TWI233358B - Preventive or recurrence-suppressive agents for liver cancer - Google Patents

Abstract

This invention is related to preventive or recurrence-suppressive agents for liver cancer and usage of the agents which contains thyroid hormone receptor agonists as the active ingredient having an effect of inhibiting the expression of liver estrogen sulfotransferase. The thyroid hormone receptor agonists are preferably compounds represented by the general formula (I) or pharmaceutically acceptable salts thereof: (I) wherein R1 and R2 are each alkyl, halogen, or the like; R3 is hydrogen, alkyl, halogen, or the like; X is hydroxyl or the like; W is O, S, -CH2, or the like; Y is alkyl, -Q-T (wherein Q is O, CH2, CH(OH), or the like; and T is optionally substituted aryl or the like), or the like; Z is hydrogen, alkoxy, or the like; and A is -NHCO-Y1-CO2R8-, -CH2CH(R9)NR10R11, or the like.

Description

1233358 V. Description of the invention

[Technical Field] The present invention relates to a (onset) prevention or recurrence inhibitor of liver cancer containing thyroid hormone receptor excitability and 1 ^, and to take this further-has the effect of reducing liver cystathione content [Background Technology] _ pf In recent years, the incidence of liver cancer has increased in many countries. According to the situation, it is believed that more than 90% of liver cancers are caused by type 6 or type c hepatitis: inflammatory disease (especially liver cirrhosis) as the underlying cause (Liao "㈣, · Xun, N · Engl. J. Med., 1993. Vol. 328, 1797). For the treatment of liver cancer, currently used methods are, for example, surgery, percutaneous ethanol injection therapy (PEIT), liver Transcatheter arterial embolization (TAE), percutaneous microwave coagulation therapy, and drug therapy with carcinogens (Yoshikawa et al., Medical Journal Vol. 35, No. 1 5 1 9- Page 1 524 (1 99 9)). In drug therapy, anthracycline-based agents (such as d ο X 〇rubici η, epirubicin, etc.), nitrosourea-based agents (such as nimust ine, etc.), metabolic antagonism Agents (such as 5-fluorourinary p-biting, etc.), anti-biomass (such as mit omy cin C, etc.), neoplastic compounds (such as cisp 1 atin, etc.), etc. Low sensitivity of cancer agents Soap treatment agent alone or low in PE IT ΤΑΕ the truth is present, i.e. there are no agents (Okada et has indeed the effect of therapeutic, Clinical Medicine, Vol. 50, No. 262~

C: \ 2D-C0DE \ 91-07 \ 911l0283.ptd Page 6 V. Description of the invention (2) 2 67 (2 0 0 1)). Hepatocarcinoma-onset disease, that is, those who have undergone a refractory disease, are more likely to have it. The difference is that the recurrence rate after radical treatment is extremely high, I) ^ ^ 714 5 ^ 19 Dirty crying η / Λ This may be due to multicenter cancers different from other cancers at the time of stolen, that is, the liver cancer is widespread: JJ (pre-cancerous cancer lesions) ', and according to the conventional surgery, ρΕιτ, etc. = Therapeutic methods Rishou cannot effectively inhibit Caused by the recurrence of liver cancer. Therefore, it is a new agent for the prevention or suppression of recurrence of liver cancer. · Thyroid hormones are indispensable for the normal development and differentiation of mammals, and "have important functions in the maintenance of metabolic constancy, such as thyroid hormones involved in lipids, sugars, and other Thanks to Xie's control. In addition, for the heart rate, the heart: shrinking the end; Lu Zhi resistance and other cardiovascular system functions also have a great impact. Element 3 of the TD & t, binding of the adrenal hormone receptor (TR). The complex formed by T3 and TR is related to the promoter subdomain of the T3 regulatory gene of the gonadotropin sequence (m) of the target gene: for activating the expression of this gene or inhibiting the expression of the gene.

Si ::::, are considered to be genes of the genes within this nucleus ^

Ledda-Columbano GM et al. Reported that when 3, 5, 3, -triiodo-L_thyroxine (T3) was administered in a rat liver chemical carcinogenesis model, this could reduce liver cancer 1233358 '~' ------ V. Explanation of the invention (3) Inhibition of material & 6 0 3-9) Lung metastasis (Cancer Res ·, 2 0 0, 6 9 (3): The first use can inhibit liver dysentery = 'The above report It has not been clarified which species of thyroid hormones are the same ^ Therefore, it is unclear whether all thyroid hormones are similar to liver cancer. Furthermore, it is considered difficult to use thyroid hormones < inhibitors, Because on your whole body, I know that the lower right, +, and Yu Qiao 丨 F use the vibration of the limbs and the heart function with frequency pulses and irregular pulses to fill the muscle atrophy. Blow ί 丨 Similar effect with thyroid hormone Various thyroid hormone receptor agonists have been reported. I and Gutigu ^ _ 1/6 () 784, _ 1/942 93 has the following disclosure: for obesity, = I = disease, atheroma Sclerosis, depression, osteoporosis, hypothyroidism, hypofunction, sacral adenoma, thyroid cancer, glaucoma (within the green ~ Arrhythmic pulses, congestive heart failure (congestive heart fai lure), and thyroid hormone receptors useful for the prevention or treatment of dermatological diseases, a pharmaceutical composition containing the ligand as an active ingredient, and a method for producing the same. The content of the disclosure is used throughout this specification. -Qin Xin Bu was disclosed in JP06 / 1 72275 as follows: Heteroatoms useful for the prevention or treatment of hyperlipidemia and atherosclerosis Acetic acid derivatives. Derivatives are medicinal compositions with active ingredients, as well as the double and native methods of the derivatives. These disclosures are in the full text of the reference book. 勹 / 芩 is used in this context In JP61 / 167643, there is the following disclosure: It is useful for the prevention or treatment of obesity, hyperlipidemia, and atherosclerosis = A ^ gland

\\ 312 \ 2d-code \ 91-07 \ 91110283a.ptd 1233358 V. Description of the invention (4) A compound with the action of a hormone, a pharmaceutical composition containing the compound as an active ingredient, and a method for manufacturing the compound. These disclosures are incorporated herein by reference in their entirety. EP1033364, EP1088819, EP1127882, EP1148054, WO00 / 51971, and W001 / 72692 have the following disclosures: Obesity, diabetes, hyperlipidemia, atherosclerosis, glaucoma, arrhythmia, skin diseases , Hypothyroidism, thyroid cancer, hypertension, congestive heart failure, depression, osteoporosis, and thyroid hormone receptor ligands useful for the treatment of hair removal, a pharmaceutical composition containing the ligand as an active ingredient , And a method for manufacturing the ligand. These disclosures are incorporated herein by reference in their entirety. In WOO 1/70687 and WOO 1/90 0 53, the following disclosures are made: · Gland hormone receptor ligands useful for the prevention or treatment of hypercholesterolemia and atherosclerosis. These disclosures are incorporated throughout this specification as a reference. It is disclosed in \ 〇0 0/3 9077 and Yang 0 1/982 5 6 for obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, sacral gland Hypofunction, sacral adenoma, thyroid cancer, 1 ^, arrhythmia, congestive heart failure, and prevention of skin diseases: ,, thyroid hormone receptor complex + for heart use, containing this complex :: 3 Pharmaceutical composition and method for producing the ligand. These 12 are incorporated herein by reference in their entirety. No valley So far, in addition to naturally occurring thyroid irritation ^, there is no prevention or recurrence of liver cancer (onset).

1233358 V. Description of the invention (5) Prime receptor ligand. [Disclosure of the invention] Xinfa a and other studies on various gonadotropin receptor agonists: Saqi discovered that a certain thyroid hormone receptor agonist can reduce the expression of liver and female migrating enzymes, and among them The fact that certain thyroid hormone stimulants can reduce the content of glutathione in the liver. Continued acid-transferase ⑽) is a kind of enzyme that regulates / converts the viscera in existing tissues, and it is known from the analysis results of KO mice that it induces

Und. Excessive manifestation of estrogen action can inhibit this enzyme. Xinpin ΓΓ Paleology, mi, 142 (12): 5342-5350). The fact that estrogen has an inhibitory effect on liver cancer is: = ^^ \\ '55 (4): pages 348-3 50)). Therefore, it has an inhibitory effect on liver and female cancer. The acting agent is considered to be useful in liver hair: H system. In addition, regarding the reduction of cystathione (GSH) in the liver, Huang ZZ et al. Reported the following: Hepat. Cellular eaFei / Compared with hanging liver, the content of cystathione in hepatocellular carcinoma is higher in the liver. Cellular sound: 〇 Increase in the amount of glutathione, and gluten V 2 p. 21), that is, the increase in the value of liver glutathione, and inhibit the liver cancer asexual reproduction cells of liver cancer as described above It is said that patients with chronic liver and fire disease have been transferred to the liver of patients with liver disease of right liver 4 and the liver disease will be converted to liver; I risk of developing cancer; . In addition, since liver cancer is characterized by multiple heart C: \ 2D-C0DE \ 91-07 \ 91110283.ptd page 10 1233358

μ μ # i Degree has cancer suppressive effect at the same time, & the small lesions that can not be completely removed by surgery and other agents are considered to be very useful for liver cancer recurrence suppression. The inventors of this case, etc., about this kind of cystathione which can reduce liver performance and preferably also reduce the inner surface of the liver: ㈡ί; the peak body volume agonist, further research ^ Shiri = 3 miles of thyroid hormone receptors The results of this step-by-step study have found that the formula (I) has an excellent effect on suppressing cancer: f, the fact that the compound can suppress =: the proliferation of cells, and can reduce the Thyroid: Now, the present invention is completed.九 Based on the results of this special research, the present invention is related to the prevention or recurrence inhibitor of liver cancer containing thyroid hormone components, and the performance of this agonist is ^ right-acting estrogen acid transferase. It has the effect of reducing the content of glutathione in the liver for the most 2 steps. Further examples of thyroid hormone receptors that are active ingredients of the present invention include the following general formula (I)

(I) [In the formula, R1 and R2 each independently represent a C ^ 3 alkylcyano group, R3 represents a hydrogen atom, a C! _3 alkyl group, a trimethyl group, a halogen atom, or a fluoromethyl group, or a halogen atom,

1233358 V. Description of the invention (7) W represents, _s—, -CH2-, -ch (〇h)-, -co-, -so-, or -S 02-, X represents a hydroxyl group, or the general formula-NH- A group represented by GV, G represents -c〇-, "s〇-, -S02-, CSNH-, or -C0NH-, and v represents C1MD alkyl, c3-8 cycloalkyl, or unsubstituted or substituted aryl 'Y Represents ci-io alkyl, trifluoromethyl, C3-8 cycloalkyl, unsubstituted or substituted

Aryl, -S (〇) 2NR4R5-, -C (0) NR4R5-, -s (0) 2R6-, 6-oxy-L 6-monohydrogen σ-ratio-3-ylmethyl, 6- Oxy-1,6-dihydro tower 11-well-3-ylmethyl, or a group represented by the general formula -QT, or X and Υ together form _NH_OC (R7) 'R4 and R5 each independently represent hydrogen Atom, q, alkyl, C3_8 cycloalkyl, cycloalkane_6 alkyl, or unsubstituted or substituted aryl, or R4 and R5 together with the bonded carbon atom to form a cyclic amine of 5 to 7 members, R6 C1M () alkyl, c3_8 cycloalkyl, C3_8 cycloalkane CV6 alkyl, or # substituted or substituted aryl, R7 represents a hydrogen atom or Ci 6 alkyl, and Q represents -0-, -CHCH, -CH ( OH)-, or -C0-, T represents an unsubstituted or substituted aryl group, an unsubstituted or substituted aryl group, a C3_8 cycloalkyl group having an oxygen atom in the ring, or a C3_8 soil which may have an oxygen atom in the ring Benzene group, z represents a hydrogen atom or cl 3 alkoxy group, or γ and z are formed together— (cfj2) m-, m represents an integer of 3 to 4, a represents -nhco-ylco2r8-, _conhch2co2r8-, ~ CH2CH (r9) NR1GRn-, or -Yic〇Ri2-, or the following formula

C: \ 2D-CODE \ 91-O7 \ 9111〇283.ptd Page 12 1233358 V. Description of the invention (8)

N-NH

N-NH Η

NH /,

NH

NH J · NH i represents a group, Y1 represents a bond, c] -6 alkylene (including methylene), R8 represents a hydrogen atom, an alkyl group, or an aromatic Cl_6 alkyl group, and R9 represents a second retarder or Ci 6 Alkoxycarbonyl group, R10 represents a hydrogen atom or Ci 6 alkyl group, 'Table, hydrogen atom, Ch alkyl group, or (^ 4 alkyl group, Y represents a bond or Ch alkyl group (including methylene), R12 represents Benzene or Ci 6 alkoxy]]: Chemical compounds or pharmacologically acceptable practice of these compounds. In another aspect, the present invention is related to, g Italian skin ethanol injection therapy, liver: It is selected from the group consisting of surgery,-in addition to hepatic arterial blockage therapy, lV H > method of liver cancer root therapy, which is used after the treatment of thyroid hormones containing thyroid hormones that contain two and inhibit the effect of ancient hard skin microwave coagulase transfer enzymes. For the prevention or recurrence of inhibitors of liver cancer. 琍 is the active ingredient. In another aspect, the present invention is a thyroid hormone receptor that exhibits inhibitory effects on acid-based transfers. = Estrogen lutein self-interferon a, NIK-333, ^ " 7. And the combination of gluten agonist and at least one kind of substance to the liver _ Xiyou & 3々 Further cholanic acid, on the other - on the situation, by preventing or recurrent inhibitors The present invention relates to manufacturing a = & < prevention or, CH = CH- by the

C: \ 2D-CODE \ 91-07 \ 91110283.ptd

Page 13 1233358 Description of the invention (9) or recurrence inhibitor The use of hepatic estrogen-continuous acid transferase inhibitors in the production of thyroid * and the use of τ-like urea hormone receptor agonists. Bud τ, in another aspect, the present invention is related to the production of iridium spp., Λ, i ”, λ is just a method for preventing or reproducing liver cancer, including administering a liver stimulus i ^

Ajr m Λ, acid-based transferases inhibit the production of effective amounts of gonadotropin receptor agonists. In the present invention, unless otherwise noted, the following terms have the following meanings. " "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or a magnetic atom. "Clj alkyl" means a linear or branched alkyl group having 1 to 3 carbon atoms. , Ethyl, propyl, isopropyl. "Gy alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and second Butyl, third butyl, pentyl, isopentyl, neopentyl, tertiary, hexyl and the like. "C1-1G alkyl" means a linear or branched alkyl group having 1 to 10 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl , Second butyl, third butyl, pentyl, isopentyl, neopentyl, third pentyl, hexyl, heptyl, isopropyl-2-fluorenylpropyl, octyl, nonyl, and the like. "C3-6 cycloalkyl" means a saturated cyclic hydrocarbon group having 3 to 6 members, and examples thereof include cyclopropyl, badbutyl, cyclopentyl, and cyclohexyl. "C3-8 cycloalkyl" means a saturated cyclic hydrocarbon group of 3 to 8 members. "For this purpose", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,

I233358 V. Description of the invention (10) Cyclooctyl. The oxygen atom in the ring is exemplified by 1,3-epoxyepoxyhexane. "Saturated 3 to 8 member ring saturated cyclic hydrocarbon group having an oxygen atom in the ring (Vs cycloalkyl group, for this purpose, tetrahydrosquenchyl group, tetrahydrosigma sigma group, 1") "Cyclo" means a 5- to 6-membered ring, such as cyclohexyl, cyclopentyl, cyclohexyl. L and a cyclic hydrocarbon group. To this end, a C: 5-6 ring having an oxygen atom in the ring A saturated cyclic hydrocarbon group having 5 to 6 members of an alkyl group is an oxoranyl group and a tetrahydropiperanyl group in an acyclic ring. · ,,,, and the like include tetrahydrosuccinic group. The oxygen atom (the methyl group of V8 cycloalkane I) is the above-mentioned C3_8 cycloalkyl group or "" means substituted with the following alkyl group. A 038 ring having an oxygen atom in the 5 coat "may have oxygen in the ring Atomyl chrysyl group of cyclopentane: the above-mentioned cycloalkyl group or "earth" means substituted with the following alkyl group. Cs6 ring with oxygen atom in the rabbit. %% alkyl group C-6 alkyl group Represents a substituent, and for this purpose, for example, cyclopropylmethyl, c ^ 6-alkylpropylethyl of CM cycloalkyl, cyclobutylmethyl, cyclobutanedi, cyclopropylethyl, 2- Cyclocyclopentylmethyl, bucyclopentylethyl , ^ Ethyl, 2-cyclobutylethyl, phenyl, cyclohexylethyl, 2-cyclohexylethyl = pentylethyl, cyclohexylmethyl "alkoxy" represents ^% carbon with 1 to 3 carbon atoms For example, a methoxy group, an ethoxy chain, or a branched alkyl group may be mentioned for this purpose, and "alkoxy" means a propoxy group or an isopropoxy group having 1 to 6 carbon atoms, For this purpose, fluorenyloxy, ethoxychain or branched alkoxylactyl, propoxy, isopropoxy,

---------- \ 2D ~ C〇D £ \ 9l · 〇7 \ 91110283.ptd Page 15 1233358

V. Description of the invention (11) is

Butoxy, isobutoxy, second butylfluorenyl, third butoxy, isopentyloxy, neopentyloxy, second pentyloxy, hexyloxy and the like. Pentyloxy and "Chalkoxycarbonyl" represent a carbonyl group substituted with a Ci-6 alkoxy group, and examples thereof include sulfanyl, ethoxyquinyl, propoxyquinyl, isopropoxy, butoxycarbonyl, and isobutyl Oxycarbonyl, second butoxycarbonyl, x-based, pentyloxycarbonyl, hexyloxycarbonyl, and the like. 1 "Cb6 Burning group" means that hydrogen atom 戍 c is not substituted. Examples include fluorenyl, ethenyl, internal, phenyl, and isobutylfluorenyl. The "Jun (c) _6" group "means substituted with Jun ^. Its examples include carboxyfluorenyl and 2-carboxyethyl. The carbonyl group of an oxocarbonyl group is an isopropyl fluorenyl group or a butyl fluorenyl group. To this end, for example, "C 6 alkoxy group (C 6 alkoxy)" represents a substituted alkyl group. Examples include methane carbonyl, η, and oxycarbonyl (^ _6 "aryl" means 1 to 3 rings = carbonyl carbonyl methyl, etc.) Examples include phenyl, naphthyl, and the like. Group 烃 hydrocarbon groups, for this purpose "Substituted aryl" means an aryl group substituted with a group selected from the group consisting of methy, carboxy (Ch alkyl), Cl-6 alkoxycarbonyl (c ^ N6 alkyl, and Cw alkoxy). To this end, ^ 6 and elementary earth, and phenyl, 4-fluorophenyl, 4-chlorophenyl, 2-diphenyl such as 2-fluorophenyl, 3-fluoro3- (2-carboxyethyl) phenyl, etc. By this radical, 2 ~ methoxyphenyl, "unsubstituted or substituted arylmethyl". It means that the aryl group is substituted with "$" or the "aryl" group is substituted. For example, hexyl, benzyl, phenylethyl, phenylethyl, and 3-phenylpropyl

1233358 V. Description of the invention (12) 2-phenylpropyl, 1-phenylpropyl, naphthyl and the like. "Ch alkylene (including fluorenylene)" means a straight or branched divalent saturated hydrocarbon chain having 1 to 6 carbon atoms. For this purpose, for example, -CH2-, -CH2CH2-, CH (CH3 )-, -CH2CH2CH2-, -ch (ch3) ch2-, -ch2ch (ch3)-, -C (CH3) 2-, _CH (CH2CH3)-, _ch2ch2ch2ch2-, -CH2CH2CH2CH2CH2-, and the like. "5- to 7-membered cyclic amine" or "5- to 7-membered cyclic amine group" means a 5- to 7-membered saturated cyclic amine group, and for this purpose, stilbyl, hexahydrostilbyl, etc. . In addition, the cyclic amine group may be substituted with 1 to 2 (6 alkyl groups as required). Such a (6-6 alkyl group may be substituted for a cyclic amino group, for example, 3,3-dimethylpyrrolidine may be mentioned. Group, 3,3-difluorenylhexahydropyridine, etc. In the substituted compound represented by the above-mentioned general formula (I) serving as an active ingredient of the present invention, R1 and R2 are each independently and preferably (^ _3 Alkyl, trisyl, or halogen atoms are further advanced by Ci _3 and * radicals or halogen atoms. Carbo is the most suitable, and fluorenyl is the most suitable. R3 is a hydrogen atom, (: 3 alkyl, or 3 A fluorofluorenyl group is preferred, and a hydrogen atom is most suitable, W is -Q- or-is more preferred, and 10- is most suitable, X is a warp group, Y is preferably a CH alkyl group, and trifluoro Methyl, -S (0) 2R6—, 6-oxy-1,6-dihydro ° 荅. Well-3-ylfluorenyl, or a group represented by the general formula -Q-T, or X and γ together Forms -NH-C = C (R7), which is represented by Ch alkyl, trifluorofluorenyl, 6-oxy-1, 6-dihydron, 3-methyl, or general formula -QT The base is further preferred, and the base represented by the general formula -QT is most suitable,

C. \ 2D-CODE \ 91-07 \ 91110283.ptd Page 17 1233358 V. Description of the invention (13) Here, R6 is more preferably substituted by unsubstituted or substituted square group, and substituted by 4 -Fluorophenyl is most suitable, R? Is preferably a hydrogen atom alkyl group, (V3 alkyl group is more preferable, of which methyl or isopropyl group is more preferable, and methyl group is most suitable, Q is _ ^ 2_ or -CH (OH) _ is preferred, and -CH (OH)-is most suitable. T is preferably unsubstituted or substituted aryl, more preferably substituted aryl, and 4-fluorophenyl is most preferred. Appropriately, Z is preferably a hydrogen atom, A is -NHC0-Y1-C02R8-, -C0NHCH2C02R8 ... or -ch2ch (r9) nh2, and -NHCO-Yi-COJ8- is more preferable. Here, Y1 is Bonding or -CH2- is preferred, and -CH2- is most suitable. The preferred aspect of the compound represented by the above general formula (I) is as follows: R1 and ^ each independently represent a C 3 alkyl group, a trifluoro group Methyl or halogen atom; a is -NHC〇- Y1-C02R8-, -C0NHCH2C02R8-, or -CH2CH (R9) NH2; γι is a bond or -CH2_; R8 is a hydrogen atom, C ^ 6 alkyl, or The aryl Ci 6 alkyl group and R 9 are a carboxyl group or a Cu alkoxy group. ^ The progress of the compound represented by the general formula (I) The preferred § steps are as follows: and R each independently represents a Cu group, a dimethyl group, 4 ·, a, '-a V ^ # — a methyl group, or a halogen atom; X is a blanket group, Υ For (: Bu 6 said, trifluoromethyl,-dihydrotaphen-3-ylmethyl, or Ω1_Τ1 & L lice i, b- to form -NH-C = C (R7)-; R6 It is a non-substituted or non-substituted radical, or X and Y are substituted together for an aryl group, and unsubstituted or substituted Guantian A 'τ is unsubstituted or a C5_6 ring alkyl group, or V / II in the ring may have an oxygen atom in the ring -NHC0-Y] -C02K8- '-CONHCH CO R8', ^ nuclear methyl group; A for H2C〇2R8-, or _CH2CH (R9) nh2; γι is C: \ 2D-OODE \ 9J- 07 \ 9J 110283.ptd

Page 18 1233358 V. Description of the invention (14) '"' " 一 '*-, Jian, Kou, or ch2, R8 is a hydrogen atom, a chloro group, or an aryl c1-6 group; R9 and Wei Or (^ _6 alkoxycarbonyl. ", A still further preferred aspect of the compound represented by the general formula (I) is as follows: R1 and R2 each independently represent an alkyl group or a halogen atom; R3 is a hydrogen atom, W is = 0-; X is a hydroxyl group; Y is a group represented by the general formula -QLT1, qi is ~ ch〇h one, T1 is an unsubstituted or substituted aryl group; Z is a hydrogen atom; A is -NHCOCO γ-; R8 is a hydrogen atom, a Cl ~ 6 alkyl group, or an aryl Ci 6 alkyl group. 2 Another still more preferable aspect of the compound represented by the above general formula (I) is as follows: R1 and R2 each independently represent c3 Group, trisylmethyl, =; χ is a group represented by the formula a Q1-T1 via a group Cl = 6-alkyl, trifluoromethyl, 6-oxyl-methyl-3-ylmethyl; Q1 is a 10-n generation! H: H whose 'T1 is an unsubstituted or substituted aryl group, unsubstituted or fleshy = G = 1 C5_6 cycloalkyl group having an oxygen atom in%, or it —Curtain into 70-yl groups, z is a lice atom or a C 3 alkoxy group, or c \ Α, ς ( ^; A is -NHC0CH2C02R8_; R8 is a hydrogen atom, a dagger, or a square alkoxide. The compound shown by the above general formula (I) is as follows: R1 and R2 are each ☆ __ Guangxi Hanxi's nephew also has a different sad atom 1--0_; x ^ # _ / not Cl-3 alkyl, trifluoromethyl, or QU_, _CH2_, acryl, methyl., Or A group represented by the formula r; group, unsubstituted or substituted arylmethyl, or ^ co ~, T1 is an unsubstituted or substituted aralkyl group, or may have & may have an oxygen atom in J Cs_6 ring-N—-; r8 is hydrogen: the m group of c; “h-6 alkyl, or aryl Ci 6 alkyl.

