TW575564B - Piperazine derivatives and process for the preparation thereof - Google Patents

Description

575564 A7 B7 V. Description of the invention (

(I) In the printed format of the Consumer Cooperative Organization of the Central Standards Bureau of the Ministry of Economic Affairs, I and I respectively represent hydrogen atoms, substituted or unsubstituted ~ cs alkyl groups, and substituted or unsubstituted 3 to 6 cyclocycloalkanes of C3 to cs. Group, substituted or unsubstituted c: 2 ~ C8 unsaturated alkyl group, keto group, substituted or unsubstituted aromatic group, substituted or unsubstituted ^ ~ alkoxy group, substituted or unsubstituted aromatic hydroxyl group, substituted or Unsubstituted amine group, Cl ~ C4 lower ester group, lower thioester group, thiol group, substituted or unsubstituted carboxyl group, epoxy group, substituted or unsubstituted Ci ~ c4 lower thioalkoxy group; or 1 and R2 simultaneously form 氲 3 ~ 4 unsaturated or saturated rings of carbonized carbide, and I, Re, r5, heart and heart respectively represent hydrogen atom, halogen atom, hydroxyl group, nitro group, Cl ~ c4 lower ester group, and Ci ~ c4 lower group Alkyl, C3 to C8 substituted or unsubstituted 3 to 6 ring alkynyl, heart to lower alkoxy, 6 to (: 4 lower thioalkoxy, substituted or unsubstituted aromatic, substituted Or unsubstituted aromatic lower alkoxy, substituted or unsubstituted lower alkylamino, or substituted or unsubstituted methyl with lower alkyl Acid ester group, or two adjacent groups of R3, R4, r5, r6 and r7 are combined with each other to form a benzene ring or a naphthalene ring; -6 _ This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X297 mm) (Please read the back, ^ Note before filling in this page)-Equipment · Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 " 1 ----__ B7 V. Invention Description (2) " '----: Department. Said oxygen atom, sulfur atom, substituted or unsubstituted amine group;, oxygen atom or ... group (here is the same as the above-mentioned R8); Y means the structural formula (1) In the compound, those which are bound at the 3-position or the 4-position of the aromatic ring to which γ is bound;,, and z refer to a hydrogen atom, a hydroxyl atom, a C! ~ C4 lower alkoxy group, and 2, a non-substituted oxidized aromatic Group, Cl ~ lower alkylamine group, cyclic amine group which may be substituted or unsubstituted up to 1 ~ 5 nitrogen atoms; A means a CH = or nitrogen atom;

Ci ~ Cs alkyl means methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, 2- Linear or branched alkyl such as methylpentyl; A lower alkyl refers to methyl, ethyl, propyl, isopropyl, η-butyl, isobutyl, butyl, etc .; C3 ~ C8 substitution Or unsubstituted 3 to 6 ring cycloalkyl refers to substituted or unsubstituted cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted cyclopropyl, substituted cyclopentyl, substituted cyclohexyl, etc. Ci ~ C4 lower ester group refers to a group in which a carboxyl group is esterified with a lower alkyl group; 仏 ~ lower alkoxy is nailoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, t-butoxy, etc .; C! ~ C4 lower thioalkoxy refers to thiomethyl, thioethyl, thiopropyl, thioisopropyl, thiobutyl, t-thiobutyl, etc .; c 1 ~ c4 lower alkylamines are nailamine, ethylamine, propylamine, butylamine, etc .; this paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm) ) (Please read the first Note: Please fill in this page again} Pack. 575564 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1. Description of the invention (3) Oxidized aromatic group refers to phenoxy, substituted phenoxy, naphthyloxy, or Substituted naphthyloxy, etc .; Cyclic amine groups that can contain 1 to 5 nitrogen atoms refer to pyrrolidinyl, pyrrolinyl, fluorinyl, pyrazolyl, pyrazolinyl, pyrazolyl, triazole Porphyrinyl, tetrazolinyl, piperazinyl, etc. The present invention is a result obtained through long-term research on related compounds with anticancer activity. The results show that the present inventors have discovered the present invention. The acid addition salt of the compound of formula (1) has superior anti-cancer effects, and the surprising fact that it has very little toxicity exists, which led to the appearance of the present invention. No, the object of the present invention is to provide an excellent anti-cancer agent. The compound represented by structural formula (1) and its acid addition salt with little effect and little toxicity. Another object of the present invention is to provide a method for producing a compound of structural formula (1) and its acid addition salt. Compounds of the present invention Is compatible with pharmacy Excipients and the like are mixed together, and the pharmaceutical preparations are generally used to manufacture medical preparations, which can be used for the prevention and treatment of various types of tumors. Therefore, another object of the present invention is to provide a structure comprising The compound of formula (1) is an active ingredient of a pharmaceutical preparation. In the present invention, the acids capable of reacting with the compound 形成 to form an acid addition salt are pharmaceutically acceptable inorganic or organic acids, such as hydrochloric acid, or acid. , Sulfuric acid, acetic acid, nitric acid and other inorganic acids, formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid and other organic acids, serine, semi-photoamine, deaminate Winter stuffed amine, grain-8- This paper size is applicable to China National Standard (CNS) A4 specification (210X297: ^^ 1 ~ 一 -----— _

A7 A7 V. Description of the invention Amino acid, lysine acid, arsenite ^ Z "Amino acids such as acid, tyrosine, proline, etc. Only lutein acids such as osmium, toluene lutein and so on. Ingredient t: Lt: 丨 ΐ Manufactured with excipients containing the compound of formula 为 as effective: ... Sub-formulations can be used, such as sweet taste 2 binding agent, Dissolving agents, dissolving aids, wetting agents, softeners, disintegrating agents, oxidation inhibitors, preservatives, secondary fillers, fragrances, etc., specifically, such as lactose, cube sugar, caramel, mannitol, Sorbitol, cellulose, glycine stilbene, silicic anhydride, talc, stearic acid, sterol, tragacanth, methyl cellulose, sodium carboxymethylcellulose, gelatin, p-aminophenyl tumour acid, Water, ethanol, ethylene glycol, polyvinylpyrrolidone, sodium chloride, potassium chloride, orange flavor, strawberry flavor, vanilla extract, etc. As for the amount of the compound of formula (1) provided by the present invention, it is based on the patient's Different ages, genders, and patient levels vary. Basically, it can be divided once a day or Several doses of about 1 mg to about 50,000 mg are administered. Formula The compound of formula (1) provided by the present invention can be manufactured using the following private formula I.

Square I

-9 (c)

H-N N

The “Zhang” scale is applicable to the Zhongguanjia Standard (CNS) A4 specification (210X297 mm) 575564

V. Description of the invention (5)

(I) In the printed format of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, the heart ^ 2 Wei 3, ^ 4, ruler 5 surgery 6 Wei 7, and 弋 2 means as described above, and Lie means _ Atom or the same leaving group as sulfofluorenyl. The compound of structural formula (b) can be effectively prepared by reacting the compound of structural formula (a) in the presence of a c (= X) -provided reagent in a common organic solvent. The compound of formula (1) can be obtained by continuously reacting with the compound of formula (c). The so-called C (= X) -based supply reagent can be used, such as 丨, carbonyldiimidazolyl, 1,1-carbonylthiodiimidazolyl, creatine phosphate, thiocreatine creatine, carbonyl Diphenoxy, phenylchloroformate, etc. In this reaction, commonly used organic solvents such as tetrachloromethane, dichloromethane, chloroform, acetonitrile, dimethylformamide and the like can be used. In addition, the reaction system is preferably performed in the presence of a combined reagent. The binding reagents that can be used in this reaction are those generally used in inorganic or organic bases. The above-mentioned inorganic or organic base of the reaction refers to sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, selenium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, amidine Pyridine, db =, etc. The amount used is preferably between 1 equivalent and 5 equivalents. The reaction is from 3 ° C to the boiling point of the solvent, preferably at (Please read the precautions on the back before filling this page)-Binding · Order 10-

575564 A7, description of the invention (5th generation to 10th (5 to 48 hours at TC), especially ι0 ~ is preferred. The amount of j-C (= x) -based supply reagent is used in Bu 15 Between equivalents, it is better to use 1 to 11 equivalents. When the above reactants are reacted with an acidic side reaction, it is best to add a test substance to remove the #substance from the reaction. After the substance is reacted, the material is silky, such as sodium hydroxide, hydroxide discharge, hydrogen storage, hydroxide hydroxide, magnesium oxide, oxidized word, potassium carboxylate, sodium carbonate, potassium carbonate, magnesium carbonate. The reaction is preferably carried out in the presence of alkali or alkaline earth metals such as magnesium bicarbonate, sodium bicarbonate, potassium bicarbonate, hydroxides, oxides, carbonates, or bicarbonates, and bases of the amine-based system. The compound represented by the above structural formula (2) can be used as

Chem., 1992, 35, 3784, 3792, etc., or a method similar to that described above. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, the paper size is applicable to Chinese National Standards (CNS) (210X297 ^^ T ^ ~~ ---------- 575564 A7 B7 V. Description of the invention (The embodiment follows the above method, and The following compounds can be prepared

In the above formula, Ri Y and Z are the same as defined above. R4, R5, R6, R7, A, X, (please read the precautions on the back before filling this page)-staff of the Central Bureau of Standards, Ministry of Economic Affairs Consumer Cooperative Cooperative Printed Example · .Ri R2 Rs R4 R5 Re Rt AXVZY 1 Me Me SH HHHHN 〇NH 〇Me 3-N 2 Me Me Human HHHHN 〇NH 〇Me 3-N 3 Me Me Me H Me Me N 〇NH OMe 3-N 4 Me Et SMe HHHHN 〇NH 〇Me 3-N 5 Me Et Human HHHHN 〇NH OMe 3-N 6 Me Et Me Me H Me Me N 〇NH OMe 3-N 7 Me Et H SH HHHN 〇NH OMe 3-N 8 Me nPr H 〇Me H 〇Me HN 0 NH OMe 3-N 9 Me nPr H Me H Me HN 〇NH OMe 3-N 10 Me nPr HFHFHN 〇NH OMe 3-N 11 Me nPr 〇 Me HHHHN 〇NH OMe 3-N 12 Et Me H 〇Me H 〇Me HN 〇NH OMe 3-N 13 Et Me H Me H Me HN 〇NH OMe 3-N 14 Et Me H OH HHHN 〇NH OMe 3-N 12- The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 575564

A V. Description of the invention (8) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Example number Ri r2 t Rs R4 Rs ^-Rc I rt!! 'AXY | ZY | 15 nPr Me H OMe H OMe HN 〇NH OMe, 3-N 16 nPr Me H Me H Me HN 〇NH OMe 3- NI 17 nPr Me H OH HHHN 〇NH OMe 3-N 18-(CH2) 3- H OMe H OMe HN 〇NH OMe 3-N 19-(CH2) 3- H Me H Me HN 〇NH OMe 3-N 20 -(CH2) 4- H OMe H OMe HN 〇NH OMe 3-N 21-(CH2) 4- H Me H Me HN 〇NH OMe 3-N | 22 Me Me H Me H Me H • N s NH OMe 3 -N 23 Me Me HFHFHN s NH OMe ~ j 3-N | __i 24 Me Me H OH HHHN s NH OMe 3-N 25 Me nPr H OMe H OMe HN s NH OMe 3-N 26 nPr Me H OMe H OMe HN s NH OMe 3-N 27 nPr Me H Me H Me HN s NH OMe 3-n!! 28 nPr Me H OH HHHN s NH OMe 3-N 丨 29-(ch2) 3- H OMe H OMe HN s NH OMe 3-N! | 30-(ch2) 3- H Me H Me HN s NH OMe 3-N 31-(CH2) 4- H OMe H OMe HN s NH OMe 3-N 32-(CH2) 4_ H Me H Me HN s NH OMe 3-N 33 Me Me H OMe H OMe HN 〇NH NHMe 3-N 34 Me Me H Me H Me HN 〇NH NHMe 3-N 35 Me Et H Me H Me HN 〇NH NHMe 3-N 36-(ch2) 3- H OMe H OMe HN 〇NH NHMe 3-N 37-(CH2) 3- H Me H Me HN 〇NH MHMe 3-N 38 Me Me H OMe H OMe HN 〇NH ^ \ q〇c 3-N 39 Me Me H Me H Me HN 〇NH \ / \ iBoc 3-N -13- (Please first Read the notes on the reverse side and fill out this page) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 575564

A V. Description of invention (9) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

Example number 丨 Ri 丨 (R2 Rs R4 II Rs! 1 > R7 AXY! Z Y 40 Me Et H 〇Me H 〇Me HN 〇NH H ~ \ b〇c 3-N 41 Me Et H Me H Me HN 〇NH H ~ \ lBoc 3-N 42 Me Me H 〇Me H 〇Me HN 〇NH N0H 3-N 43 Me Me H Me H · Me H • N 〇NH / ~ \ h 3-N 44 Me Et H 〇Me H 〇Me HN 〇NH 〇 3-N 45 Me Et H Me H Me HN 〇NH 3-N 46 Me Ac H 〇Me H 〇Me HN 〇NH OMe 3-N 47 Me Ac H Me H Me HN 〇 NH 〇Me 3-N 48 Me Ac HFHFH 'N 〇NH OMe 3 ~ N! 1 49 Me Ac H Cl H Cl HN 〇NH 1 OMe 3-N 1 50 Me Ac Me Me HHHN 〇NH OMe 3-N 1 51 Me Ac 〇Me HHH IT N 〇NH OMe 3-N 52 Me Ac H OH HHHN 〇NH OMe 3-N 53 Me Ac H 〇Me H 〇Me HNS NH: OMe! _ I 3-N 1 I t 54 Me Ac H Me H Me HNS NH OMe 3-NI 55 Me Ac H OH HHHN s NH OMe 3-N 56 Me OH human H 〇Me H 〇Me HN 〇NH OMe 3-N 57 Me OH human H Me H Me. HN 〇 NH OMe 3-N 58 Me OH Human Me Me HHHN 〇NH OMe 3-N 59 Me OH Human HFHFHN 〇NH OMe 3-N 60 Me OH Human H Cl H Cl HN 〇NH OMe 3-N 61 Me OH Human H Me HHHN 〇NH OMe 3-N 62 Me OH human H OH HHHN 〇NH OMe 3-N 63 Me OH human H 〇Me H 〇Me HN s NH OMe 3-N 64 Me OH human H Me H Me HN s NH OMe 3-N -14-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) Binding-Order 575564 A7 B7 V. Description of Invention (10) Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards

Example number Ri!! 1 i τ- \ R4 Rs Rg 1 Rv AY 7 Y 65 Me 乂 hi 1 Η 〇Me H OMe HM 0 NH OMe 3-N 66 Me XH Η Me H Me HN 〇NH OMe 3-N 67 Me OH 〇 〇Me H OMe HN 〇NH OMe 3-N 68 Me OH Η Me H Me HN 〇NH OMe 3-N 69 Me sc (= o) ch3 〇 〇Me H 0Me HN 〇NH OMe 3-N 70 Me SC (= 0) ch3 Η Me H Me HN 〇NH OMe 3-N 71 Me SH human Η 〇Me H OMe HN 〇NH OMe 3-N 72 Me SH human Η Me H Me H! .N h 〇NH OMe 3-N! 73 Me Vinyl Η OMe H OMe HN 〇NH OMe 3-N 74 Me Vinyl Η Me H Me HN 〇NH OMe 3-N i 75 Me Vinyl Η FHFHN 〇NH OMe 3-N 76 Me human Η OMe H OMe HN 〇NH OMe 3-N 77 Me Human Η Me H Me HN 〇NH OMe 3-N] 1 78 Me ^ OCH ^ OEt Η OMe H OMe HN 〇NH OMe 1 1 3-N 79 Me 0 ^ OCH ^ OEt Η OMe H OMe HN 〇NH OMe 3-N 80 Me 0 OCHii〇Et person Η Me H Me HN 〇NH OMe 1 3-N (Please read the precautions on the back before filling out this page) -Pack · Order-15- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 575564

Description of the invention (11 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs & Example 1) 1-[(5,6-dimethyl-2-methoxy-l-methyl-3_fluorenyl) amino Carbonyl] -4- (2-fluorenylthiobenzyl) piperazine a) phenyl N- (5,6-diamidino_2_methoxypyridin_3_fluorenyl) formate group 3 -Amino-5,6-dimethyl-2-methoxypyridine (152 g, 0.001 mole) and benzyl chloride (L52 g, 0.01 mole) dissolved in dichloromethane And stirred at room temperature for 2 hours. Then, the solvent was removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane = 1: 6) was used for separation and purification to obtain the above compound. Yield: 92% 'H NMR (CDC13): 2.18 (3H5s) 5 2.36 (3H5s) 5 4.〇〇 (3H5s)? 7_31 (5H, m), 8.G7 (1H, s) b) l- [ (5,6-dimethyl-2-methoxyσ than pyridinyl) aminocarbonyl] (2-methylthiophenyl) piperidinyl N- (5,6-difluorenyl-2 -Methoxydine-3-fluorenyl) formate (136 mg, 0.5 mmol) and ^ (2-methylthiophenyl) piperazine (104 mg, 0.5 mmol), dissolved in anhydrous tetrahydroa pyran After adding DBU (76 mg, 0.5 mmol), the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to remove tetrahydropyran. I column chromatography (ethyl acetate: hexane) Calcination = 1: 2), and the above compounds can be obtained after separation and purification. Yield: 59%

Melting point: 167 ~ 169 ° C! H NMR (CDC13): 2.21 (3H? S)? 2.43 (3H5s) 5 3.06 (4H? T), 16 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page}; Binding and ordering 575564 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (12) 4.09 (3H, s), 6.89 (lH, s) , 7_06 (lH, m), 7.14 (3H, s), 8.26 (lH, s) Example 2) l-[(5,6-Difluorenyl-2-methoxypyridine_3_fluorenyl) amine Pyrocarbyl] -4- (2-cumenephenyl) pie sigma phenyl phenyl N- (5,6-dimethyl-2-methoxy-tol-3-fluorenyl) formate The above compound can be obtained by reacting with 1- (2-cumylphenyl) piperazine in the same manner as in Example i above. Yield: 62%

