WO2009051417A2

WO2009051417A2 - Phenanthrene lactam derivatives having anticancer activity and method for the preparation thereof

Info

Publication number: WO2009051417A2
Application number: PCT/KR2008/006110
Authority: WO
Inventors: Jung Nyoung Heo; Bum Tae Kim; Yong Ki Min; Sang Un Choi; Hyuk Lee; Sung Youn Chang; No Kyun Park; Joa Kyum Kim; Young Ha Kim; Mi Kyung Park
Original assignee: Korea Research Institute Of Chemical Technology
Priority date: 2007-10-17
Filing date: 2008-10-16
Publication date: 2009-04-23
Also published as: KR101124350B1; WO2009051417A3; KR20090039038A

Abstract

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

Description

PHENANTHRENE LACTAM DERIVATIVES HAVING ANTICANCER ACTIVITY AND METHOD FOR THE PREPARATION THEREOF

Field of the Invention

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

Background of the Invention

Phenanthrene lactam alkaloid derivatives such as aristolactam, cepharanone and piperolactam are found in Aristolochiaceae plants (see K. W. Bentley, Nat. Prod. Rep., 23, 444, 2006), and the roots and stems of such plants have been used to a folk medicine edies in China and Taiwan. Their physiological properties are reported to be inclusive of anticancer, immune suppression (see L.-H. Hu et al., Bioorg. Med. Chem. 15, 988, 2007], anti- inflammatory (see Y.-H. Lan et al., HeIv. Chim. Acta, 88, 905, 2005], antituberculosis (see J. Nat. Prod., 67, 1961, 2004), antiviral (see D. A. Berghe et al., J. Nat. Prod., 41, 463, 1978), and neuro-protection activities (see Y. C. Kim et al., Planta Med. 70, 391, 2004).

US Patent No. 4,782,077 discloses that taliscanin, a phenanthrene lactam alkaloid derivative, is effective in treating neurological disorder, Parkinson's disease and Alzheimer's disease. Further, International Patent Publication No. WO1999/06388 discloses that an Aristolochia taliscana extract comprising phenanthrene lactams such as aristolactam B and C has antimutational, antifungal and cytotoxic activation. Korea Patent No. 144742 describes that a sauristolactam compound extracted from Saururus Chinensis shows anticancer activity.

There have been reported a number of methods for synthesizing various phenanthrene lactam compounds. For example, A. Couture et al. suggest a method for synthesizing naturally occuring cepharanone A and B by conducting an aryne-mediated cyclization reaction of phosphorylated aminocarbanion generated from halobenzamide to synthesize an isoindolinone intermediate, and conducting Horner reaction and radical cyclization reaction of the intermediate {see Synlett, 1475, 1997). They have also synthesized various aristolactam derivatives in a similar way {see J. Org. Chem. 63, 3128, 1998; J. Org. Chem. 66, 8064, 2001, Eur. J. Org. Chem. 1231, 2003; and Tetrahedron 61, 665, 2005), the aristolactam derivatives having excellent activities against rat leukemic cells {see Bioorg. Med. Chem. Lett. 12, 3557, 2002). Further, L. Castedo et al. have suggested a method for preparing an aristolactam derivative by synthesizing a dibenzochromanone derivative through photo-cyclization of enamide {see Heterocycles 19, 279, 1982), intramolecular benzyne cyclization {see Tetrahedron Lett. 30, 5785, 1989) or radical cyclization, and subjecting the dibenzochromanone to functional group modification {see Tetrahedron Lett. 33, 5145, 1992; Tetrahedron 51, 4075, 1995).

However, the above-mentioned synthetic methods suffer from the problems that a number of complicated steps must be conducted under demanding reaction conditions, and thus, they are not suitable for new phenanthrene lactam derivatives.

Summary of the Invention

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

In accordance with one aspect of the present invention, there is provided a phenanthrene lactam derivative of formula (I) or pharmaceutically acceptable salt thereof:

wherein,

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen, halogen, hydroxy, C_1-6alkyl, C_1-6alkoxy or aryloxy, or R⁴ and R⁵, R⁵ and R⁶ or R⁶ and R⁷ form together with the carbon atoms to which they are attached a dioxole moiety;

R⁸ is hydrogen or C_1-6allkyl; and

R⁹ is hydrogen; Ci_-6alkyl optionally substituted with at least one substituent selected from the group consisting of C_1-6alkyl, Ci_-6alkoxy, perfluoro Ci_-6alkyl, hydroxy, halogen, C_1-6alkylamino, diC_1-6alkylamino, C_1- ₆acyloxy, Cs.gcycloalkyl, Q.sheterocycloalkyl, Cs.gheterocycloalkyl substituted with C_1-6alkyl, C_3-8heterocycloalkylcarbonyl, C_3-8heterocycloalkyl-Ci. ₆alkoxycarbonyl, C_3-8heteroaryl, aryl, and thioaryl; C_1-6alkenyl; Ci_-6alkynyl; Cj- ₆acyl; C_1-6alkoxycarbonyl; C_1-6alkylsulfonyl; C_3-8heterocycloalkyl optionally substituted with C^alkylaryl or C_1-6alkoxycarbonyl; or aryl optionally substituted with halogen, amino, C_1-6alkyl, perfluoroC_1-6alkyl or C_1-6alkoxy.

In accordance with another aspect of the present invention, there is provided a method for preparing the phenanthrene lactam derivative of formula (I), which comprises subjecting a compound of formula (II) to a reaction with a compound of formula (III) in a solvent in the presence of a palladium compound and a base:

(I)

wherein,

R¹ to R⁹ have the same meanings as defined above, X is halogen, Ci_-6alkylsulfonyloxy or arylsulfonyloxy; and M is B(OH)₂ or B(OR¹⁰)₂, R¹⁰ being C_Malkyl, or (OR¹⁰) being a heterocyclic group having a -O-B-O moiety.

In accordance with further aspect of the present invention, there is provided a pharmaceutical composition comprising the phenanthrene lactam derivative of formula (I) or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention

The present invention provides a phenanthrene lactam derivative of formula (I) and a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt of the compound of formula (I) may be prepared using any of the conventional methods in the art, and it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid and carbonic acid; a salt of an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid and acetylsalicylic acid (aspirin); a salt of an amino acid such as glycine, alanine, vaniline, isoleucine, serine, cystein, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline; a salt of sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; a metal salt formed by a reaction with an alkali metal such as sodium and potassium; or an ammonium salt.

Preferably, the compound of formula (I) according to the present invention may be a compound, wherein R⁹ is Ci_-6alkyl substituted with at least one substituent selected from the group consisting of Ci_-6alkylamino, diCj. ₆alkylamino, C_3-8heterocycloalkyl and C_3-8heterocycloalkyl substituted with Q- ₆alkyl; or C_3-8heterocycloalkyl substituted with Q_-6alkylaryl or Q- ₆alkoxycarbonyl.

The term "cycloalkyl" as used herein refers to a cycloalkyl or cycloalkenyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane or norbornanyl.

The term "heterocycloalkyl" as used herein refers to a 3- to 8-membered ring containing at least one hetero atom selected from the group consisting of S, SO, SO₂, O, N and N-oxide, e.g., pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin- 3-yl, 1 ,2-pyrazolidin-2-yl, 1 ,3-pyrazolidin-l-yl, piperidinyl, thiomoφholinyl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiazinyl, moφholinyl, l ,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-l-yl, tetrahydroazepinyl, piperazinyl and chromanyl. The heterocycloalkyl group may be optionally substituted with at least one substituent such as halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S(O)_n (n = 1 ,2,3) or -SH, but not limited thereto.

The term "aryl" as used herein comprises an aromatic group such as naphthyl and phenanthrenyl as well as a monocyclic or bicyclic aromatic group such as phenyl and substituted phenyl. The aryl group may be optionally substituted with at least one substituent such as halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S(O)n (n = 1 ,2,3) or -SH, but not limited thereto. As shown in Reaction Scheme (A), the phenanthrene lactam derivative of formula (I) according to the present invention may be prepared by treating an isoindole compound of formula (II) with a boron compound of formula (III) in a solvent in the presence of a palladium compound and a base:

Reaction Scheme (A)

(IV) wherein, R¹ to R⁹ _; X and M have the same meanings as defined above,

wherein M is preferably B(OH)₂,

According to the present invention, the phenanthrene lactam derivative of formula (I) can be prepared by letting the compound of formula (II) react with the compound of formula (III) to obtain an intermediate compound of formula (IV), and subjecting the compound of formula (IV) to a cyclization reaction. The intermediate compound of formula (IV) may be obtained with a high selectivity by controlling the reaction condition, and the desired compound of formula (I) may be obtained by isolating the obtained intermediate compound of formula (IV) and treating it with a base.

Further, as shown in Reaction Scheme (B), the phenanthrene lactam derivative of formula (I) of the present invention may be prepared by obtaining a compound of formula (Ia) as shown in the Reaction Scheme (A), and treating the compound of formula (Ia) with P '-R⁹ in the presence of a base to obtain the compound of formula (I) substituted with R⁹.

Reaction Scheme (B)

wherein, R¹ to R⁸ and R⁹ (excluding hydrogen) have the same meanings as defined above, and P¹ is a common leaving group such as halogen, methanesulfonate, trifluoromethanesulfonate and p-toluenesulfonate groups.

The compound of formula (II) used as a starting material in the present invention is commercially available, or it may be prepared by a conventional methods {see International Patent Publication No. WO2004/ 108672 and US Patent No. 6,277,847). For example, as shown in Reaction Scheme (C), when R¹, R² and R³ of the compound of formula (II) are each hydrogen, an isoindole compound of formula (Ha) may be prepared by i) refluxing the commercially available 3-bromo-2-methylbenzoic acid of formula (a) with methanol in the presence of an acid catalyst to obtain the methyl ester compound of formula (b), ii) subjecting the methyl ester compound of formula (b) to a radical reaction using N-bromosuccinimide (NB S) to selectively synthesize the benzyl bromide derivative of formula (c), and (iii) treating the compound of formula (c) with an amine in the presence of a base. Reaction Scheme (C)

wherein, R has the same meaning as defined above. Further, when R¹ is hydrogen, while R² and R³ are each methoxy, the procedure shown in Reaction Scheme (D) may be employed as follows: the compound of formula (lib) is prepared by i) repeating the procedure of Reaction Scheme (B) except for using a dimethoxy benzoic acid (d) as a starting material, which may be prepared by the method described in [G. Grethe et al., J. Org. Chem. 33, 494, 1968], to obtain the methyl ester compound of formula (e), ii) selectively introducing a bromine substituent to carbon at position 3 of the benzene ring of the methyl ester compound (e) to obtain the compound of formula (f), iii) subjecting the compound of formula (f) to a radical reaction as described in Reaction Scheme (B) to obtain the benzyl bromide compound of formula (g), and iv) treating the benzyl bromide compound of formula (g) with an amine.

Reaction Scheme (D)

NBS, ABN

wherein, R⁹ has the same meaning as defined above. Further, the compound of formula (III) is commercially available, or it may be prepared using any of the conventional methods (see [G. R. Geen et al., Tetrahedron 54, 9875-9894, 1998], [O. Baudoin et al., J. Org. Chem., 65, 9268- 9271, 2000], [J. L. Kristensen et al., Org. Synth., 81, 134-136, 2005] and [T. Ishiyam et al., J. Org. Chem., 60, 7508-7510, 1995]).

