TW200418804A - New pyrazole compounds having antifungal activity - Google Patents

Abstract

This invention is regarding a pyrazole compound represented by the general formula (I) or its salt and a drug containing the same as the active ingredient, wherein R1, R2, R3, R4 and R5 represent each a substituent; and X represents a methine group or a nitrogen atom. The above compound is useful as a preventive or a remedy for mycosis, in particular, deep-seated mycosis caused by deep-seated fungi such as candida and aspergillus and superficial mycosis caused by fungi such as trichophyton.

Description

说明, Description of the invention: [Technical field to which the invention belongs] Prevention and treatment of mammalian fungi The present invention relates to Π salivary compounds with high antifungal activity and usefulness in infectious diseases. Ringworm, psoriasis, and skin candidiasis are represented by superficial mycosis, as well as deep-seated fungi represented by mycotic meningitis, fungal respiratory infections, true bloodemia, and true urinary tract disease disease. A deep mycosis such as candidiasis and aspergillosis, especially due to the frequent use of cancer chemotherapeutic agents and immunosuppressive agents and HIV infection and other factors that reduce the immune system in the body, have been increasing in recent years. These bacteria are effective agents. Previously effective agents for Aspergillus and Candida, although amphotericin B (amphoteriein B) and fluconazole (fluConazole) and itraconazole (azolo) compounds are known itrac〇naz〇le), etc., but can not fully meet the point of antifungal spectrum, in vivo dynamics and tolerance.

Also, azole-based agents that have been studied in this field for many years have problems in their effectiveness for severe patients and tolerance caused by long-term use of the same agents. Therefore, it is expected to develop a structure different from that of previous compounds, and to have deep fungal diseases. Compound with excellent antibacterial activity and excellent safety. Currently, the development of more effective and novel antifungal agents is progressing rapidly, although an antifungal agent having a pyrazole skeleton is proposed (U.S. Patent No. 4,712,229, International Publication No. 01/2385, and International Publication No. 98/58905). ), But has not yet obtained satisfactory effective antifungal activity.

O: \ 88 \ 88539.DOC 200418804 [Summary of the invention] Therefore, the purpose of the present invention is to report the first one—Matu i, a female with high comprehensiveness and effective for deep mycosis and superficial mycosis. Sub's are pyrazole compounds with antifungal activity. The present invention provides a pyrazole compound or a salt thereof represented by the following formula (m) -r 4:

n R1 (where R1 represents an alkyl group, an alkenyl group, a phenyl group which may have a substituent, a biphenyl group which may have a substituent, or a heteroaromatic ring group which may have a substituent; R3 represents a hydrogen atom, an alkyl group, Alkenyl, phenyl which may have substituents, biphenyl which may have substituents, or heteroaromatic ring groups which may have substituents; R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyl group, or a carboxyl group , Lower alkoxycarbonyl, carbamoyl, cyano, —CH2OH or —CH2NR6R7 (R6 and R7 are the same or different and represent a hydrogen atom or a lower alkyl group); R4 and R5 are the same or different, Represents a hydrogen atom, a fluorenyl group, a lower alkyl group, a cycloalkyl group, or a phenalkyl group, or R4 and R5 are joined together with two oxygen atoms to form an alkylene dioxy group; X represents a methine group or a nitrogen atom). The present invention also provides a medicine having an pyrazole compound or a salt thereof represented by the general formula (I) as an active ingredient. The present invention also provides a pharmaceutical composition containing

O: \ 88 \ 88539.DOC 200418804 pyrazole compound or a salt thereof and a pharmaceutically acceptable carrier. In addition, the present invention provides the use of a pyrazole compound or a salt thereof represented by the general formula I-I) in the manufacture of medical music. -Furthermore, the present invention provides a treatment method for a true urinary tract infection, which specifically comprises administering an effective amount of a pyrazole compound or a salt thereof represented by the general formula (#) . A compound of the present invention represented by the general formula ⑴ can be used as a true disease (especially a deep mycosis caused by fungi such as Candida and Aspergillus and a fungus caused by fungi such as Trichophyton) Superficial mycosis) preventive or therapeutic agent. [Embodiment] The best form for carrying out the invention is represented by the general formula ⑴ as the burning group shown by R1 and R3, for example, the carbon number is 16 (carbon number 1 to 10 is more preferable, carbon number 丨 to 6 is Especially preferred) alkyl. The alkyl group may be linear or branched, such as fluorenyl, ethyl, isopropyl'-n-butyl, n-hexyl, and n-octyl. As the alkenyl group, for example, an alkenyl group having a carbon number of 2 to 16 (more preferably, a carbon number of ^ to ⑺, and particularly preferably a carbon number of 2 to 6) is used. The alkenyl group may be linear or branched, such as vinyl, propenyl, and pentenyl. The substituents on the phenyl, biphenyl, and heteroaromatic rings shown by R1 and R3 are a halogen atom, a low-carbon alkynyl group, a low-carbon alkynyl group, and a hydroxyl group; The same or different, which means a hydrogen atom, a low-carbon alkynyl group or a low-carbon oxon group, or R8 and R9 together with a nitrogen atom to form a π ratio that may have a substituent. Amine, piperidinyl, piperidyl, (Folinolinyl or thiomorpholinyl), _ substituted low isnzyl, oxo substituted oxygen, low carbon sulfur, alcohol, slow, alkoxycarbonyl, amido, Ν-lower alkylaminosulfonyl and Ν, Ν-di-lower O: \ 88 \ 88539.DOC -9-200418804 Carboalkylaminosulfonyl. + 荣 & &# 丄 _ 4 This substituent may have 1 to 3 on a phenyl, biphenyl, or heteroaromatic ring group. Among them, a halogen atom is, for example, a fluorine atom, a chlorine atom, a bromine atom, and a fluorene atom. As a low-carbon base, a base having 1 to 6 carbon atoms (especially carbon number μ) is preferred. Specific examples are methyl, ethyl, n-propyl, isopropyl-n-butyl, and second butyl. Among them, the low-carbon burned base represented by ruler 8 and r9 is, for example, the same base. As the low-carbon alkoxy group, a carboxy group having a carbon number, especially a carbon number of 1 to 4) is preferred, and specifically, for example, a methoxy group, an ethoxy group, an isopropoxy group, and a butoxy group Wait. As those represented by R8 and R9 = low-Weiyang oxygen radicals, it is better to use Cl_6 silk radicals. Alkyl stilbene 6 alkyl is particularly preferred. 'Specifically', for example, methoxyethyl, methoxypropyl, ethoxyethyl, and ethoxypropyl. R8 and R9 together with the nitrogen atom form m each ⑦, ㈣ " ㈣, morphine is like thiomorpholine, and may be substituted on the core by a low-carbon alkynyl group, a phenyl group, or a keto group. As specific examples of the 8r9 group, for example, amine group, dimethylamino group, diethylamine group, methoxypropylamine group, etc. are called fluorene, 3-keto group, κ group, phenyl group, and N-phenyl group. Jingji, Mafulinki and Thiomorphinyl. As a substitute for a low-carbon alkyl group, an alkyl group having a carbon number of 6 (especially a carbon number of 1 to 4) substituted by 3 halogen atoms is preferred. Specifically, for example, chloromethyl, Fluoromethyl and chloroethyl. As the i-generation low-carbon compound, a compound having a carbon number of 1 to 6 (especially a carbon number of 1 to 4) substituted by three self-prime atoms is preferred, and specifically, for example, three Fluoromethoxy. As the low-carbon thio group, carbon number ^ (especially carbon number thio group is preferred, specifically, for example, methyl ethyl thio group and isopropyl thio group, etc. as fluorenyl group), Alkyl carbonyl groups of 2 to 6 can be

O: \ 88 \ 88539.DOC -10-200418804 Car 乂 =, such as ethyl alcohol and propionate. As the low-carbon oxycarbyl group, an alkoxycarbonyl group having a total carbon number of 2 to 7 is preferred. Specifically, for example, a methoxy group and T is a heteroaromatic ring group represented by R1 and R3, for example, a 5-membered ring group and 6 members having W heteroatoms selected from a milk atom, a nitrogen atom, and a sulfur atom. Ring US or 9 ~ U member fused ring group. An example of a 5-member ring is fenfenan. Than hee, spit, taste. Than saliva, Saki π sitting and San saliva. As examples of 6-member rings, such as m core, DttP well, and triple P well. Examples of the fused coat are benzoxazoline, benzoy saliva, benzo slogan, and the like. As the low-carbon radicals shown by R, R, R5, and R6AR7, a carbon radical of 1 to 6 (especially 1 to 4 carbon atoms) is preferred. Specifically, for example? And ethyl: propyl, isopropyl, n-butyl, and tert-butyl. The low-carbon silk group represented by R2 is preferably a alkoxy group having a carbon number of 1 to 6 (especially a carbon number of 1 to 4). As a representative, for example, methoxy, ethoxy, isopropoxy, and Butoxy, etc .: R is a low-carbon oxycarbonyl group with a total carbon number of 2 to 7 as the preferred brewing group, and specific examples include methoxy and ethoxy groups. The couple NW represented by rule 2 is, for example, amine methyl, dimethylamine methyl, methylamine methyl, and diethylamine methyl. The brewing group represented by R4 and R5 is preferably a fluorenyl group having 2 to 6 carbon atoms, such as an acetic acid group and a fluorenyl group. The cycloalkyl group represented by R1R5 is preferably a cycloalkyl group of carbon number Η, such as cyclopropyl, cyclopentyl, and cyclohexyl. Benzene represented by RlR5; k group is preferably phenyl_Cl_6, such as benzyl, phenethyl and phenylpropyl. Carbonyloxy is preferred as the low-carbon ethylenedioxy, such as f-dioxy and ethylenedioxy. In addition, the salt of the salivary compound ⑴ is regarded as the basis.

O: \ 88 \ 88539.DOC -11- 200418804 (I), the dissociation salts are different; in. In the case where the pyrazole compound ⑴ is basic, for example, the hydrochloride, nitrate, sulfonium bromate, p-toluenesulfonate, formate, fumarate, maleate, Malonate, No. ^ salt, #sulfonate and tartrate; in the case where the pyrazole compound ⑴ is acidic, for example, sodium, potassium, and ammonium salts. The azole compound (I) or a salt thereof exists in the form of a hydrate and various solvents, and these hydrates and solvents are also included in the present invention. In addition, in the case where isomers exist in the 啦 compound ⑴ or a salt thereof, a mixture of these isomers and an optically active substance are also included in the present invention. The pyrazole compounds represented by the general formula ⑴ this month, the compounds shown in the following Tables 1 to 8 are preferable.

O: \ 88 \ 88539.DOC 12- 200418804 Table 1

Compound number X R1 R2 R3 R4 R5 1 N Me H Ph Me Me 2 N Me H Ph Bn Bn 3 N Me H Ph HH 4 N Ph H Ph Bn Bn 5 N Ph H Ph HH 6 N Ph H Ph H Me 7 N Ph H Ph Me H 8 N -Or H Ph Bn Bn 9 NH Ph HH 10 N -o H Ph Bn Bn 11 NH Ph H. H 12 N Ph COOEt Ph Bn Bn 13 N Ph COOEt Ph HH 14 N Ph C00H Ph Bn Bn 15 N Ph C00H Ph HH 16 N Ph HVH Me 17 N Ph H-^-0H F Me Me 18 CH Ph H Ph Bn Bn 19 CH Ph H Ph HH 20 CH Ph HHHO: \ S8 \ 88539.DOC -13- 200418804 Table 2 Compound No. X R1 R2 R3 R4 R5 21 CH Ph H -Qr Bn Bn 22 CH Ph H -〇 ~ f HH 23 CH H Ph Bn Bn 24 CH H Ph HH 25 CH -Or H -〇-f Bn Bn 26 CH H -Or HH 27 CH H OMe MeO HH 28 CH -〇-f H Bn Bn 29 CH -Or H-< 3 HH. 30 CH order f FH -Or Bn Bn 31 CH 〆H -Qr HH 32 CH H -〇-f Bn Bn 33 CH -〇 ~ 0CF3 H -〇 ~ f HH 34 CH -〇 ~ 0CF3 H-/ 3 Bn Bn 35 CH -〇 ~ 〇cf3 H -〇HH 36 CH H Bn Bn O: \ 88 \ 88539.DOC -14- 200418804 Table 3 Compound No. X R1 R2 R3 R4 R5 37 GH Η -〇-FHH 38 CH-~ tBu Η -〇-f Bn Bn 39 CH- -tBu Η HH 40 CH -ο Η Me Bn Bn 41 CH -〇 Η Me HH 42 CH 〇Η n-CgH 丨 7 Bn Bn 43 CH -ο Η n-CgH 丨 7 HH 44 * 1 CH -ο Η n ^ CgHiy-CH2-45 CH Η Ph Bn Bn 46 CH ^ 3 Η Ph HH 47 CH-^ 3 Η Ph Me Me 48 * 1 CH ^ 3 Η Ph-CH2-49 CH -ο Η Ph Ac Ac 50 CH -ο Η MeO -o Bn Bn 51 CH -ο Η MeO -o HH 52 CH-^ 3 Η OMe ~ 0 Bn Bn O: \ 88 \ 88539.DOC -15-200418804 Table 4

Compound number X R1 R2 R3 R4 R5 53 CH Η OMe HH 54 CH -〇Η Bn Bn 55 CH -〇 Η --OMe HH 56 CH -〇 Η Bn Bn 57 CH -ο Η HH 58 CH-^ 3 Η Bn Bn 59 CH -ο Η HH 60 CH -ο Η Bn Bn 61 CH Η HH 62 CH Η Bn Bn 63 CH Η ~ < SHH 64 CH Η -〇-n〇2 Bn Bn 65 CH -ο Η -〇-n〇2 HH 66 CH-^ 3 Η HH 67 CH -ο Η ~ &s; HHO: \ 88 \ 88539.DOC -16- 200418804 Table 5 Compound No. X R1 R2 R3 R4 R5 68 CH -Y3 Η -〇-〇η HH 69 CH-/ 3 Η — ^ OMe OMe Me Me 70 CH 〇Η OH HH 71 CH -ο Η -〇 Bn Bn 72 CH -ο Η 3 HH 73 CH Η -〇 " 〇-F Bn Bn 74 CH- ο Η -0-0- ^ HH 75 CH -ο Η Bn Bn 76 CH -ο Η-< 3 HH 77 CH -ο Η ~ 〇s Bn Bn 78 CH Η ~ 〇 HH 79 CH Η Ph Bn Bn 80 CH Η Ph HH 81 CH Βη Η Ph Bn Bn 82 CH Βη Η Ph HH 83 CH OMe Η Ph Bn Bn O: \ 88 \ 88539.DOC -17- 200418804 Table 6 Compound No. X R1 R2 R3 R4 R5 84 CH OMe H Ph HH 85 CH —OMe H Ph Bn Bn 86 CH —OMe H Ph HH 87 CH — ^^ ~ 〇cf3 H Ph Bn Bn 88 CH H Ph HH 89 CH N—λ H Ph Bn Bn 90 CH H Ph HH 91 CH -o H Bn Bn 92 CH -o HHH 93 CH H Ph Bn Me 94 CH -o H Ph H Me 95 CH H Ph Me Bn 96 CH -o H Ph, Me H 97 CH HH Me Me 98 CH Seven HHHH 99 CH -o I Ph Bn Bn 100 CH Seven C00H Ph Bn Bn 10.1 CH C00H Ph HH 102 CH H Ph Bn Bn O: \ 88 \ 88539.DOC -18- 200418804 Table 7 Compound number X Ri R2 R3 R4 R5 103 CH N—λ ~ ^ / ~ N02 Η. Ph HH 104 CH each 2 Η Ph HH 105 CH -〇Η Ph Me Me 106 CH Η Ph HH 107 CH -〇Η Bn Bn 108 CH -〇Η-6 HH 109 CH Η Bn Bn 110 CH Η HH 111 CH -〇Η Bn. Bn 112 CH Η J1. Bn Bn 113 CH -〇Η HH 114 CH Η Bn Bn 115 CH -〇Η HH 116 CH Η Bn Bn 117 CH Η HH 118 CH ^ 3 Η 0 y—NMe, Bn Bn O: \ 88 \ 88539.DOC -19 -Table 8

Compound number X Ri R2 R3 R4 ---- 1 R5 119 CH Fly; Η * δ " " " — V-NMe2 H JV H 120 CH Η νη2 -d H ——— H 121 CH Η bo Bn Bn 122 CH-^ 3 Η HH 123 CH Η ^ ~ ^ —ΝΗ (0Η2) 30Μβ Bn Bn 124 CH Η NH (CH2), 0Me HH 200418804

Bn ·· benzyl; Ph: phenyl; Me: methyl; Et: ethyl; tBu •• third butyl; Ac: ethenyl * 1 · R and R5 are linked together and together with two oxygen atoms Methylenedioxy is formed. The α-bitumin compound represented by the general formula ⑴ of the present invention is, for example, by condensing the Wuxiang terminal (1) shown below with a ketone (2) to form an explosive ketone (3) ', making the dilute (3) and hydrazine ( 4) Reaction to obtain pyrazoline (5) or hydrazone (6), which is then oxidized to produce it.

O: \ 88 \ 88539.DOC -20- 200418804 (wherein 'Rl, R2, R3, R4, R5 and X are the same as above). In the case of the tonazole compound ⑴ ... and when 5 is a benzyl group and a methyl group, and an alkylene group is formed from r4 & r5, r4 = = r5 = pyrazole compound (1) -1 of hydrogen atom.

(Wherein R1, R2 ,, R4, R5 and χ are the same as above). By adding R4 and R5 to two hydroxyl groups of the pyrazole compound VII, the pyrazole compound (I) can be produced. Enone (3) 'by mixing aromatic aldehydes (1) and ketones (2) in alcohols such as methanol and ethanol: in sodium methyl oxide, sodium ethoxylate, third butoxide, carbon dioxide, potassium oxychloride It can be obtained by reacting at room temperature for 10 to 24 hours in the presence of an aqueous solution thereof, sodium hydroxide or an aqueous solution thereof, a base such as pyridine, piperidine and pyrrolidine, or an acid such as acetic acid and sulfuric acid. It can also be obtained by reacting at room temperature for 10 to 24 hours due to the coexistence of M κ and bite tests and acids such as acetic acid. In addition, the ketone (2) is tested with Horner Emmons or Wittig reagent-agentK ^ J ^ J. Org. Chem. 1986, 51 (23), 4342, Synthesis 1985 (1 1), 1048; J. Org. Chem. 1968, 33 (1) 'Homogeneous (3) was obtained by heating in a solvent such as dimethylformamide and tetrahydrofuran at room temperature to 100 ° C. , 35〇4) and aromatic aldehydes exist in the proper inspection but can be prepared by known methods. Among them, the aromatic aldehydes (1) and ketones (2) are commercially available O: \ 88 \ 88539.DOC -21-200418804. . By recirculating the olefins (3) and ploughing (4) in a solvent such as ethanol for 3 to 5 hours, Rotulin (5) or trace (6) can be obtained. Although hydrazine (4) is commercially available, it can be produced by the method described in Japanese Chemical Engineering's "New Experimental Chemistry Lecture 14" for the synthesis and reaction of organic compounds, ρ. 1573 ~ 1585 (1985) or a variant thereof. By dissolving pyrazoline (5) or pyrene (6) in solvents such as benzyl, benzyl, dibenzobenzene, and acetic acid, 'in 2,3-dichloro-5,6-dicyano-pyrene, 4-benzene In the coexistence of oxidants such as benzoquinone (DDq), chloranil (chloranil) and superatomic iodine compounds, it is preferable to heat at 1000 ° C for 1 to 4 hours to oxidize to produce pyrazole compound Q). In addition, in the case of the azole compound, R4 and R5 are both benzyl or methyl, or M and R5 together form an alkylene group, by using boron trifluoride, boron tribromide, and methyl sulfide. Compounds, aluminum chloride, etc., are reacted in a suitable solvent at ~ room temperature for 5 to 12 hours to obtain pyrazole compounds (4) and 5 (pyridazole compounds) (I) -1, which are also hydrogen atoms. After the above reaction, the isolation of pyrazolium from the final reaction mixture can be carried out by conventional methods such as solvent extraction, recrystallization, and column chromatography. In the case where R1 of the general formula (I) is a substituted phenyl group, a substituted biphenyl group, or a substituted heteroaromatic ring group, it can be prepared by the following reaction formula:

O: \ 88 \ 88539.DOC -22- 200418804

(Where 'R represents a phenyl, biphenyl, or heteroaromatic ring group which may have a substituent, wherein the substituent is the same as the substituent of the phenyl group having a substituent represented by R1 above, and Y represents a chlorine atom or a desert atom Or Angstrom atoms; R2, R3, R4, R5 and X are the same as above). The aromatic aldehyde (1) and ketone (2) are condensed in the same manner as the above-mentioned method to obtain ketene (3), which is then reacted with hydrazine and oxidized to obtain pyrazole (7). The pyrazole (7) is made of steel Perform coupling reactions (eg J. Am. CHEM · SOC. 2002, 124,

O: \ 88 \ 88539.DOC -23- 200418804 7421) 'Following the separation of the isomers, a pyrazole compound (D-2 can be obtained. The ligand used in this coupling reaction is, for example, n, n, _ Dimethylethylenediamine, trans-N, N, -dimethyl-1, cyclohexyldiamine, etc. as copper catalysts, such as copper powder, copper iodide (CuI), copper chloride (CuCl ) And Cu (acetate) 2 etc. As the base, for example, potassium phosphate, potassium carbonate, and carbonic acid shavings, etc. In the same manner as the above-mentioned production method, R4 of the pyrazole compound (〗) _2 is a benzyl group or a methyl group Or, in the case where R4 and R5 together form an alkylene group, by cutting the bond between 0-R4 and 0-R5, a pyrazole compound (1) _3 'with r4 = r5 = hydrogen atom can be obtained. The pyrazole compound (1) -2 is produced from the azole compound (1) -3. In the reaction on X, the compound 反应 2 or (1) _3 is isolated from the final reaction compound, and can be extracted by a conventional method such as a solvent. , Recrystallization or column chromatography, etc. The pyrazole compound ⑴ or its salt thus obtained, as shown in the following examples, has excellent antibacterial effect on various fungi, and can be used as Medicine for preventing and treating superficial and deep fungal infections of human pet animals. Medical music composition containing one or two or more pyrazole compounds ⑴ or a pharmaceutically acceptable salt thereof can be formulated by using Commonly used carriers, excipients and additives are prepared into tablets, powders, granules, fruit granules, capsules, pills, liquids, injections, suppositories, vaginal preparations, ointments, creams, gels And adhesives, etc., and administered orally or not. Also in the manufacture of solid preparations, it is better to add excipients to the pyrazole compound ⑴ South = need to add a binder, disintegrating agent, extender, Coating agent and sugar coating = after 'made into tablets, fruit granules, capsules, suppositories, etc. by the conventional method. In the case of preparing injections, the hydrazone compound is first poured into steaming water for injection.

