WO1998003509A1 - Dc-89 derivatives - Google Patents

Abstract

DC-89 derivatives represented by general formula (I) or pharmacologically acceptable salts thereof, (I) wherein (II) represents (III) or (IV) (wherein X represents C1 or Br; and R represents hydrogen or COR1), and W represents (V) or (VI). Because of having excellent antitumor effects, these compounds are useful as antitumor agents.

Description

 Specification

 DC-89 derivative

Technical field

 The present invention relates to a DC-89 derivative or a pharmacologically acceptable salt thereof, which exhibits excellent antitumor activity and is useful as an antitumor agent.

Background technology

 As compounds related to the DC-89 derivative of the present invention, DC-89A 1. DC-89A2 DC-89B1 and DC-89B2 represented by the following structural formulas are known. In addition to showing antibacterial activity against bacteria, it also has anti-femoral activity against melanomas B-16.

DC-89A1: X ^C = -CH _2- , Y ° = CI

DC-89A2: X ° = single bond, Y ° = CH ₂ C1

DC-89B1: X ° = -CH _2- , Y ° = Br

DC-89B2: X ° = single bond, Y. = CH ₂ Br

 DC-89A1 is disclosed in W087 / 06265, and DC-89A2 DC-89B1 and DC-89B2 are disclosed in JP-A-2-119787. Further, SF 2 582 A and SF 2 582 B which are the same compounds as DC-8 (JA2 and DC-89A1) are disclosed in JP-A-1-139590.

Further, DC-88A having the following structural formula is disclosed in W087 / 06265, and DC113 is disclosed in JP-A-2-77890, which shows antibacterial activity against various bacteria. Shows antitumor activity against 6 mag.

 Also, the DC-88A derivative and the DC-89 derivative are disclosed in JP-A-2-288879, JP-A-3-7287, JP-A-3-128379, JP-A-4-226988, JP-A-4-356485, and JP-A-5-51384. And JP-A-5-178858.

 The derivative of SF25882C is described in JP-A-278881, and CC-1065, which is an anti-tumour compound having a structure similar to DC-88 and DC-89, and its derivatives are described. Japanese Patent Application Laid-Open Nos. 54-64695, 60-193989, 088/04659, EP-35945, and JP-A-3-14581, respectively. Further, related derivatives are disclosed in JP-A-6-116269 and 丄 Am. Chem.So, Π7, 8917-8925 (1995).

 JP-A-5-178858 discloses the following compounds (A), (B) and (C).

Disclosure of the invention

The present invention provides a compound of the formula (I)

 (Where

Is

Or

Represents Wherein X represents C 1 or Br, R is a hydrogen atom or COR ¹ (where R ¹ is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted complex A ring group, NR ² R ³ (wherein, R ² and R ³ are the same or different and represent a hydrogen atom or a substituted or unsubstituted lower alkyl),

-N R

Wherein an oxygen atom, N-R ⁵ (wherein, R ⁵ is _t represents a hydrogen atom or a lower alkyl) or,

Represents Wherein, n R ^2a and R ^3a have the same meanings as R ^f , R ² and! ³ , respectively; or 0H ⁶ (where ii ⁶ is a substituted or unsubstituted lower alkyl) Represents). } Where W is

Wherein, Y ¹ represents an oxygen atom, (wherein, R ^ib is as defined Xiao ίΐ Symbol H ^f.) A sulfur atom or an N-lT ^b represents, Q ¹ and Q ² are the same or different and each represents a hydrogen atom , 01 (wherein, H ⁷ represents a hydrogen atom or a substituted or unsubstituted lower alkyl), N 0 ₂ , NR ′ ^b R ^3b (wherein, R ^2b and H ^3b are the above-mentioned R ^z and R ³ , respectively) Synonymous with ^3. ) or NHC0 ₂ K ^6a

(The formula width, R ^6a has the same meaning as described above.) m represents 0 or 1, and n represents an integer of 0 to 2. ] Or

[In the formula, Y ² represents an oxygen atom, a sulfur atom or NR ^f (wherein IT has the same meaning as described above.), And Q ³ and Q ⁵ have the same meaning as the above-mentioned Q ′ or Q ^z . ] Is represented. } It relates to a DC-89 derivative represented by the formula or a pharmacologically acceptable salt thereof.

 In equation (I), W is

(Wherein丫^1, Q ¹ and Q ² are as defined above.) In a DC- 8 9 derivative or a pharmaceutically acceptable salt thereof pharmacologically are preferred.

 Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds having other formula numbers.

 In the definition of the above formula (I), lower alkyl means straight or branched alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, isooctyl and the like. Examples of aryl include phenyl, naphthyl, anthranil, bienyl and the like. Heterocyclic groups include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidino, piperazinyl, homobiperazinyl, morpholino, thiomorpholino, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl Phthalazinyl, naphthyridinyl, quinoxalinyl, chenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, prinyl, viranyl, pihydridyl, tephridylyl And the like. Examples of the substituent of the substituted lower alkyl include the same or different and substituted 1 to 3 hydroxy lower alkoxy, lower alkylthio, carboxy, lower alkoxycarbonyl, amino, mono- or di-lower alkylamino, halogen, aryl, etc. Is included. Examples of the substituent of the substituted aryl and the substituted heterocyclic group include the same or different and substituted or unsubstituted substituted or unsubstituted lower alkyl, lower alkoxy, lower alkoxycarbonyl, amino, mono- or di-lower alkylamino, halogen and the like. Include. Here, in the substituent of the substituted lower alkyl, the substituted aryl and the substituted heterocyclic group, the lower alkyl portion of the lower alkoxy, the lower alkyl thio, the lower alkoxycarbonyl, the mono- or di-lower alkylamino is the same as the lower alkyl. Examples of the halogen include fluorine, chlorine, bromine and iodine atoms. The substituted or unsubstituted lower alkyl in the substituent of the substituted aryl and the substituted heterocyclic group is as defined above, and the aryl in the substituent of the substituted lower alkyl is as defined above.

Pharmacologically acceptable salts of compound (I) include, for example, hydrochloride, hydrobromic acid Inorganic acid addition salts such as salts, hydroiodide, sulfate, phosphate, nitrate and acetate, benzoate ^, maleate, fumarate, succinate, tartrate, citrate And organic acid addition salts such as salts, oxalates, glyoxylates, aspartic acid ^, and methanesulfonates.

 Next, a method for producing the compound (I) will be described.

 In the production methods shown below, if the defined group changes under the reaction conditions of the method or is inappropriate for carrying out the method, protection of functional groups commonly used in organic synthetic chemistry, By performing deprotection, etc., the desired reaction can be performed.

Method 1

 Of compound (I)

Can be produced by reacting the compound (A) described in JP-A-5-178858 with a corresponding reactive derivative of a carboxylic acid in an inert solvent in the presence of a base. it can.

(Wherein, W is as defined above.)

The base includes sodium hydride, lithium diisopropylamide, t-butoxycar- ium, triethylamine, 4-dimethylaminopyridine, and the like. It is used in an amount of 1 to 3 equivalents based on the normal compound (A). As the inert solvent, N, N-dimethylformamide (DMF), tetrahydrofuran (THF), toluene, dimethyl sulfoxide or the like is used alone or as a mixture. Examples of the reactive derivative of carboxylic acid include acid halides such as acid chloride and acid bromide, p-difluorophenyl ester, 2,4,5-trichlorophenyl ester, penfluorofluoroester, Active esters such as N-oxysuccinic acid imido ester are included. The reactive derivative is usually used in an amount of 1 to 3 equivalents based on the compound (A), and the reaction is carried out at -80 to 30 ° C and is completed in 30 minutes to 24 hours.

Method 1—2

 Compound (I) a can also be produced by reacting compound (I) b described below with a base in an inert solvent.

 (Wherein, W and X are as defined above.)

 The base includes 1,8-diazabicyclo [5.4.0] -7-indene (DBU) and the like, and is usually used in an amount of 1 to 10 equivalents to compound (I) b. As the inert solvent, acetonitrile, pyridine and the like are used alone or in combination. The reaction is usually performed at room temperature and is completed in 1 to 24 hours.

Method 2—1

 Of compound (I)

Wherein R is a hydrogen atom, and compound (I) b is obtained by converting compound (I) a into an inert solvent , Hydrochloric acid or hydrobromic acid.

(Wherein, W and X are as defined above.)

 • Hydrochloric acid or hydrobromic acid is usually used in an amount of 1 to 20 equivalents based on compound (I) a. As the inert solvent, water, DMF, THF, toluene, dioxane, acetate nitrile and the like are used alone or in combination. The reaction is usually performed at −3 to 50 ° C., and is completed in 10 minutes to 1 hour.

Method 2—2

 Compound (I) b is prepared by reacting compound (A) with hydrochloric acid or hydrobromic acid in an inert solvent, and then reacting the corresponding carboxylic acid in an inert solvent in the presence of a condensing agent. Can also be manufactured.

(Wherein, W and X are as defined above.)

 Hydrochloric acid or hydrobromic acid is generally used in an amount of 1 to 20 equivalents based on compound (A). Examples of the condensing agent include dicyclohexyl carpoimide (DCC), 1- (3-dimethylaminopropyl) 1-3-ethyl carpoimide or its hydrochloride, and usually 1 to compound (A). ~ 3 equivalents are used. As the inert solvent, water, DMF, THF, toluene, dioxane, acetonitrile and the like are used alone or as a mixture. The reaction is usually performed at room temperature and is completed in 12 to 24 hours.

Method 3-1 Of compound (I)

Wherein R is C0R ^la (where R ^la is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group). c is a compound of DC (;, 1- (3-dimethylaminopropyl) —3-ethylcarboimide or a condensing agent such as hydrochloride thereof and compound (4-dimethylaminopyridine) in an inert solvent with compound (I) b. In the presence, R ^la CO ₂ H (wherein R ^ia has the same ^{meaning as} described above) can be produced.

(In the formula, R ^la , W and X are as defined above.)

R ^la C0 ₂ H, a condensing agent and 4-dimethylaminopyridine are usually used in an amount of 1 to 10 equivalents to compound (I) b, respectively. As the inert solvent, methylene chloride, chloroform, DMF, THurethane, toluene, dioxane, acetonitrile and the like are used alone or as a mixture. The reaction is usually carried out at -50 to 50 ° C, and is completed in 0 to 48 hours.

Method 3 — 2

 Compound (I) c can also be produced by reacting compound (I) b with a corresponding acid anhydride or acid halide in an inert solvent in the presence of a base.

(Wherein, R ^la , W and X are as defined above, and V represents chlorine, bromine or iodine.)

 The acid anhydride or acid halide is usually used in an amount of 1 to 10 equivalents based on compound (1) b. As a base, potassium t-butoxy, triethylamine, pyridine, 4-dimethylaminopyridine, etc. is usually used in an amount of 1 to 10 equivalents to the compound (I) b, but when it also serves as a solvent, it is used in a large excess. . As the inert solvent, methylene chloride, chloroform, DMF, THF, toluene, dioxane, acetonitrile, pyridine and the like are used alone or as a mixture. The reaction is usually performed at −20 to 50 ° C., and is completed in 10 minutes to 10 hours.

Method 4

 Of compound (I)

R is C0R ^lb (where R ^lb is NR ² R ³ (where R ² and R ³ are as defined above) ₀ ),

■ N

It is (wherein, R ⁴ is as defined above.) Or NR ^ia NR ^{2 e} R ^{3 a} (wherein, ^a, R, and R ^{3 a} is as defined above.). ] Can be produced by the following method.

 (Process 1)

Compound (11) can be produced by reacting compound (I) b with p-nitrophenylchloroformate in an inert solvent in the presence of a base.

 (I) b (ID

 (Wherein, W and X are as defined above.)

 The p-nitrophenyl chloride form is usually used in an amount of 1 to 5 equivalents to the compound (I) b. The base includes potassium t-butoxy, triethylamine, pyridine, 4-dimethylaminoviridine, and the like. Usually, for the compound (I) b,

It is used in an amount of 1 to 5 equivalents, but when used also as a solvent, it is used in large excess. As the inert solvent, methylene chloride, chloroform, pyridine, DMF, THF, toluene, dioxane and the like are used alone or as a mixture. The reaction is usually performed at -80 to 50 t, and is completed in 10 minutes to 20 hours.

