KR20090039038A - Phenanthrene lactam derivatives having anticancer activity, method for preparing same and pharmaceutical composition containing same - Google Patents

Abstract

A phenanthrene lactam derivative having the anticancer activity is provided to prevent and treat cancer and disease with excellent anticancer activity. A phenanthrene lactam derivative having chemical formula 1 is produced by reaction of the compound of chemical formula 2 and the compound of chemical formula 3 in a solution. R1, R2, R3, R4, R5, R6 and R7R is hydrogen, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy or aryloxy. R4 and R5, R5 and R6, or R6 and R7 forms dioxol. R8 is the hydrogen or the C1-6 alkyl. The composite for preventing caner and pharmaceutical treatment comprises the phenanthrene lactam derivative of chemical formula 1 or pharmaceutically allowable salt.

Description

Phenanthrene lactam derivatives having anticancer activity, preparation method thereof, and pharmaceutical composition comprising the same {PHENANTHRENE LACTAM DERIVATIVES HAVING ANTICANCER ACTIVITY, METHOD FOR PREPARING SAME AND PHARMACEUTICAL COMPOSITION CONTAINING SAME}

The present invention relates to a novel phenanthrene lactam derivative having anticancer activity, a preparation method thereof, and a pharmaceutical composition comprising the same.

Natural products representative of phenanthrene lactam derivatives include alkaloids aristolactam, cephoranone and piperolactam, which are found in Aristolochiaceae family of plants. ( Cf. KW Bentley, Nat. Prod. Rep. , 23, 444, 2006). Traditionally, the roots and stems of these plants have been widely used as folk remedies in China and Taiwan, and their physiological activities include anticancer and immunosuppressive effects (see L.-H. Hu et al., Bioorg.Med) . Chem. 15, 988, 2007], anti-inflammatory effects (Y.-H. Lan et al, Helv. Chim. Acta, 88, 905, 2005), anti-tuberculosis effects ( J. Nat. Prod. ., 67, 1961, 2004), anti-viral effect (see:... DA Berghe et al, J. Nat Prod, 41, 463, 1978), neuroprotective action (see:. YC Kim et al, Planta Med. 70, 391, 2004).

U.S. Patent No. 4,782,077 discloses that taliscanin, a derivative of phenanthrene lactam alkaloid, is effective in treating neurological diseases, Parkinson's disease and Alzheimer's disease. In addition, WO 1999/06388 discloses that Aristolochia taliscana extracts, including phenanthrene lactams such as aristolactam B and C, exhibit antimutagenic, antifungal and cytotoxic effects. Korean Patent No. 144742 discloses that a sauriristolactam compound extracted from three hundred seconds has an anticancer effect.

As described above, various active effects of the phenanthrene lactam compound have been revealed, and attention has been drawn to the development of novel phenanthrene lactam compounds.

On the other hand, various synthetic methods for phenanthrene lactam compounds are known. For example, A. A. Couture et al. Described in Synlett , 1475, 1997 an ariline-mediated cyclization of phosphorylated amino carbanions derived from halobenzamide as a method for synthesizing separanone A and B, which are natural products. After the synthesis of isoindolinone intermediates using the reaction, a method of conducting a Horner reaction and a radical cyclization reaction has been proposed, and similarly, various aristolactam derivatives have been synthesized (see J. Org. Chem . 63, 3128, 1998; J. Org.Chem. 66, 8064, 2001, Eur. J. Org.Chem. 1231, 2003; Tetrahedron 61 , 665, 2005). In particular, aristolactam derivatives have been reported to have an excellent cytotoxic effect on rat leukemia cells ( Bioorg. Med. Chem. Lett. 12, 3557, 2002).

Meanwhile, L. L. Castedo et al. Described the cyclization by photoreaction of enamides to synthesize aristolactam derivatives ( Heterocycles 19 , 279, 1982), intramolecular benzine cyclization. Reaction of the functional groups ( Tetrahedron Lett. 33, 5145, 1992; Tetrahedron 51 , 4075, or Tetrahedron Lett. 30, 5785, 1989) . 1995).

However, the existing synthetic methods have the disadvantage that the steps are too long and complicated, and the reaction conditions are too violent to limit the synthesis of various derivatives.

Accordingly, it is an object of the present invention to provide a novel phenanthrene lactam derivative, a method for preparing it simply and efficiently, and a pharmaceutical composition comprising the same.

In order to achieve the above object, the present invention provides a phenanthrene lactam derivative of Formula 1 or a pharmaceutically acceptable salt thereof.

Where

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy or aryloxy, wherein R ⁴ and R ⁵ , R ⁵ and R ⁶ or R ⁶ and R ⁷ may form a dioxole,

R ⁸ is hydrogen or C _1-6 alkyl,

R ⁹ is hydrogen; C _1-6 alkyl, C _1-6 alkoxy, perfluoro, hydroxy, halogen, C _1-6 alkylamino, diC _1-6 alkylamino, C _1-6 acyloxy, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkyl substituted with C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl-carbonyl, C _3-8 heterocycloalkyl -C _1-6 alkoxycarbonyl, C _1-6 alkyl, optionally substituted with one or more substituents selected from the group consisting of C _3-8 heteroaryl, aryl and thioaryl; C _1-6 alkenyl; C _1-6 alkynyl; C _1-6 acyl; C _1-6 alkoxycarbonyl; C _1-6 alkylsulfonyl; C _1-6 alkylaryl or C _1-6 alkoxycarbonyl optionally substituted C _3-8 heterocycloalkyl as; Or aryl substituted or unsubstituted with halogen, amino, C _1-6 alkyl, perfluoroC _1-6 alkyl or C _1-6 alkoxy.

The present invention also provides a process for preparing a phenanthrene lactam derivative of formula (1) comprising reacting a compound of formula (2) with a compound of formula (3) in the presence of a palladium compound and a base in a solvent:

<Formula 1>

Where

R ¹ to R ⁹ are as defined above,

X is halogen, C _1-6 alkylsulfonyloxy or arylsulfonyloxy,

M is B (OH) ₂ or B (OR ¹⁰ ) ₂ , wherein R ¹⁰ is C _1-4 alkyl, or two R ¹⁰ are linked together to form a heterocycloalkyl substituted with methyl with boron and oxygen Can be).

In addition, the present invention provides a pharmaceutical composition comprising the phenanthrene lactam derivative of Formula 1 or a pharmaceutically acceptable salt thereof.

The phenanthrene lactam derivative of Formula 1 according to the present invention has anti-cancer activity and can be usefully used for the prevention and treatment of diseases related to cancer, and the phenanthrene lactam derivative of Formula 1 can be prepared in a simple manner with good yield. Can be.

The present invention provides the phenanthrene lactam derivative of Chemical Formula 1, and it should be understood to include pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts of the compounds of Formula 1 may be prepared by conventional methods in the art, for example, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. Salts with acids, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid Salts with organic acids such as (aspirin), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid, ethane Salts with sulfonic acids such as sulfonic acid, benzenesulfonic acid and toluenesulfonic acid, metal salts by reaction with alkali metals such as sodium and potassium, or salts with ammonium ions. The.

Among the compounds of formula (I) according to the present invention, R ⁹ is C _1-6 alkylamino, di C _1-6 alkylamino, C _3-8 heterocycloalkyl and C _1-6 alkyl substituted by a C _3-8 heterocycloalkyl C _1-6 alkyl substituted with one or more substituents selected from the group consisting of alkyl; Is a C _1-6 C _3-8 heterocycloalkyl alkyl substituted by alkyl or aryl C _1-6 alkoxy-carbonyl is preferable.

The term "cycloalkyl" as used herein refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo [3.2. 1] refers to a cycloalkyl group containing 0 to 2 unsaturated groups such as octane or norbornanyl.

As used herein, the term “heterocycloalkyl” refers to a 3-8 membered ring containing one or more hetero atoms selected from S, SO, SO ₂ , O, N or N-oxides, pyrrolidinyl, tetrahydrofuran 1, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromanyl, isoxazolidinyl, 1,3-oxazolidin-3-yl , Isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomo Polinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazine-2 Examples include -yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazinyl, piperazinyl and chromanyl. The heterocycloalkyl group optionally has one or more optional substituents, ie halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S (O ) n (n = 1,2,3) or may be substituted with a thiol, but is not limited thereto.

The term "aryl" as used herein includes fused groups such as naphthyl, phenanthrenyl and the like, as well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl and the like. The aryl group optionally contains one or more substituents, that is, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S (O) n ( n = 1,2,3) or thiol, but is not limited thereto.

The phenanthrene lactam derivative of Formula 1 according to the present invention may be prepared by reacting the isoindole compound of Formula 2 with the boronic compound of Formula 3 in the presence of a palladium compound and a base, as shown in Scheme 1 below:

Wherein R ¹ to R ⁹ _, X and M are as defined above.

또는

인 것이 바람직하다.M is B (OH) ₂ ,

or

Is preferably.

According to the present invention, the compounds of the formulas (2) and (3) are reacted so that once the intermediate compound of the formula (4) is formed, the cyclization reaction takes place continuously to obtain the compound of the formula (1). If necessary, only the intermediate of Chemical Formula 4 may be selectively obtained by adjusting the reaction conditions. The intermediate compound of Chemical Formula 4 may be separated and then subjected to base treatment again to obtain the desired Chemical Formula 1.

The phenanthrene lactam derivative of Chemical Formula 1 according to the present invention may also prepare a compound of Chemical Formula 1a wherein R ⁹ is hydrogen according to Scheme 1, and then react with P ¹ -R ^{9 in the} presence of a base to substitute R ^9. It can be prepared by obtaining the compound of 1, this process is shown in Scheme 2 below.

Wherein R ¹ to R ⁸ and R ⁹ (excluding hydrogen) are as defined above and P ¹ is a conventional leaving group such as halogen, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate And so on.

The compound of Chemical Formula 2 used as a starting material in the present invention may be purchased and used by conventional methods, such as those prepared or disclosed in International Patent Application Publication Nos. WO2004 / 108672 and US Pat. No. 6,277,847.

For example, when R ¹ , R ^2, and R ³ in Formula 2 are hydrogen, a commercially available 3-bromo-2-methylbenzoic acid (a) is refluxed with methanol solvent under an acid catalyst as shown in Scheme 3. To obtain a methyl ester compound (b), and then perform a radical reaction using N -bromosuccinimide (NBS) to selectively synthesize benzyl bromide compound (c), and then compound (c) with an excess of amine By reacting or reacting with an equivalent amine in the presence of a base, an isoindole compound of formula 2a can be prepared.

Wherein R ⁹ is as defined above.

On the other hand, in the formula (2) when R ¹ is hydrogen, R ² and R ³ is methoxy, as shown in Scheme 4, G. Grethe et al, J. Org. Chem. 33, 494, 1968 ], a methyl ester compound (e) is produced in the same manner as in Scheme 2 using dimethoxy benzoic acid (d) obtained from the method described in the above, and optionally 3 times of the benzene ring using bromine. Substituted bromine at the carbon position to obtain compound (f), and then subjected to a radical reaction similar to the reaction scheme 2 to obtain a benzyl bromide compound (g), and then reacted with various amines to prepare a compound of formula (2b) Can be.

Wherein R ⁹ is as defined above.

On the other hand, the compound of Formula 3 is a conventional method, for example, GR Geen et al., Tetrahedron 54, 9875-9894, 1998, [O. Baudoin et al., J. Org. Chem., 65 , 9268-9271, 2000, JL Kristensen et al., Org . Synth ., 81 , 134-136, 2005, and [T. Ishiyam et al., J. Org . Chem ., 60 , 7508-7510, 1995, or those commercially available may be purchased and used.

In the present invention, the compound of Formula 3 may be used in an amount of 1 to 3 moles, preferably 1 to 2 moles, and more preferably 1.2 moles, per 1 mole of the compound of Formula 2.

The solvent used in the present invention is not particularly limited as long as it is a solvent that dissolves the starting material and does not inhibit the reaction. For example, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether or dioxane ; Aromatic hydrocarbon solvents such as benzene, toluene or xylene; Amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone; Organic solvents such as dimethyl sulfoxide; Alcohol solvents such as methanol, ethanol, propanol, n-butanol or t-butanol; Or a mixture thereof or a mixed solvent of the solvent and water can be used. Preferably, ethanol, dioxane, toluene or mixtures thereof can be used, more preferably a mixed solvent of ethanol and toluene can be used. For example, when the ethanol and toluene mixture is used, the ratio of ethanol and toluene is in a volume ratio of 1: 1 to 1:10, preferably in a volume ratio of 1: 1 to 1: 5, more preferably 1: 2. It can be a range.

Palladium compounds used in the present invention include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tetrakis (tri- tert -butylphosphine) palladium , Palladium acetate, dichlorobis (triphenylphosphine) palladium, dichlorobis (tri- o -tolylphosphine) palladium, dichlorobis (tricyclohexylphosphine) palladium, 1,1'-bis (diphenylphosphino) Ferrocenedichloropalladium, palladium chloride, palladium hydroxide, palladium nitrate, di-μ-chlorobis (η-allyl) palladium, bis (acetylacetonato) palladium, dichlorobis (benzonitrile) palladium, dichlorobis (acetonitrile) palladium or Mixtures thereof, and the like, and preferably tetrakis (triphenylphosphine) palladium, palladium acetate, palladium chloride or palladium hydroxide. In the present invention, the palladium compound may be used in an amount of 0.001 to 0.1 mole, preferably 0.01 to 0.05 mole, more preferably 0.04 mole with respect to 1 mole of the compound of Formula 2.