Melting point: 139 ~ 140 ° C lR NMR (CDC13) δ: 2.20 (3H? S) 5 2.21 (6H5s)? 3.10 (4H9t) 5 3.64 (4H, t), 3.84 (3H, s), 5.07 (lH, s ), 5.13 (lH, s), 6.64 (1J, S), 6.98 (lH, s), 7.04 (3H, dd), 7.18 (lH, d), 7.91 (lH, s) 8.26 (lH, s) Example 3) 1-[(5,6-Difluorenyl-2-methoxy-0 to bite-3_fluoranyl) aminocarbonyl] -4- (2,3,5,6-tetramethyl Phenyl) piperazinePhenyl N- (5,6-difluorenyl-2-methoxybenzidine-3-methyl) phosphonate and 1- (2,3,5,6-tetramethyl Phenyl) piperazine can be reacted in the same manner as in Example 1 to obtain the above compound. Yield: 71%

Melting point 190 ~ 192 ° C 'H NMR (CDC13) (5: 2.21 (15H? S)? 2.42 (3H? S)? 3.17 (4H, t), 3.61 (4H, t), 4.08 (3H, s ), 6.84 (lH, s), 8.26 (lH, s) • 17- This paper size applies to China National Standard (CNS) A4 specification (2IOX297 mm) (Please read the precautions on the back before filling this page)

1T 575564 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (13) Example 4) 1-[(5-ethyl-6-methyl-2-methoxypyridine-3- 醯Yl) aminocarbamoyl] -4- (2-methylthiophenyl) brigade 11 Qin will phenyl N- (5-ethyl-6-methyl-2-fluorenyl tonyl-3- The fluorenyl) phosphonate and 1- (2-methylthiophenyl) piperazine can be reacted in the same manner as in Example 1 to obtain the above compound. Yield: 56% Melting point: 160 ~ 161 ° C! H NMR (CDCl3) (5: 1.19 (3H5t)? 2.43 (3H? S)? 2.50 (3H? S)? 2.58 (2H, q), 3.07 (4H , T), 3.69 (4H, t), 4.15 (3H, S), 6.93 (lH, s), 7.06 (lH, m), 7.14 (3H, m), 8.35 (lH, s) Example 5) l-[(5_Ethyl-6-methyl-2 -methoxy0 than bite_3_fluorenyl) hydrazine and several yl] -4- (2_cumenephenyl) The reaction was performed in the same manner as in Example 1 above to obtain the above compound. Yield: 51% Melting point: 185 ~ 187 ° C! H NMR (CDC13) 5: 1.18 (3H? T) 5 2.21 (3H? S)? 2.42 (3H? S)? 2.56 (2H, q), 3.08 ( 4H, t), 3.62 (4H, t), 4.03 (3H, s), 5.08 (lH, s), 5.13 (lH, S), 6.90 (lH, s), 7.02 (3H, m), 7.18 (3H, d), 8.25 (1H? S), ,, Example 6) W (5-ethyl-2-methoxy-6-methylpyridine_3_fluorenyl) aminocarbonyl] -4 -(2,3,5,6-tetramethylphenyl) piperazine base N- (5-ethyl-2-methoxy-6 · methyl 0 than _3_fluorenyl) carboxylic acid The ester was reacted with 1- (2,3,5,6-tetramethylphenyl) piperazine 'in the same manner as in Example 1 above to obtain the above compound. '-18-This paper size applies to Chinese national German fishermen ^ Δ 应 / 丨 Λ · ----- Γ i (Please read the precautions on the back before filling this page): Packing-、 11 575564 A7 __ B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (14) Yield: 69% Melting point: 176 ~ 177 ° CW NMR (CDC13) 5: 1.19 (3H, t), 2.21 (3H, S), 2.44 (3H, s), 2.57 (2H, q), 3.17 (4H, t), 3.62 (4H, t), 4.06 (3H, s), 6.84 (1H, s), 6.92 (1H, s), 8.30 ( 1H, s) Example 7) l-[(5-ethyl-2_methoxy-6-methylpyridin-3-amidino) aminocarbonyl] -4- (3-thiophenyl) piper The hydrazine was substituted with phenyl N- (5-ethyl-2-methoxy-6-methyl.pyridin-3-fluorenyl) formate and 1- (3-thiophenyl). The reaction was carried out in the same manner as in Example 1 above to obtain the above compound. Yield: 63% Melting point: 108 ~ 110 ° C'H NMR (CDC13) (5: 1.17 (3H5t) 5 2.37 (3H5s)? 2.49 (3H? Q)? 3.28 (4H, t), 3.60 (4H, t ), 3.98 (3H, s), 6.87 (4H, m), 6.98 (lH, s), 8.18 (lH, t) Example 8) l-[(2-methoxy-6-methyl-5 -Propyl-3-amino) aminocarbonyl] -4- (3,5-dioxophenyl) piperazine Yield: 67% Melting point: 82 ~ 84 ° C 'H NMR (CDC13) δ: 0.94 (3H? t), 1.58 (2H? m) 5 2.37 (3H5s) 5 2_49 (2H, q), 3.25 (4H, t), 3.66 (4H, t), 3.78 (6H, s), 3 · 99 (3H, s), 6.07 (3H, m), 6.88 (lH, s), 8.16 (lH, s) Mass (EI) m / z: 428.2447 Calculated value: 428.2423) -19- (Please read the back first Please pay attention to this page before filling in this page) [Packing ·,?! -1¾ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 575564 Α7 Β7 V. Description of the invention (15) Example 9) Bu [( 2-methoxy-6-methyl-5-propyl. Than pyridin-3-fluorenyl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine Phenyl N- ( 2-methoxy-6-methyl-5-propylpyridin-3-amidino) formate and 1- (3,5-dimethylphenyl) piperazine were used as in Example 1 above. identical The reaction method, the above compound can be obtained. Yield: 64%

Melting point: 145 ~ 146 ° C NMR (CDC13) 5: 0.95 (3H, t), 1.59 (2H, m), 2.29 (6H, s), 2.41 (3H, s), 3.24 (4H, t), 3.67 (4H, t), 3.98 (3H, s), 6.59 (3H, m), 6.98 (3H, s), 6.89 (lH, s), 8.17 (lH, s) Mass (I) m / z: 428.2385 ( MH, C23H32N404 Calculated: 428.2423) Example 10) l-[(2-methoxy-6-methyl-5-propylpyridin-3-amidino) aminocarbonyl] -4- (3,5- Difluorinated phenyl) piperazinePhenyl N- (2-methoxy-6-fluorenyl-5-propylpyridin-3-fluorenyl) formate and 1- (3,5-difluorinated The phenyl) piperazine can be reacted in the same manner as in Example 1 to obtain the above compound. Yield: 57% Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page)

Melting point: 121 ~ 123 ° C 'H NMR (CDC13) δ: 0.95 (3H? T)? 1.59 (2H? M) 5 2.38 (3H? S)? 2_50 (2H, q), 3.29 (3H, t), 3.66 (3H, t), 4.00 (3H, s), 6.28 (lH, m), 6.36 (2H, d), 6.87 (lH, s), 8.17 (lH, s) Example 11) 1-[(2 -Methoxy-6-methyl-5-propylpyridine-3-amidino) aminocarbonyl] -4 · (2-Methoxyphenyl) piperazine-20- This paper applies Chinese national standards ( CNS) A4 specification (21〇'297 mm) 575564 A7 _ B7 V. Description of the invention (16) The N- (2-methoxy-6-methyl-5-propyl group) is specified as 3- Acid) formate and 1- (2-methoxyphenyl) piperidine, following the example described above! By performing the reaction in the same manner, the above-mentioned compound can be obtained. Yield · 71%

Melting point: 109 ~ 110 ° CW NMR (CDCl3) (5: 0.95 (3H, t), 1.59 (2H, m), 2.37 (3H, s), 2.49 (2H, q), 3.12 (4H, t), 3.70 (4H, t), 3.89 (3H, s), 3.97 (3H, s), 6.91 (4H, m), 6.95 (lH, s), 8.19 (1H, S) Example 12) l-[(6- Ethyl-2-methoxy-5-methylpyridine-3_fluorenyl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine Phenyl N- (6-ethyl -2-Methoxy-5-methyl. Bisorcinyl) formate and 1- (3,5-dimethoxyphenyl) triphenate were carried out in the same manner as in Example 1 above. Reaction to obtain the above compound. Yield: 65%

Melting point: 115 ~ 116 ° CH NMR (CDC13) δ: 1.21 (3H, t), 2.21 (3H, s), 2.65 (2H, q), 3.27 (4H, t), 3.64 (4H, t), 3.79 ( 6H, s), 3.98 (3H, s), 6.09 (3H, m), 6.86 (lH, s), 8.12 (lH, s)

Mass (EI) m / z: 414.2240 (MH, C22H3GN4104 calculated: 414.2267) Example 13) M (6-methyl-2-methoxy-5_methylpyridine_3_fluorenyl) amino group Carbonyl] -4- (3,5-dimethylphenyl) piperazinePhenyl N- (6-fluorenyl-2-fluorenyl-5-methyl.pyridine_3_fluorenyl) carboxylic acid Ester and 1- (3,5--methylbenzyl) group, adopt the same as the above Example-21-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back first Please fill in this page again for details) $ -14 Printed by the Central Consumers ’Cooperative of the Ministry of Economic Affairs and printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Consumer ’s Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and printed by 575564 The above compounds. Yield: 61%

Melting point: 135 ~ 136 ° C! H NMR (CDC13) 5: 1.22 (3H5t) 5 2.21 (3H5s) 9 2.29 (6H5s)? 2.65 (2H, q), 3.24 (4H, t), 3.66 (4H, t) , 3.98 (3H, s), 6_59 (3H, m), 6.87 (lH, s), 8.12 (lH, s)

Mass (EI) m / z: 382.2376 (MH, C22H3 () N402 Calculated: 382.2368) Example 14) l-[(6-ethyl-2-fluorenyl-5-fluorenylpyridin-3-yl) ) Aminocarbonyl] -4- (3-hydroxyphenyl) piperazinePhenyl N- (6-ethyl-2-methoxy-5-methylpyridine_3_fluorenyl) formate with 1 -(3-hydroxyphenyl) piperazine can be reacted in the same manner as in Example 1 to obtain the above compound. Yield: 56%

Melting point: 168 ~ 170 ° CW NMR (CDC13) 5: 1.21 (3H, t), 2.20 (2H, s), 2.63 (2H, t), 3.28 (4H, t), 3.68 (4H, t), 3.98 ( 3H, s), 6.41 (lH, d), 6.55 (lH, d), 6.84 (lH, m), 6.87 (lH, s), 7.13 (lH, t), 8.10 (lH, s) Mass (EI) m / z: 370.1992 (MH, C2GH26N403 Calculated: 370.2004) Example 15) M (2-methoxy_5-fluorenyl-6-propylpyridine_3_fluorenyl) aminochiridine] -4- (3,5-dimethoxyphenyl) brigade combined the phenyl N- (2-fluorenyl-5 · fluorenyl-6-propylσ to π-donyl) formate with 1- (3 , 5-Dimethoxyphenyl), adopt the same implementation as above. 22- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling in this Page)-Binding. Order 575564 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (18) Example 1 The reaction was carried out in the same manner as in Example 1 to obtain the above compound. Yield: 57% Melting point: 121 ~ 122 ° C 4 NMR (CDC13) 6: 0.96 (3H, t), 1.67 (2H, m), 2.21 (3H, s), 2.58 (2H, t), 3.26 (4H, t), 3.68 (4H, t), 3.79 (6H, s), 3.97 (3H, s), 6.14 (3H, m), 6.89 (lH, s), 8.11 (lH, s) Mass (EI ) m / z: 428.2423 (MH, C23H32N404 Calculated: 428.2423) Example 16) 1 · [(2-methoxy-5-methyl-6-propylσ than fluoren-3-amidino) amino group Carbonyl] -4- (3,5-diethylphenyl) piperazine will be the base N- (2-methoxy-5-methyl-6-propylamido-3-amidino) phosphonic acid The ester was reacted with 1- (3,5-diethylphenyl) piperazine in the same manner as in Example 1 to obtain the above compound. Yield: 54% Melting point: 138 ~ 139 ° CW NMR (CDC13) (5: 0.96 (3H, t), 1.72 (2H, m), 2.21 (6H, s), 2.30 (3H, s), 2.59 (2H , T), 3.28 (4H, t), 3.76 (4H, t), 3.97 (3H, s), 6_70 (3H, m), 6.87 (lH, s), 8.11 (ih, s) Mass (EI ) m / z: 396.2432 (MH, C23H32N4O2 calculated: 396.2525) Example Π) l-[(2-methoxy-5-amidinopropylpyridine_3_fluorenyl) amino group]- 4- (3-¾ylphenyl) Liu He puts phenyl N- (2-fluorenyl-5-fluorenyl-6-propyl-pyridine_3_fluorenyl) carboxylic acid and H3-hydroxyphenyl ) Pipe pipe, adopt the same as the above embodiment i-23- (Please read the precautions on the back before filling this page):

， 1T -1% This paper size is applicable to China National Standard (CNS) A4 specification (210X Μ? Mm) 575564 Printed by A7 B7 of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (19) The same method Reaction to obtain the above compound. Yield: 52%

Melting point: 153 ~ 155 ° C 'H NMR (CDC13) 5: 0.95 (3H, t), 1.69 (2H, m), 2.19 (3H, s), 2.59 (2H, t), 3.22 (4H, t), 3.68 (4H, t), 3.97 (3H, s), 6.52 (lH, d), 6.87 (lH, s), 7.12 (lH, t), 8.09 (lH, s)

Mass (EI) m / z: 384.2153 (MH, C21H28N403 calculated: 384.2161) Example 18) 1- [N_ (2 · fluorenyloxy_6,7_dihydro-5H-cyclopentyl [b] pyridine- 3-fluorenyl) aminocarbonyl] -4- (3,5-dioxophenyl) piperazine will be the base N- (2-fluorenyl-6,7-dihydro-5H-cyclopentyl [b]% b bite-3_vinyl) formate and 1- (3,5-dimethoxyphenyl) trazine can be reacted in the same manner as in Example 1 above to obtain the above. Compounds. Yield: 59%

Melting point: 143 ~ 144 ° CW NMR (CDC13) 5: 2.10 (2H, m), 2.87 (4H, m), 3.12 (4H, t), 3.70 (4H, t), 3.78 (6H, s), 4.00 ( 3H, s), 6.08 (3H, m), 6.90 (1H, s) 5 8.24 (lH, s) Example I9) WN- (2-methoxy-6,7_difluorene_5h_cyclopentyl [b] Pyridin-3-fluorenyl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperidinium Phenyl N_ (2-fluorenyl-6,7-dihydro-5H- Cyclopentyl [b] pyridin-3-fluorenyl) formate and 1- (3,5-dimethylphenyl) piperazine can be reacted in the same manner as in Example 1 above to obtain The above-mentioned -24- ^ paper size applies to China National Standard (CNS) A4 specifications (--- ~ ^ (Please read the precautions on the back before filling this page).

1T 575564 A7 _______B7 V. Description of the invention (20) Compound. Yield · 55%

Melting point: 183 ~ 185 ° CH NMR (CDC13) (5: 2.08 (2H, m), 2.28 (6H, m), 2.872 (4H, m), 3.22 (4H, t), 3.67 (4H, t), 4.00 (3H, s), 6.57 (3H, m), 6.89 (1H, s) 5 8.24 (lH, s) Example 20) l-[(2-methoxy-5,6,7,8-tetramidine Pyridin-3-fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine Phenyl N- (2-methoxy-5,6,7,8-tetra The above compound can be obtained by reacting hydrogen, quinine-3-amidino) formate and 1- (3,5-dimethoxyphenyl) piperidine in the same manner as in Example 1 above. Yield: 54%

Melting point: 161 ~ 163 ° C β NMR (CDC13) 5: 1.75 (2H, m), 1.84 (2H, m), 2.67 (2H, t), 2.73 (2H, t), 3.27 (4H, t), 3.71 (4H, t), 3.79 (6H, s), 3.97 (3H5s), 6.10 (3H, m) 56.90 (lH, s) 58.07 (lH, s) Example 21) Methoxy-5,6,7 , 8-Tetrahydropyridoline_3_fluorenyl) aminocarbonyl] -4- (3,5-difluorenylphenyl) piperazine Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the note on the back first Matter ears fill in this page) Phenyl N · (2-fluorenyl-5,6,7,8-tetrahydroquinone quiline donkey base) formazan and 1- (3,5-monomethylbenzyl) Based on the method of σσ, the same method as in Example 1 was used for the reaction to obtain the above compound. Yield: 51%

Melting point: 143 ~ 144 ° CH NMR (CDC13) δ: 1.75 (2H5m) 51.84 (2H5m)? 2.30 (2H? T)? -25-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 575564 Α7 _____________ V. Description of the invention (21) 2.72 (2H, t), 3.26 (4H, t), 3.67 (4H, t), 3.97 (3H, s), 6.61 (3H, m), 6.91 (lH, s) , 8.07 (lH, s) Example 22) 1-[(5,6-Dimethyl-2-methoxymethoxy-3-methyl) aminocarbonyl] -4- (3,5-di Methylphenyl) piperazinePhenyl N- (5,6-dimethoxy-2-methoxypyrimidin-3-amidino) formate (200 mg, 0.7 mmol) and l- ( 3,5-Dimethoxyphenyl) pyrazine (154 mg, 0-7 mmol) was dissolved in anhydrous tetrahydropyran, and DBU (106 mg) was added, followed by stirring at room temperature for 2 hours. Then, the solvent was removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane = 1: 2) was used for separation and purification to obtain the above compound. Yield: 50%

Melting point: 192 ~ 193 ° C iH NMR (CDC13) (5: 2.21 (3H, s), 2.29 (6H, s), 2.36 (3H, s), 3.33 (4H, t), 3.96 (3H, s), 4.09 (4H, t), 6.57 (3H, m), 7.33 (1H, s), 8.11 (1H, s)

