells. As shown in Fig. 3, 4o strongly inhibited the cell viability of PC-3 and CAL-27 cells with IC50 values of 0.11 ± 0.05 μM and 0.12 ± 0.04 μM, respectively. In addition, 4o significantly inhibited cell migration of PC-3 and CAL-27 cells in a dose-dependent manner. To investigate whether 4o induces apoptosis in PC-3 and CAL-27 cells, the effect of 4o on Caspase-3 activity and PARP cleavage was investigated. Caspase-3 activity was assessed by staining the cells with a fluorogenic Caspase-3-substrate. 4o significantly increased Caspase-3 activity in a dose-dependent manner in PC-3 and CAL-27 cells, and 4o -induced activation of Caspase-3 was inhibited by Ac-DEVD-CHO, a specific inhibitor of Caspase-3. was completely blocked (Fig. 4A-4D). To observe the effect of 4o on PARP cleavage, immunoblotting was performed on PC-3 and CAL-27 cells. The level of cleaved PARP was significantly increased by 4o in PC-3 and CAL-27 cells ( FIGS. 4E and 4F ).

We also investigated the anticancer effect of 4s in PC-3 and CAL-27 cells. As shown in Fig. 5, 4s significantly inhibited the cell viability of PC-3 and CAL-27 cells with IC50 values of 0.07 ± 0.04 μM and 0.11 ± 0.03 μM, respectively. In addition, 4s strongly inhibited cell migration of PC-3 and CAL-27 cells in a dose-dependent manner. To investigate whether 4s induces apoptosis in PC-3 and CAL-27 cells, the effect of 4s on Caspase-3 activity and PARP cleavage was observed. 4s significantly increased Caspase-3 activity in a dose-dependent manner in PC-3 and CAL-27 cells, and 4s -induced activation of Caspase-3 was completely blocked by Ac-DEVD-CHO (Fig. 6A- 6D). In addition, the level of cleaved PARP was significantly increased by 4s in PC-3 and CAL-27 cells ( FIGS. 6E and 6F ).

As shown in Fig. 7, 4p significantly inhibited the cell viability of PC-3 and CAL-27 cells with IC50 values of 24.0 ± 8.0 and 27.6 ± 6.9 nM, respectively. In addition, 4p strongly inhibited cell migration of PC-3 and CAL-27 cells in a dose-dependent manner. To investigate whether 4p induces apoptosis in PC-3 and CAL-27 cells, the effect of 4p on Caspase-3 activity and PARP cleavage was observed. Caspase-3 activity was measured by staining the cells with a fluorogenic Caspase-3 substrate ( FIGS. 8A and 8B ). In particular, 0.3 μM 4p increased Caspase-3 activity by ~8-fold in PC-3 and CAL-27 cells, and 4p -induced activation of Caspase-3 was completely blocked by Ac-DEVD-CHO (Fig. 8C). and 8D). In addition, the level of cleaved PARP was significantly increased by 4p in PC-3 and CAL-27 cells ( FIGS. 8E and 8F ).

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 (13)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl ester, or nitrile,
R ₂ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₃ -C ₆ heterocyclic compound,
R ₃ and R ₄ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or phenyl;
R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, aryl, phenoxy, or morpholinyl;
R ₅ and R ₆ are joined together with the carbon atom to which they are attached to form a 6 membered ring with or without one or two nitrogen atoms,
R ₇ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy;
In Formula 1, the double line of the solid line and the dotted line (

) represents a single carbon-carbon bond or a double carbon-carbon bond. The method of claim 1,
In Formula 1,
R ₁ is hydrogen, halogen, or C ₁ -C ₄ alkyl ester,
R ₂ is C ₁ -C ₄ alkyl, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₅ heterocyclic compound,
R ₃ and R ₄ are each independently hydrogen, halogen, C ₁ -C ₄ alkoxy, or phenyl;
R ₅ and R ₆ are each independently hydrogen, C ₁ -C ₄ alkoxy, phenoxy, or morpholinyl;
R ₅ and R ₆ are joined together with the carbon atom to which they are attached to form a 6-membered hydrocarbon compound, or an aromatic heterocyclic compound,
R ₇ is hydrogen, or C ₁ -C ₄ alkyl. The method of claim 1,
The compound of Formula 1 is a compound having a structure of Formula 2 below:
[Formula 2]