Bases used in the present invention include at least one inorganic base selected from the group consisting of sodium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen chloride, potassium hydrogen carbonate, potassium phosphate, cesium fluoride and potassium fluoride; Alkali metal alkoxides such as sodium ethoxide, sodium tert -butoxide and potassium tert -butoxide; At least one organic base selected from the group consisting of N-methylmorpholine, N, N-dimethylaniline, 1,8-diaza bicyclo [5,4,0] -7-undecene (DBU) and triethylamine ; Or mixtures thereof, and preferably sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen chloride or potassium hydrogen carbonate, more preferably sodium carbonate, potassium carbonate or cesium carbonate. In the present invention, the base may be used in an amount of 1 to 10 moles, preferably 1 to 5 moles, more preferably 3 moles per 1 mole of the compound of Formula 2.

In the present invention, in some cases, a phosphorus compound may be further added to the reaction solution, and usable phosphorus compounds include triphenylphosphine, tri (2-methylphenyl) phosphine, bisdiphenylphosphinomethane and bisdi Phenylphosphinoethane, bisdiphenylphosphinopropane, bisdiphenylphosphinobutane, bisdiphenylphosphinopentane, bisdiphenylphosphinohexane, 2,2'-bis (diphenylphosphino) -1,1 ' Binaphthyl, tri- tert -butylphosphine, tri (4-methylphenyl) phosphine, tricyclohexylphosphine, 1,1'-bis (diphenyl phosphino) ferrocene, racemic-2-di- tert -Butylphosphino-1,1'-binaphthyl, 2- (di- tert -butylphosphino) biphenyl, 2- (di- tert -butylphosphino) -2 '-(N, N-dimethylamino ) Biphenyl, 2- (di- tert -butylphosphino) -2'-methylbiphenyl, 2- (di- tert -butylphosphino) -2 ', 4', 6'-tri-isopropyl-1 , 1'-biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2- (dicyclohexylphosphino) -2 '-(N, N-dimethylamino) biphenyl, 2- (dicyclohexylphosphino) -2', 6'-dimethoxy-1,1'-biphenyl , 2- (dicyclohexylphosphino) -2 ', 6'-di-isopropoxy-1,1'-biphenyl, 2- (dicyclohexylphosphino) -2'-methylbiphenyl, 2- (Dicyclohexylphosphino) -2 ', 4', 6'-tri-iso-propyl-1,1'-biphenyl, 2- (diphenylphosphino) -2 '-(N, N-dimethylamino ) Biphenyl, 2 '-(dicyclohexylphosphino) -2,6-dimethoxy-3-sulfonato) -1,1'-biphenyl hydrate sodium salt or mixtures thereof. Preferably triphenylphosphine, 2- (dicyclohexylphosphino) -2 '-(N, N-dimethylamino) biphenyl, 2- (dicyclohexylphosphino) -2', 6'-dimethoxy -1,1'-biphenyl or 2- (dicyclohexylphosphino) -2 ', 4', 6'-tri-isopropyl-1,1'-biphenyl, more preferably triphenylphosphine Or 2- (dicyclohexylphosphino) -2 ', 6'-dimethoxy-1,1'-biphenyl. In the present invention, the phosphorus may be used in an amount of 0.001 to 0.4 mol, preferably 0.01 to 0.2 mol, more preferably 0.05 to 0.1 mol.

In the present invention, the reaction may be carried out in an oil bath or microwave reactor (see CO Kappe, Angew. Chem. Int. Ed., 43 , 6250-6284, 2004), the reaction is 30 ℃ to 200 ℃ Preferably, it may be carried out at a reaction temperature of 100 ℃ to 180 ℃, it is preferably carried out under an inert atmosphere such as nitrogen or argon.

The reaction time may vary depending on the reactant, the solvent, the reaction apparatus or the reaction temperature, and, for example, when using an oil bath, it is preferable to stir at the reaction temperature for 1 to 20 hours, and the microwave reactor is In the case of using, reaction can be completed in a short time by stirring at said reaction temperature for 1 minute-about 1 hour.

According to the method of the present invention, the compound of Formula 1 may be prepared in a good yield by a simple method, and the prepared compound of Formula 1 has excellent activity of inhibiting the growth of cancer cells, thereby preventing cancer and related diseases. It can be usefully used for prevention and treatment.

Accordingly, the present invention provides a pharmaceutical composition for preventing and treating cancer, comprising the phenanthrene lactam derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition of the present invention may be formulated by adding a non-toxic and pharmaceutically acceptable carrier, adjuvant and excipient, etc. according to conventional methods, for example oral administration of tablets, capsules, troches, solutions, suspensions, etc. Formulations for parenteral or parenteral administration.

Excipients that may be used in the pharmaceutical compositions of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium alginate , Methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

The dosage of the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, but is based on an adult patient having a weight of 70 kg. When the general dosage is 0.01 mg to 5000 mg per day, may be divided into once or several times a day at regular intervals, depending on the judgment of the doctor or pharmacist.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Example 1: Synthesis of 5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Into the flask, 3-bromo-2-methylbenzoic acid (5.0 g, 23.3 mmol) was dissolved in 50 ml of methanol, followed by sulfuric acid. (1.5 mL) was added slowly. The mixture was warmed and stirred at reflux for 12 hours, and then the reaction temperature was lowered to room temperature. Methanol was removed under reduced pressure, ether was added to the mixture, followed by saturated sodium hydrogencarbonate. The organic layer was washed with solution, water, and saturated sodium chloride solution. Water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 4.67 g (88%) of methyl 3-bromo-2-methylbenzoate.

¹ H NMR (300 MHz, CDCl ₃ ) d 7.59 (d, 1H, J = 7.8 Hz), 7.54 (dd, 1H, J = 7.9, 0.9 Hz), 6. 94 (t, 1H, J = 7.9 Hz) , 3.77 (s, 3 H), 2.50 (s, 3 H).

<Step 2>

Methyl 3-bromo-2-methylbenzoate (4.67 g, 20 mmol) and benzene 100 ml were added to the flask, followed by N -bromosuccinimide (4.37 g, 25 mmol) and 2, 2'-azobisisobutylnitrile (0.336 g, 2 mmol) was added thereto, followed by warming and reflux stirring for 6 hours. The temperature of the reaction was lowered to 0 ° C. and then filtered to remove the precipitate. 10% sodium sulfite The solution was washed with saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained product was separated by column chromatography using silica gel to obtain 5.27 g (84%) of methyl 3-bromo-2- (bromomethyl) benzoate.

¹ H NMR (300 MHz, CDCl ₃ ) d 7.62 (d, 1H, J = 7.9 Hz), 7.49 (dd, 1H, J = 7.9, 0.9 Hz), 6. 99 (t, 1H, J = 7.9 Hz) , 4. 88 (s, 2H), 3.70 (s, 3H).

<Step 3>

In a flask, methyl 3-bromo-2- (bromomethyl) benzoate (5.27 g, 17 mmol) obtained in step 2 was dissolved in 50 mL tetrahydrofuran, followed by 40% aqueous solution methylamine (7.5 mL, 86 mmol). ) Was added and reacted at room temperature for 2 hours. The solvent was removed under low pressure, then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained product was separated by column chromatography using silica gel to obtain 3.36 g (87%) of 4-bromo-2-methylisoindolin-1-one.

¹ H NMR (300 MHz, CDCl ₃ ) d 7.68 (d, 1H, J = 7.9 Hz), 7.53 (dd, 1H, J = 7.9, 0.9 Hz), 7. 26 (t, 1H, J = 7.9 Hz) , 4. 20 (s, 2H), 3.11 (s, 3H).

<Step 4>

4-bromo-2-methylisoindolin-1-one (60 mg, 0.26 mmol), 2-formylphenylboronic acid (48 mg, 0.32 mmol), tetrakis obtained in step 4 in a microwave reactor (Triphenylphosphine) palladium (12 mg, 0.01 mmol) and cesium carbonate (259 mg, 0.80 mmol) were added and dissolved in a mixed solvent of 1 ml of ethanol and 2 ml of toluene. The reaction vessel was sealed with a cement, and then reacted at 150 ° C. for 10 minutes using a microwave reactor and cooled to room temperature. The reaction was passed through celite washing with ethyl acetate and the solvent was evaporated under reduced pressure. The obtained product was separated by column chromatography using silica gel to obtain 62 mg (99%) of the title compound, 5-methyldibenzoindol-4 ( 5H ) -one.

¹ H NMR (300 MHz, CDCl ₃ ) d 8.62-8.51 (m, 2H), 8.12-8.08 (m, 1H), 7.90-7.80 (m, 2H), 7.65-7.54 (m, 2H), 7.10 (s , 1H), 3.52 (s, 3H).

Example 2: Synthesis of 5,6-dimethyldibenzo [ cd, f ] indole-4 ( 5H ) -one

4-bromo-2-methylisoindolin-1-one (60 mg, 0.26 mmol) and 2-acetylphenylboronic acid (51 mg, 0.32 mmol) obtained in step 3 of Example 1 in a microwave reaction vessel. , Tetrakis (triphenylphosphine) palladium (12 mg, 0.01 mmol), 2- (dicyclohexylphosphino) -2 '-(N, N-dimethylamino) biphenyl (8 mg, 0.02 mmol) and carbonic acid Cesium (259 mg, 0.80 mmol) was added and dissolved in a mixed solvent of 1 ml of ethanol and 2 ml of toluene. The reaction vessel was sealed with a separator and further reacted at 120 ° C. for 5 minutes and at 150 ° C. for 10 minutes using a microwave reactor, and cooled to room temperature. The reaction was passed through celite washing with ethyl acetate and the solvent was evaporated under reduced pressure. The obtained product was separated by column chromatography using silica gel to obtain 52 mg (77%) of 5,6-dimethyldibenzoindol-4 ( 5H ) -one as the target compound.

¹ H NMR (300 MHz, CDCl ₃ ) d 8.56-8.53 (m, 2H), 8.08-8.05 (m, 2H), 7.79-7.76 (m, 1H), 7.65-7.59 (m, 2H), 3.75 (s , 3H), 2.84 (s, 3H).

Example 3: Synthesis of 3 -methoxydibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Using methyl 3-bromo-6-methoxy-2-methylbenzoate in place of methyl 3-bromo-2-methylbenzoate as starting material, methyl 3-bromo Mo-2- (bromomethyl) -6-methoxybenzoate was obtained (85%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.57 (d, 1H, J = 9.0 Hz), 6.80 (d, 1H, J = 9.0 Hz), 4.57 (s, 2H), 3.97 (s, 3H), 3.83 (s, 3 H).

<Step 2>

In a flask, methyl 3-bromo-2- (bromomethyl) -6-methoxybenzoate (620 mg, 1.8 mmol) obtained in step 1 was dissolved in 10 ml of tetrahydrofuran and the ammonium hydroxide ( 1.3 ml, 9.2 mmol) was added and stirred at room temperature for 48 hours. 30 ml of water was added to the reaction mixture, and the resulting precipitate was filtered off to obtain 349 mg (78%) of 4-bromo-7-methoxyisoindolin-1-one.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.60 (d, 1H, J = 9.0 Hz), 6.85 (d, 2H, J = 9.0 Hz), 4.30 (s, 2H), 3.98 (s, 3H).

<Step 3>

Step 4 of Example 1, using the 4-bromo-7-methoxyisoindolin-1-one obtained in Step 3 instead of 4-bromo-2-methylisoindolin-1-one as starting material In the same manner as in the target compound was obtained (72%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.68-8.66 (m, 1H), 8.52-8.49 (m, 1H), 7.89-7.86 (m, 1H), 7.59-7.54 (m, 2H), 7.45 (s , 1H), 7.27 (s, 1H), 4.19 (s, 3H).

Example 4: Synthesis of 3-methoxy-5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

In a flask, 4-bromo-7-methoxyisoindolin-1-one (151 mg, 0.63 mmol) was dissolved in 10 ml of tetrahydrofuran, sodium hydride (16 mg, 0.63 mmol) and iodomethane ( 37.8 μL, 0.75 mmol) were added and stirred at room temperature for 24 hours. The solvent was removed under low pressure, then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained product was separated by column chromatography using silica gel to obtain 111 mg (69%) of 4-bromo-7-methoxy-2-methylisoindolin-1-one.

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.54 (d, 1H, J = 8.8 Hz), 6.81 (d, 1H, J = 8.6 Hz), 4.21 (s, 2H), 3.94 (s, 3H), 3.15 (s, 3 H).

<Step 2>

Instead of 4-bromo-2-methylisoindolin-1-one as starting material, 4-bromo-7-methoxy-2-methylisoindolin-1-one obtained in step 1 above was used. In the same manner as in Step 4 of Example 1, the target compound was obtained (68%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.58 (d, 1H, J = 9.0 Hz), 8.49-8.42 (m, 1H), 7.90-7.85 (m, 1H), 7.68-7.53 (m, 1H), 7.37 (d, 1 H, J = 8.6 Hz), 4.22 (s, 3 H), 3.51 (s, 3 H).