In the present invention, the compound of formula (III) is used in an amount of 1 to 3 moles, preferably 1 to 2 moles, more preferably 1.2 moles based on 1 mole of the compound of formula (II). The solvent used in the present invention may be any of which can dissolve the starting material and to not inhibit said reaction, and examples thereof include an ether solvent such as tetrahydrofuran, 1 ,2-dimethoxyethane, diethyl ether and dioxane; an aromatic hydrocarbon solvent such as benzene, toluene and xylene; amide solvent such as N,N-dimethylformamide, N,N- dimethylacetamide and N-methylpyrrolidone; an organic solvent such as dimethylsulfoxide; an alcohol solvent such as methanol, ethanol, propanol, n- butanol and t-butanol; water, and a mixture thereof. The solvent may be preferably ethanol, dioxane, toluene and a mixture thereof, more preferably a mixture of ethanol and toluene. For example, when a mixture of ethanol and toluene is used, the volume ratio of ethanol and toluene is 1 :1 to 1 : 10, preferably 1 : 1 to 1 :5, more preferably 1 :2.

The palladium compound used herein may be 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 a mixture thereof, preferably tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride or palladium hydroxide. In the present invention, the palladium compound is used in an amount of 0.001 to 0.1 mole, preferably 0.01 to 0.05 mole, more preferably 0.04 mole based on 1 mole of the compound of formula (II).

The base used herein may be an 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 bromide and potassium bromide; an alkali metal alkoxide selected from the group consisting of sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; an organic base selected from the group consisting of N-methylmorpholine, N,N- dimethylaniline, l,8-diazabicyclo[5,4,0]-7-undecene (DBU) and triethylamine; or a mixture thereof, wherein sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen chloride or potassium hydrogen carbonate is preferred, and sodium carbonate, potassium carbonate or cesium carbonate is more preferred. 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 based on 1 mole of the compound of formula (II) .

In the present invention, a phosphate compound may be further added to the reaction solution, and the phosphate compound may be triphenylphosphine, tri(2-methylphenyl)phosphine, bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, bisdiphenylphosphinobutane, bisdiphenylphosphinopentane, bisdiphenylphosphinohexane, 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl, tri- tert-butylphosphine, tri(4-methylphenyl)phosphine, tricyclohexylphosphine, 1 , 1 '-bis(diphenylphosphino)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-ter/-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-isopropyl- 1 , 1 '-biphenyl, 2-(diphenylphosphino)-2'-(N,N- dimethylamino)biphenyl, 2'-(dicyclohexylphosphino)-2,6-dimethoxy-3- sulfonato)- 1,1 '-biphenyl hydrate sodium salt or a mixture 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, wherein triphenylphosphine or 2-(dicyclohexylphosphino)-2',6'-dimethoxy-l,r- biphehyl is preferred. In the present invention, the phosphate compound is used in an amount of 0.001 to 0.4 mole, preferably 0.01 to 0.2 mole, more preferably 0.05 to 0.1 mole based on 1 mole of the compound of formula (II).

In the present invention, the above reaction may be carried out at a temperature of 30 ^°C to 200 ^°C , preferably 100^°C to 180^°C using an oil bath or microwave reactor under an inert atmosphere of nitrogen or argon {see, C O. Kappe, Angew. Chem. Int. Ed., 43, 6250-6284, 2004).

The reaction time may vary according to the selected reaction material, solvent, reaction equipment or reaction temperature. For example, in case of using an oil bath, it is preferred to stir the reaction mixture at the set reaction temperature for 1 to 20 hours, and in case of using a microwave reactor, the reaction may be conducted by stirring the mixture at the set reaction temperature for about 1 min to 1 hour.

According to the present invention, the compound of formula (I) may be easily obtained in a high yield, which effectively inhibits the growth of a cancer, and therefore useful for preventing or treating a cancer and diseases related thereto.

Therefore, the present invention provides a pharmaceutical composition comprising the phenanthrene lactam derivate of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating a cancer.

The inventive pharmaceutical composition may be formulated by adding a nontoxic and pharmaceutically acceptable carrier, supplement, excipient and the like, in the form of an oral or parental formulation such as tablets, capsules, troches, liquids and suspensions according to the conventional methods. The excipient, which may be used in the pharmaceutical composition of the present invention, may include sweetener, binder, solubilizer, solubilizing supplement, wetting agent, emulsifϊer, isotonic agent, adsorbent, disintegrant, antioxidant, preservative, lubricant, filler, and fragrance, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stein, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethyleneglycol, polyvinylidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla essence and the like.

The present invention also includes within its scope a method for treating a mammal suffering from a cancer, which comprises administering a therapeutically effective amound of the phenanthrene lactam derivative of formula (I) or pharmaceutically acceptable salt thereof to the mammal.

Depending on the conditions of the subject to be treated, including age, body weight, sex, administration route, health state, and disease severity, the dosage of the compound of formula (I) of the subject invention or pharmaceutically acceptable salt thereof may vary. Typically, the active ingredient of the present invention is administered at a dose from 0.01 to 5,000 mg per day for an adult weighing 70 kg in a single dose or in divided doses per day at constant time intervals according to the expertise of a doctor or pharmacist.

The following Examples are intended to further illustrate the present invention without limiting its scope.

Example 1: Synthesis of 5-methyldibenzo[crf_l/]indol-4(5//)-one

<Step 1> 3-Bromo-2-methylbenzoic acid (5.0 g, 23.3 mmol) was dissolved in 50 mi of methanol, and sulfuric acid (1.5 ml) was slowly added thereto. The resulting mixture was refluxed for 12 hours and cooled to room temperature. Methanol was removed under a reduced pressure, diethyl ether was added to the resulting mixture, and the resulting organic layer was sequentially washed with saturated sodium bicarbonate, water and saturated sodium solution. The organic layer was then dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure to obtain methyl 3-bromo-2- methylbenzoate (4.67 g (88%)). ¹H NMR (300 MHz, CDCl₃) δ 7.59 (d, IH, J = 7.8 Hz), 7.54 (dd, IH, J = 7.9, 0.9 Hz), 6.94 (t, IH₅ J= 7.9 Hz), 3.77 (s, 3H), 2.50 (s, 3H).

< Step 2>

Methyl 3-bromo-2-methylbenzoate (4.67 g, 20 mmol) obtained in Step 1 and 100 mi of benzene were placed into a flask, and N-bromosuccinimide (4.37 g, 25 mmol) and 2,2'-azobisisobutylnitrile (0.336 g, 2 mmol) were added thereto. The resulting mixture was refluxed for 6 hours, cooled to 0 ^°C , and filtered to remove precipitate. The resulting solution was washed successively with 10% sodium sulfite and saturated sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain methyl 3- bromo-2-(bromomethyl)benzoate (5.27 g (84%)).

¹H ΝMR (300 MHz, CDCl₃) δ 7.62 (d, IH, J = 7.9 Hz), 7.49 (dd, IH, J = 7.9, 0.9 Hz), 6.99 (t, IH, J= 7.9 Hz), 4.88 (s, 2H), 3.70 (s, 3H).

< Step 3> Methyl 3-bromo-2-(bromomethyl)benzoate (5.27 g, 17 mmol) obtained in Step 2 was dissolved in 50 mi of tetrahydrofuran, 40% methylamine aqueous solution (7.5 mi, 86 mmol) was added thereto, and the mixture was allowed to react for 2 hours at room temperature. The solvent was removed under a low pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. The resulting organic layer was washed with saturated sodium, dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 4-bromo-2-methylisoindolin-l-one (3.36 g (87%)).

¹H ΝMR (300 MHz, CDCl₃) δ 7.68 (d, IH, J = 7.9 Hz), 7.53 (dd, IH, J = 7.9, 0.9 Hz), 7.26 (t, IH, J= 7.9 Hz), 4.20 (s, 2H), 3.11 (s, 3H). <Steρ 4>

4-Bromo-2-methylisoindolin-l-one (60 mg, 0.26 mmol) obtained in Step

3, 2-formylphenylboronic acid (48 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) and cesium carbonate (259 mg, 0.80 mmol) were dissolved in a 1 mi ethanol-2 mi toluene mixture and placed in a vessel. The vessel was sealed using aseptum, and heated for 10 min at 150^°C in a microwave reactor and cooled to room temperature. The reaction mixture was filtered through a cellite column while washing with ethyl acetate, and the solvent was evaporated under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-methyldibenzoindol-4(5H)-one (62 mg (99%)).

¹H NMR (300 MHz, CDCl₃) δ 8.62-8.51 (m, 2H), 8.12-8.08 (m, IH), 7.90-7.80 (m, 2H), 7.65-7.54 (m, 2H), 7.10 (s, IH), 3.52 (s, 3H).

Example 2: Synthesis of 5,6-dimethyldibenzo[crfj/lindol-4(5//)-one

4-Bromo-2-methylisoindolin-l-one (60 mg, 0.26 mmol) obtained in Step 3 of Example 1, 2-acetylphenylboronic acid (51 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol), 2- (dicyclohexylphosphino)-2'-(N,N-dimethylamino)biphenyl (8 mg, 0.02 mmol) and cesium carbonate (259 mg, 0.80 mmol) were dissolved in a 1 m! of ethanol-2 m# toluene mixture and placed in a vessel. The vessel was sealed using a septum, and heated for 5 min at 120^°C and for 10 min at 150^°C is a microwave reactor and cooled to room temperature. The reaction mixture was filtered through a cellite column while washing with ethyl acetate, and the solvent was evaporated under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5,6- dimethyldibenzoindol-4(5H)-one (52 mg (77%)).

¹H NMR (300 MHz, CDCl₃) δ 8.56-8.53 (m, 2H), 8.08-8.05 (m, 2H), 7.79-7.76 (m, IH), 7.65-7.59 (m, 2H), 3.75 (s, 3H), 2.84 (s, 3H).

Example 3: Synthesis of 3-methoxydibenzo[c./_Λ/]indol-4(5//)-one <Step 1>

The procedure of Step 2 of Example 1 was repeated except for using methyl 3-bromo-6-methoxy-2-methylbenzoate as a starting material instead of methyl 3-bromo-2-methylbenzoate to obtain methyl 3-bromo-2-(bromomethyl)- 6-methoxybenzoate (85%).

¹H NMR (200 MHz, CDCl₃) δ 7.57 (d, IH, J= 9.0 Hz), 6.80 (d, IH, J= 9.0 Hz), 4.57 (s, 2H), 3.97 (s, 3H), 3.83 (s, 3H).

Methyl 3-bromo-2-(bromomethyl)-6-methoxybenzoate (620 mg, 1.8 mmol) obtained in Step 1 was dissolved in 10 mi of tetrahydrofuran in a flask, ammonium hydroxide (1.3 mi, 9.2 mmol) was added thereto, and the mixture was stirred at room temperature for 48 hours. 30 mi of water was added to the reacted solution, and the resulting solution was cooled to 0^°C . The resulting precipitate was filtered to obtain 4-bromo-7-methoxyisoindolin-l-one (349 mg (78%)).

¹H NMR (200 MHz, CDCl₃) δ 7.60 (d, IH, J= 9.0 Hz), 6.85 (d, 2H, J= 9.0 Hz), 4.30 (s, 2H), 3.98 (s, 3H).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-7-methoxyisoindolin-l-one obtained in Step 3 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (72%).