O: \ 88 \ 88539.DOC -24 · 200418804 Dissolve, disperse, or emulsify in water-seeking carrier to make a liquid solution. Dissolve it when used, and use it as powder of 4 丄 m ^ /%. The administration method of the injection includes, for example, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, and intravenous drip. When preparing external preparations such as ointments, creams, gels, and liquids, the specific compound (I) is dissolved, dispersed, or emulsified in an aqueous or oily base to make it soft, creamy, liquid, or The form of a gel. The amount of pyrazole compound ⑴ administered to humans depends on the state of infection and the method of administration. For example, it is administered to adult patients for the purpose of treating candidiasis. About 0 01 to 100 mg when administered orally / kg / day, preferably about 0.01 to 50 mg / kg / day, more preferably about ^ 20 mg / kg / day. Examples Although the present invention will be specifically described below with reference to examples and examples, the present invention is not limited thereto. Reference Example 1 Production of Enone (3) The dilute ketone (3) shown in Tables 9 and 10 was produced. O: \ 88 \ 88539.DOC 25- 200418804 Table 9

Production example number X R2 R3 R4 R5 Yield (%) 1 N Η Ph Me Me 88.2 2 N Η Ph Bn Bn 66. 7 3 N Η Ph CH3C0 Me 47.0 4 N Η Ph Me H 69. 1 5 N COOEt Ph Bn Bn 77.0 6 N Η —OH Bn Me 99.0 7 N Η-OH Me Me 75. 2 8 CH Η Ph Bn Bn 95. 6 9 CH Η -F Bn Bn 39. 8 10 CH Η OMe THP THP 60: 0 MeO ' 11 CH Η Bn Bn 40.4 12 CH Η Me Bn Bn 88.8 13 CH Η n-CgH !? Bn Bn 77.9 14 CH Η MeO Bn Bn 81.0 15 CH Η OMe -d Bn Bn 78.0 O: \ 88 \ 88539.DOC -26 -200418804 Table 10 Manufacturing Example No. X R2 R3 R4 R5 Yield (%) 16 CH Η Bn Bn 99.0 17 CH Η Bn Bn 99.0 18 CH Η Cl Bn Bn 99.0 19 CH Η Bn Bn 99.0 20 CH Η no2 -d Bn Bn 92.0 21 CH Η ~ N02 Bn Bn 74.0 22 CH Η-< 3 Bn Bn 99.0 23 CH Η Bn Bn 99.0 24 CH Η Bn Bn 78.4 59 CH Η Ph Bn Bn 61.0 60 CH Η Bn Bn 72.0 61 CH Η Ph Bn Me 94.0 62 CH Η Ph Me Bn 83.0 63 CH Η Bn Bn 81.0 64 CH Η H Me Me 51.0 ΤΗΡ ·· 2-tetrahydropyranyl production example (1) In 4,5-dimethoxy-2-pyridyl Add 0.1 mol to 1.67 g (10 mmol) of formaldehyde 100 mL / L sodium hydroxide aqueous solution was added dropwise with 1.20 g (10 mmol) of acetophenone under stirring, and stirred at room temperature for 12 hours. After the reaction is completed, the crystals from O: \ 88 \ 88539.DOC -27- 200418804 are filtered and dried to obtain (E) -3- (4,5-dimethoxy-2-pyridyl M_benzyl -2-propylene-1_one 2.3 8 g (88.2%). Production Example (2) 4'5-Mu (benzyloxy) _2-carbamic acid 0.64 g (2 mmol) was dissolved in 8 ml of methanol ' 0.24 g (2 mmol) of acetophenone was added, and then 0.2 g (2.2 mmol) of sodium methoxide was added under stirring, followed by stirring at room temperature for 12 hours. After the reaction was completed, the precipitated crystals were filtered and dried to obtain (E) -3- (4,5-dimethoxy-2-fluoren (benzyloxy) -2-pyridyl) -1-phenyl-2-propen-1-one 0.56 g (66.7%). In the same manner as in Production Example 2, the olefin g of Production Examples (6) and (7) was the same. Production Example 3 Dimethyl g of 2-S isopropyl-2-phenylethylacetate was 0.45 g ( 1.76 mmol) was dissolved in 2 ml of THF, and 0.07 g (1.76 mmol) of sodium hydride was added at 0 ° C under a stream of argon, followed by stirring for 10 minutes. Then, acetic acid (6-formaldehyde) was added dropwise. A solution of fluorenyl-4-fluorenyloxy-3-carolinyl) ester 28.28 g (1.41 mmol) in 2 ml of THF and stirred at 0 C for 1 hour. After the reaction was completed, the reaction was poured into water And use Extraction with ethyl acetate. After washing with water and saturated brine, drying over sodium sulfate and distilling off the solvent. The residue was recrystallized from ethyl acetate-hexane to obtain 4-methoxy-6-[(E ) -3-keto-3 · phenyl-1-propenyl] -3-carbamyl acetate 0.20 g (47.0%) 0 Production Example 4 4-Lightyl-5-fluorenyloxy_2_ Hou. 1.39 g (10 mmol) of butylated methylformate and 1.208 (1.011111〇1) of acetophenone were dissolved in methanol 501111, and 20% (~~) sodium hydroxide was added at 0. 40 ml of aqueous solution was stirred for 4 hours at 0 ~ 10 ° C. After the reaction was completed, the reaction solution was neutralized with dilute hydrochloric acid, and the precipitated crystals were filtered and dried to obtain O: \ 88 \ 88539.DOC -28- 200418804 to ( E) -3- (4-Hydroxy-5-methoxy-2-arimidinyl) -1-phenyl-2-propen-1-one 1.63 g (69.1%) Production Example 5 0.79 g (2.5 mmol) of 5-fluorenyl (benzyloxy) -2-pyridinecarboxaldehyde and 0.4 g (2.1 mmol) of 3-keto-3 -phenylethyl acrylate were dissolved in 4 ml of benzene.唆 0_05 ml and 4 ml of acetic acid, and reflux at 120 ° C for 5 hours. After cooling, add diethyl ether 'sequentially wash with 1 ml / L hydrochloric acid, 5% (w / v) sodium bicarbonate aqueous solution and water' Sodium sulfate drying , The solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain (Z) -2-benzylfluorenyl-3- [3,4-fluoren (benzyloxy) -5- Methoxy_2-arimidinyl] -2-acrylate 0.94 g (77.0%). Production Example 8 50 ml of ethanol was added to 3.18 g (10 mmol) of 3,4-fluoren (benzyloxy) benzaldehyde and 1.2 g (10 mmol) of acetophenone, and hydroxide was added dropwise at room temperature with stirring. A 15 ml solution of potassium 0.67 g (12 mmol) in ethanol was stirred for 20 hours. After the reaction was completed, the reaction product was poured into water, and the precipitated crystals were collected by filtration and dried to obtain (E) 3- [3,4-cold (benzyloxyphenyl) small phenylpropane- 4.02 g (95.6%). In the same manner as in Production Example 8, the enones of Production Examples 9 to 11, 14 to 24, and 59 to 63 were produced. The ketene of Production Example 12 was prepared according to the method described in U.S. Patent No. 5,847,225; the ketene of Production Example 13 was prepared according to the method described in j. Chem. Soc., Perkin I I972, 3001. Production Example 64: 2.17 g (10 mmol), 3,3-diethoxy

O: \ 88 \ 88539.DOC -29- 200418804 Propane 3.90 g (30 mmol), acetic acid 0.067 g (0.3 mmol), tetrabutylammonium acetate 6.0 g (20 mmol), potassium carbonate 2.1 g (15 mmol), a mixture of 0.75 g (100 mmol) of chloride and 40 ml of DMF was stirred at 90 ° C for 13 hours. After the reaction was completed, 2 ml of 2 N hydrochloric acid was added to the reaction mixture at room temperature and stirred for 10 minutes, and then the acetal was hydrolyzed. Ethyl acetate was added, extraction was performed, and after washing with water and saturated brine, it was dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1) to obtain (E) -3- (3,4_dimethoxyphenyl) _acrylic acid as pale yellow crystals. 98 g (51.0%). Reference Example 2 Manufactured 11 ratios (5) shown in Tables 11 to I3.

O: \ 88 \ 88539.DOC -30- 200418804 Table 11

Production Example No. X R1 R3 R4 R5 Yield (%) 25 N Me Ph Me Me 49.0 26 N Me Ph Bn Bn 99.0 27 N Ph Ph Bn Bn 69. 7 28 N Ph Ph CH30CH2 Me 23.0 29 N-0 Ph Bn Bn 53.3 30 CH Ph Ph Bn Bn 55. 1 ^ 31 CH Ph -〇 ~ n〇2 Bn Bn 38. 1 32 CH Ph Bn Bn 55.6 33 CH Ph Bn Bn 74.2 34 CH ~ Qr Bn Bn 84.2 35 CH OMe MeO HH 83.9 36 CH ~ Q Bn Bn 33.1 1 37 CH F Bn Bn 94.2 38 CH ~ 〇 ^ 〇cf3 Bn Bn 82.0 39 CH Bn Bn 48.8 40 CH Bn Bn 89.9 O: \ 88 \ 88539.DOC -31-200418804 Table 12 Manufacturing Example number X Ri R3 R4 R5 Yield (%) 41 CH Ph Bn Bn 64.0 42 CH MeO Bn Bn 90.0 43 CH -〇 OMe Bn Bn 74.0 44 CH — ^ -OMe Bn Bn 55.0 45 CH -〇 Bn Bn 71.0 46 CH -Ο Bn Bn 75.0 47 CH-^ 3 Let Cl Bn Bn 79. 0 48 CH ^ 3 / 〇2 4, Bn Bn 69.0 49 CH -ο Bn Bn 60.0 50 CH -〇Ν == / — ^^ — OMe OMe Me Me 31.3 51 CH ^ 3 Bn Bn 44.0 52 CH ^ 3 ~ 〇s Bn Bn 60.0 53 CH ^ 3 Bn Bn 39.2 54 CH -〇 Bn Bn 61. 1 55 CH Ph Bn Bn 83.0 O: \ 88 \ 88539.DOC -32- 200418804 Table 13 --- ^ Manufacturing Example No. X R1 R3 R4 R5 Yield (%) CH Bn Ph Bn Bn 44.0 U 〇 一 -------- 66 CH " Of5ie Ph Bn Bn 57.0 fi7 CH —〇Μβ Ph Bn Bn 75.0 68 _ CH -〇-〇cp3 Ph Bn Bn 73.0 69 CH " Ν- λ cf3 Ph Bn Bn 99.0 ___--- 70 CH -ο Valley Bn Bn 32.0 71 CH -Ο 1 Ph Bn Me 100 _- ^ 72 CH Ph ---- Br --- Me Bn 83.0 73 CH Seven 1 Bn Bn 81.0 Production Example 25 In (E) -3- (4,5-dimethoxypyridinyl) -1-phenyl-2-propene-l-ag 0.8 1 g (3 mmol) and p-methylhydrazine 0.17 g (3.6 mmol), 10 ml of ethanol was added and refluxed for 5 hours. After the reaction was completed, the solvent was removed, and the residue was purified by alumina column chromatography (hexane · ethyl acetate = 3: 1) to obtain 4,5-dimethoxy-2- (1-methyl -3-Phenyl-4,5-dihydro-sit-5-yl) αα 0.43 g (49.0%) 〇 Production Example 26 In (E) -3- [4,5-dai (benzyloxy) -2-σΛσ 定 基] -1-phenyl-2-propene hydrazine with 0.42 g (1 mmol) and 1-methylhydrazine 0.14 g (3.0 mmol), 10 ml of ethanol was added and refluxed 2 hour. After the reaction was completed, the solvent was distilled off to obtain 4,5-cold (benzyloxy) -2- (1-fluorenyl-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl). Pyridine 0.45 g O: \ 88 \ 88539.DOC -33- 200418804 (99.0%) 0 Production Example 27 In (E) -3- [4,5-fluorenyl (benzyloxy) _2_arimidinyl] -1 To 0.42 g (1 mmol) of phenyl-2-propan-1-one and 6 g (1.5 mmol) of 1-phenylhydrazine 0.5 g, 10 ml of ethanol was added and refluxed for 2 hours. After the reaction was completed, the mixture was cooled, and the precipitated crystals were collected by filtration and dried to obtain 4,5_ (benzyloxy) -2- (1,3-diphenyl · 4,5-dihydro_1H_pyrazole-5- Group) pyridine 0.36 g (69.7%). Production Example 32 In (E) -3- [3,4- | C (benzyloxy) phenyl] small (4-phenyl) -2-propen-1-one 0.35 g (0.8 mmol) and 1-benzene To 0.13 g (1.2 mmol) of hydrazine, 4 ml of ethanol and 0.2 ml of hydrochloric acid saturated ethanol were added and refluxed for 4 hours. After cooling, the precipitated crystals were collected by filtration and dissolved in ethyl acetate, and then purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to obtain benzyl 2- (benzyloxy) _4- [3- ( 4-fluorophenyl) -1-phenyl-4,5-dihydro-1H-pyrazol-5-yl] phenyl ether 0.24 g (55.6%). Production Example 33 In-progress) -3- [3,4_home (benzyloxy) phenyl]] phenylpropenyl-i-one 0.88 g (2.0 mmol) and 1- (4-chlorophenyl) hydrazine To 049 g (3.0 mmol) of the hydrochloride salt, 10 ml of ethanol was added and refluxed for 2 hours. After the reaction was completed, the mixture was cooled, and the precipitated crystals were collected by filtration and dried to obtain benzyl 2_ (benzyloxy) _4- [3_phenylβ1_ (4_fluorophenyl) _4,5_dihydro-1Η-pyrazole_ 5-yl] phenyl ether 0.79 g (74.20 / 〇). Production Example 41 In (E) -3_ [3,4-fluoren (benzyloxy) phenyl]-丨 -phenyl-2-propene- ^ one 々 g (10 mmol) and 2-hydrazinopyridine 16 g (15 mmol), add 100 ml of ethanol and reflux for 12 hours. After the reaction is completed, cool and filter the precipitated crystals.

O: \ 88 \ 88539.DOC -34- 200418804 dried to benzyl 2- (benzyloxy) -4- [3, benzyl_1_ > (2-17 than pyridyl) _4,5, two Hydroxazole_5-yl] phenyl ether 3.27 g (64.0%). The pyrazolines of Manufacturing Examples 28 to 31 and 34 were manufactured by the same method as that of Manufacturing Example 27, the pyrazolines of Manufacturing Examples 35 to 40 were manufactured by the same method as Manufacturing Example 33, and the same method as in Manufacturing Example 41 Manufacture Examples 42 to 55 and 65 to 73 ° ratio σ Slim. Manufacture of Reference Example 3 (6) 腙 (6) shown in Table 14 was manufactured. Table 14

Production Example 5 6 In (E) -3- [4,5-Home (benzyloxy) -2- ° ratio π adenyl] _ι_phenyl_2_propionate_ 丨, — 0.84 g (2.0 mmol ) And 0.49 g of 1- (4-fluorophenyl) hydrazine hydrochloride (3 · 〇, 20 ml of ethanol was added and refluxed for 2 hours. After the reaction was completed, the precipitate was cooled by remote cooling and dried to obtain (E) -3 -[4,5- 贰 (benzyloxy), 孓 _ or O: \ 88 \ 88539.DOC -35- 200418804 group] small phenyl-2, ene "-one N- (4-fluorophenyl) 腙0.51 g (47.4%). Production Example 57 In (4_ [3,4_fluoren (benzyloxy) phenyl> 3_butene_2_one 159 ^ (44 mmol) and 2-hydrazino To 97 g of tonidine (89 inm 〇1), methylbenzyl 40w was added and returned to the machine for 4 hours. After the reaction was completed, the solvent was removed, and the residue was chromatographed on silica gel (hexane: ethyl acetate = 5: 1) Refined to obtain (E) -4- [3,4-fluoren (benzyloxy) phenyl] -3-butene_2, N- (2-carolinyl). 68 g (34.3 Production Example 58 In the same manner as in Production Example 57, from (E) -l- [3,4-fluoren (benzyloxy) benzyl] -1_undecene_3_one (Production Example 13 ) To obtain 0.33 g (80.5%) of fluoren (benzyloxy) phenyl M-undecen-3-one N_ (2-pyridyl) fluorene. 74 Dissolve 0-13 g (0.68 mmol) of (E) _3- (3,4-dimethoxyoxyphenyl) acrolein in 2 ml of ethanol and add 2-hydrazino. Ratio. Set to 0 081 g (0.74 mmol) 0.5 ml of ethanol solution, and stirred at room temperature for 0.5 hours. After the reaction, the precipitated crystals were collected by filtration and dried to obtain (E) -3_ (3,4-dimethoxy) as yellow crystals. Phenyl) -acryl > ^ (2-pyridyl) fluorene 0.12 g (62.3%). Reference Example 4 3-(3-Phenyl-1H-bisalyl-1 -yl). Compared to fluorene 3-benzene Based on 1.44 g (10 mmol), 3-carbon ° ratio of 2.05 g (10 mmol), cuprous ehua 0.19 g (1 mmol), 1,10-morphine 0.18 g (l mmol), phosphoric acid A mixture of 4-24 g (20 mmol) of tripotassium and 10 ml of toluene was stirred at 120 ° C for 14 hours under a stream of argon. After the reaction was completed, water was added to the reaction and extracted with ethyl acetate. The organic layer was mixed with water and Saturated common salt O: \ 88 \ 88539.DOC -36- 200418804 Washed with water in sequence (hexane: (79.0%) ○ Reference Example 5 After drying over sodium sulfate, the solvent was distilled off. The residue was ethyl acetate = 2: ι) purification to give the title compound h74 g 5- [3,4-wu (benzyloxy) phenyl] _3_ Phenylbiazole is (E) -3_ [3,4-fluoren (benzyloxy) phenylbenzene ^ phenyl_2_propylene_ 丨 _one 6.37 ^ (15 mmol), hydrazine monohydrate 085 g ( 15 mm〇1) and ethanol melon 1 for 4 hours under reflux. After the reaction was completed, the solvent was distilled off, and o-chloroquinone 4.14 g (59 mmol) and 60 ml of toluene were added to the residue and refluxed for 1 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was washed with water, washed with a 20% aqueous sodium hydroxide solution and saturated brine in this order, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1 to 3: 1) to obtain 41 g (63 0%) of the title compound. Example 1 Production of pyrazole compound (I) from pyrazoline (5) The compounds shown in Tables 15 to 17 were produced. O: \ 88 \ 88539.DOC -37- 200418804 Table 15 OR5