Example 5: Synthesis of 1,2-dimethoxydibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 4,5-dimethoxy-2-methylbenzoate (11.3 g, 53.8 mmol) was added to the flask and dissolved in 150 mL of chloroform. The reaction solution was cooled to 0 ° C. and bromine (2.8 mL, 53.8 mmol) was added slowly dropwise. After stirring for 4 hours at 0 ° C., the mixed solution was diluted with 10% sodium sulfite. The solution was washed with saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained product was separated by column chromatography using silica gel to obtain 14.3 g (92%) of methyl 3-bromo-4,5-dimethoxy-2-methylbenzoate.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36 (s, 1H), 3.90 (s, 6H), 3.89 (s, 3H), 2.61 (s, 3H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 167.6, 150.6, 149.4, 132.7, 126.8, 122.8, 113.3, 60.4, 56.2, 52.3, 20.4

MS (EI): found 288 ( m / z, M ⁺ ) for C ₁₁ H ₁₃ BrO ₄ , found 288 (M ⁺ , 93). 272.9 (16), 258.0 (51), 242.8 (19), 229.8 (66), 212.9 (44).

<Step 2>

Methyl 3-bromo-4,5-dimethoxy-2-methylbenzoate (24.0 g, 86 mmol) and 200 ml of benzene were added to the flask, and N -bromosuccinimide (18.0 g, 103 mmol) and 2,2'-azobisisobutylnitrile (1.4 g, 8.6 mmol) were added thereto, followed by heating to reflux for 6 hours. The temperature of the reaction was lowered to 0 ° C. and then filtered to remove the precipitate. The resulting solution is 10% sodium sulfite The solution was washed with saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained product was separated by column chromatography using silica gel to give 29.1 g (92%) of methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.26 (s, 1H), 5.16 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 166.4, 152.9, 150.1, 131.9, 126.7, 123.4, 114.3, 60.8, 56.4, 52.9, 31.4

MS (EI): calcd for C ₁₁ H ₁₂ Br ₂ O ₄ , 365.91 ( m / z, M ⁺ ), found 365.8 (M ⁺ , 31), 365.8 (16), 288.9 (100), 272.9 (4), 256.9 (21), 244.7 (8).

<Step 3>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxy obtained in step 2 instead of methyl 6-methoxy-3-bromo-2- (bromomethyl) benzoate as starting material Using benzoate, 4-bromo-5,6-dimethoxyisoindolin-1-one was obtained in the same manner as in Step 2 of Example 5 (92%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.66 (s, 1H), 7.28 (s, 1H), 4.18 (s, 2H), 3.88 (s, 1H), 3.78 (s, 1H)

^{13 C NMR (125 MHz, DMSO-} d 6) δ 169.1, 153.8, 148.7, 136.8, 129.3, 112.2, 106.0, 60.3, 56.4, 45.1.

<Step 4>

Example 4 of Example 1, using 4-bromo-5,6-dimethoxyisoindolin-1-one obtained in step 3 instead of 4-bromo-2-methylisoindolin-1-one as starting material In the same manner as in Step 4, the target compound was obtained (81%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.84 (s, 1H), 9.11 (d, 2H, J = 8.9 Hz), 7.94 (d, 1H, J = 7.9 Hz), 7.85 (s, 1H) , 7.58-7.54 (m, 2H), 7.13 (s, 1H), 4.03 (s, 3H), 4.02 (s, 3H)

^{13 C NMR (125 MHz, DMSO-} d 6) δ 168.4, 154.2, 150.3, 135.1, 134.8, 129.0, 127.5, 126.8, 125.9, 125.5, 123.3, 121.5, 119.9, 109.9, 104.6, 59.9, 56.9

MS (EI): calcd for C ₁₇ H ₁₃ NO ₃ 279 ( m / z ), found 279.1 (M ⁺ , 100), 264.1 (18), 236.1 (23), 221.1 (14), 218.1 (12), 209.1 (17), 193.1 (21), 181.1 (25).

Example 6: Synthesis of 1-hydroxy-2-methoxydibenzo [ cd, f ] indole-4 ( 5H ) -one

1,2-benzo-indole methoxydiethylene -4 (5 H) to the flask -one (279 mg, 1 mmol) and lithium chloride (420 mg, 10 mmol) was stirred and dissolved in 3 ㎖ dimethylformamide. The mixture was allowed to react for 48 hours while maintaining the temperature at 180 ° C, and then cooled to room temperature, and then the reaction was terminated with 2 ml of water. The reaction solution was extracted with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained product was subjected to column chromatography purification using silica gel and recrystallization (a mixed solvent of ethyl acetate and hexane) to obtain 175 mg (66%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.65 (s, 1H), 9.26-9.23 (m, 1H), 7.93-7.90 (m, 1H), 7.75 (s, 1H), 7.54-7.50 (m, 1H), 7.11 (s, 1H), 4.03 (s, 3H)

¹³ C NMR (125 MHz, DMSO- d ₆ ) δ 168.8, 149.3, 148.2, 135.1, 134.1, 128.6, 127.4, 126.6, 124.9, 124.3, 115.9, 114.4, 108.5, 104.3, 57.1

MS (EI): Calculated for C ₁₆ H ₁₁ NO ₃ 265 ( m / z ), found 265.1 (M ⁺ , 100), 250.1 (54), 222.1 (35), 193.1 (4), 166.1 (37), 150.0 (6), 139.0 (25), 132.6 (8).

Example 7 1,2,9- tree methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

4-bromo-5,6-dimethoxyisoindolin-1-one instead of 4-bromo-2-methylisoindolin-1-one as starting material, 5 instead of 2-formylphenylboronic acid Using the methoxy-2-formylphenylboronic acid, the target compound was obtained in the same manner as in Step 4 of Example 1 (83%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 8.64 (s, 1H), 7.87 (d, 1H, J = 8.8 Hz), 7.83 (s, 1H), 7.26-7.22 ( m, 1H), 7.08 (s, 1H), 4.037 (s, 3H), 4.031 (s, 3H), 3.90 (s, 3H)

^{13 C NMR (125 MHz, DMSO-} d 6) δ 168.1, 157.0, 153.9, 150.3, 133.1, 130.0, 128.7, 127.0, 123.4, 121.6, 119.6, 116.1, 110.0, 109.4, 104.5, 59.9, 56.9, 55.1

MS (EI): 309 for C ₁₈ H ₁₅ NO ₄ , found 309 ( m / z ), found 309.1 (M ⁺ , 100), 294.1 (22), 279.1 (5), 266.1 (18), 251.1 (17), 238.1 (12), 223.1 (10), 195.1 (7), 180.1 (13).

Example 8: Synthesis of 1,2-dimethoxy-5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material Using 4-bromo-5,6-dimethoxy-2-methylisoindolin-1-one in the same manner as in step 3 of Example 1, was obtained (98%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.26 (s, 1H), 4.23 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.20 (s, 3H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 168.1, 154.5, 149.5, 134.7, 129.6, 112.6, 106.2, 61.1, 56.6, 52.5, 29.8

MS (EI): found 285 ( m / z ) for C ₁₁ H ₁₂ BrNO ₃ , found 284.9 (M ⁺ , 95), 286.9 (96), 255.9 (100), 206.0 (42).

<Step 2>

Instead of 4-bromo-2-methylisoindolin-1-one as starting material, 4-bromo-5,6-dimethoxy-2-methylisoindolin-1-one obtained in step 1 was used. In the same manner as in Example 4, step 4, the target compound was obtained (86%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.81 (m, 1H), 7.77 (s, 1H), 7.56 (m, 2H), 6.96 (s, 1H), 4.10 (d, 6H), 3.47 (s, 3H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 168.2, 154.6, 151.3, 137.4, 135.0, 129.2, 127.8, 127.7, 127.4, 126.0, 123.2, 121.5, 120.9, 109.7, 104.3, 60.5, 57.1, 26.5

MS (EI): calcd for C ₁₈ H ₁₆ NO ₄ , 293.32 ( m / z ), found 293.0 (M ⁺ , 100) 278.0 (12), 250.0 (27), 235.0 (11), 222.0 (9).

Synthesis of (methyl dwelling lactam N) - 1- hydroxy-2-methoxy-5-methyl-dibenzo [cd, f] indole -4 (5 H) one: Example 9

As the starting material 1,2-benzo-indole methoxydiethylene -4 (5 H) - Using the on-one instead of 1,2-dimethoxy-5-methyl-dibenzo-indol -4 (5 H) obtained in Example 8 in In the same manner as in Example 6, the target compound was obtained (70%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.28 (d, 1H, J = 6.0 Hz), 7.94 (d, 1H, J = 3.0 Hz), 7.79 (s, 1H), 7.58 to 7.54 (m, 2H ), 7.30 (s, 1H), 4.05 (s, 3H), 3.04 (s, 3H)

¹³ C NMR (125 MHz, DMSO- d ₆ ) δ 167.2, 149.7, 148.2, 136.7, 133.9, 128.7, 127.5, 127.0, 126.7, 125.2, 123.0, 114.8, 114.3, 108.7, 103.8, 57.2, 26.0

MS (EI): calcd for C ₁₇ H ₁₃ NO ₃ 279.29 ( m / z ), found 279.0 (M ⁺ , 100), 264.0 (35), 236.0 (15), 180.0 (6).

Example 10 Synthesis of 2-hydroxy-1-methoxy-5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one

To the flask was placed 1,2-dimethoxy-5-methyldibenzoindol-4 ( 5H ) -one (124 mg, 0.42 mmol), bromic acid (47 μL, 0.423 mmol) and 3 ml of acetic acid. The reaction was time. After cooling to room temperature, water was added to the reaction to terminate the reaction, and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained product was separated by column chromatography using silica gel to obtain 13 mg (11%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.13 (d, 1H, J = 4.7 Hz), 7.95 (d, 1H, J = 3.0 Hz), 7.63 (s, 1H) 7.58 (m, 2H), 7.28 (s, 1H), 4.03 (s, 3H), 3.17 (s, 3H)

¹³ C NMR (125 MHz, DMSO- d ₆ ) 166.9, 148.9, 137.0, 134.6, 129.0, 127.3, 126.9, 126.4, 125.4, 120.9, 120.1, 113.8, 103.1, 59.3, 26.1

MS (EI): found 279.29 ( m / z ) for C ₁₇ H ₁₃ NO ₃ , found 279.0 (M ⁺ , 100) 264.0 (48), 236.0 (18), 180.0 (10).

Synthesis of on-5-methyl -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H): Example 11

4-bromo-5,6-dimethoxy-2-methylisoindolin-1-one is substituted with 2-formylphenylboro, instead of 4-bromo-2-methylisoindolin-1-one as starting material. 2-formyl-4,5-dimethoxyphenylboronic acid was used instead of the nickic acid, and the target compound (80%) was obtained by the same method as in Step 4 of Example 1.

^{1 H NMR (300MHz, DMSO- d} 6) δ 8.70 (s, 1H), 7.68 (s, 1H), 7.15 (s, 1H), 6.80 (s, 1H), 4.09 (s, 3H), 4.07 (s , 3H), 4.03 (s, 3H), 4.02 (s, 3H), 3.41 (s, 3H).

Example 12: 17,18- as dimethoxy-13-methyl-5,7-dioxa-13-aza-penta Sickle [10.6.1.0 ^2,10 .0 ^4,8 .0 ^15,19] nona-deca -1 Synthesis of 3,8,10,12 (19), 15,17-heptaen-14-one

4-bromo-5,6-dimethoxy-2-methylisoindolin-1-one is substituted with 2-formylphenylboro, instead of 4-bromo-2-methylisoindolin-1-one as starting material. Using 6-formylbenzo [1,3] dioxol-5-ylboronic acid in place of the nickic acid, the target compound (11%) was obtained by the same method as in Step 4 of Example 1.

^{1 H NMR (300MHz, DMSO- d} 6) δ 8.69 (s, 1H), 7.78 (s, 1H), 7.22 (s, 1H), 6.91 (s, 1H), 6.11 (s, 2H), 4.09 (s , 3H), 4.06 (s, 3H), 3.47 (s, 3H).

Example 13: Synthesis of 1,2-dimethoxy-5,6-dimethyldibenzo [ cd, f ] indole-4 ( 5H ) -one

Example 4, using 4-bromo-5,6-dimethoxy-2-methylisoindolin-1-one instead of 4-bromo-2-methylisoindolin-1-one as starting material, In the same manner, the target compound (44%) was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.34 (dd, 1H, J = 8.0 Hz, J = 1.5 Hz), 8.06 (dd, 1H, J = 7.9 Hz, J = 1.6 Hz), 7.78 (s, 1H), 7.67-7.56 (m, 2H), 4.06 (s, 3H), 4.04 (s, 3H), 3.76 (s, 3H), 2.77 (s, 3H).