¹H NMR (300 MHz, CDCl₃) δ 8.68-8.66 (m, IH), 8.52-8.49 (m, IH), 7.89-7.86 (m, IH), 7.59-7.54 (m, 2H), 7.45 (s, IH), 7.27 (s, IH), 4.19 (s, 3H).

Example 4; Synthesis of 3-methoxy-5-methyldibenzo[crf,/]iiidol-4(5//)-oiie

4-Bromo-7-methoxyisoindolin-l-one (151 mg, 0.63 mmol) was dissolved in 10 mi of tetrahydrofuran, sodium hydride (16 mg, 0.63 mmol) and iodomethane (37.8 μi, 0.75 mmol) were added thereto, and the mixture was stirred at room temperature for 24 hours. The solvent was removed under a reduced pressure, and the resulting solution was diluted with water and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 4-bromo-7-methoxy-2- methylisoindolin-1-one (111 mg (69%)).

¹H NMR (200 MHz, CDCl₃) δ 7.54 (d, IH, J= 8.8 Hz), 6.81 (d, IH, J = 8.6 Hz), 4.21 (s, 2H), 3.94 (s, 3H), 3.15 (s, 3H).

<Step 2> The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-7-methoxy-2-methylisoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (68%).

¹H NMR (200 MHz, CDCl₃) δ 8.58 (d, IH, J = 9.0 Hz), 8.49-8.42 (m, IH), 7.90-7.85 (m, IH), 7.68-7.53 (m, IH), 7.37 (d, IH, J = 8.6 Hz), 4.22 (s, 3H), 3.51 (s, 3H).

Example 5: Synthesis of l,2-dimethoxydibenzo[c</_?/]indol-4(5//)-one <Step 1>

Methyl 4,5-dimethoxy-2-methylbenzoate (11.3 g, 53.8 mmol) was dissolved in 150 mi of chloroform in a flask, and the resulting solution was cooled to 0^°C followed by slowly adding bromide (2.8 mi, 53.8 mmol) dropwise. The mixture was stirred at 0 ^°C for 4 hours. The resulting mixture was washed with 10% sodium sulfite and saturated sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain methyl 3-bromo-4,5-dimethoxy-2-methylbenzoate (14.3 g (92%)).

¹H NMR (300 MHz, CDCl₃) δ 7.36 (s, IH), 3.90 (s, 6H), 3.89 (s, 3H), 2.61 (s, 3H) 1³C NMR (125 MHz, CDCl₃) 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): theoretical value for C_nH₁₃BrO₄- 288(m/z, M⁺), real value- 288 (M⁺, 93). 272.9 (16), 258.0 (51), 242.8 (19), 229.8 (66), 212.9 (44).

Methyl 3-bromo-4,5-dimethoxy-2-methylbenzoate (24.0 g, 86 mmol) obtained in Step 1 and 200 mi of benzene were placed into a flask, and N- bromosuccinimide (18.0 g, 103 mmol) and 2,2'-azobisisobutylnitrile (1.4 g, 8.6 mmol) were added thereto followed by refluxing for 6 hours. The reacted solution was cooled to 0°C , and filtered to remove precipitate. The resulting mixture was washed with 10% sodium sulfite and saturated sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain methyl 3-bromo-2-(bromomethyl)-4,5- dimethoxybenzoate (29.1 g (92%)).

¹H ΝMR (300 MHz, CDCl₃) δ 7.26 (s, IH), 5.16 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H)

¹³C ΝMR (125 MHz, CDCl₃) 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): theoretical value for CnH₁₂Br₂O₄- 365.91(m/z, M⁺), real value- 365.8 (M⁺, 31), 365.8 (16), 288.9 (100), 272.9 (4), 256.9 (21), 244.7 (8).

<Step 3> The procedure of Step 2 of Example 5 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 as a starting material instead of methyl 6-methoxy-3-bromo-2- (bromomethyl)benzoate to obtain 4-bromo-5,6-dimethoxyisoindolin-l-one (92%).

¹H NMR (300 MHz, OMSO-d₆) δ 8.66 (s, IH), 7.28 (s, IH), 4.18 (s, 2H), 3.88 (s, IH), 3.78 (s, IH) 1³C NMR (125 MHz, DMSO-^₅) δ 169.1, 153.8, 148.7, 136.8, 129.3, 112.2, 106.0, 60.3, 56.4, 45.1.

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxyisoindolin-l-one obtained in Step 3 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (81%).

¹H NMR (300 MHz, OMSO-d₆) δ 10.84 (s, IH), 9.11 (d, 2H, J = 8.9 Hz), 7.94 (d, IH, J= 7.9 Hz), 7.85 (s, IH), 7.58-7.54 (m, 2H), 7.13 (s, IH), 4.03 (s, 3H), 4.02 (s, 3H)

¹³C NMR (125 MHz, OMSO-d₆) 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): theoretical value for C₁₇H₁₃NO₃- 21%m/z), real value- 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 l-hydroxy-2-methoxydibenzo[a/,/]indol-4(5//)-oiie l,2-Dimethoxydibenzoindol-4(5H)-one (279 mg, 1 mmol) and lithium chloride (420 mg, 10 mmol) were dissolved in 3 mi of dimethylformamide followed by stirring. The solution was reacted at 180°C for 48 hours, and then cooled to room temperature followed by adding 2 mi of water thereto to terminate the reaction. The resulting solution was extracted with ethyl acetate, the obtained organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. The resulting residue was subjected to silica gel column chromatography and to recrystalization with the mixture of ethyl acetate and hexane to obtain the title compound (175 mg (66%)). ¹H NMR (300MHz, OMSO-d₆) δ 10.65 (s, IH), 9.26-9.23 (m, IH), 7.93-7.90 (m, IH), 7.75 (s, IH), 7.54-7.50 (m, IH), 7.11 (s, IH), 4.03 (s, 3H) 1³C NMR (125 MHz, DMSO-^) 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): theoretical value for C₁₆H₁₁NO₃- 265(m/z), real value- 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: Synthesis of l,2,9-trimethoxydibenzo[c</_t/]indol-4(5/0~one

The procedure of Step 4 of Example 1 was repeated except for using A- bromo-5,6-dimethoxyisoindolin-l-one as a starting material instead of 4-bromo- 2-methylisoindolin-l-one, and 5-methoxy-2-formylphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (83%).

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

¹³C NMR (125 MHz, DMSO-^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): theoretical value for C₁₈H₁₅NO₄- 309(m/z), real value- 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 l,2-dimethoxy-5-methyldibenzo[c./j/]indol-4(5/7)- one <Steρ 1>

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate to obtain 4-bromo-5,6-dimethoxy-2-methylisoindolin- 1-one (98%).

¹H NMR (300 MHz, CDCl₃) δ 7.26 (s, IH), 4.23 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.20 (s, 3H) ¹³C NMR (125 MHz, CDCl₃) 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): theoretical value for C₁₁H₁₂BrNO₃- 285(m/z), real value- 284.9 (M⁺, 95), 286.9 (96), 255.9 (100), 206.0 (42).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-methylisoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (86%).

¹H NMR (300 MHz, CDCl₃) δ 7.88 (s, IH), 7.81 (m, IH), 7.77 (s, IH), 7.56 (m, 2H),6.96 (s, IH), 4.10 (d, 6H), 3.47 (s, 3H)

¹³C NMR (125 MHz, CDCl₃) 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): theoretical value for Ci₈H₁₆NO₄- 293.32(m/z), real value- 293.0 (M⁺, 100) 278.0 (12), 250.0 (27), 235.0 (11), 222.0 (9).

Example 9: Synthesis of l-hydroxy-2-methoxy-5-methyldibenzo[c-/,_l/]indol- 4(5//)-one (Λ'-methyl aristolactam)

The procedure of Example 6 was repeated except for using 1,2- dimethoxy-5-methyldibenzoindol-4(5H)-one obtained in Example 8 as a starting material instead of l,2-dimethoxydibenzoindol-4(5H)-one to obtain the title compound (70%).

¹H NMR (300MHz, OMSO-d₆) δ 9.28 (d, IH, J = 6.0 Hz), 7.94 (d, IH, J = 3.0 Hz), 7.79 (s, IH), 7.58-7.54 (m, 2H), 7.30 (s, IH), 4.05 (s, 3H), 3.04 (s, 3H) ¹³C NMR (125 MHz, DMSO-^₅) 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): theoretical value for C₁₇H₁₃NO₃- 279.29(m/z), real value- 279.0 (M⁺, 100), 264.0 (35), 236.0 (15), 180.0 (6).

Example 10: Synthesis of 2-hydroxy-l-methoxy-5- methyldibenzo [cdj] indol-4(5//)-one l,2-Dimethoxy-5-methyldibenzoindol-4(5H)-one (124 mg, 0.42 mmol), bromic acid (47 fd, 0.423 mmol) and 3 mi of acetic acid were placed into a flask, and the mixture was reacted at 100°C for 6 hours. The resulting solution was cooled to room temperature and water was added thereto to terminate the reaction. The resulting solution was extracted with ethyl acetate, the obtained organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain the title compound (13 mg (11%)).

¹H NMR (300MHz, OMSO-d₆) δ 9.13 (d, IH, J = 4.7 Hz), 7.95 (d, IH, J = 3.0 Hz), 7.63 (s, IH) 7.58 (m, 2H), 7.28 (s, IH), 4.03 (s, 3H), 3.17 (s, 3H) 1³C NMR (125 MHz, DMSO-^₅) δ 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): theoretical value for C₁₇H₁₃NO₃- 279.29(m/z), real value- 279.0 (M⁺,100) 264.0 (48), 236.0 (18), 180.0 (10).

Example 11: Synthesis of 5-methyl-l,2,8,9-tetramethoxydibenzo[c</_Λ/]indol- 4(5/7)-one

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-methylisoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin- 1 -one, and 2-formyl-4,5-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (80%).

¹H NMR (300MHz, DMSO-^₅) δ 8.70 (s, IH), 7.68 (s, IH), 7.15 (s, IH), 6.80 (s, IH), 4.09 (s, 3H), 4.07 (s, 3H), 4.03 (s, 3H), 4.02 (s, 3H), 3.41 (s, 3H).

Example 12: Synthesis of 17,18-dimethoxy-13-methyl-5,7-dioxa-13- azapentacyclo[10.6.1.0^{2 10}.0⁴'⁸.0^{15 19}]nonadeca-l,3,8,10,12(19),15,17-heptaen- 14-one

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-methylisoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and 6-formylbenzo[l,3]dioxol-5-ylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (11%).

¹H NMR (300MHz, DMSO-^₅) δ 8.69 (s, IH), 7.78 (s, IH), 7.22 (s, IH), 6.91 (s,

IH), 6.11 (s, 2H), 4.09 (s, 3H), 4.06 (s, 3H), 3.47 (s, 3H).

Example 13: Synthesis of l,2-dimethoxy-5,6-dimethyldibenzo[c</,/]indol-

4(5H)-one

The procedure of Example 2 was repeated except for using 4-bromo-5,6- dimethoxy-2-methylisoindolin-l-one as a starting material instead of 4-bromo- 2-methylisoindolin- 1 -one to obtain the title compound (44%).