Compound No. X R1 R3 R4 R5 Yield (%) 1 N Me Ph Me Me 65.0 0 ?. N Mp Ph Rn Rn V). 7 4 N Ph Ph Rn such as n 10 N -〇Ph Bn Bn 99.0 18 CH Ph Ph Bn Bn 85.6 21 CH Ph Bn Bn 38.5 23 CH -〇-f Ph Bn Bn 83.2 25 CH -Or -〇-f Bn Bn 79.0 27 CH OMe MeO HH 6.7 28 CH -Qr Bn Bn 90.3 30 CH F 'Bn Bn 87.0 32 CH -〇-〇CF3 Bn Bn 86.8 34 CH —ocf3 -o Bn Bn 16.5 36 CH 丨 -〇-CF3 Bn Bn 82. 1 38 CH Bn Bn 83.3 45 CH -o Ph Bn Bn 56.6 47 CH -o Ph Me Me 75.0 O: \ 88 \ 88539.DOC -38- 200418804 Table 16 Compound No. X R1 R3 R4 R5 Yield (%) 50 CH -〇N == / MeO Bn Bn 78.0 52 CH OMe Bn Bn 76.0 54 CH " 〇 Bn Bn 67. 0 56 CH " 〇 Bn Bn 71.0 58 CH Cl Bn Bn 80.0 60 CH -On Bn Bn 85. 0 62 CH -ο no2 Bn Bn 69.0 64 CH-^ 3 -〇 ~ N〇 ^ Bn Bn 83.0 69 CH -ο —OMe OMe Me Me 75.9 71 CH ~ ο -o Bn Bn 39.9 73 CH -QrO ^ Bn Bn 80. 8 75 CH Bn Bn 69.0 77 CH-^ 3 Bn Bn 54.0 9 CH Ph Bn Bn 42.0 O: \ 88 \ 88539.DOC -39- 200418804 Table 17 Compound No. X R1 R2 R3 R4 R5 ----- Product (%) 81 CH Bn H Ph-Bn Bn ----- 60.0 83 CH OMe H Ph Bn Bn 63.0 ----— 85 CH-^ OMe H Ph Bn Bn '--—— 41, 〇87 CH — ^ (y ~ 〇CF3 H Ph Bn Bn 63.0-89 CH N—x H Ph Bn Bn — 37.0 cf3 91 CH Seven H Bn Bn 68.0 93 CH H Ph Bn Me 44. 〇-- ~ 95 CH Seven H Ph Me Bn- ------ 83,0 ----------- 107 CH H Bn Bn 81. 〇 Compound 1 4,5-dimethoxy-2- (1-fluorenyl-3-benzene -1H-pyrazol-5-yl) pyridine at 4,5-dimethoxy-2- (1-methyl-3_phenyl-4,5_dihydro-1H-pyrazolyl) pyridine 0.40 g (1.4 mmol) and DDQ 0.31 g (1.4 mmol) were added with 10 ml of toluene and heated at 8 ° C for 2 hours. After cooling, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, and then washed with a saturated saline solution, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by alumina column chromatography (hexane · ethyl acetate = 4: 1) to obtain the title compound (26 g, 65.0%) as an oil. ^ -NMR (CDC13) δ: 4.00 (3Η, S) 5 4.01 (3H? S) 5 4.22 (3H? O: \ 88 \ 88539.DOC -40- 2〇4188〇4 s), 6.79 (1H, s), 7.12 (1H, s), 7.29-7 · 39 (1H, m), 7.4U 43 (2H, m), 7.83-7.85 (2H, m), 8.22 (1H, s). Compound 2 4,5-fluorene (benzyloxy) -2- (1-methyl_3-phenyl-1 selezo-5-yl)> pyridine at 4,5_fluorene (benzyloxy)- 2- (1-methyl_3-phenyldihydro-1H_pyrazalyl-5-yl) pyridine 0.45 g (1.0 mmol) and DDQ 0.34 g (1.5 mmol) were added to 1,4- 10 ml of dioxane and reflux for 2 hours. After cooling, the insoluble matter and the filtrate were concentrated, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to obtain the title of an oily substance. Compound 0.15 g (32.7%). 'H-NMR (CDC13) δ: 4.13 (3H5 s) 5 5.26 (2H5 s)? 5.28 (2H? S)' 6.69 (1H, s), 7.15 (1H, s ), 7.25-7.50 (13H, m), 7.8ΐ (2H, d, J = 7.3 Hz), 8.24 (1H, s). Compound 4 4,5_ 贰 (benzyloxy) -2- ( 1,3-diphenyl-111 "pyrazol-5-yl) 11 to 11 is determined in the same way as compound 2, starting from 4,5-fluorene (benzyloxy) _2_ (ι, 3-diphenyl- 4,5-Dihydro- ^ bi-Hydro-Hieto specific bite 'to give the title compound as an oil (99.0%).

Hz), 8 · 23 (1H, s). Compound 10 ^^ (00013) 5: 4.85 (2 ^ s), 5 < 23 (2 ^^ 6 65 3), 7.04 (1H, S), 7.20 -7.48 (1 m), 7 87 (2H, br d, J = 7 3 pyrazol-5-yl) -3-pyridinyl 4- -methoxy-6-[3-phenyl-1 _ (2-0 than α amidyl. amidinyl) _4,5 -Dihydro-1Η- O: \ 88 \ 88539.DOC -41-200418804 Mouth ratio ° -5-base] σ specific mouth setting 0.10 g (0.19 mmol) and DDQ 0.066 g (0.29 mmol ), 10 ml of toluene was added and refluxed for 4 hours. After the reaction, the solvent was removed, and the residue was extracted with ethyl acetate, washed with a 5% (w / v) aqueous sodium hydroxide solution, water, and saturated brine in that order, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (hexane · ethyl acetate = 5: 1) to obtain the title compound (0.1 g, 99.0%). h-NMR (CDC13) δ: 5.10 (2H, s), 5.21 (2H, s), 6.94 (1H, s), 7.00 (1Η, s), 7.18-7.21 (1Η, m) , 7.32-7.45 (13Η, m), 7.71-7.73 (1H, m), 7.78-7.82 (1H, m), 7.91-7 · 93 (2H, m), 8.11 (1H, s), 8.24-8.25 (1H, m) 〇Melting point: 146-148 ° G Compound 18 5_ [3,4-fluoren (benzyloxy) phenyl μ!,% Diphenyl Method: The title compound was obtained from 5_ [3,4_4 (benzyloxy) phenyl R3-diphenyl_4,5_dihydro_1Η · αbisa] (85.6%). ^ -NMR (CDCls) δ: 4.90 (2Η, 3), 5 ^ 5 (2 ^ s), 6.72 (1H s), 6.75-6.90 (3H, m), 7.25-7.47 (18H, supplement 7 μ?% (2h melting point: 82_8; ^; 5. (: Compound 21 _ [3,4K benzyloxy) phenyl] -1-phenyl_3, _fluorophenyl) Method Phenyl_3 _ ('fluorophenyl) -4,5-bis (38,5%) 〇 \' But να must j hydrogen-1Η-pyrazole to get the title 4 丨

O: \ 88 \ 88S39.DOC 42- 200418804 iH-NMR (CDC13) δ: 4.91 (2H, s) 5 5.16 (2H, s), 6.67 (1H, s), 6.77 (1H, d, J = 2.0 Hz), 6.85-6.88 (2H, m), 7.11 (2H, t, J = 8.8 Hz), 7.31-7.39 (13H, m), 7.44 (2H, d, J = 6.8 Hz ), 7.84-7.88 (2H, m) ° Melting point: 119-120 ° C Compound 23 5_ [3,4-fluoren (benzyloxy) phenyl] -1- (4-fluorophenyl) -3-benzene In the same manner as for compound 10, the method of the compound 1H-salyl is from 5- [3,4-fluoren (benzyloxy) phenyl] -1- (4-fluorophenyl) -3-phenyl-4,5. -Dihydro-1H-nizole to give the title compound (83.2%). b-NMR (CDC13) δ: 4.99 (2H, s), 5.17 (2H, s), 6.70 (1H, s), 6.75-6.85 (2Η, m) 5 6.89 (1Η, d, J = 8.3Hz), 7.01 (2Η, t, J = 8.3Hz), 7.20-7.48 (15H, m), 7.88 (2H, d, J = 8.3Hz). Melting point: 82-84 ° C Compound 25 5- [3,4_ 贰 (benzyloxy) phenyl] -1,3- 贰 (4 · fluorophenyl) _1H-Houjun Use the same method as compound 10 The title of 5- [3,4-fluorene (benzyloxy) phenyl] -1,3-fluorene (4-fluorophenyl) -4,5-dihydro-1H-pyrazole as an oil was obtained as Compound (79.0%). lH-NMR (CDC13) δ: 4.99 (2H? s) 5 5.17 (2H5 s) 5 6.65 (1H, s), 6.75-6.85 (2H, m), 6.89 (1H, d, J = 8.3Hz) , 7.01 (2H, t, J = 8.8Hz), 7.10 (2H, t, J = 8.8Hz), 7.20-7.48 (12H? M)? 7.80-7.87 (2H, m). Compound 27 O: \ 88 \ 88539.DOC -43-200418804 4- [3- (2,5-dimethoxyphenyl) _1- (4-fluorophenyl) -111 ^ pyrazol-5-yl] 1,2,2-diols in 4- [3- (2,5-dimethoxyphenyl) -1- (4-fluorophenyl) -4,5-dihydro-1H-imidazole_5_ 15 ml of ethanol was added to 0.41 g (1.0 mmol) of 1,2, benzenediol and DDQ 0.34 g (1.5 mmol), and the mixture was refluxed for 2 hours. After cooling, the reaction was concentrated, and the residue was purified by silica gel chromatography (hexane · ethyl acetate = 3: 1) to obtain the title compound (0.027 g, 6.7%). W-NMR (CDC13) δ: 3.75 (3H, s), 3.84 (3H, s), 6.54 (1H, dd, 2.4, 8 · 3Ηζ), 6.64 (1Η, d, J = 2.4 Hz), 6.71 (1Η, d, J = 8.3Hz), 6.87-6.95 (2H, m), 7.06 (1H, d, J = 8.8Hz), 7.26 (2H, t, J = UHz), 7.33 -7.43 (2H, m), 7.48 (1H, d, j = 3 4Hz), ... (1H, s), 9.10 (1H, s). Melting point: 185-186 ° C Compound 28 2- [5- [3,4-fluorenyl (benzyloxy)]-l- (4-fluorophenyl) In the same way as Compound 2, from 2 ^ fluorophenyl) -4,5-dihydro-1H, it is a compound ... (90.3%). ,, ..., day-to-day questions ^ -NMR (CDC13) δ: 4.98 (2Η ^ c '), 5.16 (2fj 6 7 & (3H, m), 7.03 (2H, t, J = 8.8HZ ), 〇9 h · 6 < · 92 m), 75 (1H, dtjJ =, 5j, 8H2), δ, 6; ^ --- 〇a3H5 8.62-8.70 (1H, m). , Br d, compound 30 5_ [3,4-fluoren (benzyloxy) phenylfluorene_ (2… monofluorobenzyl) 1 (4-fluorobenzyl O: \ 88 \ 88539.DOC -44- 200418804 group)- 1Η-nazole is prepared from 5- [3,4-fluoren (benzyloxy) phenyl] -1- (2,4-difluorophenyl) -3- (4-fluorobenzene in the same manner as in compound 10. ) -4,5-dihydro-111-nizolazole to give the title compound (87.0%). i-NMR (CDC13) δ: 5.00 (2H, s), 5.15 (2H, s), 6.68 (1H, s), 6.78-6.98 (3Η, m), 7.11 (2Η, t, J = 6.8 Hz), 7.13-7.47 (13 Η, m), 7.82-7 · 86 (2 Η, m). Melting point: 109-111 ° C Compound 32 5- [3,4-fluoren (benzyloxy) phenyl] -1- (4-trifluoromethoxyphenyl) -3- (4-fluorophenyl)- 1Η-pyrazole is prepared from 5- [3,4- 贰 (benzyloxy) phenyl] -1- (4-trifluoromethoxyphenyl) -3- (4-fluorobenzene) in the same manner as in compound 10. Radical) -4,5 · dihydro-1H-imidazole to give the title compound (86.8%). W-NMR (CDC13) δ: 4.96 (2H, s), 5.18 (2H, s), 6.66 (1H, s), 6.67 (1Η, d, J = 2.0Hz), 6.83 (1Η, dd , J = 2.0, 8 · 3Ηζ), 6.90 (1H, d, J = 8.3Hz), 7.11 (2H, t, J = 8.8Hz), 7.19 (2H, d, J = 8.8Hz), 7.31- 7.40 (10H, m), 7.45 (2H, d, J = 6.8Hz), 7.83-7.87 (2H, m) ° Melting point: 104-105 ° C Compound 3 4 2- [5_ [3,4-贰 (benzyloxy)]-l- (4-trifluorofluorenyloxyphenyl) -1Η-oxazol-3-yl] ° ratio σ is set at (Ε) -3- [3,4-fluorene (benzyloxy (Phenyl) phenyl] -1- (2-arimidinyl) -2-propen-1-one O: \ 88 \ 88539.DOC -45- 200418804 0.35 g (0.83 mmol) and 1- [4 -0.29 g (1.25 mmol) of-(trifluoromethoxy) phenyl] hydrazine hydrochloride was added with 5 ml of ethanol and refluxed for 8 hours. After the reaction was completed, the solvent was distilled off, 0.28 g (1.24 mmol) of DDQ and 5 ml of toluene were added to the residue, and the mixture was refluxed for 24 hours. After the reaction was completed, the solvent was distilled off. The residue was extracted with ethyl acetate, washed with a 5% (w / v) aqueous sodium hydroxide solution, water and saturated brine in that order, dried over sodium sulfate, and removed from the solvent. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (0.081 g, 16.5% in 2 steps). ^ -NMR (CDC13) δ: 4.96 (2H, s), 5.18 (2H, s) 5 6.82-6.91 _ (3Η, m), 7.11 (1Η, s), 7.19-7.45 (16Η, m ), 7.74-7.78 (1H, m), 8.07 (1H, d, J = 8.3Hz), 8.67 (1H, d, J = 4.4Hz). Melting point: 116.5-117.5 ° C Compound 36 5_ [3,4-fluorenyl (benzyloxy) phenyl] -1- (4-trifluorofluorenylphenyl) _3_ (4_fluorobenzyl) -1 In the same manner as for Compound 10, from 5- [3,4-fluorene (benzyloxy) phenyltrifluoromethylphenyl) -3- (4-fluorophenyl) _4,5-dihydro-1fluorene- Pyridine yielded the title compound (8 2.1%). -

'H-NMR (CDC13) δ: 5.00 (2Η, s) 5 5.19 (2H3 s) 5 6.68 (1H s), 6.80-6.82 (2H, m), 6.91 (1H, d, J = 8.8Hz), 7.12 (2H, t JUHz), 7.30-7.45 (12H, m), 7.58 (2H, d, j = 88Hz) 7.84-7.88 (2H, m). Melting point: 122-124 ° C Compound 38 O: \ 88 \ 88539.DOC -46-200418804 5- [3,4-fluorenyl (benzyloxy) phenyl] -1- (4-thyl) -1Η- Π than fluorene dibutylbenzyl) fluorobenzyl was used in the same way as compound 10, starting from 5- [3,4-bab ,, # paper (fluorenyl) phenyl] -1- (4-third butyl Phenyl) -3_ (4-fluorophenyl) _4,5-digas, oxygen-1Η- ° ratio σ to obtain the title compound (83.3%). 'H-NMR (CDC13) δ: 1.32 (9H5 s) 5 4.83 (2U,, Hook, 5.16 (2H, s), 6.67 (1H, s), 6.74 (1H, s), 6.90 (2H3 n Flying h 7 · 10 (2H, t, J = 8.3Hz), 7.26-7.44 (14H, m), 7.86 (2H, dd5 j > 5 4) Melting point: 112.5-113.5 ° C Compound 45 2- { 5- [3,4-fluoren (benzyloxy) phenyl] _3-phenyl-11 ^. Pizole odor t + (56.6%) 〇 In the same manner as for compound 10, from 2- {5_ [3 , Private (oxybenzyl) phenyl] _3-benzene & -4,5-dihydro-1H "smaller than bismuth to obtain the title compound ^ -NMR (CDC13) δ: 4.99 (2Η, s), 5.17 (2H, s), 6.74 (1H s), 6.87-6.91 (3H, s), 7.19-7.22 (1H, m), 7.29-7.48 (13H, m) 7.71-7.75 (1H, m) , 7.91-7.93 (2H, m), 8.38_8.39 (1H, m). Melting point: 95-95.5 ° G Compound 47 2_ [5- (3,4-dimethoxyphenyl) _3_phenyl- 1H_n pyrazolyl] pyridine was obtained from 2_ [5_ (3,4_dimethoxyphenyl) _3_benzyl-4,5-dihydro-1H_pyrazolyl] pyridine as an oil in the same manner as the compound ο The title compound (75.0%). H-NMR (CDC13) δ: 4.99 (2H? S) 5 5.17 (2H, s)? 6.74 (1H5

O: \ 88 \ 88539.DOC -47- 200418804 s)? 6.87-6.91 (3H5 s) 5 7.19-7.22 (1H? M) 5 7.29-7.48 (13H, m) 7.71-7.75 (1H, m), 7.91 -7.93 (2H, m), 8.38-8.39 (1H, m). Compound 50 2- {5- [3,4-fluorenyl (benzyloxy) phenyl] -3 · (2-methoxyphenylpyrazole_ ^ yl> 11 ratio) Determined in the same manner as for compound 10, from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (2-methoxyphenyl) _4,5-dihydro-1H-pyrazole-l-yl} pyridine Title compound (78.0%) iH-NMR (CDC13) δ: 3.92 (3H, s), 4.99 (2H, s), 517 (2H s), 6.89 (2H, s), 6.97 ( 1H, s), 6.98-7.04 (2H, m), 7 l8 (1H, dd, J = 5.86, 7.33Hz), 7.25-7.50 (13H, m), 7.69-7.73 (1H, m), 8.09 (1H , Dd, J = 2.0, 7.3Hz), 8.37 (1H, dd5 J = 1.〇, 4.9Ηζ). Melting point: 110-111 ° C Compound 52 2 · {5- [3,4- 贰(Benzyloxy) phenyl] -3- (3-methoxyphenylMH_u than sialo- ^ yl}. Ratio 11 is determined in the same way as compound 10, starting from 2- {5- [3,4-home ( Benzyloxy) benzyl] -3- (3-methoxyphenyl) -4,5-dihydrotoluene-l-yl} bite ratio to give the title compound (76.0%). ^ -NMR (CDCI3) δ: 3.87 (3H? S), 4.99 (2H5 s) 5 5.17 (2H5 s), 6.72 (1H, s), 6.86-6.91 (4H, m), 7.21 (1H, dd, J = 4.9, 7 · 3Ηζ), 7.29-7.49 (14H, m), 7.70-7.75 (1H, m), 8.39 (1H, d, J = 3.9Hz).

Melting point: 90-92 ° C 〇: \ 88 \ 88539.DOC -48- 200418804 Compound 54 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (4-methoxybenzene Group) -1 oxazolyl-1-yl} ° ratio σ is determined in the same way as compound 10, from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (4- (Methoxyphenyl) -4,5-dihydro-1'-pyrazole-l-yl} pyridine to give the title compound (67.0%). W-NMR (CDC13) δ: 3.84 (3H, s), 4.99 (2H, s), 5.17 (2H, s), 6.66 (1Η, s), 6.86-6 · 96 ( 5Η, m), 7.17-7.46 (12Η, m), 7.14-7 · 19 (1H, m), 7.84 (2H, dd, J = 2.0, 6.8Hz), 8.37 (1H, dd, J = 1.0 , 4 · 9Ηζ). Melting point: 167-170 ° C Compound 5 6 2- {5_ [3,4-fluorenyl (benzyloxy) phenyl] -3- (2-chlorophenyl) -111-pyrazol-1-yl} In the same manner as in Compound 10, 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (2-chlorophenyl) -4,5-dihydro-1H-pyridine Azole-l-yl} pyridine gave the title compound (71.0%). h-NMR (CDC13) δ: 5.00 (2H, s), 5.17 (2H, s), 6.89 (3H, brs), 6.95 (1Η, s), 7.20-7.49 (15Η, m), 7.70-7.75 (1Η , M), 7.95 (1H, dd, J = 2.0, 7.3Hz), 8.40 (1H, d, J = 4.4Hz). Melting point: 113-114 ° C Compound 58 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (3-chlorophenyl) -1Η-η-pyzol-l-yl} . Bipyridine O: \ 88 \ 88539.DOC -49- 200418804 In the same way as Compound 10 'from 2_ {5 · [3,4 · 贰 (benzyloxy) phenyl] -3- (3-lactylphenyl ) -4,5-dihydro_1Η "Bisa. Bakibby α diidine gave the title compound (80.0%).