Example 14 Synthesis of 8-benzyloxy-5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one

The desired compound (94%) was obtained by the same method as Step 4 of Example 1, using 2-formyl-4-benzyloxyphenylboronic acid instead of 2-formylphenylboronic acid as starting material.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (d, 1H, J = 8.0 Hz), 8.43 (d, 1H, J = 8.8 Hz), 7.80 (t, 1H, J = 7.5 Hz), 7.53-7.36 (m, 5H), 7.25-7.24 (m, 2H), 7.02 (s, 1H) 5.24 (s, 2H), 3.50 (s, 3H).

Example 15 Synthesis of 8-benzyloxy-1,2-dimethoxy-5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one

4-bromo-5,6-dimethoxy-2-methylisoindolin-1-one is substituted with 2-formylphenylboro, instead of 4-bromo-2-methylisoindolin-1-one as starting material. Using the 2-formyl-4-benzyloxyphenylboronic acid instead of the nickic acid, the target compound (96%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.12 (d, 1H, J = 9.09 Hz), 7.73 (s, 1H), 7.52-7.34 (m, 5H), 7.26-7.23 (m, 2H), 5.23 ( s, 2H), 4.09 (s, 3H), 4.06 (s, 3H), 3.47 (s, 3H).

Example 16: Synthesis of 1,2-dimethoxy-8-hydroxy-5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one

The compound obtained in Example 15 was placed in a flask and dissolved in methanol. 10% Pd / C was added, hydrogen balloons were connected, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was filtered through Celite and distilled under reduced pressure to obtain the target compound (99%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.90 (d, 1H, J = 9.0 Hz), 7.75 (s, 1H), 7.25 (d, 1H, J = 2.7 Hz), 7.18 (s, 1H) , 7.03 (dd, 1H, J = 9.0, 2.7 Hz), 4.00 (s, 3H), 3.97 (s, 3H), 3.34 (s, 3H).

Example 17 Synthesis of 5-benzyl-1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material Using benzylamine instead of methylamine, 2-benzyl-4-bromo-5,6-dimethoxyisoindolin-1-one (99%) was obtained by the same method as in Step 3 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39-7.26 (m, 6H), 4.79 (s, 2H), 4.12 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H).

<Step 2>

Using 2-benzyl-4-bromo-5,6-dimethoxyisoindolin-1-one obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material, In the same manner as in Step 4 of Example 1, the target compound (75%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.22-9.19 (m, 1H), 7.85 (s, 1H), 7.74-7.71 (m, 1H), 7.54-7.51 (m, 2H), 7.24-7.39 (m , 5H), 6.87 (s, 1H), 5.17 (s, 2H), 4.11 (s, 3H), 4.08 (s, 3H).

Synthesis of on-5-benzyl -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H): Example 18

Instead of 4-bromo-2-methylisoindolin-1-one as the starting material, 2-benzyl-4-bromo-5,6-dimethoxyisoindolin-1-one obtained in step 1 of Example 17 was substituted. Using the 2-formyl-4,5-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid, the target compound (56%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300MHz, CDCl ₃ ) δ 8.68 (s, 1H), 7.74 (s, 1H), 7.34-7.21 (m, 5H), 7.04 (s, 1H), 6.78 (s, 1H), 5.09 (s , 2H), 4.08-3.96 (m, 12H).

Example 19 Synthesis of 1,2-dimethoxy-5-ethyldibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material Was substituted with methylamine to obtain 4-bromo-5,6-dimethoxy-2-ethylisoindolin-1-one (80%) in the same manner as in Step 3 of Example 1 .

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.23 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.65 (q, 2H, J = 7.2 Hz) , 1.27 (t, 3H, J = 7.2 Hz).

<Step 2>

Example 1 Example 4 Using 4-bromo-5,6-dimethoxy-2-ethylisoindolin-1-one instead of 4-bromo-2-methylisoindolin-1-one as starting material, In the same manner as in Step 4, the target compound (71%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23-9.20 (m, 1H), 7.84-7.79 (m, 2H), 7.59-7.54 (m, 2H), 7.01 (s, 1H), 4.10 (s, 3H ), 4.06 (s, 3H), 4.02 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz).

Example 20 Synthesis of 1,2-dimethoxy-5-isopropyldibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2-isopropylisoindolin-1-one (88%) in the same manner as in step 3 of Example 1, using isopropylamine instead of methylamine Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.25 (s, 1H), 4.56 (hep, 1H, J = 6.9 Hz), 4.11 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H) , 1.23 (d, 6H, J = 6.9 Hz).

<Step 2>

Instead of 4-bromo-2-methylisoindolin-1-one as the starting material, 4-bromo-5,6-dimethoxy-2-isopropylisoindolin-1-one obtained in step 1 was used. In the same manner as in Step 4 of Example 1, the target compound (62%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24-9.20 (m, 1H), 7.83-7.78 (m, 2H), 7.59-7.54 (m, 2H), 7.15 (s, 1H), 4.93 (heptet, 1H , J = 6.9 Hz), 4.09 (s, 3H), 4.06 (s, 3H), 1.63 (d, 6H, J = 6.9 Hz).

Example 21 Synthesis of 1,2-dimethoxy-5- (2-methoxy) ethyldibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (2-methoxy) ethylisoindolin in the same manner as in Step 3 of Example 1, using 2-methoxyethylamine instead of methylamine -1-one was obtained (88%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.11 (s, 1H), 4.22 (s, 2H), 4.15 (t, 2H, J = 5.6 Hz), 4.11 (s, 3H), 4.06 (s, 3H) , 3.75 (t, 2H, J = 5.6 Hz), 3.36 (s, 3H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (2-methoxy) ethylisoindolin- obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material Using 1-one, the target compound (66%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23-9.20 (m, 1H), 7.85-7.72 (m, 2H), 7.80-7.54 (m, 2H), 7.11 (s, 1H), 4.15 (t, 2H , J = 5.6 Hz), 4.11 (s, 3H), 4.06 (s, 3H), 3.75 (t, 2H, J = 5.6 Hz), 3.36 (s, 3H).

Example 22: 1,2-dimethoxy-5-profile jildi benzo [cd, f] indole -4 (5 H) - one Synthesis of

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2-propazylisoindolin-1-one was obtained in the same manner as in Step 3 of Example 1, using propazylamine instead of methylamine (98). %).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34 (s, 1H), 4.44 (d, 2H, J = 2.5 Hz), 4.36 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H) , 2.31 (t, 1 H, J = 2.5 Hz).

<Step 2>

Instead of 4-bromo-2-methylisoindolin-1-one as the starting material, 4-bromo-5,6-dimethoxy-2-propazioisoindolin-1-one obtained in step 1 above was used. In the same manner as in Step 4 of Example 1, the target compound (53%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.28-9.26 (m, 1H), 8.28-8.26 (m, 1H), 7.57-7.48 (m, 3H), 7.07 (s, 1H), 4.11 (s, 3H ), 4.05 (s, 3H), 3.92 (s, 2H), 1.25 (s, 1H).

Example 23 Synthesis of 5- (cyclopropylmethyl) -1,2-dimethoxydibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2-propazioisoindolin-1-one (98%) in the same manner as in step 3 of Example 1, using cyclopropylmethanamine instead of methylamine )

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.05 (s, 1H), 4.22 (s, 2H), 4.11 (s, 3H), 4.06 (s, 3H), 3.85 (d, 2H, J = 6.8 Hz) , 1.28-1.26 (m, 1 H), 0.55-0.45 (m, 4 H).

<Step 2>

Example 1 Using 4-bromo-5,6-dimethoxy-2-propazioisoindolin-1-one instead of 4-bromo-2-methylisoindolin-1-one as starting material In the same manner as in Step 4, the target compound (53%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.28-9.26 (m, 1H), 8.28-8.26 (m, 1H), 7.57-7.48 (m, 3H), 7.07 (s, 1H), 4.11 (s, 3H ), 4.05 (s, 3H), 3.92 (s, 2H), 1.25 (s, 1H).

Example 24 Synthesis of 1,2-dimethoxy-5-phenethyldibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2-phenethylisoindolin-1-one (66%) in the same manner as in step 3 of Example 1, using phenethylamine instead of methylamine Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.30-7.17 (m, 6H), 4.07 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.84 (t, 2H, J = 7.2 Hz), 2.97 (t, 2H, J = 7.2 Hz).

<Step 2>

Example 1 Using 4-bromo-5,6-dimethoxy-2-phenethylisoindolin-1-one instead of 4-bromo-2-methylisoindolin-1-one as starting material, Example 1 In the same manner as in Step 4, the target compound (66%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.18-9.14 (m, 1H), 7.71-7.67 (m, 2H), 7.53-7.48 (m, 2H), 7.26-7.15 (m, 5H), 6.73 (s , 1H), 4.12 (t, 2H, J = 7.2 Hz), 4.07 (s, 3H), 4.00 (s, 3H), 3.07 (t, 2H, J = 7.3 Hz).

Example 25 Synthesis of 1,2-dimethoxy-5- (pyridin-4-ylmethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (pyridin-4-ylmethyl) iso in the same manner as in step 3 of Example 1, using 4- (aminomethyl) pyridine instead of methylamine Indolin-1-one (82%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.58 (dd, 2H, J = 6.6, 4.2 Hz), 7.39 (s, 1H), 7.20 (dd, 2H, J = 6.9, 5.7 Hz), 4.80 (s, 2H), 4.11 (s, 2H), 3.954 (s, 3H), 3.951 (s, 3H).

<Step 2>

4-bromo-5,6-dimethoxy-2- (pyridin-4-ylmethyl) isoindolin-1-one instead of 4-bromo-2-methylisoindolin-1-one as starting material In the same manner as in Step 4 of Example 1, the target compound (58%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24 (t, 1H, J = 3.6 Hz), 8.55 (d, 1H, J = 6.0 Hz), 7.87 (s, 1H), 7.75-7.72 (m, 1H) , 7.59-7.52 (m, 2H), 7.24 (s, 2H), 6.83 (s, 2H), 5.24 (s, 2H), 4.18 (s, 3H), 4.13 (s, 3H).

Example 26 Synthesis of 1,2-dimethoxy-5- (thiophen-3-ylmethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (thiophen-3-ylmethyl in the same manner as in step 3 of Example 1, using 3- (aminomethyl) thiophene instead of methylamine ) Isoindolin-1-one (98%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36 (s, 1H), 7.24 (d, 1H, J = 1.1 Hz), 7.05-7.04 (m, 1H), 6.99-6.96 (m, 1H), 4.96 ( s, 2H), 4.20 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (thiophen-3-ylmethyl) isoyne obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material Using dolin-1-one, the target compound (63%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23-9.20 (m, 1H), 7.83-7.79 (m, 2H), 7.60-7.54 (m, 2H), 7.21 (s, 1H), 7.12 (s, 1H ), 7.00-6.91 (m, 2H), 5.32 (s, 2H), 4.07 (s, 3H), 3.86 (s, 3H).

Example 27 Synthesis of 1,2-dimethoxy-5- (4-methoxyphenyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (4-methoxyphenyl) isoindolin- in the same manner as in step 3 of Example 1, using 4-methoxyaniline instead of methylamine 1-one (90%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65-7.48 (m, 4H), 7.01 (s, 1H), 4.20 (s, 2H), 4.18 (s, 3H), 4.14 (s, 3H), 3.90 ( s, 1 H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (4-methoxyphenyl) isoindolin- obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material Using 1-one, the target compound (86%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.26-9.24 (m, 1H), 7.88 (s, 1H), 7.77-7.64 (m, 1H), 7.65-7.48 (m, 4H), 7.11-7.09 (m , 2H), 7.01 (s, 1H), 4.18 (s, 3H), 4.14 (s, 3H), 3.90 (s, 1H).

Example 28 Synthesis of 5- (4- t -butylphenyl) -1,2-dimethoxydibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-2- (4- t -butylphenyl) -5,6-dimethoxyisoindolin in the same manner as in Step 3 of Example 1, using 4- t -butylaniline instead of methylamine -1-one (89%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, 2H, J = 8.9 Hz), 7.45 (d, 2H, J = 8.9 Hz), 7.40 (s, 1H), 4.68 (s, 2H), 3.94 (s, 3 H), 3.92 (s, 3 H), 1.26 (s, 9 H).

<Step 2>

4-Bromo-2- (4- t -butylphenyl) -5,6-dimethoxyisoindolin- obtained in Step 1, instead of 4-bromo-2-methylisoindolin-1-one as starting material Using 1-one, the target compound (70%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.28-9.25 (m, 1H), 7.90 (s, 1H), 7.90-7.88 (m, 1H), 7.77-7.76 (m, 4H), 7.24-7.22 (m , 2H), 7.11 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 1.34 (s, 9H).

Example 29 Synthesis of 1,2-dimethoxy-5- (2-morpholinoethyl) dibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzo obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (morpholinoethyl) isoindolin- in the same manner as in step 3 of Example 1, using 2-morpholinoethanamine instead of methylamine 1-one (98%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.33 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.74-3.67 (m, 6H), 2.63 ( t, 2H, J = 6.6 Hz), 2.54-2.49 (m, 4H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (morpholinoethyl) isoindoline-1- obtained in step 1, instead of 4-bromo-2-methylisoindolin-1-one as starting material Using the ON, the target compound (42%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23 (t, 1H, J = 5.2 Hz), 7.84-7.80 (m, 2H), 7.60-7.54 (m, 2H), 7.04 (s, 1H), 4.12- 4.07 (m, 8H), 3.69 (t, 4H, J = 4.5 Hz), 2.76 (t, 2H, J = 6.9 Hz), 2.58 (t, 4H, J = 4.5 Hz).