In Formula 2,
R ₁ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl ester, or nitrile,
R ₂ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₃ -C ₆ heterocyclic compound,
R ₇ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl, or halogen,
R ₈ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy;
R ₉ and R ₁₀ are each independently hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy;
wherein X and Y are each independently nitrogen or carbon. 4. The method of claim 3,
In Formula 2,
R ₁ is hydrogen, halogen, or C ₁ -C ₄ alkyl ester,
R ₂ is C ₁ -C ₄ alkyl, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C ₅ heterocyclic compound,
R ₃ and R ₄ are each independently hydrogen, halogen, C ₁ -C ₄ alkoxy, phenyl, or halogen,
R ₇ is C ₁ -C ₄ alkyl, or hydrogen,
R ₈ is C ₁ -C ₄ alkoxy, hydroxy, or hydrogen,
R ₉ and R ₁₀ are each independently C ₁ -C ₄ alkyl, or hydrogen,
wherein X and Y are each independently nitrogen or carbon. The method of claim 1,
In Formula 1,
R ₁ is hydrogen, halogen, or C ₁ -C ₄ alkyl ester,
R ₂ is C ₁ -C ₄ alkyl, phenyl substituted with one or more non-hydrogen substituents, or naphthalenyl;
R ₃ and R ₄ are each independently hydrogen, halogen, C ₁ -C ₄ alkoxy, or phenyl;
R ₅ and R ₆ are each independently hydrogen, C ₁ -C ₄ alkoxy, phenoxy, or morpholinyl,
R ₇ is hydrogen. 4. The method of claim 1 to 3,
R ₂ is

;

;

;

;

;

;

;

;

;

; or

phosphorus compound. 3. The method of claim 2,
The 6-membered hydrocarbon compound is benzene or cyclohexene. 3. The method of claim 2,
The aromatic heterocyclic compound is a pyridine or pyrimidine compound. 6. The method of claim 5,
R ₂ is

;

;

;

; or

phosphorus compound. The method of claim 1,
The compound of Formula 1 is,
5-benzoylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(3-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(2,5-dimethoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-methylbenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(2-naphthoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-([1,1'-biphenyl]-4-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-fluorobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-chlorobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-bromobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(furan-2-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-acetylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-benzoyl-7-hydroxybenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-benzoyl-7-methoxybenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-benzoylpyrrolo[1,2-b]isoquinoline-6,9-dione;
5-(4-chlorobenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-7-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-(4-fluorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-(4-chlorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione;
5-(2-naphthoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-7,8-dimethoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
11-benzoylindolizino[7,6-g]quinoline-5,12-dione;
6-benzoylindolizino[6,7-g]quinazoline-5,12-dione;
5-benzoyl-8-phenoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-8-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-7-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione;
2-bromo-5-(4-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
2-bromo-8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione;
ethyl5-(4-methoxybenzoyl)-6,11-dioxo-6,11-dihydrobenzo[g]pyrrolo[1,2-b]isoquinoline-2-carboxylate;
ethyl8-methoxy-5-(4-methoxybenzoyl)-6,9-dioxo-6,9-dihydropyrrolo[1,2-b]isoquinoline-2-carboxylate;
5-(4-methoxybenzoyl)-12-methylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-benzoyl-8,9-dimethyl-6a,7,10,10a-tetrahydrobenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione; or
5-benzoyl-8,9-dimethylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione; phosphorus compound. A pharmaceutical composition for preventing or treating cancer comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient. 12. The method of claim 11
The cancer is prostate cancer, pharmaceutical composition. 12. The method of claim 11
The cancer is oral cancer, pharmaceutical composition.

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