 (Process 2)

Compound (11) in an inert solvent in the presence of a base, R ² R ³ NH [Formula (HI) a] (wherein R ² and R ³ are as defined above),

HN

(Wherein, R ⁴ has the same meaning as described above) or KNR ^5a NR ^2a R ^3a [Formula (111) a] (wherein, R ^5a , R ^2a and R ^3a have the same meanings as described above). Compound (I) d can be produced by reacting Compound (HI) a with Compound (1) c.

 (II) (I) d

Wherein R ^lc is NR ² R ³ (wherein R ² and R ³ are as defined above) One NR "

(Wherein, R ⁴ is as defined above.) Or ^{Nf a NR 2 a R 3 a} ( wherein, ^a, R ^{Z a} and R ^{3 a} is as defined above.) Represents, W and X Is as defined above. ]

 The base includes triethylamine, pyridine, 4-dimethylaminopyridine and the like, and is usually used in an amount of 1 to 5 equivalents to the compound (11), but when used as a solvent, it is used in a large excess. As the inert solvent, methylene chloride, chloroform, DMF, T111 ″, toluene, dioxane, pyridine and the like are used alone or as a mixture. The reaction is usually performed at -80 to 50 ° C, and is completed in 10 minutes to 24 hours.

Method 5

 Of the compounds (1)

Wherein R is C0R ^{ld wherein} K ′ ^d is OR ⁶ (wherein is as defined above). Is produced by reacting compound (I) e with C1 C0 ₂ R ⁶ (wherein R ⁶ is as defined above) in an inert solvent in the presence of a base. can do.

(In the formula, R ⁶ , W and X are as defined above.)

C1 C0 ₂ R ⁶ can be used from 1 to 10 equivalents relative to the normal Compound (I) b. Bases include t-butoxycar- ium, triethylamine, pyridine, and 4-dimethylaminopropyl. Gin and the like, which are usually used in an amount of about 5 to 5 equivalents to the compound (I) b, but are used in a large excess when they also serve as a solvent. As the inert solvent, methylene chloride, chloroform, DMF, THF, toluene, dioxane, pyridine and the like are used alone or as a mixture. The reaction is usually performed at -40 to 50 ° C, and is completed in 10 minutes to 10 hours.

 The product in each of the above steps can be isolated and purified by a method used in ordinary organic synthesis. For example, after completion of the reaction in each step, if necessary, water, an acid, a buffer, an aqueous solution of sodium hydrogen carbonate, etc. are added to the reaction solution, and the mixture is extracted with a water-insoluble solvent such as ethyl acetate, chloroform, ether. . The extract is washed with water, aqueous sodium hydrogen carbonate, saline, etc., dried over anhydrous sodium sulfate, etc., and the residue obtained after evaporation of the solvent is subjected to column chromatography using silica gel, Purify by layer chromatography, high-performance liquid preparative chromatography, recrystallization, etc.

 When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, the compound may be purified as it is, and when compound (I) is obtained in a free form, compound (I) may be purified using an appropriate solvent. The salt may be formed by dissolving or suspending in water and adding an appropriate acid.

 In addition, the reaction intermediate can be used in the next step without isolation and purification. Compound (I) or a pharmacologically acceptable salt thereof may be present in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Further, all possible isomers including the optically active form of compound (I) and mixtures thereof are also included in the present invention.

Table 1 shows the structures and compound numbers of typical compounds belonging to compound (I), and Table 2 shows their starting compounds. In each table, Me and Boc represent methyl and t-butoxycarbonyl, respectively.

 A type 'B type'

 Table 1 (1

Compound number Type X

 A

B Br CON NCH ₃ OMe

Four -

 ΑThai 7 'B Taifu'

 Table 1 (2

Compound number ^W '' type XR

 l

15 B Br CON NCH _3. HBr

17 B Br CONMeNH,

18 A

 NO?

 19 B Br COCH,

B type '

 Table 1 (3

Compound number w * Type X R

 A type 'B type'

 Table 1 (4)

Compound number ^w 'type XR

 NHBoc

Table 2 (1 R C0 ₉ R ² PNP \\ / Factory ^NO ? Compound Φ ^Rl FT

S OMe PNP

 MeO.

 d OMe PNP

Table 2 (2 R ¹ CQ ₂ R ² Compound Φ No. R ¹

Next, the pharmacological activity of the representative compound (1) will be described by test examples.

Test example 1 He La S ₃ cell growth inhibition test

To each well of a 24-well culture plate, 0.75 ml of HeLaS ₃ cells adjusted to 2.67 × 10 ⁴ cells / ml in MRM medium containing 10% fetal bovine serum and 2 mM dalmin was dispensed. After culturing overnight at 37 ° C in a carbon dioxide incubator, 0.25 ml of the compound (I) appropriately diluted with the medium was added to each bottle.

After culturing the cells in a carbon dioxide incubator for 72 hours, the culture supernatant was removed, and the cells were dispersed and recovered with a trypsin / ethylenediaminetetraacetic acid (EDTA) solution. The cell number is measured using a cell force counter, and the number of cells without treatment is compared with the number of cells treated with a known concentration of compound (I) to determine the amount of compound (I) that inhibits cell growth by 50%. It was calculated the concentration (IC _5.). Table 3 shows the results.

Test Example 2 Therapeutic effect on sarcoma 180 tumor

5x10 sarcoma 180 tumors were implanted subcutaneously in the axillary region in five i-groups of male ddY mice weighing 18 to 20 g. After transplantation, 0.2 ml of physiological saline containing Compound (I) at the concentrations shown in Table 1 was administered intravenously. 7 days after transplantation, C / C [T: mean tumor volume of test group (mm ³ ), C: mean tumor volume (mm ³ ) of control group (intravenous saline 0.2 ml)] It was measured.

 Table 3 shows the results.

Test example:] Hemotoxicity test (Effect on platelet count)

 Each drug was administered once into the tail vein of male ddY mice (body weight 20 ± lg) in the same amount as in Test Example 2, and blood was collected from the orbital venous plexus of the mice 7 days later. The platelet count was measured with a microcell counter -CC-180A (Toa Medical Electronics), and the platelet count in mice without drug administration relative to the control (%)

Table 3 shows the results. 251

Table 3 Compound ic 50 T / C ιίιι.platelet

 (ηΜ) (mg / kg) (%)

1 2.9

 3 230 8.0 0.35 84

 4 1.9

 6 200 8.0 0.09 94

 7 2.9 2.0 0.47 98

 10 95 8.0 0.33 42

 11 1.2

 12 0.67

 13 0.19

 15 3.2 8.0 0.06 42

 16 0.082 0.5 0.22 87

 17 0.27 2.0 0.07 91

 18 100

 19 220 8.0 0.65

 20 140

 21 70

 22 87

 23 17

 25 1.4

 26 1.6 2.0 0.55 92

 27 0.21

 28 0.15 0.5 0.36 110

 29 35 2.0 0.08

 30 0.14

 31 0.28 0.5 0.36 119

 32 0.24 1.0 0.17 95

 34 0.27 0.25 0.20

35 0.20 0.25 0.36 From Table 3, it is clear that compound (T) has low hematological toxicity and exhibits an excellent antitumor effect.

 Compound (I) or a pharmacologically acceptable salt thereof can be used alone or together with at least one pharmaceutically acceptable adjuvant as an antitumor composition. For example, the compound (I) or a salt thereof is dissolved in an aqueous solution of physiological saline, glucose, lactose, mannitol, or the like to prepare a pharmaceutical composition suitable for injection, or the compound (1) or a salt thereof. Is freeze-dried according to a conventional method, and sodium chloride is added thereto to prepare a powder injection. The present pharmaceutical composition can contain additives known in the pharmaceutical field, for example, pharmaceutically acceptable salts and the like, if necessary.

 The dose of this composition varies depending on the age, symptoms, etc. of the patient, but is administered as 0.001 to lmg / kg / day as compound (I) to mammals including humans. Dosing may be, for example, once a day (single dose or continuous dose) or intermittently i-! Once or twice a week, administer 1 冋 intravenous injection. In addition, if desired, intravenous administration, intraperitoneal administration, intrathoracic administration, and the like can be performed in the same dosage and administration form. If desired, oral administration is possible in the same dosage and administration form. Oral dosage forms include tablets, capsules, powders, granules, ampoules and the like, which include pharmaceutical auxiliaries well known in the art of manufacture.

 Hereinafter, examples of the present invention will be described. The physicochemical properties shown in the following examples were measured by the following instruments.

 N R JEOL JNM-GX270 (270MHz)

 JNM-EX270 (270MHz)

 Hitachi R- 9011 (90MHz)

 MS Shimadzu QP-1000

 U-honden JMS-D300

 JMS-SX102

 1 R JASCO 1 R-810

 HORIBA FT200

For preparative thin-layer chromatography, use a silica gel plate (Silicagel 60F2i _JS 0.5 mm 20 x 20 cm) manufactured by Merck and silica gel for column chromatography.

-1 2- As for Le, we used Wako Pure Chemical Co., Ltd. ^ ヮ Ko-Igel C-200.

 Compounds ap described in the Examples are shown in Reference Examples described later.

BEST MODE FOR CARRYING OUT THE INVENTION

Example 1: Synthesis of Compound 1

 After adding 3 ml of DMFO to 4.7 mg (0.118 mmol) of 60% sodium hydride, 0.4 ml of a DMF solution of 25 mg (0.097 bandol) of compound (A) was added, and the mixture was added under an argon atmosphere. The mixture was stirred with C for 2 hours and 30 minutes. To this reaction mixture was added 0.4 ml of a DMF solution of 30.7 mg (0.112 mmol) of compound a, and the mixture was stirred for 1 hour and 40 minutes. To this reaction mixture, a 0.01 M phosphate buffer at pH 7 was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform: methanol = 100: 1) to obtain 28 mg of Compound 1 (yield 73%).

 'H-NMR (270 Hz, CDC) δ (ppm); 11.91 (1H, brs), 7.93 (1H, d, J = 14.9 Hz), 7.0 (1H, d, J = 5.0 Hz), 7.31 ( lH.d, J = 3.3Hz), 7.07 (1H, dd, J = 5.0, 3.9Hz), 6.79 (lH, br), 6.63 (lH, d, J = 15.2Hz), 4.23 (1H, d , J = 10.9Hz), 4.16 (1H, dd, J = 10.9, 4.6Hz), 3.81 (3 H, s), 3.54-3.63 (lH, m), 2.63 (3H, s), 2.38 (1H, dd , J = 7.3, 3.0Hz), 1.30 (lH, dd, J = 4.3, 3.6Hz)

FABMS (m / z); 397 (M + 3) ⁺ , 395 strokes ⁺

 IR (KBr) v (cm: 1701, 1670, 1606, 1487, 1390, 1294, 1248, 1217, 1109.1072 Example 2: Synthesis of compound 2

1.32 ml of acetonitrile and 15.21 of 48% hydrobromic acid were added to 26.6 mg (0.0674 mmol) of compound 1, and the mixture was stirred at room temperature for 1 hour. Next, the solvent was removed from the reaction mixture under reduced pressure. The obtained crude product was dissolved in a mixed solvent of methylene chloride (1.32 ml) and toluene (0.53 ml), and at -78 ° C, 40.8 mg (0.20 mmol) of p-nitrophenyl chloroformate and 37.6 1 of triethylamine were dissolved. (0.270 mmoi) and stirred for 65 minutes. Next, 26.2 l (0.236 mmol) of N-methylbiperazine was added to this solution, and the mixture was stirred at -78 to 0 ° C for 1 hour and 25 minutes. To this reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The port-form layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. . The obtained crude product was purified by thin-layer chromatography (chloroform: methanol-9: 1) to obtain 31.6 mg of Compound 2 (yield: 78%).

¹ HN R (270MHz, CDCl ₃ ) δ (ppm); 9.45 (1Η, s), 8.19 (lH, brs), 7.94 (1H, d, J = 14.9Hz), 7.38 (lH, d, J = 5.0Hz ), 7.30 (1H, d, J = 3.3Hz) .7.07 (1H, dd, J = 5.9, 3.6Hz), 6.72 (lH.d, J = 14.9Hz), 4.46-4.58 (lH, m), 4.42 (1 (1, d, J = 10.6Hz), 4.29 (1H ₍ dd, J = 9.6, 8.9Hz), 3.94 (3H, s), 3.79 (lH, dd, J = 9.9, 2.7Hz), 3.73 ( 2H.br), 3.63 (2H, br), 3.20 (lH, dd, J = 10.2,9.9Hz), 2.47 (4H, br), 2.43 (311, s), 2.34 (3H, s)

FABMS (m / z); 603, 601 (M + H) ⁺

lR (Br) v (cm; 1697, 1645, 1435, 1421, 1406, 1292,〗 217,]] 51, 1093, 1005 Example 3: Synthesis of compound 3

 To 19.7 mg (0.0328 mmol) of the compound 2, ethanol (.98 ml) and methanol (0.49 ml) and then 6.86 N hydrogen chloride-ethanol solution (9.561) were added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The solvent was removed from the reaction solution under reduced pressure to obtain 19.8 mg of compound 3.