¹H NMR (300MHz, DMSO-^₅) δ 9.34 (dd, IH, J = 8.0 Hz, J = 1.5 Hz), 8.06 (dd,

IH, J = 7.9 Hz, J = 1.6 Hz), 7.78 (s, IH), 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[c</_j/]indol-4(5//)- one

The procedure of Step 4 of Example 1 was repeated except for using 2- formyl-4-benzyloxyphenylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (94%).

¹H NMR (300 MHz, CDCl₃) δ 8.48 (d, IH, J= 8.0 Hz), 8.43 (d, IH, J= 8.8 Hz), 7.80 (t, IH, J= 7.5 Hz), 7.53-7.36 (m, 5H), 7.25-7.24 (m, 2H), 7.02 (s, IH) 5.24 (s, 2H), 3.50 (s, 3H).

Example 15: Synthesis of 8-benzyloxy-l,2-dimethoxy-5- methyldibenzo [cdj\ indol-4(5//)-one The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-methylisoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin- 1 -one, and 2-formyl-4-benzyloxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (96%).

¹H NMR (300 MHz, CDCl₃) δ 9.12 (d, IH, J = 9.09 Hz), 7.73 (s, IH), 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 l,2-dimethoxy-8-hydroxy-5- methyldibenzo [cdj\ indol-4(5//)-one The compound obtained in Example 15 was dissolved in methanol in a flask. 10% Pd/C was added thereto, and the resulting mixture was stirred at room temperature for 3 hours after connecting a hydrogen balloon thereto. After completion of the reaction, the resulting solution was filtered with a cellite and distilled under a reduced pressure to obtain the title compound (99%).

¹H NMR (300 MHz, DMSO-J₆) δ 8.90 (d, IH, J = 9.0 Hz), 7.75 (s, IH), 7.25 (d, IH, J = 2.7 Hz), 7.18 (s, IH), 7.03 (dd, IH, J = 9.0, 2.7 Hz), 4.00 (s, 3H), 3.97 (s, 3H), 3.34 (s, 3H).

Example 17: Synthesis of 5-benzyl-l,2-dimethoxydibenzo[c./,/lindol-4(5.fl)- one

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2-

(bromomethyl)benzoate, and benzylamine instead of methylamine to obtain 2- benzyl-4-bromo-5,6-dimethoxyisoindolin- 1 -one (99%). ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.26 (m, 6H), 4.79 (s, 2H), 4.12 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H).

<Steρ 2> The procedure of Step 4 of Example 1 was repeated except for using 2- benzyl-4-bromo-5,6-dimethoxyisoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (75%).

¹H NMR (300 MHz, CDCl₃) δ 9.22-9.19 (m, IH), 7.85 (s, IH), 7.74-7.71 (m, IH), 7.54-7.51 (m, 2H), 7.24-7.39 (m, 5H), 6.87 (s, IH), 5.17 (s, 2H), 4.11 (s, 3H), 4.08 (s, 3H).

Example 18: Synthesis of 5-benzyl-l,2,8,9-tetramethoxydibenzo[crf_j/]indol- 4(SH)-one

The procedure of Step 4 of Example 1 was repeated except for using 2- benzyl-4-bromo-5,6-dimethoxyisoindolin-l-one obtained in Step 1 of Example 17 as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and 2- formyl-4,5-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (56%).

¹H NMR (300MHz, CDCl₃) δ 8.68 (s, IH), 7.74 (s, IH), 7.34-7.21 (m, 5H), 7.04 (s, IH), 6.78 (s, IH), 5.09 (s, 2H), 4.08-3.96 (m, 12H).

Example 19: Synthesis of l,2-dimethoxy-5-ethyldibenzo[c./_ϊ/]indol-4(5//)- one

(bromomethyl)benzoate, and ethylamine instead of methylamine to obtain 4- bromo-5,6-dimethoxy-2-ethylisoindolin- 1 -one (80%). ¹H NMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 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 = 12 Hz).

<Step 2> The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-ethylisoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (71%).

¹H NMR (300 MHz, CDCl₃) δ 9.23-9.20 (m, IH), 7.84-7.79 (m, 2H), 7.59-7.54 (m, 2H), 7.01 (s, IH), 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 l,2-dimethoxy-5-isopropyldibenzo[α/,/]indol- 4(5#)-one <Step 1>

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and isopropylamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-isopropylisoindolin-l-one (88%).

¹H NMR (300 MHz, CDCl₃) δ 7.25 (s, IH), 4.56 (hep, IH, J= 6.9 Hz), 4.11 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 1.23 (d, 6H, J= 6.9 Hz).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-isopropylisoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (62%).

¹H NMR (300 MHz, CDCl₃) δ 9.24-9.20 (m, IH), 7.83-7.78 (m, 2H), 7.59-7.54 (m, 2H), 7.15 (s, IH), 4.93 (heptet, IH, J = 6.9 Hz), 4.09 (s, 3H), 4.06 (s, 3H), 1.63 (d, 6H, J= 6.9 Hz). Example 21: Synthesis of l,2-dimethoxy-5-(2- methoxy)ethy ldibenzo [cdj\ indol-4(5/-0-one

<Steρ 1> The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and 2-methoxyethylamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(2-methoxy)ethylisoindolin- 1 -one (88%).

¹H NMR (300 MHz, CDCl₃) δ 7.11 (s, IH), 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> The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(2-methoxy)ethylisoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (66%).

¹H NMR (300 MHz, CDCl₃) δ 9.23-9.20 (m, IH), 7.85-7.72 (m, 2H), 7.80-7.54 (m, 2H), 7.11 (s, IH), 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: Synthesis of l,2-dimethoxy-5-propargy ldibenzo [c</,y]indol- 4(5H)-one

<Steρ 1>

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of

Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and propargylamine instead of methylamine to obtain

4-bromo-5,6-dimethoxy-2-propargylisoindolin- 1 -one (98%).

¹H NMR (300 MHz, CDCl₃) δ 7.34 (s, IH), 4.44 (d, 2H, J = 2.5 Hz), 4.36 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.31 (t, IH, J= 2.5 Hz).

The procedure of Step 4 of Example 1 was repeated except for using A- bromo-5,6-dimethoxy-2-propargylisoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (53%).

¹H NMR (300 MHz, CDCl₃) δ 9.28-9.26 (m, IH), 8.28-8.26 (m, IH), 7.57-7.48 (m, 3H), 7.07 (s, IH), 4.11 (s, 3H), 4.05 (s, 3H), 3.92 (s, 2H), 1.25 (s, IH).

Example 23: Synthesis of 5-(cyclopropylmethyl)-l,2- dimethoxydibenzo [cd,f\ indol-4(5//)-one

<Step 1> The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and cyclopropylmethaneamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-propargylisoindolin-l-one (98%).

¹H NMR (300 MHz, CDCl₃) δ 7.05 (s, IH), 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, IH), 0.55-0.45 (m, 4H).

<Step 2> The procedure of Step 4 of Example 1 was repeated except for using A- bromo-5,6-dimethoxy-2-propargylisoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (53%).

Example 24: Synthesis of l,2-dimethoxy-5-phenethyldibenzo[c</_t/]indol- 4(5H)-one <Step 1>

Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and phenethylamine instead of methylamine to obtain

4-bromo-5,6-dimethoxy-2-phenethylisoindolin- 1-one (66%).

¹H NMR (300 MHz, CDCl₃) 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).

<Steρ 2>

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-phenethylisoindolin- 1-one as a starting material instead of 4-bromo-2-methylisoindolin- 1-one to obtain the title compound (66%).

¹H NMR (300 MHz, CDCl₃) δ 9.18-9.14 (m, IH), 7.71-7.67 (m, 2H), 7.53-7.48 (m, 2H), 7.26-7.15 (m, 5H), 6.73 (s, IH), 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 l,2-dimethoxy-5-(pyridin-4- ylmethyl)dibenzo [cdj] indol-4(5/-0-one

(bromomethyl)benzoate, and 4-(aminomethyl)pyridine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(pyridin-4-ylmethyl)isoindolin- 1-one (82%).

¹H NMR (300 MHz, CDCl₃) δ 8.58 (dd, 2H, J = 6.6, 4.2 Hz), 7.39 (s, IH), 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).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(pyridin-4-ylmethyl)isoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (58%).

¹H NMR (300 MHz, CDCl₃) δ 9.24 (t, IH, J = 3.6 Hz), 8.55 (d, IH, J= 6.0 Hz), 7.87 (s, IH), 7.75-7.72 (m, IH), 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 l,2-dimethoxy-5-(thiophen-3- ylmethyl)dibenzo [cdj] indol-4(5//)-one

Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and 3-(aminomethyl)thiophene instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(thiophen-3-ylmethyl)isoindolin- 1 -one

(98%).

¹H NMR (300 MHz, CDCl₃) δ 7.36 (s, IH), 7.24 (d, IH, J = 1.1 Hz), 7.05-7.04 (m, IH), 6.99-6.96 (m, IH), 4.96 (s, 2H), 4.20 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(thiophen-3-ylmethyl)isoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (63%).

¹H NMR (300 MHz, CDCl₃) δ 9.23-9.20 (m, IH), 7.83-7.79 (m, 2H), 7.60-7.54 (m, 2H), 7.21 (s, IH), 7.12 (s, IH), 7.00-6.91 (m, 2H), 5.32 (s, 2H), 4.07 (s, 3H), 3.86 (s, 3H).

Example 27: Synthesis of l,2-dimethoxy-5-(4- methoxypheny l)dibenzo [cd,f\ indol-4(5//)-one <Steρ 1>

Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and 4-methoxyaniline instead of methylamine to obtain

4-bromo-5,6-dimethoxy-2-(4-methoxyphenyl)isoindolin- 1 -one (90%).

¹H NMR (300 MHz, CDCl₃) δ 7.65-7.48 (m, 4H), 7.01 (s, IH), 4.20 (s, 2H),

4.18 (s, 3H), 4.14 (s, 3H), 3.90 (s, IH).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(4-methoxyphenyl)isoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (86%).

¹H NMR (300 MHz, CDCl₃) δ 9.26-9.24 (m, IH), 7.88 (s, IH), 7.77-7.64 (m, IH), 7.65-7.48 (m, 4H), 7.11-7.09 (m, 2H), 7.01 (s, IH), 4.18 (s, 3H), 4.14 (s, 3H), 3.90 (s, IH).

Example 28: Synthesis of 5-(4-f-butylphenyl)-l,2- dimethoxydibenzo[α/,/]indol-4(5//)-one <Step 1>

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and 4-t-butylaniline instead of methylamine to obtain 4-bromo-2-(4-*-butylphenyl)-5,6-dimethoxyisoindolin- 1 -one (89%).

¹H NMR (300 MHz, CDCl₃) δ 7.74 (d, 2H, J = 8.9 Hz), 7.45 (d, 2H, J = 8.9 Hz), 7.40 (s, IH), 4.68 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.26 (s, 9H).

<Step 2> The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-2-(4-t-butylphenyl)-5,6-dimethoxyisoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (70%).

¹H NMR (300 MHz, CDCl₃) δ 9.28-9.25 (m, IH), 7.90 (s, IH), 7.90-7.88 (m, IH), 7.77-7.76 (m, 4H), 7.24-7.22 (m, 2H), 7.11 (s, IH), 4.00 (s, 3H), 3.99 (s, 3H), 1.34 (s, 9H).