C: \ 2D-mDE \ 91-07 \ 91110283.ptd Page 19 1233358 V. Description of the invention (20) A c5_6 cycloalkyl group having an oxygen atom in the bad, or may be in a c5_6 cycloalkylfluorenyl group, having in% The oxygen atom Z10 represents a hydrogen atom or a q group]. Flow chart 1 ―3 alkoxy group, or “and” together to form a quaternary group.

(II) Step 1 • -►- HOOC ^ COOR40 (III)

NHCO ^ COOR40 R3〇 (IV) or its reactive functional derivative Step 2 Removal of protecting group) (hydrolysis)

NHCO ^ COOR R30 (I,) (wherein L represents a hydrogen atom or a protecting group for a hydroxyl group, R, R1Q, R2O, R3O, γ10, and z1G are as defined above, R4. Represents Ci 6 alkyl, W2〇 represents -〇-, -S-, CH2-, -CH (0H) ~, or -C0-) Step 1 The compound (II) and 1 to 2 equivalents of the compound (III) In the presence of a condensing agent such as amine, di (3-diamidopropyl) -3-ethanedicarbodiimide hydrochloride, ethyl cyanodilate, diphenylphosphonium azide, etc., in acetonitrile, N, In an inert solvent such as N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like, the reaction is performed at a temperature of 0 ° C to room temperature for 1 to 24 hours, thereby obtaining the compound (IV ).

1233358 V. Description of the invention (21) In addition, the reactive functional derivatives such as halides, mixed anhydrides, and active esters of the compound (II) and 1 to 20 equivalents of the compound (π I) are kept in a solvent-free state. Or in an inert solvent such as tetrahydrofuran, dichloromethane, etc., in the presence or absence of a base such as potassium carbonate, triethylamine, pyridine, etc., and at a temperature generally set between 0 ° C and the reflux temperature By reacting for 20 minutes to 24 hours, compound (IV) can be obtained. Step 2 In the case where the obtained compound (IV) needs to be removed from the protective group of the hydroxyl group, the removal of the protective group can be performed according to the type of the sulfo group and appropriately treated according to the ordinary method. 0 The obtained compound (IV) needs to be oxidized. Occasion ί__ Peroxyacids such as peroxybenzoic acid and peroxyacetic acid are used as oxidants. In the solvent of the two products: and = in the solvent, and usually set (TC ~ to > dish of > The reaction order is 5 ~ 2 4 under the plate degree, and the sulfoxide derivative or the sulfone derivative of this #.], And then, the corresponding compound (IV) obtained in the process can be obtained, which makes the ester group pass In the case of hydrolysis, the corresponding carboxylic acid derivative is required according to the conventional ϋ creature or 飒 derivative. The hydration method can be used to perform the hydrolysis to obtain the formula (I a) shown in the above general formula (丨,) of the present invention. The compounds shown can also be produced according to the following formulas: "", Reaction Scheme 2 shown in Scheme 2 above

1233358 V. Description of the invention (22)

(Removal of Protected Base)

(la) (The formula / is based on 'Heart, at °' 3 °, ", and 2 〖〇 as defined above) Meng: Ϊ i in the inert solvent such as two-gas sintering under the use of dioxide, and in 0 ° c ~ back

The type of the protecting group is as follows: == 72 hours later, if necessary, the compound (la) which depends on the hydroxyl group. Among the compounds represented by), which can be obtained by removing the protecting group by hanging method S, the following general formula is represented by the above general formula (Γ (I b)) according to the reaction shown in the following scheme 3 Compounds can also be produced by:

(L, R, R 'R' R 'π in the formula, and the definitions are the same as above) Compound (VI) is used in a polar solvent such as methanol, acetic acid, etc. using sodium borohydride, sodium triacetoxyborohydride, etc. It is reduced under the reducing agent, and is usually reduced at a temperature of 0 ° C to room temperature for 1 to 48 hours. If necessary, it is appropriately treated according to the type of the protective group of the hydroxyl group according to a conventional method to remove the protective group. Available

1233358 V. Description of the invention (23) to compound (I b). Furthermore, the compound (VI) is in the presence of a catalyst such as palladium on carbon, platinum oxide, etc. in a solvent of tetrahydrofuran, methanol, ethanol, ethyl acetate, etc., and the temperature is usually set from room temperature to reflux temperature The compound (lb) can be obtained by subjecting it to hydrogenation reduction under a pressure of 1 to 5 atmospheres for 1 to 48 hours, and then appropriately treating the protecting group according to the type of the hydroxyl protecting group as necessary to remove the protecting group. Among the compounds represented by the general formula (I ') of the present invention, the compounds represented by the following general formula (I c) can also be produced according to the reaction shown in the following scheme 4:

(W3G in the formula represents a hydroxymethylene group or a carbonyl group, and L, R, R1G, R2G, R3G, Y10, and Z1 have the same definitions as above.) Compound (VII) is used in a solvent such as dichloromethane for three times. Ethylsilane and trifluoroacetic acid or boron trifluoride diethyl ether complex, and the reduction is usually set at a temperature of 0 ° C ~ reflux temperature for 1 ~ 4 8 hours, if necessary, according to the protective group of the hydroxyl group This kind is appropriately treated in a conventional manner to remove a protecting group, whereby a compound (I c) can be obtained.

C: \ 2D-00DE \ 91-07 \ 91110283.ptd Page 28 1233358 V. Description of the invention (24) Furthermore, compound (VII) is dissolved in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, acetic acid, etc. In the presence of a catalyst such as palladium on carbon, etc., and it is exposed to hydrogenation reduction under the pressure of usually set room temperature to reflux temperature and pressure of 5 to 5 air pressure for 1 to 48 hours, if necessary, it is protected by a hydroxyl group. The type of the group is appropriately treated in a conventional manner to remove the protecting group, whereby the compound (Ic) can be obtained. Among the compounds represented by the above general formula (I,) of the present invention, the compounds represented by the following general formula (I d) can also be produced according to the reaction shown in the following scheme 5: ϋϋ5

NHCO ^ COOR R30 Step 2 Removal of Methyl | | Derivation to Carboxylic Acid

(Id) NHCO ^ COOR R30 (where x1G represents a halogen atom or a hydroxyl group, z2G represents a hydrogen atom or (^ 3 alkoxy, R, R1Q, R2Q, R3 °, T1G, and W1G are as defined above) Step 1 The compound (VI II) and 1 to 2 equivalents of the compound (IX) are prepared in a solvent such as dichloromethane in the presence of a Lewis acid such as titanium tetrachloride or a trivalent vermiculite xanthate in a solvent such as dichloromethane and in a conventional setting. The compound (X) can be obtained by carrying out the tritiation reaction according to the Freud-Quarft reaction at a temperature of ° c to room temperature for 3 to 7 2 hours.

C: \ 2D-roDE \ 91-07 \ 91110283.ptd Page 29 1233358 V. Description of the invention (25) Step 2 The obtained compound (X) is tetrachlorinated in a solvent such as dichloromethane, etc. In the presence of Lewis acid, it is treated for 3 to 72 hours at a temperature usually set from room temperature to reflux temperature, or tin tetrachloride and trihalide (such as trichloride) in a solvent such as dichloromethane. Boron, boron tribromide, etc.) and the compound (Id) can be obtained by treating the compound at a temperature of -78 C to the reflux temperature for 1 to 24 hours. In addition, in the case of a compound when r is a lower alkyl group, the ester group can also be converted into a carboxyl group at the same time in the compound represented by the general formula (I ') of the present invention, which is represented by the following general formula (I e) The compounds shown can also be produced according to the reactions shown in Scheme 6 below: Scheme 6

NHCO, / COOR R30 (XI) (removal of acne base)

NHCO ^ COOR R30 (wherein L, R, R 'R2G, R3., T'W2G, and Z2O have the same definitions as above) Compound (XI) is used in polar solvents such as methanol, acetic acid, etc. Reducing agents such as sodium and sodium triethylphosphonium borohydride are reduced below 0 ° C ~ room temperature, which is usually set for 1 ~ 48. After 8 hours, if necessary, follow the type of keto The compound (I e) can be obtained by proper treatment in a conventional manner to remove the protecting group.

C: \ 2D-CODE \ 91-07 \ 91110283.ptd Page 30 1233358

V. Explanation of the invention (26) Furthermore, the compound (XI) is present in the presence of a catalyst (such as palladium carbon, platinum oxide, etc.) in a solvent of tetrahydrofuran, methanol, ethanol, ethyl acetate, etc., and in general The temperature of the set room temperature to the reflux temperature and the pressure of 5 to 5 atmospheres are subjected to hydrogenation reduction for 1 to 48 hours, and if necessary, the protective group is appropriately treated according to the type of the protective group of the hydroxyl group according to a conventional method to remove the protective group. Compound (Ie) is obtained. Among the compounds represented by the general formula (I,) of the present invention, the compounds represented by the following general formula (I f) can also be produced according to the reaction shown in the following scheme 7: Scheme 7

(XIII)

NHCO ^ -COOR R30 (XIV) Step 2 Rearranged v

NHCO ^ COOR R30 (If) (wherein T3G represents an unsubstituted or substituted aryl group, X2G represents a halogen atom, R, R10, R2G, R3G, W1G, and Z20 have the same definitions as above) Step 1 Make compound (XII) and 1 to 1.5 equivalents of the compound (XI11) in a solvent such as acetone, N, n-dimethylformamide, dimethylphosphine, etc., in the presence of a base such as potassium carbonate, carbonic acid, and the like, and The reaction is usually performed at a temperature ranging from room temperature to reflux temperature for 1 to 48 hours, thereby obtaining a compound (x 1V).

C: \ 2D-CODE \ 91-07 \ 91110283.ptd Page 31 1233358 V. Description of the invention (27) Step 2 The obtained compound (X IV) is inert under solvent-free or dichloromethane etc. In the presence of a strong acid such as trifluoroacetic acid in the solvent, the compound (I f) can be obtained by treating the compound at a temperature of from room temperature to reflux temperature for 1 to 48 in order to cause rearrangement. Among the compounds represented by the general formula (I ') of the present invention, the compounds represented by the following general formula (I g) can also be produced according to the reaction shown in the following scheme 8: Scheme 8

(Removal of Hydroxyl) 10-10

NHCO ^ COOR r30 R20 (lg) (wherein Q30 represents a hydroxymethylene group or a carbonyl group, and L, R, R1% R20, R30, Ti〇, W2〇, and Z2G have the same meanings as above.) Compound (XV ) Use diethylsilane and trifluoroacetic acid in solvents such as methane, and reduce it at the temperature of 0 ° c ~ reflux temperature usually set for 1 ~ 48 hours, if necessary, according to the protective group of hydroxyl group This kind is appropriately treated in a conventional manner to remove a protecting group, whereby a compound (I g) can be obtained. Furthermore, the compound (XV) is present in the presence of a catalyst (such as palladium on carbon) in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, acetic acid, etc., and the temperature is usually set from room temperature to reflux temperature. Temperature and pressure of 1 ~ 5 bar

Page 32 1233358 V. Description of the invention (28) After 1 to 48 hours of reduction by contact hydrogenation, if necessary, the protective group is appropriately treated in accordance with the type of the protective group of the hydroxyl group to remove the protective group, thereby obtaining the compound (Ig). Among the compounds of the above-mentioned general formula (Π) in which the above-mentioned manufacturing method is used as a starting material, the compounds of the following general formula (II a) can be produced according to the reaction shown in the following flow chart 9, for example: 9

Peroxoate or hydrofluoride (XVI)

Sm)

(XX) Restore

Step 3V

(Ila) [W4G in the formula represents an oxygen atom or a sulfur atom, and Y3G represents a Cu alkyl group or a 6-chloro-3-daphthyridinyl group or a general formula -Q1G-T1G (where Q1G and T1Q are as defined above) As shown in the base, Y4Q represents a C ^ _6 alkyl group or a 6-pass-3-tower well group or the general formula _Q1G_T1G (where Q1G and T in the formula are as defined above) Group, Z30 and Z4G represent a hydrogen atom or (: a 3 alkoxy group, or Y3G and Y4G combine to form a tetramethylene group, 1 ^, 1 ^, 1 ^ 2 (), 1 ^ 3 (), 乂 2 ( ), Ya 1 (), and 210 are as defined above].

C: \ 2D-CODE \ 91-07 \ 91110283.ptd Page 33 1233358 V. Description of the invention (29) ---- Step 1 Make compound (XVI) and 0.7 ~ 1.5 equivalents of compound (XVII) In the presence of steel, triethylamine, etc., the reaction is performed in an inert solvent such as diazomethane and at a temperature of 0 ° C ~ room temperature, which is usually set for 12 to 72 hours. The compound (XX) can be obtained by treating with acetic acid in the presence of sodium acetate and treating it at a temperature of 0 ° C. to warm for 1 to 5 hours, and then adding water for hydrolysis. Step 2 Make the compound (XV III) and 0.7 to 1.5 equivalents of the compound (XIX) in the presence of a base such as potassium carbonate in the inertness of disulfoxide, diethylacetamide and the like. In the medium, and the reaction is carried out at a temperature of 0 c to reflux temperature set for 3 to 24 hours, if necessary, according to the type of the protective group of the hydroxyl group, it is appropriately treated according to a conventional method to remove the protective group, thereby obtaining a compound. (XX). Step 3 The obtained compound (XX) is in the presence of a catalyst (such as palladium carbon, platinum oxide, etc.) in a solvent such as tetrahydroπfuran, methanol, ethanol, ethyl acetate, etc. The compound (Ila) can be obtained by contacting hydrogenation at a temperature ranging from room temperature to reflux temperature and a pressure of 5 to 5 atmospheres for 1 to 48 hours. Among the compounds of the above general formula (11), in which the above-mentioned production method is used as a starting material, the compounds of the following general formula (lib) can be produced according to the reaction shown in the following flow chart 10, for example: 1 0

C: \ 2D-CODE \ 91-07 \ 91110283.ptd Page 34 1233358 V. Description of the invention (30)

L1 °-0 ^^ r1 ° yyN (r5G) 2 Step 2 L1 ° —

N (R50) 2 f ^ WSiS3. '秘 έι〇 όή 2〇

ZZ10 OH R20 ζ Ο R

(XXIV) Removal of protective group of amine group (removal or introduction of protective group of hydroxyl group)

Z10 OH R20 (lib) (wherein L1Q represents a protecting group for a hydroxyl group, a protecting group for an R5Q amino group, and the definitions of L, R1G, R20, R3G, X2G, Y1G, Y4G, Z1G, and Z4 ° are as above) Steps 1 The compound (XX II) is dissolved in an inert solvent such as tetrahydrofuran, and then reacted with 1 to 1.5 equivalents of an organic lithium such as third butyl lithium at a temperature of -100 to -78 ° C for 20 minutes to 1 hour. Reaction with 0.7 to 1.5 equivalents of compound (XX I) at a temperature of -1 0 0 to room temperature for 30 minutes to 2 hours, if necessary, according to the type of the protective group of the hydroxyl group, it is appropriately treated in accordance with a conventional method to By removing the protecting group, a compound (XXI II) can be obtained. Step 2 Compound (XX IV) is used in polar solvents such as methanol, acetic acid, tetrahydrofuran, etc. under a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, etc., and at 0 ° C to reflux Reduction at the temperature of 1 ~ 4 8 hours

C: \ 2D-mDE \ 91 -07 \ 91110283 .ptd Page 35 1233358 5. In the description of the invention (31), the compound (XXI I I) can be obtained from this. Furthermore, the compound (XXIV) is present in the presence of a catalyst (such as palladium carbon, platinum oxide, etc.) in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, etc., and the room temperature is usually set at room temperature. The compound (XXIII) can be obtained by subjecting it to hydrogenation reduction at a temperature of ~ reflux temperature and a pressure of 1 to 5 atmospheres for 1 to 48 hours. Step 3 Regarding the obtained compound (XX Π I), according to the type of the protecting group of the amine group, it is appropriately treated in accordance with the conventional method to remove the protecting group, and if necessary, according to the type of the protecting group of the hydroxyl group, it is appropriately treated in accordance with the ordinary method to remove the protecting group. In this way, the compound (lib) can be obtained. Among the compounds of the above general formula (11) used in the above-mentioned production method as starting materials, the compounds of the following general formula (Πc) can follow, for example, the following flow chart 11 The response shown is to the maker ...

Soil 10 3 甴 20 ---- ^ OH F (XXIV) Coffee II) Step 3 Removal of protective group of amine group 7 Removal or introduction of protective group of hydroxyl group)

Flow chart U 〇 R20 (lie) _

C: \ 2D-CODE \ 91-O7 \ 9lll0283.ptd Page 36 1233358 V. Description of the invention (32) (where L, L10, R1., R2 °, R30, R5. Χ20 νιη are as above), x , Y1G, Y'z] ◦, and Z4◦ Define step i Dissolve the compound (XXv I) in tetrahydrofluorene M ~ 1.5 equivalents of the third butyl chain and other inert solvents such as 1

, ^-; 〇! R: 80 ° C ^ S ^ T left, ot ~ room temperature; 〇 Who 72 two = the amount of compound, if necessary, according to the type of the protective group of the base press /, 2: 3: Minutes to 2 hours 'Base' This compound can be obtained (XX IV). Step 2 to protect the compound (XXI II) in chloroform enthalpy (4 to aw) oxidizing agent such as manganese permanganate, potassium permanganate, etc. Use a single oxygen ^ ^ ^ 0 t ~: Oxidation at a temperature of 1 to 72 hours. In this way, the compound (XXIV) obtained in step 3 can be treated according to the type of the protective group of the amine group according to the type of ^ 1 s to remove the protective group, and if necessary, appropriately treated according to the type of the protective group of the hydroxyl group according to the ordinary method to remove the protective group. A protecting group can be obtained by this. Among the compounds of the above-mentioned general formula (II) in which the above-mentioned production method is used as a starting material, the compounds of the following general formula (I 丨 d) can be produced according to the reaction shown in the following flow chart 12: Flow chart 1 2

I233358 V. A statement of explanation (33) do.

(XXVII) Removal of protective group of reduced amine group (removal or introduction of protective group of hydroxyl group) L—O.

(lid)

(In the formula, L will be combined with trifluoroethane, and it will be properly treated by conventional methods. Or, ethyl acetate, and the normal type of the base (lid) < Next, the flow chart U, L1G, R'R'R30, R5G, W3O, Y1 (), and Z1G are defined as shown in Figure 13 below. The substance (XXVI I) is in a solvent such as dioxane. Use triethyl oxalate acid, and usually set the temperature of 0 ° C ~ reflux temperature for 1 ~ 48 hours, after the protective group is removed by appropriate method according to the general method of the type of amine protective group, if necessary, Depending on the kind of the protective group of the hydroxyl group, the protective group is removed by treatment, whereby the compound (丨 丨 d) can be obtained. Set compound (XXVII) in the presence of a catalyst (such as palladium carbon, etc.) in a solvent such as tetrahydrofuran, methanol, ethanol, acetic acid, etc., and set the temperature from room temperature to reflux temperature and a pressure of 5 to 5 atmospheres After reduction by hydrogenation for 1 to 48 hours, the type of the protective group according to the amino group is treated to remove the protective group. If necessary, the protective group is treated according to the normal method to remove the protective group if necessary. Thus, the compound can be obtained. ≫ Production method The compound of the general formula (II e) of the compounding surface of the general formula (丨 丨) used as a starting material can be produced according to the reaction shown in the following, for example.