Mass (EI) m / z: 384.1992 Calculated value: 384.1983) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Example 23) ^ [(5 ^ 二 曱 基_2-Methoxypyridine_3-fluorenyl) amino Ik group] -4- (3,5-difluorinated phenyl) σchenazine Phenyl N- (5,6-difluorenyl-2 -Methoxypyridine_3_fluorenyl) carboxylic acid hydrazone is reacted with 1- (3,5-difluorinated phenyl) trazine in the same manner as in Example 22 to obtain the above compound. Yield: 47% -26-This paper is suitable for financial standard S (CNS) A4 specifications 575564 A7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (22) Melting point: 60 ~ 62 ° C 4 NMR (CDC13 ) 5: 2_21 (3H, s), 2.36 (3H, S), 3.39 (4H, t), 3.96 (3H, s), 4.10 (3H, t), 6.29 (3H, m), 7.33 (lH, s ), 8.14 (1H, S) Known Example 24) Dimethyl-2-methoxypyridin-3-yl) aminoamino] -4- (3-phenyl -(5,6-dimethyl-2-methoxypyridinyl) formate and 1- (3-hydroxyphenyl) piperazine can be reacted in the same manner as in Example 22 above to obtain The above compounds. Yield: 43% Melting point: 185 ~ 186 ° C 泔 NMR (CDC13) & 2.14 (3H, S), 2.36 (3H, s), 3.25 (4H, t), 3.89 (3H, s), 4.09 (4H , T), 6-30 (lH, d), 6.36 (2H, m), 7.03 (lH, t), 7.48 (lH, s), 8.56 (lH, s) Example 25) l-[(2- Methoxy-6-methyl-5_propylpyridine_3_fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine phenyl N- (2-methyl Oxy_6_methyl-5-propoxypyridinyl), methyl and 1- (3,5-monomethoxyphenyl) σ Chen He, the reaction was carried out in the same manner as in Example 22 above. , And the above compounds can be obtained. Yield: 55% Melting point: 143 ~ 144 ° CW NMR (CDCl3) d: 0.93 (3H, t), l_66 (2H, m), 2.17 (3H, S), 2.65 (2H, t), 3.85 (4H, t), 3.79 (6H, s), 3.98 (3H, s), 4.15, (Please read the precautions on the back before filling this page); clothing, 11 d 0 Bn —ii a--27- 575564 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 i. Invention Description (23) (4H, t), 6.11 (3H, m), 7.43 (lH, s), 8.25 (lH, s) (Example 26) 1-[(2-methoxy-5 -methyl-6-propylpyridine-3-amino) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine Phenyl N- (2-fluorenyl-5-methyl-6-propoxy group 0-methyl-3-fluorenyl) formic acid with 1- (3,5-monomethoxyphenyl) σ base The reaction was carried out in the same manner as in Example 22 above to obtain the above compound. Yield: 52%

Melting point: 183 ~ 184 ° C NMR (CDCl3) 6: 0.98 (3H, t), 1.72 (2H, m), 2.17 (3H, s), 2.62 (2H, t), 3.39 (4H, t), 3.79 ( 6H, s), 3.96 (3H, s), 4.19 (4H, t), 6.15 (3H, m), 7.42 (lH, s), 8.08 (lH, s)

Mass (EI) m / z: 444.2171 (Calculated value of ΜΚ / υ 计算 ηΚΟΑ: 444.2195) Example 27) l-[(2-methoxy-5-methyl-6-propyl0 is more specific than 3-methyl group ) Aminocarbonyl] -4- (3,5-difluorenylphenyl) piperazine converts phenyl N- (2-methoxy-5_methyl-6-propoxyα to pyrenyl) 曱The ester was reacted with 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 22 above to obtain the above compound. Yield: 49%

Melting point: 195 ~ 197 ° C! H NMR (CDC13) δ: 0.98 (3H? T) 5 1.73 (2H? M)? 2.18 (6H, s)? 2.34 (3H, s), 2.62 (2H, t), 3.47 (4H, t), 3.96 (3H, s), 4 · 〇ΐ -28- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling in this Page), τ 575564 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (24) (3H, m), 6.59 (3H, m), 7.02 (lH, s), 7.99 (lH, s)

Mass (EI) m / z: 412.2266 Calculated value: 412.2296) Example 28) Benzyl-5-methyl-6-propyl ton. Ding-3-amino) aminocarbonyl] -4- (3-hydroxyphenyl) piperazine will be phenyl N_ (2-methoxy-5-fluorenyl-6-propoxyα than pyridin_3_ The fluorenyl) formate was reacted with 1- (3-transphenyl) nitro, in the same manner as in Example 22 above, to obtain the above compound. Yield: 48%

Melting point: 160 ~ 162 ° C 1HNMR (CDCl3) 5: 0.98 (3H? T)? 1.72 (2H9m) 5 2.22 (3H5s) 5 2_61 (3H, t), 3.31 (4H, t), 3.95 (3H, s) , 4_10 (4H, t), 6.45 (3H, m), 7.12 (lH, t), 7.41 (lH, s), 8.08 (lH, s)

Mass (EEI) m / z: 400.1969 Calculated: 400.1932) Example 29) W (2-methoxy-6,7-difluoren-5H-cyclopentyl [b] pyridin-3-fluorenyl) amine Carbonyl] -4- (3,5-dimethoxyphenyl) piperazine The phenyl N- (2-methoxy-6,7-dihydro-5H-cyclopentyl [b] piperidine_ The 3-bromoyl) phosphonic acid g is intended to react with 1- (3,5-dimethoxyphenyl) sigmaquinone in the same manner as in Example 22 above to obtain the above compound. Yield: 55%

Melting point: 169 ~ 17 (TC W NMR (CDC13) 5: 2.10 (2H, m), 2.89 (4H, m), 3.30 (4H, t), -29- This paper size applies to China National Standard (CNS) A4 specifications (21〇X297 mm) (Please read the notes on the back before filling this page):

1T 575564 A7 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Invention Description (25 3.77 (6H, s), 3.98 (3H, s), 4.20 (4H, t), 6.05 (3H, m), 7.37 (lH S), 8-25 (lH, s) Example 30) l- [N- (2-methoxy-6,7-dihydro-5H-cyclopentyl [b] pyridin-3-amidino) amine Carbonyl group] -4- (3,5-dimethylphenyl phenyl phenyl group N- (2-methoxy-6,7-dihydro-5H-cyclopentyl group The fluorenyl) formate and 1- (3,5-dimethylphenyl) piperazine were reacted in the same manner as in Example 22 above to obtain the above compound. Yield: 53%

Melting point: 159 ~ 161 ° C iH NMR (CDC13) 5: 2.09 (2H, m), 2.28 (6H, m), 2.87 (4H, m), 3.67 (4H, t), 4.00 (3H, s), 4.21 (4H, t), 6.57 (3H, m), 6.93 (lH, s), 8.24 (lH, s) Example 31) l-[(2-fluorenyl-5,6,7,8_tetrahydro Pyridin-3-fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine Phenyl N- (2-methoxy-5,6,7,8-tetra The above compound can be obtained by carrying out the reaction in the same manner as in Example 22 above, and carrying out the reaction in the same manner as in Example 22 above. Yield: 56%

Melting point: 160 ~ 161 ° C 泔 NMR (CDC13) 5: 1.77 (2H, m), 1.83 (2H, m), 2.70 (2H, t), 2.76 (2H, t), 3.38 (4H, t), 3.79 (6H, s), 3.96 (3H, s), 4.16 (4H, m), 6.12 (3H, m), 7.45 (lH, s), 8.03 (lH, s) Example 32) l-[( 2-methoxy-5,6,7,8-tetrahydrofluorolin-3-amidino) amine 30 This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the Note for this page, please fill in this page) Order 575564 V. Description of the invention (26 Printed carbonyl group of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs] -4- (3,5-dimethylphenyl) piperazine will be phenyl N- ( 2-methoxy-5,6,7,8-tetrahydrofluorinylfluorenyl) formate and 1- (3,5-dimethylphenyl) piperazine were used in the same manner as in Example 22 above. The reaction is carried out by the method to obtain the above compounds. Yield: 54% Melting point: 200 ~ 201 ° C 泔 NMR (CDC13) (5: 1.77 (2H, m), 184 (2H, m), 2 34 (6h, s ), 2.71 (3H, t), 2.75 (3H, t), 3.47 (4H, t), 3.97 (3H, s), 4.42 (4H, t), 6.35 (3H, m), 6.91 (lH, s) , 7.91 (lH, s) Example 33) l-[(5,6-dimethyl · 2-methylaminopyridin-3-yl) ) Aminocarbonyl > 4- (3,5-dimethylphenyl) piperidine N- (5,6-dimethoxy-2-methylaminopyridine_3_fluorenyl) formamidine The above compound can be obtained by reacting with 1- (3,5-monomethoxyphenyl) group in the same manner as in Example 1 above to obtain the above compound. Yield: 53% Melting point: 150 ~ H NMR (CDC13) δ: 2.29 (3H5s)? 2.48 (3H? S) 5 3.29 (3H? S)? 3.45 (3H, s), 3.77 (6H, s), 3.79 (4H, t), 6.10 (3H, m), 7.40 (1H, S) Example 34) l-[(5,6-Difluorenyl-2-methylaminopyridine-3_fluorenyl) aminocarbonyl] _4_ (3,5-difluorenyl Phenyl) piperazineA benzyl N- (5,6-dimethyl-2-methylaminopyridine_3_fluorenyl) formate and 1- (3,5-dimethylphenyl) piperazine The reaction was carried out in the same manner as in Example 1 above to obtain the above compound. (Please read the notes on the back before filling out this page): Packing · -1% -31-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 B7 V. Description of the invention (27) Yield · 52%

Melting point: 160 ~ 162 ° C NMR (CDC13) 5: 2.30 (9H, s), 2.48 (3H, s), 3.31 (4H, t), 3.46 (3H, s), 3.78 (4H, t), 6.60 ( 3H, m), 7.41 (lH, s) Example 35) 1-[(5 · Ethyl-6-methyl-2-methylaminopyridine-3_fluorenyl) Womenylweilyl] -4- (3,5-Difluorenylphenyl) σ bottom σ Qin will be a phenyl N- (5-ethyl-6-methyl-2-methylamino) ^. __3_ ethyl group formate and 1- (3,5-dimethylphenyl) is used to carry out the reaction in the same manner as in Example 1 to obtain the above compound. Yield: 56%

Melting point: 143 ~ 145 ° C! Η NMR (CDC13) δ: 1.22 (3H5t)? 2.28 (6H? S) 5 2.52 (3H5s)? 2.72 (2H, q), 3.29 (4H, t), 3.45 (3H, s), 3.78 (4H, t), 6.59 (3H, m), 7.41 (lH, s) Example 36) 1 _ [(2-amido-6-6,7-dihydro-5H-cyclopentyl [b ] Pyridine-3-fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyoxyphenyl) piperazine Phenyl N- (2.methylamino-6,7-dihydro-5H- Cyclopentyl [b]. Pyridin-3-amidino) phosphonate and l- (3,5-dioxophenyl) piperazine were reacted in the same manner as in Example 1 above, and The above compounds can be obtained. Yield: 49%

Melting point: 148 ~ 150 ° C NMR (CDC13) 5: 2.09 (2H, m), 2-95 (4H, m), 3.30 (4H, t), 3.47 (3H, s), 3.77 (4H, t) , 3.80 (6H, s), 6.10 (3H, m), 7.49 -32- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling in this Page); Pack. Order 575564 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention ((1H, S) Example 37) H (2_amido_6,7_digas.cyclopentyl _. D-3--3-yl) aminocarbonyl group 4_ (3,5_dimethylphenyl) piperazine will be phenyl N_ (2-methylaminocyclofluorenyl [leaf ratio 3 3 sides,) 曱The acid and vinegar were reacted with H3,5.dimethylphenyl) hexyl by the same method as in Example 1 above to obtain a complex. Yield: 48% Melting point: 185 ~ 187 ° CW > JMR (CDC13) (5: 2.14 (2H, m), 2.29 (6H, s), 2.95 (4H, m), 3.32 (4H, t), 3.47 (3H, s), 3.79 (4H, t), 6.59 (3H, m), 7.private, (1H, S) Example 38) l-{[5,6-dimethyl_2- (4, -t-butylcarbonylpiperazine), than pyridin-3-amidino) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine phenyl N_ [5,6_dimethyl The group _2_ (4, -t-butylcarbonylpiperazine is more specific than the 3-3- & yl] phosphonate ester and i- (3,5-dimethoxyphenyl substrate, as in Example 1 above. The above-mentioned compound can be obtained by performing the reaction in the same method. Yield: 58% Melting point: 74 ~ 75 ° C 4 NMR (CDC13) 6: 1.46 (9H, s), 2.20 (3H, s), 2.21 (2H, S ), 2.90 (4H, t), 3.20 (4H, t), 3.55 (4H, t), 3.65 (4H, t), 3.98 (3H, s), 6.02 (3H, m), 8.20 (lH, s) Example 39) l-{[5,6-dimethyl-2- (4'-t-butylcarbonylpiperazine), than -33 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 male %)

----- J (Please read the notes on the back before filling out this page) -Installation · -Order · η0 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 ------ ---- B7 5 、 Invention ~ —σ 疋 _3-fluorenyl) aminocarbonyl] -4_ (3,5_dimethoxyphenyl) piperazine will be phenyl N- [5,6-dimethyl-2- (4 , -T-butylcarbonylpiperazine) piperidine-3-fluorenyl] formate and 1- (3,5-dioxophenyl) piperazine were carried out in the same manner as in Example 1 above. The reaction is performed to obtain the above-mentioned compound. Yield: 56%

Melting point: 155 ~ 156 ° C NMR (CDC13) ^: 1.48 (9H5s)? 2.22 (3H? S)? 2.29 (6H? S) 5 2_35 (3H, s), 2.95 (4H, t), 3.25 (4H, t), 3.57 (4H, t), 3.67 (4H, t), 6.59 (3H, m), 8.21 (lH, s) (Example 40) l-{[5-ethyl-6-fluorenyl-2 -(4, -t-butylcarbonylpiperazine) pyridine-3-amidino) aminocarbonyl] -4_ (3,5-dimethoxyphenyl) piperazine Phenyl N- [5-ethyl · 6 · methyl-2- (4, -t-butylcarbonylpiperazine) ° pyridin-3-amidino] formate and 1- (3,5-dimethoxyphenyl) piperazine, The reaction was carried out in the same manner as in Example 1 above to obtain the above compound. Yield: 52%

Melting point: 119 ~ 120 ° C 泔 NMR (CDC13) 5 丄 25 (3H, t), 1.48 (9H, s), 2.38 (3H, s), 2.51 (2H, q), 2.96 (4H, t), 3.27 (4H, t), 3.58 (8H, m), 3.78 (6H, s), 6.08 (3H, m), 8.24 (lH, s) Example 41) l-{[5-ethyl-6-formaldehyde 2- (4'-t-butyl-jiki-sigma-zine), pyridin-3-fluorenyl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine, phenyl N- [5 -Ethyl-6-fluorenyl- 2- (4'-t-butyl-chiki-sigma diazine) -34- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ( Please read the notes on the back before filling out this page} -Order · Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 575564 A7 ___ B7 V. Description of the Invention (3〇) Pyridine-3-fluorenyl] formate and i- (3,5-Dimethylphenyl) piperazine can be reacted in the same manner as in Example 1 above to obtain the above compound. Yield: 50%

Melting point: 126 ~ 128 ° C NMR (CDC13) δ: 1.20 (3H? T) 51.49 (9H? S) 5 2.29 (6H5s) 3 2.39 (3H, s), 2_52 (2H, q), 2.98 (4H, t ), 3.23 (4H, t), 3.59 (8H, m), 6.59 (3H, m), 7.58 (lH, s), 8.26 (lH, s) Example 42) 1 _ [(5,6- Dimethyl-2-piperazinepyridine-3_fluorenyl) aminocarbanyl] -4- (3,5-dimethoxyphenyl) σbaseσQin Jiang1-{[5,6- 一Methyl-2- (4'-t-butyl-Chlorochi), mouth-to-mouth bite_3_acid) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine ( 〇.218g, 〇4 house mol) 'baked in' monochloromethane · Shishoki melamine = 2: 1 (10ml), and gradually add anisole (0.26g, 2.4mmol) and aluminum chloride (0.3 g, 2.4 mmol), and then stirred at room temperature for 20 minutes. Then add steamed crane water (50ml), and perform the test with saturated sodium bicarbonate. Then use chloroform to extract the solvent, remove the solvent by concentration under reduced pressure, and then use column chromatography (methanol: two Chloropane = 8: 1). After separation and purification, the above compounds can be obtained. Yield: 89% Melting point: Oily NMR (CDC13.21 (3H, s), 2.35 (3H, S), 3.02 (4H, t), 3.34 (4H, t), 3.59 (4H, t), 3.62 (4H, t), 3.78 (6H, s), 6.08 (3H, m), 8.18 (lH, s) -35-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (please first Read the notes on the back and fill out this page) Order • 575564 A7 B7 V. Description of the invention (31) ~~ — (1H, S) Implementation Example 43) 1-[(5,6_dimethyl_24 hydrazine唆 -3 side group) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine the phenyl group [5,6-difluorenyl_2_ (4, _t_butylcarbonylpiperazine) ) Pyridine-3-amidino] aminocarbonyl 4- (3,5-dimethylphenyl) piperazine, which was reacted in the same manner as in Example 42 above to obtain the above compound. Yield: 85%

Melting point: 103 ~ 105 ° CH NMR (CDC13) 5: 2.16 (3H, s), 2.24 (6H, s), 2.40 (3H, s), 3.30 (4H, t), 3.44 (4H, t), 3.50 ( 4H, t), 3-81 (4H, t), 6.95 (3H, m), 7.72 (1H, s) Example 44) Ethyl-6-fluorenyl-2-piperazine. Pyridine_3_fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine Phenyl N-{[5-ethyl-6-fluorenyl_2- (4 , -T-butylcarbonylpiperazine) amidin-3-fluorenyl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) pyridine, following the same method as in Example 42 above The reaction is performed to obtain the above-mentioned compound. Yield: 88%

Melting point: 68 ~ 70 ° C! H NMR (CDC13) δ: 1.20 (3H, t), 2.40 (3H, s), 2.52 (2H, q), 2.75 (4H, t), 3.32 (4H, t), 3.70 (8H, m), 3.78 (6H, s), 6.09 (3H, m), 7.68 (lH, s), 8.23 (lH, s) Example 45) 1-[(5-ethyl-6-曱 基 -2- 旅 嘻. Than 唆 _acid) amine-36- This paper size applies to the Chinese National Standard (CNS) M specifications (210X297 mm) (Please read the precautions on the back before filling out this page)-Install · Ordered by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and printed by 575564 A7 '-^ ___B7 V. Invention (321 ^^-carbonyl) -4- (3,5-II Methylphenyl) piperidine will be phenyl N-{[5-ethyl-6-methyl, Hokiji base) mouth ratio 唆 -3-fluorenyl] amino group} -4- (3 , 5-Dimethylphenyl) hydrazone, the same method as described in Example 42 above was used for the reaction to obtain the above compound. Yield: 85%