^ H-NMR (CDC13) δ: 4.99 (2H, s), 5.17 (2H, s), 6.71 (1H S), U6-6.91 (3H, m), 7.20_7.46 (14Hm) 7 72_7 79 (2H 7.93 (1H, brs), 8.40 (1H, d, J = 3.9Hz) Melting point: 107-110 ° C Compound 6 0 2] 5_ [3,4_wu (benzyloxy) phenyl] _3_ (4 · Chlorophenyl) _m "bizole small base bispyridine In the same way as compound 10, from 2_ {5_ [3,4 _ ((benzyloxy) phenyl] -3--3-4-murylphenyl) -4,5_dihydrobisulfalyl} determined to give the title compound (85.0%). ^ -NMR (CDC13) δ: 4.99 (2H, s), 5.17 (2H, s), 6.85-6.91 (3H , m), 7.20-7.45 (14H, m), 7.70-7.74 (1H, m), 7.85 (2H, d J-8.3Hz), 8.40 (1H, dd, J = 2.0, 4.9Hz). Melting point: 123-126 ° G Compound 62 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (3_nitrobenzene *)-1Η_πpyzol_ 丨 · yl}. In the same way as compound 10, from 2- {5 __ [3,4_ 贰 (benzyloxy) phenyl] 3 (3-Shi Xiao basic group) _4,5_dihydro-1 H_D ratio 嗤 -1-group } Ton σ gives the title compound (69.0%). 'H-NMR (CDC13) δ: 5.00 (2H5 s) 5 5.18 (2H5 s), 6.80 (iH?

O: \ 88 \ 88539.DOC -50- 200418804 s), 6.86-6.92 (3H, m), 7.24-7.47 (13H, m), 7.57-7.61 (1H m) 7.73-7.78 (1H, m), 8.19 (1H, dd, J = i.5, 8 · 3Ηζ), 8 27 (ih d J = 7.8Hz), 8.41 (1H, dd, J = 2.0, 4 · 9Ηζ), 8.73 (1H, s) . Melting point: 113-117 ° G Compound 64 2- {5- [3,4-Mu (benzyloxy) phenyl] _3_ (4_acylphenyl) _old "smaller than sialyl} gas-1Η ·· ° Blessing than 嗤 -1-kibidine

In the same square group as compound 10] -3- (4-Azylphenyl) -4,5-di compound (83.0%). W-NMR (CDC13) δ: 4 99 y (2H, s), 5.18 (2Η. S), 6.85-6.92 (3H, m), 7.26-7 45 Π ^, S), 6.81 (1H, • Bucket) (UH, m), 7 71 1 to 8.02 (2H, d, J = 8.8HZ), 8.28 (· · · 78 (1H, m), UH, d5 J = 8.8Hz, "J = 1 · 0, 4 · 9Ηζ). ), 8.43 (1H, dd, melting point: 145-148 ° C, J bisazole + group on compound 69 in the same ancient JL as compound 10 ^ fenzhi method, from 2_ [3, radical) -4,5-di The hydrogen-1Η-σ bisha member (3,4-dioxan "lean group) is synonymously obtained as the oil beetle species (75.9%). The title compound of the narrow ^ -NMR (CDC13) δ · ^,. 3.73 (3H, s), 3.90 (deduction S), 3.99 (3H, S), 6.75 (1H s) 6 79 (ih (3H, s), 3 93 (3h, (1H, d, J = 8.3Hz) , 6.89-6.95 (2h, called, 7 a d 'J == 2.0 Hz), 6.84 (1H, dd, J = 2_0, 8_3HZ), 7 4' · '7 · 26 UH, m), 7 43 , D, J = 7.8HZ) 7 q, 7.S5 (1H, d,

O: \ 88 \ 88539.DOC 200418804 J = 2.0Hz), 7.76 (1H, ddd, J = 2.0, 7.8, 7.8Ηζ), 8.45_8 · 46 (1H, m) o Melting point: 119-122 ° C Compound 71 2- [5- [3,4-fluorenyl (benzyloxy)]-1- (2 · -pyridylpyrazole_3-yl] pyridine In the same manner as in Compound 10, from 2- [5 -[3,4-fluorene (benzyloxy)]-l- (2-pyridyl) -4,5-dihydro-1H-pyrazol-3-yl] pyridine to give the title compound (39.9%). B- NMR (CDC13) δ: 4.98 (2H, s), 5.16 (2H, s), 6.85-6.91 (3Η, m), 7.13 (1Η, s), 7.22-7.45 (13Η, m), 7.71 -7.76 (2Η, m), 8.14 (1H, d, J = 7.8Hz), 8.44 (1H, dd, J = 0.9, 4.3Hz), 8.60 (1H, dd, J = 3.9, 4.9Hz) ° Melting point : 122-123 ° C Compound 73 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (4'-fluoro [1,1'_biphenyl] 4-yl)- 1Η-σ ratio 嗤 -1 -yl} σ ratio In the same manner as in Compound 10, 2- {5- [3,4-, (benzyloxy) phenyl] fluoro [1, Γ-biphenyl ] 4-yl) -4,5-dihydro-lH-upyrazol-1-yl "pyridine to give the title compound (80.8%). W-NMR (CDC13) δ: 5.00 (2H, s), 5.18 ( 2H, s), 6.77 (1H, s), 6.88-6.93 (2Η, m), 7.12-7.16 (2Η, m), 7.22-7 · 46 (13Η, m) 7_59-7 · 62 (4H, m), 7.72-7.76 (1H, m), 7.96 (2H, d, J = 8.3Hz), 8.42-8.43 (1H, m).

Melting point: 118-120 ° CO: \ 88 \ 88539.DOC -52- 200418804 Compound 75 2_ {5- [3,4- 贰 (benzyloxy) phenyl] -3- (2-thienyl) -1Η · Amidazol-l-yl} Orbital from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (2-thienyl) -4 in the same manner as in compound 10. , 5-Dihydro-lH-u-pyzol-l-yl} pyridine to give the title compound (69.0%). W-NMR (CDC13) δ: 4.98 (2H, s), 5.16 (2H, s), 6.63 (1H, s), 6.84-6.90 (3Η, m), 7.06-7.09 (1Η, m) 7.18-7.21 (1Η, m), 7.28-7.48 (13H, m), 7.70-7.74 (1H, m), 8.36 (1H, d, J = 4.9Hz). Melting point: 124-126 ° C Compound 77 2- {5- [3,4_fluoren (benzyloxy) phenyl] -3- (3-thienyl) _1H_imidazol-l-yl} In the same manner as in Compound 10, from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (3-thienyl) -4,5-dihydro-1H-pyrazole-1 -Yl} pyridine to give the title compound (54.0%). b-NMR (CDC13) δ: 4.98 (2H, s), 5.17 (2H, s), 6.62 (1H, s), 6.84-6.90 (3Η, m), 7.20 (1Η, dd, J = 4.9, 7. · 3Ηζ), 7.25-7.45 (12H, m) 7.58 (1H, dd, J = 1.5, 4. · 9Ηζ), 7.68-7 · 73 (2H, m), 8.39 (1H, d, J = 3.4Hz). Melting point: 110-113 ° C Compound 79 2- {5- [3,4_fluoren (benzyloxy) phenyl > 3- (2-arimidinyl) _1H-aromidazole-1-O: \ 88 \ 88539.DOC -53- 200418804 group} -1,3-benzopyrene is the same as compound 10 from 2_ {5_ [3,4_ 家 (benzyloxy) phenyl] _3_ (2_pyridine Group) _4,5-dihydro-1H-pyrazolyl) -1,3-benzothiazole to give the title compound (42.0%). ^ (〇〇013) 5: 5.14 (2 ^ s)? 5.24 (2H? S)? 6.75 (1H? S)? 6.99 (1H, d, J-8.3Hz)? 7.15 (1H? Dd? J =: 2.4? 8.3Hz) 5 7.23-7.50 (16H, m), 7 • 21 (m, d, J = 7 3Hz), 7 8i (ih, d, J-6.8Hz), 7.93 (2H, d, J = 8.3Hz).

Melting point: 142.5-143.5 ° C Compound 81 1-benzyl-5- (3,4-fluorenyl-benzyloxy_phenyl) -3-phenyl-1fluorene · σbiazole in the same manner as compound 10 The title compound (600%) was obtained from benzyl-5_ (3,4-fluorene · benzyloxy_benzyl) -3-phenyl-4,5-dihydro-1H ^ pyrazole. " H-NMR (CDC13) δ ··· 4.3 (2H, s), 5.19 (2H, s), 5 29 (2H s), 6.84-6.93 (3H, m), 7.05 (2H, d, J = 6.8Hz), 7. 2 cut 46 (16h m), 7.84 (1H, d, J = 7.3Hz). 'Melting point: 120-12TC compound 83% (3,4-fluorene · benzyloxyphenyl) -1- (3-methoxyphenyl) -3-benzyl In the same way as compound 10, from 5_ ( 3,4-Hydroxybenzylphenyl M- (3-methoxyphenyl) -3-phenyl-4,5-dihydro-1H-pyrazole gives the title compound as a pale oil ( 63.0%). KNMR (CDC13) δ: 3.73 (3H, s), 4.98 (2H, s), 5 23 (2h s), 6.74 (1H, s), 6.83-6.97 (3H, m), 7 · 26, 7.51 (17 melons) 〇AS ^ 8539.D〇c -54- 200418804 7.88_7.90 (2H, m). Compound 85 5- (3,4 benzyloxyphenyl H_ (4 _Methoxyphenyl) _3_ 笨 基 _ιη + In the same manner as in Compound 10, from 4 ^^ 4- 贰 -Benzyloxyphenyl VH4-methoxyphenyl) -3_phenyl · 4, 5. Dihydrogen, saliva to give the title compound (41.0%) as a pale yellow oil. ^ -NMR (CDC13) δ: 3.81 (3Η, s), 4.94 (2H, s), 5.15 (2H, s) , 6.70 (1H, s), 6.81-6.88 (5H, m), 7.25_7 '(2H, dd, J = 0.8, 8. Shi). 7.44 (15H, m), 7.89 Compound 87 5- (3,4 -贰 -benzyloxyphenyl) _3_phenyldifluorofluorenoxyphenyl) _1H_pyridine In the same manner as in Compound 10, (3,4-fluorene-section) Phenyl) -3-benzyl-: U (4_trifluoromethoxyphenyl) _45__ ,,.,. ,, 'Qi-1 pyrazole is obtained as a pale yellow, the title compound (63.0%) . , 5.18 (2H, s), 6.72 (1H, 13Hz), 7.28-7 · 46 (15H, dd, J = 1.0, 8.3Hz). lH " NMR (CDCI3) δ: 4.99 (2H? s) s), 6.8 (K6 · 82 (2H, m), 6 91 (iH dhm), 7.57 (2H, d, j = 8 3Hz), 7 89 (^ compound 89 '= phenylfluoromethyl in the same way as compound 10, ~ yl) -3-phenyl-4,5-dihydro-old "is smaller than olfactory Benzene title compound (37.0%). 4_trifluoromethyl-pyrimidine

O: \ 88 \ 88539.DOC '55-200418804 iH-NMR (CDC13) δ: 5.09 (2H, s), 5.21 (2H, s), 6.77 (1H, s), 6.84-6.93 (3H , M), 7.22-7_47 (14H, m), 7.96 (2H, m), 8.91 (1H, d, J = 5.4Hz). Melting point: 115-117 ° C Compound 91 2- [5- (3,4-Carboxyfluorenylphenyl) _3- (2,4-Digasphenyl) -111-11 Group] -pyrene ratio In the same manner as in compound 10, 2- [5- (3,4-fluorene-benzyloxyphenyl) -3- (2,4-difluorophenyl) _4,5_ Dihydro_1H-Azol-1-yl] -Amidin gives the title compound (68.0%). ! H-NMR (CDC13) δ: 4.99 (2H5 s) 5 5.17 (2H? S)? 6.83-6.96 (6H, m), 7.21-7.45 (12H, m), 7.71 (1H, dt, J = 1.8, 7.8Hz), 8.13 (1H, dd, J = 2.0, 6.8Hz), 8.41 (1H, d, J = 3.4Hz). Melting point: 125-128 ° C Compound 93 2- [5- (4-fluorenyl-3-methoxyphenyl) -3-phenyl-111-. Bijun-1-yl] 11 to 17 is determined in the same manner as for compound 10, from 2- [5- (4-benzyloxy-3-fluorenoxyphenyl) -3-phenyl-4,5-di Hydrogen-1H-pyrazol-1-yl] -pyridine gave the title compound (44.0%). ^ NMR (CDC13) δ: 3.72 (3H, s), 5.16 (2H, s), 7.22-7.53 (10Η, m), 7.77 (1Η, dt, J = 2.0, 7.8Ηζ), 7.93 (2Η, d, J = 8.8Hz), 8.44 (1H, d, J = 3.0Hz). Melting point: 111-113 ° C Compound 95 O: \ 88 \ 88539.DOC -56- 200418804 2- [5- (3-benzyloxy-4-methoxyphenyl) -3-phenyl-1H-role Azol-1-yl] pyridine In the same manner as in Compound 10, from 2- [5- (3-benzyloxy-4-methoxyphenyl) -3-phenyl-4,5-dihydro · 1H -Pyrazole-1 -yl] -pyridine to give the title compound (83.0%). TH-NMR (CDC13) δ: 3.87 (3H? S) 5 4.96 (2H? S) 5 6.72 (1H? S), 6.81-6 · 93 (3H, m), 7.16-7.46 (10H, m) , 7.70 (1H, dt, ^ J = 2.0, 7.8 Hz), 7.92 (2H, d, J = 8.3 Hz), 8.37 (1H, dt, J = 1.0, ^ 4 · 9Ηζ). m Melting point: 89-91 ° C Compound 107 2- [5- (3,4-fluorenyl-benzyloxyphenyl) -3- (3-bromophenyl) -1Η ^ pyzol-1_yl]- In the same manner as in compound 10, the compound was prepared from 2- [5- (3,4-fluorene-benzyloxyphenyl) -3- (3-bromophenyl) -4,5-dihydro · 1fluorene- Pyrazol-1-yl] -pyridine gave the title compound (81.0%). h-NMR (CDC13) δ: 4.99 (2Η, s), 5.17 (2Η, s), 6.71 (1Η, φ s), 6.91-6.84 (2Η, m), 7.21-7.39 (11Η, m), 7.43-7.52 (3Η, m), '7.74 (1H, dt, J = 1.9, 8 · 3Ηζ), 7.81-7.84 (1H, m), 8.09 (1H, t,' J = 1.9Hz), 8.39 -8.41 (1H, m).

Melting point: 127-129 ° C Example 2: Production of pyrazole compound (I) from europium (6) Production of the compounds shown in Table 18. O: \ 88 \ 88539.DOC -57- 200418804 Table 18

Compound No. X Rl R2 R3 R4 R5 Yield (%) 8 NH Ph Bn Bn 58.0 0 40 CH H Me Bn Bn 64. 7 42 CH-< 3 H n-C8Hl7 Bn Bn 90.0 97 CH -o HH Me Me 14. 2 Compound 8 4,5-fluorenyl (benzyloxy) -2-〇 (4-fluorophenyl) -3-phenyl-1H-nazol-5-yl] pyridine in (E) -3- [4,5-fluoren (benzyloxy) -2-n than pyridyl] -1-phenyl-2-propen-1-one N-(4-fluorophenyl) 腙 0.50 g (0.95 mmol) and 10 ml of toluene was added to DDQ 0.24 g (1.04 mmol) and refluxed for 2 hours. After the reaction was completed, the solvent was distilled off, and the residue was extracted with ethyl acetate, washed with a 5% (w / v) aqueous sodium hydroxide solution, water, and saturated brine in that order, dried over sodium sulfate, and removed from the solvent. The residue was purified by silica gel chromatography (hexane · ethyl acetate = 3: 1) to obtain 0.29 g (58.0%) of the compound. W-NMR (CDC13) δ: 4.99 (2H, s), 5.22 (2H, s), 6.73 (1H s), 6.96 (1Η, s), 7.04 (1Η, t, J = 8.8 Hz), 7.25-7 · 44 (l5H '7.85-7.92 (2H, m), 8.17 (1H, s).' 'Melting point · 91-92 ° C compound 40 O: \ 88 \ 88539.DOC -58-200418804 2 (5 [3'4-Han (benzyloxy) phenyl] _3_methyl-oxopyrazine + yl ^ pyridine in the same way as compound 8 'Cong Wei, 4_Han: 7% is taken ^ NMR (CDCi3) s · 2 37 (3H, s), * π (twist, s), ws), 6.22 (1H, s), 6 79_6 81 (2h, (, m), 6.86 6.88 (1H s) 7.15-7 · 1 "1Η, phase coffee ,, 7.62-7.67 〇H, m), 8.39_8.4〇 (1H, m) .... (Melt melting point: 153_154t compound 42 2 -{5- [3,4_Da (benzyloxy) phenyl] _3_octyl W-Small Parker bite diol 8 in the same way, starting from vicinal, 4-fluorenyloxybenzene (soil 9〇 〇%). N (2m) 腙 to give the title compound ^ -NMR (CDC13) δ: 0.88 (3Η, t, J = 6.8Hz) 5 1.24-1.41 (8H,), 1.67 1.73 (4H, m), 2.70 (2H, t, J = 7.8Hz), 4.97 (2H, s), 5-16 (2H, s), 6.24 (lH, s), 6.80-6.81 (2H, m), 6.86.6.88 (1H, m ), 7.15-7.18 (1H, m), 7.24-7.46 (11H, m), 7.63-7 .67 (1H, m), 8.38-8 · 39 (1H, m). Melting point: 65-66¾ Compound 97 2- [5- (3,4-dimethoxyphenyl) _1H "is smaller than saliva In the same manner as in compound 8, the compound] _n-pyridine was used to obtain the title compound (i) 4.2% from (E) -3- (3,4_dimethoxyphenyl) · 2-propenefluorene · (2heptyl) 腙).