1233358 V. Description of the invention (34) ch3o.

Z20

nhcocf3 Step 1 γΙΟ ^ 20 ^ R30 (XXVI)]). X10

R30 nhcocf3 (IX) Removal of methyl trifluoroacetamidine (introduction of protective group of hydroxyl group) (XXIX) Step 2

(lie) (wherein L, R10, R20, R3G, T1., W20, X10, and Z2G are as defined above) Step 1 Make compound (XX VI II) and 1 to 1.5 equivalents of compound (IX) in four In the presence of a Lewis acid or triflate xanthate, such as gasified titanium, in a solvent such as dichloromethane, and at a temperature generally set between 0 ° c and room temperature in accordance with Freud-Quarfte The halogenation reaction of the reaction is performed for 3 to 7 2 hours, whereby the compound (XXIX) can be obtained. Step 2 The obtained compound (X XIX) is dissolved in a solvent such as two-gas sintering in the presence of Siqi ’s Lewis acid or “Chenqi” and stinky acid-acetic acid in a solvent at a generally set room temperature. It is treated at a temperature of ~ reflux temperature for 3 ~ 7 2 hours, or in a single gas sintering process.> The grain media has four gaseous tin and three _fossils (such as trichlorin, two> stinky fossils, etc.) In the presence and at a temperature generally set to -7 8 to reflux temperature, it is treated for 1 to 24 hours to remove methyl groups, and then to remove the trimethyl ethyl group in the presence of a base according to a conventional method. An appropriate protecting group is introduced into the warp group, whereby the compound (II e) can be obtained. In the compound of the above-mentioned general formula (II) used as the starting material in the above-mentioned manufacturing method, the compound of the general formula (Ilf) below ′ may be as follows:

C: \ 2D-CODE \ 91-07 \ 91110283.ptd 1233358 £, description of invention (35) The reaction shown in Figure 14 is made by the manufacturer: Figure 1 4

(XXX)

nh2 R30 010 (wherein M represents a protecting group of a hydrogen atom or an amine group, L, R10, R2Q, R3G, but 10W20, and Z2G have the same meanings as above), and the compound (XXX) is in methanol, acetic acid, etc. In a polar solvent, a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, and the like is used, and the reduction is performed at a temperature of 0 t to reflux. ~ "After an hour, the compound (II f) can be obtained by appropriately treating the protective group according to the type of the sulfonyl group of the amino group, if necessary, to obtain the compound (II f). Furthermore, the compound (XXX) is dissolved in tetrahydrofuran, methanol, and ethanol. In the presence of a catalyst (such as palladium on carbon, platinum oxide, etc.) in a solvent such as ethyl acetate and the like, and it is subjected to hydrogenation reduction at a temperature generally set from room temperature to reflux temperature and a pressure of 5 to 5 atmospheres. After 1 to 48 hours, if necessary, depending on the type of the amine-based protective group, the protective group may be removed by appropriate treatment in accordance with a conventional method, thereby obtaining the compound (Ilf).丨 丨) The compounds of the following formula (II g) can be produced according to the reactions shown in the following scheme 15:

C: \ 2D-OODE \ 91-O7 \ 91110283.ptd Page 40 1233358 V. Description of the invention (36)

丨 Rearrangement Step 2 Removal of protective group of amine group) Introduction of protective group of hydroxyl group)

(Wherein L, M, R10, R20, R30, T30, w2q, χ2., And Z2 () are as defined above) Step 1 Compound (XXXI) and 1 to 1.5 equivalents of compound (Xu !) In solvents such as acetone, Ν, Ν-dimethymidine, diamidine, etc., in the presence of potassium carbonate, cesium carbonate, etc., and at room temperature to reflux temperature usually set. The reaction is carried out at a temperature of 1 to 48 hours, whereby a compound (XXX ί ί) can be obtained. Step 2 The obtained compound (XXXI I) is in the absence of a solvent or in the presence of a strong acid such as trifluoroacetic acid in an inert solvent of methane and the like, and at a temperature usually set from room temperature to reflux temperature It is treated for 1 to 48 hours, so that after the rearrangement effect occurs, the protective group is appropriately treated according to the type of amine group according to the ordinary method when necessary, and the appropriate protective group is introduced into the basic group according to the ordinary method when necessary. Compound (II g) can be obtained. Among the compounds of the above-mentioned general formula (II) in which the above-mentioned production method is used as a starting material, the compounds of the following general formula (II h) can be produced according to the reaction shown in the following flow chart 16:圚 1 6

C: \ 2D-CODE \ 91-07 \ 91110283.ptd Page 41 1233358 V. Description of the invention (37)

NH-M (Removal of Amine Group) 10 1 10 20 (XXXIII)

(Ilh) (wherein L, M, Q3O, R'R'R'T'W20, and z2O have the same definitions as above) Compound αχχι11) is used in a solvent such as dichloromethane and triethylsilane Under fluoroacetic acid, and after reducing at the temperature of 0 ° C to the reflux temperature usually set for 1 to 48 hours, if necessary, according to the type of the amine-based protective group, it is appropriately treated in accordance with a conventional method to remove the protective group. Compound (Uh) 'is obtained. Furthermore, compound (XXXIII) is present in the presence of a catalyst (such as palladium carbon, etc.) in a solvent of tetrahydrobenzanol, methanol, ethanol, ethyl acetate, acetic acid, etc. And it is usually exposed to hydrogenation and reduction at a temperature ranging from room temperature to reflux temperature and a pressure of 1 to 5 atmospheric pressure for 1 to 48 hours. If necessary, it should be properly treated in accordance with the conventional method to remove it according to the type of amino group containing manganese group. A protecting group can be used to obtain a U character (II h). Among the chemical characters of the above general formula (Π) in which the above-mentioned manufacturing method is used as a starting material, the compounds of the following general formula (Π i) can be obtained according to, for example, The following flow σ course of the reaction shown in Figure 17 to the maker: & Flow chart 17

Removal of NH-M1 from the protective group of Y1G

(Ili) (XXXIV)

1233358 V. Description of the invention (38) (wherein M1 represents a protecting group of an amine group, R6Q represents a halogen atom, L, RIG, R20, W2G, Y1G, and Z1G have the same meanings as above). Compound (XXXIV) is used in a solvent such as dioxane, 1,2-dichloroethane, tetrahydrofuran, etc., and a halogenating agent such as N-fluoro-6- (trifluorofluorenyl) pyrenium-2 -sulfonate is used. The compound (II i) can be obtained by halogenating at room temperature to reflux temperature for 1 to 2 to 4 hours, and then appropriately treating the protective group according to the type of the amino group to remove the protecting group. . Among the compounds of the above general formula (II) used as starting materials in the above manufacturing method, the following compounds of the general formula (II j) can be produced according to the reaction shown in the following flow chart 18: Flow chart 1 8 to Τ- · 0—〇Ｍ〇 < λχχV II) or cyclic alkane which may have an oxygen atom in the ring;

See [where T4G represents an unsubstituted or substituted aryl group, or a cycloalkyl group which may have an oxygen atom in the ring, T5D represents an unsubstituted fluorenyl group, an arylmethyl group, a cycloalkyl group which may have an oxygen atom in the ring, Or a cycloalkanemethyl group having an oxygen atom in the ring, and L, R] D, R2i), R3i), W4D, X2G, and Z2 ° are as defined above].

C: \ 2D-CX) DE \ 91 -07 \ 91110283 .ptd P.43 1233358 V. Description of the invention (39) Compound (XXXV) or (XXXVI) with 5 equivalents of compound (XXXVII) Or (XXXVIII) In an inert gas atmosphere such as argon, in an inert solvent such as tetrahydrofuran, dioxane, etc., in the presence of a base such as potassium third butoxide, sodium hydride, etc., and usually set 〇。 The reaction is carried out at a reflux temperature of 1 to 2 for 4 hours and then in tetrahydrofuran. There are catalysts (such as palladium on carbon, hydrogen button) in the solvents of sodium, methanol, ethanol, ethyl acetate, etc., and the temperature is usually set from room temperature to reflux temperature and \ ~ 5 pressure The compound (II j) can be obtained by subjecting it to hydrogenation reduction under pressure for 1 to 48 hours. Among the compounds of the above general formula (丨 丨) in which the above-mentioned manufacturing method is used as a starting material, the compounds of the following general formula (11 k) can be produced according to the reaction shown in the following flow chart 19: Flowchart 1 9

(Wherein L, R1G, R2G, R3G, T1G, ', and Z2〇 have the same definitions as above) The compound (XXX IX) has a catalyst in a solvent such as tetrahydrofuran, methanol, ethanol, and ethyl acetate ( (Such as palladium on carbon, platinum oxide, etc.), and contact with hydrogenation reduction under the pressure of 1 ~ 5 atmospheric pressure usually set at room temperature to reflux temperature and after 1 ~ 4 8 hours, if necessary The type of the protecting group is appropriately treated in a conventional manner to remove the protecting group, thereby obtaining a compound.

C: \ 2D-CODE \ 91-07 \ 91110283.ptd Page 44 1233358 V. Description of the Invention (40) (Ilk). Among the compounds of the above-mentioned general formula (II) in which the above-mentioned production method is used as a starting material, the compounds of the following general formula (111) can be produced according to the reaction shown in the following flow chart 20: 2 0

(Wherein L, Q30, R10, R20, R30, T1% W40, and Z20 are as defined above) Here, the compound (XL) is dissolved in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, acetic acid, etc. In the presence of a catalyst (such as palladium on carbon, etc.), and subjected to hydrogenation reduction for 1 to 48 hours at a temperature usually set from room temperature to reflux temperature and a pressure of 1 to 5 atmospheres, thereby obtaining a compound ( I 11). Among the compounds of the above-mentioned general formula (XX) used in the above-mentioned production method, the following compounds of the general formula (XXa) can be produced according to the reaction shown in the following flow chart 21: Flow chart 2 1

C: \ 2D-C0DE \ 91-07 \ 911I0283.ptd Page 45 1233358 V. Description of the invention (41) (where R1Q, R2G, R 'T1% W4G, X1◦ and Z2G are as defined above) Make the compound (XL I) and 1 to 1.5 equivalents of the compound (IX) in the presence of a Lewis acid or trifluorosulfonic anhydride of titanium tetraoxide, etc. in a solvent of digas methane, etc. Compound (XXa) can be obtained by carrying out the tritiation reaction according to the Friede-Crafts reaction at a temperature of 0 ° C to room temperature for 3 to 7 2 hours. Among the compounds of the above general formula (XX) used in the above manufacturing method, the following compounds of the general formula (XXb) can be produced according to the reaction shown in the following scheme 22: Scheme 2 2

(Wherein L, R10, R2., R3., Γ °, W4G, and Z2G have the same definitions as above) Compound (XXX IX) is used in a polar solvent such as methanol, acetic acid, etc. using sodium borohydride and triethylphosphonium oxide The compound (XXb) can be obtained by reducing it under a reducing agent such as sodium borohydride and at a temperature generally set to 0 ° C to room temperature for 1 to 48 hours. Among the compounds of the above general formula (XX) used in the above manufacturing method, the following compounds of the general formula (XXc) can be produced according to the reaction shown in the following scheme 23:

C: \ 2D-roDE \ 91-07 \ 91110283.ptd Page 46 1233358 V. Description of the invention (42)

W40 '

N〇2 Step 1 R30 20 (XLII) j30 αΐ] ΐ) x20 τ-30

, 20

ν〇2 R30 (XL11I) rearrangement (introduction of protected group) Step 2

T30 Z, 20 > 1〇 W40

n〇2 R30 (XXc) (wherein L, R1G, R20, R30, but 30, boundary 40, χ20, and Z2. The definition is as above) Step 1 Compound (XLI I) and 1 ~ 1 · 5 Equivalent compounds (χι 丨 丨) in solvents such as acetone, N, N-dimethylformamide, dimethylsulfoxide, etc., in the presence of potassium carbonate, carbonic acid, etc. The reaction is carried out at a temperature ranging from room temperature to reflux temperature for 1 to 48 hours, whereby a compound (XL 丨 丨 I) can be obtained. Step 2 The obtained compound (XL III) is in the absence of a solvent or in the presence of a strong acid such as difluoroacetic acid in an inert solvent of methane and the like, and at a temperature usually set from room temperature to reflux temperature The compound (XXc) can be obtained by subjecting it to treatment for 1 to 48 hours so that after a rearrangement effect occurs, an appropriate protecting group is introduced into a hydroxyl group by a conventional method as necessary. Among the compounds of the above general formula (χχ) used in the above manufacturing method, the compounds of the following general formula (X X d) can be produced according to the reaction shown in the following scheme 24:

C: \ 2D-O0DE \ 91-07 \ 91110283.ptd Page 47 1233358 V. Description of the invention (43)

(XL) (XXd) (wherein L, Q3., R1., R'R3., T1G, W4G, and Z2G are as defined above) Compound (XL) is used in a solvent such as dioxane The compound (xxd) can be obtained by reducing under ethanesilane and trifluoroacetic acid at a temperature generally set to 0 ° c to reflux temperature for 1 to 48 hours. The compound represented by the above general formula (X V I) can be produced by a conventional method. For example make the formula (XL IV)

(XL IV) (L, Y4 (), and Z3G in the formula have the same definitions as above) After the phenol derivative and tris (trifluoroacetamidine) are packed and condensed, this is treated with peroxyacid or hydrofluoric acid. Treatment can produce compounds of general formula (XVI). The compound represented by the general formula (XV I I I) can be produced by a conventional method. For example, the compound represented by the above general formula (XXI) is oxidized under conditions of Baeyer-Villiger using peroxyacids such as m-gas peroxybenzoic acid, etc., and the resulting formate is hydrolyzed and compared if necessary. MSNewman et al. (J. Org · Chem ·, Vol. 31, pp 3 9 8 0-3 9 8 4 (1 9 6 6)) ) Of compounds. According to the formula (XXI)

C: \ 2D-CODE \ 91-07 \ 91110283.ptd Page 48 1233358

V. Description of the invention (44) For example, the general formula (XLV) L10-0 γ40

(XLV) (wherein, the definitions of Υ4 «, and Z4Q are as described above), the Benpan derivative is dreamed of by using the method of monokidronyl bond and tetrakisdification to make the above general formula (XIX The compound shown in) can be produced according to a conventional method < For example, when W3 in the above general formula (XV II) is an oxygen atom ^ Do not react with trifluoromethanesulfonic anhydride for esterification, after N-methyl is slightly < 1 the same, dimethyl In an inert solvent such as formamidine, a compound of the general formula (XIX) can be produced by hot stirring in the presence of lithium. Furthermore, the compound represented by the general formula σ (XVI I) is, for example, a compound of general formula (XLVI)

(XLV1) (The definitions of R1G, R2G, R3G, and W4G in the formula are as described above.) The stupid or thiophenol derivatives shown in the formula use acetic acid-nitric acid, trifluoroacetic acid-sodium nitrite, or Nitrate under a nitrating agent such as fluoroboric acid, etc., and compare the method of MS · Newman, etc. (J · Org · Chem ·, ν〇 ^^ ρρ · 3980-3984 (1966)) with a nitro derivative if necessary. Transformed into a sulphur-derived derivative, thereby making it. The compound represented by the above general formula (XX I I) can be compared with conventional methods.

1233358

V. Description of Invention (45) Manufacture. For example, the compound represented by the above general formula (XIX) is reduced in a solvent such as acetic acid, ethyl acetate, tetrahydrofuran, ethanol, product emulsification, or deduction— # The catalyst is reduced by the contact hydrogenation method. Inversely, the compound of the general formula (XX 丨 丨) can be produced by t _ around the amine group. The compound represented by the general formula (XXXV) can be as shown by butan (χχχνυ) The compounds are compounded in methanol, acetic acid, etc. in the above 4 compounds such as tetrahydrogen, dimethyl methane, etc. :: So: the alcoholized benzene, etc., are converted to triphenylphosphine in a solvent based on the compound The reaction can produce the target A. A protective group such as a hydroxyl group or an amine group is used above: " Protective Groups in 〇rganic square H, for example, in

〇ynthesis TW

Greene et al., Wi ley (1 999) have some respects, +, and. · Conditions are appropriately selected and used. The compound obtained by the above-mentioned production method can be isolated and purified separately according to the reaction. / Hemedia Shitofa Temple) The compound represented by the above general formula (1) serving as an active ingredient of the present invention can be made into a pharmacologically acceptable extract according to a common method, = compound and inorganic acid (such as hydrochloric acid, hydrogen Acid, hydroiodic acid, sulfur ^ Tian Yan, ^ from this compound and organic acids ΛΛΛ methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, succinic acid, succinic acid, tartaric acid, reaction Butenedioic acid, butyric acid, oxalic acid, malonic acid, succinic acid, lactic acid, M fruit acid, carbonic acid, _ day

1233358

As an example of excipients, the addition salt formed by dianfan, corn dianfan, crystalline silicon dioxide, phosphoric acid, aspartic acid, etc., is formed by the chemical compounds such as sodium salt, potassium salt, wading salt, etc. The sigma-substance formed by the chemical compound δ and inorganic basic acid, lysine, tyramine, etc. and organic base (such as the above-mentioned generalized salt serving as the active ingredient of the present invention. Including the hydrate of the compound, and The solvent formed by the compounding solvent (such as ethanol, etc.) shown by the χ ^ = substance and medicine $ In the case where the above-mentioned one serving as the active ingredient of the present invention contains an asymmetric carbon atom, the compound shown in 1) The compound of s, and its mixture are two or two as shown in the above general formula (1), which also includes the active ingredient of R, and in the case of filling, the compound also includes cis: Examples of pseudonyms for preventing or re-arranging liver cancer of the present invention include, for example, powders and granules: each. It refers to oral preparations (oral preparations) such as keycaps and two capsules, or non-oral preparations such as body preparations, sitting preparations, and patches. Wang Shecha, these pharmaceutical composition systems can be based on their agents, binding agents, disintegrating agents, solvents 1 to 2 = flocculants, tinctures, agents, buffers, painless agents, antiseptics, etc. After adding pharmaceutical additives, they can be prepared in accordance with the adjustments in the field. Examples include organic excipients such as lactose, sugar, D-mannose-like cellulose, and inorganic excipients such as sodium carbonate and calcium carbonate. The ammonium salt glutamate also includes the compounds in the allowable compounds. What is different in the hair? Treatment: M agent moxibustion agent, ointment 1, slip agent, hanging green flavor correction method, sugar alcohol, and Examples of light smoothing agents 1233358 5. Description of the invention (47) include stearic acid, magnesium stearate, sodium stearate, talc, sodium lauryl sulfate, magnesium lauryl sulfate, silicon dioxide, and the like. Examples of the binding agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, gum arabic, gelatin and the like. Examples of the disintegrating agent include the following: internal cross-linked carboxymethyl cellulose (Croscarmellose Sodium), sodium starch starch, corn starch, crotonidone and the like. Examples of the solvent include water for injection, alcohols (e.g., ethanol, propanol, isopropanol, 1,2-propanediol, etc.), polyethylene glycol, sesame oil, corn oil, olive oil, and castor oil. Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, ethanol'triethanolamine, sodium carbonate, and sodium citrate. Examples of suspending agents include interfaces such as lauryl sulfate, sodium, laurylamine propionic acid, stearyl triethanolamine, vaporized alkyl dimethyl benzylamine, and vaporized benzethonium chloride. Active agents, and hydrophilic polymers (such as polyvinyl alcohol, polyvinyl pyrrolidine = m cellulose nano, methyl cellulose, η-based cellulose, ethyl cellulose, propyl cellulose, etc.). : Examples of chemical agents include glucose 'sodium gluconate, glycerol, D-mannitol and the like. For buffering agents: (such as phosphates, acetates, and carbonic acid, examples of salt-containing analgesics are given, such as ^ alcohol, etc. = liquid. Is etc. # 本 ethanol, dehydrated acetic acid, sorbic acid

Examples of flavor correctors include sodium sulfenimidine

1233358 V. Description of the invention (48) Winter; sweeteners such as benzyl alanine, stevioside (Stevi0side), such as tartrazine, tartaric acid, malic acid, etc., and acidifiers such as lemon, lime (11 me ), Orange, menthol, etc. The agent is prepared by adding an appropriate excipient to the active ingredient as needed, and fully mixing it at Tsuzawa Betsuji.剜 ingot II ί 2 active ingredients are added with appropriate excipients as needed, collapse ί, 2: II ::, smoothing agent, etc., and then prepared by compression molding. When this coating is appropriately applied according to the need, the π + 杳 house Γ can be used to make leather red, sugar-coated tablets, enteric-coated tablets, and the like. 1i f Add effective excipients and smoothness to the effective ingredients / knives as required. After mixing thoroughly, or after forming granules or fine granules according to the conventional method, fill in appropriate capsules and prepare. 4 The medical composition of Yue Yue is used in the actual treatment. It has: "The compound represented by the general formula ⑴ or its pharmacologically acceptable). The administration 1 is based on the age of the patient. And, iti A i-Tu 14 other 'weight' diseases and treatments in the case of oral administration, adults in the range of ~ 101, and in the case of non-oral administration, adults give daily Within the amount, it can be divided into several times or divided into several times! :: In the range of °, 1 ... 3〇-, the compound shown in the above general formula 或 or t is selected from interferon α, ΝΙΚ-333, and 3: a medicine that can be combined with at least one substance of the next two de-acid acids "as given by the following administrators: make the test medicine Xigu ^ ^ ^ " Λ #). ^ Binding agent , Slip agent, dilute page 53C: \ 2D- (DDE \ 91 -07 \ 91110283a .ptd 1233358 V. Description of the invention (49) Release agents, buffers, isotonic agents, powders, stabilizers, Dissolution adjuvants such as human agents, emulsifiers, oral administration or parenteral administration. At this time: the first combination of pharmaceutical composition can be used in the preparation Borrow; ^ The field of preparation is also possible. The same object is given the time of the flying object (μ…, w ㈣, w ㈣: the second choice of bile? _ Prime medicine, the formulation of medicine It can be selected according to the age of the disease and the combination of shells, the symptoms, the time of administration, the shape of the medicine, the type of treatment, and the body. It can be appropriately selected. The combination of French and Chinese medicines is particularly suitable for the pharmaceutical composition of the present invention. Used for liver cancer risk diseases (for example, type B or ^ person j can be treated with radical hepatitis (hepatectomy, left cutaneous B% injection therapy, hepatic artery embolization therapy, treatment, etc.) and liver cancer Patients with recurrence of danger. Skin-type wave coagulation [Best embodiment of the invention] The following reference examples, examples, and test examples are used to further "content of the invention", but the present invention is not subject to the "ping Refined test example 1 Receptor binding test Recombinant human gonadotropin receptive cells or spots that have been expressed in insect cells (Miyamoto T et al., J Biol Chem, 272 (12) 7752_8 «

1233358 V. Description of the invention (50) (199 9)) In the buffer solution of 0.4M KC1, ImM MgCl2, 10mM Tris-HC1, ImM dithiothreitol (pH8 · 0) and L-3, 5, 3,-[1251] -Triiodothyronine (made from [1251] -T3, 0.95 nM, 160Ci / mmol, NEN radioisotope is diluted by Sigma T3) and the drug with the specified concentration are used in glass test tubes. 5mL / tube is kept in an ice bath for 16-48 hours. After the incubation was completed, an ion exchange resin (n Muromachi Chemical M Corporation, Dowex 1-X8, 80 mg / mL) suspended in the above-mentioned buffer solution was added to 0.5 ml L / 1 ube to stir the test tube. After the resin was precipitated, it was also repeatedly stirred twice, using a centrifugal separator (KUBOTA, 8800) cooled to 1 ° C, and centrifuged at 1,000 rpm for 5 minutes. The supernatant 0.5 m 1 was transferred into different test tubes, and the radioactivity in the supernatant was measured with a 7 counter to determine the amount of T 3 bound to the receptor. In addition, regarding the amount of the recombinant recombinant gonadotropin receptor used in this binding experiment, in the above-mentioned experimental system, a dose-response curve of the amount of the receptor added was prepared in advance, and the T3 binding amount was used to form the amount of the receptor added. Properly counted dosages can be obtained within a proportional range. Regarding the Kd value of T3, the concentration of [125I] -T3 was changed to measure the binding amount, and a Scatchord-type drawing was performed according to a conventional method, and the Kd value of T3 was calculated based thereon. The K i value of T 3 according to this law is respectively 0.268 η and 0. 304 η for α and the called recipient. Regarding the calculation of the K i value, the K i value was calculated from the I Csq value of each drug according to the following calculation formula, and the results are shown in Table 1 below.