Melting point: 100 ~ 102 ° C NMR (CDC13) ^: 1.20 (3H, t), 2.28 (6H, s), 2.39 (3H, s), 2.65 (2H? Q)? 2.76 (4H! ≫ t)? 3.00 (4H? T)? 3.23 (4H? T), 3.70 (4H? T)? 6.58 (3H, m), 7.66 (lH, s), 8.24 (1H, S)? Example 46) l-[( 5-ethenyl-2-methoxy-6-methylpyridinium) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine Phenyl N- (5-ethyl Fluorenyl-2-fluorenyloxy-6-methylpyridine_3_fluorenyl) formate (200mg, 0_67 mmol) and l- (3,5-dimethoxyphenyl) travelazine (150mg , 0.67 millimolar), dissolved in anhydrous tetrahydrofuran (15ml), and added DBU (100mg, 0.67 millimolar), and then stirred at room temperature for 2 hours. Then, the solvent was removed by concentration under reduced pressure, and the above compound was obtained after separation and purification by column chromatography (ethyl acetate: hexane = 1: 2). Yield: 83%

Melting point: 149 ~ 151 ° C β NMR (CDC13) 5: 2.57 (3H, m), 2.65 (3H, s), 3.28 (4H, t, J = 4.65Hz), 3.70 (4H, t, J = 4.65Hz ), 3.79 (6H, s), 4.06 (3H, s), 6.09 (lH, s), 6.14 (2H, d), 6.94 (lH, s), 8.87 (lH, s) -37- Applicable to this paper standard China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page); Packing _ 575564

Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, Example 47) 1-[(5 -Acetyl-2-methoxy-6-methyl tonidine-3-amidino) aminocarbonyl] -4- ( 3,5_Dimethylphenyl) piperazine converts the basic group N_ (5-ethyldonyl_2_methoxy_6_methyl.) More than 1- (3, 5-Difluorenylphenyl) piperidine was reacted in the same manner as in Example 46 to obtain the above compound. Yield: 82% Melting point: 66 ~ 69 ° C NMR (CDC13) 5: 2.31 (6H? S)? 2.57 (3H? S)? 2.65 (3H? S)? 3.〇8 (4H, t), 3.30 (4H, t), 4.10 (3H, s), 6.71 (2H5d), 6_94 (lH, s), B.89 (1H, s) Example 48) 1 _ [(5-ethylamido-2-methoxy -6-methylpyridine_3-fluorenyl) aminocarbonyl] -4- (3,5-difluorophenyl) piperazine Phenyl N- (5-ethylfluorenyl-2-methoxy The above-mentioned compound can be obtained by carrying out a reaction in the same manner as in Example 46 above for the methyl-6-methylpyridinyl) formate and 1- (3,5-difluorophenyl) piperazine. Yield: 77% Melting point: 180 ~ 181 ° C ^ NMR (CDC13) d: 2.57 (3H, s), 2.65 (3H, s), 3.33 (4H, t, J = 5.0Hz), 3.74 (4H, U = 5.0Hz), 4.07 (3H, s), 6.37 (1H, s), 6.46 (2H5d), 6.93 (lH, s), 8.85 (1H, s) (Example 49) 丨-[(5- 乙Fluorenyl-2-methoxymethylpyridine_3_fluorenyl) aminopropyl] -4- (3,5-dichlorinated phenyl) pyrazine phenyl N- (5-ethylfluorenyl 2-methoxy-6-methyl.pyridine-3_fluorenyl) formate and 1- (3,5-dichlorophenyl) piperazine were used as in Example -38 above-this Paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)-one to one-----*-(Please read the precautions on the back before filling this page);

, 1T d —5 *-575564 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 V. Description of the invention (34) ^ 46 The same method can be used to obtain the above compounds. Yield: 8 1% Few points: oily old wake R (CDCl3) 5: 2 57 (3H s), 2 65 (3H s), 3 34 (4H t), 3-78 (4H, t), 4.04 (3H, s), 6.93 (3H, m), 8.80 (lH, s) Example 50) l-[(5-ethylfluorenyl-2-methoxy-6-methylpyridine-3-fluorenyl ) Aminocarbonyl] -4- (2,3-dimethylphenyl) piperazine The phenyl N- (5 · ethylfluorenyl-2-methoxy-6-methyl alpha than pyridin-3- 醯The above-mentioned compound can be obtained by reacting the methyl) formate with 1- (2,3-dimethylphenyl) piperidine in the same manner as in Example 46 described above. Yield: 81%

Melting point: 173 ~ 174 ° C! H NMR (CDC13) δ: 2.29 (6H? S) 52.58 (3H? S)? 2.65 (3H5s), 2.98 (4H, t), 3.70 (4H, t), 4.06 ( 3H, s), 6.91 (lH, d), 6.97 (lH, s), 7.10 (lH, t), 8-89 (lH, s) (Conventional Example 51) 1-[(5-acetoxy_2-fluorene Ethyl-6-methylamidine-3-donyl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine will be the radical N_ (5-ethyldonyl-2-methoxy- The 6-methyl η-ratio-3-SI group) formate and 1- (2-methoxyoxyphenyl) amidine are reacted in the same manner as in Example 46 to obtain the above compound. Yield: 79%

Melting point: 153 ~ 154 ° C lR NMR (CDC13) (5: 2.58 (3H9s)? 2.65 (3H5s)? 3.15 (4H? T)? 3.73 (4H, t) 5 3.90 (3H, s), 4.06 (3H, s), 6.91 (lH, d), 6.96 -39- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page); Packing-575564 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards A7 B7 V. Description of Invention (35) (lH, d), 6.97 (lH, s), 7.10 (lH, t), 8.89 (lH, s) Example 52) [( 5-ethylfluorenyl-2-fluorenyloxy-6-fluorenylpyridin-3-fluorenyl) aminocarbonyl] -4- (3-hydroxyphenyl) piperazine Phenyl N- (5-ethylfluorenyl 2-methoxy-6-methylpyridin-3-amidino) phosphonate and 1- (3-hydroxyphenyl) piperazine were reacted in the same manner as in Example 46 above, but The above compound is obtained. Yield: 76% Melting point: Oily iH NMR (CDC13) 5: 2.60 (3H, s), 2.72 (3H, s), 3.34 (4H, t), 3.79 (4H, t), 3.98 (3H, s) , 6.45 (3H, m), 6.98 (lH, m), 8.97 (lH, s) Example 53) l-[(5-ethylamido-2-methoxy-6-methylpyridine-3- (Methenyl) aminoamino] -4- (3,5-dimethoxyphenyl) σ Chen Hei phenyl N- (5-ethenyl-2_methoxy-6_fluorenylpyridine- The 3-fluorenyl) formate and 1- (3,5-dimethoxyphenyl) piperidine were reacted in the same manner as in Example 22 above to obtain the above compound. Yield: 77%

Melting point: 167 ~ 169 ° C 'Η NMR (CDC13) δ: 2.58 (3H, s), 2.68 (3H, s), 3.47 (4H, t), 3.81 (6H, s), 4.05 (3H, s), 4.36 (4H, t), 6.42 (3H, m), 7.49 (1H, s), 9_05 (1H, s) Example 54) 1-[(5-Ethyl-2-yloxy-6 -Methylpyridin-3-fluorenyl) aminoweilyl] -4- (3,5-difluorenylphenyl) σphenyl, N- (5-ethylfluorenyl-2-methoxy- 6-Aminopyridine-3-Amino) 曱 -40- This paper is suitable for Guancai County (CNS) Α4 ·· (210X ^ 97 公 ^ 7-~ (Please read the precautions on the back before filling this page ); Equipment-printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 575564 A7 _____B7 V. Description of the invention (36) Ester and 1- (3,5-dimethylphenyl) π Chen Hee, the same as in the above examples The above-mentioned compound can be obtained by performing the reaction in the same manner as in Example 22. Yield: 75%

Melting point: 176 ~ 177 ° C 4 NMR (CDC13) δ: 2.34 (6H, s), 2.58 (3H, s), 2.68 (3H, s), 3.48 (4H, t), 4.06 (3H, s), 4.43 (4H, t), 7.05 (4H, t), 7.05 (3H, m), 7.52 (lH, s), 9.04 (lH, s) Example 55) l-[(5-ethylfluorenyl-2-methyl Oxy-6-methylpyridin-3-amidino) aminocarbonyl] -4- (3-hydroxyphenyl) piperazine Phenyl N- (5-ethylamido-2 -methoxy-6 · The above compound can be obtained by reacting methyl 3-methyl 3-carboxylate) with 1- (3-hydroxyphenyl) travelrazine in the same manner as in Example 22 above. Yield: 71%

Melting point: 114 ~ 115 ° C 4 NMR (CDC13) Heart 2.56 (3H, S), 2.75 (3H, s), 3.68 (4H, t), 4.05 (3H, s), 4.45 (4H, t), 7.30 ( 4H, m), 9.03 (lH, s)

Mass (EI) m / z: 458.2527 (MH, C23H3 () N404 Si Calculated: 458.1987) Example 56) 1-{[(5- (1 · hydroxyethyl) -2-fluorenyl-6-fluorene Pyridyl-3-amino] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine Phenyl N-[(5-ethylfluorenyl-2-fluorenyloxy-6- Methylpyridin-3-yl) -4- (3,5-dioxophenyl) piperazine (ioon ^ O.23 mmol), dissolved in absolute ethanol (15 ml) and added After the sodium pentoxide (gggmg) is stirred, stir at room temperature for 2 hours. -41-This paper size _ applicable to China; ^ (CNS) A4 size (210X297 mm 1 ---- (Please read the back first) Note for refilling this page), 11 -1¾. 575564 A7 B7 V. Description of the invention (37) Then the ethanol was removed by concentration under reduced pressure, and then column chromatography was used (ethyl acetate: hexane = 2 : 1), the above compound can be obtained after separation and purification. Yield: 97%

Melting point: 124 ~ 126 ° C lH NMR (CDC13) 5: 1.48 (3H5d) 52.42 (3H5s) 5 3.27 (4H? T)? 3.69 (4H, t), 3.79 (6H, s), 3.99 (3H, s) , 5_03 (lH, q), 6.09 (lH, s), 6.15 (2H, d), 6.90 (lH, s), 8.46 (lH, s) Example 57) l-{[((5- (l-hydroxyl Ethyl) -2-methoxy-6-methylpyridine-3-fluorenyl] aminocarbonyl} -4- (3,5-dimethylphenyl) piperazine 1-[(5-ethyl Fluorenyl-2-methoxy-6-methyl-2-methyl-3-amino) aminopropyl] -4- (3,5-dimethylphenyl), as described in Example 56 above. The reaction was performed in the same manner to obtain the above compound. Yield: 95%

Melting point: 153 ~ 154 ° CH NMR (CDC13) accounts for: 1.48 (3H, d), 2.30 (6H, s), 2.42 (3H, s), 3.26 (4H, t), 3.68 (4H, t), 3.99 ( 3H, s) 5 5.05 (lH, q), 6.71 (2H, d), 6.96 (lHg, s), 8.46 (lH, s) Example 58 printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. L-{[ (5- (l-hydroxyethyl) -2-methoxy-6-methyl, pyridin-3-amino] aminocarbonyl group 4- (2,3-dimethylphenyl) piperazine will be 1 -[(5-ethylfluorenyl-2-fluorenyloxy-6-methylpyridinyl) aminocarbonyl] -4- (2,3-difluorenylphenyl) piperazine, as in the above examples The above compounds can be obtained by reacting in the same manner as 5 6. Yield: 96%

575564 Printed by A7 B7, Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 5. Explanation of the invention (38) Melting point: 100 ~ 102 ° c iH NMR (CDC13) (5: 1.47 (3H, d), l_59 (3H, s), 2.25 (3H, S), 2.28 (3H, s), 2.43 (3H, m), 2.93 (4H, t), 3.66 (4H, t), 3.99 (3H, s), 5.05 (lH, q), 6.93 ( 3H5m), 7.11 (lH, m), 8.48 (lH, s) Example 59) l-{[((5- (l-hydroxyethyl) -2-methoxyfluorenylpyridine · 3-fluorenyl] amine Carbonyl} -4- (3,5-difluorinated phenyl) piperazine will be 1-[(5-acetoxy-2-amido-6-methyl-4-methyl-3-amino) amino The group] -4- (3,5-difluorinated phenyl) group was reacted in the same manner as in Example 56 to obtain the above compound. Yield: 97%

Melting point: 184 ~ 186 ° C 4 NMR (CDC13) 5: 1.48 (3H, d), 2.50 (3H, s), 3.30 (4H, t), 3.70 (4H, t), 4.11 (3H, s), 5_06 (lH, q), 6.33 (1H, S), 6.42 (lH, s), 8.54 (lH, s) Example 60) 1-{[(5- (1-hydroxyethyl) · 2-fluorenyloxy _6-Methyltoluene-3-fluorenyl] aminocarbonyl} -4- (3,4-digasified phenyl) piperazine 1-[(5-ethylfluorenyl-2-methoxy- The 6-methylpyridin-3-amidino) aminoweiyl] -4- (3,4-digasified phenyl) group is reacted in the same manner as in Example 56 above to obtain the above. Compound. Yield: 95%

Melting point: 197 ~ 200 ° C 4 NMR (CDC13) H_46 (3H, d), 2.41 (3H, s), 3.28 (4H, t), 3.66 (4H, t), 3.96 (3H, s), 5.20 (lH , Q), 7.02 (3H, m), 8.42 (1H, S) -43- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) 1.575564 A7 B7 V. Description of the invention (39) Example 61) 1-{[((5- (1-hydroxyethyl) -2-fluorenyl-6-fluorenylpyridin-3--3- & yl] Alkyl quinolyloxyphenyl) sigma Qin will be 1-[(5-ethyl & & yl-2-methoxy-6-methyl sulfonyl-3-acid) aminocarbonyl ] -4- (3-methoxyphenyl) piperazine was reacted in the same manner as in Example 56 to obtain the above compound. Yield: 97%

Melting point: 88 ~ 90 ° CW NMR (CDC13) (5: 1.47 (3H, d), 2.42 (3H, s), 3.11 (4H, t), 3.70 (4H, t), 3.89 (3H, s), 3.99 (3H, s), 5.03 (lH, q), 6_89 (3H, m), 6.94 (1 H, s), 7.05 (lH, m), 8.48 (lH, s) Example 62) l-{[ (5- (l-Ethyl) -2-methoxy-6-methyl u is more than n-3-Synyl] amino-chino} -4- (3-Ethyl) σ Chen Hei 1-[(5-Ethylfluorenyl-2-methoxy-6-methylpyridin_3_fluorenyl) aminoquinyl] -4- (3-hydroxyphenyl) piperidine, as described above Example 56 The reaction was carried out in the same manner to obtain the above compound. Yield: 87%

Melting point: 191 ~ 196 ° C Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) W NMR (CDC13) 5: 1.47 (3H, d), 2.41 (3H, s) , 3.27 (4H, t), 3.79 (4H, t), 3.98 (3H, s), 5.04 (lH, q), 6.57 (3H, m), 6.90 (lH, s), 7.13 (lH, t) , 8.41 (lH, s) Example 63) l-{[(((5- (l-hydroxyethyl) -2-oxo-6-fluorenylpyridinium_3-prolinyl] aminophenyl)}- 4- (3,5-Dimethoxyphenyl) sigma 1-[(5 -acetoxy-2-amidooxy-6-fluorenyl-2-phenyl-3-Si) aminoweiyl ] -4- (3,5 -dimethoxybenzyl) brigade 1: 7 Qin 'adopts the same as above-44- This paper size is applicable to Chinese National Standard (CNS) A4 specification (21 × 7mm) 575564 A7 ______ B7__ 5. Description of the invention (40) Example 5 6 The reaction was carried out in the same manner as described above to obtain the above compound. Yield: 87%

Melting point: 189 ~ 190 ° C 'H NMR (CDC13) δ: 1.47 (3H? D)? 2.43 (3H? S) 5 3.35 (4H? T)? 3.78 (6H, s), 3.97 (3H, s), 4.09 (4H, t), 5.05 (lH, q), 6.07 (3H, m), 7.35 (lH, S), 8.42 (lH, s) Example 64) 1-{[(5 · (1-hydroxyethyl ) -2-methoxy-6-methylpyridine-3-amino] aminocarbonyl} -4- (3,5-dimethylphenyl) piperazine 1-[(5-ethoxy -2-Methoxy-6-methyl. Titanium-3-fluorenyl) aminoweilyl] -4- (3,5-dimethylphenyl) pyridine, the same as in Example 56 above The reaction was carried out to obtain the above compound. Yield: 88%

Melting point: 170 ~ 172QC W NMR (CDC13) (5: 1.46 (3H, d), 2.29 (6H, s), 2.43 (3H, s), 3.43 (4H, t), 3.97 (3H, s), 4.10 ( 4H, t), 5.06 (lH, q), 6.60 (3H, m), 7.37 (lH, s), 8.40 (lH, s) Example 65) l-{[(5- (l-hydroxy-1- (Methylethyl) _2_methoxy_6_ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) d-pyridine-3-fluorenyl] aminocarbonyl group 4- (3,5-Dioxophenyl) piperazine 1-[(5-ethylamido-2-methoxy-6-methylpyridin_3_fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (214 mg, 050 mmol) was dissolved in tetrahydrofuran (10 ml), and boron magnesium formamidine (0.5 mU. 50 millimoles), and then stirred for 15 minutes, and then concentrated under reduced pressure to remove the solvent, co-take with ethyl acetate and dry filter, and then use column chromatography (ethyl acetate: t Ji-45- This paper size is applicable to China National Standard f (CNS) A4 specifications (210 × 297Α4Υ ~ *-----_____ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 " ^ --- B7 '· μι · ι ............... ιι 丨 丨 丨 · · ι ,, 5. Description of the invention (41) Alkan = 1: 2), proceed The above compounds can be obtained after isolation and purification. Yield · 84%