O: \ 88 \ 88539.DOC -59- 200418804 Η-NMR (CDC13) δ: 3.70 (3H, s), 3.89 (3H, s) 5 6.49 (1H, d, J-2.0Hz), 6.73 ( 1H, d, J = 2.0Hz), 6.81-6.87 (2H m), 7.22-7.26 (1H, m), 7.43 (1H, d, J = 8.3Hz), 7.73-7.78 (2H, m),

8.43-8.44 (1H, m) o Melting point: 84-85 ° C Example 3: 4,5-fluorene (benzyloxy) -2- (l, 3 · diphenyl-4-ethoxycarbonyl ·; ^ · Production of pyrazol-5-yl) pyridine (Compound 12) Ethyl (Z) -2-benzyl-3- [3,4-fluorenyl (benzyloxy) -2-carolinyl] acrylate 1.29 g (2.6 mmol) was dissolved in 6 ml of N, N, -dimethylformamide and 3 ml of acetic acid. 0-5 ml of phenylhydrazine was added and stirred at room temperature for 12 hours. After the reaction was completed, it was dissolved in ethyl acetate, washed with 1 mol / L sodium hydroxide aqueous solution, water, and saturated saline, followed by washing with 'Naganu sulfate' and distilling off the solvent. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to obtain 1.41 g (93.0%) of the title compound as an oily substance. 1 H-NMR (CDC13) δ: 0.99 (3Η, t, J = 7.3Ηζ), 4.10 (2H, q, J = 7.3Hz), 5.23 (2Η, s), 5.26 ( 2Η, s), 7.57 (1Η, s), 8.25 (1Η, s). Example 4: Production of pyrazole compound (I) (R4 = R5 = Hydrogen, the compounds shown in Tables 19 to 22. Production of 7 · 27_7 · 48 (20H, m) 5)) O: \ 88 \ 88539.DOC -60- 200418804 Table 19

OH

(I) R3 Compound No. XR! R2 R3 Yield (%) 3 N Me H Ph 80.3 5 N Ph H Ph 65. 5 9 N -〇-FH Ph 41. 9 11 N -〇H Ph 52.3 13 N Ph COOEt Ph 35.0 19 CH Ph H Ph 68.7 22 CH Ph H -Or 89. 1 24 CH H Ph 76.0 26 CH H 68. 1 29 CH -〇 ~ f H ~ o 51.8 31 CH 〆H -Or 46. 3 33 CH- 〇 ^ 〇cp3 H 72 · 2 35 CH -〇-〇cp3 H -〇86, 2 37 CH -〇 ~ cp3 H -〇-f 64. 3 39 CH -〇-tBu H 52.0 41 CH -〇H Me 73 1 43 CH -7} H n-C8Hi7 50.0 46 CH H Ph 62.5 O: \ 88 \ 88539.DOC > 61-200418804 Table 20 Compound No. X R1 R2 R3 Yield (%) 51 CH -〇Η MeO- ο 63.0 53 CH N == / Η OMe ~ 6 88.0 55 CH -〇 Η ^ · ~~ ΟΜθ 7.0 57 CH -〇 Η 53.0 59 CH Ο Η 25.0 61 CH-^ 3 Η -〇 ^ α 76.0 63 CH- ^ 3 ν νο2 87.0 65 CH -ο Η-& 0kν〇2 54.0 66 CH -ο Η 19.0 67 CH -ο Η / 0Η 18.0 68 CH -〇 Ο -〇-〇η 10.0 70 CH -〇 Ο 74.6 72 CH -Ο Η -Ο 20. 5 74 CH -Ο Η 10.8 76 CH -〇 Η -ο 55.0 78 CH-< 3 Η ~ 〇 35. 0 80 CH ~ co Η Ph 84.0 O: \ 88 \ 88539. DOC -62- 200418804

Table 21 Compound number X R1 R2 R3 R4 R5 82 CH Bn Η Ph HH 84 CH OMe Η Ph HH 86 CH-< ^ " ~ ^ ~ 〇Μβ Η Ph HH 88 CH ~ 〇 ~ 〇CF3 Η Ph HH 90 CH Ν—Λ 邙 3 Η Ph HH 92 CH Η- HH 94 CH -〇 Η Ph H Me 96 CH Η Ph Me H 98 CH -ο Η HHH 101 CH VII C00H Ph HH 103 CH Η Ph HH 104 CH Η Ph HH 106 CH Η Ph HH 108 CH -〇Η HH 110 CH -〇Η HH 113 CH -〇Η HH 115. CH Η (S ~ 6 HH 117 CH -〇Η HH 119 CH Η V-NMet HH 122 CH Η HH 124 CH Heptamidine NH (CH2) jOMe HHO: \ 88 \ 88539.DOC -63-200418804 Compound 3 6- (1-methyl-3-phenyl-1H_pyrazol-5-yl > 3,4_pyridine Diol was dissolved in 0.15 g (0.33 mmol) of 4,5-fluorenyl (benzyloxy) _2_ (ι · methylphenyl-1Η_pyrazol_5_yl) pyridine (compound 2) in ethanol 40 mi 10% (w / v) 0.50 g / carbon was added, and hydrogenation was performed at 2.0 atmospheres for 2 hours. After the reaction was completed, the catalyst was filtered off, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography ( Chloroform: methanol = 100: 1) was purified to obtain the title compound 0.07 g (80 · 30/0). HN MR (DMSO-d6) δ: 4.06 (3Η, s), 6.96 (1Η, s), 7.03 (1H, brs), 7.30 (1H, t, J = 7.3Hz), 7.41 (2H , Br t, J = 7.3Hz), 7.77-7.85 (2H, m), 7.96 (1H, brs). Melting point: 283-285 ° G Compound 5 6- (1,3 · one base-111 -. Biwa_5_yl) -3,4- ° specific bitediol In the same way as compound 3, from 4,5-fluorene (benzyloxy) -2- (1,3-diphenyl-1 More than sial-5-yl) pyridine (compound 4) gave the title compound (65.5%). W-NMR (DMSO-d6) δ: 6.60 (1Η, brs), 7.16 (1Η, s), 7.30-7.50 (8H, m), 7.74 (1H, brs), 7.87-7.95 (1H, m). Melting point: 277-279 ° C Compound 9 6- [l- (4-fluorophenyl) -3-phenyl_1H-oxazol-5-yl] -3,4-anhydrodiol is the same as compound 3 Method: The title compound was obtained from 4,5-fluorene (benzyloxy) -2- [l- (4-fluorophenyl) -3-phenyl-1H · «pyrazol-5-yl] pyridine (compound 8). (41.9%) 〇'H-NMR (DMSO-d6) δ: 6.68 (1H? Brs), 7.17 (1H5 s)? 7.27 O: \ 88 \ 88539.DOC -64-200418804 (2H, t, J = 8.8 Hz), 7.30-7.44 (3H, m), 7.45 (2H, t, J = 8.8Hz) 7.75 (1H, br s), 7.85-7.95 (2H, m). Melting point: 282-284 ° C Compound 11 6- [3-Phenyl-1- (2-pyridylpyrazol-5-ylb 3,4-pyridinediol) 4-benzyloxy-6- [3-phenyl-1- (2-pyridylpyrazol-5-yl] -3-pyridyl ether (Compound 10) gave the title compound (52.3%). A-NMR (CDC13) δ 6.88 (1H, s), 7.00 (1H, s), 7.39-7.52 (5Η, m), 7.88-7 · 90 (2Η, m), 7.99-8.03 (1Η, m), 8.10-8.12 (1Η, m), 8.46-8.47 (1Η, m), 13.65 (1Η, birs). Melting point: 235-237 ° C Compound 13 5 (4,5- In the same way as the compound 3, the ethyl-2-11 ratio is 1,4-biphenyl_11 ^ -11 to the fluorene-4_weilic acid ethyl ester, from 4,5_fluorene (benzyloxy) _2_ (1,3_biphenyl-4-ethoxycarbonyl-1H_pyrazol_5-yl) pyridine (compound 12) gave the title compound (35.0%). ^ -NMR (CDC13) δ: 0.89 (3Η, t, J = 7.4Hz), 4.10 (2H, q, J = 7.3Hz), 7.21-7.42 (10H, m), 7.46 (1H, s), 7.54 (1H, s). Melting point: 127-129. (: Compound 19 4- (1,3_biphenyl-iH-C ^^ 5-yl) -1,2-benzyl diol 2 The same method as compound 3, from 5_ [3,4_ 寒 ( Benzyl) phenyl] # Biphenyl-1H-pyrazole (Compound 丨 8) to give the title compound (μ.?%). O: \ 88 \ 88539.DOC -65- 200418804 ^ -NMR (DMSO-d6) δ · ^ rm η T N port, (1H, dd, J = 2.0, 8.3Hz), 6.67 (1H, d, J—2.0Hz), 6.71 (] only, (H, d, J = 8.3HZ), 6 95 nH λ 7.28- 7.49 (8H, m), 7.85-7 94, · (,), s) 0 4 (2H, m), 8.97 (lH, s) 9.12 (1H, melting point: 182-183 ° C Compound 22 4- [ 3- (4-Fluorophenyl) -1-phenyl, oxazole-5_yl] 4,2-benzyldiol In the same manner as in compound 3, ^ 5- [3,4_ 贰 (benzyl (Oxy) phenyl] -1-phenyl-3- (4-fluorophenyl) -1Η-pyrazole (compound 2υ gives the title compound (89.1%) as an amorphous form. ^ -NMR (DMSO-d6) δ : 6.56 (1Η, dd5 J = 2.4, 8.3Hz) 6 68 (1H, d, J = 2.4Hz), 6.72 (1H, d, J = 7.8Hz), 6.95 (1H s)

7.24-7.44 (7H, m), 7.92 · 7 · 95 (2H, m), 8.99 (1H, s), 9.12 (1H S) 〇 Compound 24 4- [l- (4-fluorophenyl ) -3-phenyl-1H-nazol-5-yl] -1,2-benzyldiol In the same manner as in Compound 3, from 5- [3,4-fluoren (benzyloxy) phenyl]- 1- (4-Phenylphenyl) -3 -phenyl-IΗ-Laσ sitting (compound 23) gave the title character (76.0%).

^ -NMR (DMSO-d6) δ: 6.57 (1H5 dd, J-2.05 8 3Hz) 6.60-6.78 (2H, m), 6.95 (1H, s), 7_20-7 · 50 ( 7H, m), 7.89 (2H d, J = 7.3Hz), 8.99 (1H, s), 9.13 (1H, s).

Melting point: 198-200 ° C Compound 26 O: \ 88 \ 88539.DOC -66- 200418804 4- [l, 3- 贰 (4_fluorophenyl) -1Η_σbiazole-5_yl] _ 丨, 2 Benzene—, In the same manner as in Compound 3, from the 5_ [3,4_fluorenedi) phenyl group ... (4-Benzylphenyl (Compound 25)), the title compound (681%) was obtained. B-NMR (DMS0_d6 ) δ: 6.57 (1H, for example, J = 2 0, 8zhen, 6 ^ (1H, cl, wind 0Hz), 6.73 (1H, d, J = 7 8Hz), 6% (7.20- 7.44 ( 6H, m), 7 88_7 98 (2H, m), 9 0i (ih, Bu s), 9M (1H, br s). Melting point: 193_194 ° C Compound 29 4 [1- (4-fluorobenzene Group) _3_ (2_ pyridylpyrazolyl]-丨,]-benzenediol In the same manner as in Compound 3, from 2- [5- [3,4-fluorene (benzyloxyfluorophenyl)- 1H-pyrazol-3-yl] pyridine (Compound 28) to give the title compound (51.8%) 〇'H-NMR (DMSO-d6) δ: 6.58 (1H? Dd, J = 2.〇, 7.8Hz)? 6.66 (1H, d, J = 2.0Hz), 6.73 (1H, d, J = 7.8Hz), 7.00 (1H, s), 7.20- 7.45 (5H, m), 7.85 (1H, dt, J = 1 .5, 7 · 8Ηζ), 8.00 (1H, d, J = 7.8Hz), 8.58-8.66 (1H, m), 9.01 (1H, brs), 9.15 (1H, brs). Melting point: 128- 134 ° C The compound 3 1 4- [1- (2,4-difluorophenyl) -3- (4-fluorobenzyl) -111-nizol-5-yl] -1,2-benzenediol is used in combination with compound 3 In the same way, from 5- [3,4-fluorene (benzyloxy) phenyl] -1- (2,4-difluorophenyl) -3- (4-fluorophenyl) _111_. 3〇) The title compound was obtained (46.3%). O: \ 88 \ 88539.DOC -67- 200418804 W-NMR (DMSO-d6) δ ···· 55 (1H, dd, J = 2.4, 8 · 3Ηζ) , 6.65 (1H, d, J = 2.4Hz), 6.70 (1H, d, J = 7.8Hz), 7.01 (1H, s), 7.23-7.28 (3H, m), 7.40-7.45 (1H, m ), 7.63-7.68 (1H, m), 7.90-7.94 (2H, m), 8.99 (1H, s), 9-13 (1H, s). Melting point: 193-195 ° C Compound 33 4- {3 -(4-fluorophenyl) -l- [4- (trifluorofluorenyloxy) phenyl] -1H-oxazol-5-yl] -1,2-benzenediol In the same manner as in Compound 3, The title compound was obtained from 5- [3,4-fluorene (benzyloxy) phenyl] -1- (4-trifluoromethoxyphenyl) _3- (4-fluorophenyl) 1H-imidazole (compound 32) (72.2%). W-NMR (DMSO_d6) δ: 6.57 (1H, dd, J = 2.4, 7 · 8Ηζ), 6.68 (1H, d, J = 2.4Hz), 6.74 (1H, d, J = 8.3Hz) , 6.98 (1H, s), 7.27 (2H, t, J = 8.8Hz), 7.41-7.47 (4H, m), 7.92-7.96 (2H, m), 9.03 (1H, s), 9 · 17 (1H, s). Melting point: 155_156 ° C Compound 35 4 · {3- (2-σ than fluorenyl) -l- [4- (trifluorolmethoxy) phenyl] -1Η_Πbisal-5-yl} -1, 2-Benzenediol was prepared from 2- [5- [3,4-fluoren (benzyloxy)]-1- (4-trifluorofluorenoxyphenyl) -1′-pyrazole- 3-yl] pyridine (Compound 34) gave the title compound (86.2%) as an amorphous form. iH-NMR (DMSO-d6) δ: 6.59 (1Η, dd, J = 2.0, 8 · 3Ηζ), 6.67 (1H, d, J = 2.0Hz), 6.74 (1H, d, J = 8.3Hz), 7.01 (1H, s), O: \ 88 \ 88539.DOC -68- 200418804 7.34-7.38 (1H, m), 7.43-7.50 (4H, m) 5 7.86-7.88 (1H, m), 8.0 ( 1H, d, Bu 7.8Ηζ), 8.63 (1H, d, J 2 3-9Hz), 9.03 (1H, s), 9.17 (1H, s). Compound 37 4- {3_ (4-fluorobenzyltrifluoromethyl) phenyl than sialo-5_yl] _ι, 2_benzenediol In the same manner as in Compound 3, from 5- [3,4-fluorene ( Benzyloxy) benzene / yl] -1- (4-trifluoromethylphenyl) -3- (4-fluorophenyl) -1H-orbitazole (Compound 36) The title compound (64.3%) was obtained. ® iH-NMR (DMSO-d6) δ: 6.60 (1H, dd, J = 2.0, 7.8Hz), 6.68 (1H, d, J = 2.0Hz), 6.76 (1H, d, J = 8.3Hz), 7.02 (1H, s), 7.28 (2H, t, J = 8.8Hz), 7.56 (2H, d, J = 8.3Hz), 7.80 (2H, d, J = 8.3Hz), 7.94-7 · 98 (2H, m), 9.07 (1H, brs), 9.19 (1H, brs). Melting point: 172-173 ° C Compound 39 4- [l- [4_ (third butyl) phenyl] _3- (4-fluorophenyl) -1） -pyrazol-5-yl] -1,2- φ benzyl glycol 'In the same way as compound 3, from 5_ [3,4_ 贰 (benzyloxy) benzene \ yl l · 1- (4-thirdbutylphenyl) -3- (4-fluoro Phenyl) -1H-Nazole (Compound 38) gave the title compound (52.0%). ^ -NMR (DMSO-d6) δ: 1.30 (9H? S)? 6.55-6.57 (1H? S), 6.68-6.72 (1H, s), 6.91 (1H, s), 7.23-7.27 (6H, m), 7.43 (2H, d5 J = 8.3Hz), 7.90-7.93 (2H, m), 8.97 (1H, br s), 9.12 (1H, br s). O: \ 88 \ 88539.DOC -69- 200418804 Melting point: 204-206 ° C Compound 41 4- [3-Methyl-1- (2- ° ratio. Amorphous group) -111- ° than Salyl-5-yl ] -1,2 · benzyl alcohol In the same manner as in compound 3, from 2_ {5_ [3,4_ 贰 (benzyloxy) phenyl] -3-methyl-m-sialyl-i • yl} Alpha ratio bite (compound 4) gives the title compound (73.1%). ^ -NMR (DMSO-d6) δ: 2.24 (3Η, s), 6.2? 〇H §) 6.43-6.46 (1H, m), 7.33- 7.36 (1H, m), 7.49 (1H, d, J = 8 3H ^ 7.89-7.94 8.32-8.33 (lH, m), 8.84 (1H, s), 8.96 (1 ^ s) o, melting point: 228- 231 ° C Compound 43 4- [3-octyl is smaller than (2 ') ratio. The base group> 1H "is better than salyl-5 · ylbenzyldiol in the same way as compound 3, k2- {5_ [3,4 -贰 (benzyloxy) phenyl] octyl-1H-r- 嗤 ++} bite (compound 42) to give the title compound (50.5%). 咻 (CDCl3) s: 0.88 (3H, t, j = 6 others), i 27 _ is called 1.61-1. «(4H, m), 2,62 (2H, t, J = 7 8Hz), η? ⑽ 6.37-6.38 (1H, m), 6.64-6.72 ( 2H, m), 7.20-7.26 (2H, m), 7.69-7.73 (1H, m) 8.32-8.33 (1H, m). Melting point: 124-125 ° C Compound 46 -L-Native-1- (2 -Pyridinyl 丨 Zapirazole_5_yl] -丨, 2_benzenediol In the same way as compound 3, the electricity is k 2- {5- [3,4- 贰 (benzyloxy,