1 HNR (270MHz, DMSO-de) δ (ppm); 12.08 (1Η, s), 10.49 (1H, br), 8.09 (Π1, brs), 7.77 (lH, d, J = 15.2Hz), 7.71 (lH, d, J = 5.0Hz), 7.58 (1H, d, J = 2.6Hz), 7.17 (lH, dd, J = 4.3,4.3Hz), 6.86 (lH, d, J = 14.9Hz), 4.31-4.51 (3H, m), 4.20-4.30 (2H, br), 3.8 4 (3H, s), 3.80 (lH, dd, J = 9.2,2.0Hz), 3.40-3.56 (7H, m), 2.85 (3H, s), 2.68 (3H, s)

 IR (KBr) v (cm — '): 1716, 1695, 1647, 1435, 1408.〗 340, 1250, 1221, 1171.1093 Example 4: Synthesis of compound 4

 After adding 0.3 ml of DMF to 4.7 mg (0.118 mmol) of 60% sodium hydride, 0.4 ml of a DMF solution of 25 mg (0.097 mmol) of compound (A) was added, and the mixture was stirred at -20 ° C for 2 hours and 30 minutes under an argon atmosphere. did. To this reaction solution, 0.4 ml of a DMF solution of 34.lmg (0.112 mmol) of compound b was added, and the mixture was stirred for 1 hour. Next, 0.01 M phosphate buffer at pH 7 was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified by silica gel chromatography (form: methanol = 100: 1) to obtain 32.5 mg of Compound 4 (yield 79%).

¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ 0D) δ (ppm); 7.64 (1H, d, J-15.2 Hz), 6.87 (lH, s). lH.br), 6.49 (lH.d, J = 15.2Hz), 6.29 (lH, s), 4.11 (1H, d, J-10.9Hz), 4.04 (lH, dd, J-10.6,4.3Hz). 3.70 (6H, s), 3.46-3.9 (1H, m), 2.27 (1H, dd, J = 7.3,3.3Hz), 1.20 (lH, dd, J = 4.3,4.0Hz)

FABMS (m / z); 425 (M + H) +

 IR (Br) v (cm— '): 1701, 1606, 1549, 1450, 1387, 1360, 1277, 1217, 1109, 1070 Example 5: Synthesis of Compound 5

 To 22.7 mg (0.0535 mmol) of compound 4 were added 3 ml of acetonitrile 1.) and 48% hydrobromic acid 12. The mixture was stirred at room temperature for 40 minutes, and the solvent was removed from the reaction mixture under reduced pressure. The obtained crude product was dissolved in a mixed solvent of methylene chloride (1.13 ml) and toluene (0.45 ml), and at -78 ° C, 32.4 mg (0.161 mmol) of p-nitrophenyl chloroformate and triethylamine were added. 29.81 (0.214 mmol) was added, and the mixture was stirred for 20 minutes. Next, 20.81 (0.187 mmol) of N-methylbiperazine was added to this solution, and the mixture was stirred at -78 to 0 C for 30 minutes. To this reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with black hole form. The chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The resulting crude product was purified by thin-layer chromatography (form: methanol = 9: 1) to obtain 30.2 mg of Compound 5 (89% yield).

 'H-NMR (270 MHz, CDCl3) δ (ppm); 9.51 (1H, s), 8.17 (] H, brs), 7.79 (lH, d, J = 15.2 Hz), 6.95 (lH, s), 6.69 ( lH, d, J = 14.9Hz), 6.33 (lH, s), 4.51 (lH, br), 4.40 (lH, d, J = 10.2Hz), 4.27 (lH, dd.J = 9.9,8.6Hz), 3.93 (3H, s), 3.8K3H, s), 3.78 (1H, brd, J = 10. lllz), 3.72 (2H, br), 3.62 (2H, br). 3.19 (lH, dd, J = 10.2, 9.9Hz), 2.48 (4H, br), 2.4K3H, s), 2.33 (3H, s)

FAB S (m / z); 633,631 (M + H) ⁺

 IR (KBr) v (cm —; 1699, 1645, 1551, 1433, 1404, 1383, 1348, 1292, 1215, 1151, 109

Three

Example 6: Synthesis of compound 6

To 18.6 mg (0.0295 mmol) of compound 5, 0.93 ml of ethanol and 0.46 ml of methanol and then 8.6 fi \ of 6.86 N hydrogen chloride-ethanol solution were added, and the mixture was stirred at room temperature for 2 hours and 40 minutes. The solvent was removed from this reaction solution under reduced pressure to obtain 19.6 _{mg of} compound 6. ¹ H-NMR (270MHz, DMSO-de) δ (ppm); 12.09 (1H, s), 10.53 (1H, br), 8.08 (Π1, brs), 7 61 (lH, d, J = 14.9Hz) , 7.32 (1H, s), 6.87 (1H, d, J = 14.9Hz), 6.78 (lH, s), 4.28-4.56 (3H, m), 4.05-4.26 (2H, br), 3.84 (311 , s), 3.81- 3.82 (1H, br), 3.77 (3H, s), 3.41-3.60 (7H, br), 2.85 (3H, s), 2.68 (3H, s)

 IR (Br) v (cm; 1716, 1697, 1647, 1551, 1435, 1406, 1221, 1157, 1093

Example 7: Synthesis of compound 7

 1.81 ml of acetonitrile and 19.57 u1 of 48% hydrobromic acid were added to 19.9 mg (0.0431 minol) of compound 4, and the mixture was stirred at room temperature for 60 minutes. Next, the solvent was removed from the reaction mixture under reduced pressure. The obtained crude product was dissolved in 1.81 ml of methylene chloride, and at 0, 12.6 I (0.134 mmol) of acetic anhydride and 16.8 mg (0.138 mmol) of 4-dimethylaminopyridine were added, followed by stirring for 60 minutes. To this reaction mixture was added 0.01 M phosphate buffer (pH 7), and the mixture was extracted with black hole form. The port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: methanol = 20: 1) to obtain 22.lmg of Compound 7 (94% yield).

'Η- NMf 270MHz, C () Cl ₃ ) δ (ppm); 9.15 (1H, s), 8.24 (lH, brs), 7.80 (III, d, J = H.9Hz), 6.94 (1H, s) , 6.69 (lH, d, J = 14.9Hz), 6.33 (1H.s), 4.48-4.59 (IH, m), 4.4K1H, d, J = 10.2Hz), 4.28 (111, dd, J = 9.1. 8.9Hz), 3.94 (3H, s), 3.82 (3H, s), 3.80 (lH, brs), 3.22 (lH, brd, J = 10.6Hz), 2.57 (311, s), 2.34 (3H, s )

FABMS (m / z); 549, 547 (M + H) "

 IR (Br) v (cm "'); 1767, 1697, 1645, 1551, 1435, 1408, 1348, 1205, 1188, 1088 Example 8: Synthesis of Compound 8

After adding 0.3 ml of DMF to 4.7 mg (0.118 mmol) of 60% sodium hydride, 0.4 ml of a DMF solution of 25 mg (0.097 mmol) of compound (A) was added, and the mixture was stirred at -20 under an argon atmosphere for 2 hours and 20 minutes. did. To this reaction solution, 0.4 ml of a DMF solution of 32.6 mg (0.107 mmol) of compound c was added, and the mixture was stirred for 2 hours and 20 minutes. To this reaction mixture was added 0.01 M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (closure: medium: 200: 1 to 100: 1), 25.8 mg (yield 63%) of compound 8 was obtained.

^{1 H-NMR (270 Hz,} CDCl 3) δ (ppm);. 11.69 (1Η, br), 7.79 (1H, d, J = 14.8Hz), 7. OOdH.d, J = 4 OHz), 6.79 ( lH, br), 6.32 (1H, d, J = 14.8Hz) .6.18 (1H, d, J = 4.OHz), 4.19 (1H, d, J = 10.6Hz), 4.] 3 (lH, dd J = 10.9,4.3Hz), 3.94 (3H, s), 3.80 (3H, s), 3.53-3.5 8 (lH, m), 2.63 (3H, s), 2.36 (1H, dd, J = 7.4, 3.1Hz), 1.28 (1H, dd, J = 4.6,3.6Hz) FAB S z); 425 (M + H) ⁺

Example 9: Synthesis of compound 9

 0.79 ml of acetonitril and 8.5 u1 of 48% hydrobromic acid were added to 15.9 mg (0.0375 mmol) of compound 8, and the mixture was stirred at room temperature for 30 minutes. Next, the solvent was removed from the reaction mixture under reduced pressure. The obtained crude product was dissolved in a mixed solvent of methylene chloride (0.79 ml) and toluene (0.32 ml) .At -78, p-nitrophenyl chromate formate 22.7 mg (0.113 mmo!) And triethylamine 20.9〃 (0.150 mmol) and stirred for 30 minutes. Next, 14.6 l (0.131 mmol) of N-methylbiverazine was added to this solution, and the mixture was stirred at -78 to 0 t for 30 minutes. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The port-form layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: methanol = 9: 1) to obtain 17.2 mg of Compound 9 (yield 73%).

'H-NMR (270MHz, CDC) δ (ppm); 9.23 (lH, brs), 8.19 (lH, brs), 7.80 (1H.d, J = 14.8 Hz), 6.97 (lH, d, J = 4. OHz). 6.40 (1H, d, J = 14.8Hz). 6.17 (lH, d.J = 4.OHz), 4.53 (1H.brt, J = 9.2Hz), 4.39 (lH, d.J = 10.2 Hz), 4.26 (1H, dd, J = 9.9, 8.9Hz), 3.95 (3H.s), 3.94 (3H, s), 3.79 (lH, dd, J = 9.9,2.3Hz), 3.73 (2H.br ), 3.62 (2H, br), 3.20 (1H, dd, J = 10.2,9.9Hz) ₍ 2.51 (3H, s), 2.48 (4H, br), 2.35 (3H, s)

FABMS (m / z); 603,601 (+ H) ⁺

IR (KBr) v (cm- ¹ ); 1726, 1697, 1643, 1485, 1404, 1290, 1215, 1151, 1098

Example 10: Synthesis of compound 10

To 12.1 mg (0.0192 mmol) of compound 9 were added 0.60 ml of ethanol and 0.30 ml of methanol, and then 5.6 u1 of 6.86 N hydrogen chloride-ethanol solution, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The solvent was removed from this reaction solution under reduced pressure to obtain 11.7 mg of compound 10. ¹ H-NMR (270 MHz.DMSO-de) δ (ppm); 12.06 (1H, brs), 10.53 (lH, br), 8.07 (1H, brs), 7.64 (lH, d, J = 15.2 Hz), 7.25 (1H, d, J = 4.0Hz), 6.50 (1H, d, J = 14.9Hz), 6,38 (lH, d, J = 3.6Hz), 4.10-4.52 (5H, m), 3.94 (3H, s), 3.84 (3H, s), 3.78-3.81 (1H, m), 2.86 (3H, s), 2.67 (311, s)

 IR (KBr) v (cm: 1716.1697, 1637, 1541, 1437, 1417, 1406, 1250, 1219, 1095 Example 11 1: Synthesis of Compound 11

 After adding 0.3 ml of DMF to 4.7 mg (0.118 mmol) of 60% hydrogenated sodium hydroxide, 0.4 ml of a DMF solution of 25 mg (0.097 mmol) of compound (A) was added, and the mixture was stirred at -20 ° C for 2 hours under an argon atmosphere. Stir for 30 minutes. To this reaction solution was added 0.4 ml of a DMF solution containing 37.4 mg (0.107 mmol) of compound d, and the mixture was stirred for 3 hours. To this reaction mixture was added 0.01 M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatographic chromatography (form: chloroform = 9: 1) to obtain 29.6 mg of Compound 1i (yield 67Q / 6).