Melting point: 146 ~ 148 ° CH NMR (CDC13) 5: l_64 (6H, s), 2.64 (3H, s), 3.25 (4H, t), 3.67 (4H, t), 3.78 (6H, s), 3.99 (3H, s), 6.07 (3H, m), 6.86 (lH, s), 8.47 (lH, s) Example 66) 1 _ {[(5- (1-hydroxy-1-methylethyl) _2_form Oxy_6-methyl0-pyridin-3-fluorenyl] aminocarbonyl} 4- (3,5-dimethylphenyl) piperidinium will be 1-[(5-ethylfluorenyl-2-methoxy -6-methylpyridin-3-amidino) aminocarbonyl] -4_ (3,5-dimethylphenyl) piperazine can be reacted in the same manner as in Example 65 to obtain the above compound. Yield: 81% Melting point: Oily W NMR (CDC13) (5: 1.64 (6H, s), 2.29 (6H, s), 2.65 (3H, s), 3.24 (4H, t), 3.67 (4H, t), 3.99 (3H, s) 5 6.59 (3H, m), 7.05 (1H, s) 5 8.48 (lH, s) Example 67) 1 _ {[(5- (1-hydroxy-1-methylpropyl ) _2_methoxy-6-methylmethylpyridin-3-fluorenyl] aminocarbonyl group 4- (3,5-dimethoxyphenyl) piperazine 1-[(5-ethylfluorenyl- 2-methoxy-6-methylpyridine_3_fluorenyl) aminoweilyl] -4- (3,5-dimethoxyphenyl) brittle (2img, 0.50 mmol) , Dissolved in tetrahydropyran (10ml), and gradually add After boring the courtyard (0.5ml, 1.5ml house mole), it was shed for 1 minute, and then the solvent was removed by concentration under reduced pressure, and then it was extracted with ethyl acetate and dried. Then use column chromatography (ethyl acetate: hexano-46-) This paper size applies the Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the precautions on the back before filling this page) i__

-, 1T 575564

Description of the invention (printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 垸 = 1: 2), the above compounds can be obtained after separation and purification. Yield: 76%

Melting point: 127 ~ 129 ° C 泔 NMR (CDC13) (^ 0.83 (3H, t), 1.63 (3H, s), 1.94 (2H, m), 2.61 (3H, s), 3.26 (4H, t), 3.68 (4H, t), 3.79 (6H, S), 3-99 (3H, s), 6.08 (3H, m), 6.86 (lH, s), 8.44 (lHG, s) Example 68) l-[[( 5- (l-hydroxy · 1-methylpropyl) -2-methoxy-6 · methylcarbamidine-3_fluorenyl] aminocarbonyl group 4- (3,5 · dimethylphenyl) piper Hei 1-[(5-ethylfluorenyl-2-fluorenyloxy-6-fluorenyl σ is more than 3-amino) aminocarbonyl] -4- (3,5-difluorenylphenyl) Alas, the same method as described in Example 67 was used for the reaction to obtain the above compound. Yield: 74%

Melting point: 164 ~ 165 ° C iH NMR (CDC13) core 0.83 (3H, t), 1.60 (3H, s), 1.95 (2H, m), 2.29 (6H, s), 2.61 (3H, s), 3.23 ( 4H, t), 3.67 (4H, t), 3.99 (3H, s), 6.59 (3H, m), 6_87 (lH, s), 8.45 (lH, s) Example 69) l- [5-({ [4- (3,5-Dimethoxyphenyl) piperazine] carbonyl} amino) -6-methoxy-2-methyl0 than fluoren-3-yl] ethyl ethyl mercaptan ester A benzene bowl (262 mg, 1.0 mmol) was dissolved in tetrahydro. Bran (15 ml) was added with diethyl azodicarboxylic acid vinegar (157 α ΐ, ι · 〇mmol), and the mixture was stirred at 0 ° C for 30 minutes. Add 1-{[5_ (1_hydroxyethyl) _ 2--2-methoxy-6-fluorenyl ° bipyridin-3-fluorenyl] amino weibeb 4- (3,5-dimethoxy Phenyl phenyl) hydrazone (213 mg, 0.5 mmol) and thiol acetate (72 // 1, 1.0 mmol), dissolved in tetrahydro. Than (15mi), and gradually added -47- This paper size is suitable for wealth and wealth (CNS) A Vision grid (21GX297 mm factory ----- (Please read the precautions on the back before filling this page) I pack-order 575564 A7 ------- Β7 V. Description of the invention (43) First (please read the precautions on the back before filling this page) After adding, stir under Ot: for 1 hour, and at room temperature After stirring for 丨 hours, the solvent was removed by concentration under reduced pressure, and then extracted with ethyl acetate, dried and filtered, and then subjected to column chromatography (ethyl acetate · hexane = 1: 2). The above compounds can be obtained after isolation and purification. Yield: 62% Melting point: Oily 4 NMR (CDC13) 5: 1.55 (3H, s), 2.20 (3H, s), 2.39 (3H, s), 3.15 (4H, t), 3.57 (4H, t), 3.69 (6H, s), 3.90 (3H, s), 4.74 (lH, q), 6.01 (3H, m), 6.89 (lH, s), 8.33 (lH, s Example 70) l- [5-({[4_ (3,5-dimethylphenyl) piperazine] carbonyl} amino) -6-methoxy-2-methylpyridine-3-fluorene Ethyl] ethyl thiol ester 1-{[(((5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-amidino] aminocarbonyl} -4- (3 , 5-dimethylbenzene Piperazine was reacted in the same manner as in Example 69 to obtain the above compound. Yield: 60% Melting point: Oily W NMR (CDC13) (5: 1.60 (3H, d), 2.26 (6H , S), 2.52 (3H, s), 3.20 (4H, t), 3.64 (4H, t), 3.96 (3H, s), 4.80 (lH, q), 6.56 (3H, m), 6.91 (lH, s), 8.38 (lH, s) Example 71) l-{[2-methoxy-6-methyl-5- (1-sulfamethoxy)] amino Weicyl} -4- (3,5-dimethoxyphenyl) Pytyl will l- [5-({[4- (3,5-dimethoxyphenyl) piperazine] carbonyl} amino 6-methoxy-2-methylsigmadol_3-S & yl] ethyl ethyl mercaptan vinegar (180mg, -48-) This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 〇 '乂 297 mm) 575564 A7 ____ B7 V. Description of the invention (44) 0_37 House Morr) 'Dissolved in tetrahydro σ biran (15mi), lithium lithium hydride (15 mg, 0.4 morr) ), Stir for 20 minutes, then add 2N hydrochloric acid, and then remove the solvent by concentration under reduced pressure. 'Extracted with dichloromethane and dried and filtered, Concentrated under reduced pressure and then applied to the row and by column chromatography (ethyl acetate: hexane = U), obtained was separated and purified after the above compounds. Yield: 88% dots, oily β NMR (CDCl3) 5: 1.42 (3H, d), 2.39 (3H, s), 3.25 (4H, t), 3.66 (4H, t), 3.76 (6H, s) , 3.96 (3H, s), 5.02 (lH, q), 6.17 (3H, m), 6.87 (1H, s), 8.41 (1H, s) Example 72) Methoxy-6-methyl-5- (1-Sulfamethoxy)] aminocarbonyl 4- (3,5-dimethylphenyl) piperazine angered 1_ [5-({[4_ (3,5-dimethylphenyl) Group} amino group) -6-methoxy-2-methylpyridin-3-fluorenyl] ethyl ethyl mercaptan ester, which was reacted in the same manner as in Example 71 above to obtain the above compound. Yield: 87% Melting point: Oily NMR (CDC13) ά: 1.43 (3H? D) 52.28 (6H5s) 5 2.40 (3H? S)? 3.25 (4H, t), 3.72 (4H, t), 5.03 (lH , Q), 6.64 (3H, m), 6.88 (lH, s), 8.42 (1H? S) Example 73) l-[(2-methoxy-6-methyl-5-vinylpyridine_3 _Fluorenyl) aminocarbonyl} -4- (3,5-dioxophenyl) piperazine-49- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the back first Please note this page, please fill in this page), \ 呑 Printed by the Central Consumers ’Cooperative of the Ministry of Economic Affairs 564 Five-Year Invention Description (45 A7 B7 Printed by the Consumer ’s Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs shall print 1 {[5 (1-hydroxyethyl Group) _2_methoxy_6_methylpyridine-3 • fluorenyl) aminoweilyl} _4- (3,5-dimethoxyphenyl) morphazine, dissolved in chloroformic acid (15ml) After adding pyridine p-toluenesulfonate (60mg, 〇23mmol), the solution was flowed for 16 hours, and then the chloroformic acid was removed by concentration under reduced pressure, and then column chromatography (ethyl acetate) was performed. ·· Hexane = 1 _2), the above compounds can be obtained after separation and purification. Yield: 93% Melting point: 140 ~ 141 ° CH NMR (CDC13) 5: 2.43 (3H, s), 3.27 (4H, t), 3.69 (4H, t), 3.79 (6H, s), 4.00 (3H, s), 5.25 (lH, d), 5.65 (lH, d), 6.08 (lH, s), 6.13 (2H, d), 6.82 (lH, d), 6_91 (lH, s), 8.53 (lH, s) ) Mass (I) m / z: 412.2119 (MH, C22H28N404 Calculated: 412.2110) Example 74) 1 _ [(2-methoxy-6-fluorenyl-5-vinylpyridine_3_fluorenyl) amine Weilyl} _4- (3,5-dimethylphenyl) brigade 1-{[5- (1-hydroxyethyl) · 2-methoxy-6-methylpyridin-3-yl ) Amino-Weiquib 4- (3,5-dimethylphenyl) brittle, the same method as described in Example 73 above was used to perform the reaction to obtain the above compound. Yield: 94% Melting point: 131 ~ 132 ° C! H NMR (CDC13) 5: 1.57 (3H? S) 52.31 (6H5s)? 2.43 (1H? S)? 3.25 (4H, t), 3.68 (4H, t ), 4.00 (3H, s), 5.25 (lH, d), 5.65 (lH, d), 6.60 (3H, m), 6.82 (lH, d), 6.92 (lH, s), 8.53 (lH, s) Mass (EI) m / z: 380_2236 (MH, C22H28N402 Calculated value: (Please read the precautions on the back before filling in this page) i I — — f — —Package · .4 -50- This paper size applies to Chinese national standards (CNS) A4 specification (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 s ------ 5. Description of the invention (46) 380.2212) Example 75) M (2-methoxy -6-methyl-5_vinylpyridine_3_fluorenyl) aminocarbonyl} -4- (3,5-difluorinated phenyl) piperin 1-{[5- (1-hydroxyethyl Group) —2-methoxy-6_methylpyridine_3_fluorenyl group] methynyl. Group} -4- (3,5_ monofluorinated phenyl) travelazine, the same as in Example 73 above The reaction is carried out to obtain the above compounds. Yield: 93%

Melting point: 160 ~ 161 ° CH NMR (CDC13) 3: 2.44 (3H, s), 3.30 (4H, t, J = 5.52Hz), 3.68 (4H, t, J = 5.5Hz), 4.01 (3H, s) , 5.26 (lH, d), 5.65 (lH, d), 6.30 (lH, s), 6.39 (2H, d), 6.81 (lH, d), 8.53 (lH, s)

Mass (EI) m / z: 412.2102 (MH, C22H28N404 Calculated value: 412.2110) Example No. 76) ^ [(^-Isopropylphenyl-^-methoxy-stone-methyl ring bite ^ -fluorenyl group ) Aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine 1-{[5- (1-hydroxy-1-fluorenethyl) -2_methoxy_6_methyl Pyridyl, 3-fluorenyl) aminocarbonyl} -4- (3,5-dioxophenyl) piperazine can be reacted in the same manner as in Example 73 to obtain the above compound. Yield: 96%

Melting point: 83 ~ 85 ° C iH NMR (CDC13) 5: 2.01 (3H, s), 2.38 (3H, s), 3.25 (4H, t), 3.66 (4H, t), 3.78 (6H, s), 3.99 (3H, s), 4.86 (lH, s), 5.30 (lH, s), 6.11 (3H, m), 6.90 (lH, d), 8.18 (lH, s) -51-This paper size applies to Chinese national standards (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling out this page. • Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 ___ B7 _ V. Description of the invention (47) — ^ Implementation Example 77) 1-[(5-Isopropylphenyl-2-methoxymethylpyridine_3_vinyl) aminoamino} -4- (3,5-dimethylphenyl) i7 Add 1-{[5- (1-hydroxy-1-methylethyl) -2_methoxymethylpyridine-3-fluorenyl) aminocarbonyl} -4- (3,5-dimethylphenyl) Piperazine was reacted in the same manner as in Example 73 described above to obtain the above compound. Yield: 93%

Melting point: 140 ~ 142 ° C lH NMR (CDC13) 5: 2.01 (3H? S) 52.29 (6H5s) 5 2.28 (3H? S)? 3.23 (4H, t), 3.66 (4H, t), 3_99 (3H, s), 4.86 (lH, s), 5.18 (1H, s), 6.59 (3H, m), 6.91 (lH, S), 8.18 (lH, s) Example 78) ethyl-2- { l_ [5-({[4- (3,5-dimethoxyphenyl) piperidinium] carbonyl} amino) -6-fluorenyloxy-2-methyl Oxy} acetate will be 1-{[5- (1-hydroxy) -2-fluorenyloxy-6-methylmethylpyridin-3-amidino] aminoweiyl} -4- (3,5-di (Methoxyphenyl) pyrazine (0.5 mmol), dissolved in dimethylformamide (15 ml), and sodium hydride (18.5 mg, 0.5 mmol) was added. 'Stir at room temperature for 15 After minutes, the solvent was removed by concentration under reduced pressure, and the above-mentioned compound was obtained after separation and purification by column chromatography (ethyl acetate: Kojiri = 1: 2). Yield: 89% Melting point: Oily NMR (CDC13) 5: 1.25 (3H, t), 1.34 (3H, d), 2.42 (3H, s), 3.00 (4H, t), 3.29 (4H, t), 3.74 (6H, s), 3_97 (3H, S), 4.16 (4H, s), -52- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back first (Fill in this page again.) I installed-、 ... !! 575564 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Invention Description (48) 4.53 (lH, q), 6.03 (3H, m), 7_58 (lH, s) Example 79) 4- {1- [5-({[4- (3,5-dimethoxyphenyl) piperazine] amido} amino) -6-methoxy- 2-methylpyridin-3-fluorenyl) ethoxybutyric acid'butyric acid will 1-{[5- (1- -Ethyl) -2 -methoxy-6 · methyl 0 to bite -3 -Acid group] amine group} -4- (3,5-dimethoxyphenyl) piperidine (107 mg, 0.25 mmol) and dimethylaminopyridine (3 mg, 〇_〇25 Millimolar), dissolved in pyridine, added anhydrous succinic acid (50mg, 0.5mmol), and stirred at room temperature for 5 hours. 'After adding distilled water, extraction with dichloromethane was performed. The organic layer was washed with 1N hydrochloric acid, and then After the solvent was removed by reduced pressure to be concentrated and purified by column chromatography (dichloromethane: methanol = 20: 1) 'obtained was separated and purified after the above compounds. Yield: 78%

Melting point: 158 ~ 160 ° CW NMR (CDC13) δ: 1.42 (3H, d), 2.43 (3H, s), 2.61 (4H, m), 3.24 (4H, t), 3.66 (4H, t), 3.76 ( 6H, s), 3.95 (3H, s), 5.94 (lH, q), 6.04 (3H, m), 6.89 (lH, s), 8.13 (lH, s) Example 80) 4- {1- [5 -({[4- (3,5-Difluorenylphenyl) trazine] Jinyl} amino) -6-fluorenyloxy-2-methylaronidine-3-fluorenyl) ethoxy}- 4-Oxybutyric acid will be 1-{[5- (1_hydroxyethyl) -2-fluorenyloxy-6-fluorenylpyridin-3-fluorenyl] aminocarbanyl} -4- (3,5 -Difluorenylphenyl), and the reaction was performed in the same manner as in Example 79 above to obtain the above compound. Yield: 76% -53- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 × 297 mm) (Please read the precautions on the back before filling this page) i__Order 575564 A7 B7 1. Invention Instructions (49)

Melting point: 138 ~ 140 ° C 4 NMR (CDC13) (5: 1.43 (3H, d), 2.27 (6H, s), 2.55 (3H, s), 2.65 (4H, m), 3.24 (4H, t), 3.69 (4H, t), 3.95 (3H, s), 5.95 (lH, q), 6.60 (3H, m), 6.88 (lH, s), 8.11 (lH, s) (Please read the precautions on the back before (Fill in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 54 This paper size applies to China National Standard (CNS) A4 (210X297 mm) 575564

AB V. Description of the invention (50) Employees' cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China m: Example: number | Ri and R2 R3 R1 R5 Rg R? Re A i Z-YI 81 -CH = CH-CH = CH- H OMe H OMe HHN 〇OMe 3-N 82 -CH = CH-CH = CH- H Me H Me HHN 〇OMe 3-N 83-CH = CH-CH = CH- Me Me HHHHN 〇OMe 3-N 84 -CH = CH-CH = CH- H F. HFHHN 〇I OMe 3-N 85 -CH = CH-CH = CH- H Cl H Cl HHNI 〇OMe 3-N 86 -CH = CH-CH = CH- FHHHHHN 〇OMe 3-N 87 -CH = CH-CH = CH- Cl HHHHHN 〇OMe 3-N 88 -CH = CH-CH = CH- H Cl HHHHN 〇OMe 3-N 89 -CH = CH-CH = CH-H OH HH • HHN 〇OMe 3-N 90 -CH = CH-CH = CH- 〇Me HHHHHN 〇OMe 3-N | 91 -CH = CH-CH = CH- SMe HHHHHN 〇OMe 3-N 92 -CH di-CH- CH = CH-H. AHH ^ HHN 〇OMe 3-N 93 · ^ -CH = CH-CH = CH- HHHHHN 〇OMe 3-N 94-CH = CH-CH = CH- OMe HH Me HHN 〇OMe 3-N 95 -CH = CH-CH = CH- 〇Me HH Ph HHN 〇OMe 3-N 96 -CH = CH-CH = CH- Me HH OMe HHN 〇OMe 3-N 97 -CH = CH-CH = CH- -Benzo- HHHHN 〇 OMe 3-N 98 -CH = CH-CH = CH- H OMe H OMe H Me N 〇OMe 3-N 99 -CH: CH-CH = CH- H OMe H OMe H Et N 〇OMe 3-N 100- CH = CH-CH = CH- H OMe H OMe H iPr N 〇OMe 3-N 101 -CH = CH-CH = CH- H OMe H OMe HN 〇OMe 3-N 102 -CH = CH-CH = CH- H OMe H OMe H Benzyl N 〇OMe 3-N 103 -CH = CH-CH = CH- H Me H Me H Me N 〇OMe 3-N 104 -CH = CH-CH = CH- H Me H Me H Et N 〇OMe 3-N 105 -CH = CH-CH = CH- H Me H Me H iPr N 0 OMe ： 3-N (Please read the notes on the back before filling this page) -55- This paper size is applicable to China National Standard (CNS) A4 Specification (210X 297 mm) 575564 A7 B7 V. Invention Description (51 Printed by the Consumers' Cooperative of the Standards Bureau of the Ministry of Economic Affairs