Example 29: Synthesis of l,2-dimethoxy-5-(2- morpholinoethyl)dibenzo [cdj\ indol-4(5//)-one

(bromomethyl)benzoate, and 2-morpholinoethaneamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(moφholinoethyl)isoindolin-l-one (98%).

¹H NMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 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).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(moφholinoethyl)isoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (42%).

¹H NMR (300 MHz, CDCl₃) δ 9.23 (t, IH, J = 5.2Hz), 7.84-7.80 (m, 2H), 7.60- 7.54 (m, 2H), 7.04 (s, IH), 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: Synthesis of l,2,9-trimethoxy-5-(2- morpholinoethyl)dibenzo[a/,/]indol-4(5//)-°^ne The procedure of Step 2 of Example 29 was repeated except for using 2- formyl-5-methoxyphenylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (37%).

¹H NMR (300 MHz, CDCl₃) δ 8.79 (d, IH, J = 2.5 Hz), 7.79 (s, IH), 7.73 (d, IH, J = 8.7 Hz), 7.23 (dd, IH, J = 8.7 Hz, J = 2.6 Hz), 6.99 (s, IH), 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: Synthesis of l,2,8,9-tetramethoxy-5-(2- morpholinoethyl)dibenzo[c</_t/]indol-4(5//)-one

The procedure of Step 2 of Example 29 was repeated except for using 2- formyl-5,6-dimethoxyphenylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (51%).

¹H NMR (300 MHz, CDCl₃) δ 8.76 (s, IH), 7.74 (s, IH), 7.21 (s, IH), 6.94 (s, IH), 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: Synthesis of 17,18-dimethoxy-13-(2-(morpholino-4-yl)ethyl)- 5,7-dioxa-13-azapentacyclo[10.6.1.0^{2 10}.0⁴'⁸.0^{15 19}]nonadeca- l,3,8,10,12(19),15,17-heptaen-14-one

The procedure of Step 2 of Example 29 was repeated except for using 6- formylbenzo[l,3]dioxol-5-ylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (60%). ¹H NMR (300 MHz, CDCl₃) δ 8.79 (d, IH, J = 8.7 Hz), 7.64 (s, IH), 7.10 (d, IH, J = 8.7 Hz), 7.03 (s, IH), 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 l,2-dimethoxy-5-(2-(piperidin-l- yl)ethyl)dibenzo[α/,/]indol-4(5Η)-one

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and 2-(piperidin-l-yl)ethaneamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(2-(piperidin-l- yl)ethyl)isoindolin-l-one (99%).

¹H NMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 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> The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(2-(piperidin-l-yl)ethyl)isoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (77%).

¹H NMR (300 MHz, CDCl₃) δ 9.22 (t, IH, J = 6.3 Hz), 7.84-7.79 (m, 2H), 7.60- 7.53 (m, 2H), 7.08 (s, IH), 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: Synthesis of l,2,9-trimethoxy-5-(2-(piperidin-l- yl)ethyl)dibenzo[c</,/]indol-4(5/0-one

The procedure of Step 2 of Example 33 was repeated except for using 2- formyl-5-methoxyphenylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (40%). ¹H NMR (300 MHz, CDCl₃) δ 8.79 (d, IH, J = 2.6 Hz), 7.80 (s, IH), 7.74 (d, IH, J = 8.7 Hz), 7.22 (dd, IH, J = 10.7 Hz, J = 8.0 Hz), 7.06 (s, IH), 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: Synthesis of l,2,8,9-tetramethoxy-5-(2-(piperidin-l- yl)ethyl)dibenzo [cd,f\ indol-4(5/0-one

The procedure of Step 2 of Example 33 was repeated except for using 2- formyl-5,6-dimethoxyphenylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (67%).

¹H NMR (300 MHz, CDCl₃) δ 8.77 (s, IH), 7.76 (s, IH), 7.23(s, IH), 7.00 (s, IH), 4.11-4.05 (m, 14H), 2.72 (t, 2H, J = 7.4 Hz), 2.55 (s, IH), 1.65-1.57 (m, 4H), 1.49-1.45 (m, 2H).

Example 36: Synthesis of 17,18-dimethoxy-13-(2-(piperidin-l-yl)ethyl)-5,7- dioxa-13-azapentacyclo[10.6.1.0^{2 10}.0⁴'⁸.0¹⁵'¹⁹]nonadeca-l,3,8,10,12(19),15,17- heptaen-14-one

The procedure of Step 2 of Example 33 was repeated except for using 6- formylbenzo[l,3]dioxol-5-ylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (42%).

¹H NMR (300 MHz, CDCl₃) δ 8.81 (d, IH, J = 8.7 Hz), 7.70 (s, IH), 7.13 (d, 1H, J=8.7 Hz), 7.10 (s, IH), 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-l,2-dimethoxy-5-(2-(piperidin-l- yl)ethyl)dibenzo[α/,y]indol-4(5//)-one The procedure of Step 2 of Example 33 was repeated except for using A- chloro-2-formylphenylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (47%).

¹H NMR (300 MHz, CDCl₃) δ 9.11 (d, IH, J = 8.9 Hz), 7.76 (s, 2H), 7.45 (dd, IH, J = 8.8 Hz, 2.2 Hz), 6.94 (s, IH), 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 l,2-dimethoxy-8-fluoro-5-(2-(piperidin-l- yl)ethyl)dibenzo [cdj\ indol-4(5//)-one The procedure of Step 2 of Example 33 was repeated except for using A- fluoro-2-formylphenylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (52%).

¹H NMR (300 MHz, CDCl₃) δ 9.19 (dd, IH, J = 9.9, 2.7 Hz), 7.76 (s, IH), 7.45 (dd, IH, J = 9.1, 6.0 Hz), 7.29-7.23 (m, IH), 6.99 (s, IH), 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 l,2-dimethoxy-6-methyl-5-(2-(piperidin-l- yI)ethyl)dibenzo[c</*/]indol-4(5#)-one

The procedure of Example 2 was repeated except for using 4-bromo-5,6- dimethoxy-2-(2-(piperidin-l-yl)ethyl)isoindolin-l-one obtained in Step 1 of Example 33 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (23%).

¹H NMR (300 MHz, CDCl₃) δ 9.33 (dd, IH, J = 6.5, 1.6 Hz), 8.09 (dd, IH, J = 7.7, 1.59 Hz), 8.07 (s, IH), 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; Synthesis of 5-(2-(dimethylamino)ethyl)-l,2,8- trimethoxydibenzo[α/,/]indoI-4(5//)-one <Steρ 1>

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and N,N-dimethylethylenediamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(2-

(dimethylamino)ethyl)isoindolin- 1 -one (98%).

¹H ΝMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 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).

<Steρ 2>

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(2-(dimethylamino)ethyl)isoindolin- 1 -one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and 2-formyl-5-methoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (36%).

¹H ΝMR (300 MHz, CDCl₃) δ 8.77 (d, IH, J = 2.6 Hz), 7.78 (s, IH), 7.73 (d, IH, J= 8.7 Hz), 7.26 (dd, IH, J= 8.7, 2.7 Hz), 6.98 (s, IH), 4.11-4.04 (m, 8H), 3.98 (s, 3H), 2.71 (t, 2H, J= 13 Hz), 2.36 (s, 6H).

Example 41: Synthesis of 5-(2-(dimethylamino)ethyl)-l,2,8,9- tetramethoxydibenzo [cdj] indol-4(5//)-one

The procedure of Step 2 of Example 40 was repeated except for using 2- formyl-5,6-dimethoxyphenylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (42%).

¹H ΝMR (300 MHz, CDCl₃) δ 8.79 (s, IH), 7.77 (s, IH), 7.25 (s, IH), 6.99 (s, IH), 4.12-4.04 (m, 14H), 2.70 (t, 2H, J- 7.2 Hz), 2.37 (s, 6H).

Example 42: Synthesis of 17,18-dimethoxy-13-(2-(dimethylamino)ethyl)- S^-dioxa-lS-azapentacycloIlO.ό.l.O^^.O^.O^'^Jnonadeca- l,3,8,10,12(19),15,17-heptaen-14-one

The procedure of Step 2 of Example 40 was repeated except for using 6- formylbenzo[l,3]dioxol-5-ylboronic acid as a starting material instead of 2- formylphenylboronic acid to obtain the title compound (18%).

¹H NMR (300 MHz, CDCl₃) δ 8.80 (d, IH, J = 8.7 Hz), 7.70 (s, IH), 7.11 (d,

IH, J = 8.7 Hz), 7.04 (s, IH), 6.17 (s, 2H), 4.08-4.04 (m, 8H), 2.70 (t, 2H, J =

7.1 Hz), 2.35 (s, 6H).

Example 43: Synthesis of 5-(2-(pyrrolidin-l-yl)ethyl)-l,2,8,9- tetramethoxy dibenzo [cdj] indol-4(5//)-one

Example 5 as a starting material instead of methyl 3-bromo-2-

(bromomethyl)benzoate, and 2-(pyrrolidin-l-yl)emaneamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(2-(pyrrolidin-l- yl)ethyl)isoindolin-l-one (96%).

¹H NMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 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>

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(2-(pyrrolidin- 1 -yl)ethyl)isoindolin- 1 -one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and

2-foπnyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (25%).

¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, IH), 7.77 (s, IH), 7.24 (s, IH), 7.01 (s, IH), 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 l,2-dimethoxy-5-(3-methylbutan-2- yl)dibenzo [cd,f\ indol-4(5//)-one

<Steρ 1> The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and 3-methylbutane-2-amine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(3-methylbutan-2-yl)isoindolin- 1 -one (87%).

¹H NMR (300 MHz, CDCl₃) δ 7.35 (s, IH), 4.14 (s, 2H), 4.13-4.07 (m, IH), 3.93 (d, 6H, J = 5.4 Hz), 1.90-1.83 (m, IH), 1.30 (d, 3H, J = 6.8 Hz), 1.04 (d, 3H, J = 6.6 Hz), 0.86 (d, 3H, J = 6.7 Hz).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(3-methylbutan-2-yl)isoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound ( 16%).

¹H NMR (300 MHz, CDCl₃) δ 9.24 (dd, IH, J = 5.3, 1.6 Hz), 7.82 (d, IH, J = 4.5 Hz), 7.80 (s, IH), 7.58-7.54 (m, 2H), 7.12 (s, IH), 4.30-4.25 (m, IH), 4.11 (s, 3H), 4.07 (s, 3H), 2.46-2.40 (m, IH), 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)-l,2- dimethoxydibenzo [cdj] indol-4(5//)-one

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and N,N-diethylaminoethaneamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(2-

(diethylamino)ethyl)isoindolin- 1 -one (89%) .

¹H ΝMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 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).

The procedure of Step 4 of Example 1 was repeated except for using A- bromo-5,6-dimethoxy-2-(2-(diethylamino)ethyl)isoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (62%).

¹H ΝMR (300 MHz, CDCl₃) δ 9.24-9.21 (m, IH), 7.85 7.82 (m, IH), 7.79 (s, IH), 7.60-7.55 (m, 2H), 7.07 (s, IH), 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: Synthesis of 5-(2-(diethylamino)ethyl)-l,2,8,9- tetramethoxydibenzo [c-/j/]indol-4(5/-f)-one

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(2-(diethylamino)ethyl)isoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and 2-formyl-5,6- dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (42%).