Ki (nM) = [IC50] / (l + Kd / 0. 95) (Table 1)

C: \ 2D-C0DE \ 91-07 \ 91110283a.ptd Page 55 1233358 V. Description of the invention (51) Compound number K i 値 (ηΜ) for β receptors K i 値 (ηΜ) for α receptors 39 0.69 20.41 Hepatic glutathione content, hepatic estrogen acid transferase expression level, and changes in T4 concentration in blood were evaluated using F3 44 / N (n Japan LSC '· Company) 9-week-old male mice. The drug was administered once a day for 2 consecutive days. The drug was dissolved in 0 1 M NaCl, 0.01 M NaOH, and 40% ethanol, and was administered subcutaneously at 30 nmol / kg and 1 ml / kg, and a control group was administered with a vehicle. On the second day after the administration on the second day, blood was collected from the lower abdominal aorta whole blood under ether anesthesia, and the centrifugation of the serum was performed after the coagulation. 3,5,3,5 -tetra moth-L- Transcriptine (T4) is an indicator of systemic effects, and was measured using a commercially available set of radioimmunoassay instruments (π Rongyan Chemical Co., Ltd., I-AC 1 6). For the determination of glutathione (GSH) contained in the liver, 20 times the weight of 5% metaphosphoric acid (m / v) was added to 0.2 to 0.5 g of rat liver, and a homogenizer made of Teflon was used. After homogenization, quantification was carried out using a manual attached to the market under a commercially available kit for evaluation of glutathione (`` Karubiokemu · ', Cat. No. 354102). 'The expression level of estrogen acid transferase (EST) in the liver is under the expression level of EST-encoded mRNA as an indicator, as described below. Take 50 ~ 100mg of mouse liver, imL, Isogen "( (Registered trademark) ("N i pp〇nj ean" company) n Omn imi xerπ (registered trademark) (n Yamato Scientific Corporation, # η) to homogenize. To this is added a gas imitation

1233358 V. Description of the invention (52) After 0.1 mL, shake vigorously for 15 seconds, and let it stand at room temperature for 5 minutes, then centrifuge at 12 ° C for 15 minutes at 4 ° C. Separate the supernatant separately and add isopropyl alcohol (0.5 mL), let it stand at room temperature for 5 to 10 minutes, and then centrifuge at 120 ° C for 10 minutes at 12 ° C. Remove the supernatant, add 70% ethanol 1! ^ To the sediment, stir and press 75 0 (^ 2,4. (: Centrifugal separation at temperature for 5 minutes. Shen Dianwu was air-dried and dissolved in tr 丨s Ethylene diamine tetraacetic acid buffer solution (ρΗ8 · 0) 0 · 5mL as the total RNA solution. Measure the absorbance of the RNA solution (26 0 and 280 nm). Each sample uses RNA 100ng for reverse transcription reaction. -Polymerase chain reaction (rt-PCR) reaction. RT-PCR reaction is under the use of a commercially available set of GeneAmp1 '(registered trademark) RT-PCR instrument (Perkin-Elmer), except for the special description Otherwise, all were performed according to the contents of the attached manual. For RT reactions, random hexamers attached to the instrument were used as primers. Furthermore, 5, -GGATATCCGAAGAGAAGAGGTGTGAAGC-3, and 5 'were used in the PCR reaction. -TCAGAGCTCTGCTCTAAATTTCACAGG-3 'primer to expand the end of 295 base to DNA. Using 1.2% neutral agar gel to swim the PCR reaction product, and lend the amplified specific band to an imaging solution ( "Fluoro-SMultilmager" (registered trademark), Bio -Rad company) analyzed it as an indicator of the relative amount of mRNA encoding estrogen mineral acid transferase contained in total RNA. These results are shown in Table 2. (Table 2) GSH content in liver, liver EST code Changes in mRNA expression and T4 in blood

\\ 312 \ 2d-code \ 91-07 \ 91110283a.ptd Page 57 1233358 V. Description of the invention (53) Group GSH (nmol / g) EST (optional unit) Ding in blood 4 Ug / dL) Control group 6966 2222 1213 土 108 3.84 土 0.25 Compound 69 5650] 46 * 788 土] 35 * 2.41 0 · 14 ** Compound 70 5324 土 178 * 520 ± 28P 2.29 土 0 · 20 ** Compound 77 5869 土 156 * 505 Soil 8〇u 2.56 Soil 0.11M Compound 78 4957 Soil 143 " 460 Soil 39 ** 2 · 03 ± 0 · 08 ** Compound 79 629] Soil 275 510 ± 7 3.26 ± 0 · Π * D 3 5853 ± 2〇7 * 684 ± 133 * 0.67 ± 0.03 ^ Values: mean ± standard deviation *, **, and ***: P < 0 · 05,0 · 01, and 0.001 vs control group (Student (William Sealy Gosset pen name, The same applies hereinafter) t test)

In this way, the compounds of the present invention significantly reduce the GSH content in the liver and the expression of liver EST, and have a very slight effect on T4 (an indicator of systemic effects) in the blood, showing a liver-selective effect. Test Example 3 Inhibition of cell proliferation in vitro (in vitro) was treated as human liver cancer cells Hep G 2 cells ("|, 4-工 ^ I Dainippon Pharmaceutical Co., Ltd.) in a 24-well test plate at 104 cells / well Sowing and cultivating DMEM with + _, 10% FCS. For 1 in the presence of fun: with Sumiferon300 (registered commercial rod), " the test compound and interferon α to The medium was used afterwards. Dilute ^ ^ + 9 at intervals of 213 '(Sumitomo Pharmaceutical " company's product), and replace the contents with 4 liters, and continue to cultivate for 12 days. + ^ 3 Fruit culture. Remove the supernatant at the end of the culture.

\\ 312 \ 2d-code \ 91-07 \ 91110283a.ptd Page 58 1233358 V. Description of the invention ---- Use for nutrition-ice-cold Dulbecco phosphate buffer solution (PBS) O. 5mL After washing once, add pancreas Protease to detach cells from the test plate and perform Trypan

Blue staining to determine the number of viable cells. The measurement results are shown in Table 3. (table 3)

HePG2 cell proliferation inhibitory group viable cell number ~ cell / hole) control group + 76 compound 70 10 / iM 8+]. 54 ... IFN 100 IU / mL + 64 ... IFN 1000 IU / mL + 13 ^ IFN] 0000 IU / mL 28… Compound 70 10 / iM + IFN 100 IU / mL Compound 70 10 mM + IFN] 000 IU / mL 02…, # Compound 70] 0; uM + IFN 10000 IU / mL 5.6 + 0 44 * "# Value: Mean ± SD ** and ***: P < 0.01 and 001 vs. Control group #: No P < 0.01 vs Compound 70 Test Example 4 Use in rat liver tumor suppression test Fischer F 3 4 4 male rats were given diethylnitrosamine (DEN, 150 mg / kg) in a single intraperitoneal administration at 7 weeks of age. Starting at 9 weeks of age, 2-acetamidine (2-AAF, 7.5 mg / kg) was given orally over 2 weeks, and at 2__AFF

\\ 312 \ 2d-code \ 91-07 \ 91110283a.ptd Page 59 1233358

V. Description of the invention At the age of 10 weeks during (55), 2/3 partial hepatectomy is performed on this: ulcer. This% male rats were divided into test drug-administered groups and seduced I liver tumors in accordance with the test group (long r 隹 / ugly: ^, ，), and the test drugs were suspended in 0.5% carboxyfluorene-based fibers | and / Group) Those who become 40, 100, and 25 // g / kg of each dosage can start to orally administer the test drug to the group for 3 weeks. In the same manner as in the case of ^ week-old m ^^^^, a 0.5% carboxymethyl cellulose aqueous solution was administered to the control group. a On the administration start date and administration of the test drug administration group and the control group: Heavy: And the first 2 days and the end of the administration of the drug will be measured before it! The compound of the present invention

The results obtained are shown in Tables 4 and 5 below. They have no effect on body weight, but increase the amount of bait released (Table 4) Weight group given on the first day of weight ig) Weight given on the last day (g) Control group 260.4 soil] 2.2 273.4 soil] 3.] Compound 70 40 40 pg / kg 259.4 ± 12.2 282 · 8 ± 15 · 0 Compound 70 100 pg / kg 260.1 Soil] 〇. 〇284.5 Soil]]. 7 Compound 70 250 pg / kg 259.8 soil] 0.4 284.3 soil] 1.7 Value: Mean ± SD (Table 5) Feed intake

1233358 Group bait ingestion on the 2nd day of administration (g) Food intake on the last day (g) Control group 15. 6 Soil I · 4 15.6 ±]. 7 Compound 70 40 pg / kg 14.8 ± 1.2 ^ .4 + 1.51 Compound 70] 〇〇pg / kg] 5.7 ± 1.0] 7.5 ± ι · 〇 * Compound 70 250 pg / kg 16. 0 ± 1.4 17.5 ± 1.] »5. Description of the invention (56) Values · Mean ± standard deviation * P < 0.05 On the next day after the final administration, all rats were necropsied and the liver was fixed with bufalin buffered acid. Based on this liver, the anti-placental glutathione S-transferase (GSTP) antibody (Nab Medical Institute "company (Kabushikikaisha) Igakuseibutugakukenkyusho)) was used to prepare immunohistochemically stained sections. About these sections, the area ratio of GSTP-positive mutant nests was calculated according to the following formula (full-automatic image analysis device "LUZEX3", Nikon Corporation). The results are shown in Table 6. Number of GSTP-positive mutation nests (GS / cm2) = -------- Area ratio of GSTP-positive mutation nests (%) Total area of liver Total area of GSTP-positive mutation nests Total area of liver ( Table 6) Number of GSTP-positive mutant nests and area ratio of GSTP-positive mutant nests

C: \ 2D-OODE \ 91-07 \ 91]] 〇283a.ptd Page 61 1233358 V. Description of the invention (57) Group and dosage GSTP-positive mutant nest number (pieces / cm2) Area ratio of GSTP-positive mutant nest ( %) Control group 59.4 ±] 〇 · 4 62.] ± ΐ] · ι Compound 70 40 / zg / Kg 47 · 2 ± 3 ·] 40.7 ± 8.9 ** Compound 70】 〇〇 // g / Kg 34 · 3 ± 3 · 5 ** 37.2 ± ΙΙ · 3 “Compound 70 250m g / Kg 32.9 ± 3.9 ** 3] · 6 ± 7 · 7 ** Value: Mean ± standard deviation: ρ < 0 · 0 1 person In this way, the compound of the present invention significantly reduces the number of nests and the area ratio of the mutant nests exhibited by the existing GSTP (the standard enzymes of cancer or precancerous lesions). Those who no longer 'collect blood from the abdominal aorta at the time of autopsy, A 7 丨 50 type automatic analysis device (Yi Li Manufacturing Co., Ltd.) was used to determine the amount of alanine aminotransferase (ALT) i, alkaline phosphatase (ALp), lactate dehydrogenase (ldh) in plasma, And the amount of T-glutamine transferase (GGT). The measurement results are shown in Table 7. (Table 7) 'Group ALT (U / l) ALP (U / l) LDH (U / l) GGT (IU / l ) Control group 107.75 ± 28.50 1126.88 ± 99.49 943. 13 342.22 43. 50 ± 12.27 Compound 70 250 pg / kg 102.50 ± 16.45 1163.38 soil 83 · 20 596.50 soil 284.93 > 15.75 ± 5.09m *: ρ < 0.05, ***: ρ < 〇 · 〇〇1, so the compound of the present invention makes LDH, And GGT (marker enzymes increased in blood under cancer or precancerous conditions) were significantly reduced, and did not affect ALT and ALP. 1233358 V. Description of the invention (58) So 'the compound of the present invention has a significant effect on body weight, food intake, and liver There was no adverse effect on the function, and it showed a significant inhibitory effect on liver tumors. Test Example 5 Cardiotoxicity was administered to 6-week-old normal Wistar male rats, and the drugs (test compound and T 3) were administered orally once a day. 14 days after administration, and the next day after the final administration, the whole blood was collected under B-scale anesthesia, and the heart was cut out to determine the weight. The drug was suspended or dissolved in 5% ethanol and 0.5% carboxysulfamidine. After basal cellulose (CMC) was administered at 5 mL / kg, the control group was administered with a vehicle. The measurement results are shown in Table 8. (Table 8) Heart weight group and dose (nmo 1 / kg) Heart weight (% by weight) ;) Compound 70 0 0.307 Soil 0.008 Compound 70 5 0.310 Soil 0.008 Compound 70 15 0.321 Soil 0.014 Product 70 50 0.333 soil 0.012 compound 70 150 0.334 soil 0 · 0] 0 compound 70 500 0.316 soil 0.017 d3 0 0.322 soil 0.011 d3 10 0.314 soil 0.012 d3 30 0.338 soil 0.008 d3 100 0.369 soil o.oor d3 300 0.425 ± 0.007 Value: Mean ± SD ** and *** · ρ < 〇 · 〇1 and (K001VS control group (Student's t test)

C: \ 2D-CODE \ 91-07 \ 91110283a.ptd Page 63 1233358

V. Explanation of the invention (59) Thus, T3 shows an increase in the weight of the heart depending on the amount of use starting from 100 nmol / kg. In contrast, the compound of the present invention has a very slight effect on the heart. Test Example 6: Winning toxicity test: Five male ICR rats at 6 weeks of age were orally administered with a test drug dissolved in 0.5% dimethylcellulose and 5 ° / ◦ ethanol. After 3 hours of administration, observe whether any deaths have occurred. The obtained results are shown in Table 9 below.

No deaths were observed at the dosage of 100 mg / kg, showing extremely high safety. (Table 9) Compound No. Dosage (mg / kg) Death Example 7 0 10 0 0/5 Reference Example 1 1-Narrow oxygen-2-cumene 21.8 g of 2-isopropylphenol was dissolved in acetonitrile 1001 ^ To this, 18.8 mL of α-bromotoluene and 27 g of potassium carbonate were added, and the mixture was heated under reflux for 29 hours. The backmix was concentrated under reduced pressure ', and the resulting residue was added with water and extracted with ethyl acetate. The organic layer was sequentially washed with an aqueous solution of sodium hydroxide, water, and saturated brine, and then dehydrated and dried with anhydrous magnesium sulfate, and then concentrated to obtain 357 g of buprofen cumene.

1233358 V. Description of the invention (60) 'H-NMR (CD C 1 3) δ ppm: 1.24 (6H, d, J = 6.9Hz), 3.42 (1H, seven-line, J = 6.9Hz), 5.08 (2H, s), 6.88_6.97 (2H, m), 7. 12-7.17 (1H, m), 7. 22-7.25 (1H, m), 7.30-7.47 (5H, m) Reference example 2 1 The same method was used to synthesize the following compounds. 2,6 -Diyeoxyacetophenone'H-NMR (CDC.1 3) δ p pm: 2.50 (3H, s), 5.09 (4H, s), 6.60 (2H, d, J = 8.4Hz), 7.19 (1H, t, J = 8.4Hz), 7.23-7.45 (10H, m) 1-benzyloxy-5, 6, 7, 8-tetrahydronaphthalene'H-NMR (CDC 1 3) δ p pm: 1 68-1. 90 (4H, m), 2.60-2.90 (4H, m), 5.06 (2H, s), 6.65-6.78 (2H, m), 6.98-7.12 (1H, m), 7.22-7.53 ( 5H, m) Reference Example 3 2, 3, 6-trigas-4-stone benzene, 2.58 g of 3. 3, 6-triphenol was suspended in 15 mL of trifluoroacetic acid, and sodium nitrite was added to this 4 0 2g, stirred overnight at room temperature. The reaction mixture was added to a mixed solution of 100 mL of ice water and 100 mL of dioxane, and the mixture was stirred at room temperature for 2 hours. The organic layer was separated and the aqueous layer was extracted with dioxane. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was crystallized by ethyl acetate and hexane to obtain 2, 3, 6-trigas-4-nitrophenol 3.28 g. ] H — NMR (CDC 1 3) δ ppm: 6.47 (1H, s), 8.01 (1H, s) Reference Example 4

Page 65 C: \ 2D-C0DE \ 91-07 \ 91110283a.ptd 1233358 ------------ 5. Description of the invention (61) The following compounds were achieved in the same manner as in Reference Example 3. Of synthesis. 2,3,6-trimethyl-4-nitrobenzene 3H-NMR (CDC 1 3) δ p pm: 2.24 (3H, s), 2. 27 (3h s) 2.42 (3 H, s), 5. 13 ( 1H, s), 7.61 (1H, s) '' Reference Example 5 4-Block-3,5 -Dimethylstilbene makes difluorometsalic acid 2,6-dimethyl-4 -stilbene g5 g was dissolved in 30 mL of N, N-methylacetamide, lithium Iodide I2.3 g was added thereto, and the mixture was stirred under an argon atmosphere at a temperature of 150 t for 3.5 hours. The reaction mixture was diluted with water 'and extracted with ethyl acetate. The organic layer was washed with water, saturated food, and f in order, and then treated with activated carbon. The dried stomach was dehydrated with anhydrous magnesium sulfate, and then concentrated under reduced pressure. Hexane was added to the obtained residue to crystallize it, and 4-moth-3,5-dipyridine n-benzene 5.21 was avoided. —NMR (CDC 1 3) δ p pm: 2.58 (6H, s), 7.89 (2H, s) Reference Example 6 4-iodo-3, 5-xylylamine, and 4-aid-3, 5 -difluorene 4.58 g of n-benzene was dissolved in ethyl acetate 1 ′. To this was added 458 mg of platinum (IV) oxide, and the mixture was stirred at room temperature under a hydrogen atmosphere at normal pressure for 3 hours. 06g。 Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure 'to give 4-iodo-3,5-xylylamine 4.06g. 3H-NMR (CDC 1 3) δ ppm: 2.37 (6H, s), 3.55 (2H, brs), 6.46 (2H, s) Reference Example 7

1233358 V. Description of the invention (62) 3-M-phenylenepropionate hydrazone S is intended to dissolve 8.7 g of 3-methylbenzaldehyde and 12 ml of trimethylphosphorocarboxacetate in 20 mL of tetrahydrofuran. Add the third butoxy bell 9-9g (total) in the next few times. Stir overnight under an argon atmosphere at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was sequentially washed with 2 m ο 1 / L sodium hydroxide aqueous solution, water, and saturated brine, dehydrated and dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 3-m-toluene methyl acrylate 10 · 8g. 6.28 g of the obtained 3-m-toluene acrylate was dissolved in 20 mL of ethyl acetate, 10% palladium carbon catalyst 6351112 was added thereto, and the mixture was stirred at room temperature and under an argon atmosphere under normal pressure. One night. Filter off the insoluble matter and decompress the mash? Chen is thin, and 3-methyl-m-phenylene propionate g 6 3 0 g is obtained. 'H-NMR (CDC 1 3) δ p pm: 2.32 (3H, s), 2.62 (2H, t, J = 7.9H z), 2.91 (2H, t, J = 7.9Hz), 3.67 (3H, s ), 6.97-7.03 (3H, m), 7.13-7.21 OH, m) Reference Example 8 Methyl 3-bromo-3-(3-bromoammonium) propionate is methyl 3-m-toluenepropionate 丨 · 15g of AN monobromobutanediimide 1 32g was dissolved in 15 mL of carbon tetracarbonate, and heated under reflux for 4 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain the residue> Shixi gel column chromatography (solvent: ethyl acetate ~ hexane) Purification gave 9-9 mg of ethyl 3-bromo-3- (3-bromotoluene) propionate. 1H-NMR (CDC 1 3) ό ppm: 3.21 (1H, dd, J = 6.1, 16.3Hz), 3.34 OH, dd,] = 9.0, 16.3Hz), 3.71 (3H, s), 4.48 (2H, s ), 5.38 (1H, dd, J = 6.1, 9.0Hz), 7.31-7.40 (3H, jn), 7.44 qh, brs)

1233358 V. Description of the invention (63) Reference Example 9 Ethyl acetate (tetrahydrobran-4 -yl) ethyl acetate dissolves arsenite and acetic acid trimethyl g 1 · 0.7 m L in tetramethylene complex 15 m L To this, 7.26 g of potassium third butoxide was added, and the mixture was stirred for 5 minutes under an argon atmosphere and room temperature. To the reaction mixture was added tetrahydropiperan-4-one 5.0 mL, and the mixture was stirred overnight at 60 ° C under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (the elution solvent was ethyl acetate-hexane) to obtain ethyl (tetrahydrotripan-4-yl) acetate. g aims 2.72g. 'H-NMR (CDC13) 5 P Pm: 1.23-1.32 (3H, m), 2.31-2.35 (2H, m), 3.00-3.05 (2H, m), 3.73-3.81 (4H, m) 5 4.1 1- 4.20 (2H, m), 5.67-5.99 (1H, m) Reference Example 1 Ethyl 4-tetrahydropiperan ethyl acetate 2.72 g of (tetrahydropiperan-4-yl) acetic acid was dissolved in tetrahydrofuran 15 mL was added, and 424 mg of 10% palladium-carbon catalyst (50% water content) was added thereto, and the mixture was stirred overnight at room temperature and under atmospheric pressure and atmospheric pressure. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 3.97 g of ethyl 4-tetrahydropiranate. 1H — NMR (CDC 1 3) δ ppm:]. 26 (3H, t,] = 7.1 Hz), 1.28-1.40 (2H, m), 1.61-1.69 (2H, m), 1.96-2.07 〇H, m), 2.21-2.28 (2H, m), 3.36 -3.46 (2H, m), 3.92-3.97 (2H, m), 4.14 (2H, q, J = 7.1 Hz)

C: \ 2D-CODE \ 91-07 \ 91110283a.ptd Page 68 1233358 V. Description of the invention (64) Reference example 1 1 4-Tetrahydrothranoacetic acid Add 20 mL of ethanol and 20 mL of 1 mol / L sodium hydroxide aqueous solution to 4 -3.90 g of ethyl tetrahydropiran, and stirred for 20 minutes under an argon atmosphere at a temperature of 60 ° C. The reaction mixture was concentrated under reduced pressure, and the obtained residue was added with water and washed with diethyl ether. The aqueous layer was neutralized with concentrated hydrochloric acid, saturated saline was added thereto, and extraction was performed with diethyl ether. The organic layer was dehydrated and dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 4 -tetrahydrofuranacetic acid 2. 2 3 g.