Example 30: 1,2,9- trimethoxy-5- (2-Dimorpholino Reno ethyl) dibenzo [cd, f] indole -4 (5 H) - one Synthesis of

The desired compound (37%) was obtained by the same method as Step 2 of Example 29, using 2-formyl-5-methoxyphenylboronic acid instead of 2-formylphenylboronic acid as starting material.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (d, 1H, J = 2.5 Hz), 7.79 (s, 1H), 7.73 (d, 1H, J = 8.7 Hz), 7.23 (dd, 1H, J = 8.7 Hz, J = 2.6 Hz), 6.99 (s, 1H), 4.12-4.06 (m, 8H), 3.99 (s, 3H), 3.70 (t, 2H, J = 4.5 Hz), 2.75 (t, 2H, J = 6.9 Hz), 2.58 (t, 4H, J = 4.3 Hz).

Example 31: 1,2,8,9- tetra-methoxy-5- (2-Dimorpholino Reno ethyl) dibenzo [cd, f] indole -4 (5 H) - one Synthesis of

The desired compound (51%) was obtained by the same method as Step 2 of Example 29, using 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid as starting material. .

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 7.74 (s, 1H), 7.21 (s, 1H), 6.94 (s, 1H), 4.11-4.04 (m, 14H), 3.70 ( t, 4H, J = 4.5 Hz), 2.75 (t, 2H, J = 6.9 Hz), 2.58 (t, 4H, J = 4.4 Hz).

Example 32: 17,18-dimethoxy-13- (2- (morpholino-4-yl) ethyl) -5,7-dioxa-13-azapentacyclo [10.6.1.0 ^2,10 .0 ^{4 8} 0.0 ^15,19] nona-deca -1,3,8,10,12 (19), 15,17- cyclohepta yen synthesis of 14-one

Using the 6-formylbenzo [1,3] dioxol-5-ylboronic acid instead of 2-formylphenylboronic acid as starting material, the target compound (60% )

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (d, 1H, J = 8.7 Hz), 7.64 (s, 1H), 7.10 (d, 1H, J = 8.7 Hz), 7.03 (s, 1H), 6.17 (s, 2H), 4.08-4.04 (m, 8H), 3.69 (m, 4H), 2.74 (t, 2H, J = 6.7 Hz), 2.58 (m, 4H).

Example 33 Synthesis of 1,2-dimethoxy-5- (2- (piperidin-1-yl) ethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (2- in the same manner as in step 3 of Example 1, using 2- (piperidin-1-yl) ethanamine instead of methylamine (Piperidin-1-yl) ethyl) isoindolin-1-one (99%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.35 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.72 (t, 2H, J = 6.6 Hz) , 2.58 (t, 2H, J = 6.6 Hz), 2.44 (s, 4H), 1.61-1.47 (m, 4H), 1.45-1.41 (m, 2H).

<Step 2>

4-bromo-5,6-dimethoxy-2- (2- (piperidin-1-yl) ethyl) isoyne instead of 4-bromo-2-methylisoindolin-1-one as starting material Using dolin-1-one, the target compound (77%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.22 (t, 1H, J = 6.3 Hz), 7.84-7.79 (m, 2H), 7.60-7.53 (m, 2H), 7.08 (s, 1H), 4.12- 4.07 (m, 8H), 2.71 (t, 2H, J = 7.5 Hz), 2.54 (t, 4H, J = 4.5 Hz), 1.64-1.57 (m, 4H), 1.48-1.42 (m, 2H).

Example 34: 1,2,9- trimethoxy-5- (2- (piperidin-1-yl) ethyl) dibenzo [cd, f] indole -4 (5 H) - one Synthesis of

The desired compound (40%) was obtained by the same method as Step 2 of Example 33, using 2-formyl-5-methoxyphenylboronic acid instead of 2-formylphenylboronic acid as starting material.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (d, 1H, J = 2.6 Hz), 7.80 (s, 1H), 7.74 (d, 1H, J = 8.7 Hz), 7.22 (dd, 1H, J = 10.7 Hz, J = 8.0 Hz), 7.06 (s, 1H), 4.14-4.09 (m, 5H), 4.06 (s, 3H), 3.99 (s, 3H), 2.75 (t, 2H, J = 7.3 Hz) , 2.58 (m, 4H), 1.63 (m, 4H), 1.46 (m, 2H).

Example 35: 1,2,8,9- tetra-methoxy-5- (2- (piperidin-1-yl) ethyl) dibenzo [cd, f] indole -4 (5 H) - one Synthesis of

The desired compound (67%) was obtained by the same method as Step 2 of Example 33, using 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid as starting material. .

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 7.76 (s, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 4.11-4.05 (m, 14H), 2.72 ( t, 2H, J = 7.4 Hz), 2.55 (s, 1H), 1.65-1.57 (m, 4H), 1.49-1.45 (m, 2H).

Example 36: 17,18-dimethoxy-13- (2- (piperidin-1-yl) ethyl) -5,7-dioxa-13-azapentacyclo [10.6.1.0 ^2,10 .0 ^4,8 .0 ^15,19] nona-deca -1,3,8,10,12 (19), 15,17- cyclohepta yen synthesis of 14-one

Using the 6-formylbenzo [1,3] dioxol-5-ylboronic acid instead of 2-formylphenylboronic acid as starting material, the target compound (42% )

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.81 (d, 1H, J = 8.7 Hz), 7.70 (s, 1H), 7.13 (d, 1H, J = 8.7 Hz), 7.10 (s, 1H), 6.17 (s, 2H), 4.11-4.05 (m, 8H), 2.73-2.70 (m, 2H), 2.52 (m, 4H), 1.63-1.56 (m, 4H), 1.46-1.43 (m, 2H).

Example 37: Synthesis of 8-chloro-1,2-dimethoxy-5- (2- (piperidin-1-yl) ethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

Using 4-chloro-2-formylphenylboronic acid instead of 2-formylphenylboronic acid as starting material, the target compound (47%) was obtained by the same method as Step 2 of Example 33.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.11 (d, 1H, J = 8.9 Hz), 7.76 (s, 2H), 7.45 (dd, 1H, J = 8.8 Hz, 2.2 Hz), 6.94 (s, 1H ), 4.09-4.04 (m, 8H), 2.53 (t, 2H, J = 7.2 Hz), 2.54-2.51 (m, 4H), 1.63-1.56 (m, 4H), 1.48-1.43 (m, 2H).

Example 38 Synthesis of 1,2-dimethoxy-8-fluoro-5- (2- (piperidin-1-yl) ethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

The target compound (52%) was obtained by the same method as Step 2 of Example 33, using 4-fluoro-2-formylphenylboronic acid instead of 2-formylphenylboronic acid as starting material.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.19 (dd, 1H, J = 9.9, 2.7 Hz), 7.76 (s, 1H), 7.45 (dd, 1H, J = 9.1, 6.0 Hz), 7.29-7.23 ( m, 1H), 6.99 (s, 1H), 4.11-4.05 (m, 2H), 4.10 (s, 3H), 4.06 (s, 3H), 2.70 (t, 2H, J = 7.1 Hz), 2.57-2.51 (m, 4H), 1.65-1.46 (m, 4H), 1.48-1.42 (m, 2H).

Example 39 Synthesis of 1,2-dimethoxy-6-methyl-5- (2- (piperidin-1-yl) ethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

4-Bromo-5,6-dimethoxy-2- (2- (piperidine-) obtained in step 1 of Example 33 instead of 4-bromo-2-methylisoindolin-1-one as starting material Using 1-yl) ethyl) isoindolin-1-one, the target compound (23%) was obtained in the same manner as in Example 2.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.33 (dd, 1H, J = 6.5, 1.6 Hz), 8.09 (dd, 1H, J = 7.7, 1.59 Hz), 8.07 (s, 1H), 7.77-7.59 ( m, 2H), 4.36 (t, 2H, J = 7.2 Hz), 4.06 (s, 3H), 4.04 (s, 3H), 2.82 (s, 3H), 2.69 (t, 2H, J = 7.2 Hz), 2.55-2.53 (m, 4H), 1.59-1.57 (m, 4H), 1.43-1.42 (m, 2H).

Example 40: 5- (2- (dimethylamino) ethyl) -1,2,8- tree methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (2- (dimethylamino) ethyl) in the same manner as in step 3 of Example 1, using N, N -dimethylethylenediamine instead of methylamine Isoindolin-1-one (98%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.32 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.72 (t, 2H, J = 6.5 Hz) , 2.58 (t, 2H, J = 6.4 Hz), 2.28 (s, 6H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (2- (dimethylamino) ethyl) isoyne obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material The desired compound (36%) was obtained in the same manner as in Step 4 of Example 1, using dolin-1-one as the 2-formyl-5-methoxyphenylboronic acid instead of 2-formylphenylboronic acid. Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.77 (d, 1H, J = 2.6 Hz), 7.78 (s, 1H), 7.73 (d, 1H, J = 8.7 Hz), 7.26 (dd, 1H, J = 8.7, 2.7 Hz), 6.98 (s, 1H), 4.11-4.04 (m, 8H), 3.98 (s, 3H), 2.71 (t, 2H, J = 7.3 Hz), 2.36 (s, 6H).

Example 41: 5- (2- (dimethylamino) ethyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

The desired compound (42%) was obtained by the same method as Step 2 of Example 40, using 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid as a starting material. .

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 7.77 (s, 1H), 7.25 (s, 1H), 6.99 (s, 1H), 4.12-4.04 (m, 14H), 2.70 ( t, 2H, J = 7.2 Hz), 2.37 (s, 6H).

Example 42: 17,18- dimethoxy-13 (2- (dimethylamino) ethyl) -5,7-dioxa-13-aza-cyclo-penta [10.6.1.0 ^2,10 .0 ^4,8 .0 ^{15 , 19]} nona-deca -1,3,8,10,12 (19), 15,17- cyclohepta yen synthesis of 14-one

Using the 6-formylbenzo [1,3] dioxol-5-ylboronic acid instead of 2-formylphenylboronic acid as starting material, the target compound (18%) was prepared in the same manner as in Step 2 of Example 40 )

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.80 (d, 1H, J = 8.7 Hz), 7.70 (s, 1H), 7.11 (d, 1H, J = 8.7 Hz), 7.04 (s, 1H), 6.17 (s, 2H), 4.08-4.04 (m, 8H), 2.70 (t, 2H, J = 7.1 Hz), 2.35 (s, 6H).

Example 43: 5- (2- (pyrrolidin-1-yl) ethyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (2- in the same manner as in step 3 of Example 1, using 2- (pyrrolidin-1-yl) ethanamine instead of methylamine (Pyrrolidin-1-yl) ethyl) isoindolin-1-one (96%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.32 (s, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.75 (t, 2H, J = 6.6 Hz) , 2.75 (t, 2H, J = 6.6 Hz), 2.6 (s, 4H), 1.75-1.68 (m, 6H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (2- (pyrrolidin-1-yl) obtained in Step 1, instead of 4-bromo-2-methylisoindolin-1-one as starting material ) Ethyl) isoindolin-1-one using the 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid, the same method as in Step 4 of Example 1 The target compound (25%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 7.77 (s, 1H), 7.24 (s, 1H), 7.01 (s, 1H), 4.11-4.05 (m, 14H), 2.89 ( t, 2H, J = 7.1 Hz), 2.67 (m, 4H), 1.83 (m, 4H).

Example 44 Synthesis of 1,2-dimethoxy-5- (3-methylbutan-2-yl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (3-methylbutan-2- in the same manner as in step 3 of Example 1, using 3-methylbutan-2-amine instead of methylamine I) Isoindolin-1-one (87%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (s, 1H), 4.14 (s, 2H), 4.13-4.07 (m, 1H), 3.93 (d, 6H, J = 5.4 Hz), 1.90-1.83 ( m, 1H), 1.30 (d, 3H, J = 6.8 Hz), 1.04 (d, 3H, J = 6.6 Hz), 0.86 (d, 3H, J = 6.7 Hz).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (3-methylbutan-2-yl) iso is obtained in Step 1 instead of 4-bromo-2-methylisoindolin-1-one as starting material. Using indolin-1-one, the target compound was obtained in the same manner as in Step 4 of Example 1 (16%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24 (dd, 1H, J = 5.3, 1.6 Hz), 7.82 (d, 1H, J = 4.5 Hz), 7.80 (s, 1H), 7.58-7.54 (m, 2H), 7.12 (s, 1H), 4.30-4.25 (m, 1H), 4.11 (s, 3H), 4.07 (s, 3H), 2.46-2.40 (m, 1H), 1.60 (d, 3H, J = 6.7 Hz), 1.15 (d, 3H, J = 6.6 Hz), 0.85 (d, 3H, J = 6.7 Hz).