¹U NMR (300 MHz, CDCl₃) δ 8.79 (s, IH), 7.77 (s, IH), 7.24 (s, IH), 6.98 (s, IH), 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= 7.1Hz).

Example 47: Synthesis of 5-(3-(dimethylamino)-2,2-dimethylpropyl)-l,2- dimethoxydibenzo [cd,J] indol-4(5//)-one <Step 1>

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and N,N,2,2-tetramethylpropane-l,3-diamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(3-(dimethylamino)-2,2- dimethylpropyl)isoindolin- 1 -one (81%).

¹H ΝMR (300 MHz, CDCl₃) δ 7.19 (s, IH), 4.23 (s, 2H), 3.81 (s, 6H), 3.36 (s, 2H), 2.23 (s, 6H), 2.21 (s, 2H), 0.91 (s, 6H).

<Steρ 2>

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(3-(dimethylamino)-2,2-dimethylpropyl)isoindolin-l- one obtained in Step 1 as a starting material instead of 4-bromo-2- methylisoindolin-1-one to obtain the title compound (22%).

¹U ΝMR (300 MHz, CDCl₃) δ 9.24 (dd, IH, J = 5.5, 1.6 Hz ), 7.86-7.83 (m, IH), 7.81 (s, IH), 7.58-7.55 (m, 2H), 7.11 (s, IH), 4.12 (s, IH), 4.08 (s, IH), 3.85 (s, IH), 2.38 (s, IH), 2.34 (s, IH), 1.07 (s, IH).

Example 48: Synthesis of 5-(3-(dimethylamino)-2,2-dimethylpropyl)- 1 ,2,8,9-tetramethoxy dibenzo [cdj\ indol-4(5//)~^one

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(3-(dimethylamino)-2,2-dimethylpropyl)isoindolin-l- one obtained in Step 1 of Example 47 as a starting material instead of 4-bromo- 2-methylisoindolin-l-one, and 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (11%).

¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, IH), 7.78 (s, IH), 7.25 (s, IH), 7.05 (s, IH), 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-«-butylamino)butyl)-l,2- dimethoxy dibenzo [cd,f\ indol-4(5//)-one

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and N,N-di-«-butylbutane-l,4-diamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(4-(di-rc- butylamino)butyl)isoindolin- 1 -one (96%).

¹H ΝMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 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> The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(4-(di-n-butylamino)butyl)isoindolin- 1 -one as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (42%).

¹H ΝMR (300 MHz, CDCl₃) δ 9.24-9.21 (m, IH), 7.83-7.81 (m, IH), 7.80 (s, IH), 7.60-7.55 (m, 2H), 7.05 (s, IH), 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 l,2-dimethoxy-5-(3- morpholinopropyl)dibenzo [cdj\ indol-4(5//)-one

<Step 1> The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and 4-morpholinopropane-l -amine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(3- moφholinopropyl)isoindolin-l-one (78%).

¹H NMR (300 MHz, CDCl₃) δ 7.28 (s, IH), 4.31 (s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 3.54-3.47 (m, 6H), 2.28-2.24 (m, 6H), 1.79-1.71 (m, 2H).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(3-moφholinopropyl)isoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (41%).

¹H NMR (300 MHz, CDCl₃) δ 9.25-9.21 (m, IH), 7.81-7.79 (m, 2H), 7.58-7.55 (m, 2H), 7.09 (s, IH), 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: Synthesis of 5-(3-morpholinopropyl)-l,2,8,9- tetramethoxydibenzo[c</,/]indol-4(5//)-one

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(3-moφholinopropyl)isoindolin-l-one as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and 2-formyl-5,6- dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (43%).

¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, IH), 7.78 (s, IH), 7.22 (s, IH), 7.04 (s, IH), 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 l,2-dimethoxy-5-(3-(2-methylpiperidin-l- yl)propyl)dibenzo[α/,/]indol-4(5//)-one <Step 1>

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and 3-(2-methylpiperidin-l-yl)propane-l-amine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(3-(2- methylpiperidin- 1 -yl)propyl)isoindolin- 1 -one (98%).

¹H NMR (300 MHz, CDCl₃) δ 7.17 (s, IH), 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, IH), 1.53-1.42 (m, 4H), 1.24-1.15 (m, 2H), 0.95 (t, 3H, J= 6.2 Hz).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(3-(2-methylpiperidin- 1 -yl)propyl)isoindolin- 1 -one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin- 1-one to obtain the title compound (22%).

¹H NMR (300 MHz, CDCl₃) δ 9.23 (dd, IH, J= 5.3, 1.7 Hz), 7.89-7.86 (m, IH), 7.78 (s, IH), 7.62-7.55 (m, 2H), 7.16 (s, IH), 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, IH), 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: Synthesis of 5-(3-(2-methylpiperidin-l-yl)propyl)-l,2,8,9- tetramethoxydibenzo[c</_t/]indol-4(5//)-one

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(3-(2-methylpiperidin- 1 -yl)propyl)isoindolin- 1 -one as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and 2-formyl- 5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (8%).

¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, IH), 7.78 (s, IH), 7.24 (s, IH), 7.01 (s, IH), 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, IH), 2.35-2.30 (m, IH), 2.19-2.11 (m, IH), 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-(l,2-dimethoxy-4-oxodibenzo[α/,_[/]indol- 5(4//)-yl)piperidine-l-carboxylate

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and ethyl 4-aminopiperidine-l-carboxylate instead of methylamine to obtain ethyl 4-(4-bromo-5,6-dimethoxy-l-oxoisoindolin-2- yl)piperidine- 1 -carboxylate (90%) .

¹H NMR (300 MHz, CDCl₃) δ 7.34 (s, IH), 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> The procedure of Step 4 of Example 1 was repeated except for using ethyl 4-(4-bromo-5,6-dimethoxy- 1 -oxoisoindolin-2-yl)piperidine- 1 -carboxylate obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin- 1-one to obtain the title compound (13%).

¹H NMR (300 MHz, CDCl₃) δ 9.23 (dd, IH, J= 6.0, 3.4 Hz), 7.85-7.82 (m, IH), 7.81 (s, IH), 7.61-7.56 (m, 2H), 7.15 (s, IH), 4.67-4.61 (m, IH), 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, 7= 7.1 Hz). Example 55; Synthesis of ethyl 4-(l,2,8,9-tetramethoxy-4- oxodibenzo[c</_t/]indol-5(4//)-yl)piperidine- 1-carboxylate

The procedure of Step 4 of Example 1 was repeated except for using ethyl 4-(4-bromo-5,6-dimethoxy- l-oxoisoindolin-2-yl)piperidine- 1-carboxylate as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and 2- formyl-5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (52%).

¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, IH), 7.78 (s, IH), 7.25 (s, IH), 7.12 (s, IH), 4.72-4.64 (m, IH), 4.49-4.38 (m, IH), 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 l,2-dimethoxy-5-(l-benzyIpiperidin-4- yl)dibenzo [cd J]indol-4(5H)-one

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and l-benzylpiperidine-4-amine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(l-benzylpiperidin-4- yl)isoindolin-l-one (86%).

¹H NMR (300 MHz, CDCl₃) δ 7.34-7.25 (m, 6H), 4.28-4.25 (m, IH), 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> The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(l-benzylpiperidin-4-yl)isoindolin-l-one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin-l-one to obtain the title compound (57%). ¹H NMR (300 MHz, CDCl₃) δ 9.24-9.21 (m, IH), 7.88-7.85 (m, IH), 7.79 (s, IH), 7.61-7.53 (m, 2H), 7.42-7.27 (m, 6H), 4.57-4.48 (m, IH), 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 f-butyl 4-((l,2-dimethoxy-4- oxodibenzo[c</_t/]indol-5(4//)-yl)methyl)piperidine-l-carboxylate

<Steρ 1> The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and t-butyl 4-(aminomethyl)piperidine-l-carboxylate instead of methylamine to obtain t-butyl 4-((4-bromo-5,6-dimethoxy-l- oxoisoindolin-2-yl)methyl)piperidine- 1 -carboxylate (89%) .

¹H NMR (300 MHz, CDCl₃) δ 7.29 (s, IH), 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, IH), 1.65-1.51 (m, 4H), 1.37 (s, 9H), 1.06-0.89 (m, 4H).

The procedure of Step 4 of Example 1 was repeated except for using t- butyl 4-((4-bromo-5,6-dimethoxy- 1 -oxoisoindolin-2-yl)methyl)piperidine- 1 - carboxylate obtained in Step 1 as a starting material instead of 4-bromo-2- methylisoindolin- 1 -one to obtain the title compound (13%).

¹H NMR (300 MHz, CDCl₃) δ 9.25-9.22 (m, IH), 7.86-7.83 (m, IH), 7.81 (s, IH), 7.60-7.56 (m, 2H), 6.99 (s, IH), 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, IH), 1.78-1.69 (m, 2H), 1.58 (s, 4H), 1.45 (s, 5H), 1.39- 1.24 (m, 2H).

Example 58: Synthesis of l,2-dimethoxy-5-((l-ethylpyrrolidin-2- yl)methyl)dibenzo [cdj] indol-4(5/7)-one <Step 1>

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and (l-ethylpyrrolidin-2-yl)methaneamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(l-ethylpyrrolidin-2- yl)methyl)isoindolin-l-one (88%).

¹H NMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 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, IH, J = 14.1, 3.9 Hz), 3.48 (dd, IH, J = 14.0, 6.2 Hz), 3.20-3.18 (m, IH), 2.93 (dd, IH, J = 11.9, 7.4 Hz), 2.74 (s, IH), 2.33 (q, IH, J = 7.0 Hz), 2.17 (q, IH, J = 8.2 Hz), 1.93-1.85 (m, IH), 1.75-1.66 (m, 3H), 1.16 (t, 3H, J= 7.2 Hz).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-( 1 -ethylpyrrolidin-2-yl)methyl)isoindolin- 1 -one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin- 1-one to obtain the title compound (40%).

¹H NMR (300 MHz, CDCl₃) δ 9.24-9.21 (m, IH), 7.84-7.81 (m, IH), 7.79 (s, IH), 7.60-7.55 (m, 2H), 7.08 (s, IH), 4.11 (s, 3H), 4.07 (s, 3H), 4.03 (dd, IH, J = 9.3, 5.8 Hz), 3.91 (q, IH, J = 7.9 Hz), 3.24 (m, IH), 3.06-2.96 (m, 2H), 2.44 (q, IH, J = 7.1 Hz), 2.23 (q, IH, J= 8.6 Hz), 1.89-1.68 (m, 5H), 1.18 (t, 3H, J = 7.2 Hz).

Example 59: Synthesis of 5-(4-(diethylamino)-l-methylbutyl)-l,2,8,9- tetramethoxydibenzo [cdj\ indol-4(5//)-one

<Step 1> The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and N,N-diethyl-l-methylbutane-l,4-diamine instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(4-(diethylamino)-l- methylbutyl)isoindolin- 1 -one (98%).

¹H NMR (300 MHz, CDCl₃) δ 7.33 (s, IH), 4.53-4.46 (m, IH), 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).