1H — NMR (CD CI 3), p pm: 1. 3b] · 43 (2Η, m),]. 63-1. 73 (2Η, m),] · 97-2 · 10 (1H, m) , 2. 27-2.32 (2H, m), 3.37-3.45 (2H, m), 3.9, 3.99 (2H, m), 9.5-11.2 OH, brs) Reference Example 1 2.4-Tetrahydropropaneacetamidine Gas was added to 2-2 3 g of 4 -tetrahydrolananacetic acid, while 3.4 m L of sulfur chloride was added. (: Stir at temperature for 20 minutes. Concentrate the reaction mixture under reduced pressure and add toluene to the residue obtained at 5Q. After concentration under reduced pressure, add 7 toluene to the residue obtained and concentrate under reduced pressure to obtain 4-tetrahydropipe. Ethyl Acetyl Chloride 2. Hydrazine, * δ °

'H-NMR (CDC 1 3) δ p pm: 1. 32-1. 42 (2H, m), J.64-]. 73 (2H m)) 2.05-2.20 OH, m), 2.80-2.86 ( 2H, m), 3.37-3.46 (2H, m), 3 > 92 ^ 4 ^ (2H, m) Reference example 1 3

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1233358

In the same manner as in Reference Example 12, cyclohexylacetamidine chloride I was synthesized by the following compound: 3H-NMR (CDC 1 3) (5 ppmro.go.j claw), 2.75 (2H, d, J = 6.9Hz) U (5H, m), 1.59-2.00 (6H, I Case Study 1 4 4 Monobenzyloxy-3 -hydroxybenzaldehyde makes 3,4-dihydroxybenzaldehyde 175.0. Methyl formamide 60 0 In ^, 175 g of potassium ^ and potassium acetate were suspended in N, and 15 mL of mobenzyl was added in two drops, and the mixture was stirred. Dilute hydrochloric acid was added to the reactant to make it acidic: Stir for 6 hours. After taking the deposit from the second reaction, wash it with diethyl scale to obtain 4-glyoxy-3-hydroxybenzaldehyde i79 g. ^ H ^ NMR (CDCI3) δ ppm: 5.21 (2H , s), 5.82 〇H, s), 7.04 (1H, d, J = 8.3Hz), 7.33-7.52 (7H, m), 9.84 (ih, s) Reference example 1 2-Benzyl milk-5-( 1,3-Dipentyl-2-yl) benzene was dissolved in 2.38 g of 4-etho-3-hydroxybenzaldehyde, and 15 mL of benzene was added. To this was added 5 · 5 7 g of ethylene glycol and p-toluene yellow. The acid was 198 mg, and the mixture was heated under reflux in a gas atmosphere overnight while removing water. After cooling to room temperature, the reaction mixture was washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution. Organic ^ After dehydration and drying with anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain 2 \ f-5-(1,3 ~ di A pentane-2 -yl) benzene S fraction 2.7〇g ~

Chapter 70

1233358 Description of the invention (66) ^ -NUR (CDC13) ^ ppm: 3.96-4.04 (2H, m), 4.06H 14 (2H ^), 5.12 (2H, s), 5.68 OH, s), 5.73 (1H, s ), 6.9l (1H? D, J = 8 3Hz) 6 96 OH, dd,] = 2.0, 8.3Hz), 7.08 OH, d, J = 2.0Hz), 7.33-7.45 (5H ,,), I test Example 1 6 2 ~ [4-benzyloxy-3-(4-fluorophenoxy) benzyl] -1,3 one-two 4-pentyl ring p-octyl-5-(1,3-di-4 pentyl ring group) 506 mg of benzylphenol, 260 mg of dihydroxy (4-fluorofluoro) borane, 338 mg of copper (II) acetate, and 4A (1/16) 50 |) mg of molecular sieve, 19 mL of dichloromethane and triethylamine were added. 'While stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to obtain 2- [4-benzyloxy-3_ (4-fluoro Phenoxy) benzene] -1,3-dipentanyl 35 61112. iH — NMR (CDC 1 3) δ p pm: 3. 95-4. 05 (2H, m), 4.05-4.15 (2H, π〇, 5.10 (2Η, s), 5.70 (1Η, s), 6.85- 7.05 (5H, m), 7.10-7.40 (7H m) Urgent_Examination example 1 7 Phenoxy-3-(4-fluorophenoxy) benzoic acid makes 2- [4-fluorenoxy-3- (4-fluorobenzene (Oxy) benzene] -ι, 3-di. 356 mg of pentane was dissolved in 20 mL of tetrahydrofuran, and 20 mL of lmoi / L hydrochloric acid was added thereto, followed by stirring under an argon atmosphere and a temperature of 60 ° C for 30 minutes. The mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dehydrated and dried with anhydrous magnesium sulfate, and then was subjected to deflation under reduced pressure to obtain 4-octyl- 3-40 mg of 3- (4-fluorophenoxy) benzaldehyde.

1233358 V. Description of the invention (67) iH — NMR (CDC 1 3) δ ppm: 5.20 (2H, s), 6.90-7.05 (4H, m), 7. 13 (1H, d, J = 8.4Hz), 7.22 -7.38 (5H, m), 7.49 OH, d,] = 2.0Hz), 7.61 (l H, dd, J = 2.0, 8.4Hz), 9.88 (1H, s) Example 1 8 4-octyl- 3- (4-tetrahydropiperanyloxy) benzaldehyde dissolves tetrahydropiperan-4-ol 717 and triphenylphosphine 3.15g in tetrahydrofuran 2ymL 'to this under argon atmosphere and add 4 under ice cooling 5.44 mL of a toluene solution of 0% diethyl azodiacetate and 2.29 g of 4-eco-3-hydroxybenzaldehyde. After stirring at room temperature overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent solvent: ethyl acetate-hexane) to obtain 16-octyloxy_3 — (4-tetrahydropiperanyloxy) benzaldehyde 1.16g. ] H-NMR (CDC13) (5 ppm: 1.80-1.90 (2Hj m), 1.98-2.06 (2H, m), 3.53-3.58 (2H, m), 3.95-4.04 (2H, m), 4.52-4.61 ( 1H, m), 5.22 (2H, s) '7.05 (1H, d, J = 8.2Hz), 7.30-7.48 (7H, m), 9.84 (] H, s)

Reference Example 1 Q 4-Phenoxy-3- (4-fluorophenoxy) benzene was dissolved in 4-chlorooxy-3- (4-fluorophenoxy) benzaldehyde 2 40 mg in dichloromethane i0mL 'P Then, 37.5 mg of sodium bicarbonate and 257 mg of m-aeroperoxybenzoic acid were added, and they were stirred at room temperature overnight. The reaction mixture was diluted with water 'and extracted with dichloromethane. Saturate the organic layer with water and saturate

C: \ 2D-CODE \ 91-07 \ 9l] l〇283a.ptd page 72! 233358 (68) "-washed with sodium bicarbonate aqueous solution, saturated brine, dehydrated and dried with anhydrous magnesium sulfate And concentrated under reduced pressure. The obtained residue was dissolved in 3 mL of ethanol. To this was added 2 ini / L sodium hydroxide aqueous solution 2 mi, and the mixture was stirred for 30 minutes under an argon atmosphere and a temperature of 60 ° C. The reaction mixture was concentrated under reduced pressure, and 2 mo 1 / L hydrochloric acid was added to the obtained residue to neutralize it. The reaction mixture was diluted with a saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, dehydrated and dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (the developing solvent was hexane-ethyl acetate). (Ester) was purified to give 4-41-oxy-3- (4-randomoxy) i41mg at a stupid age. 2H ~ NMR (CDC 1 3) (5 p pm: 4.62 (1H, s), 5.02 (2H, s), 6.49 〇H, dd, J = 3.0, 8.8Hz), 6.52 (1H, d, J = 3.0 Hz), 6.89 (1H, d, J = 8.8Hz), 6.88-7.03 (4H, m), 7.20-7.44 (5H, m) tCase 2 0 The following method was implemented in the same way as Reference Example 19 Synthesis of compounds. 4-Benzyloxy-3- (4-tetrahydrofuranoxy) phenol — NMR (CDC 1 3) δ ppm: 1.78-1.88 (2H, m), 1.95 ^ 2.04 (2H, m), 3.50-3.58 (2H, m), 3.95-4.02 (2H, m), 4.41-4.47 (1H, m), 4.69 OH, s), 5.03 (2H, s), 6.35 (1H, dd, 1 = 2.9, 8.6Hz), 6.50 ( 1H, d, J = 2.9Hz), 6.81 OH, d, J = 8.6Hz), 7.27-7.47 (5H, m) Reference example 2 1 Monothiothiamidate 0- (2,6 -dimethyl-4 -Nitrobenzene)

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&Amp;, 2,6 diyl: 4 dif benzene age 2 0 g was dissolved in 5 mL of N, N-dimethyl methylamine, and triethylenediamine 26. was added under stirring at room temperature. y Methionine formamidine chloride 2 2 · 2 g, and stirred at 7 5 ° C for 30 minutes ^ and left to cool, the reaction mixture was added with 100 mL of water, and insolubles were filtered: ° 0 -(2, 6-Difluorene-4-nitrobenzyl) ester 25 · Og The solution was washed with diethyl ether, and then dehumidified and dried to obtain dimethylsilicon ° regardless of r 〇a ^ ma τ ± ^ \ _____ Λ T Acid'H-NMR (CDC 1 3) δ p pm: 2.26 (6H, s), 3.41 (3H, s), 3.49 (3H, s), 7.98 (2H, s) Reference Example 22 Dimethionine S -(2, 6-Dioxo-4-nitrophenyl) ester causes dimethyl thiamine acetic acid 0- (2,6-dioxo-4-nitrophenyl) ester 25 · Og to melt at 180 ° C, and Stir for 0 hours. After allowing to cool, 25.0 g of S- (2,6-difluorene-4-nitrophenyl) dimethyl thiamine formate was obtained. : H —NMR (CDC 1 3) δ ppm: 2.52 (6H, s), 3.02 (3H, brs), 3.19 (3H, brs), 7.99 (2H, s) Reference example 2 3 2,6 -Difluorene- 4-Stilbene benzene sulfide suspended dimethyl thiamine carboxylic acid S- (2,6-difluorene-4-nitrophenyl) ester 25 · g in 2mol / L sodium hydroxide aqueous solution 2000moi and methanol 200ml, and incubate at 90 ° C for 6 hours. After allowing to cool, 1 mo 1 / L hydrochloric acid was added to the reaction mixture to make it acidic, and extraction was performed with ethyl acetate. The organic layer was washed with saturated saline and dehydrated and dried by anhydrous magnesium sulfate.

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The obtained residue was suspended in 50 mL of hexane and 5 mL of diethyl ether. 56g。 After insoluble matter was taken out, washed with hexane to obtain 5- (2, 6 ~ dimethyl-4-nitrophenoxy) -2-methoxybenzoic acid 5. 56g. — NMR (CDC 1 3) 6 ppm: 2.20 (6H, s), 3.92 (3H, s), 6.93-7. 16 (3H, m), 8.01 (2H, s), 10.40 OH, s) Reference example 2 5 The following compounds were synthesized in the same manner as in Reference Example 24. 4-Narrow oxygen-3-isopropylbenzidine] H ~ NMR (CDC 1 3) 6 Ppm: 1.27 (6H, d, J = 6.9Hz), 3.42 (1H, seven-line,] = 6.9Hz), 5 ·] 8 (2H 's), 7.01 (] H, d, J = 8.4Hz), 7.33-7.47 (5H, m), 7.69 (1H, dd, J = 2.1, 8.4Hz), 7.80 OH, d, J = 2.1Hz), 9.88 (1H, s)

Page 75 C: \ 2D-CODE \ 91-07 \ 91110283a.ptd 1233358 V. Description of the invention (71) Bis (4-benzyloxy_3_cumene) tetrafluoroborate 镌 is stirred under ice-cold agitation Nitrous nitric acid 20 · mL was added dropwise with 5 5 · 9 mL of acetic anhydride. To the reaction mixture was added 11.8 g, followed by the dropwise addition of 34.2 mL of trigas acetic acid, and the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. After adding 500 m L of acetic anhydride and 1000 g of 1-benzyloxy-2 -isopropyl to the obtained residue under ice cooling, trifluoroacetic acid 37. 5 m L was added dropwise to this. Incubate at 4 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was successively added with 50 mL of methanol, 20 mL of 10% aqueous sodium hydrogen sulfite solution, and 125O mL of 2M sodium tetrafluoroborate aqueous solution, followed by stirring for 2 hours. After the precipitate was coagulated, the supernatant was removed. The residue was suspended in hexane, and the insoluble matter was collected by filtration, washed with hexane, and dehumidified and dried at a reduced pressure and a temperature of 40 ° C to obtain tetrafluoroacid bis 1 (4-deoxy-3-isopropyl Benzene) Scandium 5 5. 9 6g. i ij_j —NMR (CDC I 3) δ ppm: 1.2002H, d, J = 6.9Hz), 3.35 (2H, seven-line, | = 6.9 Hz), 5.11 (4H, s), 6.95 (2H, d,] = 8.9Hz), 7.26-7.53 〇H 'm), 7.69 (2H, d, J = 2.4Hz), 7.78 (2H, d, J = 2.4, 8.9Hz) Refer to Example 2 7 to The following compounds were synthesized in the same manner as in Reference Example 26. Tetrafluoroborate bis (3-ethylfluorene-2, 4-dibenzyloxybenzene) fluorene 1H_NMR (CDC 1 3) δ p pm: 2.49 (6H, s), 4.98 (4H, s), 5. Π (4H, s), 6.73 (2H, d, J = 9.1Hz), 7.3H7.45 (20H, m), 7.48 (2H, d, J = 9.1

C: \ 2D-C0DE \ 91-07 \ 91110283a.ptd Page 76 1233358 V. Description of the invention (72) Tetrafluoroborate bis (4-benzyloxy-5, 6, 7, 8_tetrahydro-1-naphthalene)鍈 1H — NMR (CD C 1 3) 6 p pm: 1. 56-1. 90 (8H, m), 2.56-2.90 (BH, m), 5.08 (4H, s), 6.78 (2H, d, J = 8.9Hz)? 7.17-7.58 (] 〇H, m), 7.73 (2H? D, J = 8.9Hz) Reference Example 28 1-Hydroxy-4- (2, 6-dioxan-4-nitrophenoxy ) -5, 6,7, 8-tetrahydronaphthalene makes 45 mg of 2,6-difluorene-4-nitrophenol, bis (4-benzyloxy-5, 6, 7, 8-tetrahydro-1- 20 mg of naphthalene) hydrazone and 54 mg of copper powder were suspended in 10 mL of digas methane at room temperature. To this was added triethylamine 0.1 mL while stirring, and the mixture was stirred at room temperature for 4 days. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by acetic acid (e.g. acetic acid), to obtain 44.4 mg of oxygen, 4,4,2,6,6-tetrahydronaphthalene. Monthly milk) 5, W-NMR (CDCl3) δ ppm: 1.7 (H.94 (4H, 仏 2 i8 (6H, s), 2 68-2.95 (4H, m), 4.97 (2H, s) '5 · 94 (1H, d,] = 8 · 8Ηζ), 6 48 (] H, d, J = 8.8 Hz), 7.20-7.50 (5H, m), 8.00 (2H, s) Reference example 2 9 is now available The following compounds 5 to 3 gas benzene synthesis d, J = 6.9Hz), 3.39 (1H, 8.8Hz), 6.78 (1H, (5H, m), 7.95 OH, s) are the same as in Reference Example 28 The method is 4- (4-benzyloxy-3-cumyloxy) ~ 2, 3】 H-NMR (CDC 1 3) P Pm: 1.22 (gh sevenfold line, J = 6.9Hz), 5.03 (2H , S), 6.42 (1H, μ, d, J = 8.8Hz), 6.89 (1H, d, J = 3.1Hz), 7.29-7.57

1233358 V. Description of the invention (73) 4-(4-Narrow-oxy-3-cumyloxy) -3,5-dimo-n-nitrobenzene — NMR (CDC 1 3) (5 ppm: 1.22 (6H, d, J = 6.9Hz), 3.40 OH, sevenfold,] = 6.9Ηζ), 5.04 (2H, s) ', 6.43 (] H, dd' J = 3.1, 8.9Ηζ), 6.80 OH 'd, J = 8.9 Hz), 6-86 (1H, d, J = 3.1Hz), 7.32-7.46 (5H, m), 8.51 (2H, s) 4- (4-benzyloxy-3 -cumyloxy) -2, 3, 5-trimetholine aH-NMR (CDC 1 3) δ ppm: 1.20 (6H, d, 3 = 6. 9Hz), 2.14 (3H, s), 2 ″ 5 (3H, s), 2.41 (3H, s), 3.38 (] H, seven-line, J = 6.9Hz), 5.0] (2H,

s), 6.28 OH, dd, J = 3.1, 8.8Hz), 6.74 (1H, d, J = 8.8Hz), 6.79 (1H, d, J = 3. 1Hz), 7.28-7.47 (5H, m) , 7.58 (1H, s) 1- [2, 6-Dioxo-3-(2,6-dimethyl-4-nitrophenoxy) phenyl] ethanone ^ -NMR (CDC13) 5 ppm: 2.25 (6H , s), 2.45 (3H, s), 5.00 (2H, s), 5.21 (2H, s), 6.23 (1H, d, J = 9.0Hz), 6.50 (1H, d, J = 9.0Hz), 7 27-7.43 (8H, m), 7.43-7.47 (2H, m), 8.02 (2H, s) 1-octyl-4- (2,3, 6-trigas-4 -nitrophenoxy) -5 , 6,7,8-Tetralin 1H-NMR (CDC 1 3) δ p pm: 1. 77-1. 88 (4H, m), 2.73-2.82 (2H, m), 2.87-2.93 (2H, m), 4.99 (2H, s), 6.04 (1H, d, J = 8.8Hz), 6.53 OH, d, J = 8.8Hz), 7.28-7.44 (5H, m), 7.94 (1H, s) 3- Gas-6- [5- (2, 6-Dihydrazone-4-nitrophenyloxy) -2-hydrazone oxygen]] Teng] H — NMR (CDC 1 3) δ ρ pm: 2.18 (6Η, s), 3.77 (3Η, s), 4.27 (2H, s), 6.51 (1H, dd, J = 3.1, 8.9Hz), 6.75 (1H, d, J = 8.9Hz), 6.78 (1H, d, J = 3.1Hz ), 7.30 (1H, d, J = 8.8Hz), 7.38 (1H, d, J = 8.8Hz), 7.99 (2H, s) Reference example 3 0

Page 78 C: \ 2D_CODE \ 91-07 \ 91110283a.ptd 1233358 V. Description of the invention (74) 1- [6-Lead oxygen-3- (2,6_ dimethyl-4-nitrobenzyloxy)-2 1_ [2, 6-Dioctyloxy-3- (2, 6-Dioctyl-4-Nitrostetranium g, trifluoroacetic acid / water / dimethylsulfide (7: 3: n = stupid) ethyl ketone π not α The last name is 汸 g, 人, 人 / / 1〇 社, and at room temperature, I was prepared. The reaction mixture was concentrated under reduced pressure, and the water was added, followed by extraction with dioxane. The residue was μ. The organic layer was treated with an aqueous solution of sodium bicarbonate, saturated brine, and Φ ##, and then concentrated under reduced pressure to dehydrate the resulting product to obtain 1- [6- 芊 oxo- 3- (2,6-Difluorene-4-nitrobenzyloxy) acetone 1. 8 1 g.] H — NMR (CDC 1 3) < 5 p pm: 2.24 (6H, s), 2.67 (3H, s), 5.07 (2H, s), 6.25 OH, d, J = 9.0Hz), 6.43 (1H, d, J = 9.0Hz), 7.33-7.45 (5H, m), 8.00 (2H, s), 13.67 (1H, s) Reference Example 3 1 1- [6-Narrow oxygen-3-(2,6 -difluorene-4 -nitrophenoxy)-2-fluorenol] ethyl ketone makes 1- [6-benzyloxy -3- (2,6-Difluorene-4-nitrophenoxy) -2-hydroxybenzyl] ethyl ketone 1 · 8 1 g was dissolved in tetrahydrooctane 15 m L. To this was added carbonic acid absolute 1 under ice-cooling. . 5 9 g, while slowly adding iodopanane 0.56 mL. After stirring overnight under argon atmosphere at room temperature, the reaction mixture was concentrated under reduced pressure, and 30 mL of ethyl acetate was added to the obtained residue. Stir for 30 minutes. After filtering by celite (—mobile filter aid) to remove insoluble matter, the filtrate is concentrated under reduced pressure to obtain [6 -benzyloxy-3-(2, 6 -dimethyl-4 -nitrophenoxy) )-2-Phenoxybenzene] ethanone 1.8 7g. 3H-NMR (CDC13) δ ppm: 2.23 (6H, s), 2.57 (3H, s), 4.02 (3H, s), 5.00 (2H, s), 6.20 OH, d, J = 9.0Hz), 6.48 (1H, d, J-9.0Hz), 28-7.40 (5H, m), 8.02 (2H, s)

C: \ 2D-CODE \ 91-07 \ 91110283a.ptd Page 79 1233358 V. Description of the invention (75) --- Reference example 3 2 1- [3- (4-Amino-2, 6-xyloxyl ) One 6-one oxygen one 2-methoxybenzyl] ethene j makes 1-[6-benzyloxy-3-(2,6 ~ dipyridin-4_nitrophenoxy) -2- oxonyl] ketone-l 87g suspended in 5omL of ethyl acetate, 5% platinum-carbon catalyst_200mg was added thereto, and stirred at room temperature and under a hydrogen atmosphere under normal pressure for ^ h. After the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure to obtain 丨-[3 "-2,6-dioxophenoxy) -6-benzyl-2-oxophenyl] ethanone 1.742. Group-NMR (CDCI3) δ ppm: 2.i2 (6H, s), 2.55 (3H, s), 4.00 (3H, s), 4.98 (2H, s), 6.18 (1H, d, J = 9.〇hz), 6.45 (2H , brs), 6.47 (1H, d, J = 9.0Hz), 7.26-7.39 (5H, m) Reference Example 33 1-[6 卞 oxo-3-(4-monobenzylamine_2,6-xyloxyl ) -2-methoxybenzyl] ethoxyl j dissolves 1-[3-(4-amino-2,6-dioxophenoxy) -6-etho-2-oxophenyl] ethanone 1. 74g To 30 mL of N, N-dimethylformamide, 1.62 mL of α-benzylbenzene, 6.14 g of potassium carbonate, and 226 mg of potassium block were added, and the mixture was stirred under an argon atmosphere at 80 ° C. 7 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was passed through silicon. Purified by gel column chromatography (the dissolution solvent was ethyl acetate-hexane) to obtain 1- [6-benzyloxy-3- (4-dioxamine-2,6-dioxophenoxy) -2 -Methoxyphenyl] ethyl ketone 1.35g. 'H-NMR (CD C) 3) δ p pm: 2.01 (6H, s), 2.54 (3H, s), 4.00 (3H, s), 4.60 (4H, s), 4.97 (2H, s), 6.32 (1H, d, J = 9.0Hz), 6.45 OH, d, J = 9.0Hz), 6.47 (2H, s), 7.22-7.38 (1 5H, m)

1233358 V. Description of the invention (76) Reference Example 34 The following compounds were synthesized in the same manner as in Reference Example 33. N, N-dibenzyl-4-iodo-3,5-dimethyltoluidine'H-NMR (CDC 1 3) δ p pm: 2.34 (6H, s), 4.59 (4H, s), 6.52 (2H, s ), 7.20-7. 27 (6H, m), 7.27-7.35 (4H, m) Reference Example 3 5 (4-benzyloxy-3 -cumene) (4-diethylamine-2, 6-difluorene Benzene) ethanol dissolves 1 ^, 1 ^ -dibenzyl-4-4--3,5-xylylamine 65911 ^ in 5 mL of dehumidified tetrahydrofuran, and adds 1 at a temperature of -1 00 ° C. 6M n-pentane solution of third butyl lithium 1. 4 4 m 1. After being dropped in this state for 10 minutes, a tetrahydrofuran 5 mL solution of 392 mg of 4-oxo-3 -cumylaldehyde was added dropwise thereto. After stirring in this state for 15 minutes, the temperature was raised to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dehydrated and dried with anhydrous sulfuric acid, and then concentrated under reduced pressure to obtain (4-benzyloxy-3-cumene) (4-dibenzylamine-2,6-dioxobenzene) methanol 96411 ^ . 】 H-NMR (CDC 1 3) δ ppm: 1.17-1.28 (6H, m), 2.00 〇H, d? J = 4.0Hz), 2.16 (6H, s), 3.34-3.44 (1H, m), 4.61 (4H, s), 5.05 (2H, s), 6. 22 (1H, d, J = 4.0Hz), 6.44 (2H, s), 6.80 (1H, d, J = 8.4Hz), 6.87-6.92 ( 1 H, m), 7.22-7.46 0 6H, m) Reference Example 36 In the same manner as in Reference Example 35, the following compounds were synthesized.