Example 45 Synthesis of 5- (2- (diethylamino) ethyl) -1,2-dimethoxydibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material In the same manner as in Step 3 of Example 1, using N, N -diethylaminoethanamine instead of methylamine, 4-bromo-5,6-dimethoxy-2- (2- (diethylamino ) Ethyl) isoindolin-1-one (89%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.35 (s, 2H), 3.92 (d, 6H, J = 4.6 Hz), 3.68 (t, 2H, J = 6.6 Hz), 2.71 (t, 2H, J = 6.6 Hz), 2.58 (q, 4H, J = 7.1 Hz), 1.02 (t, 6H, J = 7.2 Hz).

<Step 2>

4-bromo-5,6-dimethoxy-2- (2- (diethylamino) ethyl) isoindoline-1-instead of 4-bromo-2-methylisoindolin-1-one as starting material Using the ON, the target compound (62%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24-9.21 (m, 1H), 7.85 7.82 (m, 1H), 7.79 (s, 1H), 7.60-7.55 (m, 2H), 7.07 (s, 1H) , 4.11 (s, 3H), 4.07 (s, 3H), 4.06 (t, 2H, J = 7.1 Hz), 2.86 (t, 2H, J = 7.1 Hz), 2.68 (q, 4H, J = 7.1 Hz) , 1.07 (t, 6H, J = 7.1 Hz).

Example 46: 5- (2- (diethylamino) ethyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

4-bromo-5,6-dimethoxy-2- (2- (diethylamino) ethyl) isoindoline-1-instead of 4-bromo-2-methylisoindolin-1-one as starting material The target compound (42%) was obtained by the same method as Step 4 of Example 1, using 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid. .

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 7.77 (s, 1H), 7.24 (s, 1H), 6.98 (s, 1H), 4.19 (s, 3H), 4.08 (s, 3H), 4.07 (s, 3H), 4.06 (s, 3H), 4.04 (t, 2H, J = 7.8 Hz), 2.84 (t, 2H, J = 7.0 Hz), 2.67 (q, 4H, J = 7.1 Hz), 1.07 (t, 6H, J = 7.1 Hz).

Example 47 Synthesis of 5- (3- (dimethylamino) -2,2-dimethylpropyl) -1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2 in the same manner as in Step 3 of Example 1, using N, N , 2,2-tetramethylpropane-1,3-diamine instead of methylamine -(3- (dimethylamino) -2,2-dimethylpropyl) isoindolin-1-one (81%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.19 (s, 1H), 4.23 (s, 2H), 3.81 (s, 6H), 3.36 (s, 2H), 2.23 (s, 6H), 2.21 (s, 2H), 0.91 (s, 6H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (3- (dimethylamino) -2,2 obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material Using dimethylpropyl) isoindolin-1-one, the target compound (22%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24 (dd, 1H, J = 5.5, 1.6 Hz), 7.86-7.83 (m, 1H), 7.81 (s, 1H), 7.58-7.55 (m, 2H), 7.11 (s, 1H), 4.12 (s, 1H), 4.08 (s, 1H), 3.85 (s, 1H), 2.38 (s, 1H), 2.34 (s, 1H), 1.07 (s, 1H).

Example 48: 5- (3- (dimethylamino) -2,2-dimethylpropyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

4-Bromo-5,6-dimethoxy-2- (3- (dimethylamino)-obtained in step 1 of Example 47 instead of 4-bromo-2-methylisoindolin-1-one as starting material Step of Example 1, using 2,2-dimethylpropyl) isoindolin-1-one in place of 2-formylphenylboronic acid, using 2-formyl-5,6-dimethoxyphenylboronic acid In the same manner as in 4, the target compound (11%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 7.78 (s, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 4.12 (s, 3H), 4.08 (s, 3H), 4.07 (s, 3H), 4.05 (s, 3H), 3.84 (s, 2H), 2.38 (s, 6H), 2.34 (s, 2H), 1.07 (s, 6H).

Example 49 Synthesis of 5- (4- (di- n -butylamino) butyl) -1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- in the same manner as in Step 3 of Example 1, using N, N -di- n -butylbutane-1,4-diamine instead of methylamine (4- (di- n -butylamino) butyl) isoindolin-1-one (96%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.25 (s, 2H), 3.92 (d, 6H, J = 3.9 Hz), 3.64 (t, 2H, J = 7.4 Hz), 2.53 -2.41 (m, 6H), 1.89-1.82 (m, 2H), 1.47-1.23 (m, 8H), 0.90 (t, 6H, J = 7.2 Hz).

<Step 2>

4-bromo-5,6-dimethoxy-2- (4- (di- n -butylamino) butyl) isoindolin instead of 4-bromo-2-methylisoindolin-1-one as starting material Using -1-one, the target compound (42%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24-9.21 (m, 1H), 7.83-7.81 (m, 1H), 7.80 (s, 1H), 7.60-7.55 (m, 2H), 7.05 (s, 1H ), 4.11 (s, 3H), 4.07 (s, 3H), 3.99 (t, 2H, J = 7.2 Hz), 2.56 (t, 2H, J = 7.2 Hz), 2.42 (t, 4H, J = 7.1 Hz ), 2.01-1.91 (m, 2H), 1.47 1.23 (m, 8H), 0.89 ((t, 6H, J = 7.0 Hz).

Example 50 Synthesis of 1,2-dimethoxy-5- (3-morpholinopropyl) dibenzo [ cd, f ] indole-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (3-morpholinopropyl) in the same manner as in step 3 of Example 1, using 4-morpholinopropan-1-amine instead of methylamine Isoindolin-1-one (78%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.28 (s, 1H), 4.31 (s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 3.54-3.47 (m, 6H), 2.28- 2.24 (m, 6 H), 1.79-1.71 (m, 2 H).

<Step 2>

4-bromo-5,6-dimethoxy-2- (3-morpholinopropyl) isoindolin-1-one is used instead of 4-bromo-2-methylisoindolin-1-one as starting material In the same manner as in Step 4 of Example 1, the target compound (41%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.25-9.21 (m, 1H), 7.81-7.79 (m, 2H), 7.58-7.55 (m, 2H), 7.09 (s, 1H), 4.16 (s, 3H ), 4.07 (s, 3H), 4.03 (d, 2H, J = 6.7 Hz), 3.70 (t, 4H, J = 4.6 Hz), 2.48-2.42 (m, 6H), 2.06-1.99 (m, 2H) .

Example 51: 5- (3-Dimorpholino Reno propyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

4-bromo-5,6-dimethoxy-2- (3-morpholinopropyl) isoindolin-1-one, instead of 4-bromo-2-methylisoindolin-1-one as starting material, The target compound (43%) was obtained by the same method as Step 4 of Example 1, using 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 7.78 (s, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 4.13 (s, 3H), 4.08 (d, 6H, J = 3.1 Hz), 4.05 (s, 3H), 4.03 (d, 2H, J = 6.9 Hz), 3.71 (t, 4H, J = 4.7 Hz), 2.47 (m, 6H), 2.04-1.99 ( m, 2H).

Example 52 Synthesis of 1,2-dimethoxy-5- (3- (2-methylpiperidin-1-yl) propyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy in the same manner as in step 3 of Example 1, using 3- (2-methylpiperidin-1-yl) propan-1-amine instead of methylamine 2- (3- (2-methylpiperidin-1-yl) propyl) isoindolin-1-one (98%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.17 (s, 1H), 4.31 (s, 2H), 3.80 (d, 6H, J = 6.1 Hz), 3.50 (t, 2H, J = 7.6 Hz), 2.78 -2.62 (m, 2H), 2.32-2.23 (m, 2H), 2.10-2.03 (m, 1H), 1.53-1.42 (m, 4H), 1.24-1.15 (m, 2H), 0.95 (t, 3H, J = 6.2 Hz).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (3- (2-methylpiperidine-) obtained in Step 1, instead of 4-bromo-2-methylisoindolin-1-one as starting material Using 1-yl) propyl) isoindolin-1-one, the target compound (22%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23 (dd, 1H, J = 5.3, 1.7 Hz), 7.89-7.86 (m, 1H), 7.78 (s, 1H), 7.62-7.55 (m, 2H), 7.16 (s, 1H), 4.12 (s, 3H), 4.07 (s, 3H), 3.21-3.12 (m, 2H), 2.93-2.78 (m, 3H), 2.63-2.59 (m, 1H), 2.37- 2.27 (m, 2H), 1.91-1.70 (m, 5H), 1.46-1.33 (m, 2H), 1.28 (d, 3H, J = 6.5 Hz).

Example 53: 5- (3- (2-methylpiperidin-1-yl) propyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

4-bromo-5,6-dimethoxy-2- (3- (2-methylpiperidin-1-yl) propyl instead of 4-bromo-2-methylisoindolin-1-one as starting material Isoindolin-1-one in the same manner as in step 4 of Example 1, using 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid Compound (8%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 7.78 (s, 1H), 7.24 (s, 1H), 7.01 (s, 1H), 4.12 (s, 3H), 4.08 (d, 6H, J = 3.0 Hz), 4.05 (s, 3H), 3.97 (t, 2H, J = 7.1 Hz), 2.89-2.80 (m, 2H), 2.51-2.41 (m, 1H), 2.35-2.30 (m , 1H), 2.19-2.11 (m, 1H), 2.05-1.96 (m, 2H), 1.68-1.56 (m, 2H), 1.36-1.21 (m, 4H), 1.04 (d, 2H, J = 6.2 Hz ).

Example 54 Synthesis of Ethyl 4- (1,2-dimethoxy-4-oxodibenzo [ cd, f ] indol-5 ( 4H ) -yl) piperidine-1-carboxylate

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material Ethyl 4- (4-bromo-5,6-dimethoxy-1- in the same manner as in step 3 of Example 1, using ethyl 4-aminopiperidine-1-carboxylate instead of methylamine Oxoisoindolin-2-yl) piperidine-1-carboxylate (90%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34 (s, 1H), 4.45-4.31 (m, 3H), 4.18-4.12 (m, 4H), 3.92 (d, 6H, J = 6.1 Hz), 2.92 ( t, 2H, J = 12.2 Hz), 1.87-1.69 (m, 4H), 1.28 (t, 3H, J = 7.2 Hz).

<Step 2>

Ethyl 4- (4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl) piperidine- instead of 4-bromo-2-methylisoindolin-1-one as starting material Using 1-carboxylate, the target compound (13%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.23 (dd, 1H, J = 6.0, 3.4 Hz), 7.85-7.82 (m, 1H), 7.81 (s, 1H), 7.61-7.56 (m, 2H), 7.15 (s, 1H), 4.67-4.61 (m, 1H), 4.46-4.38 (m, 2H), 4.23 (q, 2H, J = 7.1 Hz), 4.11 (s, 3H), 4.08 (s, 3H) , 2.98 (t, 2H, J = 12.6 Hz), 2.45-2.39 (m, 2H), 1.93-1.89 (m, 2H), 1.33 (t, 3H, J = 7.1 Hz).

Example 55 Synthesis of Ethyl 4- (1,2,8,9-tetramethoxy-4-oxodibenzo [ cd, f ] indol-5 ( 4H ) -yl ) piperidine-1-carboxylate

Ethyl 4- (4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl) piperidine- instead of 4-bromo-2-methylisoindolin-1-one as starting material Using the 1-carboxylate, 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid, the target compound (52% )

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 7.78 (s, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 4.72-4.64 (m, 1H), 4.49- 4.38 (m, 1H), 4.23 (q, 2H, J = 7.1 Hz), 4.11-4.07 (m, 12H), 2.99 (t, 2H, J = 12.7 Hz), 2.47-2.33 (m, 2H), 1.94 -1.89 (m, 2H), 1.34 (t, 3H, J = 7 .1 Hz).

Example 56 Synthesis of 1,2-dimethoxy-5- (1-benzylpiperidin-4-yl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material 4-bromo-5,6-dimethoxy-2- (1-benzylpiperi) in the same manner as in step 3 of Example 1, using 1-benzylpiperidin-4-amine instead of methylamine Din-4-yl) isoindolin-1-one (86%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34-7.25 (m, 6H), 4.28-4.25 (m, 1H), 4.21 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.54 (s, 2H), 3.00 (d, 2H, J = 11.9 Hz), 2.18 (dt, 2H, J = 11.4, 2.6 Hz), 1.90-1.79 (m, 4H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (1-benzylpiperidin-4-yl obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material Using isoindolin-1-one, the target compound (57%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24-9.21 (m, 1H), 7.88-7.85 (m, 1H), 7.79 (s, 1H), 7.61-7.53 (m, 2H), 7.42-7.27 (m , 6H), 4.57-4.48 (m, 1H), 4.10 (s, 3H), 4.07 (s, 3H), 3.63 (s, 2H), 3.10 (d, 2H, J = 11.4 Hz), 2.63-2.49 ( m, 2H), 2.25 (t, 2H, J = 11.2 Hz), 1.86 (d, 2H, J = 11.3 Hz).