Example number Ri and R2 R3 R4 Rg f Rs AX z Y 106 -CH = CH-CH = CH- H Me H Me H Benzyl N 〇OMe 3-N 107 -CH = CH-CH = CH- HYHHH Me N 〇 OMe 3-N 108 -CH = CH-CH = CH-H. Ah HHH Et N 〇OMe 3-N 109 -CH = CH-CH Di-CH- H OMe 'H OMe HHNS OMe 3-N 110 -CH = CH-CH = CH- H Me H 丨 Me HHNS OMe 3-N 111 -CH = CH-CH = CH- HFHFHHN s OMe 3-N 112 -CH = CH-CH = CH- H Cl H Cl HHN s OMe 3-N 113 -CH = CH-CH = CH- H 〇Me HHHHN s OMe 3-N 114 -CH = CH-CH = CH- H 〇Me H OMe H • HN 〇Me 3-N 115 -CH = CH-CH = CH- H Me H Me HHN 〇Me 3-N 116-CH = CH-CH = CH- Me Me HHHHN 〇Me 3-N 117 -CH = CH-CH = CH- HFHFHHN 〇Me 3-N 118〆-CH = CH-CH = CH- H Cl H Cl HHN 〇Me 3 -N 119 -CH = CH-CH = CH- 〇Me HHHHHN 〇Me 3-N 120 -CH = CH-CH = CH- FHHHHHN 〇Me 3-N 121 -CH = CH-CH = CH- Cl HHHHHN 〇Me 3-N 122 -CH = CH-CH = CH- SMe HHHHHN 〇Me I 3-N 123 -CH = CH-CH = CH- 〇Me HH Me HHN 〇Me 3-N 124 -CH = CH-CH = CH --Benzo- HHHHN 〇Me 3-N 125 -CH = CH-CH = CH- H OMe H OMe HHN s Me 3-N 126 -CH = CH-CH = CH- H Me H Me HHN s Me 3-N 127 -CH = CH-CH = CH- HFHFHHN s Me 3-N 128 -CH = CH-CH = CH- H OMe H OMe HHN 〇 2-Py 4-N 129-CH = CH-CH = CH-H OMe H OMe HHN 〇3-Pv 4-N 130 -CH = CH-CH = CH- H OMe H OMe HHN 〇2-Tienyl .4-N 131 -CH = CH-CH = CH- H Me H Me HHN 〇 3- Py 4-N -56- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Please read the notes on the back before filling out this page 575564 A7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Explanation (52) Example 81) 1-[(2-methoxyfluorinoline_3_fluorenyl) aminocarbonyl] _4_ (3,5- «monomethoxyphenyl) πασσa) will Phenyl N- (2-methoxyoxoline-3-amino) formate-3-amino-2-methoxyquinoline (4g, 23 mmol) and phenyl chloride formate (4.04 g, 25 mol), dissolved in methylene chloride, and stirred at room temperature for 2 hours. Then, the dichloromethane is removed by concentration under reduced pressure, and the compound is obtained by column chromatography (hexane: diethyl ether = 8: 1) and separation and purification. Yield: 75% Melting point: oily> iMR (CDCl3) 5: 4.01 (3H, s), 7.30 (5H, s), 7.41 (lH, t), 7.70 (lH, d), 7.71 (lH, d) ), 8.71 (lH, s) b) l-[(2-methoxyquinolin-3-amidino) aminocarbonyl; | _4_ (3,5_dimethoxyphenyl) N- (2-methoxyα-quinolin-3-amidino) formate (148 mg, 0.5 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (112 mg (0.5 mol), was dissolved in anhydrous tetrahydro σ ratio, and DBU (117 mg, 0.75 mmol) was added, followed by stirring at room temperature for 2 hours. Then the tetrahydro-α-pyran is removed by concentration under reduced pressure, and then column chromatography (hexane: ether = 5: 1) is used for separation and purification to obtain the above compound. Yield ·· 81% Melting point: 200 ~ 201 ° C ιϋ NMR (CDC13) ^: 3.31 (4H? TJ-5.0Hz)? 3.74 (4H? T) 5 -57- This paper applies Chinese national standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

, 1T .— In-

I-ί I 575564 A7 B7 V. Description of the invention (53) 3.79 (6H, s), 4.17 (3H, s), 6.09 (lH, s), 6_17 (2H, s), 7.35 (lH, t), 7.49 (lH, t), 7.71 (lH, d), 7.78 (lH, d), 8.78 (m, S)

Mass (EI) m / z: 390.2066 (MH, C23H26N402 Calculated: 390.2055) Example 82) l-[(2-methoxyn-quinolin-3-amidino) aminocarbonyl] -4- (3, 5-Difluorenylphenyl) piperazine is a compound of phenyl N- (2-methoxyn quinine-3-g-branyl) formate and ι_ (3,5-dimethylphenyl). The reaction was carried out in the same manner as in Example 81 above to obtain the above compound. Yield: 79%

Melting point: 143 ~ 145 ° C 4 NMR (CDC13) (5: 2.30 (6H, s), 3.29 (4H, t), 3.80 (4H, t), 4.18 (3H5s), 6.62 (3H, m) 57.36 (lH , T), 7.49 (lH, t), 7.71 (lH, d), 7.78 (lH, d), 8.79 (lH, s)

Mass (EI) m / z: 390.2066 (MH, C23H26N402 Calculated: 390.2055) Example 83) l-[(2-methoxyquinoline · 3-fluorenyl) aminocarbonyl] _4_ (2,3-di Methylphenyl) Piperazine Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The acid ester is reacted with 1- (2,3-monomethylphenyl) and reacted in the same manner as in Example 81 to obtain the above compound. Yield: 83%

Melting point: 174 ~ 175 ° C] H NMR (CDC13) 5: 2.20 (3H? S)? 2.39 (3H5s)? 3.28 (4H5t), -58- This paper size is applicable to China National Standard (CNS) A4 specification (210X297) Centimeter) 575564

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs • 69 (4H, t), 3_93 (3H, S) 55.98 (lH, S), 6.30 (lH, t), 6.37 (lH, S), 6.39 (1H, s ), 6.63 (1H, s) Example 84) l-[(2-methoxyquinoline-3_fluorenyl) aminocarbonyl > 4- (3,5-difluorophenyl) σchenazine Benzomethoxy sigmaquinine-3-fluorenyl) formate and fluorene- (3,5-difluorophenyl) piperazine can be reacted in the same manner as in Example 8 丨 above, but The above compound is obtained. Yield: 78% Melting point: 158 ~ 159 ° C! H NMR (CDC13) δ: 3.32 (4H5tJ = 5.0Hz) 53.72 (4H5t? J = 5.0Hz), 4.19 (3H, s), 6.29 (1 H, s ), 6.39 (2H, d), 7.36 (lH, t), 7.50 (lH, t), 7_71 (lH, d), 7.81 (1 H, d), 8_78 (lH, s) Example 85) 1- [(2-Methoxyquinolin-3-amidino) aminocarbonyl] -4- (3,5-dichlorophenyl) piperidine Phenyl N- (2-methoxyquinoline-3 -Fluorenyl) phosphonate and 1- (3,5_ mono-gasified phenyl) quinone, which were reacted in the same manner as in Example 81 above, to obtain the above compound. Yield: 56% Melting point: 156 ~ 158 ° C lH NMR (CDC13) δ: 3.33 (4H? T)? 3.73 (4H5t) 54.21 (3H? S) 5 6.79 (lH, s), 6.83 (lH, d) , 6.93 (lH, t), 7.26 (lH, t), 7.38 (lH, t), 7.52 (1H, t), 7.71 (lH, d), 7.83 (lH, d) Mass (EI) m / z_.430.0977 (calculated value of MH, C21H2 () N402 Cl · · 430.0963) -59- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Packing and ordering 4 575564 A7 B7 V. Description of the invention (55 Printed sheet of paper by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, Example 86) l-[(2-methoxypyridin-3-fluorenyl) amine Carbonyl] -4- (2-Gasated benzyl) Ϊ7Ϊ1717 will be phenyl N- (2-methoxylin-3-yl) formate with (2-fluorinated phenyl) Piperazine was reacted in the same manner as in Example 81 to obtain the above compound. Yield: 81% Melting point 15 6 ~ 15 8 ° CW NMR (CDCl3) (5: 3.18 (4H, t), 3.74 (4H, t), 4.18 (3H, s), 6.99 (2H, q) J .07 (2H, m), 7.35 (2H, m), 7.50 (lH, t), 7.70 (lH, d), 7.77 (lH, d) Example 87) l-[(2-methoxyfluorene Phenolin-3-amidino) aminocarbonyl] -4- (2-gasified benzyl) σdihexyl radical N- (2-methoxyuquinolin-3-amidino) phosphonate and ι_ The (2-gasified phenyl) methanazine was reacted in the same manner as in the above Example 81 to obtain the above compound. Yield: 78% Melting point: 79 ~ 80 ° Gw NMR (CDC13) (5: 3.32 (4H, t), 3_74 (4H, t), 4.20 (3H, s), 6.82 (2H, q), 6.94 (2H , M), 7.34 (2H, m), 7.48 (lH, d), 7.70 (lH, d), 7.78 (lH, d) κ Example 88) l-[(2-Methoxylin-3- Fluorenyl) aminocarbonyl] -4- (3-chlorophenyl) piperazinePhenyl N_ (2-methoxyquinolin-3-amidino) fluorenate and i- (3-chlorobenzene Base) Pyrazine, followed the same method as in Example 81 above (please read the precautions on the back before filling out this page) i Packing-, ordering-Am -60- Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 ___B7 _ 5. Explanation of the Invention (^)

The JO reacts to obtain the above compounds. Yield: 73%

Melting point: 97 ~ 98 ° CW NMR (CDC13) core 3.31 (4H, t), 3.73 (4H, t), 4.18 (3H, s), 6.82 (lH, d), 6.87 (lH, d), 6.92 (lH , S), 7.21 (lH, t), 7.32 (lH, s), 7.37 (lH, t), 7.51 (lH, t), 7.70 (lH, d), 7.78 (lH, d), 8.80 (lH, s) Example 89) l-[(2-Methoxyfluorin-3-yl) aminocarbonyl] -4- (3-hydroxyphenyl) piperazine Phenyl N- (2-methoxy u Quineline-3-fluorenyl) phosphonate and 1- (3-transphenyl) trazine can be reacted in the same manner as in Example 81 to obtain the above compound. Yield: 75%

Melting point: 190 ~ 191 ° C lU NMR (CDC13) 5: 3.33 (4H? T)? 3.80 (4H? T)? 4.19 (3H5s)? 6.47 (lH, d), 6.82 (2H, d) J.16 ( lH, t), 7.32 (lH, S), 7.37 (lH, t), 7.51 (lH, s), 7.72 (lH, d), 7.78 (lH, d), 8.78 (lH, s) Example 90) l-[(2-methoxyquinolin-3-amidino) aminocarbonyl] -4_ (2-hydroxyphenyl) piperidinylphenyl N- (2-methyloxylin-3-yl) The acetic acid ester and 1- (2- light phenyl) piperazine were reacted in the same manner as in Example 81 to obtain the above compound. Yield: 88%

Melting point: 159 ~ 161 ° CW NMR (CDC13) 3.28 (4H, t), 3.71 (4H, t), 3.81 (3H, s), -61-This paper is applicable to national standards of the country ㈠Europe tears thin) '— (Please read the precautions on the back before filling this page)

575564 A7

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4.18 (3H, s), 6.52 (2H5s), 6.62 (lH, s), 7.23 (lH, t), 7.31-7.53 (3H, m), 7.72 (2H, m ), 8.81 (lH, s) throughout Example 91) l-[(2-methoxyoxoline_3-fluorenyl) aminocarbonyl] _4_ (2-fluorenylthiophenyl) piperazine Ν · (2-methoxyoxoline-3-fluorenyl) formate and 1- (2-methylthiophenyl) group were reacted by the same method as in Example 81 above, but The above compound is obtained. Yield: 78% Melting point: 147 ~ 149 ° C iH NMR (CDC13) δ: 2.44 (3H, s), 3.07 (4H, t), 3.75 (4H, t), 4.18 (3H, S), 7.13 (3H , M), 7.18 (lH, d), 7.39 (2H, m), 7.70 (3H, m)? 8.81 (lH? S) Example 92) l-[(2-methoxyquinoline-3- 醯(Amino) aminocarbonyl] · 4- (3-isopropoxyphenyl) branched phenyl N- (2-methoxyoxoline-3-fluorenyl) formate with 1- (3-isopropyl The oxyphenyl) piperazine was reacted in the same manner as in Example 81 to obtain the above compound. Yield: 93% Melting point: 111 ~ 113 ° C 'H NMR (CDC13) 5: 1.34 (6H, d), 3.30 (4H, t), 3.74 (4H, t), 4.18 (3H, s), 4.55 ( lH, m), 6.49 (2H, s), 7.05 (lH, s), 7.20 (lH, t), 7-32 (lH, s), 7e37 (lH, t), 7.50 (lH, t), 7.70 (lH, d), 7.77 (lH, d), 8.80 (1H, s) Example 93) l-[(2-methoxyoxyquinolin-3-amidino) aminocarbonyl] -4- -62- This paper size applies the Chinese National Standard (CNS) A4 specification (2ΐ〇χ 297 mm) (Please read the precautions on the back before filling this page)-Pack.

1T d 575564 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (58) (3-Cyclopropylmethyloxyphenyl) piperazine Phenyl N- (2-methoxy4lin The above-mentioned compound can be obtained by reacting 3--3-methyl) formate with 1- (3-cyclopropylmethyloxyphenyl) piperazine in the same manner as in Example 81 described above. Yield: 90%

Melting point: 146 ~ 147 ° C 4 NMR (CDC13) 6: 0.36 (2H, t), 0.65 (2H, m), 1.28 (lH, m), 3.31 (4H, t), 3.75 (4H, t), 3_80 (2H, d), 4.18 (3H, s), 6.50 (lH, s), 6.60 (2H, s), 7.19 (lH, t), 7.32 (lH, s), 7.37 (lH, t), 7.50 ( lH, t), 7.70 (lH, d), 7.77 (lH, d), 8.79 (lH, s) Example 94) l-[(2-methoxyquinolin-3-amidino) aminocarbonyl] The 4- (2-fluorenyl-5-methylphenyl) phenyl group is a mixture of phenyl N- (2-methoxyσquinine-3_acid) phosphonate and 1- (2-fluorenyloxy) The methyl-5-methylphenyl group can be reacted in the same manner as in Example 8 above to obtain the above compound. Yield: 76%

Melting point: 115 ~ 116 ° C iH NMR (CDC13) 6: 2.30 (3H, s), 3.14 (4H, t), 3.75 (4H, t), 3.87 (3H, s), 4.18 (3H, s), 6.79 (2H, m), 6.84 (lH, d), 7.35 (2H, m), 7.50 (lH, t), 7.72 (lH, d), 7.77 (lH, d), 8_82 (lH, s) Example 95) l-[(2-methoxy.quinolin-3-amidino) aminocarbonyl] -4- (2-methoxy-5-phenylphenyl) piperazine and phenyl N- ( 2-Methoxy u-quelin-3-St-yl) phosphonate and ι_ (2-Methoxy-5-phenylphenyl), which are the same as in Example 8 丨 -63- The standard applies to China National Standard (CNS) Α4 specification (2ι〇 × 297 mm) (please read the precautions on the back before filling out this page)-Equipment · Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative 575564 A7 -____ B7 V. DESCRIPTION OF THE INVENTION The methods (59) ~~ can be reacted to obtain the above compounds. Yield: 77%

Melting point: 122 ~ 123 ° C 4 NMR (CDC13) (5: 3.38 (4H, t), 3.86 (4H, t), 4.97 (3H, s), 4.18 (3H, s), 7.05 (2H, m), 7.34-7.45 (6H, m), 7.50 (lH, t), 7.56 (2H, d), 7.71 (2H, d), 7.78 (2H, d) 58.88 (lH, s) Example 96) l-[( 2-Methoxyphosphonium-3-fluorenyl) aminocarbonyl] (5-methoxy-2-methylphenyl) piperazine Phenyl N- (2-methoxy4-lin-3-ol The above-mentioned compound can be obtained by the same method as described in Example 81 above, in which the formic acid ester and 1- (5-methoxy-2-methylphenyl) piperazine are reacted. Yield: 82%

Melting point: 128 ~ 130 ° C 1H NMR (CDC13) δ: 2.30 (3H, s), 3.37 (4H, t), 4.84 (4H, t), 3.78 (3H, s), 3.97 (3H, s), 7.05 (2H, m), 7.13 (lH, d), 7.38 (3mm, m), 7.62 (lH, d), 7.80 (lH, s), 8.88 (lH, s) Example 97) 1- [ (2-methoxyquinolin-3-amidino) aminocarbonyl] -4- (1-naphthyl) pyridine Phenyl N- (2-methoxyfluorin-3-yl) fluorenic acid The ester was reacted with 1- (1-naphthyl) piperazine in the same manner as in Example 81 to obtain the above compound. Yield: 68%

Melting point: 158 ~ 160 ° C NMR (CDC13) 6: 3.22 (4H, t), 3.86 (4H, t), 4.20 (3H, s), -64- This paper size is applicable to China National Standard (CNS) A4 specifications ( 210X 297mm) .1 I! 丨 丨 · 0 (Please read the precautions on the back before filling out this page} • Installation ·-Order _ Printed by the Central Consumers Bureau of the Ministry of Economy Staff Consumer Cooperative 575564 A7 __________B7 V. Description of the invention ( 60) 7.13 (lH, d), 7.38 (2H, m), 7.43 (lH, t), 7.53 (3H, m), 7.62 (lH, d), 7.72 (lH, d), 7.80 (lH, d) , 7.86 (lH, d), 8.24 (lH, s), 8.84 (1H, S) Example 98) 1- [N- (2-methoxypyridin-3-fluorenyl) -N-methylamino A few bases] · 4- (3,5-dimethoxyphenyl) Pyridine 1 [(2-methoxyfluorin-3-yl) aminocarbonyl] -4- (3,5 · di Methoxyphenyl) Luhe (106 mg, 0.25 mmol), dissolved in dimethylformamide (15 ml), and sodium hydride (6.0 mg, 0.25 mmol) was added to the chamber. After stirring at room temperature for 15 minutes, add melamine (35 mg, 0.25 mmol) and stir at room temperature for 16 hours. The difluorenamide is then removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane = 1: 2) is used for separation and purification to obtain the above compound. Yield: 93%