 'HNR (270 Hz, CDC) δ (ppm); 12.04 (1H, brs), 7.75 (lH, d, J = 15.2Hz). 6.77 (1H, brs), 6.42 (lH.d.J = 15.2Hz) ), 5.96 (lH, s), 4.19 (111, d, J = 10.9Hz), 4.12 (lH, dd, J = 10.9, .0Hz), 3.90 (3H, s), 3.82 (3H, s), 3.78 (3H, s), 3.52-3.58 (lH, m), 2.6 "3H, s), 2.34 (lH, dd, J = 7.3, 3.0Hz), 1.27 (1H, dd, J = 4.0, 4.0Hz)

FABMS (m / z); 457, 455 (+ H) ⁺

 IR (KBr) v (cm: 1701, 1603, 1452, 1389, 1292, 1248, 1215, 1174, 1109, 991 Example 11 1: Synthesis of compound 12

 After adding 0.3 ml of DMF to 5.3 mg (0.133 mmol) of 60% sodium hydride, compound (A)

0.4 mg of a 25 mg (0.097 mmol) DMF solution was added, and the mixture was stirred at -20 ° C for 2 hours and 30 minutes under an argon atmosphere. To this reaction mixture was added 0.4 ml of a DMF solution of 32.6 mg (0.107 country) of compound e, and the mixture was stirred for 3 hours and 30 minutes. To this reaction mixture was added 0.01 M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: methanol = 15: 1) to give 25 g of compound 1.

(62% yield). 'H-NMR (270MHz, CDCI3 + CD3OD) δ (ppm); 7.52 (1H, d, J = 15.2Hz), 6.81 (1H, d, J = 1.7Hz), 6.60 (lH, br), 6.46 ( 1H, d, J = 15.2Hz), 6.33 (1H, d, J = 1 .7Hz), 4.15 (1H, d, J = 10.9Hz), 4.07 (lH, dd, J = 10.9, 4.6Hz), 3.85 (3H, s), 3.75 (31), s), 3.47-3.5 (lH, m), 2.50 (3H, s), 2.32 (lH ₍ dd, J = 7.6,3.6Hz), 1.24 (1H, dd , J = 5.0, 3.3Hz)

FAB S (m / z); 427, 25 (M + H) +

 IR (KBr) v (cm-'): 1701, 1668, 1620, 1601, 1485, 1454, 1392, 1292, 1219, 1109, 1072 Example 13: Synthesis of Compound 13

 After adding 3 ml of DMFO to 5.6 mg (0.40) ol of 60% sodium hydride, 0.5 ml of a DMF solution of 30 mg (0.116 ol) of compound (A) was added, and the mixture was added at -20 ° C under an argon atmosphere. For 2 hours and 30 minutes. To this reaction solution was added 0.5 ml of a DMF solution containing 50.8 mg (0.128 mmol) of compound f, and the mixture was stirred for 2 hours and 45 minutes. To this reaction mixture was added 0.01M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform: methanol = 100: 1 to 70: 1) to obtain 43.9 mg of compound 13 (yield 73%).

'H-NMR (270 MHz, CDCI ₃ ) 8 (ppm); 11.88 (1H, br), 10.64 (lH, brs), 7.65 (1H.d, J = l 5.5 Hz), 7.23 (lH, d, J = 17.2Hz), 6.73 (lH, s), 6.58 (1H, s), 6.43 (1H, brs), 4.23-4.27 (2H, br). 3.86 (3fl, s), 3.84 (3H, s) , 3.80 (3H, s), 3.64 (3H, s), 3.37 (111, br), 2.35 (3H, s), 2.22 (lH, br), L53 (lH.br)

FABMS (m / z); 520,518

 IR (KBr) v (cm-one; 1705, 1660, 1608, 1464, 1390, 1360, 1294, 1219, 1109

Example 14: Synthesis of compound 14

1.32 ml of methylene chloride and 187 mg of a 5% hydrobromic acid-methanol solution were added to 20.0 mg (0.0386 mmol) of the compound 13, and the mixture was stirred at room temperature for 30 minutes. Next, 63 mg of a 5% solution of monohydrobromic acid in methanol was added, and the mixture was further stirred for 40 minutes. To this reaction mixture, 23.3 mg (0.116 mmol) of p-nitrophenyl chloroformate and 21.5 1 (0.154 mmol) of triethylamine were added at -78 t, and the mixture was stirred for 25 minutes. Next, 15.0 wI (0.135 mmol) of N-methylbiverazine was added to this solution, and the mixture was stirred at -78 to 0 ° C for 30 minutes. To this reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with chloroform. K The roloform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: methanol = 15: 1) to obtain 21.3 mg of compound 14 (76% yield).

 Ή-NMR (270MHz, CDC) δ (ppm); 9.45 (1H, s), 8.61 (lH.s), 8.24 (111, s), 7.32 (1H, d, J = 15.2Hz), 6.78 (1H, s), 6.42 (lH, s), 6.20 (1H, d, J = 15.2Hz), 4.32- 4.43 (1H, m),.) 1 (311, s), 4.04-4.21 (2H, br), 3.99 (3H, s), 3.90 (6H, s), 3.71-3.87 (5H, m), 3.29 (lH, dd, J = 10.6, 10.2Hz), 2.58 (4H, br), 2.40 (3H.s), 1.88 (3H, s)

FAB S (m / z); 726, 724 (M + H) ⁺

IR (KBr) v (cm- ¹ ); 1701, 1647, 1464, 1458, 1429, 1414, 1292, 1155, 1095

Example I 5: Synthesis of compound 15

 To 16.1 mg (0.0222 mmol) of compound 14 was added 1.6 ml of dried ethyl acetate, and 107.8 mg of a 5% solution of monohydrobromic acid in methanol was added, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was removed from this reaction solution under reduced pressure to obtain 16.5 mg of compound 15.

Ή-NR (270MHz, DMSO-de) δ (ppm); 12.0 (1Η, s), 11.9 (1H, s), 9.87 (1H, br) .8.13 (1H, s), 7.56 (lH, d , J = 15.2Hz), 7.30 (lH, d, J = 15.2Hz), 6.86 (lH, s), 6.79 (lH, d, J = 1.7llz), 4.37-4.59 (3H, m), 4.00 (3H , s), 3.86 (3H.s), 3.80 (6H, s), 3.71 (lH, br), 3 53-3.58 (511, br), 3.15-3.34 (4H, br), 2.90 (3H, d , J = 4.0Hz), 2.69 (3H, s) IR (KBr) v (cm; 1699.1695, 1645, 1470, 1435, 1423, 1416, 1254, 1219, 1095 Example 16: Synthesis of compound No. 6

To 19.5 mg (0.0377 mmol) of Compound 13 were added 1.30 ml of methylene chloride and 183 mg of a 5% hydrobromic acid-ethanol solution, and the mixture was stirred at room temperature for 35 minutes. Next, _{61 mg} of a 5% hydrobromic acid-ethanol solution was added, and the mixture was further stirred for 40 minutes. To this reaction mixture, 10.71 (0.113 mmol) of acetic anhydride and 13.8 mg (0.113 mmol) of 4-dimethylaminopyridine were added, and the mixture was stirred at 0 ° C for 60 minutes. Further, 0.07 M phosphate buffer of pH 7 was added, and the mixture was extracted with black hole form. The port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by liquid preparative chromatography (acetonitrile: water = 70: 30) to obtain 13.7 mg of compound 16 (57% yield). _{Ή-NMR (270MHz, CDC1 3} ) δ (ppm): 8.68 (1H, brs), 8.55 (1H, brs), 7.56 (1H, d, J = 15.2 Hz), 6.79 (lH, s), 6.60 (lH , s), 6.46 (1H, d, J = 15.2Hz) .4.42-4.53 (lH, m), 4.33 (lH.d, J = 10.2Hz), 23 (lH, dd, J = 9.9,8.6Hz) , 4.11 (3H, s), 3.96 (3H, s), 3.95 (3H, s), 3.90 (3H, s), 3.78 (lH, dd, J = 9.7,2.5Hz), 3.31 (1H, dd, J = 10.2, 10.2Hz), 2.4 4 (3H, s) .2.34 (3H, s)

FABMS z); 642, 640 (+ H) ⁺

 IR (KBr) v (cm; 1678, 1643, 1468, 1306, 1217, 1201, 1122, 1107, 1088

Example 17: Synthesis of compound 17

 To 30.Omg (0.058 mmol) of Compound 13 was added 1.41 ml of methylene chloride and 282 mg of a 5% solution of hydrobromic acid in methanol, and the mixture was stirred at room temperature for 30 minutes. Next, 94 mg of a 5% hydrobromic acid-methanol solution was added, and the mixture was further stirred for 20 minutes. To this reaction mixture, 35.lmg (0.174mmol) of p-diethylamine and 0.14mmol of triethylamine (0.29%) were added at -78 ° C, and the mixture was stirred for 25 minutes. Next, to this solution was added methylhydrazine 15.41 (0.29 marl), and the mixture was stirred at -78 to 0 for 30 minutes. To this reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: methanol = 25: 1) to obtain 28.lmg of compound 17 (yield 72%).

¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ OD) δ (ppm); 8.11 (IH, s) .7.46 (lH, d, J = 15.2 Hz), 6.72 (1H, s), 6.66 (lH, d , J = 15.2Hz) .6.53 (lH, s), 4.27-4.39 (lH, br), 4.30 (1H, d, J = 10.2Hz), 4.10 (lH, dd, J = 9.9,9.2Hz), 4.02 (3H, s), 3.89 (3H ₍ s), 3.86 (3H, s), 3.83 (3H, s), 3.70 (lH, dd, J = 9.6,2.3Hz), 3.28 (3H, brs), 3.20 (IH, dd, J = 10.2, 9.9Hz), 2.30 (3H, s)

FABMS (m / z); 672,670 (M + H) ⁺

 IR (KBr) v (cm — ri; 170], 1697, 1645, 1466, 1414, 1350, 1306,] 219, 1159, 1109, 109 0

Example 18: Synthesis of compound 18

After adding 5 ml of DM to 14.9 mg (0.372 country ol) of 60% sodium hydride, the compound (A ) 80 mg (0.310 mmol) of DMF solution]. Lml was added, and the mixture was stirred at -20 ° C for 2 hours and 40 minutes under an argon atmosphere. To this reaction solution, 1. Jml of a DM solution of 99.3 mg (0.341 mmol) of compound g was added, and the mixture was stirred for 1 hour and 50 minutes. To this reaction mixture was added 0.01 M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform: methanol = 100: 1) to obtain 95.2 mg of Compound 18 (81% yield).

 Ή-NR (270MHz, CDCI3 + CD3OD) δ (ppm); 7.61 (IH, d, J = 1.7Hz), 7.03 (1H, d, J = 2.0Hz), 6.37 (1H, s), 4.20 (lH , dd, J = 10.2,4.6Hz), 4.09 (IH, d, J = 10.9Hz), 3.82 (3H, s), 3.74 (3H, s), 3.47- 3.52 (111, m), 2.48 (3H, s), 2.37 (111, dd, J = 7.6,3.6Hz), 1.33 (lH, dd, J = 5.0,4.0Hz)

FAB S (m / z); 411 (M + H) ⁺

 IR (KBr) v (cm); 1703, 1610, 1506, 1489, 1383, 1315, 1294, 1269, 1215, 1107 Example 19: Synthesis of compound 19

 To 20 mg (0.0526 mmol) of compound 18 were added 1.28 ml of acetate nitrile and 17.91 of 48% hydrobromic acid, and the mixture was stirred at room temperature for 50 minutes. Next, the solvent was removed from the reaction mixture under reduced pressure. The obtained crude product was dissolved in 1.28 ml of methylene chloride, and at 0 ° C, 15.I (0.163 mmol) of sulfuric anhydride and 20.5 mg (0.168 mmol) of 4-dimethylaminopyridine were added, and the mixture was stirred for 2 hours and 40 minutes. did. To this reaction mixture was added 0.01M phosphate buffer (pΠ7), and the mixture was extracted with black hole form. The port-form layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (black-mouthed form: methanol = 15: 1) to obtain 24.lmg of Compound 19 (86% yield).

¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm); 8.80 (IH, s), 7.91 (IH, brs), 7.62 (lH, d, J = l.3 Hz), 7.lKlH.d, J = 1.3Hz), 4.34-4.48 (3H, m), 3.94 (3H, s), 3.92 (3H, s), 3.76 (lH, dd, J = 9.9,2.6Hz), 3.30 (IH, dd, J = 9.9 , 8.9Hz), 2.63 (3H, s), 2.36 (3H, s)

FABMS (m / z); 535, 533 (M + H) +

IR (KBr) v (cm): 1763, 1697, 1643, 1506, 1498, 1417, 1398, 1306, 1201, 1107 Example 20: Synthesis of compound 10 3 ml of DM) was added to 5.6 mg of 60% sodium hydride (0.139 mol), 0.4 ml of a DMF solution of 30 mg (0.116 mol) of compound (A) was added, and the mixture was added under argon atmosphere at -20 ° C. The mixture was stirred for 40 minutes. To this reaction solution was added 0.4 ml of a DMF solution of 46.lmg (0.128 mmol) of compound h, and the mixture was stirred for 2 hours and 40 minutes. To this reaction mixture was added 0.01 M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform: methanol = 100: 1), and then purified by thin-layer chromatography (chromaform: methanol = 20: 1). 34.8 mg (yield: 62%) of compound 20 was obtained.