C: \ 2D-C0DE \ 91-07 \ 91110283a.ptd Page 81 1233358 V. Description of the invention (77) (4-dibenzylamine-2, 6-dioxobenzene) (4-methoxybenzene) methanol] H — NMR (CDC 1 3) δ ppm: 1.99 (1H, d,] = 3.9Hz)? 2.16 (6H, s), 3.79 (3H, s), 4.61 (4H, brs), 6.21 (1H? D, J = 3.9Hz), 6.43 (2H, s), 6.82-6.86 (2H; m), 7.18-7.36 (12H, m) [4-benzyloxy-3_ (4-fluorophenoxy) benzene] (4-Diye Amine_2,6-xylene) methanol 1H-NMR (CDC I 3) δ ppm: 3.96 (1H, d, J = 3.8Hz), 2.14 (6H, s), 4.60 (4H, s), 5.04 ( 2H, s), 6.17 (1H, d, J = 3.8Hz), 6.40 (2H, s), 6. 82-6.88 (2H, m), 6.90-7.00 (4H, m), 7.06 (1H, d, J = l.lHz), 7.] 4-7.38 (15H, m) [4-fluoren-3- (4-tetrahydropiperanyloxy) benzene] (4-dihexylamine-2, 6-xylene ) Alcohol] H-NMR (CDC 1 3) δ p pm: 1. 73-1. 83 (2H, m), 1.89-1.96 (2H, m), 2.12 (1H, brs), 2.13 (6H, s ), 3.43-3.50 (2H, m), 3.93-3.99 (2H, m), 4.39-4.44 (1H? M), 4.60 (4H, s), 5.07 (2H, s), 6.16 (1H, d, J = 3.2Hz), 6.42 (2H, s), 6.72-6.76 (1H, m), 6.84-6.86 (1H, m), 7.01-7.03 (1H, m), 7.22-7.37 (13H, m), 7.39- 7.44 (2H, m) Reference example 3 7 4-[4- Oxy-3- (4-fluorophenoxy) phenoxy] -3,5-dimethybenzene makes 4-narrowoxy-3- (4-fluorophenoxy) phenol 141 mg and 4-gas-3, 5- 101 mg of difluorene nifedipine was dissolved in 3 mL of N, N-dimethylacetamidamine, 188 mg of potassium carbonate was added thereto, and the mixture was stirred overnight at 150 ° C under an argon atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and dehydrated and dried by anhydrous sulfuric acid.

C: \ 2D-C0DE \ 91-07 \ 91110283a.ptd page 82 1233358 V. Description of the invention (78) After drying, the solution was concentrated under reduced pressure, and the obtained residue was subjected to a silica gel thin layer chromatography (developing solvent (Hexane-ethyl acetate) was purified to obtain 127 mg of 4- [4-oxo-3- (4-fluorophenoxy) phenoxy] -3,5-dimethybenzene. ] H-NMR (CDC I 3) δ p pm: 2.20 (6Η, s), 5.0] (2Η, s), 6.36 (1H, dd, J = 3.0, 9.0Hz), 6.52 (1H, d, J = 3.0Hz), 6.85-6.95 (3H, m), 6.95 -7.02 (2H, m), 7.17-7.20 (2H, m), 7.23-7.31 (3H, m), 7.98 (2H, s) Reference examples 3 8 The following compounds were synthesized in the same manner as in Example 37. 4-[4-Methoxy-3-(4-tetrahydropiperanyloxy) phenoxy] -3,5-dipyridine n-benzene ^ -NMR (CDC13) (5ppm: 1.75-1.85 (2H, m), 1.95 -2.00 (2H, m), 2.21 (6H, s), 3.50-3.56 (2H, m), 3.95-4.02 (2H, m), 4.42-4.48 OH, m), 5.04 (2H, s), 6.12 ( 1H, dd, J = 3.0, 8.8Hz), 6.55 (1H, d, J = 3.0Hz), 6.8] (1H, d, J = 8.8Hz), 7.28-7.44 (5H, m), 7.99 (2H, s) Reference Example 3 9 (4-benzyloxy-3 -cumene) (4-dibenzylamine-2, 6-dioxanyl) methanone (4-benzyloxy-3-cumene) (4 858 mg of di-narrow amine-2,6-dioxobenzene) methanol was dissolved in 10 mL of dichloromethane, and 5.36 g of manganese dioxide was added thereto, followed by vigorous stirring at room temperature for 3 days. After insoluble matter was filtered off, the filtrate was concentrated under reduced pressure to obtain (4-fluorenoxy-3 -cumene) (4-dibenzylamine-2, 6-xylene) fluorenone 36 mg 0

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^ H-NMR (CDC13) a ppm:]. 25 (6H > d >] = M 2.02 (6H, 6.44 (2H, J = 2.0, 8. s), 3.39 (1H, seven lines, J = 6.9 Hz), 4.64 (4H, s), 5. · 3 (2H, s) 's), 6.85 (1H, d, J = 8.6Hz), 7.23-7.45 (1 5H, m), 7.50 () H 6Hz ), 7.91 (1H, d, J = 2.0Hz), reference example 4 0 6 to [5-(2, 6-dimethyl-4-nitrophenyloxy)-2-forma + mm rc; lactam]-2H -Mouth-to-mouth sequence -3-_ 1 r jealous 钿 M6—dimethanol) -2-methoxyxin] Da Geng l, .37 g, add 50 mg of acetam sodium and 10 mL of acetic acid, and under a nitrogen atmosphere It was heated under reflux for 2 hours. Water (10 mL) was added to the reaction mixture, and after stirring for 30 minutes, it was extracted with methane gas. The organic layer was washed successively with 丨 m〇 丨 / L sodium hydroxide aqueous solution, water, and saturated brine, and dehydrated and dried by anhydrous magnesium sulfate to 'shrink under reduced pressure' to obtain 6 — [5-(2 6 -Dimethyl-4-nifedioxy) -2-oxoxine]-211-. answer. Well -3 ~ _290mg. — NMR (CDC 13) δ ppm: 2.19 (6H, s), 3.78 (3H, s), 3.86 (2H, s), 6.50 (1H, dd, J = 2.8, 8.8Hz), 6.68 (1H, d, 1 = 2.8Hz), 6.75 OH, J = 8.8Hz), 6.83-6.87 (1H, m), 7.14-7.18 (1H, m), 8.00 (2H, s) Reference example 41 6-[5- (2, 6-Dimethyl_4 -nitrophenoxy) -2 -Hydroxyoctyl]-2H_Dagen-3-one makes 6-[5-(2, 6 -Diphenyl-4 -nitrophenoxy) -2- 一90 mg of oxybenzyl] -2H-daphthrin-3-one was dissolved in 10 mL of acetic acid, 10 mL of 48% hydrobromic acid was added thereto, and the mixture was heated under reflux under an argon atmosphere for 2 days. The reaction mixture was diluted with water and extracted with dioxane. Use the organic layer sequentially with water, water and saturation

1233358 V. Description of Invention (80)

The mixed bath solution of common salt solution was washed, and concentrated under reduced pressure by using anhydrous magnesium sulfate to obtain 6- [5 一 （2,6 一 二甲 一 4— 二 粍 = 后 / 横] -2H-Dagen-3 -139 mg of ketone. Milk)-2-1 NMR (CDCl3 + CD3〇D) ppm ι 2.19 (6H, s) 3 86 (2H s), 6.44 (1H, dd, J = 3.0, 8.8Hz) , 6.61 (1H, d, J = 3.0Hz), 6.73 (1H, d, j = 8.8Hz), 6.86-6.92 (1H, m), 7.25-7.32 OH, m), 7.99 (2H, s) Reference examples 4 2 5-(2,6 -Diamidine-4 -Shi Xiao Phenoxy) -2 -Benzamide 5- (2, 6_dimethyl-4 -nitrophenoxy) -2-methoxybenzaldehyde 5.56 g was dissolved in 40 mL of digas methane, and the three-gasification side was added dropwise under ice-cold stirring: 95 mL of digas methane solution was stirred at room temperature for 24 hours. With stirring under ice, add 0 mL of methanol to the reaction mixture, add dilute hydrochloric acid, and extract with ethyl acetate. The organic layer was washed with saturated brine, dehydrated and dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 5-(2,6-difluorene-4 -stone phenoxy)-2-benzyl Jun 4. 51g. ] H — NMR (CDC 1 3) δ P pm: 2.23 (6H, s), 6.77 (1H, d, J = 3.0H z), 6.98 OH, d, 1 = 9.1Hz), 7.10 (1H, dd, J = 9.1, 3.0Hz), 8.04 (2H, s), 9.75 (1H, s), 10.72 OH, s) Reference example 4 3 2 -Benzyloxy-5-(2, 6 -Difluorene-4-nitrobenzene Oxy) phenylbenzaldehyde suspends 5-(2,6 -difluorene-4 -nitrophenoxy)-2- via phenylarsinic acid 4.85 g and potassium carbonate 2.33 g in 25 mL of N, N -dimethylformamide. , Stir in the cold. To the reaction mixture was added α-motoluene 2.40 m L dropwise, and at room temperature,

C: \ 2D-CODE \ 91-07 \ 91110283a.ptd Page 85 1233358 V. Description of the invention (81) '______ with stirring for 24 hours. The reaction mixture was added to the reaction mixture with a thin plate 7 to make it acidic, and extracted with ethyl acetate. The organic layer was cleaned, and the M helmet was washed with saturated saline. ^ After dehydration and drying with refined anhydrous magnesium sulfate, the pressure was reduced under the conditions of π, 焱, and apricot. The obtained residue was purified by silica gel column chromatography (solvent to obtain 2-narrow oxygen-5- (2 '6-dimethyl_4_nitrophenoxy) benzyl ester), and the sentence -… I ^ — The research / combination medium is hexane-ethyl acetate 6.20g, (CDC) 3) δ ρ_: 2] 9 ⑽, s), 5.15 ⑽, m), 7.3〇-7_5〇 , M), 8.0] (2H, s),] 0.47 (] H, s) 'S), 6.97-7. Reference Example 4 4 [2-benzyloxy-5-(2, 6-1]甲 4 淡 # ",. A methyl 4-nitrate oxygen) benzene] acetol in sodium borohydride 6 62mg county floated to Qiaodan 忒 9η τ This addition of 2-narrow oxygen, 5 r9 β In the heart / presence of 20mL of furanofuran, 5mL of methanol was added, and in the chamber, and / or the next No. 4: [nitrophenoxy] benzoic acid 6.6 taboo, drop of hydrochloric acid to make it acidic see " 6 hour. The reaction mixture was diluted with saturated brine and extracted with ethyl acetate. The organic layer was concentrated under use to obtain "1.2 dihydroanhydrous sulphate. After dehumidifying and drying, 6.50 g of reduced pressure was obtained. Breast milk 5-1 (2,6-difluorene-4-nitrophenoxy) benzene] methanol JH ~ NMR (CDC13) δ ppm: 2.21 (6H, s), 4.67 (2H, s), 5.06 (2H, s), 6.55 (1H, dd, J = 3.l, 8.8Hz), 6.77 ^ 6.88 ( 2H, m), 7.31-7.47 (5H, m), 8.00 (2H, s) Reference example 4 5

1233358 V. Description of the invention (82) [5- (2,6-Difluorene-4-nitrophenoxy) -2-fluorenoxybenzene] fluorenol 1H —NMR (CD C 1 3) δ ppm: 2.21 (6H, s), 2.28 (1H, t, J-5.3H z), 3.83 (3H, s), 4.63 (2H, d, J = 5.3Hz), 6.56 OH, dd, J = 3.1, 8.9Hz), 6.76 ( 1H, d, J = 8.9Hz), 6.78 (1H, d, J = 3. 1Hz), 8.01 (2H, s) Reference example 4 6 2-Master oxygen-5- (2,6 -dimethyl-4-4_ N-phenoxynyl chloride was used to dissolve 95 mg of [2-henoxy-5- (2, 6-dimethyl-4-nitrophenoxy) benzene] methanol in 30 mL of diethyl ether, and the solution was added dropwise under ice-cooling stirring. 1 mL of thionyl group was vaporized and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried with anhydrous sulfuric acid. After magnesium was dehumidified and dried, it was concentrated under reduced pressure to obtain 845 mg of 2-fluorenyl-5_ (2,6_dimethyl-4-nitrophenoxy narrow chloro) 〇'H-NMR (CDC 1 3) δ p pm: 2.21 (6H, s), 4.62 (2H, s), 5.08 (2H, s), 6.60 (1H, dd, J = 3.1, 8.9Hz), 6.79-6.89 (2H, m), 7.30-7.47 (5H, m ), 8.01 (2H, s) Reference Example 4 7 The following compounds were synthesized in the same manner as Reference Example 4 6. 5- (2, 6-Difluorene-4-nitrophenoxy) -2-fluorenyloxy-methyl chloride'H-NMR (CDC 1 3) δ p pm: 2.21 (6H, s), 3.84 (3H, s), 4.58 (2H, s), 6.62 (1H, dd, J = 3. 1, 8.9Hz), 6.78 OH, d, J = 8.9Hz), 6.83 (1H, d, J = 3. 1Hz), 8.01 (2H , s)

C: \ 2D-OODE \ 91-O7 \ 91110283a.ptd Page 87 1233358 V. Description of the Invention (83) Reference Example 48 Chlorinated [2-octyl-5- (2, 6-dihydrazine-4-nitrobenzene Oxygen] Triphenyl scales make 2-octyl-5- (2,6-dimethyl-4-nitrophenyloxy) -narrow base gas 5.22g and triphenylphosphine 6. Og suspended in toluene 100mL, and heated Reflux for 12 hours. After allowing to cool, the precipitate was filtered and washed with diethyl ether to obtain 6.47 g of [2-fluorenyloxy-5- (2, 6-difluorene-4-nitrophenyloxy) narrow] triphenyl town. 2Η-NMR (DMS〇-d6) δ ppm: 1.95 (6H, s), 4.60 (2H, s), 4. 93 (2H, d, J = 14.9Hz), 6.23-6.33 (1H, m), 6.89 -7.02 (2H, m), 7.10-7.18 (2H, m), 7.27-7.38 (3H, m), 7.46-7.70 (1 2H, m), 7.79-7.92 (3H, m), 8.0 4 (2H, s) Reference Example 4 9 The following compounds were synthesized in the same manner as in Reference Example 4 8. Gasification of [5-(2,6-dimethyl-4 -stone phenoxy) -2-methoxybenzyl] triphenyl town 1H-NMR (CDC 1 3) δ ppm: 2.03 (6H, s), 3.19 ( 3H, s), 5.47 (2H, d, J = 14.4Hz), 6.50-6.54 (1H, m), 6.64-6.67 OH, m), 6.70-6.73 (1H, m), 7.56-7.62 (6H, m ), 7.67-7.78 (9H, m), 7.90 (2H, s) Reference Example 5 0 4-[2-Hydroxy-5-(2, 6 -dimethyl-4 -nitrophenoxy) benzylidene] tetrahydro 500 mg of [2-octyloxy-5-(2,6 -dimethyl-4-stone phenoxy) fluorene] triphenyl scale was suspended in piperan in dimethylforma > ^ 50mL, and this was at room temperature. Add 30 mg of sodium hydride and stir: stir for 15 minutes. Tetrahydro brigade was added to the reaction mixture. south

Page 88 C: \ 2D-OODE \ 91-O7 \ 91110283a.ptd 1233358 V. Description of the invention (84) -4-one 0.1 mL, and at room temperature, 20 mg of tetrahydropiran. Dilute hydrochloric acid was added dropwise to make it fully acidic for half a day. The reaction mixture was washed with saturated brine = extracted with ethyl acetate. After drying, the solution was concentrated under reduced pressure, and the obtained ▲, 'were dried by anhydrous magnesium sulfate (the dissolution solvent was hexane-acetic acid acetate, and the residue was subjected to silica gel column chromatography (2,6-two A-4-Shi Xiao Ce Qi) 6 ^ „:)” was purified to obtain 4- [2, oxygen 2 ~ 5 ^^-NMR (CDC 1 3) δ p pm: 2.21 (6Η 0 '44 (aw \ 61 (2H, t, J = 5.5Hz), 3.75 (2H, 1, J = 5.5Hz), 5 3 >, 幺 H, s), 6 33 Πρ 〇,

6.47 (1H, dd,] = 3.1, 8.9Hz), 6.60 (1H, dj = q 1U x · 9 S; J, * 1Hz), 6. 80 (ih d 1-0 9Hz), 7.26-7.48 (5H , m), 8.00 (2H, s) 'u' Reference Example 5 1 In the same manner as in Reference Example 50, eight of the following compounds 4- [4-fluorenoxy-3- (2-fluorenoxystyrene) ) Phenoxybenzidine, Dimethylpyrene & Cheng] H-NMR (CDC I 3) δ p pm: 2.00 (6H, s), 3.69 (3H, s), 3.83 (3H, s), 6.17 (IH , d, J = 3.0Hz), 6.63-6.75 (5H, m), 6.80-6.84 (IH, m), 6.93-6.98 (IH, m), 7.11-7.16 OH, m), 7.81 (2H, s) Reference Example 5 2 4-(4-Amino- (2, 6-xylyloxy) -2-[2- (3-tetrahydrofuran)? Phenyl group] Suspended 376 mg of bromide triphenyl scale in 20 mL of tetrahydrofuran Add 11 2 mg of potassium third butoxide at room temperature and stir for 15 cents. # Add 2-benzyloxy-5- (2, 6-dihydrazine-4-nitrophenoxy) to the reaction mixture. ) Stupid Jun 250 mg, and stirred at room temperature for 6 hours. Dilute the reaction mixture, swallow 7

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Hydrochloric acid 'was used to make it fully acidic' and the saturated ethyl acetate layer was used for extraction. After dehydrating and drying the machine with anhydrous magnesium sulfate under reduced pressure, (Λ-^ Ρ °. &Quot;# ', J ^ ^ M ^ ^ ^ ^ ^ ^ ^ ^ = Analysis of the refrigerant for the own house_acetic acid ethyl acetate Vinegar) purified to obtain an olefin compound 2 The olefin compound obtained is dissolved in 10 mL of ethanol and ethylene acetate: Solvent 'To this, add 1 hidden carbon catalyst Λ under ice cold to a mild hydrogen atmosphere and under normal hydrogen atmosphere Under the M to pounce and mix 24 small 4. After the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and subjected to Shixi gel column chromatography (the elution solvent was hexane-acetic acid di-purification-= found = 4-amino-1 (2,6-xylyloxy) ) _2_ [2_⑷tetrazine) ethyl] 120nig at this age. 2H ~ NMR (CDC13) δ P pm: 1.48-1.74 (3H, m), 1.98-2.12 (7H, m), 2.14-2.27 (1H, m), 2.48-2.66 (2H, m), 3.33-3.42 ( 1H, m), 3.53 (2H, brs), 3.69-3.79 (1H, m), 3.81-3.96 (2H, m), 5.05-5.30 (1H, m), 6.32 (1H, dd, J = 2.8, 8.7 Hz), 6.39-6.52 (3H, m), 6.60 (1H, d, J = 2.8Hz) Reference example 5 3 4- (4-octyloxy-3 -cumyl p-toluidinesulfonate) -3,5 -Dimethylaniline gives 6.0 g of 2, 6-dimethyl-4-nitrobenzenethiol, 28.3 g of bis (4-methyloxy-3-cumene) tetrahydroborate, and 2 · 7 lg of copper powder Suspend in 100 mL of dichloromethane at room temperature. 6 mL of triethylamine was added to the solution while stirring, and the mixture was stirred at room temperature for 5 days. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. After the obtained residue was dissolved in 300 mL of ethyl acetate, 1 mo 1 / L hydrochloric acid, 1 mo 1 / L sodium hydroxide aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated water were sequentially used for this.