O: \ 88 \ 88539.DOC -70- 200418804 group] -3-phenyl-1H-pyrazole-l-yl} pyridine (Compound 45) to give the title compound (62_5%). (H-NMR (DMSO-d6) δ: 6.56 (1H, dd, J = 7.8, 2.0Hz), 6.67 (1H, d, J = 2.0Hz), 6.70 (1H, d, J = 8.3Hz), 6 99 (1H, s), 7.30-7.40 (1H, m), 7.40-7.50 (3H, m), 7.62 (1H, d, J = 8.3Hz), 7.98 (1H, ddd, J = 7.8, 7.8, 2.0Hz), 7.90-8.00 (2H, m), 8.41 (1H, dd, 4.9, 1.5Ηζ), 8.92 (1H, brs), 9.06 (1H, brs). Melting point: 212-214 ° C Compound 5 1 4- [3- (2-methoxyphenyl) -l_ (2-radylyl) -111-pyrazol-5-yl] -1,2-benzenediol is the same as compound 3 The method is obtained from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (2 • methoxyphenyl) -1hydrazine-l-yl} pyridine (compound 50). Title compound (63.0%). Ifi-NMR (DMSO-d6) δ: 3.90 (3H, s), 5.62 (1H, d, J = 8.3Hz), 6.65-6.69 (2H, m), 6.91 (1H, s), 7.01 (1H, t, J = 7.8Hz), 7.13 (1H, d, J = 8_3Hz), 7.33-7 · 42 (2H, m), 7.61 (1H, d, J = 7.8Hz), 7.93 · 7 · 99 (2H, m), 8.40 (1H, d, J = 4.9Hz), 8.90 (1H, s), 9.01 (1H, s) Melting point: 206-208 ° C Compound 53 4- [3- (3-methoxyphenyl) -1- (2-armidinyl) -111 ^ pyzol-5-yl] -1,2-benzene The alcohol was prepared in the same manner as in Compound 3 from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (3-fluorenoxyphenyl) -1）-. Pyzol-l-yl } Pyridine (compound 52) to give the title compound (88.0%). O: \ 88 \ 88539.DOC -71-200418804 h-NMR (DMSO-d6) δ: 3.82 (3H, s), 6.54 (1H, dd, J = 2.0, 8 · 3Ηζ), 6.65 (1H, d, J = 1.7Hz), 6.68 (1H, d, J = 8.3Hz), 6.92 (1H, dd, J = 2.0, 8.3Hz), 6.99 ( 1H, s), 7.35 (1H, t, J = 7.8Hz), 7.41-7-50 (3H, m), 7-60 (1H, d, J = 7.8Hz), 7.98 (1H, dd, J = 2.0, 7.8 Hz), 8.40 (1H, td, J = 1.0, 4.9 Hz), 8.89 (1H, brs), 9.04 (1H, brs). Melting point: 211-214 ° C Compound 55 4- [3- (4-methoxyphenyl) -1- (2-arimidinyl) -1 H-aromidazol-5-yl] -1,2-benzene Diol was prepared from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (4-methoxyphenyl) -1Η-pyrazole-1-yl in the same manner as in Compound 3. } Pyridine (Compound 54) gave the title compound (77.0%). lH-NMR (DMSO-d6) δ: 3.84 (3H? s)? 6.62-6.83 (3H? m), 6.94 (2H, d, J = 8.3Hz), 7.20-7.23 (1H, m), 7.34-7.38 (1H, m), 7.17 (1H, t, J = 6.4Hz), 7.85 (2H, d, J = 8.3Hz), 8.45 (1H, d, J = 3.9Hz). Melting point: 205 -209 ° C Compound 72 4- [1,3-fluorenyl (2-pyridyl) -111-oxazol-5-yl] -1,2-benzenediol In the same manner as in Compound 3, from 2- [ 5- [3,4-fluoren (benzyloxy)]-1- (2-pyridyl) -1′-pyrazol-3-yl] pyridine (compound 71) gave the title compound (20.5%). b-NMR (DMSO-d6) δ: 7.22 (1H, s), 7.49-7.52 (3H, m), 7.58 (1H, s), 7.84 (1H, t, J = 7.2Hz) , 8.00 (1H, dt, J = 1.4, O: \ 88 \ 88539.DOC -72- 200418804 7 · 8ηζ) 5 8.27 (1Η? D5 J-7.8HZ), 8.38 (1Η, t? J-7.8Hz) , 8.75 (1H, sJ = 4.3Hz), 8.89 (1H, mountain J = 8.7Hz), 9.65 (1H, d, J-7.3Hz). Melting point:> 300 ° C Compound 74 4- [3_ (4, -fluoro [1,1'-bibenzyl] -4-yl) -1H-pyrazol-5-yl] -1,2-benzene Diols were treated in the same manner as compound 3 'from 2- {5_ [3,' 贰 (benzyloxy) phenyl] _3_ (4, · fluoro [1, biphenyl] -4-yl) -ιΗ_pyridine Zol-1-yl} pyridine (Compound 73) gave the title compound (10.8%). iH-NMR (DMS〇-d6) δ: ό · 56 (1Η, dd, J = 7.8, 2.0ΗZ), 6.66 (! H, d, J = 2.0Hz), 6.68 (1H, d, J = 8.3Hz), 7.04 (1H, s) 7.28_7 · 32 (2H, m), 7.42-7.45 (1H, m) 5 7 · 63 (1H, d, J = 8.3Hz), 7.73_7 · 79 (4H, m), 7.97-8.02 (3H, m), 8.41-8.42 (1H, m) 8.91 (1H, br s), 9.06 (1H, br s). Melting point: 249-251 ° C Compound 80 4 [1 (1,3 • benzyl-2-?-2-oxo) -3 • phenyl-1 {-pyrazine, 5-yl] 1 2 Benzyl alcohol 5 ~ In the same way as for compound 3, from 2_ {5_ [3,4, benzyloxy) phenyl] -3- (2-pyridyl) lupyronyl}], 3-benzothiazole (compound π) to give the title compound (84.0%). ^ H-NMR (DMSO-d6) δ: 6.81 (1H, d, Ι = δ.3Ηζ), 6.9〇 (1Hj dd, J = 2.0, 7.8Ηζ), 6.99 (1H, d, J = 2.〇 Hz), 7.17 (1H s) 7.41-7.53 (5H, m), 7.74 (1H, d, J = 7.8Hz), 7.97 (2H, d! O: \ 88 \ 8S539.DOC -73- 200418804 J = 7.3 Hz), 8.10 (1H, d, J = 7.8HZ), 9.13 (1H, S), 9.31 (1H, S). Melting point: 197_199 ° C Compound 57 4- [3- (2-chlorophenyl) _1_ (2-pyridyl) _1H-pyrazol_5-yl] -1, 2-benzenediol will be 2- {5_ [ 3,4-fluoren (benzyloxy) phenyl] _3- (2-chlorophenyl) -1Η · Razol-1-yl} ° Dissolved in chloroform (Compound 54) 0.22 g (0_4 mmol) in dichloromethane Add 10 g of boron tribromide-methyl sulfide complex at room temperature and stir. 39 g (4.4 mmol) and stir for 12 hours. After the reaction was completed, water was added to the reaction mixture, and the pH was adjusted to about 6.0 with saturated sodium bicarbonate, followed by extraction with chloroform. The organic layer was dissolved in sulfuric acid. The residue was purified by chromatography (chloroform: methanol = 100: 1) to obtain the title compound (0.03 g) (53%). WNMR (DMSO-d6) δ. 6 S1 < m, ^ · 6.51.6.69 (3H, m), 7.07 (1H, s), 7.M-7.53 (3H, m), 7.62 (1H, d, J = 7 8Hz), 7M (ih d J = 7.8HZ), 7.95-8.〇1 (2H, m), 8 41 (1H, d, j = 2M 8M (1H, brs), 9.06 (1H, brs). Melting point: 228-231 ° C Compound 59 4- [3- (3-chlorophenyl) -l- (2mMH "than sialylbenzene · benzenediol in the same way as compound 57, from Noisy [M · Wu (benzyloxy) benzyl] _3_ (3_Phenylphenyl HH_D is smaller than hydrazone}. Specific bite (compound is called to get compound (25.0%). ^ TNMR (DMSO-d6) δ: 6.54 ( 1H d Bu 7… UW, d5 J-7.3HZ), 6.66-6 69 (2H, m), 6.93 (1H, s), 7.43 J 45 AH,, 45 (3H, m), 7.56 (1H, d J = 5.4Hz)? 7.63 (1H5 d? J = 7.8Hz) 7 88ΠΗ ^ τ '/ 』8 (1H, d, J = 4.8HZ), 7.99 O: \ 88 \ 88539.DOC -74- 200418804 ( 1H, t, J = 7.3Hz), 8.41 (1H, d, J = 2.4Hz), 8.91 (1H, brs), 9.06 (1H, brs). Melting point: 224-227 ° C Compound 61 4- [3- (4-Chlorophenyl) -1- (2-silidinyl) -111-silazol-5-yl] -1,2-benzenediol In the same manner as in Compound 57, From 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (4 -Chlorophenyl) -111-pyrazol-1-yl} pyridine (compound 60) to give the title compound (76.0%). W-NMR (DMSO-d6) δ: 6.54 (1H, dd, J = 2.0, 8 · 3Ηζ), 6.64 (1H, d, J = 2.0Hz), 6.68 (1H, d, J = 8.3Hz), 7.01 (1H, s), 7.43 (1H, dd, J = 4.9, 6.8Hz ), 7.50 (2H, d, J = 8.3Hz), 7.60 (1H, d, J = 8.3Hz), 7.93 (2H, d, J = 8.3Hz), 7.98 (td, J = 1.5, 7.8Hz), 8.40 (1H, d, J = 3.4Hz), 8.90 (1H, brs), 9.06 (1H, brs). Melting point: 235-237 ° C Compound 63 4- [3_ (3-nitrophenyl) -1- (2-Pyridinyl) -111-amidazol-5-yl] -1,2-benzenediol In the same manner as in Compound 57, 2- {5- [3,4-fluoren (benzyl (Oxy) phenyl] -3- (3-nitrophenylbiazole-l-yl} pyrazine (compound 62) gave the title compound (87.0%). b-NMR (DMSO-d6) δ: 6.65-6.70 (2H, m), 7.21 (1H, s), 7.46 (1H, dd, J = 5.4, 7.3Hz), 7.64 (1H, d, J = 7.3Hz ), 7.76 (1H, t, J = 8.3Hz), 8.01 (1H, t, J = 7.3Hz), 8.21 (1H, d, J = 7.8Hz), 8.36 (1H, d, J = 7.8Hz), 8.44 (1H, d, J = 3.4 Hz), 8.69 (1H, bs), 8.92 (1H, brs), 9.09 (1H, brs). O: \ 88 \ 88539.DOC -75- 200418804 Melting point: 225-227 ° C Compound 65 4- [3- (4-nitrophenyl) -1- (2-arimidinyl) -111-arazole -5-yl] -1,2-benzenediol In the same manner as in Compound 57, from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (4-nitrophenyl ) -1Η-. Biazole-l-ylpyridine (Compound 64) gave the title compound (54.0%). b-NMR (DMSO-d6) δ: 6.54 (1H, dd, J = 2.44, 8 · 3Ηζ), 6.65 (1H, d, J = 2.0Hz), 6.69 (1H, d, J = 8.3 Hz), 7.20 (1H, s), 7.47 (1H, dd, J = 4.9, 7.3Ηζ), 7.62 (1H, d, J = 7.8Hz), 8.01 (1H, td, J = 2.0, 7.8Hz), 8.19 (2H, d, J = 8.8Hz), 8.31 (2H, d, J = 9.3Hz), 8.44 (1H, dd, J = 1.0, 4.9Hz), 8 95 (1H, brs), 9 "0 (1H, brs). Melting point: 197-210 ° C Compound 6 6 4- [3- (2-hydroxyphenyl) -l_ (2-armidinyl) -1Η-arazol-5-yl] -1,2-benzenediol In the same manner as for Compound 57, from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (2-methoxyphenyl) -1fluorene-imidazol-1-yl} Pyrimidine (compound 50) gave the title compound (%). W-NMR (DMSO-d6) δ: 3.90 (3H, s), 5.62 (1H, d, J = 8.3Hz), 6.65-6 · 69 (2H, m) 5 6 · 91 (1H, s), 7 · 01 (1H, t, J = 7.8Hz), 7.13 (1H, d, J = 8.3Hz), 7.33-7.42 (2H, m), 7.61 (1H, d, J = 7.8Hz), 7.93- 7.99 (2H, m), 8.40 (1H, d, J = 4.9Hz), 8.90 (1H, s), 9.01 (1H, s). Melting point: 137-140 ° C Compound 67 O: \ 88 \ 88539.DOC -76- 200418804 4- [3- (3-hydroxyphenyl) -1- (2-arimidinyl) -1H-aromatazole- 5-yl] -1,2-benzenediol In the same manner as in Compound 57, from 2- {5- [3,4_fluorene (benzyloxy) phenyl] -3- (3-methoxyphenyl ) -1H-pyrazole-l-yl} pyridine (Compound 52) to give the title compound (18.0%). iH-NMR (DMSO-d6) δ: 6.54 (1H, dd, J = 2.0, 8 · 3Ηζ), 6.63 (1H, d, J = 2.0Hz), 6.67 (1H, d, J = 8.3 Hz), 6.75 (1H, dd, J = 2.0, 6.8Hz), 6.87 (1H, s), 7.20-7.24 (1H, m), 7.30-7.32 (2H, m), 7.41 (1H, dd, J = 4.9, 7 · 3Ηζ), 7.59 (1H, d, J = 8.3Hz), 7.95-8.00 (1H, m), 8.39 (1H, d, J = 3.4Hz), 8.89 (1H, s) , 9.03 (1H, s), 9.39 (1H, s). Melting point: 228-232 ° C Compound 6 8 4- [3- (4-hydroxyphenyl) -1- (2-azidinyl) -111-azimidazole-5_yl] 1,2-benzenediol In the same manner as for Compound 57, from 2- {5- [3,4-fluorenyl (benzyloxy) phenyl] -3- (4-methoxyphenyl) -1fluorene-lazole-l-yl} Pyrimidine (compound 54) gave the title compound (10.0%). iH-NMR (DMSO-d6) δ: 6.52 (1H, dd, J = 2.0, 8 · 3Ηζ), 6.62 (1H, d, J = 2.0Hz), 6.67 (1H, d, J = 8.3Hz) , 6 · 81-6 · 83 (2H, m), 7 · 39 (1H, dd, J = 4.9, 7 · 3Ηζ), 7.58 (1H, d, J = 7.8Hz), 7.71 (1H, d , J = 8.8Hz), 7.94-7.98 (1H, m), 8.37 (1H, d, J = 2.9Hz), 8.87 (1H, s), 9.01 (1H, s), 9.49 ( 1H, s). Melting point: 159-159.5 ° C Compound 70 4- [3- (3,4-dihydroxyphenyl) -1- (2-arimidinyl) -111-tonazol-5-yl] -1, 2 -Benzene O: \ 88 \ 88539.DOC -77- 200418804 The diol will be 2- [3,5-wu (3,4-dimethoxyphenyl) phenyl] -α than 嗤 _ 1 _yl}. (Compound 67) 0.21 g (0.5 mmol) was dissolved in 5 ml of dichloromethane, 2.5 ml (2.5 mmol) of boron trioxide (1 M methyl chloride solution) was added, and the mixture was stirred at 0 ° C to room temperature for 3 minutes. hour. After the reaction was completed, the reaction product was poured into ice water, and the precipitated crystals were collected by filtration, washed with ethyl acetate and ethanol in this order, and dried to obtain 0.14 g (74.6%) of the title compound. h-NMR (DMSO-d6) δ: 6.52 (1H, dd, J = 2.0, 7 · 8Ηζ), 6.62 (1H, d, J = 2.0Hz), 6.67 (1H, d, JWJHz), 6.75 (1H, s), 6.78 (1H? D? J = 8.3Hz)? 7.16 (1H? Dd9 1 = 2.0, 8.3Hz), 7.32 (1H5 d J-2_0Hz), 7.37-7.41 (1H5 m) , 7.57 (1H, d, J = 8.3Hz), 7 96 (1H, dd, J = 2.0, 7.8Hz), 8.37-8.38 (1H, m). Melting point: 255-260 ° C Compound 76 4- [l- (2-pyridyl) -3_ (2-thienyl) -lH-pyrazole I-based compound; 1,2-benzyl glycol is the same as compound 57 Method from 2- {5- [3,4-fluoren (benzyloxy) phenyl] -3- (2-fluorenyl) -1 ^ _. The ratio 嗤 _1-yl} 11 to 11 (Compound 75) gave the title compound (55.0%). 'H-NMR (DMSO-d6) δ: 6.52 (1H? Dd? J-1.95, 8.3Hz) 5 6 23 (1H, d, J = 2.0Hz), 6.67 (1H, d, J = 8.3Hz), 6.88 (1H, s) 7 13 (1H, t, J = 4.9Hz), 7.42 (1H, dd, 1 = 4.9, 6.8Hz), 7.51-7 · 56 (3h m), 7.97 (1H, td, J-1.47, 7.33Ηζ), 8.41 (ih, d, J = 3.41Hz) 8.91 (1H, s), 9.06 (1H, s). ’

Melting point: 218-219 ° CO: \ 88 \ 88539.DOC -78- 200418804 Compound 78 4- [l- (2-pyridyl) -3_ (3-thienyl) _1H_pyral, main base 1, 2-Benzenediol is treated in the same manner as compound 57 from 2-μ ". {5- [3,4-fluorenyl (benzyloxy) phenyl M, phenyl) _1H 35.0%) 咻 face (then 0_d6) s: 3.9 () (3H, s), 5 62 (iHd 6.65-6.69 (2H, m), 6.91 (1H, s), 7.〇1 (1H5t J = 7 8Hz)? ⑽ d, ㈣Shi), 7.33 · 7.42 (2H, m), 7 6ι (ih, seven Η D3-7.99 (2H, m), please (1H, d, ㈣ 9Hz) 8 ' (1H, s). V, ', ιυΐ melting point · 190-195 ° C compound 82 4- (1-benzyl-3-phenyl-11 > 1-degree ratio 嗤 _5-yl) -1, 2-benzyl alcohol was obtained from compound 81 (87%) in the same manner as compound 70. lH_NMR (deleted, δ: 5.37 (2H, 8), 6.70-6.83 (4H m) 7.05 (2H, ^ ™ Z ), 7.21-7.31 (4Hsm) 57.37.7.41 (2H5m; 7.82 (2H, d, J = 7.3Hz), 9.05 (1H, s), 9.18 (iH, s) 〇 'Melting point: 200-202 ° C Compound 84 4-Π- (3-methoxyphenyl) _3_phenylHH_n than sal_5D_i, 2-benzenediol was obtained from compound 83 (38%) in the same manner as compound 3. ^ -NMR (DMSO-d6) δ: 3.71 (3Η, s), 6.58 (1H? Dd, J = 1 9 > 8.3Hz), 6.70 (2H, m), 6.87-6.94 (4H, m), 7.29.7.36 (2H, m)} 7.43 (2H, u = 7.8Hz), 7.9 () (2H, m), 8% recognize 9 n other

O: \ 88 \ 88539.DOC -79- ^^ 18804 s) ο Melting point: 185-187. (: Compound 86 HH4-methoxyphenyl) -3_phenyl] _ 出 _command. S_5_yl], 2-benzenediol was obtained from compound 85 (55.0%) in the same manner as compound 3. • H-NMR (CDC13) δ: 3.78 (3Η, s), 6.55 ^ J = i 7.81Ηζ), 6.66-6.71 (2H, m), 6.90 (1H, s), 6 97 (2h, Ton J = 9.3Hz), 7.25 (2H, d, J = 8.8Hz), 7.327-44 (3H, m), 7.87 (2H, d, J = 8.3Hz), 8.95 (1H, s), 9.09 (1H , S). Melting point: 214-216 ° C Compound 88 4- [3-Phenyl is called fluoromethoxy) phenyl alcohol In the same manner as in Compound 3, Compound 87 (69.0%) was obtained. i-NMR (CDa3) δ: i.72 (2H, bs), 6 62 6 77 (3H, m), 6-70 (1H, s), 7.36-7.47 (5H, m), 7.56 (2H, d , J = 8.8Hz), 7.87 (2H, d5 J = 8.3Hz).

Melting point: 179-182 ° C Compound 90 4- [3-phenyl small [4- (trilfyl) _2 "" Memidinyl Mh cardioyl ", benzene difluorene in the same way as compound 3 Compound 89 was obtained (69%). ^ H-NMR (DMSO-d6) δ: 6.56-6.7l (3H, m), 7.09 (1Η, s) 7.38-7.49 (3Η, m), 7.95 (2Η, d, J = 6.8Hz), 8. 〇3 (ιη, d O: \ 88 \ 88539.DOC -80- 200418804 J = 4.9Hz), 8.91 (1H, s), 9.07 (1H, s), 9 2ι (ih, & Bu 4 9Hz). Melting point: 107-113 ° C Compound 92 4- [3- (2,4-difluorophenyl) -1- (2-arimidinyl) _1Η_α 比 azole_5_ylbenzene u and benzenediol Compound 3 was obtained from Compound 91 in the same manner (38%). W-NMR (DMS0_d6) δ: 6.53 (1H, d, J = 7 8Hz), 6 63 (ih, M, 6.67 (1H, d, J = 8.3Hz), 6.81 (1H, d, j = 3 4Hz), 7 Μ 2〇 (1H, m), 7.33-7.38 (1H, m) 7.43-7.46 (1H, m) j 7.61 (1H, d, J = 7_8Hz), 7.97_8_05 (2H, m) , 8.42 (1H, s), 8 9i (ih, s), 9 〇6 (1H, s). Melting point: 244-247 ° C Compound 94 2-pyrazol-5-yl] phenol is used in combination with compounds 3 Obtained in the same manner from Compound 93 (64%).

(H-NMR (DMSO-d6) δ: 3.61 (3H, S), 6 8.3Ηζ) 5 6.80 (1H? D5 J = 1.5Hz) 5 7.11 (iH 70 (2H, dq, J = 2.0, s), 7.35-7.48 (4H, m), 7.67 (1H, d, J = 7.8Hz) 7_92 (2H, dt, J = 2.0, 7 · 8Ηζ), 8.42 (1H, dd, J = 1.5 d, J = 8.8Hz), 8.01 (1H,, 4.9Ηζ), 9.25 (1H, s). Melting point: 117-119 ° C Compound 96 pyzol-5-yl] phenol 2-fluorenyloxy 5- [3- Phenyl-1- (2-armidinyl) _ι · Η was obtained from compound 95 in the same manner as in compound 3 (47.0%). LH-NMR (DMS 0-d6) 5: 3.76 (3H, S) , 6.67 (2H, m), 6.88 O: \ 88 \ 88539.DOC -81-Chuan 0418804 m), 7.05 (1H, s), 7.35-7.47 (4H, m), 7.66 (1H, d, J = 7.8 Hz), 7.92 (2H, d, J = 7.3Hz), 8.〇〇 (1H, dt? J = 2.05 7.8Hz)? 8.40 (1H, m), 9_07 (1H, s) . Melting point: 90-92 ° C Compound 98 cardio [1_ (2-pyridyl) · 1Η-pyrazol-5-yl] phenol-1,2-benzyldiol was obtained from compound 97 in the same manner as compound 70 ( 39.5%). ^ -NMR (DMS〇.d6) δ: 6.45-6.48 (2H5 m)? 6.58 (1H5 d5 J, 2.0Hz), 6.65 (1H, d, J = 7.8Hz), 7.40 (1H, dd, J = 4.9, 7 · 3Ηζ), 7.53 (1H, d, Bu 7.8Hz), 7.68 (1H, d, > 2 · 0Ηζ), 7 96 (1H, dd, J 2.0, 7.3Hz), 8.37 (1H, dd, J = 1_0, 4.9Hz), 8_86 (1H, s), 8.99 (1H, s). Melting point: 151-154 ° C < Compound 101 (3'4-monophenylphenyl) _3-phenyl-amidyl) -IH-Ab salivary 4-weiwei acid from compound in the same manner as compound 3. 100 (69.0%). h-NMR (DMSO-d6) δ ······································································································································) 4H, m), 7.51 (1H, d, J ~ 7.8Hz), 7.70 (2H, dd, J = 1.2, 8.3Hz), 7.94 (1H, dt, J = 2.0, 7 · 8Ηζ), 8.39 ( 1H, m), 9.02 (1Η, s), 9.14 (1H, s). Melting point: 223-226 ° C Compound 103 4_ [l- (5-Nitro_2_〇bipyridyl) _3_phenyl_1Η_πpyzol-5_yl-1,2-benzenediol to interact with the compound 70 was obtained in the same manner from Compound 102 (58.0%).