Example 57 Synthesis of t -butyl 4-((1,2-dimethoxy-4-oxodibenzo [ cd, f ] indol-5 ( 4H ) -yl) methyl) piperidine-1-carboxylate

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material T -butyl 4-((4-bromo-5) in the same manner as in step 3 of Example 1, using t -butyl 4- (aminomethyl) piperidine-1-carboxylate instead of methylamine , 6-dimethoxy-1-oxoisoindolin-2-yl) methyl) piperidine-1-carboxylate (89%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.29 (s, 1H), 4.63 (s, 2H), 3.89 (s, 3H), 3.79 (s, 3H), 3.38 (d, 2H, J = 7.3 Hz) , 1.91-1.88 (m, 1H), 1.65-1.51 (m, 4H), 1.37 (s, 9H), 1.06-0.89 (m, 4H).

<Step 2>

T -butyl 4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin- obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material Using the 2-yl) methyl) piperidine-1-carboxylate, the target compound (13%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.25-9.22 (m, 1H), 7.86-7.83 (m, 1H), 7.81 (s, 1H), 7.60-7.56 (m, 2H), 6.99 (s, 1H ), 4.12 (s, 3H), 4.08 (s, 3H), 3.86 (d, 2H, J = 7.1 Hz), 2.67 (t, 2H, J = 12.3 Hz), 2.17-2.05 (m, 1H), 1.78 -1.69 (m, 2H), 1.58 (s, 4H), 1.45 (s, 5H), 1.39-1.24 (m, 2H).

Example 58: Synthesis of 1,2-dimethoxy-5-((1-ethylpyrrolidin-2-yl) methyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material In the same manner as in Step 3 of Example 1, using (1-ethylpyrrolidin-2-yl) methanamine instead of methylamine, 4-bromo-5,6-dimethoxy-2- (1 Ethylpyrrolidin-2-yl) methyl) isoindolin-1-one (88%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.54 (d, 2H, A of ABq, J = 17.5 Hz), 4.28 (B of ABq, J = 17.5 Hz), 3.92 (d, 6H, J = 3.2 Hz), 3.83 (dd, 1H, J = 14.1, 3.9 Hz), 3.48 (dd, 1H, J = 14.0, 6.2 Hz), 3.20-3.18 (m, 1H), 2.93 (dd, 1H , J = 11.9, 7.4 Hz), 2.74 (s, 1H), 2.33 (q, 1H, J = 7.0 Hz), 2.17 (q, 1H, J = 8.2 Hz), 1.93-1.85 (m, 1H), 1.75 -1.66 (m, 3H), 1.16 (t, 3H, J = 7.2 Hz).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (1-ethylpyrrolidin-2-yl obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material Using the methyl) isoindolin-1-one, the target compound (40%) was obtained by the same method as Step 4 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.24-9.21 (m, 1H), 7.84-7.81 (m, 1H), 7.79 (s, 1H), 7.60-7.55 (m, 2H), 7.08 (s, 1H ), 4.11 (s, 3H), 4.07 (s, 3H), 4.03 (dd, 1H, J = 9.3, 5.8 Hz), 3.91 (q, 1H, J = 7.9 Hz), 3.24 (m, 1H), 3.06 -2.96 (m, 2H), 2.44 (q, 1H, J = 7.1 Hz), 2.23 (q, 1H, J = 8.6 Hz), 1.89-1.68 (m, 5H), 1.18 (t, 3H, J = 7.2 Hz).

Example 59: 5- (4- (diethylamino) -1-methylbutyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material In the same manner as in Step 3 of Example 1, using N, N -diethyl-1-methylbutane-1,4-diamine instead of methylamine, 4-bromo-5,6-dimethoxy- 2- (4- (diethylamino) -1-methylbutyl) isoindolin-1-one (98%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33 (s, 1H), 4.53-4.46 (m, 1H), 4.15 (d, 2H, J = 3.8 Hz), 3.92 (d, 6H, J = 3.2 Hz) , 2.58-2.43 (m, 6H), 1.69-1.58 (m, 2H), 1.52-1.39 (m, 2H), 1.29 (d, 2H, J = 6.8 Hz), 1.07-0.98 (m, 7H).

<Step 2>

4-Bromo-5,6-dimethoxy-2- (4- (diethylamino) -1- obtained in step 1 above instead of 4-bromo-2-methylisoindolin-1-one as starting material Methylbutyl) isoindolin-1-one using the 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid, the same method as in Step 4 of Example 1 The target compound (11%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 7.76 (s, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 4.74-4.67 (m, 1H), 4.11- 4.05 (m, 12H), 2.50-2.39 (m, 5H), 2.23-2.09 (m, 1H), 1.92-1.75 (m, 2H), 1.59 (d, 3H, J = 7.0 Hz), 1.56-1.37 ( m, 2H), 0.95 (t, 6H, J = 7.1 Hz).

Example 60: 5- (3- (2-oxopyrrolidin-1-yl) propyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one Synthesis of

<Step 1>

Methyl 3-bromo-2- (bromomethyl) -4,5-dimethoxybenzoate obtained in step 2 of Example 5 instead of methyl 3-bromo-2- (bromomethyl) benzoate as starting material In the same manner as in Step 3 of Example 1, using 1- (3-aminopropyl) pyrrolidin-2-one instead of methylamine, 4-bromo-5,6-dimethoxy-2- ( 3- (2-oxopyrrolidin-1-yl) propyl) isoindolin-1-one (98%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.31 (s, 1H), 4.27 (s, 2H), 3.92 (d, 6H, J = 4.3 Hz), 3.62 (t, 2H, J = 7.4 Hz), 3.44 (t, 2H, J = 7.1 Hz), 3.35 (t, 2H, J = 7.2 Hz), 2.39 (t, 2H, J = 8.2 Hz), 2.04-1.91 (m, 4H).

<Step 2>

4-bromo-5,6-dimethoxy-2- (3- (2-oxopyrrolidin-1-yl) propyl instead of 4-bromo-2-methylisoindolin-1-one as starting material Isoindolin-1-one in the same manner as in step 4 of Example 1, using 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid Compound (10%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 7.77 (s, 1H), 7.27 (s, 1H), 6.99 (s, 1H), 4.12 (s, 3H), 4.08 (d, 6H, J = 2.7 Hz), 4.06 (s, 3H), 3.97 (t, 2H, J = 7.4 Hz), 3.48-3.40 (m, 4H), 2.39 (t, 2H, J = 8.3 Hz), 2.08- 1.99 (m, 4 H).

Example 61 Synthesis of 8-benzyloxy-1,2-di (hexyloxy) -5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one

<Step 1>

4-bromo-5,6-dimethoxy-2-methylisoindolin-1-one (280 mg, 0.98 mmol) obtained in Example 8 was added to the flask, dissolved in 5 mL of methylene chloride, and cooled to O ° C. I was. Borontribromide (1M methylene chloride solution, 2.44 mL, 2.44 mmol) was slowly added dropwise to the resulting solution and stirred for 30 minutes under a stream of nitrogen. 5 mL of water was added to the reaction to stop the reaction, and 20 mL of water was added to wash the organic layer. The organic layer was distilled off under reduced pressure and the remaining material was dissolved in 5 mL of dimethylformamide. Potassium carbonate (1.35 g, 9.8 mmol) and 1-bromohexane (0.55 mL, 3.9 mmol) were added to the resulting solution, and the mixture was stirred at room temperature for 36 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then dissolved in 50 mL of ethyl acetate, washed twice with 10 mL of water and once with 10 mL of saturated sodium chloride solution. Dried over anhydrous magnesium sulfate, filtered, the filtrate was distilled under reduced pressure and purified by chromatography to give 4-bromo-5,6-bis (hexyloxy) -2-methylisoindolin-1-one (315 mg) , 76%) was obtained as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.29 (s, 1H), 4.21 (s, 2H), 4.08-4.01 (m, 4H), 3.19 (s, 3H), 1.86-1.79 (m, 4H), 1.53-1.46 (m, 4H), 1.36-1.33 (m, 8H), 0.93-0.89 (m, 6H).

<Step 2>

4-Bromo-5,6-bis (hexyloxy) -2-methylisoindolin- instead of 4-bromo-5,6-dimethoxy-2-methylisoindolin-1-one as starting material Using 1-one, the target compound (98%) was obtained in the same manner as in Example 15.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.25-9.13 (m, 1H), 7.85 (s, 1H), 7.48-7.14 (m, 7H), 6.84 (s, 1H), 5.21-5.16 (m, 2H ), 4.19-4.04 (m, 4H), 3.74-3.40 (m, 3H), 1.88-1.82 (m, 4H), 1.49-1.30 (m, 12H), 0.89-0.83 (m, 6H).

Example 62 Synthesis of 8-hydroxy-1,2-di (hexyloxy) -5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one

The compound obtained in Example 61 was placed in a flask and dissolved in methanol. 10% Pd / C was added, hydrogen balloons were connected, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was filtered through Celite and distilled under reduced pressure to obtain the target compound (97%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.95 (d, 1H, J = 9.0 Hz), 7.50 (s, 1H), 7.13 (d, 1H, J = 2.4 Hz), 6.93 (s, 1H) , 6.93-6.90 (dd, J = 2.4, 9.0 Hz), 4.09 (t, J = 6.6 Hz), 4.03 (t, J = 6.3, 9.0 Hz), 3.25 (s, 3H), 1.85-1.78 (m, 4H), 1.52-1.30 (m, 12H), 0.89-0.82 (m, 6H).

Test Example 1: Anticancer Effect Test

In order to determine the anticancer activity of the compounds according to the present invention was carried out SRB analysis (Sulforhodamine B assay) as follows.

1) Cell Culture

The cancer cell lines used in the experiments are all human-derived cancer cell lines, lung cancer cell line A549, ovarian cancer cell line SK-OV-3, breast cancer cell line MDA-MB-231 and BT-474, skin cancer cell line A431, colon cancer cell line HCT15, MES-SA, a uterine cancer cell line, and MES-SA / DX5 cells, a multidrug resistant cell line derived therefrom, were used.

As a cell culture medium, a medium supplemented with 5% FBS of RPMI1640 solution containing glutamine, sodium monocarbonate, gentamycin, and amphotericin was used. All cells were incubated at 37 ° C., 5% carbon dioxide, 95% air and 100% humidity and passaged every 3-5 days.

2) Cancer cell proliferation inhibitory activity test

Each cell was aliquoted into a 96-well plate and incubated for 24 hours to allow the cells to adhere to the plate bottom. After the cells adhered to the plate bottom surface, the culture solution was removed, and each test compound was incubated for 72 hours in an incubator with 100 [mu] l per well for each concentration. At this time, doxorubicin and paclitaxel were used as controls. After the incubation, the culture solution was removed and each well was treated with 10% TCA solution, then TCA was removed, washed five times with tap water, and dried at room temperature. SRB, a cell surface protein staining reagent, was dissolved in 0.4% SRB in 1% acetic acid solution and dispensed into each well and left for 30 minutes at room temperature to stain cells. After washing five times with 1% acetic acid solution and dried at room temperature. SRB was eluted by adding 10 mM Trisma base solution (pH 10.5) to the stained cells. The absorbance of each plate was measured at 520 nm wavelength (using microplate reader). After confirming the viability of cells per well from the measured absorbance (OD ₅₂₀ ) value, cancer cell proliferation inhibitory concentration (IC ₅₀ ) was calculated by nonlinear regression analysis. The results are shown in Table 1.

From Table 1, it can be seen that the phenanthrene lactam derivative of Formula 1 according to the present invention exhibits cancer cell proliferation inhibitory activity against various cancer cells.

On the other hand, doxorubicin tested as a control compound is very good cancer cell proliferation inhibitory activity itself, but the toxicity is too strong to damage to normal cells, paclitaxel is a natural product has a disadvantage in that it is expensive to synthesize the complex structure. In contrast, the phenanthrene lactam derivative of Formula 1 according to the present invention exhibits excellent anticancer effect and has low toxicity as shown in the acute toxicity test results of Test Example 2, which is particularly useful when a high dose of anticancer agent is required. Can be.

Test Example 2: Acute Toxicity Test

Seven-week old female ICR mice (23.98 to 25.81 g) were purchased and purified for 7 days at room temperature 23 ± 3 ° C., relative humidity 55 ± 15%. Thereafter, eight-week old mice (23.61 to 26.56 g) were divided into five groups per group, and then the compound of Example 33 was mixed orally administered with an excipient (0.5% CMC-Na) as a test compound (2000 mg / Kg, 1000). mg / Kg, 500 mg / Kg, and unadministered control). 14 days after the administration, the appearance and live death were recorded. The mortality was examined by necropsy. As a result, the minimum lethal dose (MLD) of a single oral administration of the test compound to female mice exceeded 2,000 mg / Kg, indicating that the compound according to the present invention was almost non-toxic.