Melting point: 88 ~ 89 ° C iH NMR (CDCl3) 5: 2.93 (4H, t), 3.17 (3H, s), 3.34 (4H, t), 3.72 (6H, s), 4.15 (3H, t), 5.95 (2H, s), 5.98 (lH, s), 7.40 (lH, t), 7.61 (2H, m), 7.73 (lH, s), 7.84 (lH, d) Example 99) 1- [N- Ethyl-N- (2-Methoxyquinolin-3-acid) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine 1-[(2-methoxy Quinoline-3-amidino) aminocarbonyl] _4- (3,5-dimethoxyphenyl) travelazine (106mg, 0.25 mmol), dissolved in dimethyl formamidine (15ml) ) 'And sodium hydride (6.0 mg, 0.25 mmol) was added. Stir at room temperature for 16 hours. Then use reduced pressure concentration to apply Dijia-65- this paper size to Chinese National Standard (CNS) A4 specifications (21 × 297 mm) I --------— (Please read the precautions on the back before filling This page) Order 575564 A7 B7 V. Description of the invention (61) (Please read the precautions on the back before filling in this page) After the methamidamine is removed, use column chromatography (ethyl acetate: hexane = 1: 2). After separation and purification, the above compound can be obtained. Yield: 91%

Melting point: 118 ~ 120 ° C NMR (CDC13) (5: 1.16 (3H, t), 2.89 (4H, t), 3.30 (4H, t), 3.63 (2H, m), 3.71 (6H, s), 4 13 (3 H, s), 5.93 (2H, s), 5.98 (1 H, s), 7.41 (lH, t), 7.60 (lH, t), 7.66 (lH, d), 7.71 (lH, s ), 7.84 (lH, d) Mass (EI) m / z: 450.2206 (MH, C25H3GN404 calculated: 450.2227) Example 100) 1-[(N-isopropyl-N- (2-methoxyquinoline -3-fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, 1 [(2-fluorenyloxyline-3 -Fluorenyl) aminocarbonyl] _ (4- (3,5-dimethoxyphenyl)) (106 mg, 0.25 mmol), dissolved in dimethylformamide (15 ml), and sodium hydride was added (6.0 mg, 0.25 mmol), and stir at room temperature for 15 minutes, then add 2-Ehuan propylene (42 mg, 0.25 mmol), and stir at room temperature for 16 hours. Then concentrated under reduced pressure After removing the dimethylformamide, and then separating and purifying it by column chromatography (Ethyl Acetate, Kiyain = 1: 2) ', the above compound can be obtained. Yield: 87%

Melting point: 123 ~ 125 ° CW NMR (CDC13) H.21 (6H, d), 2.79 (4H, t), 3.29 (4H, t), 3.70 (6H, s), 4.08 (3H, s), 4.41 ( lH, m), 5.90 (2H, s), 5.96 (lH, s), 7.43 (lH, t), 7,63 (lH, t), 7.69 (lH, d), 7.75 (lH, S), 7.83 (lH, d) -66-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 575564 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (62) Example 101) 1-[(N-Cyclopropylmethyl_v- (2.methoxyquinolin-3-fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperidine 1 [(2-methoxyαquinine-3-amidino) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperidine (106 mg, 0.25 mmol), dissolved in dimethyl Methylamine (15 ml), and sodium hydride (62 mg, 0.26 mmol) was added, and after 15 minutes of incubation at room temperature, then desertified methylcyclopropane (22 mg, 0.26 mmol) was added. ), And allowed to stir at room temperature for 16 hours. Then, the monomethyl formate was removed by decompression and pressure reduction, and then separated by column chromatography (ethyl acetate: hexane = 1: 2). After refining Obtain the above compound. 78% harvest rate ··

Melting point: 118 ~ 120 ° C iH NMR (CDC13) (5: 0.41 (2H, m), 0.85 (2H, m), 1.28 (lH, m), 2.88 (4H, t), 3.24 (4H, t), 3.42 (2H, d), 3.71 (6H, s), 4.13 (3H, s), 5.94 (3H, s), 7.44 (lH, d), 7.62 (lH, d), 7-78 (3H, m) Example 102) 1-[(N-benzyl-N- (2-methoxyoxoline_3_fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine 1 [(2-methoxyfluorin-3-yl) aminocarbonyl] 4- (3,5-dimethoxyphenyl) piperidine (114 mg, 0.27 mmol) was dissolved in difluorene Carbamate (15ml), sodium hydride (6.6mg, 0.27mmol) was added, and after stirring at room temperature for 15 minutes, bromide (46mg, 〇_27mmol) was added at room temperature The mixture was stirred for 16 hours. The monomethyl feamine was removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane = 1: 2) was used for separation and purification to obtain the above compound. -67- This paper size applies to China National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page)-Packing _575564 Employees ’Central Bureau of Standards, Ministry of Economic Affairs, Consumer Consumption Cooperation Printed A7 B7 V. Invention description (63) Yield: 90% Melting point: Oily NMR (CDC13) 5: 2.92 (4H, t), 3.39 (4H, t), 3.72 (6H, s), 4.13 (3H, s), 4.79 (2H, s), 6.01 (3H, m), 7.21 (lH, m), 7.25 (2H, m), 7.25 (2H, m), 7.33 (3H, m), 7.51 ( 2H, s), 7.57 (2H, m), 7.81 (2H, d) Example 103) l- [N- (2-methoxyquinolin-3-amidino) -N-methylaminorozine Yl] -4- (3,5 -dimethyllactylphenyl) bridging 1 [(2-methoxycarbin-3-acyl) aminoweiyl] -4- (3,5-di Methoxyphenyl) was used to carry out the reaction in the same manner as in Example 9 to obtain the above compound. Yield: 92%

Melting point: 142 ~ 143 ° C NMR (CDC13) 2.27 (6H, d), 2.90 (4H, t), 3.17 (3H, s), 3.34 (4H, t) 54.15 (3H, s), 6.41 (2H, s), 6_49 (lH, s), 7.40 (lH, t) 7.63 (lH, t), 7.65 (lH, d), 7.73 (lH, s), 7.84 (lH, d) Example 104) 1- [N-ethyl-N_ (2-fluorenyloxy quinine molybdenum group) -Aminomethylaminocarbonyl] -4- (3,5-diamidinophenyl) piperazine will be 1 [(2-methyl The oxyquinoline-3-amido) aminocarbonyl]-'(3,5-dimethylphenyl) pyrazine was reacted in the same manner as in Example 99 to obtain the above compound. Yield: 89%

Melting point: 84 ~ 86 ° C -68 _ This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm factory one " " " '^^^ f Please read the precautions on the back before filling in this page ;} • Printed 575564 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (64) iH NMR (CDCl3) (5: 1.16 (3H, t) 52.21 (6H, s), 2.87 (4H, t ), 3.30 (4H, t), 3.64 (2H, q), 4.13 (3H, t), 6.40 (2H, s), 6.48 (lH, s), 7.40 (1 H, t), 7.62 (1 H, t), 7.66 (lH, d), 7.71 (lH, s), 7.84 (lH, d) Example 105) 1- [N · Isopropyl-N- (2-methoxypyridin-3- 喳) -)-N-fluorenylaminocarbonyl] · (4- (3,5-dimethylphenyl) piperidine] [[(2-Methoxylin-3-donyl) aminoweilyl]- 4- (3,5-dimethylphenyl) piperidine was reacted in the same manner as in Example 100 above to obtain the above compound. Yield: 84% Melting point: 114 ~ 115 ° CW NMR (CDC13) 6: 1.21 (6H, d), 2-20 (6H, s), 2.77 (4H, t), 3.28 (4H, t), 4_08 (3H, s), 4_39 (lH, m), 6.37 (2H , S), 6.46 (lH, s), 7.41 (lH, t), 7.63 (lH, t), 7.69 (lH d), 7.75 (lH, s), 7.83 (lH, d) Example 106) 1- [N_benzyl-N- (2-methoxypyridin-3-yl) -N-methylamine Carbonyl] -4- (3,5 · dimethylphenyl) piperazine 1 [(2-methoxyfluorin-3-yl) aminocarbonyl] -4- (3,5-dimethyl The above compound can be obtained by reacting the same method as in Example 102 above. Yield: 90% Melting point: Oily iH NMR (CDC13) 5: 2.24 (6H, s), 2.87 (4H, t), 3.31 (4H, t), 4.13 (3H, S), 4.80 (2H, s) , 6.42 (3H, s), 7.49 (lH, t), 7.62 (2H, m), 7.72 (2H, m) Example 107) l- [N- (2-methoxyoxoline-3-fluorenyl ) -N-fluorenylamine-69- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) i Order 4 575564 A7 B7 5 2. Description of the invention (65) kikyridyl] -4- (3-isopropoxyphenyl) σchenazine 1 [(2-methoxyfluorin-3-yl) aminocarbonyl]-'(3 Isopropoxyphenyl) piperazine can be reacted in the same manner as in Example 98 to obtain the above compound. Yield: 92% Melting point: Oily W NMR (CDC13) (5: l_28 (6H, d), 2.97 (4H, t), 3.18 (3H, s), 3.37 (4H, t), 4.14 (3H, s ), 4.49 (lH, m), 6.41 (3H, m), 7.13 (1 μm, m), 7.40 (lH, t), 7.62 (lH, t), 7.66 (lH, d), 7.74 (lH, s) ), 7.84 (lH, d)? Example 108) 1 _ [N_Ethylthio (2.methoxymethoxyline_3_fluorenyl) _N · methylaminocarbonyl] -4- (3- Isopropoxyphenyl) Luhe uses 1 [(2-methoxyoxoline-3-fluorenyl) aminocarbonyl] -4- (3-isopropoxyphenyl) piperazine as in the above examples The reaction can be carried out in the same manner as above to obtain the above compound. Yield: 87% Melting point: Oily W NMR (CDC13) (5: 1.16 (3H, t), 1.34 (6H, d), 2.89 (4H, t), printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please (Read the notes on the back before filling out this page)

3.30 (4H, t), 3.63 (2H, m), 4.13 (3H, s), 4.55 (lH, m), 6.49 (2H, S), 7.05 (lH, s), 7.20 (lH, t), 7.32 (lH, s), 7.37 (lH, t), 7.50 (lH, t), 7.70 (lH, d), 7.77 (lH, d), 8.80 (lH, s) Example 109) 1-[(2- (Methoxylin-3-fluorenyl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) brittle phenyl N- (2-methoxyquinoline-3- 醯Base) thioformate (56mg, -70-) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 575564 A7 66 5. Description of the invention (0.5 pen mole) and i- (3 , 5-monomethoxyphenyl) σ Chen π Qin (Himg, 0.5 mmol) was dissolved in anhydrous tetrahydrofuran, and DBU (117 mg, 0.75 mmol) was added, and at room temperature The mixture was stirred for 2 hours. Then the tetrahydropyran was removed by concentration under reduced pressure, and then the column compound (hexane: ether = 5: 1) was used for separation and purification to obtain the above compound. Yield: 76 %

Melting point: 171 ~ 172 ° C 4 NMR (CDCl3) 5: 3.41 (4H, t), 3.81 (6H, s), 4.17 (3H, s), 4.2l (4H, t), 6.21 (lH, s), 6.20 (lH, d), 7.38 (1H, t), 7.54 (lH, t), 7.74 (lH, d), 7.81 (lH, d), 8.96 (lH, s) Example 110) l- [ (2-Methoxyline-3-fluorenyl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) σ Chen Hei Phenyl N- (2-methoxyoxoline The above-mentioned compound can be obtained by reacting 3--3-methyl) thioformate with 1- (3,5-monomethylphenyl) α-phenylene in the same manner as in Example 109 above. Yield: 79%

Melting point: 170 ~ 171 ° C β NMR (CDC13) d: 2.30 (6H, s), 3_38 (4H, t), 4.09 (3H, s), 4.l7 (4H, t), 6_63 (3H, m) , 7.38 (lH, t), 7.54 (lH, t), 7.72 (lH, d), 7.81 (lH, d), 8.96 (lH, s) Example 111) l-[(2-fluorenyloxyfluorene) Phenolin-3-amidino) aminothiocarbonyl] -4- (3,5-difluorinated phenyl) piperazine Phenyl N- (2-methoxyfluorinoline_3-fluorenyl) thio The formate and the (3,5-difluorinated phenyl) sulfonium are used in the same manner as in the above-mentioned Example 109. 71- This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm). —--------- Clothing-(Please read the precautions on the back before filling out this page) Order printed by the Central Consumers Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative 575564 A7 B7 5. The method of invention description (67) is carried out to obtain the above compounds. Yield: 78% Melting point: 140 ~ 142 ° C 4 NMR (CDC13) 5: 3.44 (4H, t), 4.20 (4H, t), 4.25 (3H, s), 6.33 (2H, m), 6.45 (lH , D), 7.41 (lH, t), 7.56 (lH, m), 7.72 (lH, m), 7_97 (lH, m), 8.96 (lH, s) Example 112) l-[(2-fluorene Quinoline-3-fluorenyl) aminothiocarbonyl] -4- (3,5-dichlorinated phenyl) i-phenyl N- (2-fluorenyloxyquinine-3-S & The above-mentioned compound can be obtained by the same method as in the above-mentioned Example 109, in which the thio-thiophosphonate and 1- (3,5-dichlorophenyl) amidine are reacted. Yield: 62% Melting point: 181 ~ 183 ° C iH NMR (CDCl3) 5: 3.44 (4H, t), 4.20 (4H, t), 4.26 (3H, s), 6.77 (lH, s), 6.88 (2H , T), 7.41 (lH, t), 7.59 (lH, t), 7.70 (2H, m), 8.01 (lH, t), 8.11 (lH, s), 8.93 (lH, s) Example 113) 1 -[(2-methoxyquinolin-3-amidino) aminothiocarbonyl> 4- (3-methoxyoxyphenyl) piperazine will be phenyl N- (2-methoxyquinoline- The above-mentioned compound can be obtained by reacting the 3-fluorenyl) thiophosphonate with 1- (3-methoxyoxyphenyl) piperidine in the same manner as in the above-mentioned Example 109. Yield: 81% Melting point: Oily W NMR (CDCl3) 5: 3.17 (4H, t), 3.89 (3H, s), 4.17 (4H, t), -72- This paper is suitable for financial standards (CNS) ) A4 specification (mm) 1 ~ " '(Please read the precautions on the back before filling this page):

1T d 575564 A7 B7 V. Description of the invention (68 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 6.90 (4H, m), 7.34 (lH, t), 7.48 (lH, t), 7.70 (lH, d), 7.77 (lH, d), 8.80 (1H, s) Example 114) 1-[(2-methylquinolin-3-amidino) aminocarbonyl] -4- (3,5-dimethoxybenzene Group) Piperazine a) The basic N_ (2-methyl cylinol-3 ·· yl) formate-3-amino-2-amidinophosphonium (4 g, 25 mmol) and phenyl chloride The formate (4.04 g, 25 mmol) was dissolved in dichloromethane and stirred at room temperature for 2 hours. The dichloromethane was removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane = 1: 10) was used for separation and purification to obtain the above compounds. Yield: 88% 4 NMR (CDC13) (5: 2.77 (3H, s), 7.3G-7.53 (9H, m), 8.67 (1H, S) b) l-[(2-methylpyridin-3-3 -Fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) fluorene α-phenylene N- (2-methylfluorinylfluorenyl) formate (14 mg, 〇5 Mol) and 1- (3,5-dimethoxyphenyl) piperazine (11211 ^, 0.5 mol was dissolved in anhydrous tetrahydropyran, and DBu (ii7mg, 075 premol ) 'And stir for 2 hours under the dish. Then use concentrated under reduced pressure? Tetrahydropyran to remove it, and then use column chromatography (ethyl acetate hexanox ⑥-1: 2) to separate and purify it. The above compounds can be obtained

Yield: 84% Melting point: 199 ~ 200 ° C -73-

(Please read the precautions on the reverse side before filling out this page); Equipment · Introduction 4 575564 A7 B7 Five Invention Instructions (69 W NMR (CDCl3) 5: 2.81 (3H, s), 3.30 (4H, t), 3.76 ( 4H, t), 3.80 (6H, s), 6.08 (lH, s), 6.12 (2H, d), 7.48 (lH, t), 7.62 (lH, t), 7.71 (lH, d), 8.03 (lH, d), 8.59 (lH, s)

Mass (EI) m / z: 390.2066 (MH, C23H26N402 Calculated: 390.2055) Example 115) 1-[(2-Amidinofluorin-3-yl) aminocarbonyl] -4- (3,5- Dimethylphenyl) piperazinePhenyl N- (2-fluorenyl-3-methyl) thioformate and 1- (3,5-difluorenylphenyl) piperazine were used. The reaction was carried out in the same manner as in the above Example 114 to obtain the above compound. Yield: 86%

Melting point: 230 ~ 232 ° C 4 NMR (CDCl3) c5: 2.31 (6H, s), 2.82 (3H, s), 3.29 (4H, t), 3.76 (4H, t), 6.60 (3H, s), 7.49 (lH, t), 7.63 (lH, t), 7.73 (lH, d), 8.05 (lH, d), 8.61 (lH, s) Example 116) l-[(2-methylphosphonium-3- Fluorenyl) aminocarbonyl] -4- (2,3-monofluorenylphenyl) pyridine will combine phenyl N- (2-fluorenyl n quinolinyl) thioformate with ι_ (2,3-di The fluorenylphenyl) piperidine was reacted in the same manner as in the above Example 114 to obtain the above compound. Yield: 81%