¹ H-NMR (270 Hz, CDCl ₃ + CD ₃ OD) δ (ppm); 7.03 (1Η, s), 6.70 (lH, br), 6.40 (2H, br), 4.21 (lH.dd, J = 10.9 , 4.6Hz), 4.08 (1H, d, J = 10.9Hz), 3.77 (3H, s), 3.76 (3H, s), 3.45-3.51 (lH, m), 2.54 (3H, s), 2.35 (1H, dd, J = 7.6,3.3Hz), 1.45 (9H, s), L 34 (1H, dd, J = 5.0, 3.6Hz)

FAB SWz); 481 (M + H) +

 IR (KBr) v (cm: 1705, 1701, 1653, 1608, 1587.1450, 1381, 1296, 1269, 1215, 1159, 1107

Example 21: Synthesis of compound 21

 To 2.6 mg (0.0652 ol) of 60% sodium hydride, 1 ml of DMFO was added, and then 0.3 ml of a DMF solution of 14 mg (0.0543 mmol) of compound (A) was added, and the mixture was stirred at -20 ° C for 2 hours under an argon atmosphere. For a minute. To this reaction solution was added 0.3 ml of a DMF solution of 24.7 mg (0.0597 mmol) of compound.i, and the mixture was stirred for 2 hours and 20 minutes. To this reaction mixture, a 0.01 M phosphate buffer at pH 7 was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: methanol = 20: 1) to obtain 14 mg of compound 21 (yield: 48%).

'H-NMR (270MHz, CD 3 0D) δ (ppm); 7.65 (1Η, s), 7.40 (1H, s), 7.37 (2H, br), 6.73 (1H, s), 4.30 (lH, dd, J = 10.9,4.3Hz), 4.16 (lH, d, J = ll.2Hz), 4.02 (3H, s), 3.83 (6H, s), 3.52-3.6] (lH, m), 2.57 (3H, s ), 2.43 (1H, dd. J = 7.7,3.4Hz), 1.44 (1H, dd, J = 5.0, 4.0Hz) FABMS (m / z); 533 (M + H) +

IR (KBr) v (cm ¹ ); 1701, 1653, 1603, 1 78, 1498, 1437, 1398, 1381, 1309, 1254, 110 7

Example 12: Synthesis of compound 21

 To 25 mg (0.052 mmol) of compound 20 were added 2 mi of 1,2-dichloroethane and 252 mg (0.156 mmol) of a 5% hydrobromic acid-ethanol solution, and the mixture was stirred at 50 ° C for 2 hours and 20 minutes. Thereafter, 587 mg (0.364 mmol) of a 5% hydrobromic acid-ethanol solution was added, and the mixture was further stirred for 5 hours and 10 minutes. To this reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with a black hole form. The pore-form layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 24 mg of an amino compound.

To the above 24 mg (0.052 mmol) of the amino acid suspension, 1.2 ml of THF, 18.2 mg (0.0624 mmol) of DFO.2mU compound i, 11.8 g of cyanophosphate decyl phosphate (DECP); υ1 (0.078 mmol) and triethylamine 21.7 1 (0.0156 ol) was added sequentially, and the mixture was stirred at 0 ° C to room temperature for 16 hours. Next, 0.01 M phosphate buffer at pH 7 was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: methanol = 12: 1) to obtain 12.2 mg of Compound 22 (36% yield). - NMH (270MHz, CDCh + CD 3 0D) δ (ppm);. 7.55 (1H (d, J = 2.0Hz) 7.31 (211, br), 7.24- 7.26 (2H, br), 7.19 (lH, s) , 6.70 (1H, s), 6.57 (111, d, J = 2.0Hz), 6.29 (lH, s), 4.2 KlH.dd, J = l 1.2,4.6Hz), 4.07 (lH, dJ = ll.2Hz ), 3.97 (3H, s), 3.87 (3H, s), 3.77 (3H, s), 3.76 (3H, s), 3.49-3.53 (1H, m), 2.5K3H, s), 2.38 (1H, dd) , J = 7.3,3.3Hz), 1.38 (lH.dd.J .6,4.0Hz)

FABMS (m / z); 655 (M + H) ⁺

lR (KBr) v (cm ¹ ); 1701, 1684, 1653, 1647, 1578, 1560, 1437, 1381, 1309, 1257, 110 9

Example 3 Synthesis of Compound 23

26 mg (0.0541 mmol) of compound 20 in 1,2-dichloromethane 2 ml and 5% bromide 875 mg (0.541 mmol) of a hydrochloric acid-ethanol solution was added, and the mixture was stirred at 60 ° C for 4 hours. To this reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The port-form layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain 21.6 mg of an amino compound.

 To 21.6 mg (0.0541 ol) of the amino compound, THF3m was added, and 23.5 mg (0.0649 mmol) of compound k, 12.3 mmol (0.0812 mmol) of DECP, and 22.6〃1 (0.162 mmol) of triethylamine were sequentially added, and the mixture was added at 0 ° C. Stirred at ~ room temperature for 16 hours. Next, 0.0] M phosphate buffer (pH 7) was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: mesanol = 12: 1) to obtain 17.5 mg of compound 23 (yield: 45%).

^L H-NMR (270 MHz, CDCl3 + CD ₃ QD) δ (ppm); 8.81 (1Η, brs), 8.61 (1H, brs), 7.30 (1H, s), 7.15 (1H, brs), 7.05 (1H, brs), 6.75 (1H, brs), 6.69 (1H, brs), 6.58 (1H, s), 6.55 (lH, brs), 6.36 (1H, s), 4.20 (1H, dd, J = l 1.1 , 4.5Hz), 4.06 (1H, d, J = 10.6Hz), 3.82 (3H, s), 3.80 (3H, s), 3.75 (3H, s), 3.74 (3H, s), 3.42-3.50 (lH, m), 2.9 (3H, s), 2.32 (lH, dd, J-7.8,3.5Hz), 1.43 (9H, s), 1.32 (1H, dd, J = 4.9, 4.0Hz)

FABMS (m / z); 725 (M + H) "

lR (KBr) v (cm- ^; ): 1701, 1653, 1635, 1616, 1583, 1458, 1398, 1381, 1263, 1161 Example 24: Synthesis of Compound 14

 To 17.5 mg (0.0241 mmol) of compound 23 were added 9 ml of acetonitrile 1.] and 117 mg (0.0723 mmol) of a 5% solution of monohydrobromide in methanol, followed by stirring at room temperature for 60 minutes. Next, the solvent was removed from the reaction mixture under reduced pressure. The obtained crude product was dissolved in methylene chloride 1.】 9 n »l, and at 0 ° C, 7.04〃1 (0.0747 mmol) of acetic anhydride and 9.41 mg (0.0771 mmol) of 4-dimethylaminoviridine were added, and the mixture was added for 2 hours. Stirred for minutes. To this reaction mixture was added 0.01 M phosphate buffer (pH 7), and the mixture was extracted with chloroform. The port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: medium = 12: 1) to obtain 15.24 mg (yield: 74%) of compound 24.

_{1H-NMR (270MHz) CDCl3 +} CD 3 0D) δ (ppm); 8.82 (lH.brs), 8.27 (lH, brs), 7.74 (lH, br s), 7.26 (1H, s), 7.08 (lH, s), 7.08 (1H, d, J = l.7Hz), 6.70 (lH, s), 6.63 (lH, s), 6.56 (lH, brs) , 4.31 (lH.d, J = 10.9Hz), 4.12-4.22 (lH, m), 4.05 (1H.dd, J = 9.6,9.2 Hz), 3.84 (3H, s), 3.83 (3H, s), 3.80 (3H, s). 3.73 (3H, s), 3.63 (1H, dd, J = 9.6, 2.OHz), 3.22 (lH, dd, J = 9.2,9.2Hz), 2.43 (3H, s), 2.32 (3H, s), 1.45 (9H, s)

FABMS (m / z); 849, 847 (+ H) ⁺

IR (KBr) v (cm- ¹ ); rat 1641, 1587, 1541, 1489, 1443, 1404, 1367, 1252, 1205, 1190, 1107

Example 15: Synthesis of compound 25

 After adding 0.3 ml of DMF to 5.6 mg (0.139 mmol) of 60% sodium hydride, 0.5 ml of DMF solution of 30 mg (0.116 bandol) of compound (Λ) was added, and the mixture was added at -20 ° C under argon atmosphere. The mixture was stirred for 40 minutes. To this reaction solution was added 0.5 ml of a DMF solution containing 40.5 mg (0.128 mmol) of compound L, and the mixture was stirred for 2 hours and 30 minutes. To the reaction mixture was added pII7 0.01M phosphate buffer and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform: ethanol = 150: 1 to 100: 1) to obtain 27.4 mg of compound 25 (yield 54%).

^{1 H-NMR (270MHz, DMSO} -de) δ (ppm); 12.39 (1H, s), 8.15 (lH, d, J = l.7Hz), 7.56 (lH.d, J = 1.7Hz), 7.52 ( lH, d, J = 15.2Hz), 7.04 (1H, d, J = 15.2Hz), 6.91 (lH.br), 4.35 (1 Hd, J = 10.6Hz), 4.19 (lH, dd, J = 10.7, 4.8Hz), 3.82 (3H, s), 3.73 (3H, s), 3.45-3.51 (lH.m), 2.46 (3H, s), 2.10 (1H, dd, J = 7.4, 3.lHz) , 1.29 (1H, dd, J = 4.3, 3.6Hz) FABMS (m / z); 437 (M + H) +

IR (KBr) v (cm- ^l ); 1668, 1614, 1583, 1506, 1495, 1433, 1394, 1311, 1294, 1279, 124 6

Example 16: Synthesis of compound 16

To 19.7 mg (0.0451 mmol) of compound 25, 1.2 ml of acetonitrile and 219 mg (0.135 mmol) of a 5% solution of hydrobromic acid in methanol were added, and the mixture was stirred at room temperature for 50 minutes. Next, the solvent was removed from this reaction mixture under reduced pressure. The obtained crude product was dissolved in 1.2 ml of methylene chloride, and at 0 ° C, 12.81 (0.135 mol) of acetic anhydride and 16.5 mg (0.135 mmol) of 4-dimethylaminoviridine were added, followed by stirring for 1 hour and 30 minutes. . This reaction mixture Was added to a 0.01 M phosphate buffer at pH 7 and extracted with black hole form. The port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (form: chloroform: 30: 1) to obtain 22.4 mg of Compound 26 (89% yield).

 'H-NMR (270 MHz, DSO-d 6) δ (ppm); 12.02 (1H, s), 8.13 (lH, d, 0 Hz), 8.06 (lH, brs), 7.65 (lH, brs), 7.50 (1H, d, J = 15.2Hz), 7.21 (1H, d, J = 15.2Hz), 4.49-4.55 (1H, m), 4.45 (lH, d, J = 10.2Hz), 4.35 (1H, dd , J = 9.9, 9.6Hz), 3.85 (3H, s), 3.8K3H, s), 3.79 (lH, dd, J = 11.6, 2.3Hz), 3.42 (1H, dd, J = 9.2, 9.2Hz), 2.65 (3H, s), 2.38 (

3H, s)

 FABMS (m / z): 561, 559 (M + H) +

lR (KBr) v (cm '); 1689, 1684, 1653, 1647, 1508, 1497, 1491, 1437, 1414, 1309, 120 0

 ¾Example 27: Synthesis of compound 27

 To 37.2 mg (0.93 mmol) of 60% sodium hydride, 1 ml of DMF was added, and 3.5 ml of a DMF solution of 200 mg (0.775 mmol) of the compound (A) was added, followed by stirring at −20 ° C. for 2 hours and 30 minutes under an argon atmosphere. To this reaction solution was added 3.5 ml of a DMF solution containing 343 mg (0.891 mmol) of compound m, and the mixture was stirred for 2 hours. To this reaction mixture was added a 0.01 M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform: methanol = 150: 1 to 100: 1) to obtain 233.lmg of compound 27 (yield 59%).