Claims (14)

Phenanthrene lactam derivative of formula 1 or a pharmaceutically acceptable salt thereof: Formula 1

Where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy or aryloxy, wherein R ⁴ and R ⁵ , R ⁵ and R ⁶ or R ⁶ and R ⁷ may form a dioxole, R ⁸ is hydrogen or C _1-6 alkyl, R ⁹ is hydrogen; C _1-6 alkyl, C _1-6 alkoxy, perfluoro, hydroxy, halogen, C _1-6 alkylamino, diC _1-6 alkylamino, C _1-6 acyloxy, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkyl substituted with C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl-carbonyl, C _3-8 heterocycloalkyl -C _1-6 alkoxycarbonyl, C _1-6 alkyl, optionally substituted with one or more substituents selected from the group consisting of C _3-8 heteroaryl, aryl, and thioaryl; C _1-6 alkenyl; C _1-6 alkynyl; C _1-6 acyl; C _1-6 alkoxycarbonyl; C _1-6 alkylsulfonyl; C _1-6 alkylaryl or C _1-6 alkoxycarbonyl optionally substituted C _3-8 heterocycloalkyl as; Or aryl substituted or unsubstituted with halogen, amino, C _1-6 alkyl, perfluoroC _1-6 alkyl or C _1-6 alkoxy. The method of claim 1, One or more substituents selected from the group consisting of C _3-8 heterocycloalkyl, wherein R ⁹ is C _1-6 alkylamino, diC _1-6 alkylamino, C _3-8 heterocycloalkyl and C _1-6 alkyl C _1-6 alkyl substituted with; C _1-6 alkylaryl or C _1-6 alkoxycarbonyl C _3-8 the phenanthrene lactam derivative or a pharmaceutically acceptable salt thereof of formula (1), characterized in that the heterocycloalkyl alkyl substituted with. The phenanthrene lactam derivative of claim 1 or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of: 1) 5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one, 2) 5,6-dimethyldibenzo [ cd, f ] indole-4 ( 5H ) -one, 3) 3-methoxydibenzo [ cd, f ] indole-4 ( 5H ) -one, 4) 3-methoxy-5-methyldibenzo [ cd, f ] indole-4 ( 5H ) -one, 5) 1,2-dimethoxydibenzo [ cd, f ] indole-4 ( 5H ) -one, 6) 1-hydroxy-2-methoxydibenzo [ cd, f ] indole-4 ( 5H ) -one, 7) 1,2,9- tree methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 8) 1,2-dimethoxy-5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 9) 1-hydroxy-2-methoxy-5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 10) 2-hydroxy-1-methoxy-5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 11) 5-methyl -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 12) 17,18-dimethoxy-13-methyl-5,7-dioxa-13-azapentacyclo [10.6.1.0 ^{2,10 4,8} .0 ^15,19 ] nonadeca-1,3, 8,10,12 (19), 15,17-heptaen-14-one, 13) 1,2-dimethoxy-5,6-dimethyldibenzo [ cd, f ] indole-4 ( 5H ) -one, 14) 8-benzyloxy-5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 15) 8-benzyloxy-1,2-dimethoxy-5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 16) 1,2-dimethoxy-8-hydroxy-5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 17) 5-benzyl-1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one, 18) 5-benzyl -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 19) 1,2-dimethoxy-5-ethyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 20) 1,2-dimethoxy-5-isopropyldibenzo [ cd, f ] indole-4 ( 5H ) -one, 21) 1,2-dimethoxy-5- (2-methoxy) ethyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 22) 1,2-dimethoxy-5-profile jildi benzo [cd, f] indole -4 (5 H) - one, 23) 5- (cyclopropylmethyl) -1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one, 24) 1,2-dimethoxy-5-phenethyldibenzo [ cd, f ] indol-4 ( 5H ) -one, 25) 1,2-dimethoxy-5- (pyridin-4-ylmethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 26) 1,2-dimethoxy-5- (thiophen-3-ylmethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 27) 1,2-dimethoxy-5- (4-methoxyphenyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 28) 5- (4- t -butylphenyl) -1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one, 29) 1,2-dimethoxy-5- (2-morpholinoethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 30) 1,2,9- trimethoxy-5- (2-Dimorpholino Reno ethyl) dibenzo [cd, f] indole -4 (5 H) - one, 31) 1,2,8,9- tetrahydro-methoxy-5- (2-Dimorpholino Reno ethyl) dibenzo [cd, f] indole -4 (5 H) - one, 32) 17,18-dimethoxy-13- (2- (morpholino-4-yl) ethyl) -5,7-dioxa-13-azapentacyclo [10.6.1.0 ^{2,10 4,8} . 0 ^15,19] nona-deca -1,3,8,10,12 19, 15,17- 14-yen hepta-one, 33) 1,2-dimethoxy-5- (2- (piperidin-1-yl) ethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 34) 1,2,9- trimethoxy-5- (2- (piperidin-1-yl) ethyl) dibenzo [cd, f] indole -4 (5 H) - one, 35) 1,2,8,9- tetrahydro-methoxy-5- (2- (piperidin-1-yl) ethyl) dibenzo [cd, f] indole -4 (5 H) - one, 36) 17,18-dimethoxy-13- (2- (piperidin-1-yl) ethyl) -5,7-dioxa-13-azapentacyclo [10.6.1.0 ^2,10 .0 ^4,8 .0 ^15,19] nona-deca -1,3,8,10,12 19, 15,17- 14-yen hepta-one, 37) 8-chloro-1,2-dimethoxy-5- (2- (piperidin-1-yl) ethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 38) 1,2-dimethoxy-8-fluor-5- (2- (piperidin-1-yl) ethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 39) 1,2-dimethoxy-6-methyl-5- (2- (piperidin-1-yl) ethyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 40) 5- (2- (dimethylamino) ethyl) -1,2,8- tree methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 41) 5- (2- (dimethylamino) ethyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 42) 17,18-dimethoxy-13- (2- (dimethylamino) ethyl) -5,7-dioxa-13-azapentacyclo [10.6.1.0 ^{2,10 4,8} .0 ^15,19 Nonadeka-1,3,8,10,12 (19), 15,17-heptaen-14-one, 43) 5- (2- (pyrrolidin-1-yl) ethyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 44) 1,2-dimethoxy-5- (3-methylbutan-2-yl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 45) 5- (2- (diethylamino) ethyl) -1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one, 46) 5- (2- (diethylamino) ethyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 47) 5- (3- (dimethylamino) -2,2-dimethylpropyl) -1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one, 48) 5- (3- (dimethylamino) -2,2-dimethylpropyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 49) 5- (4- (di- n -butylamino) butyl) -1,2-dimethoxydibenzo [ cd, f ] indol-4 ( 5H ) -one, 50) 1,2-dimethoxy-5- (3-morpholinopropyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 51) 5- (3-Dimorpholino Reno propyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 52) 1,2-dimethoxy-5- (3- (2-methylpiperidin-1-yl) propyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 53) 5- (3- (2-methylpiperidin-1-yl) propyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 54) ethyl 4- (1,2-dimethoxy-4-oxodibenzo [ cd, f ] indol-5 ( 4H ) -yl) piperidine-1-carboxylate, 55) ethyl 4- (1,2,8,9-tetramethoxy-4-oxodibenzo [ cd, f ] indol-5 ( 4H ) -yl) piperidine-1-carboxylate, 56) 1,2-dimethoxy-5- (1-benzylpiperidin-4-yl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 57) t -butyl 4-((1,2-dimethoxy-4-oxodibenzo [ cd, f ] indol-5 ( 4H ) -yl) methyl) piperidine-1- carboxylate, 58) 1,2-dimethoxy-5-((1-ethylpyrrolidin-2-yl) methyl) dibenzo [ cd, f ] indol-4 ( 5H ) -one, 59) 5- (4- (diethylamino) -1-methylbutyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole -4 (5 H) - one, 60) 5- (3- (2-oxopyrrolidin-1-yl) propyl) -1,2,8,9- tetrahydro methoxydiethylene benzo [cd, f] indole - 4 (5 H) - one, 61) 8-benzyloxy-1,2-di (hexyloxy) -5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one, and 62) 8-hydroxy-1,2-di (hexyloxy) -5-methyldibenzo [ cd, f ] indol-4 ( 5H ) -one. A process for preparing a phenanthrene lactam derivative of formula (1) comprising reacting a compound of formula (2) with a compound of formula (3) in the presence of a palladium compound and a base in a solvent: Formula 1

Formula 2

Formula 3

Where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy or aryloxy, wherein R ⁴ and R ⁵ , R ⁵ and R ⁶ or R ⁶ and R ⁷ may form a dioxole, R ⁸ is hydrogen or C _1-6 alkyl, R ⁹ is hydrogen; C _1-6 alkyl, C _1-6 alkoxy, perfluoro, hydroxy, halogen, C _1-6 alkylamino, diC _1-6 alkylamino, C _1-6 acyloxy, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _1-6 alkyl substituted with C _3-8 heterocycloalkyl, C _3-8 heterocycloalkyl-carbonyl, C _3-8 heterocycloalkyl -C _1-6 alkoxycarbonyl, C _1-6 alkyl, optionally substituted with one or more substituents selected from the group consisting of C _3-8 heteroaryl, aryl and thioaryl; C _1-6 alkenyl; C _1-6 alkynyl; C _1-6 acyl; C _1-6 alkoxycarbonyl; C _1-6 alkylsulfonyl; C _1-6 alkylaryl or C _1-6 alkoxycarbonyl optionally substituted C _3-8 heterocycloalkyl as; Or aryl substituted or unsubstituted with halogen, amino, C _1-6 alkyl, perfluoroC _1-6 alkyl or C _1-6 alkoxy, X is halogen, C _1-6 alkylsulfonyloxy or arylsulfonyloxy, M is B (OH) ₂ or B (OR ¹⁰ ) ₂ , wherein R ¹⁰ is C _1-4 alkyl, or two R ¹⁰ are linked together to form a heterocycloalkyl substituted with methyl with boron and oxygen Can be). The method of claim 4, wherein M is B (OH) ₂ ,

or

Production method characterized in that. The method of claim 4, wherein Method for producing a phenanthrene lactam derivative of formula (1) by the reaction of the compound of formula (2) and the compound of formula (3) to the intermediate compound of formula (4) after the cyclization reaction:

Wherein R ¹ to R ⁹ are as defined in claim 4. The method of claim 4, wherein A process for preparing an intermediate compound of formula (4), which is produced by the reaction of a compound of formula (2) with a compound of formula (3), is isolated and then subjected to base treatment: Formula 4

Wherein R ¹ to R ⁹ are as defined in claim 4. The method of claim 4, wherein The palladium compound is tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tetrakis (tri- tert -butylphosphine) palladium, palladium acetate, dichloro Bis (triphenylphosphine) palladium, dichlorobis (tri- o -tolylphosphine) palladium, dichlorobis (tricyclohexylphosphine) palladium, 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium, chloride Palladium hydroxide, palladium hydroxide, palladium nitrate, di-μ-chlorobis (η-allyl) palladium, bis (acetylacetonato) palladium, dichlorobis (benzonitrile) palladium, dichlorobis (acetonitrile) palladium and mixtures thereof Production method characterized in that selected from the group. The method according to claim 4 or 7, The base is sodium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen chloride, potassium hydrogen carbonate, potassium phosphate, cesium fluoride, potassium fluoride, sodium ethoxide, sodium tert -butoxide, potassium tert -butoxide , N-methylmorpholine, N, N-dimethylaniline, 1,8-diaza bicyclo [5,4,0] -7-undecene (DBU), triethylamine and mixtures thereof Manufacturing method characterized in that. The method of claim 4, wherein A phosphorus compound is further added to the solvent. The method of claim 10, The phosphorus compound is triphenylphosphine, tri (2-methylphenyl) phosphine, bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, bisdiphenylphosphinobutane, bisdiphenylphosph Pinopentane, bisdiphenylphosphinohexane, 2,2'-bis (diphenylphosphino) -1,1'-binapryl, tri- tert -butylphosphine, tri (4-methylphenyl) phosphine, tri Cyclohexylphosphine, 1,1'-bis (diphenyl phosphino) ferrocene, racemic-2-di- tert -butylphosphino-1,1'-binaphtyl, 2- (di- tert - butylforce Pino) biphenyl, 2- (di- tert -butylphosphino) -2 '-(N, N-dimethylamino) biphenyl, 2- (di- tert -butylphosphino) -2'-methylbiphenyl, 2- (di- tert -butylphosphino) -2 ', 4', 6'-tri-isopropyl-1,1'-biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2- (di Cyclohexylphosphino) -2 '-(N, N-dimethylamino) biphenyl, 2- (dicyclohexylphosphino) -2', 6'- Dimethoxy-1,1'-biphenyl, 2- (dicyclohexylphosphino) -2 ', 6'-di-isopropoxy-1,1'-biphenyl, 2- (dicyclohexylphosphino ) -2'-methylbiphenyl, 2- (dicyclohexylphosphino) -2 ', 4', 6'-tri-iso-propyl-1,1'-biphenyl, 2- (diphenylphosphino) -2 '-(N, N-dimethylamino) biphenyl, 2'-(dicyclohexylphosphino) -2,6-dimethoxy-3-sulfonato) -1,1'-biphenyl hydrate sodium salt and Method for producing a mixture characterized in that it is selected from the group consisting of. The method of claim 4, wherein The solvent is tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, dioxane, benzene, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone , Dimethyl sulfoxide, methanol, ethanol, propanol, n-butanol, t-butanol, mixtures thereof and mixtures thereof with water. The method of claim 12, Wherein said solvent is a mixed solvent of ethanol and toluene. A pharmaceutical composition for preventing or treating cancer, comprising as an active ingredient a phenanthrene lactam derivative according to claim 1 or a pharmaceutically acceptable salt thereof.