1233358

V. Description of the invention (86)-Fresh hoof ^,,, minus; washing the strips' to dehydrate and dry the organic layer with anhydrous magnesium sulfate, and then concentrating at 1 t to obtain the p-toluidinesulfonate compound. The obtained p-amine compound was dissolved in two consisting of 100 mL of ethanol and 20 mL of ethyl acetate. Ling media 'Add this several times under ice cold 丨 〇% palladium-carbon catalyst 2 · 〇 to combine ^)' while stirring at room temperature and hydrogen atmosphere under normal pressure for 24 hours to remove insoluble After filtering, the filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl alcohol. After that, a saturated sodium bicarbonate aqueous solution, saturated food and water were successively used for washing. The organic layer was dehydrated and dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the elution solvent was hexane-ethyl acetate) to obtain 4-(4 -Benzyloxy-3 -isopropylbenzyl p-toluidinesulfonate) -3,5-dimethylbenzylamine 371. 'H-NMR (CDC 1 3) δ P Pm:]. 16 (6H, d, J = 6.9Hz), 2.34 (6H, s), 3.32 (1H, seven-line, J = 6.9Hz), 3.67 (2H , Brs), 4.98 (2H, s), 6.49 (2H, s), 6.57 〇H, dd, J = 2.0, 8.5Hz), 6.70 (ih, d,) = 8.5Ηζ), 6.96 (] H, d, J = 2.0 Hz), 7.26-7.50 (5H, m) Reference Example 5 4 2 Cyclohexane-1- [5- (2, 6-Dimethyl-4-nitrophenoxy)-2-hydroxybenzene ] Ethyl ketone, and 2-cyclohex-1- [5- (2,6-dimethyl-4-nitrophenoxy) -2-methoxybenzene; | ethyl ketone makes 3,5-methyl-4- (4 -5.0 g of methoxyphenoxy) n-benzene and 7.35 g of cyclohexylacetamidine were dissolved in 25 mL of dioxane, and 10 mL of titanium tetrachloride was added dropwise thereto under ice-cooling stirring. After stirring under an argon atmosphere at room temperature for 20 hours, ice water was slowly added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure:

1 111

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1233358 V. Description of the invention (87) The residue obtained was purified by silica gel column chromatography (solvent: hexane-ethyl acetate), and 2 -cyclohexyl_ 1 _ [5 _ (2,6-difluoren-4-nitrophenoxy) -2-hydroxyphenyl] ethanone 0.69g, and 2-cyclohex-1- [5- (2,6-dimethylformate] -4 -nitrophenoxy) -2-oxophenyl] ethyl ketone 2. 74g. 2-Cyclohexan-1- [5- (2,6-dihydrazone-4-nitrophenoxy) -2-hydroxyphenyl] ethanone 2H-NMR (CDC) 3) 6 p pm: 0.7-1. 35 (5H, m), 1.60-1.95 (6H, m), 2.23 (6H, s), 2.67 (2H, d, J = 6.7Hz), 6.84-7.00 (2H, m), 7.07 (1H, d, J = 2.6Hz), 8.04 (2H, s), 12.07 OH, s) 2-cyclohexyl-1- [5- (2,6-dimethyl-4-nitrophenoxy) -2-methoxybenzene] ethyl Ketone 1H — NMR (CDC 1 3) ό p pm: 0.88-1.35 (5H, m), 1.45-2.00 (6H,

m), 2.20 (6H, s), 2.81 (2H, d, J = 6.7Hz), 3.86 (3H, s), 6.82 (1H, dd, J = 3.1, 9.0Hz), 6.87 (1H, d, J = 9.0Hz), 7.01 (1H, d, J = 3.1Hz), 8.00 (2H, s) Reference Example 5 5 In the same manner as in Reference Example 54, the following compounds were synthesized. [5- (2, 6-Dimethyl-4-nitrophenoxy) -2-hydrazone] (2-methoxybenzo) methanone'H-NMR (CDC 1 3) S p pm: 2.22 (6H, s), 3.60 (3H, s), 3.66 (3H, s), 6.77-6.84 (2H, m)? 6.88-6.93 (2H? m), 6.96-7.03 (1H? m), 7.40 -7.47 (1H, m), 7.51-7.55 (1H, m), 7.99 (2H, s) Reference example 5 6 [5- (2,6-dimethyl-4-nitrophenoxy) -2-hydroxybenzene] (2-fluorene Benzene) methanone, and [5- (2, 6-Difluorene-4-nitrophenoxy) -2-hydroxyphenyl] (2-hydroxybenzene) fluorenone make [5- (2, 6-Difluorene-4 -Nitrophenoxy) -2-fluorenoxybenzene] (2-methoxyphenyl) methanone

C: \ 2D-CODE \ 91-07 \ 91110283a.ptd Page 92 1233358 V. Description of the invention (88) --- 1. 1. oig is dissolved in 30mL of dichloromethane, and 1M trichloride is added dropwise under ice cooling. After 12 mL of the fossil pentoxide gas methane solution, stir at room temperature overnight. 2. Add the reaction mixture to 200mL of ice water and 50mL of digas methane, Θ 'human liquid II, and stir overnight at room temperature. The organic layer was separated and the aqueous layer, digas methane, was extracted. The organic layers were combined, and this was sequentially washed with a saturated aqueous solution of sodium hydrogen hydroxide and a saturated sodium chloride solution, dried with anhydrous magnesium sulfate, dried, and concentrated under reduced pressure. The obtained residue was purified by a silica gel tube = decantation method (the dissolution solvent was ethyl acetate-hexane) to obtain [51 (^, 6-1, dimethyldi-4 :, phenoxy), 2-2, Benzene] (2-methoxybenzophenone) ketone and [5-((2,6-'difluorene-4-nitrophenoxy) -2-hydroxyphenyl] (2-hydroxybenzene) methanone (38:62 ) 1 48 mg ° [5- (2, 6-Difluorene-4-nitrophenoxy) -2-hydroxybenzene] (2-fluorenylbenzophenone) H-NMR (CDC13) δ ppm: 2.23 (6H , s), 3.73 (3H, s), 6.72 (1H, d, J = 3.0Hz), 6.78-6.86 (2H, m), 6.87-7.05 (2H, m), 7.27-7.32 (1H, m), 7.43-7.53 (1H, m), 8. 〇〇 (2H, s), 11.99 (1H, s) [5- (2,6-Difluorene-4-nitrophenoxy) _2_hydroxybenzene] (2_ Hydroxybenzophenone H-NMR (CDCI3) δ ppm: 2.23 (6H, s), 6.77-6.92 (2H, m), 6. 95-7 06 (3H, m), 7.39-7.54 (2H, m) , 8.00 (2H, s), 10.〇8 (1H, s), 10.6. Reference Example 5 7 Dimethyl + Shishophenoxy) -2 ^ benzyl] ethyl ketone makes 2 yi-1-[ 5 — (2, 6_dimethyl-1, 4-nitrophenyloxy) ~ 2, 2.62g of dimethyl is dissolved in digas, and it is added under cold search.

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! 233358 V. Description of the invention (89) 13.2mL of boron trichloride digas methane solution, and stir at room temperature for 24 hours. After the reaction mixture was added dropwise with 10 mL of methanol under ice-cooling stirring, dilute hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dehydrated and dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 2-cyclohex-1- [5- (2,6-dimethyl-4—nitrophenoxy) — 2-monohydroxybenzene] ethyl ketone 2.45g 〇-NMR (CDC13) δ PPm: 0.77-1.35 (5H, m), (6H > m) '2.23 (6H' s), 2.67 (2H 'd, j = 6.7Hz), 6.84-7.00 (2H, m) 7 (】 jj d, J = 2.6Hz), 8.04 (2H, s), 12.07 (1H, s) '' · 'Reference example 5 8 2 (2-ring Hexylethyl) -4-(2,6 -dimethyl-4-nitrophenoxy) I the secret ambassador 2-cyclohexanedifluorene ~ ^ 2.60g > after 50mL of Tanyu diqijia 'stir this at room temperature 10 mL of diacetic acid and 5.5 mL of triethyl acetic acid were given below, and they were given at room temperature for two hours. The reaction mixture was diluted with water, and the organic layer was made with ethyl acetate. Saturated sodium bicarbonate aqueous solution and saturated water were used to extract the strips. After dehydration and drying with anhydrous sulfuric acid, it was shrunk under reduced pressure: 7 The residue was washed. After Shixi gel column chromatography (the elution solvent is hexane_acetate, the purification of 1 was obtained, and 2- (2-cyclohexylethyl) ~ 4 gas 2 6-dijiu acetone) was obtained. 2.0g. Xiao Benrui) ⑴―NMR (CDC 1 3) δ P Pm: 0 · 80-] · 01 (2Η, m),]. 〇7 一] 35 (4Η m), 1.37-1.50 (2H? M), 1.57-1.80 (5H, m), 2.21 (6H, s), 2.45 ^ 2 60 (2H m), 4.56 (1H, s), 6.39 (1H, dd, J = 3.0, 8.6Hz), 6.53 (1H, d, J = 3 〇Hz) '6.65 (1H, d, J = 8.6Hz), 8.00 (2H, s)'

1233358 V. Description of the invention (90) Reference example 59 In the same manner as in Reference example 5 8, the following compounds were synthesized. 4- (2,6-difluorene-4 4-stone phenoxy)-2-[2-(4-tetrahydrobromide σ south) ethyl] benzene 1H —NMR (CD C 1 3) δ p pm: 1 27-1. 38 (2H, m), 1.47-1.56 (3H, m), 1.61-1.68 (2H, m), 2.21 (6H, s), 2.53-2.60 (2H, m), 3.32-3.40 ( 2H, m), 3.93-3.99 (2H, m), 4.62 (1H, s), 6.38 (1H, dd, 1 = 3.0, 8.6Hz), 6.5 6 (1H, d, J = 3.0Hz), 6.63 ( 1H, d, J = 8.6Hz), 8.00 (2H, s) Reference example 6 0 2-[6-Benzamidine-3- (4-dimethylamine-2, 6-xylyloxy) -2-hydrazone Benzene] propan-2-ol dissolves 1.32 g of 1- [6-etooxy-3-(4-dioctylamine-2, 6-xyloxy-2-oxobenzene] ethanone in 100 mL of tetrahydrooctane, To this, 1.05M lithium diethyl ether solution 4.05ml (total) was added in fractions at a temperature of -78 ° C. After stirring in this state for 30 minutes, the reaction mixture was gradually warmed up. To room temperature. To the reaction mixture was added 40 mL of a saturated aqueous solution of ammonium hydroxide, and after stirring for 10 minutes, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then It was concentrated under reduced pressure to obtain 2-[6-benzyloxy-3-(4-diamidamine- 2,6-dioxophenoxy) -2-methoxybenzene] propan-2-ol 1. 37 g.} H-NMR (CDC 1 3) δ p pm: 1.72 (6H, s), 2.02 (6H, s ), 4.03 (3H, s), 4.61 (4H, s), 5.00 (2H, s), 6.25 (1H, d, J = 9.1Hz), 6.47 (2H, s), 6.53 (1H, d, J = 9.1Hz), 7.22-7.42 (1 5H, m) Reference example 6 1

C: \ 2D-OODE \ 91-O7 \ 91110283a.ptd Page 95 1233358 V. Description of the invention (91) N, N-Dibenzyl- [4-(4-Ethoxy-3 -isopropene-2 -methoxy) Stupid oxygen) a 3 5_ diphenylamine, a make 2-[6_ " V oxygen-3- (4-dioctylamine-2, 6_ dimethylbenzyloxy)-2 a methoxyphenylpropan-2-ol 1.37 g was dissolved in 20 mL of dichloromethane, and 10 mL of concentrated hydrochloric acid was added thereto, followed by vigorous stirring for 20 minutes. The reaction mixture was subjected to overnight, and the aqueous layer was extracted with ethyl acetate. Combine the organic layers, and do this along with Ertian Wen. ^ U, —, Liu Zuo a ”human μ 丨 only-people use 2mol / L lice sodium hydroxide solution, saturated saline solution to wash, after drying, Concentrated under reduced pressure, so that "Shao &," ,, water & I magnesium dehumidification chromatography (the dissolution solvent is ethyl acetate,: / slag passes through a silica gel tube column master _ [4_ ( 4 octyloxy 3_isopropyl 1,2 and hexamethylated to give 898mg of N, N-di. Methamphetamine) -3,5-dimethyl] aniline Η-NMR (CDCI 3) δ p pm : 2. 03 (6H, s \ (3H, s), 4.60 (4H, s), 4.97 (2H, s), 4.99 (] H s) '2.12 (3H' S), 3.95 (] H, d, > 9.0ΗZ), 6.44⑽d, J = 9.0 Hz), 6.47 'S, 5.35 (1H, s), 6.22 m) H, s), 7.23_7.44 () 5H, Reference Example 6 2 4-(2, 6-Difluorene-4 -nitrophenoxy) benzene test results in 4- (4-methoxyphenoxy) -3, 5-dimethyldepletion 9nq ^ 2 ·, right This solution was dropped at the temperature of -7 generations ^ Ben 2 from _ dissolved in diqijiaxuan ^ Ί, π ^ ^ 口 口 1M boron tribromide solution in dichloromethane 1 50 # g, then at room temperature 室温_ #, c ^ person ^ meaning .. r Λ T mb, sigh together. Add ice 'tax to the reaction mixture After 1 hour, the reaction mixture was taken out with dichloromethane. The machine was washed with a solution of a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and under reduced pressure? Chen Xi, the obtained record>, 杳 传 m _ U / 忖 ”meaning residue / should be crystallized with methane and hexane, and pay 4- (2,6-dimethyl-4-nitrate Stable oxygen) phenol 84mg.

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Page 96 1233358 V. Description of the invention (92): H (CDC… ppm: 2 2i (6H, s), 4 49 (iH, s), 65 (2H, m), 6.72-6.78 (2H, ηι ), 8. 〇〇 (2H s) iCase 6 3 3- [3- [4- (2, 6-dimethyl-4 ~ nitrophenoxy) phenoxymethyl] benzene] propylene makes 4- (2 , 6-Dimethyl-4-shisha phenoxy) * Pan 400mg final Mo_3 one Potassium 7⑽claw 'was heated and refluxed for 3 days. The spleen was placed at a concentration of 2 g, and the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and acetic acid 7 舻 was not used for you. Shishi 'catty. 0 Wen Yi S said to be taken. The organic layer was washed with saline and washed with water, and then dried by dehydration, drying, and dehydration. The obtained residue was purified by Shixi gel column chromatography (eluent: ethyl acetate-hexane under m:>), and 3_ [3_ [4 一 (2,6_ 二 曱 Μ 曱) was obtained. ,: ,, oxygen) phenoxyfluorenyl] benzene] methyl acrylate 604 mg. 屮 -NMR (CDCl3) δ ppm: 2.2] (6H, s), 38i (3H, s), 502 2H, s ), 6.46 OH, d, J = 16.0Hz), 6.65-6.80 (2H, m), 6.85-6.90 (2H, m) 7.3H.50 (3H, m), 7.57 〇H, brs), 7.70 (] h, d, j =] 600 Hz), 800 ( 2h, 's) Reference Example 6 4 3- [3- [5- (2,6-Dimethyl-4_nitrophenoxy) 2_hydroxyl] benzene] acrylic acid 3- [3- [4- (2 , 60-mg of 6-dimethyl-4-nitrophenyloxy) phenoxymethyl] benzene ^ methyl ester was added with 4 mL of trifluoroacetic acid, and heated to reflux overnight. -Add the saturated sodium bicarbonate aqueous solution and acetic acid acetate to the mixture and stir for 1 hour. The reaction mixture was subjected to liquid separation, and water was extracted: the ethyl acetate was extracted at room temperature. The organic layers were combined, washed with saturated food, dried with anhydrous magnesium sulfate, and dried under reduced pressure. Make income

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1233358 V. Description of the invention (93) The residue obtained is purified by Shixi gel column chromatography (the dissolution solvent is ethyl acetate-hexane) to obtain 3- [3- [5- (2,6- 二Metronidoxy) 2] Benzene] Acrylic acid acrylate 204 mg.

2H ~ NMR (CDC 1 3) δ P pm: 2.19 (6Η, S), 3.81 (3Η s) 3 94 (2H, s), 6.38 OH, d, J = 16.0Hz), 6.45 (, H (dd, J = 3.0; 8.7Hz) 6 56 '(] H-: ΙΙΤ98 (;; /;) Η, d, ί = δ · 7Ηζ), 7.18 " · 40 (4H > m) * 7 · 64 ^ ^ Reference Example 6 5 3-[3-[5-(4-Amino-2,6 ~ dimethylformaldehyde ⑤, 0 make 3- [3- [5- (2,6-dihydrazine a verse] benzene] c) Sour vinegar 20 is finely dissolved in tetrahydrocytane 30mL / ben = 2—W] benzene] acrylic acid solution 2mL, and in an argon atmosphere, 2mol / L sodium hydroxide water was added overnight. The reaction mixture ^ Stir at 5 ° C / L hydrochloric acid, and wash the residue with 2 mol of water with ethyl acetate / Chenj, and wash it with water. 2) Anhydrous 2: Stroke: "The organic layer is obtained by using saturated table salt. 3-[3-[5-(2 6 _ times, after dehumidification and drying, concentrated under reduced pressure, 198 mg. Use the obtained 3: "A / 4-nitrophenoxy) -_ 2-by-narrow] benzene ] Acrylic acid hydroxyamidine] benzene] acrylic acid, it was achieved by 蛊 ~ [5_ (2 '$ 厂 甲 _4_nitrophenoxy) -2 one tμ 6. The same method as described in Reference Example 66 was achieved. 6 ~ 2 Toluene) -2-Hydroxybenzyl] benzene] propionic acid] H-NMR (CDC13) δ pPm.2 π. Z), 2.88 (2H, t, Bu 7.8Ηζ), 3.87 (2H · 2 '(6H, s), 2.57 ⑽, U] = 7.8 · m), 6.66 (] H, d, J = 8.7Hz), 7.0 (M.〇5 (S, 6.42 (2H, s), 6.43 · 6 · 48 (2H, UH, (7.15--7.19 OH, m) Reference Example 66

1233358

4- (4-Amino-2, 6 ~ xyloxy) -2- (4-tetrahydropiperanylmethyl) phenol makes 4- [2_ (Phenoxy) subsection] 202 mg of tetrahydropiperan is dissolved in a mixed solvent consisting of 10 mL of ethanol and 2 mL of ethyl acetate, and this is added in portions under ice cooling; [0% palladium carbon catalyst 50 mg (total) / And, it was stirred at room temperature under a hydrogen atmosphere and under normal pressure for 24 hours. After removing insoluble matters, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate) to obtain 4- (4-monoamino-2, 6-Dioxophenoxy) -2- (4-tetrahydropiperanylmethyl) phenol 11911 ^. ^ -NMR (CDC1S) 6 p pm: 1.26-1.41 (2H, m), 1.49-1. 6J (2H, m), 1.74-1.88 (1H, m), 2.03 (6H, s), 2. 42- 2.52 (2H, m), 3.26-3.40 (2H, in), 3.55 (2H, brs), 3.89-4.00 (2H, m), 5.30 (] H, brs), 6.31 (1H, dd, J = 3.0, 8.6Hz), 6.39-6.48 (3H, m), 6.56 (1H, d, J = 3.0Hz) Reference Example 6 7 In the same manner as in Reference Example 66, the following compounds were synthesized. Bu [5- (4-Amino-2, 6-xyloxy) -2 -hydroxyphenyl] -2-cyclohexanone * H-NMR (CDC 1 3) δ p pm: 0.75-1. 38 (5H, ηι), 1.45-1.95 (6H, m), 2.04 (6H, s), 2.67 (2H, d, J = 6.7Hz), 3.54 (2H, brs), 6.44 (2H, s), 6.87 (1H, d, J = 9.0Hz), 6.94 (1H, dd, J = 2.9, 9.0Hz), 7.07 (1H, d, J = 2.9 Hz), 12.00 OH, s) 4-(4 -amino -2,6-xylyloxy) -2_ (2-cyclohexylethyl) benzene 1H —NMR (CDC I 3) pm: 0. 85-0. 98 (2H, m), 1.08-1.33 ( 4H, m), 1.40-1.50 (2H, m), 1.59-1.81 (5H, m), 2.03 (6H, s), 2.48-2.58 (2H, m), 3.50 (2H, brs), 4.52 (1H, brs), 6.38 OH, dd, J = 3.1, 8.6Hz), 6.42 (2H, s), 6.56 (1H, d, J = 8.6Hz), 6.58 〇Hy d, J = 3.1Hz)

C: \ 2D-00DE \ 91-07 \ 91110283a.ptd Page 99 1233358 V. Description of the invention (95) 4-(4-amino-2, 6-xylyloxy 2-isopropyl-3-methoxyphenol 2H-NMR (CDC 1 3 + CD3OD) δ ppm: 1.39 (6H, d, J = 7.1Hz),

2 · 05 (6H, s), 3.55 (1H, sevenfold line, ί = 7 · 1Ηζ), 3.96 (3H, s), 6.02 (1H, d, J = 8.8Hz), 6.24 (1H, d , J = 8.8Hz), 6.47 (2H, s) 4-[4-fluorenyl-3- [2- (2-methoxyphenyl) ethyl] phenoxy] _3, 5-dimethyltoluidine'H-NMR (CDC 1 3) S ppm: 2.01 (6H, s), 2.80-2.90 (4H, m), 3. 48 (2H, brs), 3.75 (3H, s), 3.80 (3H, s), 6.41 (2H , s), 6.44 (1H, dd, J = 3.1, 8.8Hz), 6.59 (1H, d, J = 3. 1Hz), 6.67 (1H, d, J = 8.8Hz), 6.82-6.85 (2H, m ), 7.03-7.06 (1H, m), 7.12-7.18 (1H, m) (4-amino-2, 6-diphenylbenzene) (4-hydroxy-3-cumene) ketone 1H-NMR ( CDC I 3) ό ppm: 1.22 (6Η, d, J = 6.9Hz), 2.03 (6H, s), 3.25 (1H, seven-line, J = 6.9Hz), 6.40 (2H, s), 6.64_6 .68 (lH, m), 7.34-7.41 (1H, m), 7.81 (1H, brs) 4- (4-amino-2, 6-diphenylene) -2-isopropylphenol'H-NMR ( CDC 1 3) δ p pm: 1.19 (6H, d, J = 6. SHz), 2. 15 (6H, s), 3.08 (2H, brs), 3.21 (] H, seven line, J = 6.9Hz) , 3.86 (2H, s), 6.45 (2Η, s), 6.51-6.59 (2H, m), 6.89-6.92 OH, m) 4- (4-methoxybenzyl) -3, 5-dimethyltoluidine ] H — NMR (CDC 1 3) ό p pm: 2. 14 (6H, s); 3 .48 (2H, brs), 3.76 (3H, s), 3.88 (2H, s), 6.43 (2H, s), 6.74-6.78 (2H, m), 6.90-6.93 (2H, m) 4-(4 -Amino-2, 6-xyloxy) -2-(4-fluorophenoxy) phenol