 'H-NMR (270 MHz, CDC) δ (ppm); 11.38 (1Η, brs), 7.68 (1H, d, J = 15.2 Hz), 7.01 (1H, brs), 6.79 (lH.br), 6.50 (lH , s), 6.48 (1H, d, J = 14.8Hz), 6.34 (1H, brs), 4.19 (1H, d, J = 10.9Hz), 4.13 (lH, dd, J = 10.9,4.3Hz), 3.81 (3H, s), 3.67 (3H, s), 3.55-3.57 (lH, m), 2.61 (3H, s), 2.35 (1H, dd, J = 7.4.3.5Hz), 1.50 (9H, s). 1.28 (1H, dd, J = 4.9, 3.6Hz)

 FABMS (m / z); 507 (M + H) +

IR (KBr) v (cm: 1701, 1684, 1653, 1616, 1608, 1576, 1387, 1290, 1244.1219, 116 3 Example 18: Synthesis of compound 28

 To 10 mg (0.0197 mmol) of compound 27, 0.6 ml of methylene chloride and 63.8 mg (0.0394 mmol) of a 5% hydrobromic acid-methanol solution were added, and the mixture was stirred at −20 ° C. for 20 minutes. Next, 5.6 L / I (0.0591 solid 11101) and 7.2 mg of 4-dimethylaminopyridin (0.0591 ss.ol) were added to the reaction solution, and the mixture was stirred for 45 minutes. To this reaction mixture was added 0.01 M phosphate buffer of pH 7 and extracted with black hole form. The port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (cloth form: methanol = 25: 1) to obtain 10.3 mg of compound 28 (83% yield).

¹ H-NMR (270 Mllz ₍ CDCh) δ (ppm); 9.76 (lH, brs), 8.26 (1 H, s), 7.22 (1 H, d, J = 15.9 Hz), 6.63 (lH, s), 6.43 (lH , d, J = 1.7Hz), 6.28 (1H, d, J = 14.8Hz), 6.18 (lH.s), 4.43 -4.53 (lH, m), 4.23-4.29 (2H, m), 3.96 (3H, s), 3.76 (1H, dd, J = 9.6, 2.6Hz), 3.44 (3H, s), 3.38 (lH, dd, J = 10.2, 10.1Hz), 2.51 (3H, s), 2.38 (3H, s ), 1.54 (9H, s) FAB S (m / z); 631, 629 (+ H) +

 IR (KBr) v (cm- '): 1716, 1697, 1686, 1576, 1414, 1400, 1367, 1200, 1188, 1159 Example 19: Synthesis of compound I9

 To 25 mg (0.0494 mmol) of compound 27, 1.25 ml of methylene chloride and 160 mg (0.0988 water) of a 5% hydrobromic acid-methanol solution were added, and the mixture was stirred at −20 ° C. for 20 minutes. To this reaction solution were added, at -78, 29.9 mg (0.148 mmol) of p-nitrotrophyl chloroformate and 20.7 l (0.148 mmol) of triethylamine, followed by stirring for 20 minutes. Next, to this solution was added N-methylbiperazine 19.21 (0.173 mmol), and the mixture was stirred at -78 to 0 ° C for 30 minutes. To this reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with chloroform. The chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin layer chromatography (form: methanol = 12: 1) to obtain 25.8 mg of compound 29 (73% yield).

'H-NMR (270 MHz, CDC) δ (ppm); 9.52 (1H, s), 8.20 (lH, s), 7.61 (1H, d, J = 14.9 Hz), 6.88 (lH, s) .6.55 (lH , s), 6.52 (1H, d, J-14.9Hz), 6.35 (1H, s), 4.45-4.56 (lH, m), 4.38 (lH, d, J = 10.2Hz), 4.25 (111, dd, J = 10.2,8.9Hz), 3.94 (3H, s), 3.77 (1 dd , J = 9.9, 2.311z), 3.60 (3H, s), 3.57-3.75 (4H, br), 3.22 (1H, dd, J = 10.2,9.9Hz) .2.48 (7H, brs), 2.33 ( 3H, s), 1.5K9H, s)

FAB S (m / z); 715, 713 (+ H) +

IR (KBr) v (cm ¹ ); 1701, 1576, 1446, 1402, 1385, 1292, 1238, 1217, 1157 Example 30: Synthesis of compound 30

 To 40 mg (0.155 mmol) of the compound (A) were added 2.2 ml of ethyl acetate and 226 ml (1.55 mmol) of 6.86 N hydrochloric acid, and the mixture was stirred at room temperature for 60 minutes. The solvent was removed from the reaction solution under reduced pressure, and 2 ml of DMF, 72.2 mg (0.186 mmol) of compound n and 88.9 mg (0.465 mmol) of 11- (3-dimethylaminopropyl) -13-ethylcarposimid hydrochloride (EDCI) were added. The mixture was added sequentially, and stirred at room temperature for 17 hours and 30 minutes. To this reaction mixture was added 0.01M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chloroform: methanol = 10: 1) to obtain 32 mg of Compound 30 (yield 31%).

lH-NMR (270MHz, CDC) ₃ + CD ₃ 0D δ (ppm): 8.74 (1Η, brs), 7.69 (1H, s), 7.58 (lH, d, J = 14.9Hz), 7.31 (lH, brs ), 7.18 (lH.s), 6.75 (lH, s), 6.67 (lH, s), 6.55 (1H.s), 6.52 (lH, d, J = 15.5Hz), 4.30 (lH, d, J = 9.9Hz), 4.24-4.33 (lH, br), 4.14 (lH, dd, J = l 0.2,8.9Hz), 3.83 (3H, s), 3.78-3.83 (1H, m), 3.80 (3H, s), 3.63 (3H, s), 3.19 (111, dd, J = 10.6, 10.2Hz), 2.59 (3H, s), 1.4K9H, s)

FABMS (m / z); 667, 665 (M + H) +

 IR (KBr) v (cm-; 1657, 1635, 1585, 1489, 1446.1404, 1367, 1296.1248, 1161.109

Three

Example 31: Synthesis of compound 31

To 12.9 mg (0.0194 mmol) of compound 30 were added L acetonitrile, 0.5 ml of pyridine and 14.5 l (0.097 mmol) of DBU, and the mixture was stirred for 2 hours and 40 minutes. To the reaction mixture was added 0.0IM phosphate buffer at pH 7, and extracted with black hole form. The port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (form: chloroform: 10: 1) to obtain 8.4 mg of Compound 3I (yield 69%). ^{1 H-NMR (270MHz, CDC} 1 3 + CD 3 0D) <5 (ppm): 8.87 (1H, s), 7.61 (1H, d, J = 15.2Hz), 7.34 (lH.s), 6.78 (1H , s), 6.64 (2H, brs), 6.58-6.62 (lH, br), 6.54 (lH, s), 6.43 (lH, d, J = 15.2Hz), 4.13 (lH, d, J = 10.9Hz) , 4.05 (1H, dd, J = 10.9,4.6Hz), 3.79 (3H, s), 3.73 (3H.s), 3.61 (3H, s), 3.46-3.52 (lH, m), 2.48 (3H , s), 2.29 (1H, dd, J = 7.4, 3.5 Hz), 1.1 (9H, s), 1.22 (lH, dd, J = 4.3,4.0Hz)

FABMS (m / z); 629 (M + H) +

 IR (KBr) v (cm- '): 1705, 1651, 1605, 1564, 1452, 1387, 1288, 1244, 1217, 1165 Example 32: Synthesis of Compound 32

To 20 _mg (0.0301 imnol) of the compound 30 was added dichloromethane 2.2%, acetic anhydride 8.511 (0.0903 mmol) and 4-dimethylaminopyridine 11.0 mg (0.0903 mmol), and the mixture was stirred for 65 minutes. To this reaction mixture, a 0.01 M phosphate buffer of PH7 was added, and the mixture was extracted with chloroform. The port-form layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by thin-layer chromatography (chromatography form: methanol = 12: 1) to give 18.32 g (yield 86%) of Compound 32.

'H-NMR (270MHz, CDCl3 + CD ₃ OD) δ (ppm); 8.62 (1H, s), 8.07 (1H, brs), 7.56 (lH, d, J = 14.9Hz), 7.22 (111, brs) , 7.14 (1H, s), 6.75 (lH, s), 6.62 (H, s), 6.53 (lH, s), 6.47 (lH, d, J = 15.2Hz), 4.32-4.43 (lH, m), 4.32 (1H, d, J = 9.9Hz), 4.18 (lH, dd, J = 8.9, 8.9Hz) .3.86 (3H, s), 3.81 (3H, s), 3.80-3.84 (lH .m), 3.59 (3H.s) .3.23 (lH, dd, J = 10.9, 10.2Hz), 2.56 (3H, s), 2.30 (3H, s), 1.43 (911, s)

FABMS (m / z); 709, 707 (M + H) ⁺

Any Br) v (cm- ¹ ): Rats 1637, 1576, 1444, 1402, 1367, 1348, 1205, 1163, 1090 Example 33: Synthesis of Compound 33

To 30 mg (0.116 mmol) of compound (A) were added 1.6 ml of ethyl acetate and 1691 (1.16 mmol) of 6.86 N hydrochloric acid, and the mixture was stirred at room temperature for 60 minutes. The solvent was removed from this reaction solution under reduced pressure, 1.5 ml of DMF, 71. Img (0.139 mmol) of compound o, and 66.5 mg (0.348 mmol) of EDCl were sequentially added, and the mixture was stirred at room temperature for 19 hours and 15 minutes. To this reaction mixture was added 0.01 M phosphate buffer at pH 7 and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product is diluted The residue was purified by layer chromatography (cloth form: methanol = 12: 1) to obtain 25.5 mg of compound 33 (yield: 28%).

^L H-NMR (270MHz, CDC + CDjOD) δ (ppm); 8.50 (1Η, s), 8.47 (1Η, s), 7.96 (1Η, s), 7.55 (lH, d, J = 15.2Hz) , 7.14 (lH, s), 7.08 (lH, s), 7.04 (lH, s), 6.76 (1H, s), 6.72 (lH.s), 6.62 (lH, s), 6.56 (1H, s), 6.42 (1H, d, J = 14.8Hz), 4.22-4.32 (lH, m), 4.24 (lH, d, J = 10.9Hz), 4.11-4.15 (lH, m), 3.86 (3H, s), 3.83 (6H, brs) .3.73-3.80 (1 H.br), 3.18 (lH, dd, J = 10.2, 10.2Hz), 2.60 (3H, s), 1.46 (9H, s)

FABMS (m / z); 789, 787 (M + H) ⁺

Example 34: Synthesis of Compound 3

 Using the same method as in Example 31, 18.9 mg of compound 34 (yield 62%) was obtained from 32 mg of compound 33.

¹ HNR (270MHz, CDCl3 + CD, 0D) δ (ppm); 8.91 (IH, s), 8.73 (lH, s), 7.60 (1H, d, J = 14.9Hz), 7.27 (1H, s) , 7.26 (lH, s), 7.ll (lH.s), 6.76 (111, s), 6.74 (lH, d.J = l.7Hz), 6.68 (lH, br). 6.65 (lH, s) , 6.58 (lH, s), 6.40 (IH, d, J = 14.9Hz), 4.12 (lH, d, J = 10.6Hz), 4.06 (111, dd, J = ll.1,4.5Hz), 3.83 ( 3H, s), 3.80 (3H, s), 3.74 (3H, s), 3.59 (3H, s), 3.47-3.54 (lH, m), 2.48 (3H, s), 2.29 (1H.dd, J = 7.4.3.5Hz), 1.42 (9 H, s), 1.22 (lH, dd, J = 4.6, 3.6Hz)

FABMS (m / z); 751 (M + H) ⁺

 IR (KBr) v (cm; 1701, 1653, 1605, 1560, 1489, 1458.1389, 1286, 1244, 1167 Example 35: Synthesis of compound 35

 Using the same method as in Example 32, 19.9 mg (yield 74%) of compound 35 was obtained from 25.5 mg of compound 33.