O: \ 88 \ 88539.DOC -82- 2〇4188〇4 'H-NMR (DMSO-d6) δ: 6.63-6.88 (3H5 m)? 7.09 (1H5 s) 5 7 · 38_7 · 50 (4H, m), 7-80-7.95 (3H, m), 8.74 (2H, dd, J = 2.9, 8.8Hz), 8.94 (1H, s), 9.12 (2H, d, J = 2.9Hz). Melting point · 122-125 ° C Compound 104 4_ [1_ (5_Amino-2-pyridyl) -3-phenyl-1H-oxazol-5-yl-1,2-benzenediol and compound 3 Similarly obtained from compound 103 (3 4.0%). iH-NMR (DMSO-d6) δ: 5.54 (2H, br), 6.52 (1H, dd, J = 2.0, 8.3Hz), 6.64-6 · 67 (2H, m), 6.87 (1H, s), 7.02-7.05 (1H, m), 7 · 12 (1H, d, J = 8.3Hz), 7.30-7.33 (1H, m), 7.40-7 · 43 (2H, m), 7 · 74 (1H, d, J = 2.5Hz), 7.85-7.87 (2H, m) 5 8.86 (1H, s), 9.00 (1H, s). Melting point: 134-137 ° C Compound 106 4- [3-phenyl_i_ (3_d than pyridyl) _1H_D than pyrazole_5_yl] -benzenediol was obtained from compound 105 in the same manner as compound 70 (24%). tNMR (CDCl3) δ · 6.58 (1H, dd, J = 2 0, 8 3Hz), 6 68 (ih, d, J = 2.4Hz), 6.74 (1H, d, J = 8.3Hz), 7 〇i (ih, s) 7 36 · 7 38 OH, m), 7.43-7.50 (3H, m), 7.76-7.79 (1Hj m), 7.91 (2H, d, Bu 7.3Ηζ), 8.54 ( 1H, s), 8.55 (1H, s), 9 〇4 (ih, ㈣, 9 i8 (ih, brs). Point. 2 3 8-2 41 〇C compound 108 heart [3_ (3_ 漠 笨 基 Η_ (2_σ than fluorenyl) · 3_benzyl · 1ΗK5 · yl, 2_benzene O: \ 88 \ 88539.DOC -83-418804 A diol was obtained from compound 107 in the same manner as compound 70 (26. / 〇). A-NMR (DMS0_d6) δ: 6.53 (1H, dd, J = 2 0, 7 8Hz), 6 63 〇H, d, J = 1.9Hz), 6.68 (1H, d, J = 7 8Hz), 7 ”(ih, s), 7.40-7.46 (2H, m), 7.56 (1H, d, J = 8 3Hz), 7 63 (m, d, J = 7.8Hz), 7.93 (1H, d , J = 7.8Hz), 7.98-8.02 (1H, m), 8.1 (1H, s), 8.41 (1H, d, J = 3.9Hz), 9.01 (1H, s), 9.17 (1H, s) Melting point: 206-210 ° C Compound 110 4 [3- (3-morpholinyl) _i- (2-4ba amidinyl) _ lH-at σ-situ-5_yl] 2-benzenediol to react with compound 3 (72.0%) was obtained from Compound 10 in the same manner. ^ NMR (DMSO-d6) δ: 3.17 (4H? t5 J = 4.4Hz) 5 3.76 (4H, t? J 4.4Hz), 6.53 (1H, dd, J = 1.9, 8.3Hz), 6.63 (1H, d, J = 1.9Hz ), 6.67 (1H, d, J = 7.8Hz), 6.94 (1H, dd, > 1.9, 8.3Hz), 7.03 (1H, s), 7.27-7.46 (4H, m), 7.61 ( 1H, d, J = 7.8Hz), 7.99 (1H, dt, J == 19, 7 · 8Ηζ), 8.40-8.41 (1H, m), 8.99 (1H, s), 9.15 (1H, s) Melting point: 206-209. Compound 113 4-dihydroxyphenyl) -1- (2-. (Pyridyl) _iH-oxazol-3-yl] phenyl-2-. Pyrrolidone was obtained from compound 112 (87.0%) in the same manner as in compound 3. ^ -NMR (DMSO-d6) δ: 2.08 (2H? Quint, J = 7.4Hz), 2.52 (2H, t, J = 8.3Hz), 3.91 (2H, t, J = 6.8Hz), 6.54 ( 1H, dd, J = 2.0, 8 · 3Ηζ), 6.63-6.69 (2H, m), 7.01 (1H, s), 7.42-7.46 (2H, m), O: \ 88 \ 88539.DOC -84-^ ^ 18804 7.60-7.70 (3H, m), 8.00 (1H, dt, J = 2 〇〇 ^ person 〇, 8.3Ηζ), 8.13 (1H, s), «• 41 -8.42 (1H, m), 9.00 (1H, s), 9.16 (1H, s). Melting point: 169-1 71. 〇 < Compound 115 MW, -phenylfluorenyl] phenyl) phenyl] _2 "than bite_2.yl benzene-1,2-diol was obtained from compound 114 in the same manner as compound 3 (2 〇5%). Heart (CDCl3) S: 3.35_3.4〇 (8H, Go 6.58 (ih, d,: 2.0 Hz), 6.67 (1H, s), 6.68-6.75 (2H , M), 6.89 (1H, t,: ^ · 3Ηζ), 6.91-7.01 (2H, m) 7.22-7.34 (6H, m), 7.41 (1H, d, m) 8.3Hz), 7.56 (1H, brs ), 7.73-7.77 (1H, m), 8.34-8.37 (1H, melting point: 126_129 ° C < dagger 117 (5-% present_3-base_2_ ° ratio σfix_2-base_2Η_ϋ Bisal-3-yl) -benzene-1,2-diol was obtained from compound U6 (82.0%) in the same manner as compound 3. NMR (DMSO-d6) δ: 6.55 (1H? Dd5 J = 2.0 8.3Hz) 6.65-6 · 70 (2H, m), 7.16 (1H, s), 7.38-7.57 (5H, m), 7.64-7 · 67 (2H, m), 7.75-7.77 (2H, m), 7.92 (1H, d, J = 7.8Hz), 8.0 (1H, td, J = 1.5, 7.8 · ζ), 8.18 (1H, s), 8.41-8.42 (1H , M), 9.0 (1H, s), 9.16 (1H, s). Melting point: 228-232 ° C Compound 119 3-〇 (3,4-dihydroxyphenyl) -1_pyridine_2 -Yl-111-pyrazol-3-yl] -1 ^, 1 ^ di

O: \ 88 \ 88539.DOC -85- 200418804 Methylbenzylamine was obtained from compound 11 8 (97.0%) in the same manner as in compound 3. H-NMR (DMSO-d6) δ: 2.94 (3H, brs), 3.01 (3H, brs), 6.54 (1H, dd, J = 2.0, 7.8Ηζ), 6.63 (1H, d, J = 2.0Hz), 6.66 (1H, d 'J-7.8Hz), 7.08 (1H, s), 7.37 (1H, d, J = 7.8Hz), 7.43-7.46 (1H, m) , 7.50 (1H, t, J = 8.0Hz), 7.63 (1H, d, J = 7.8Hz), 7.91 (1H, s), 7.96-8.02 (2H, m), 8.40-8 42 (1H, m), 9.00 (1H, s), 9.16 (1H, s). Melting point: 125-128. . Compound 122 4- [3- (3-Piperidinephenyl) _1- (2-pyridyl) -11 ^ _pyrazol-5-yl] -1,2-benzenediol was prepared in the same manner as in Compound 3. Compound 123 was obtained (82.0%). 'H-NMR (DMSO-d6) δ: 1.55-1.57 (2H? M)? 1.63-1.64 (4H, m), 3.18-3.21 (4H, m), 6.53 (1H, dd, J = 1.9, 8.3Hz ), 6.63 (1H, d, J-1.9Hz), 6.67 (1H, d, JUHz), 6.92 (1H, d, J = 7.8Hz), 7.00 (1H, s), 7.23- 7.30 (2H, m), 7.41-7.42 (2H, m), 7.61 (1H, d, J = 7.8Hz), 7.98 (1H, dt, J = 1.9, 7. · 3Ηζ), 8.40-8 · 41 (1H, m), 8.97 (1H, s), 9.13 (1H, s). Melting point: 135-137 ° C: Compound 124 4_ [3-3-[(3- 3-oxopropyl) amino] phenyl-: ι_ (2-αbipyridyl) _ih-. Biazol-5-yl] -1,2-benzenediol was obtained from compound 121 (67.0%) in the same manner as in compound 3. ^ -NMR (DMSO-d6) δ: 1.79 (2H5 quint, J = 6.4)? 3.08-3.12 O: \ 88 \ 88539.DOC -86- 200418804 (2H, m), 3.25 (3H, s), 3.43 ( 2H, t, J = 6.4Hz), 5.65 (1H, bs), 6.51-6 · 57 (2H, m), 6.61 (1H, d, J = 2.0Hz), 6.67 (1H, d, J = 7.8Hz) 5 6 · 87 (1H, s), 7.04-7.15 (2H, m), 7.40-7.43 (1H, m), 7.59 (ih, d, J = 8.3Hz), 7.99 (1H, dt, J = 1.9, 7 · 8Ηζ), 8.39-8.41 GH, m), 8.98 (1H, s), 9 · 12 (1H, s). Melting point: 123-126 ° C Example 5 Production of 6- (l, 3-diphenyl-1H-pyrazole_5-yl) _4-methoxy-3-pyridinol hydrochloride (compound 6) . In (E) -3- [4-methoxy-5 · (methoxymethoxy) _2-. ratio. Amidyl] -1-phenyl-2_propen-1_one To 0.25 g (0.84 mmol) of phenyl hydrazine, -27 g (2.53 mmol) of phenylhydrazine and 10 ml of ethanol were added and refluxed for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the residue were added toluene 10 ... and DDQ 0.29 g (1.27 mmol) 'and stirred at 80 ° for 12 hours. After completion of the reaction, it was extracted with ethyl acetate ', washed sequentially with saturated sodium bicarbonate and saturated brine, and dried over sodium sulfate', and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: hexane = 3: 1). 5 ml of trifluoroacetic acid was added to the obtained compound, and the mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, washed sequentially with saturated sodium bicarbonate and saturated brine, and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: hexane = 3: 1), and then the residue was hydrochloride with 4 mol / L hydrochloric acid-ethyl acetate to obtain the title compound (0074 g, 211. / 〇). ^ -NMR (DMSO-d6) δ: 3.80 (3H5 s) 3 7.24 (1H? S) 7.39-7.50 (9H, m), 7.91 · 7 · 93 (2H, m), 8.14 (1H, s), 1 〇93

O: \ 88 \ 88539.DOC -87- 200418804 (1H, brs) 〇 Melting point: 164-170 ° G Example 6 2- (l, 3-diphenyl-1H-pyrazole_5-yl)- Production of 5-methoxy-4-pyridinol hydrochloride (compound 7). The ratio of 2- (1,3-diphenyl-1H-pyrazol-5-yl) -5-methoxy-4-[(4-methoxybenzyl) oxy] °. To 0.20 g (4.3 mmol), add 10 ml of acetic acid and stir at 90 ° C for 2 hours. After cooling, the solution was neutralized with 1 mo 1 / L sodium hydroxide aqueous solution, extracted with chloroform, dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 2) to obtain 6- (1,3 · diphenyl • 1H-pyrazol-5-yl) _4_methoxy-3-pyridine. 0.15 g (98.0%) of alcohol. This was used as a hydrochloride salt with 4 mol / L hydrochloric acid-ethyl acetate to obtain 0.086 g (47.3%) of the title compound. ^ -NMR (DMSO-d6) δ: 3.93 (3H5 s) 5 7.00 (iH) s)? 7.39-7 · 50 (9H, m), 7.92 (2H, d, J = 8.0 Hz), 8.22 (1H, s).

Melting point: 144-148 ° C Example 7: 5- [4,5-fluoren (benzyloxy) -2-carolinyl μm, 3-diphenylpyrazole-4-weilic acid (Compound 14) Manufacture. 4,5-fluorenyl (benzyloxy) _2_ (1,3_diphenyl_4_ethoxycarbonyl) H_pyrazolyl) In the same manner as in compound 3 of Example 4, the same method is used. To give & the title compound (26.0%). H_NMR (CDC13) δ ······································.

Melting point: 253-255 ° CO: \ 88 \ 88539.DOC • 88-200418804 Example 8: 5- (4,5-dihydroxy-2-pyridyl) -i, 3-diphenyl-1H-pyridine Production of azole-4-carboxylic acid (compound 15). 0.26 g (0.65 mmol) of 5- (4,5-dihydroxy-2-pyridyl) -1,3-diphenyl-1H-pyrazole-4 carboxylic acid (compound 13) was dissolved in 5 ml of ethanol 2 ml of 2 mo 1 / L sodium hydroxide aqueous solution was added and the mixture was stirred for 12 hours. After the reaction was completed, 1 mol / L hydrochloric acid was added to the reaction solution, and the precipitated crystals were filtered to obtain 0.081 g (33.0%) of the title compound. 'H-NMR (DMSO-d6) δ: 7.27-7.38 (12H5 m)? 7.74 (1H5 s) 5 8 · 11 (1H, s).

Melting point 188-190 ° C Example 9: 6- [3- (3,5-difluoro-4-hydroxyphenyl) -1-phenyl_1H_pyrazole_5_ylmethoxy-3_ Production of pyridyl alcohol (compound 16). 2 [3- (3,5-monogas-4 -fluorenylbenzyl) _1_phenyl · fluorene-π ratio 唆 _5] 4 methoxy-5-benzyloxypyridine The compound used in Example 4 3 Same method 'to give the title compound (70.0%). h-NMR (DMSO-d6) δ ·· 72 (3Η, s), 7 · 03 (1Ή 7 22

(Out, s), 7.31-7.55 (7H, m), 8.29 (1H, s), 9.66 (1H, 1A v n, s), 10.24 (1H, s). Melting point: 143-ld Example 10: 4- [5_ (4,5_dimethoxy_2-0 than pyridyl) "_ Stupid mold- · 1ϋ_ϋbissalyl] -2,6_difluorophenol (Compound 17) Production. 2 {3_ [4- (benzyloxy> 3,5-difluorophenyl] -1-phenyl, bisazolyl 4,5-diamidoxypyridyl Compound 3 of Example 4 was treated in the same manner as described above to obtain the title compound (14.0%).

O: \ 88 \ 88539.DOC -89- 200418804 b-NMR (CDC13) δ: 3.62 (3H, s), 3.98 (3H, s), 6.57 (1H, s), 6.70-6 71 (1H, m), 6.84 (1H, s), 7.34-7.42 (7H, m), 8.15 (1H, ten)

Melting point 220-223 ° C Example 11 Production of 4- [3- (4-aminobenzylphenyl_1H_npyrazole-5_yl] _1,2_benzenediol (Compound 2) In the same manner as in the compound 3 of Example 4, from benzyl 2- (benzyloxy) -4- [3- (4-stone acid phenyl) _1-phenyl_4,5-dihydro- 111- ° Bijun_5-yl] phenyl ether (to produce 31 compounds) to give the title compound (24 2%). H-NMR (DMSO-d6) δ: 5.19 (2H, br), 6.51-6.70 ( 6H, m), 7.28-7.41 (5H, m), 7.54 (2H, d, J = 8.3Hz), 8.93 (1H, s), 9.06 (1H, s). Example 12: 2- Production of (acetamyloxy) -4- [3-phenyl-1- (2-rotidinyl) -111-pyrazolyl] phenyl acetate (compound 49). 4- [3- Phenyl-1- (2-11 ratio of bityl) -1; ^ -11 ratio of fluorenyl_5-yl] -1,2-benzenediol (compound 46) was ethylated with acetic anhydride and sodium acetate to give the title Compound (62.0%) ω-NMR (CDC13) δ: 2.26 (3H, s), 2.30 (3H, s), 6.84 (1H, s), 7.16-7.26 (4Η, m) 5 7.34 · 7.38 (1Η, m), 7.42-7 · 46 (2Η, m) 7.67-7.69 (1H, m), 7.81 (1H, ddd, J = 2.0, 7.8, 7.8HZ), 7.92-7.94 (2H, m), 8.37-8.38 (1H, m ). Melting point: 122-125 ° C Example 13 Production of pyrazole compound (1) with low carbon dialkylene oxide

O: \ 88 \ 88539.DOC -90- 200418804 Manufacture the compounds shown in Table 22. Table 22

Compound No. X — " — Rl R2 R3 R4 R5 Yield (%) 44 CH H n ~ C8H17-(¾-71.0 48 CH H Ph-CH2-96. 6 Compound 44 2- [5 气 丨, 3-benzene And dioxolane 5-yl) -3-octyl-1H-pyrazol_1-yl] pyridine 4- [3-octyl-pyridyl) _1H-pyrazole_5-yl] _ι, 75.0 mg (0.22 mm) of 2-benzyl glycol (Compound 43) was dissolved in 10 ml of N, dimethylformamide, and 0.1 g (0.30 mmol) of cesium carbonate and bromochloroethane were added. 0.04 g (0.31 mmol), and stirred at room temperature for 3 hours. After the reaction was completed, water was added to the reaction solution and extracted with ethyl acetate. After washing with water, it was dried over sodium sulfate and the solvent was distilled off. The residue was recrystallized from hexane: ethyl acetate (1: 1) to obtain 0 055 g (71.0%) of the title compound as an oil. 'H-NMR (CDC13) δ: 8.41 (1H? D, J = 4.9Hz) 5 7.69-7.73 (1H? M), 7.37 (1H, d, 7.8Hz), 7.18 (1H, m), 6.70 -6.75 (3H, m), 6.27 (1H, s), 5.97 (2H, s), 2.71 (2Hmt, J = 7.8Hz), 1.68-1.74 O: \ 88 \ 88539.DOC -91- 200418804

(2H, m), 1.28-1.42 (ioH compound 48 m), 0.88 (3H, t, > 6.8Ηζ). -Find the base -1 Η-ϋ ratio u sitting _ group] π ratio η, from 4- [3-benzyl 4- (2-pyridine 2- [5- (1,3-benzodioxolane_ 5_ group) _3 In the same way as compound 44, group) 1H t_5 group] -i, 2_benzenedi_ (the compound is called to give the title compound as an oil (96.6%). WR (CDCl3) S: 8 · 42 (1H, d, J = 49Hz), 7% (2H, d, J = 7.3Hz), 7.77-7.81 (1H, m), 7.58 (1H, d, j = 73Hz), 7.37-7.45 (3H, m), 7.22-7.26 (1H, m), 6.77-6.83 (4H, m), 5.98 (2H, s). Example 14 Compound 99 2- [5- (3,4-fluorene- Benzyloxy-phenyl) -4-iodo-3_phenyl_11 ^ pyzol-1-yl]-° pyridine Compound 451_64 g (3.0 mmol), N-succinimide 1.48 g (6.5 mmol), a mixture of 0.1 ml of HC1 and 12 ml of DMSO, and stirred at room temperature for 1 hour. After the reaction, the precipitated crystals were filtered, washed sequentially with water, hexane-ethyl acetate, and dried to obtain 1.80 g (89.0%) of the title compound. B-NMR (CDC13) δ ·· 5 · 09 (2H, s), 5.18 (2H, s), 6.85-6.97 (3Η, m), 7.16 (1Η, m), 7.26-7.48 (14Η, m), 7.67 (1Η, dt, J = 1.5, 7.8Hz), 7.92 (2H, dd, J = ll, 8.3Hz), 8.33 (1H, dd, J = 1.5, 4.5Hz).