The procedure of Step 4 of Example 1 was repeated except for using 4- bromo-5,6-dimethoxy-2-(4-(diethylamino)- 1 -methylbutyl)isoindolin- 1 -one obtained in Step 1 as a starting material instead of 4-bromo-2-methylisoindolin- 1-one, and 2-formyl-5,6-dimethoxyphenylboronic acid instead of 2- formylphenylboronic acid to obtain the title compound (11%).

¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, IH), 7.76 (s, IH), 7.22 (s, IH), 7.09 (s, IH), 4.74-4.67 (m, IH), 4.11-4.05 (m, 12H), 2.50-2.39 (m, 5H), 2.23-2.09 (m, IH), 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: Synthesis of 5-(3-(2-oxopyrrolidin-l-yl)propyl)-l,2,8,9- tetramethoxy dibenzo [cdj] indol-4(5//)-one

The procedure of Step 3 of Example 1 was repeated except for using methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate obtained in Step 2 of Example 5 as a starting material instead of methyl 3-bromo-2- (bromomethyl)benzoate, and l-(3-aminopropyl)pyrrolidin-2-one instead of methylamine to obtain 4-bromo-5,6-dimethoxy-2-(3-(2-oxopyrrolidin-l- yl)propyl)isoindolin- 1 -one (98%).

¹H NMR (300 MHz, CDCl₃) δ 7.31 (s, IH), 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>

The procedure of Step 4 of Example 1 was repeated except for using A- bromo-5,6-dimethoxy-2-(3-(2-oxopyrrolidin- 1 -yl)propyl)isoindolin- 1 -one as a starting material instead of 4-bromo-2-methylisoindolin-l-one, and 2-formyl- 5,6-dimethoxyphenylboronic acid instead of 2-formylphenylboronic acid to obtain the title compound (10%).

¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, IH), 7.77 (s, IH), 7.27 (s, IH), 6.99 (s, IH), 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, 4H).

Example 61: Synthesis of 8-benzyloxy-l,2-di(hexyloxy)-5- methyldibenzo[α/,/]indol-4(5//)-one

<Step 1> 4-Bromo-5,6-dimethoxy-2-methylisoindolin-l-one (280 mg, 0.98 mmol) obtained in Example 8 was dissolved in 5

of methylene chloride in a flask, and the mixture was cooled to 0^°C . Borontribromide (IM methylene chloride, 2.44 mi, 2.44 mmol) was slowly added thereto dropwise, and stirred under a nitrogen flow for 30 min. 5 mi of water was added thereto to terminate the reaction. The obtained organic layer was washed with 20 mi of water, distilled under a reduced pressure, and the resulting residue was dissolved in 5 mi of dimethylformamide. Potassium carbonate (1.35 g, 9.8 mmol) and 1- bromohexane (0.55 mi, 3.9 mmol) were added to the solution, and the mixture was stirred at room temperature for 36 hours. The reacted solution was filtered, and the filtrate was concentrated under a reduced pressure. The concentrated was dissolved in 50 mi of ethyl acetate, and washed twice with 10 mi of water and once with 10 mi saturated sodium chloride. The resulting solution was dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled under a reduced pressure follwed by purifing with a chromatography to obtain 4-bromo-5,6-bis(hexyloxy)-2-methylisoindolin-l-one (315 mg, 76%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 7.29 (s, IH), 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).

<Step2> The procedure of Example 15 was repeated except for using 4-bromo-

5,6-bis(hexyloxy)-2-methylisoindolin-l-one as a starting material instead of 4- bromo-5,6-dimethoxy-2-methylisoindolin-l-one to obtain the title compound (98%).

¹H NMR (300 MHz, CDCl₃) δ 9.25-9.13 (m, IH), 7.85 (s, IH), 7.48-7.14 (m, 7H), 6.84 (s, IH), 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-l,2-di(hexyloxy)-5- methyldibenzo [cd,f\ indol-4(5//)-one

The compound obtained in Example 61 was dissolved in methanol in a flask. 10% Pd/C was added thereto, and the mixture was stirred at room temperature for 3 hours after connecting a hydrogen balloon. After completion of the reaction, the resulting solution was filtered with a cellite and distilled under a reduced pressure to obtain the title compound (97%).

¹H NMR (300 MHz, DMSO-^) δ 8.95 (d, IH, J= 9.0 Hz), 7.50 (s, IH), 7.13 (d, IH, J = 2.4 Hz), 6.93 (s, IH), 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: Test of anticancer effect

In order to analyze the anticancer activity of the compound of the present invention, SRB (Sulforhodamine B) assay was performed as follows.

1) Cell culture

The cancer cell lines used in this experiment were derived from human, and they were lung cancer cell line A549, ovarian cancer cell line SK-O V-3, breast cancer cell line MDA-MB-231 and BT-474, skin cancer cell line A431, colon cancer cell line HCT 15, and uterine cancer cell line MES-SA and multi drug resistant cell line MES-SA/DX5 derived therefrom.

The cell culture solution used in this experiment was RPMI 1640 containing glutamine, mono sodium carbonate, gentamycin and amphotericin, and supplemented with 5% FBS. All cells were cultured under a condition of 37 ^"C , 5% CO₂, 95% air and 100% humidity, and subcultured every 3-5 days.

2) Test of cancer cell proliferation inhibitory activity A 96-well plate was inoculate with each cell line and cultured for 24 hours until the cells adhered to the bottom of the plate. Then, the culture solution was removed, and 100 μi of each test compound was introduced into each well at various concentrations, followed by culturing in an incubator for 72 hours. Doxorubicin and paclitaxel were used as control groups. After the culture was finished, the culture solution was removed, and the each well was treated with 10% trichloroacetic acid (TCA), followed by removing the TCA solution, washed 5 times with tap water, and dried at room temperature. 0.4% sulforhodamine B (SRE added cell surface protein staining agent), solution in 1% aqueous acetic acid was added to each well, and left standing at room temperature for 30 min to stain the cells. Each well was washed 5 times with 1% aqueous acetic acid and dried at room temperature. The stained cells were treated with 1OmM Trisma base solution (pH 10.5) to elute SRB. The absorbance of each plate was measured at 520 nm using a microplate reader. The cell viability per each well was checked by assessing the measured absorbance (OD₅₂o), and cancer cell proliferation inhibitory concentration (IC₅₀) was calculated by nonlinear regression analysis. The results are shown in Table 1. Table Ia

Table Ib

As shown in Table 1, the phenanthrene lactam derivatives of formula (I) of the present invention showed significant cancer cell proliferation inhibitory activity against various cancer cells.

Further, doxorubicin, a control compound, showed excellent cancer cell proliferation inhibitory activity, but inhibited too high toxicity to damage normal cells, while paclitaxel, a natural compound, showed problems arising from its complex structure which is costly to synthesize. However, the phenanthrene lactam derivatives of formula (I) of the present invention, which showed excellent anticancer activities but no toxicity as shown in Test Example 2, are effective when a high dose of an anticancer drug must be administered.

Test Example 2: Acute toxicity test

7 weeks old female ICR mice (23.98 to 25.81 g) were purchased and acclimated to a condition of room temperature (23± 3 "C) and a relative humidity of 55±15% for 7 days before this experiment. Then, 8 weeks old mice (23.61 to 26.56 g; n= 5) were orally administered with a mixture of the compound of Example 33 (a test compound) and an excipient (0.5% CMC-Na) (2,000 mg/Kg, 1,000 mg/Kg, 500 mg/Kg, and control group without administration). The mice were observed for 14 days after the administration to record their external conditions and the fatality rate. Dead mice were necropsied to observe gross lesions. As a result, minimum lethal dose (MLD) of the test compound according to the single administration to a female mouse was more than 2,000 mg/Kg, which means that the inventive compound is practically nontoxic.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made and also fall within the scope of the invention as defined by the claims that follow.

Claims

What is claimed is:

1. A phenanthrene lactam derivative of formula (I) or a pharmaceutically acceptable salt thereof:

wherein,

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen, halogen, hydroxy, Ci_-6alkyl, Ci_-6alkoxy or aryloxy, or R⁴ and R⁵, R⁵ and R⁶ or R⁶ and R⁷ form together with the carbon atoms to which they are attached a dioxole moiety;

R⁸ is hydrogen or C_1-6allkyl; and

R⁹ is hydrogen; C_1-6alkyl optionally substituted with at least one substituent selected from the group consisting of C_1-6alkyl, Cj_-6alkoxy, perfluoro

Ci_-6alkyl, hydroxy, halogen, C_1-6alkylamino, diCi_-6alkylamino, C_1-6acyloxy, Q-

₈cycloalkyl, C_3-gheterocycloalkyl, Q.gheterocycloalkyl substituted with Q-

₆alkyl, C_3-8heterocycloalkylcarbonyl, C_3-8heterocycloalkyl-C i _-6alkoxycarbonyl,

C_3-8heteroaryl, aryl, and thioaryl; C_1-6alkenyl; Ci_-6alkynyl; C_1-6acyl; C_1- ₆alkoxycarbonyl; C_1-6alkylsulfonyl; C_3-8heterocycloalkyl optionally substituted with Ci_-6alkylaryl or C_1-6alkoxycarbonyl; or aryl optionally substituted with halogen, amino, Ci_-6alkyl, perfluoroCi_-6alkyl or Ci_-6alkoxy.

2. The phenanthrene lactam derivative of formula (I) or pharmaceutically acceptable salt thereof of claim 1 , wherein

R⁹ is Ci_-6alkyl substituted with at least one substituent selected from the group consisting of Ci_-6alkylamino, diC_1-6alkylamino, Q.gheterocycloalkyl and Q.gheterocycloalkyl substituted with Q_-6alkyl; or Q.gheterocycloalkyl substituted with Ci_-6alkylaryl or C_1-6alkoxycarbonyl.

3. The phenanthrene lactam derivative of formula (I) or pharmaceutically acceptable salt thereof of claim 1 , which is selected from the group consisting of:

1 ) 5-methyldibenzo[cc?,/|indol-4(5H)-one,

2) 5,6-dimethyldibenzo[cJ,/|indol-4(5H)-one,

3) 3-methoxydibenzo[cd,/]indol-4(5H)-one,

4) 3-methoxy-5-methyldibenzo[cfi?_Λ/]indol-4(5H)-one, 5) l,2-dimethoxydibenzo[c(i,/|indol-4(5H)-one,

6) 1 -hydroxy-2-methoxydibenzo[cJ,/|indol-4(5H)-one,

7) 1 ,2,9-trimethoxydibenzo[cfi?,/|indol-4(5H)-one,

8) 1 ,2-dimethoxy-5-methyldibenzo[cd,/|indol-4(5H)-one,

9) 1 -hydroxy-2-methoxy-5-methyldibenzo[c4/]indol-4(5H)-one, 10) 2-hydroxy-l-methoxy-5-methyldibenzo[c-f,/|indol-4(5H)-one,

11) 5-methyl-l,2,8,9-tetramethoxydibenzo[cJ,/|indol-4(5H)-one,

12) 17,18-dimethoxy- 13-methyl-5,7-dioxa- 13- azapentacyclo[10.6.1.0²'¹⁰.0⁴'⁸.0^{15 19}]nonadeca-l,3,8,10,12(19),15,17-heptaen- 14-one, 13) l,2-dimethoxy-5,6-dimethyldibenzo[ccf,/lindol-4(5H)-one,