_{lH-NMR (270MHz.CDCl3 + CD 3} 0D) δ (ppm); 8.63 (IH, s), 8.4J (IH, s), 8. J3 (1H, s), 7. 52 (lH, d, J = 14.8Hz), 7.12 (lH, s), 7.06 (lH, s), 7.05 (lH, s), 6.68 (lH, s), 6.66 (lH, s), 6.56 (lH, s), 6.49 (lH , s), 6.43 (IH, d, J = 15.2Hz), 4.28-4.40 (lH, m), 4.28 (lH.d, J = 11.6Hz), 4.14 (IH, dd, J = 9.6, 9.2Hz) ), 3.86 (3H, s), 3.82 (3H, s), 3.79 (3H, s), 3.75dH.br), 3.48 (3H, s), 3.17 (lH, dd, J = 10.2, 10.2Hz), 2.49 (3H, s), 2.34 (3H, s), 1.46 (9H, s)

FABMS (m / z); 830, 828 (M + H) ⁴

-l- IR (Br) v (cm "'); 1695, 1645, 1585, 1446, 1402, 1367.1250, 1205, 1163, 1092 Reference example a: Synthesis of compound a

 3-(2-Chenyl) acrylic acid 500 mg (3.24 mol), methylene chloride 20 ml, p-nitrophenol 766 mg (5.51 recitation ol), triethylamine 1.54 ml (1) .02 mol and Mukoyama A reagent (2-chloro-1-methylpyridinium iodide) I407mg (5.51mmol) was added in sequence, and the mixture was stirred under reflux (bath temperature 50 ° C) for 2 hours and 30 minutes. An aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform) to obtain 842 mg of Compound a (yield 94%). 'II-N R (270MHz, CDCl3) δ (ppm); 8.30 (2H, d, J = 9.2Hz), 8.01 (1H, d, J = 15.8Hz) .7.4 8 (lH, d, J = 5.0Hz ), 7.37 (lH, d, J = 4.6Hz), 7.36 (2H, d, J = 9.2Hz), 7.12 (lH, dd, J = 5.0,3.6Hz), 6.41 (lH.d, J = 15.8Hz)

FABMS z); 276 (M + H) ⁺

Reference example b: Synthesis of compound b

4—Promo 2—Thiophenaldehyde (2 gU, 0.47 mmol), ethanol (12 ml), NH ₄ C1 (80 mg) and triethylorthoformate (2,61 ml, 15.71 referred to ol) are added sequentially, and the mixture is added at 60 ° C. for 2 hours. For a minute. Water was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2.975 g (yield: quantitative) of 1-Jetoxymethyl-4-promothiophene.

1-Diethoxymethyl 14-Promothiophene 1 g (3.77 mmol) in methanol 14 mU CuO 10 mg, Kl 21 mg and 28 wt%-sodium methoxide (NaOMe) methanol solution 7.27 g (37.7 mmol) ) Were added successively in an autoclave and reacted at 120 ° C. for 11 hours. The reaction mixture was filtered through celite, 0.5N hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (hexane: ethyl acetate-10: 1) to obtain 544 mg (yield 67%) of 1-ethoxymethyl-4-methoxythiophene. 10 ml of methanol and 4 ml of 4N hydrochloric acid were added to 496 mg (2.29 mmol) of 2-methoxyethoxy-4-methoxythiophene, and the mixture was stirred at room temperature for 30 minutes. 0.5 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 335 mg (yield: quantitative) of 4-methoxy-2-thiophenaldehyde.

 2 ml of THF and 1 ml of a THF solution of 630 mg (2.81 s) of triethylphosphonoacetate were added to 112 mg (2.81 s) of 60% hydrogenated sodium, and the mixture was stirred at 0 t for 5 minutes under an argon atmosphere. . Next, 2 ml of a THF solution of 337 mg (2.37 octol) of 4-methoxy-2-thiophenealdehyde was added to the reaction solution, and the mixture was stirred for 1 hour. Ice and 0.5 N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (hexane: ethyl acetate = 15: 1), and 424 mg of ethyl 3- (4-methoxy-2-phenyl) acrylate was obtained (yield: 84). %) Obtained. Next, 414 mg (1.95 rec.ol) of 3- (4-methoxy-2-cyenyl) acrylic acid ester was mixed with 9 ml of methanol and 1.46 ml of a 4N aqueous hydroxide solution of water (5.85 rec.ol). Was added and stirred at 50 ° C. for 1 hour. To this reaction mixture, 0.5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 36Img of 3- (4-methoxy-2-phenyl) acrylic acid (yield: Quantitative) obtained.

 Using a method similar to that of Reference Example a, 150 mg (yield: 91%) of compound b was obtained from 100 mg (0.543 mmol) of 3- (4-methoxy-2-phenyl) atalylic acid.

1! Toro (270MHz, CDC) δ (ppm): 8.29 (2H, d, J = 8.9Hz), 7.86 (1H, d, J = l 5.5Hz), 7.35 (2H, d, J = 8.9Hz), 7.02 (lH, s), 6.43 (lH, s), 6.38 (1H, d, J = 15.8Hz) .3.83 (3H, s)

EIMS (m / z); 305 (M) ⁺

Reference example c: Synthesis of compound c

2 — To 3.028 g (4.4 mmol) of iodothiophene, 12 ml of methanol was added, and 569 mg of CuO and 8.277 g (43.2 mmol) of a 28 wt% Na0Me ethanol solution were added. The mixture was stirred under reflux for 23 hours and 30 minutes. The reaction mixture was filtered through celite, water was added to the filtrate, and dimethyl ether was added. Extracted. The getyl ether layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 326 mg (yield: 20%) of 2-methoxythionone.

 To 326 mg (2.86 mmol) of 2-methoxythiophene, 5 ml of dried THF was added, followed by 1.6 M of n-butyllithium (n-Bu1 in hexane solution 2.7 mi 29 mmol) at -78 with a syringe. Then, the mixture was stirred for 25 minutes. Next, l) a solution of 251 mg (3.43 concealed) of MF in THF 1.5 ml was added, and the mixture was stirred for 1 hour and 20 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Then, 27-lmg of 5-methoxy-2-thiothiophene aldehyde (yield 670) was obtained. Obtained.

 Using the same method as in Reference Example b, 74 mg (yield 58%) of compound c was obtained from 248 mg (1.44 mol) of 5-methoxy-2-thiopheninaldehyde.

'H-NMR (270MHz, CDCl ₃ ) δ (ppm); 8.28 (2H, dJ = 9.2Hz), 7.85 (1H, d, J = 15.5Hz), 7.3 4 (2H, d, J = 9.2Hz), 7, 06 (1H, d, J = 4.3Hz), 6.22 (1H, d, J = 4.3Hz), 6.08 (1H, d, J = l 5.2Hz), 3.97 (3H, s)

FABMS (m / z); 306 (M + H) +

Reference example d: Synthesis of compound d

 According to the method of J.M. Barker et al., J.C.S. Perkin I, 2483 (1975), 2,5-dimethoxy-3-thiothiophene aldehyde was obtained.

 Using a method similar to that of Reference Example b, 139 mg (yield 73%) of compound d was obtained from 250 mg (1.76 mmol) of 2,5-dimethoxy-3-thiophenealdehyde.

_{1H-NMR (270MHz, CDCl 3} ) 5 (ppm); 8.28 (2H, d, J = 9.2Hz), 7.86 (lH, d, J = 15.8Hz), 7.3 5 (2H, d, J = 9.2Hz) , 6.13 (111, d, J = 15.8Hz) .6.02 (1H, s), 3.95 (3H, s), 3.87 (3H, s)

FABMS (m / z); 336 (M + H) ⁺

Reference example e: Synthesis of compound e

30 g of methylene chloride and 2.97 g (22.3 mmol) of methylene chloride were added to 1 g (8.92 mmol) of 3-thiophenealdehyde, and the mixture was stirred at room temperature for a while. Next, 1 ml of Br ₂ 426 u 1 methylene chloride solution was added to the reaction solution, and the mixture was stirred under reflux for 1 hour and 40 minutes. . Water was added to the reaction mixture, and the mixture was extracted with chloroform. The port-form layer was washed with 5% sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (hexane: ethyl acetate = 30: 1) to obtain 1.029 g (yield: 60%) of 1-bromo-14-thiophenaldehyde.

 To 1.006 g (5.27 mmol) of 2-bromo-1-thiophenealdehyde was added 8 m of ethanol, 40 mg of NH.C1 and 1.31 ml (7.91 mmol) of triethylorthoformate were sequentially added, and the mixture was stirred at 60 ° C. for 50 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain L-363 g (yield 98%) of 1-bromo-14-ethoxymethylthiophene.

 2-Promo 4-200 mg (0.754 mmol) of ethoxymethylthiophene, 1.5 ml of methanol, 30 mg of CuO, 6.3 mg of K1 and 28% by weight-727 mg of NaOMe methanol solution (3.77 ooi), sequentially in autoclave In addition, the reaction was carried out at 120 ° C for 8 hours] for 0 minutes. Next, 15 mg of CuO and 436 mg of a 28 wt% NaOMe methanol solution were added to the reaction solution, and the mixture was reacted for 22 hours. The reaction mixture was filtered through celite, 4N hydrochloric acid was added to the filtrate, and after stirring for a while, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel chromatography (hexane: ethyl acetate = 20: 1-10:

Purification by 1) yielded 67 mg (63% yield) of 2-methoxy-4-thiophene aldehyde.

 Using a method similar to that of Reference Example b, 239 mg (yield: 64%) of compound e was obtained from 1-methoxy-14-thiophenaldehyde.

 'H- MRi TOMHz.CDC) δ (ppm); 8.29 (2H, d, J = 9.2Hz), 7.69 (lH, d, J = 15.8Hz), 7.35 (2H, d, J = 9.2Hz), 6.91 (1H, d, J = l.6Hz), 6.42 (1H, d, J = l.3Hz), 6.28 (1H, d, J = 15.8Hz), 3.94 (3H, s)

FAB S (m / z); 306 (M + H) +

Reference example f: Synthesis of compound f

5,6,7 —Trimethoxyindole-1 2 —Rubonic acid methyl ester 265mg (1.00 (15 ml) of dry THF was added to the mixture (3 mol), and 3 ml (3 mol) of a 1 M diisobutylaluminum hydride (DIBAL) / toluene solution was added at 0 ° C., followed by stirring for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over sodium sulfate anhydride, and the solvent was removed under reduced pressure. 237 mg of 1-hydroxymethyl-5,6,7-trimethylxindole was obtained (yield: Quantitative) obtained.

CT0 ₃ of 348 mg (3.48 mmol) in pyridine 1.51ml was added and撹袢20 minutes at room temperature. To this reaction solution was added 2 ml of methylene chloride, and a solution of 276 mg (l.16 ol) of 2-hydroxymethyl_5,6,7-trimethoxyindole in methylene chloride was added, followed by stirring at 0 ° C to room temperature for 17 hours. . 0.5 N hydrochloric acid was added to the reaction mixture, followed by filtration. 0.5 N hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1), and 98 mg of 5,6,7-trimethoxyindole-12-carboxyaldehyde was obtained (yield 36%). ) Obtained. Using the same method as in Reference Example b, compound f was obtained from 5,6,7-trimethoxyindole-2-carboxyaldehyde (yield 67%).

^L H-NMR (270 MHz, CDCl3) δ (ppm); 8.44 (1H, brs), 8.30 (211, d, J = 8.9 Hz), 7.84 (lH, d, J = 15.8 Hz), 7.37 (2H, d , J = 9.2Hz), 6.82 (1H, d, J = 2.0Hz), 6.80 (1H, s), 6.34 (lH, d, J = 15.8Hz), 4.10 (3H, s), 3.94 (3H, s ), 3.90 (3H, s)

FAB S z); 339 (+ H) +

Reference example g: Synthesis of compound g

 According to the method of M. Bialer et al., Tetrahedron, M '^ 2389 (1978), methyl 1-methyl-4-122-2-pyrroloxycarboxylate was obtained.

 To 300 mg (l. 63 reference ol) of 1-methyl-4-nitro-2-pyrroloxycarboxylic acid methyl ester, add 9 ml of ethanol and I.22 ml (4.89 mmol) of 4N aqueous hydroxide water solution at 50 ° C. The mixture was stirred for 1 hour and 20 minutes. A 0.5N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 265 mg of 1-methyl-4-212-tro-2-pyrrocarboxylic acid (96% yield) Obtained.

Using the same method as in Reference Example a, 1 —Methyl-4 —Nitro-1 —Pyrrolecal 80.6 mg (yield 47%) of compound g was obtained from lOOmg of boric acid.