Melting point: 171-173 ° C

O: \ 88 \ 88539.DOC -92- 200418804 Example 15 Compound 100 5- (3,4-fluorenyl-benzyloxyphenyl-3-phenyl) -1- (2-armidinyl) -111- Amidazol-4-carboxylic acid compound 99 0.34 g (0.5 mmol), Pd (OAc) 2 0.00248 g (0.011 mmol), PPh3 0.0234 g (0.089 mmol), KI 0.0851 g (0.5 mmol) ), A mixture of 0.198 g (2.0 mmol) of AcOK and 1.5 ml of DMF, stirred under a carbon monoxide stream at room temperature for 18 hours. After completion of the reaction, water and dilute hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to obtain 0.095 g (3 4.0%) of the title compound. ! H-NMR (CDCls) δ: 5.06 (2H? S)? 5.15 (2H? S)? 6.86-6.87 (2H, m), 6.97 (1H, d5 J = 1.5Hz), 7.19-7.44 (15H, m ), 7.65 (1H, dt, J = 2.0, 7.8Hz), 7.74-7.77 (2H, m), 8.36-8 · 37 (1H, m) 0 Melting point: 201-203 ° C Example 16 Compound 102 2- [5- (3,4-Wu-fluorenyloxybenzyl) -3 -phenyl-fluorene-sigma ratio-1-yl] -5 -nitro-α ratio. 5- [3,4-fluoren (benzyloxy) phenyl] -3_phenyl "bizole was determined to be 0.216 g (0.5 mmol) and cuprous iodide 0.06 g (0.06 mm). 〇i), l, 10-morpholinyl 0.0129 g (0.07 mmol), cesium carbonate 0.36 g (1.1 mmol), 2-bromo-5-nitropyridine 0.115 g (0.56 mmol), 1 0.5 ml of 4-dioxane, stirred under argon gas flow at 100 ° C for π hours. After the reaction, the insoluble matter was filtered, O: \ 88 \ 88539.DOC -93- 200418804, and the liquid was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (013 g, 46.0%). H-NMR (CDC13) δ 5.12 (2H, s), 5.24 (2H, s), 6.75 (1H, s), 6.87-6.97 (3Η, m), 7.22-7.50 (13Η , M), 7.90-7.94 (3Η, m), 8.45 (1H, dd, J = 2.5, 8.8Hz), 8.85 (1H, d, J = 2.4Hz). Melting point: 139-143 ° C Example 17 Compound 105 3- [5_ (3,4-methylolphenyl) -3 -phenyl- -yl]. The ratio of 3- (3-phenyl-1H-cyclohexyl-1-yl) is determined by the ratio of 11.11 g (〇-5 mmol), 0.217 g (1-mmol) of 4-bromo-o-dimethoxybenzene. , Pd (OAc) 2 0.011 g (0.05 mmol), BINAP 0.003 g (0.05 mmol), carbon shavings 0.326 g (1 mmol), tetra-n-butylammonium bromide 0.177 g (0.55 mmol) and DMF2 · 5 ml, and stirred under argon flow at 130 ° C for 80 hours. After the reaction, water was added to the reaction and extracted with ethyl acetate. The organic layer was sequentially with water and saturated brine. After washing and drying with sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane · ethyl acetate = 2: 1) to obtain the title compound (0.073 g, 41.0%). -NMR (CDC13) δ: 3.72 (3H, s), 3.90 (3H, s) 5 6.74 (1H, s), 6.82-6.83 (3Η, m), 7.26-7 · 46 (4Η , M) 5 7.74 (1Η, d, J = 8.3Hz), 7.91 (2H, d, J = 7.3Hz), 8.54 (1H, dd, J = 1.0, 4.9Hz), 8.68 (1H, d, J = 2.4Hz) 0 Melting point: 138-140 ° C Example 1 8 O: \ 88 \ 88539DOC -94- 200418804 Compound 109 4- {3- [5- (3,4-fluorenylbenzyloxyphenyl) ) -1- (pyridin-2-yl) -111-pyrazol-3-yl] benzene }-Morpholine Compound 107 0.59 g (1 mmol), Morpholine 0.13 ml (1.5 mmol), Pd2 (dba) 3 0.093 g (0.1 mmol), BINAP 0.195 g (0.3 mmol), NaOtBu A mixture of 0.274 g (2.8 5 mmol) and 5 ml of toluene was stirred at 110 ° C. for 12 hours. After the reaction was completed, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine. After washing and drying with sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 0.409 g (67.0%) of the title compound. H-NMR (CDC13) δ: 3.24 (4H, t, d = 4.4Hz), 3.88 (4H, t, d = 4.4Hz), 4.99 (2H, s), 5.17 (2H, s), 6.71 (1H, s), 6.84-6.92 (4H, m), 7.18-7.22 (1H, m), 7.29-7 · 70 (14H, m), 7,71-7.75 (1H, m), 8.38- 8.39 (1H, m). Melting point: 129-131 ° C Compound 114 l- {3- [5- (3,4-fluorenyl-benzyloxyphenyl) -1_ „pyrimidazole_3_yl] -phenyl} -4-benzene Giprophen was obtained in the same manner as compound 109 (76 2 0 / 〇). ^ -NMRCCDC ^) δ: 3.36-3.43 (8H,,), 5.00 (2 ^ s), 5.18 (2H, s), 6.73 (1H, s) 6.88_6.9l (4Hm) 6 98_70i (4H, m), 7.20.7.49 (15H, m), 7.59 (1H, s), 7.72-7.76 (1H, m) , 8.39-8.40 (1H, m).

Melting point: 61-64 ° CO: \ 8S \ 88539.DOC -95. 200418804 Compound 12 1 2- [5_ (3,4-C ¥ Oxyphenyl dephenyl) 4. Pyridyl-1_yl] pyridine A pale yellow oil was obtained in the same manner as in Compound 109 (76%). H-NMR (CDC13) δ: 1.57 "· 6ΐ (2H, m), 1.70-1.75 (4H, m), 3.22 (4H, t, J = 5.4Hz), 4.99 (2H, s), 5. · 17 (2H, s), 6.71 (1H, s), 6.86-6.94 (3H, m), 7.18-7.21 (ih, m), 7.26-7.52 (15H, m), 7.73 (1H, dt5 J = 2.0, 8.2Hz), 8.36-8.38 (1H, m). Example 19 Compound 116 2- [3-Biphenyl-4-yl-5- (3,4-benzobenzyloxyphenyl) -17 to fluoren-1-yl] -12 to 11 Compound 107 596.1 mg (1.00 mmmol), phenylboronic acid 162.5 mg (1.33 mmol), Pd (PPh3) 4 69.5 mg (0.06 mmol), 2 M Na2C03 9 mmol, 14 mL of toluene and 1 mL of ethanol, stirred at 100 ° C for 18 hour. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 0.363 g (62.0 ° / °) of the title compound. iH-NMR (CDC13) δ: 5.00 (2H, s), 5.17 (2H, s), 6.78 (1H, s), 6.87-6.92 (3Η, m), 7.20-7 · 22 (1Η, m), 7.27-7.51 (15Η, m), 7.56-7.59 (1H, m), 7.66-7.68 (2H, m), 7.74 (1H, dt, J = 2.0, 7.8Ηζ) , 7.88_7_91 (1H, m) 8.14-8.15 (1H, m), 8.38-8.40 (1H, m).

Melting point: 114-115 ° CO: \ 88 \ 88539.DOC -96- 200418804 Example 20 Compound 111 2_ [5- (3,4 · fluorene-benzyloxyphenyl) _3- (3-iodophenyl) · 1Η_π !: azole-1-yl] -π than pyridine. Compound 107 0.589 g (l mmol), cuprous elfide 0.022 g (0.11 mmol), Nal 0.3 03 g (2 mmol), trans · N, N -A mixture of 0.0383 g (0.27 mmol) of dimethyl-1,2-cyclohexanediamine and 1, 4_dioxane at 12 ° C was stirred for 12 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and dried over sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to obtain 0.553 g (87.0%) of the title compound. 'H-NMR (CDC13) δ: 4.99 (2Η, s) 5 5.17 (2H? S) 5 6.70 (1H, s), 6.84-6.90 (3H, m), 7.15 (1H, t, J = 8.3Hz) , 7.20-7 · 24 (1H, m), 7.28-7.39 (9H, m), 7.43-7.45 (2H, m), 7.65-7.68 (1H, m), 7.71-7.75 (1H, m), 7.84-7.87 (1H, m), 8.30 (1H, t, J = 1.5Hz), 8.39-8.41 (1H, m).

Melting point: 123-124 ° C Example 21 Compound 112 1-3- [5- (3,4-fluorenylbenzyloxyphenyl) -1- (2-arimidinyl) -111 ^ Phenyl-3-yl ] -Phenyl-2-pyrrolidone: Compound 111 0.635 g (l mmol), 2-σbilodrogodone 0.085 mL (1.1 mmol), Cul 0.0223 g (0.117 mmol), trans-N, A mixture of 0.0316 g (0.22 mmol) of N-difluorenyl-1,2-cyclohexanediamine, 0.447 g (2.0 mmol) of K3PO4, and 1 mL of 1,4-dioxane was stirred at 110 ° C for 12 hours. . After the reaction was completed, O: \ SS \ 88539.DOC -97- 200418804 was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 3) 'to give the title compound (90.0%). Η-NMR (CDC13) δ: 2.18 (2H, quint J = 7.3Hz), 2.63 (2H, t, J = 7_8Hz), 3.95 (2H, t, J = 7.3HZ), 4.99 ( 2H, s), 5.17 (2H, s), 6.76 (1H, s) 6.85-6.91 (3H, m), 7.20-7.23 (1H, m), 7.29-7.47 (12H, m), 7.69-7.75 (3H, m), 8.06 (1H, s) 8.38 · 8 · 40 (1H, m). Melting point · 106-109 ° C Compound 12 0 4- [5- (3-Aminophenyl) _2-n than pyridin_2_yl_2Η_σbizole_3_yl] _benzene-; 1,2 _Diol was synthesized by the same method as compound 112 {3- [5_ (3,4_fluorenylbenzyloxyphenyl) -1-pyridin-2-yl-1H-pyrazole_3_yl] _phenyl} Benzyl carbamate was then reduced in the same manner as 14 compound 3 to obtain (55%). Η-NMR (DMSO-d6) δ: 5.13 (2H, brs), 6.51-6.56 (2H, m), 6.61 (1H, d, J = 2.0Hz), 6.67 (1H, d, J = 8.3 Hz), 6.81 (1H, s), 7.01 7.09 (2H, m), 7.16 (1H, t, j = 2 0Hz), 7 4〇_7 43 (1H, m), · 59 (1H, d, J-7_8Hz), 7.98 (1H, dt, J = 2.0, 7.8Hs), 8.38-8.40 (H, m), 8.99 (1H, s), 913 (iH, m). Melting point: 192-194 ° C Example 22 Compound 11 8 3 [5 (3,4-benzyloxyphenyl) is small. Bipyridyl_2_yl, -succinyl] dimethylbenzylamine

O: \ 88 \ 88539.DOC -98- 200418804 A mixture of compound 111 0.656 g (1.03 mmol), Pd2 (dba) 3 0.0258 g (0.028 mmol), POC13 0.316 g (2.06 mmol), and 10 mL of DMF in an argon stream and Stir at 110 ° C for 24 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 3) to obtain 0.418 g (70.0%) of the title compound as a pale yellow oily substance. W-NMR (CDC13) δ: 3.01 (3H, brs), 3.13 (3H, brs), 4.99 (2H, s), 5.17 (2H, s), 6.75 (1H, s), 6.85-6.91 (3H, m), 7.20-7.23 (1H, m), 7.27 vertical 7.48 (13H, m), 7.73 (1H, dt, J = 2.0, 8 · 3Ηζ), 7.95-7.98 (2H, m), 8.38- 8.40 (1H, m). Example 23 Compound 123 {3- [5- (3,4-fluorenylbenzyloxyphenyl) -i-n than pyridin-2-yl-iH-. Biazole-3_yl] • phenyl}-(3-methoxypropyl) amine compound 107 1188.9 mg (2.02 mmol), 3-methoxypropylamine 0.31 mL (3.0 mmol), Cul 43.0 mg (0.26 mmol), N, N, -diethyl salicylamine 157.8 mg (0.82 mmol), K3P04 855.2 mg (4.02 mmol) and 1,4-dioxane 5.0 · 0 mL in a mixture of 9 It was stirred at 0 ° C for 24 hours. After completion of the reaction ', water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (5191 g, 43.0%) as a yellow oil. ^ -NMR (CDC13) δ: 1.91 (2H? Quintet, J = 6.4Hz)? 3.30 (2H5 O: \ 88 \ 88539.DOC • 99- 200418804 t, J 2 6. 4Ηζ), 3.36 (3H, s) , 3.52 (2H, t, J = 6.4Hz), 4.00 (1H, brs), 4.99 (2H, s), 5.17 (2H, s), 6.59-6.69 (1H, m), 6.70 (1H, s), 6.84-6.90 (3H, m), 7.18-7.24 (3H, m), 7.27-7.38 (10H, m), 7.43-7.49 (2H, m), 7.70-7.74 (1H, m) , 8.36-8.38 (1H, m). Table 23 shows the σ-ratio compounds (I) obtained in Examples 14 to 23. Table 23 OR5

--N Compound No. X Rl R2 R3 R4 R5 99 CH I Ph Bn Bn 100 CH -o C00H Ph Bn Bn 102 CH H Ph Bn Bn 105 CH -c H Ph Me Me 109 CH H Bn Bn 111 CH H Bn Bn 112 CH H Bn Bn 114 CH -OH Bn Bn 116 CH -o H s Bn Bn 118 CH -o H V-NMe, -o Bn Bn 120 CH -o HHH 121 CH -o H \ y〇Bn Bn 123 CH H (CHjJjOMe Bn Bn O: \ 8S \ 88539.DOC -100- 200418804 Example 24: Determination of antifungal activity Antifungal activity (1) Resistance to Candida albicans and C. krusei in test tubes The measurement of fungal activity was performed in accordance with NCCLS procedure M27-A. Test compound solution: The test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a solution with a maximum concentration of 6.4 mg / ml, and diluted with DMSO Prepare a two-fold dilution series. Add these solutions to the test medium at a ratio of 1% (ν / ν). Test medium ·· RPMI 1640 10.44 g is dissolved in 900 ml of distilled water, and MOPS buffer (0.1 65 M) and dissolve it. Then, adjust the pH to 7.0 with a 5 mol / L sodium hydroxide aqueous solution, add distilled water to 1000 ml, and then Sterilization and use. Inoculation liquid: Candida albicans ATCC90028 and Candida krusei ATCC625 8 in Sabro glucose agar medium, cultured at 35 ° C for 24 hours, subcultured again under the same conditions, taken Five colonies with a diameter of 1 mm or more were suspended in 5 ml of sterilized physiological saline. After the permeability of the suspension was adjusted to McFarland 0.5, the test medium was diluted 1000 times to prepare an inoculum. Antifungal activity determination: Dilute each concentration of the test specimen prepared with the test medium into 96-hole round-bottomed traces of Pinggu, 100 pL each, and add 100 pL of the above inoculum (final bacteria concentration: 0.5 ~ 2.5 × 103 cells / mL), and then cultured at 35 ° C for 48 hours. After the end of the culture, the absorbance at 600 nm was measured, and compared with the control group without the added agent, the inhibition was O: \ 88 \ 88539.DOC -101 -200418804 The minimum pharmaceutical concentration for reproduction of more than 80% bacteria is considered as MIC (pg / mL). (2) Determination of the antifungal activity of Aspergillus and Trichophyton in a test tube The following operations were performed in accordance with NCCLS procedure M38-P. Test compound solution and test medium ... Refer to the test method for antifungal activity against Candida albicans and C. krusei in a test tube as described above. Inoculation of spore fluid: Aspergillus flavus IFM 41935 and A. fumigatus IFM40808 were cultured in corn dextrose agar medium at 27 ° C for 7 days, and the spores were suspended in 0.05% (w / v) Tween 80 in sterilized physiological saline and passed it through a cell filter (pore size 70 μm). This was prepared in a test medium to a concentration of 6.0 × 10 4 conidia / mL. In addition, alamar BlueTM was added to the culture medium at a final concentration of 10% (w / v). For Trichophyton mentagrophytes IFM 40769 and Trichophyton rubrum IFO6204, in a high-salt medium (neoheptone 0.1% (w / v), glucose 0.2% (w / v), magnesium sulfate · 7 hydrates 0.1% (w / v), dihydrogen _ 0.1% (w / v) and cyclolipid 2.0% (w / v)) after culturing at 27 ° C for 14 days, the spores Suspend in a sterile physiological saline solution to which 0.05 ° / 〇 (w / v) Tween 80 was added, and pass it through a cell filter. This was prepared in a test medium to a concentration of 2.0x105 conidia / mL. Determination of antifungal activity ... Dilute each concentration of the test specimen prepared with the test medium into 96-hole round-bottomed traces of Pinggu, 100 pL per hole, and add the above-mentioned inoculum spore solution1. 〇pL. The Aspergillus fungus was then cultured at 35 ° C for 48 hours (final spore concentration: 3.0 X 104 conidia / mL) and the trichophyton fungus was cultured at 27 ° C for 72 hours (final spore concentration: 1.Ox O : \ 88 \ 88539.DOC -102- 200418804 ί 5 conidia / mL). After the end of the culture, the absorbance at 570 nm (refer to 600 nm) was measured for Aspergillus fungi, and visually judged for Hydratia, and compared with the control group without the added agent, the minimum inhibition of the reproduction of more than 50% of bacteria The concentration of the agent is taken as the MIC (pg / mL). Table 24 shows the measurement results of the antifungal activity MIC (pg / mL) of the compound of the present invention and the control. Table 24 Compound No. Antifungal Activity (MlC ^ g / ml) C. alb C. kru A. fla A. fum T. men T. rub 43 2 0.5 > 64 2 2 2 46 1 0.5 4 1 1 67 0.5 0.5 2 1 0.5 0.5 72 1 1 4 2 1 1 110 0.5 0.5 > 64 8 0.5 0.5 113 0.5 0.5 > 64 16 0.25 0.5 115 4 0.5 > 64 64 0.5 1 119 0.5 0.5 64 32 0.5 0.5 120 0.5 0.25 16 16 0.5 0.5 FLCZ 0.25 32 > 64 > 64 16 8 The symbols in the table are as follows. C. alb. Candida albicans ATCC 90028 C. kru: Candida krusei ATCC 6258 A. fla: Aspergillus flavus IFM 41935 A. fum: Aspergillus fumigatus IFM 40808 T. men: Trichophyton irritans IFM 40769 T · Rub: Trichophyton rubrum IFO 6204 FLCZ: fluconazole O: \ 88 \ 88539.DOC -103-200418804 It can be understood from the table that the compound of the present invention is effective for various deep mycosis and superficial mycosis Shows excellent antibacterial activity. Especially for Aspergillus, compared with fluconazole, which is a control drug, it has particularly excellent antibacterial activity. O: \ 88 \ 88539.DOC -104-

Claims (1)

200418804 Patent and application patent garden: 1. A pyrazole compound or a salt thereof, whose formula is shown by the following general formula (I): OR5 / N—N R1 (wherein “R1” represents an alkyl group, an alkenyl group, a phenyl group which may have a substituent, a biphenyl group which may have a substituent, or a heteroaromatic ring group which may have a substituent; R3 represents a hydrogen atom. , Alkyl, alkenyl, phenyl which may have a substituent, biphenyl which may have a substituent, or heteroaromatic ring group which may have a substituent; R2 represents a hydrogen atom, a halogen atom, a low-carbon alkyl group, a low-carbon alkane Oxy, carboxyl, lower alkoxycarbonyl, chloromethyl, cyano, -CH2OH or _CH2NR6R7 (R6 and R7 are the same or different, 'represents a hydrogen atom or a lower alkyl group); R4 & R5 is the same or different, and represents a hydrogen atom, a fluorenyl group, a lower alkyl group, a cycloalkyl group, or a phenylalkyl group, or R and R together form two alkylene dioxy groups; X represents a secondary fluorene Radical or nitrogen atom). _ 2 · A medicine which uses the pyrazole compound or its salt as the active ingredient in the scope of patent application item 1. ‘3. An antifungal agent using the pyrazole compound or a salt thereof as described in the scope of application for the patent as an active ingredient. 4. A pharmaceutical composition containing the pyrazole compound or its salt 'as claimed in item 1 of the scope of patent application, and a pharmaceutically acceptable carrier. 5. Such as the application of the scope of the patent application No. 0 bisal compound or its salt in the pharmaceutical O: \ S8 \ 88539.DOC 200418804 manufacturing use. 6. If the application of the scope of patent application No. 5 is used, the medicine is used as an antifungal agent. 7. A method for treating a fungal infection, which is characterized by administering a pyrazole compound or a salt thereof as described in item 1 of the scope of patent application. O: \ 88 \ 88539.DOC 200418804 柒. Designated representative map: (I) The designated representative map in this case is: None (II) The component representative symbols of this representative map are simply explained: 捌, if there is a chemical formula in this case, please disclose the best Chemical formula showing the characteristics of the invention ... OR5 O: \ 88 \ 88539.DOC -6-