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V. Description of the invention (96) iH — NMR (CD C 1 3 + CD 3〇D) ρ pm: 2.00 (6Η, s), 6.34-6.41 (2Η, m), 6.37 (2H, s), 6.86 OH , d, J = 8.7Hz), 6.93-7.05 (4H, m) 4-(4-amino-2, 6-dioxophenoxy)-2- (4-tetrahydropiperane) NMR (CDC 1 3) δ p pm: 1.73Ί. 83 (2H, m), 2.01-2.07 (2H, m), 2.04 (6H, s), 3.53 (2H, brs), 3.53-3.60 (2H, m), 3.95-4.00 (2H, m), 4.38-4.46 (1H, m), 5.24 (1H, brs), 6.14 (1H, dd, 3 = 2.8, 8.7Hz), 6.14 (2H, s), 6.49 OH, d, J = 2.8Hz), 6.75 (1H, d, J = 8.7Hz) 4-(4-amino-2, 6_dimethylformamidine) -2-(4-tetrahydropiperanyloxy) benzyl Phenol] H-NMR (CDC 1 3 + CD3〇D) δ ppm: 1.72-1.80 (2H, jn), 1.97 -2.04 (2H, m), 2.14 (6H, s), 3.48-3.57 (2H, m), 3.85 (2H, s), 3.93-4.0 〇 (2H, m), 4.33-4.60 (1H, m), 6.45 (2H, s), 6.45-6.50 (1H, m), 6.54-6. 56 (1H, m), 6.76-6.80 (] H, m) Reference Example 6 8 l- (4-amino-2,6-xylyloxy) -4-octyl-5, 6, 7, 8-tetra Hydronaphthalene dissolves 1-neoxy-4-(2, 6-dimethyl-4-nitrophenoxy) -5,6, 7, 8 -tetrahydroqin 1 5 · 5mg in 5mL of ethanol and 1mL of tetrahydrofuran Constitutive Co-solvent, to which was added 1 billion fractional New% carbon catalyst 5 m g (total) under ice-cooling, and stirred for 24 hours at the room temperature under hydrogen atmosphere under normal pressure and be. After removing the solubles, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by a silica gel column reductive method (solvent: hexane-ethyl acetate) to obtain (4-amino group q-2, Omg。 6-xylylene) -4-narrow oxygen-5, 6, 7, 8-tetraphthalene 14. Omg. ] H — NMR (CDC 1 3) ό p pm: 1.70-1.94 (4H, m), 2.04 (6Hy s), 2. 68-2.95 (4H, m), 3.47 (2H, s), 4.96 (2H, s), 6.02-6.12 (1H, m), 6.38-6. 54 (3H, m), 7.20-7.50 (5H, m)

C: \ 2D-C0DE \ 91-07 \ 91110283a.ptd Page 101 1233358 V. Description of the Invention (97) Reference Example 6 9 In the same manner as in Reference Example 68, the following compounds were synthesized. 4- (4-benzyloxy-3 -cumyloxy) -2, 3, 5-trichloroaniline 1H_NMR (CDC 1 3) 6 ppm: 1.21 (6H, d, J = 6.9Hz), 3.37 〇H, Seven-line,] = 6.9Hz), 4.19 (2H, brs), 5.0] (2H, s), 6.42 OH, dd, J = 3 ·], 8. 8Hz), 6.76 (1H, d, J = 8.8Hz ), 6.82 (1H, s), 6.88 (1H, d, J = 3.1Hz), 7.29 -7.47 (5H, m) 4-(4-benzyloxy-3 -cumyloxy) -3, 5 -di Bromoaniline 1H — NMR (CDC 1 3) δ ppm: 1.21 (6H, d, J = 6.9Hz), 3.37 (1H, seven-line, J = 6.9Hz), 3.71 (2H, brs), 5.0] (2H, s), 6.45 (] H, dd, J = 3.1, 8.9Hz), 6.77 〇H, d, J = 8.9Hz), 6.85 (1H, d, J = 3.1 Hz), 6.90 (2H, s) , 7.28 -7.46 (5H, m) 4- (4-octyloxy-3 -cumyloxy)-2,3,5-tritoluidine] H-NMR (CDC 1 3) ό p pm: 1.19 (6H, d, J = 6.9Hz), 2.03 (3H, s), 2.05 (3H, s), 2.08 (3H, s), 3.36 (1H, seven line, J = 6.9Hz), 3.46 (2H, brs), 4.99 (2H, s), 6.33 (1H, dd, J = 3.0, 8.8Hz), 6.46 (1H, s), 6.72 (1 H, d, J = 8.8Hz), 6.80 (1H, d, J = 3.0Hz ), 7.27-7.46 (5H, m) 4- (4-benzyloxy-5, 6, 7, 8-tetrahydro-1-naphthyloxy) -2, 3, 5-trichloroaniline

] HN: MR (CDC 1 3) δ p pm: 1. 75-1. 88 (4H, m), 2.74-2.80 (2H, m), 2.87-2.95 (2H, m), 4.18 (2H, s) , 4.98 (2H, s), 6.10 OH, d, J = 8.8H z), 6.52 (1H, d, J = 8.8Hz), 6.82 (1H, s), 7.28-7.45 (5H, m)

Page 102 C: \ 2D-CODE \ 91-07 \ 91110283a.ptd 1233358 V. Description of the invention (98) 6- [5- (4-Amino-2,6-dioxophenoxy) -2-hydroxylamine ] -211-Diporphin-3-one ^ -NMR (CDC 1 3 + CD3OD) 0 ppm: 2.01 (6H, s), 3.84 (2H, s), 6.43 (2H, s), 6.50 (1H, dd, J = 3.0, 8.7Hz), 6.55 (1H, d,] = 3.0Hz), 6.70 (1H, d, J = 8.7Hz), 6.86 (1H, d, J = 9.7Hz), 7.26 (1H, d, J = 9.7Hz) 4- (4-amino-2,6-xylyloxy)-2- [2- (4-tetrahydropiperan) ethyl] phenol 1H —NMR (CDC 1 3) δ p pm : 1.23-1. 35 (2H, m), 1.45-1.55 (3H, m), 1.60-1.68 (2H, m), 2.04 (6H, s), 2.52-2.58 (2H, m), 2.73 (2H, s), 3.31-3.40 (2H, m), 3.91-3.98 (2H, m), 6.39 (1H, dd, J = 3.0, 8.7Hz), 6.4 4 (2H, s), 6.54 (1H, d, J = 3.0Hz), 6.59 OH, d, J = 8.7Hz) 4- (4-Hanoxy-3 -cumyloxy) -3,5-dimethyltoluidine'H-NMR (CDC 1 3) δ ppm: 1.19 (6Η, d, J = 6.9Hz), 2.04 (6H, m), 3.36 (1H, seven lines, 1 = 6.9Hz), 4.99 (2H, s), 6.38 (1H, dd, J = 3.0, 8.8

Hz), 6.42 (2H, s), 6.73 (1H, d, J = 8.8Hz), 6.79 OH, d, J = 3.0Hz), 7.23-7.48 (5H, m) Reference example 7 0 N- [4- Ethyl 4- (4-octyloxy-3 -cumyloxy) -3,5-xylene] aminoammonium acid 1.3 7g was dissolved in digas simmered 30 m L, to which 0.67 m L was added. Under ice-cold stirring, ethyl carbonate SI 0. 0 47 ml was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 5 mL of dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and dried, and then concentrated under reduced pressure to obtain a residue.

C: \ 2D-C0DE \ 91-07 \ 91110283a.ptd Page 103 1233358 V. Description of the invention (99) Purified by silica gel column chromatography (solvent: hexane-ethyl acetate) to obtain 4 7 g。 N- [4- (4-benzyloxy-3 -cumeneoxy) -3,5-xylene] carbamic acid ethyl acetate 1. 4 7 g. 1H-NMR (CDC 1 3) ppm: 1. J9 (6H, d, J = 6.9Hz), 1.32 (3H) t, J = 7.1Hz), 2.11 (6H, s), 3.37 (1H, 7-line, J = 6.9Hz), 4 · 23 (2H, q, J 2 7.1Hz), 5.00 (2H, s), 6.35 (1H, dd, J = 3.0, 8.8Hz), 6.50 (1H, brs ), 6.73 (1H, d, J = 8.8Hz), 6.78 (1H, d, J = 3.0Hz), 7.11 (2H, s), 7.23-7.48 (5H? M) Reference example 71

N- [4- (4-Phenyloxy-3 -cumyloxy)-2-fluoro-3,5 -xylyl] carbamate acetamidine I makes N- [4- (4-Phenyloxy-3 -isopropylbenzene) Phenoxy) -33.6-dioxophenyl] carbamate 743.6mg was dissolved in 1,2 dioxane and 50mL was added. To this was added N-fluoro-6- (trifluorofluorenyl) fluorene ingot-2- After the sulfonate was stirred at room temperature for 15 minutes, it was then heated under reflux for 12 hours. After allowing to cool, 20 mL of dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate). Omg。 And to obtain N-[4- (4-benzyloxy-3-cumyloxy) -2-fluoro-3,5-dioxophenyl] aminoacetic acid ethyl ester 348.0M. — NMR (CD C 1 3) δ ppm: 1.19 (6H, d, J = 6.9Hz), 1.34 (3H, t, J = 7.] Hz), 1.96-2.20 (6H, m), 3.36 (] H , Seven lines, J = 6.9Hz), 4.26 (2H, q, J = 7.1Hz), 5.00 (2H, s), 6.34 (1H, dd, J = 3.1, 8.8Hz), 6.66-6.84 (2H , m), 7.16-7.53 (5H, m), 7.73-7.92 (1H, m)

C: \ 2D-OODE \ 91 -07 \ 9m〇283a.ptd P.104 1233358 V. Description of the invention (100) Reference example 7 2 4- (4-octyloxy-3-cumyloxy) -2 2-fluoro 340 mg of N- [4- (4-Ethyloxy-3 -cumyloxy) -1,2-fluoro-3,5-diphenylphenyl] carbamic acid ethyl acetate was dissolved in ethanol. 'To this, 8 mL of imio / L sodium hydroxide aqueous solution was added, and it stirred at 90 t for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated food and water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to Shixi gel column chromatography (the solvent was hexane-ethyl acetate). ) Purified to give 200 mg of 4- (4-benzyloxy-3-cumyloxy) -2-fluoro-3,5-diphenylaniline. ^ -NMR (CDC13) δ PPm: 1.19 (6H, d, J = 6.9Hz), 1.93-2.10 (6H, m), 3.36 (1H, J = 6.9Hz), 3.57 (2H, brs), 5.00 (2H , s), 6 .; 6 OH, dd, J = 3.1, 8.8Hz), 6.51 (1H, d, J = 9.9Hz), 6.73 (1H, d, j = 8 8Hz) 6.77 (1H, d, J = 3.1Hz), 7.20-7.54 (5H, m) '' · Reference Example 73 (4-amino-2, 6-xylene) (4-Narrow-oxy-3 -cumene) ketone, (4- Amino-2, 6-dibenzobenzene) (4-hydroxy-3-cumene) 86 mg of methanone was dissolved in 15mL of furfuran, and palladium carbonate and bromobenzone 3 6 // L were added under ice-cooling. While stirring under an argon atmosphere at room temperature overnight. ^ Residues obtained in addition to $ ㈣mm㈣ were purified by Shixi gel 4-layer chromatography (developing solvent was hexane-ethyl acetate) to obtain (4-amino-2,6-xylene) (4 -Oxygen-cumene) fluorenone 28mg. iH-NMR (CDCl3) δ ppm: 1.24 ⑽, d, Η ·, 2. s), 3.39 (1H, seven-line ,; 1 = 6 · 9Ηζ), 3.66 (2H, brs) 5] W9u, ' , Jos), 6.39 (2H,

1233358 V. Description of the invention (101) ^ --- s), 6.83-6.88 (1H, m), 7.32-7.44 (5H, m), 7.48-7.53 (1H, m), 7.88 (1H, brs) Reference examples 7 4 2,2,2-trifluoro-N-[4- (4_fluorenylbenzyl) -3,5-xylene] acetamide makes 4-(4-methoxynarrow) -3, 5-di 662 mg of methylbenzylamine was dissolved in 30 mL of dichloromethane, and after adding cytidine 2 6 6 // L, trifluoroacetoxane 4 2 0 // L 'was added under ice-cooling and the mixture was administered at room temperature. Mix overnight. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was sequentially washed with water, a saturated sodium bicarbonate aqueous solution, and a saturated saline solution, dried with anhydrous sulfuric acid, wet-dried, and concentrated under reduced pressure to obtain 2,2,2-trifluoro-N-[4-(4 ~ Grandfather) -3,5-Diphenylbenzene] Ethylamine 83611 ^. — 2H-NMR (CDC 1 3) δ p pm: 2. 25 (6H, s), 3. 76 (3H, s) 3 97 (2H, s), 6.75-6.83 (2H, m), 6.86-6.92 (2H, m), 7.27 (2H, s), 7.73 (1H brs) Reference example 75 2,2,2-Trigas-N-[4-[3- (4-Gas benzyl alcohol)] 4_ Jing Ye ] 一 3 5 Benzene] acetamide 'makes 2,2,2-trigas 1- [4- (4-methoxy section) _3,5-xylene] acetamide

836 mg was dissolved in 2 mL of digas, and 4 fluorobenzene tritium gas and 11 hng of gasification were added thereto, and the mixture was stirred overnight at room temperature. 20 mL of water was added to the reaction mixture, and after stirring at room temperature for 30 minutes, the reaction mixture was extracted with methane gas. The organic layer was washed successively with water and a saturated aqueous solution of sodium bicarbonate, dehydrated and dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (the developing solvent was hexane).

C: \ 2D-OODE \ 91-O7 \ 91110283a.ptd 1233358 V. Description of the invention (102) Alkane-ethyl acetate) was purified to obtain 2,2,2-trifluoro-N-[4-[3-( 4-Fluorobenzidine)-4 -Chrysene] -3,5 -methylbenzyl] acetamide 48mg. -NMR (CDC 1 3) δ p pm: 2.22 (6H, s), 3 94 (2H, s), 6.98 OH, d, J = 8.6Hz), 7.07-7.20 (4H, m), 7.26 (2H, s), 7.55-7.61 (2H, m), 7.75 (1H, brs), 11.68 (1H, s) Reference Example 7 6 [5- (4-amino-2, 6-dimethylformer) -2 ~ hydroxy Benzene] (4-fluorobenzene) fluorenone makes 2,2,2-difluoro-N- [4- [3- (4-fluorobenzylhydrazone) -1,4-hydroxyphenyl] -3,5-dibenzobenzene 45 mg of acetamidine was added to 3 mL of ethanol, and 3 mL of lm01 / L sodium hydroxide aqueous solution was added thereto, and the mixture was stirred under an argon atmosphere at a temperature of 60 t for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in water, and extracted with methane gas. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and dried, and then concentrated under reduced pressure to obtain [5- (4-amino-2,6-dihydrazone]. )-2-Benzene] (4-fluorobenzene) methyl S with 26mg.

'H-NMR (CDC 1 3 + CD3〇D) δ P pm: 2.11 (6H, s) 3 85 (2H

s), 6.42 (2H, s), 6.95 (] H, d, J = 8.5Hz), 7.10-7.17 (2H, m) ’716 (1H

d, J = 2.0Hz), 7.22 (1H, dd, J = 2.0, 8.5Hz), 7.57-7.64 (2H reference example 7 7 4-(4-amino-2, 6-dioxophenoxy) -2 -(2 ~ cyclohexyl hydroxyethyl) phenol suspended 5.6 mg of sodium borohydride in tetrahydrofuran under 10 mL, and added 1- [5-(4-amino-2,6-dicarbamidine) (Oxy) -2 -hydroxybenzene] -2 -cyclohexyl ethyl ketone 52.3nig 'was stirred at room temperature for 6 hours. The reaction mixture was diluted

C: \ 2D-CODE \ 91-07 \ 91110283a.ptd Page 107 1233358 V. Description of the invention (103) Release water and extract with ethyl acetate, μ ^. Use saturated food for organic layer g | im water After acid dehydration and drying, ▲ concentration under reduced pressure ^ = > check ... gel column chromatography (solvent solvent is hexane ===) purification, and 4_ (4_amino group ~ 2 6 is obtained _Xylyloxy) _2-1-hydroxyethyl) phenol 5.0 mg. Yi Ji ^ H-NMR (CDC13) δ ppm: 0.73-1.94 〇3H, m), 2.03 (6H, s), 6H) TJT (Sh 4,75'4 * 93 〇H, m), 6 * 30 ' 6 * 50 (3H, m), 6.50 〇H, d, J = 8 6Hz), 6.60 (1H, d, J = 2.8Hz), 7.29 〇H, d, J = 3.] Hz) Reference example 78 A This milk)-2-Search this] (2-Benzyl) acetol to make [5- (2,6-Difluorene-4—Nitrosaurus, 9,…, / rr_r9-WA This milk) 2 hydroxy This] A mixture of (2-oxobenzophenone) ketone and r, _ ^-n-phenoxy) -2-benzyl] (2-benzyl) methanone • mg 'in ethyl acetate 2 OmL, This added platinum (IV) oxide mg & was allowed to fall for 2 hours under the atmosphere of f and hydrogen and under normal pressure. The filtrate was concentrated under reduced pressure except for the insoluble compounds, and the obtained residue was subjected to a thin layer chromatography on silica gel (Zhang Ye bow w, Gan a ,,,,,, stomach τ, and the developing bath medium was hexane-acetic acid). Ethyl ester (3: 1)) was purified to give 42 mg of [5- (4-amino group ~ 2,6-xylene) methanone and [5- (4-amine group ο c milk)) 72 mg of this methanol. Private group '2,6-xylyloxy) _2_Benzene] (2_Benzyl) methyl [5-((4-Amino_2'6 ~ xylyloxy) -2-hydroxybenzene] (2-methyloxy (Benzene) methanone] H-NMR (CDCl3) 5 ppm: 2〇5 (6Hs), (mS) > 6-4〇 (2H > S) '6 · 68'6 · 7 ^^,), 77 -, S4〇hm; 6 8; -69]

Oran ") 6.98 · 7 · 03 〇H, 7'32-7 · 36 —i9 〇, ',) ,,,

Page 108 1233358 V. Description of the invention (104) [5- (4-amino-2, 6-dioxophenoxy) -2-hydroxybenzene] (2-hydroxybenzene) methanol'H-NMR (CDC 1 3 ) 8 ppm: 2.04 (6H, s), 3.48 (2H, brs), 3.86 (1H, brs), 6.11 (1H) brs), 6.38 (2H, s), 6.43-6.46 (1H, m), 6.54- 6.57 OH, m), 6.68-6.73 (1H, m), 6.81-6.85 (2H, m), 6.88-6.92 (1H, m), 7.1 8-7.26 (1H, m) Reference example 7 9 1- [5 -(2,6 -Difluorene-4 -Shixiao phenoxy) -2- via benzene]-2-(4-tetrahydroguaran) ethyl ketone makes 4- (4-oxophenoxy) -3, 199 mg of 5-dihydrazine is dissolved in 15 ml of dichloromethane. To this is added 4 -tetrahydropyranacetamethane 4 7 3 mg, and tetra tetra titanium is added dropwise at 2. 6 mL, at room temperature. Stir for 2 days. The reaction mixture was poured into 100 ml of ice water, and 30 ml of dichloromethane was added thereto, followed by stirring for 20 minutes. The reaction mixture was separated, and the aqueous layer was extracted by dichloromethane. The organic layers were combined and washed successively with 1 mo 1 / L hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, and saturated saline solution. After dehydration and drying with anhydrous sulfuric acid, it was concentrated under reduced pressure. The obtained residue was subjected to silica gel. Purified by gel thin layer chromatography (developing solvent is hexane-ethyl acetate) to obtain 1- [5- (2, 6-dimethyl-4 _ nitrophenoxy) -2-viabenzene] -2- ( 4_ Tetrazolane) 96 mg of acetamidine. 1H-NMR (CDC 1 3) pm: 1.33-1.43 (2H, m), 1.60-1.70 (2H, m), 2.14-2.28 (1H, m), 2.23 (6H, s), 2.77-2.82 ( 2H, m), 3.38-3.47 (2H, m), 3.92-3.97 (2H, m), 6.86 (1H, dd, J = 3.0, 9.1Hz), 6.97 OH, d, J = 9. 1Hz), 7.15 OH, d, J = 3.0Hz), 8.04 (2H, s), 11.98 (1H, s)

C: \ 2D-C0DE \ 91-07 \ 91110283a.ptd Page 109 1233358 Case No. 91110283 Month Revised Replacement Page Schematic Description (:: \ Overall \ 91 \ 911 10283 \ 91110283 (Replace) -l. ptc page 142

Claims (1)

ΜψΚ 91110283% Amendment 94.2 2 * 18 Replace this VI. Please refer to Example 1Γ — 1. A liver cancer onset prevention or recurrence inhibitor, which contains a compound represented by the following general formula (I) or is equivalent to pharmacology Academically acceptable salt as active ingredient: X A R3 ⑴ [wherein R1 and R2 each independently represent a fluorenyl group or a halogen atom; R3 represents a hydrogen atom; W represents -0-; X represents a radical; Y represents isopropyl, 6-oxy-1,6_ Dihydrodagen-3 -ylfluorenyl or (4-fluorophenyl) hydroxymethyl; Z represents a hydrogen atom; A represents -NHCO-Y ^ COJ8-, -C0NHCH2C02H or -CH2CH (NH2) C02H; Y1 represents a bond Or -CHg-; R8 represents a hydrogen atom or an ethyl group]. 2. The inhibitory agent for the prevention or recurrence of liver cancer according to item 1 of the scope of patent application, wherein R1 and R2 are fluorenyl groups; Y is isopropyl or (4-fluorophenyl) hydroxyfluorenyl; A is -NHCO- Y1-C02R8 or -C0NHCH2C02H; Y1 is a bond or -CH2-, C: \ Overall files \ 91 \ 91110283 \ 91110283 (replacement) -l.pt (p.143 1233358 _ case number 91Π0283_ year month day _ charm _ 6. Application scope of patent R8 is hydrogen atom or ethyl group. 3. Such as The patent application scope item 2 is a liver cancer onset prevention or recurrence inhibitor, in which A is -NHC0CH2C02H. 4. A liver cancer onset prevention or recurrence inhibitor, which contains a compound selected from the following group or is equal to pharmacology Scientifically acceptable salt as an active ingredient: 4- [3-[(4-Gasbenzene) by hydrazone] -4-byphenoxy] -3,5-dimethylmalonic acid; 4- (4- Hydroxy-3 -cumyloxy) -3,5-difluorenylpropanediolide; 3,5-dibromo-3 '-(6-oxy-1,6-dihydrodagen-3- Amidino) -L-fluorenyladenosine, N- [4- [3-[(4-fluorophenyl) hydroxyfluorenyl] -4-hydroxyphenoxy] -3, 5-diphenylbenzene] -grass Ethylamine; and N- [3,5-dimethyl-4- (4-hydroxy-3-cumyloxy) benzamidine] aminoacetic acid. 5. — Prevention or recurrence suppression of liver cancer Agent containing 4_ [3-[(4_fluorophenyl) hydroxymethyl] -4-hydroxyphenoxy] -3,5_diamidinomalonic acid or a pharmacologically acceptable salt thereof as effective ingredient. (:: \ Total file \ 91 \ 911 10283 \ 911 10283 (replace) -l.ptc page 144