 'H-NMROOMHz.CDCh) δ (ppm); 8.33 (2H, d, J = 9.0Hz), 7.71 (2H, br), 7.40 (2H.d, J = 9.0Hz), 4.05 (3H, s)

FABMS (m / z); 292 (M + H) ⁺

Reference example h: Synthesis of compound h

 To 500 mg (2.72 mmol) of 1-methyl-4-nitro-1-2-pyrroloxycarboxylic acid methyl ester was added 7 ml of DMF and 150 mg of 10% palladium / carbon (10% Pd / C), and hydrogen at room temperature under i atm. For 4 hours and 40 minutes. Thereafter, 100 mg of 10% Pd / C was added, and the mixture was stirred for 4 hours. Next, water was added to the reaction mixture, which was filtered through celite, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain the 4-amino compound as Omg (yield 98%).

 To 208 mg (l.35 mmol) of the above 4-amino compound, TllFIOml, 10 m of water, 1 m of a THF solution of 737 mg (3.38 mmol) of di-t-butyl dicarbonate and 1 m of a saturated aqueous solution of sodium hydrogen carbonate were sequentially added, and the reaction was carried out. The solution was kept at pH 7-8 and stirred at room temperature for 2 hours 20 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel chromatography (hexane: ethyl ester == 4: 1) to give 1-methyl-4- (t-butoxycarbonylamino) pyrroyl-2-carboxylic acid methyl ester Was obtained (yield 87%).

 Using the same method as in Reference Example g, 1-methyl-4- (t-butoxycarbonylamino) pyrro-l-2-yl-carboxylic acid methyl ester was converted to I-methyl-41- (t-butoxycarbonylamino) pyrro 1 roux 2—I got rurubonic acid. Then, Compound h was obtained (88% yield) using the same method as in Reference Example a.

 'HN RC TOMHz.CDC) δ (ppm); 8.29 (2H, d, J = 8.6Hz), 7.35 (2H, d, J = 8.6Hz), 7.21 (lH'brs)' 6.91 (lH, d, J = 1.6Hz), 6.30 (1H, brs), 3.9K3H, s), 1.51 (9H, s) FAB S (m / z); 362 (M + H) +

Reference Example i: Synthesis of Compound i

Compound i was obtained (75% yield) in the same manner as described in G. He et al., J. Am. Chem. Soc., Ii5_, 7061 (1993). 7/02516 lH-NMR (90MHz, CDC) δ (ppm); 10.20 (lH, brs), 8.16 (1H, d, J = l.8Hz), 7.55 (lH, d, J = 2.0Hz), 7.40 ( lH, d, J = 1.8Hz), 6.84 (1H, d, J = 2. OHz), 3.95 (3H, s), 3.83 (3H, s)

 FABMS (m / z); 293 (+ H) +

Reference Example. Synthesis of i: Compound

 Using the same method as in Reference Example a, 60 mg (yield 86%) of compound j was obtained from 49.2 mg of compound i.

^J H-NMR (90 MHz, DMSO-d ₆ ) δ (ppm); 10.35 (1H, brs), 8.33 (2H, d, J = 9. OHz), 8.19 (1H, d, J = 2.0 Hz), 7.62 (lH, d, J = 1.8Hz), 7.58 (2H, d, J = 9.OHz), 7.52 (lH, d, J = 2.OHz), 7.21 (lH, d, J = 1.8Hz), 3.97 (3H, s), 3.91 (3H, s)

FABMS (m / z); 413 (M + H) +

Reference example k: Synthesis of compound k

 Compound k was obtained in the same manner as in the literature described in Reference Example i.

Ml-NMR (270 MHz, CDCI3 + CD3OD) δ (ppm); 7.32 (1Η, d, J = 2.OHz), 6.76 (111, d, J = 2.OHz), 6.76 (lH, brs), 6.54 ( 1 brs), 3.80 (6H, s), 1.42 (9H.s)

FABMS (m / z); 363 (M + H) ⁺

Reference Example L: Synthesis of Compound

 1.31 ml of fuming nitric acid was added dropwise to 15 ml of acetic anhydride at -20 over the following 25 minutes. A drop of concentrated sulfuric acid was added dropwise to the reaction solution, and a mixed solution of 2.95 ml (27.5 ml) of methyl-2-pyrrolealdehyde and 15 ml of acetic anhydride was added dropwise over 1 hour, -20. (The mixture was stirred for 2 hours below. After that, the reaction solution was brought to 0 ° C, a solution of 28.6 g of sodium hydroxide in 250 ml of water was added, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with a chloroform port. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.The obtained crude product was subjected to silica gel chromatography (hexane: g ethyl acetate = 5: 1). To 2: 1) to give 495 mg (yield 12%) of 1-methyl-4-nitro-12-pyrrolaldehyde.

 Using a method similar to that of Reference Example b, compound L was obtained from 52-methyl-1-nitro-1-pyrrolealdehyde (52% yield).

'Η- NMH (270MHz, CDCI ₃ ) δ (ppm); 8.32 (2H, d, J = 8.9Hz), 7.71 (1H, d, J = 15.3Hz), 7.6 5 (lH, d, J = l.5Hz), 7.38 (2H, dJ = 8.9Hz), 7.27 (lH, brs), 6.50 (1H, d, J = 15.3Hz),

3.84 (3H, s)

ElMS (m / z); 317 (M) ⁺

Reference example m: Synthesis of compound m

LiAlH ₄ 22.4mg (0.591minol) to THF1.5ml and 1-methyl-4 one (t one butoxy Karuboniruami Roh) one 2 - in THF 3ml pyrophosphoric one Rukarubon acid methyl ester 50 mg (0.197 hide ol) was added, at room temperature for 2 hours Stirred for 10 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 35.3 mg (yield 79%) of a 2-hydroxymethyl compound.

 To 9 mg (ll. Mol) of manganese dioxide, 7 ml of getyl ether and 126 mg (0.557 mmol) of the above-mentioned 2-methyloxymethyl ester were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure to obtain 9-8.4 mg (yield 79%) of 1-methyl-4- (t-butoxycarbonylamino) _2-pyrrolaldehyde. Using the same method as in Reference Example b, 87.2 mg (yield: 47%) of compound m was obtained from 1-methyl-14- (t-butoxycarbonylamino) -2-pyrrolealdehyde IIO.Smg.

¹ HN R (270MHz, CDCl ₃ ) δ (ppm); 8.28 (2H, d, J = 8.9Hz), 7.71 (1H, d, J = 15.5Hz), 7.3 4 (2H, d, J = 8.9Hz) .7.12 (1H, brs), 6.51 (lH.d.J = l.7Hz), 6.28 (lH, brs), 6.21 (1H, d.J = 15.2Hz), 3.70 (3H, s), 1.51 (9H , s)

FABMS z); 388 (M + H) +

Reference Example n: Synthesis of Compound n

1-Methyl-1- (t-butoxycarbonylamino) -1-9-pyrroloxycarboxylic acid 99.7 mg (0.415 mmol) in THF 3 ml, 1-Methyl-4-amino 2- 2-pyrrolylcarboxylic acid methyl ester 64 mg ( 0.415 mol), DECP81 (0.581 mmol) and triethylamine 116 l (0.83 mmol) were sequentially added, and the mixture was stirred at 0 ° C to room temperature for 3 hours. Next, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then dried under reduced pressure. The solvent was removed. The resulting crude product is subjected to silica gel chromatography (hexane

: Ethyl acetate = 1: 1) to obtain 137 mg (yield: 88%) of 2-methyl ester of compound k.

 To 125 mg (3.3 mmol) of LiAlH. Were added 8.28 ml of THF and 16 ml of a THF solution of 414 mg (1 mmol) of the 2-methyl ester of compound k, and the mixture was stirred at room temperature to 50 ° C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 293 mg of 2-hydroxymethyl compound (yield: 76%).

 To 404.3 mg (1.161 mmol) of the above 2-hydroxymethyl compound were added 15 ml of THF and 1.5 Mg of manganese dioxide (17.415 mol), and the mixture was stirred at 50 ° C for 6 hours and 40 minutes. To the reaction mixture was added chloroform, filtered through celite, and the solvent was removed under reduced pressure to obtain 248.6 mg of 2-formyl compound (yield: 62%).

 Using the same method as in Reference Example b, 92.1 mg (yield: 72%) of compound n was obtained from 110.7 mg of the 2-formyl compound.

¹ H-NMR (270 MHz, CDCl3 + CD ₃ OD) δ (ppm); 7.51 (111, d, J = 15.5 Hz) .7.30 (lH, d.J = 1.7 Hz), 7.29 (lH, brs), 7.28 (lH, brs), 6.76 brs), 6.58 (lH, brs), 6.52 (lH, d, J = l.7Hz), 6.02 (lH.dd, J = 15.8Hz), 3.83 (3H, s), 3.62 (3H, s), 1.44 (911, s)

FABMS (m / z): 389 (M + H) +

Reference example o: Synthesis of compound o

And IAlH ₄ in THF 6.7ml of 213mg was THF6.7m in (5.616Mmol) Compound p 350 meters g (Reference Reference Example p below id) (0.702 mmol) was added and stirred for 6 hours and 30 minutes at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 262.6 mg of 2-hydroxymethyl compound (yield 80%).

 Using the same method as in Reference Example n, 220.3 mg (yield 55%) of 2-formyl compound was obtained from 400 mg of 2-hydroxymethyl compound.

 Using the same method as in Reference Example b, 288.4 mg of compound o was obtained from 305 mg of 2-formyl form.

(86% yield).

¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ 0D) δ (ppm); 8.79 (lH.br), 8.69 (lH, br), 7.58 (lH, d, J = 15.5Hz), 7.38 (lH, d, J = l.3Hz), 7.14 (1H, d, J = l.7Hz), 7.14 (lH, br), 6.82 (lH, d, J = 2.0Hz), 6.81 (lH, brs), 6.66 (1H, brs), 6.61 (1H, d, J = 1.3 Hz), 6.09 (lH, d, J = 15.5 Hz), 3.93 (3H, s), 3.90 (3H, s), 3.69 (3 s), 1.51 (9H, s)

FABMS (m / z): 51 "Cheom +

Reference Example P: Synthesis of Compound p

 Compound p was obtained in the same manner as in the literature described in Reference Example i.

1H-NR (270 Hz, CDC + CD30D) δ (ppm); 8.65 (1H, brs), 8.50 (lH, brs), 7.41 (lH.d, J = 2.OHz), 7.20 (lH, dJ = 1.7 Hz), 6.89 (1H, d, J = 2. OHz), 6.79-6.84 (2H, m), 6.76 (lH.d, J = 1.7Hz), 6.64 (lH, brs), 3.9K3H, s), 3.89 (31, s), 3.88 (3H, s), 3.8K3H, s), 1.5K9H, s)

Industrial applicability

 According to the present invention, a DC-89 derivative or a pharmacologically acceptable salt thereof, which exhibits excellent antitumor activity and is useful as an antitumor agent, is provided.

Claims

The scope of the claims

 Equation π)

Is

·.

Represents Here, X represents a C1 or Br, R is a hydrogen atom or C0R ¹ (wherein, R ¹ represents a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ariru, substituted or unsubstituted heterocyclic group, NR ^{2 3:,} (wherein, R ² and R ³ are a hydrogen atom or a substituted or is identical or different represents a lower alkyl substituted.)

[Wherein, R or oxygen atom, NR ^f (wherein ^ represents a hydrogen atom or lower alkyl,) or

\

Represents / ^CHI . ], NR ^ia NR ^2a R "(where f ^a , R ^2a and R ^la are the above ^, R ^: And R ³ as synonymous. ) Or OR ⁶ (wherein R ⁶ represents a substituted or unsubstituted lower alkyl). } Where W is

[In the formula, Y ¹ represents an oxygen atom, a sulfur atom or N—R ′ ^b (wherein, R ^ib has the same ^{meaning as} the above IT.), And Q ¹ and Q ² are the same or different and represent a hydrogen atom, OR ⁷ (wherein, R ⁷ represents a hydrogen atom or substituted or unsubstituted lower alkyl), N 0 ₂ , NR ^3b R ^3b

(Wherein, R ^{2 b} and ^b have the same meanings as R ² and R ³ , respectively), or NH ₂ O ^6a (wherein, li ^{6 a} has the same meaning as R ⁶ ). m represents 0 or 1, and n represents an integer of 0 to 2. ] Or

Wherein, Y ² is an oxygen atom, a sulfur atom or N- (wherein, IT ^epsilon is the ^ and Ru synonymous der.) Represent, Q ^3, Q ⁴ and is synonymous with above for Q ¹ in or Q ² is there. ] Is represented. } DC-89 derivative represented by the formula or a pharmacologically acceptable salt thereof.

 2. W is

(Wherein Y Qi and Q ² have the same meanings as described above.).