14) 8-benzyloxy-5-methyldibenzo[cc?,/]indol-4(5H)-one,

15) 8-benzyloxy- 1 ,2-dimethoxy-5-methyldibenzo[cc?,/lindol-4(5//)-one,

16) 1 ,2-dimethoxy-8-hydroxy-5-methyldibenzo[ct/_!/]indol-4(5H)-one,

17) 5-benzyl- 1 ,2-dimethoxydibenzo[cύ?,/]indol-4(5H)-one, 18) 5-benzyl- l,2,8,9-tetramethoxydibenzo[c^,/]indol-4(5H)-one,

19) 1 ,2-dimethoxy-5-ethyldibenzo[c-i/|indol-4(5H)-one,

20) 1 ,2-dimethoxy-5-isopropyldibenzo[c4/]indol-4(5H)-one,

21) 1 ,2-dimethoxy-5-(2-methoxy)ethyldibenzo[cf/,/|indol-4(5H)-one, 22) 1 ,2-dimethoxy-5-propargyldibenzo[cJ,/]indol-4(5H)-one, 23) 5-(cyclopropylmethyl)- 1 ,2-dimethoxydibenzo[c4/]indol-4(5H)-one,

24) 1 ,2-dimethoxy-5-phenethyldibenzo[cJ,/|indol-4(5H)-one,

25) 1 ,2-dimethoxy-5-(pyridin-4-ylmethyl)dibenzo[cc?,/Iindol-4(5H)-one,

26) 1 ,2-dimethoxy-5-(thiophen-3-ylmethyl)dibenzo[cf/_Λ/]indol-4(5//)- one,

27) 1 ,2-dimethoxy-5-(4-methoxyphenyl)dibenzo[cJ,/|indol-4(5H)-one,

28) 5-(4-t-butylphenyl)- 1 ,2-dimethoxydibenzo[cc?,/]indol-4(5H)-one,

29) l,2-dimethoxy-5-(2-moφholinoethyl)dibenzo[cβ?,/]indol-4(5H)-one, 30) l,2,9-trimethoxy-5-(2-morpholinoethyl)dibenzo[ci/,/|indol-4(5H)- one,

31) 1 ,2,8,9-tetramethoxy-5-(2-moφholinoethyl)dibenzo[c.i,/]indol- 4(5H)-one,

32) 17, 18-dimethoxy- 13-(2-(moφholino-4-yl)ethyl)-5,7-dioxa- 13- azapentacyclo[10.6.1.0²'¹⁰.0⁴'⁸.0^{15 19}]nonadeca-l,3,8,10,12(19),15,17-heptaen-

14-one,

33) 1 ,2-dimethoxy-5-(2-(piperidin- 1 -yl)emyl)dibenzo[c*//|indol-4(5H)- one,

34) 1 ,2,9-trimethoxy-5-(2-(piperidin- 1 -yl)ethyl)dibenzo[cή?,/|indol- 4(5H)-one,

35) l,2,8,9-tetramethoxy-5-(2-(piperidin-l-yl)ethyl)dibenzo[cc?,/]indol- 4(5H)-one,

36) 17, 18-dimethoxy- 13-(2-(piperidin- l-yl)ethyl)-5,7-dioxa- 13- azapentacyclo[10.6.1.0^{2 10}.0⁴'⁸.0^{15 19}]nonadeca-l,3,8,10,12(19),15,17-heptaen- 14-one,

37) 8-chloro- 1 ,2-dimethoxy-5-(2-(piperidin- 1 - yl)ethyl)dibenzo[c(i,/|indol-4(5H)-one,

38) 1 ,2-dimethoxy-8-fluoro-5-(2-(piperidin- 1 - yl)ethyl)dibenzo[c-i/)indol-4(5H)-one, 39) l,2-dimethoxy-6-methyl-5-(2-(piperidin-l- yl)ethyl)dibenzo[cf/,/]indol-4(5H)-one,

40) 5-(2-(dimethylamino)ethyl)- 1 ,2,8-trimethoxydibenzo[cc/,/|indol- 4(5H)-one,

41) 5-(2-(dimethylamino)ethyl)-l,2,8,9-tetramethoxydibenzo[ci/,/|indol- 4(5H)-one,

42) 17, 18-dimethoxy- 13-(2-(dimethylamino)ethyl)-5,7-dioxa- 13- azapentacyclo[10.6.1.0^{2 10}.0⁴'⁸.0^{15 19}]nonadeca-l,3,8,10,12(19),15,17-heptaen- 14-one, 43) 5-(2-(pyτrolidin- 1 -yl)ethyl)- 1 ,2,8,9-tetramethoxydibenzo[c</,/]indol- 4(5H)-one,

44) l,2-dimethoxy-5-(3-methylbutan-2-yl)dibenzo[c(i,/]indol-4(5H)-one,

45) 5-(2-(diethylamino)ethyl)- 1 ,2-dimethoxydibenzo[<4/]indol-4(5H)- one,

46) 5-(2-(diethylamino)ethyl)- 1 ,2,8,9-tetramethoxydibenzo[cfi?,/|indol- 4(5H)-one,

47) 5-(3-(dimethylamino)-2,2-dimethylpropyl)- 1 ,2- dimethoxydibenzo[cc/,/|indol-4(5H)-one, 48) 5-(3-(dimethylamino)-2,2-dimethylpropyl)- 1,2,8,9- tetramethoxydibenzo[cJ,/|indol-4(5H)-one,

49) 5-(4-(di-n-butylamino)butyl)- 1 ,2-dimethoxydibenzo[cJ,/|indol- 4(5H)-one,

50) l,2-dimethoxy-5-(3-moφholinopropyl)dibenzo[c^,/]indol-4(5H)-one, 51) 5-(3-morpholinopropyl)- 1 ,2,8,9-tetramethoxydibenzo[cfi?,/|indol-

4(5H)-one,

52) 1 ,2-dimethoxy-5-(3-(2-methylpiperidin- 1 - yl)propyl)dibenzo[cJ,/|indol-4(5H)-one,

53) 5-(3-(2-methylpiperidin- 1 -yl)propyl)- 1 ,2,8,9- tetramethoxydibenzo[cf/,/]indol-4(5H)-one,

54) ethyl 4-( 1 ,2-dimethoxy-4cdibenzo[cfi?,/]indol-5(4H)-yl)piperidine- 1 - carboxylate,

55) ethyl 4-(l,2,8,9-tetramethoxy-4-oxodibenzo[cJ,/]indol-5(4H)- yl)piperidine- 1 -carboxylate, 56) 1 ,2-dimethoxy-5-(l-benzylpiperidin-4-yl)dibenzo[ci/,/|indol-4(5H)- one,

57) t-butyl 4-((l,2-dimethoxy-4-oxodibenzo[c£/,/]indol-5(4H)- yl)methyl)piperidine- 1- carboxylate,

58) 1 ,2-dimethoxy-5-(( 1 -ethylpyτrolidm-2-yl)methyl)dibenzo[c4/]indol- 4(5H)-one,

59) 5-(4-(diethylamino)- 1 -methylbutyl)- 1 ,2,8,9- tetramethoxydibenzo[c-i,/]indol-4(5H)-one,

60) 5-(3-(2-oxopyrrolidin-l-yl)propyl)- 1,2,8,9- tetramethoxydibenzo[cJ/|indol- 4(5H)-one,

61 ) 8-benzyloxy- 1 ,2-di(hexyloxy)-5-methyldibenzo[c4/]indol-4(5H)- one, and

62) 8-hydroxy- 1 ,2-di(hexyloxy)-5-methyldibenzo[cΛ?,/|indol-4(5H)-one.

4. A method for preparing the phenanthrene lactam derivative of formula (I) of claim 1, which comprises subjecting a compound of formula (II) to a reaction with a compound of formula (III) in a solvent in the presence of a palladium compound and a base:

wherein,

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen, halogen, hydroxy, Ci_-6alkyl, C_1-6alkoxy or aryloxy, or R⁴ and R⁵, R⁵ and R⁶ or R⁶ and R⁷ form together with the carbon atoms to which they are attached a dioxole moiety;

R⁸ is hydrogen or C_1-6allkyl;

R⁹ is hydrogen; C^alkyl optionally substituted with at least one substituent selected from the group consisting of Ci_-6alkyl, C_1-6alkoxy, perfiuoro C_1-6alkyl, hydroxy, halogen, Ci_-6alkylamino, diC_1-6alkylamino, Ci_-6acyloxy, C_3-

₈cycloalkyl, C_3-8heterocycloalkyl, C₃.₈heterocycloalkyl substituted with C_1-

₆alkyl, C_3-8heterocycloalkylcarbonyl, C_3-8heterocycloalkyl-C _{\ -6}alkoxycarbonyl,

C_3-8heteroaryl, aryl, and thioaryl; Ci_-6alkenyl; C_1-6alkynyl; C_1-6acyl; C_1-

₆alkoxycarbonyl; C_1-6alkylsulfonyl; C_3-8heterocycloalkyl optionally substituted with Ci_-6alkylaryl or Ci_-6alkoxycarbonyl; or aryl optionally substituted with halogen, amino, Ci_-6alkyl, perfluoroCi_-6alkyl or C_1-6alkoxy;

X is halogen, Ci_-6alkylsulfonyloxy or arylsulfonyloxy; and

M is B(OH)₂ or B(OR¹⁰)₂, R¹⁰ being C_1-4alkyl, or (OR¹⁰) being a heterocyclic group having a -O-B-O moiety.

5. The method of claim 4, wherein M is B(OH)₂,

or

B

6. The method of claim 4, wherein the phenanthrene lactam derivative of formula (I) is prepared by letting the compound of formula (II) react with the compound of formula (III) to obtain an intermediate compound of formula (IV), and subjecting the compound of formula (IV) to a cyclization reaction:

wherein, R¹ to R⁹ have the same meanings as defined in claim 4.

7. The method of claim 6, which further comprises isolating the intermediate compound of formula (IV) and treating the compound of formula (IV) with a base.

8. The method of claim 4, wherein the palladium compound is selected from the group consisting of 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 and a mixture thereof.

9. The method of claim 4 or 7, wherein the base is 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 bromide, potassium bromide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, N- methylmorpholine, N,N-dimethylaniline, l,8-diazabicyclo[5,4,0]-7- undecene(DBU), triethylamine and a mixture thereof.

10. The method of claim 4, which further comprises adding a phosphate compound to the solvent.

11. The method of claim 10, wherein the phosphate compound is selected from the group consisting of triphenylphosphine, tri(2- methylphenyl)phosphine, bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, bisdiphenylphosphinobutane, bisdiphenylphosphinopentane, bisdiphenylphosphinohexane, 2,2'-bis(diphenylphosphino)-l,r-binaphthyl, tri- /ert-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-ter/-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-l,r-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 a mixture thereof.

12. The method of claim 4, wherein the solvent is selected from the group consisting of tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, dioxane, benzene, toluene, xylene, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, propanol, n-butanol, t-butanol, water and a mixture thereof.

13. The method of claim 12, wherein the solvent is a mixture of ethanol and toluene.

14. A pharmaceutical composition comprising the phenanthrene lactam derivative of formula (I) or pharmaceutically acceptable salt thereof of claim 1 as an active ingredient for preventing or treating a cancer.

15. A use of the phenanthrene lactam derivative of formula (I) or pharmaceutically acceptable salt thereof of claim 1 for the manufacture of a medicament for preventing or treating a caner.