Melting point: 169 ~ 170 ° C Ή NMR (CDC13) (5: 2.28 (6H, d), 2.84 (3H, s), 3.30 (4H, t), 3.76 (4H, t), 6.94 (2H, m), 7.11 (lH, t), 7.49 (lH, t), 7.63 (lH, d), (Please read the notes on the back before filling out this page) Staff of the Bureau of Standards of the Ministry of Economic Affairs t Co-printed by cooperatives 0 —mtt {In OMmmKaB — ^ f · -74 575564 5. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______ B7 Invention Description (7〇) 7.72 (lH, d), 8.64 (lH, s) Example 117) 1 _ [(2- Fluorenylquinoline-3-fluorenyl) aminocarbonyl] -4- (3,5-mono-gasified phenyl) group σ-Phenyl N- (2-methylquinolin-3-fluorenyl) thio The formate and 1- (3,5-difluorophenyl) piperazine were reacted in the same manner as in Example 114 above to obtain the above compound. Yield: 81% Melting point: 238 ~ 240 ° C NMR (CDC13) δ: 2.81 (3H, t), 3.34 (4H, t), 3.77 (4H, t), 6.32 (lH, t), 6_39 (2H, d), 7.49 (lH, t), 7.63 (lH, t), 7.72 (lH, d), 8.03 (lH, d), 8.58 (lH, s) Example 118) l-[(2-fluorenylquine Phenolin-3-amidino) aminocarbonyl] -4- (3,5-dichlorophenyl) piperazine Phenyl N- (2-methyl.quinolin-3-amidino) thiocarboxylic acid The ester was reacted with 1- (3,5-dichlorophenyl) piperazine in the same manner as in Example 114 above to obtain the above compound. Yield: 65% Melting point: 247 ~ 249 ° C 1H NMR (CDC13) 5: 2.79 (3H, s), 3.33 (4H, t), 3.75 (4H, t), 6.78 (2H, s), 6.87 (lH , S), 7.49 (lH, t), 7.63 (lH, t), 7.72 (lH, d), 8.56 (1H, s) Example 119) 1-[(2-methylquinolin-3-fluorenyl ) Aminocarbonyl] -4- (2-methoxyoxyphenyl) Chen Hei Phenyl N- (2-methyl0 quinine-3-acid) thioformate and 1- (2- -75 -This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page) • Binding and ordering 575564 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (71) Methoxyphenyl) Pyrex, the same method as described in Example 114 was used to obtain the above compound. Yield: 83% Melting point: 135 ~ 136 ° C! H NMR (CDC13 ) 5: 2.82 (3H? S)? 3.18 (4H? T)? 3.79 (4H? T) 5 3.91 (3H, s), 6.88 (lH, d), 6.97 (2H, S), 7.07 (lH, m) ), 7.48 (lH, t), 7.62 (lH, t), 7.72 (lH, d), 8.04 (lH, d), 8.63 (lH, s) Example 120) 1-[(2-methylfluoroline -3-fluorenyl) aminocarbonyl] -4- (2-ratified phenyl) σ嗦 Phenyl N- (2-methyl-4-lin-3-yl) thioformate and 1- (2-fluorinated phenyl) pie were reacted in the same manner as in Example 114 above. , And the above compounds can be obtained. Yield: 84% Melting point: 201 ~ 203 ° CiH NMR (CDCl3) 5: 2.84 (3H, s), 3.20 (4H, t), 3.80 (4H, t) 5 6.99 (2H, m), 7_07 (2H, m), 7.49 (lH, t), 7.62 (lH, t), 7.71 (lH, d), 8.04 (lH, d), 8.62 (lH, s) Example 121) l-[(2-fluorenylquine Phenolin-3-amidino) aminocarbonyl] -4- (2-chlorophenyl) piperazinePhenyl N- (2-methylfluorin-3-yl) thiophosphonate and 1- (2-Chlorophenyl) Lu He, the same method as described in Examples 1 to 4 above was used to perform the reaction to obtain the above compound. Yield ·· 72% Melting point: 180 ~ 181 ° C -76- (Please read the precautions on the back before filling in this page) i Binding · Order-4 This paper size applies to China National Standard (CNS) M specifications Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 ------ ____ B7 V. Description of the invention (72) 1H NMR (CDC13): 2.83 (3H, s), 3.16 (4H, t), 3.80 (4H, t ), 7.04 (3H, m), 7.40 (lH, d), 7.49 (lH, t), 7.63 (lH, t), 7.71 (lH, d), 8.05 (lH, d), 8.62 (lH, s) Example 122) Methylquinoline-3-fluorenyl) aminocarbonyl] -4- (2-methylthiophenyl) The above-mentioned compound can be obtained by the same method as in Example 4 above for the reaction of the thio) thioester with 1- (2-methylthiophenyl) piperidine. Yield: 76%

Melting point: 165 ~ 166 ° C lR NMR (CDCl3) (5: 2.45 (3H? S)? 2.85 (3H5s)? 3.11 (4H? T)? 3.79 (4H, t), 7.05 (lH, m), 7.15 ( 3H, d), 7.49 (lH, t), 7.63 (lH, t), 7.69 (lH, d), 8.07 (lH, d), 8.62 (lH, s) Example 123) 1-[(2-A Quinoline-3-fluorenyl) aminocarbonyl] -4- (2-fluorenyl-5-methylphenyl) piperazine Phenyl N- (2-methylfluorin-3-yl) The thiophosphonate is reacted with 1- (2-methoxy-5-methylphenyl) α-qin in the same manner as in Example VII 4 above to obtain the above compound. Yield: 80% Melting point: Oily 1H NMR (CDC13) 5: 2.30 (3H, s), 2.72 (3H, s), 3.17 (4H, t), 3.70 (4H, t), 3.87 (3H, s) , 6.77 (lH, s), 6.82 (2H, s), 7.73 (4H, m), B.60 (1H5s) Example 124) 1-[(2-Amidinofluorin-3-yl) amino Carbonyl] -4- (1- -77- This paper size applies to Chinese National Standards— (CNS) A4 Specification (210X297mm) ~~ (Please read the precautions on the back before filling out this page) k Pack · d Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 575564 A7 — B7___ V. Description of the invention (73) Qin Ji) The brigade mixed phenyl N- (2-methylphilin-3-methyl) thioformate with 1 _ The (1-naphthyl) piperazine can be reacted in the same manner as in Example 114 above to obtain the above compound. Yield: 64%

Melting point: 220 ~ 222 ° C! H NMR (CDC13) 5: 2.83 (3H5s)? 3.23 (4H? T)? 3.80 (4H? T)? 6.91 (lH, s), 7.12 (lH, d) 57.44 (lH , D), 7.50 (3H, m), 7.61 (2H, m), 7.73 (lH, d), 7.86 (lH, d), 8.05 (lH, d), 8.23 (lH, d), 8.64 (l H S) Example 125) 1-[(2-fluorenyl4lin-3-fluorenyl) aminothiocarbonyl]-4- (3,5-dimethoxyphenyl) bridging a) Benzene N- (2-methyletaquinine-3-amidino) thioformate-3-amino-2-methylquinoline (4g, 25 mmol) with phenyl chloride (4.32 g, 25 mmol), dissolved in dichloromethane, and stirred at room temperature for 2 hours. The dichloromethane is removed by concentration under reduced pressure, and the above compound is obtained after separation and purification by column chromatography (ethyl acetate: hexane) = 1: 2. Yield · 78% 'H NMR (CDC13) δ: 2.77 (3H, s)? 7.09-7.90 (9H5m)? 9.14 (1H, S) b) W (2-Tylquinolin-3-amidino) amino group Thiocarbonyl] -4- (3,5-dimethoxyphenyl) bridging phenyl N- (2-methylfluorin-3-yl) thioformate-78- paper size Applicable to China National Standard (CNS) 8 4 specifications (210X 297 mm)

In ---------(Please read the notes on the back before filling this page) Order 4 575564 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (74) (147mg, 0.5 Mmol) and 1- (3,5_dimethoxyphenyl) piperidine (112 mg, 0.5 mmol), dissolved in anhydrous tetrahydropyran, and DBU (117 mg, 0.75 mmol) Then, it stirred at room temperature for 2 hours. The tetranitrosigma thiopyran was removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane = 1: 2) was used for separation and purification to obtain the above compounds. Yield: 86%

Melting point: 199 ~ 200 ° CW NMR (CDC13) 5: 2.81 (3H, s), 3.35 (4H, t), 3.79 (6H, s), 4.14 (4H, t), 6.07 (3H, s), 7.49 ( 2H, d), 7.68 (2H, m), 8.01 (lH, s), 8.07 (lH, d) Example 126) 1-[(2-fluorenylαquinolin-3-amidino) aminothio Carbonyl] _ 4- (3,5-dimethylphenyl) bridging phenyl N- (2-methylαquinolin-3-amidino) thioformate with 1- (3,5- Dimethylphenyl) was reacted in the same manner as in Example 125 above to obtain the above compound. Yield: 81%

Melting point: 196 ~ 197 ° C lH NMR (CDC13) (5: 2.27 (6H? S)? 2.81 (3H? S) 93.31 (4H? T)? 4.11 (4H, t), 6.53 (2H, s), 6.58 (lH, s), 7.48 (2H, t), 7.67 (2H, m), 7.96 (lH, s), 8.04 (lH, d) Example 127) l-[(2-methylpyridin-3- Amidino) aminothiocarbonyl > 4- (3,5-didecyl phenyl) --79- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm) (Please read the notes on the back before filling out this page)-Binding · 575564 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation 5. Description of the invention (75) (2,3-difluorophenyl) piperazine was reacted in the same manner as in Example 125 above to obtain the above compound. Yield: 74% Melting point 211 ~ 213 ° CiH NMR (CDCl3) 5: 2.85 (3H, s), 3_43 (4H, t), 4.22 (4H, t), 6.33 (2H, m), 7.49 (lH5t ), 7.64 (lH, d), 7.72 (lH, t), 8.16 (2H, m) Example 128) l-{[2_ (pyridinyl) quinolin-4-amidino] aminothiocarbonyl] 4- (3,5-Dimethoxyphenyl) piperidine is a phenyl N- [2- (ab 唆 -2-S-basket) formate (17 lmg, 0.5 mmol) and 1- (3,5-Dioxophenyl) piperazine (iiimg, 0.5 mmol), dissolved in anhydrous tetrahydrofuran, and added DBU (117 mg, 0.75 mmol) at room temperature Stir for 2 hours. The tetrahydro-0-bifuran was removed by concentration under reduced pressure, and then column chromatography (dichloromethane: methanol = 20: 1) was used for separation and purification to obtain the above compounds. Yield: 73% Melting point: 97 ~ 98 ° ClH NMR (CDC13) 5: 3.34 (4H? T)? 3.79 (6H5s)? 3.90 (4H5t)? 6.07 (lH, s), 6.12 (2H, s), 7.43 (lH, t), 7.50 (lH, t), 7.68 (lH, t), 7.93 (lH, t), 8.26 (lH, d), 8.59 (lH, d), 8.80 (lH, d), 8.98 ( lH.s) Mass (EI) m / z: 5 17.3244 (MH, C31H27N503 calculated: 517.2113) Example 129) 1-{[2- (pyridin-3-amidino) pyridin-4-amidino] amine Jiji-80- (Please read the precautions on the back before filling this page) 1. Fill in the items again. Binding · Order 4 This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 575564 Α7 Β7 5. DESCRIPTION OF THE INVENTION The (76) yl] -4- (3,5-dimethoxyphenyl) pyridine is a phenyl N- [2-〇bpyridin-3-amidino) formate (171 mg, 0.5 mmol) Ear) and 1- (3,5-dimethoxyphenyl) Luhe (1 imimg'0.5 mmol), dissolved in anhydrous tetrahydropyran and added DBU (117 mg, 0_75 mmol) , And stirred at room temperature for 2 hours. Then, the tetrahydrohydrofuran was removed by concentration under reduced pressure, and then column chromatography (dichloromethane: methanol = 20: 1) was used for separation and purification to obtain the above compounds. Yield: 67%

Melting point: 95 ~ 96 ° C 'H NMR (CDC13) 5: 3.36 (4H5t) 53.87 (6H5s) 5 3.90 (4H? T)? 6.08 (1 H, s), 6.12 (2H, s), 7.50 (lH, t), 7_71 (lH, t), 7.93 (lH, t), 8.25 (lH, d), 8.53 (lH, d), 8.67 (lH, s), 8.73 (lH, d), 9.53 (1H.s ) Example 130) 1-{[2- (thiazin-2-fluorenyl) quinolin-4-fluorenyl] aminocarbonyl] -4- (3,5-dioxophenyl) piperazine Phenyl N_ [2- (thiazin-2-fluorenyl) formate (173 mg, 0.5 mmol) and 1- (3,5--methoxyphenyl) sigma (11 img, 0.5 Millions), printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs-«batch of clothing-(Please read the precautions on the back before filling out this page) Dissolved in anhydrous tetrahydron πan, and added DBU (117mg, 0.75 mmol), and stirred at room temperature for 2 hours. Then, the tetrahydrofuran was removed by concentration under reduced pressure, and then the same was obtained after separation and purification by column chromatography (ethyl acetate: hexane = 1: 1). Yield: 61% Melting point: Oily 'H NMR (CDC13) δ: 3.37 (4H5t)? 3.59 (6H5s)? 3.97 (4H? T), -81-This paper is in accordance with the Chinese Standard (CNS) A4 ( 2ϋmm) a ---

7.01 (3H, m), 7.49 (lH, t), 7.69 (lH, t), 7.93 (lH, t), 8.20 (lH, d), 8.52 (lH, d), 8.64 (iH, s), 8.7 l (lH, s), 9.53 (lH, s) Example 131) l-{[2- (pyridin-3_fluorenyl) fluorin-4-4-fluorenyl] aminochiridyl] -4- (3, 5-Dimethylphenyl) PyrazinePhenyl N_ [2 decapyridin_3_fluorenyl) formate U71mg, 0.5 mmol) and 1- (3,5-monomethylphenyl) pie Azine (95 mg, 0.5 mmol) was dissolved in anhydrous tetramethylfuran, and DBU (117 mg, 0.75 mmol) was added, followed by stirring at room temperature for 2 hours. After the tetrahydrofuran was removed by concentration under reduced pressure, column chromatography (ethyl acetate: hexane = 1: 1) was used for separation and purification to obtain the above compounds. Yield: 64%

Melting point: 211 ~ 213 ° C lU NMR (CDC13) δ: 2.31 (6H? S)? 3.32 (4H5t)? 3.85 (4H? T)? 6.6l (3H, s), 7.47 (lH, t), 7.55 ( lH, t), 7-72 (lH, t), 7.86 (lH, t), 8.25 (lH, d), 8.53 (lH, d), 8.66 (lH, s), 8.72 (lH, d), 9.37 (lH .s) In the case of the compound of the formula (1) provided by the present invention, when Y is -NR, it can be prepared according to the following equation Π. (Please read the precautions on the back before filling out this page)-Binding and printing Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

R 8 providing agent -82- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 575564

Printed by the Ministry of Economic Affairs, the Standard Consumer Council

Ri, R2, R3, R4, R5, R6, r?, R8, a, X5Z # ^ qi "The compound shown in the above structural formula 申 applies" R "for mutual enjoyment, and the structural formula can be efficiently produced ( lb). The Rs supply reagent used in this reaction refers to the lower alkyl halides, C1-Cs lower alkyl sulfonates, substituted or unsubstituted cycloalkyl halides, and aryl radicals. ', Q3 — substituted or unsubstituted cycloalkyl sulfonates, aryl sulfonates and the like. 8 and 4 CrC8 lower alkyl halides refer to methylene chloride, bromide, iodide methane, ethane chloride, ethane bromide, ethane iodide, butane chloride, butane bromide, Butane iodide, pentane chloride, pentane bromide, pentane bromide, ethyl bromide acetate, and the like. The CrCg lower alkyl esters refer to methyl acetic acid, ethyl sulfonate, propyl sulfonate, butyl sulfonate, pentyl sulfonate, and the like. ', The so-called CfC8 substituted or unsubstituted cycloalkyl group refers to cyclopropane chloride, brominated cyclopropane, iodinated cyclopropane, cyclobutane chloride, brominated cyclobutane, cyclobutane iodide, chlorine Cyclopentane, brominated cyclopentane, -83- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

575564 '' ^ — ____ ________ B7 V. Description of the Invention (79) Cyclodane iodide, cyclohexane chloride, cyclohexane bromide, cyclohexane iodide, methylcyclopropane, bromomethyl ring Propane, methylcyclopropane iodide, methylcyclobutane chloride, methylcyclobutane bromide, methylcyclobutane iodide, methylcyclopentane chloride, methylcyclopentane bromide, iodine ^ Methylcyclopentane, methylcyclohexane chloride, methylcyclohexane bromide, methylcyclohexane iodide, etc. ^ The so-called aryl functional compounds refer to benzyl chloride, benzyl bromide, iodine Benzyl chloride, benzamidine chloride, benzamidine bromide, benzamidine iodide, toluidine chloride fc, toluidine bromide, petrolatum toluene, and the like. The so-called CfC8 substituted or unsubstituted cycloalkylsulfonic acid esters refer to cyclopropyl% acid ester, cyclobutylsulfonic acid ester, cyclophenothiylsulfonic acid ester, cyclohexylsulfonic acid, methylcyclopropyl, The methyl ring has a base acid vinegar, a methyl ring phenothisulfonate, a methyl cyclohexyl sulfonate, and the like. The aryl sulfonates refer to benzyl sulfonate, benzamidine sulfonate, toluenyl sulfonate and the like. Dissolve the compound represented by the above structural formula (la), and the alkyl group and the arylating agent in a solvent such as dimethylformamide, and perform the operation for 30 minutes at a temperature range of 25 to 80 ° C. By reacting for 20 hours, a compound represented by the formula VII belonging to the target compound can be obtained. Among them, the effective amount of the calcining group and the arylating agent is from 10 equivalents to 15 equivalents. In the provincial reaction, the organic solvents generally used are preferably tetrahydropyran, dichlorin, acetonitrile, dimethylformamide and the like. When the reaction proceeds, an acidic substance is generated as the reaction proceeds.

The paper size is 575564 X-A7. Description of the invention (8 () Calcium hydroxide, magnesium hydroxide, basic materials; ^ Such as sodium hydroxide, hydroxide, magnesium carbonate, bicarbonate, emulsification, Carbon, potassium carbonate, compounds, oxides, sodium carbonate, sodium bicarbonate, potassium bicarbonate, and other metal-testing metals or soil-testing metals are reacted by ^^ bicarbonate, and the presence of bases in organic amine-based systems Example (Please read the precautions on the back before filling out this page} According to ^^ method, the following compounds can be prepared

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

Et Et e Μ e Μ 44 45

139 140 141 Me Me Me Me Me 142 Me Me 143 Me Et This paper size applies to Chinese National Standard (CNS) Α4 size U10X297 mm) 575564

A B V. Description of Invention (81 Printed by Staff Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs

Example number Rr R-2 1 ^ rV / 1 Flc j R? Rs | AI j! X! Zy! I 146 Me nPr II OMe H OMe H Me N 0 OMe 3-N 147 Et Me H 〇Me H OMe H Me N 〇OMe 3-N 148 nPr Me II OMe H OMe H Me N 〇OMe 3-N 149 Me Ac H OMe H OMe H Me N 〇OMe 3-N 150 Me Ac II OMe II OMe H Et N 〇OMe 3 -N 151 Me Ac H Me H Me H Me N 〇OMe 3-N 152 Me II OMe H OMe H Me N 〇OMe 3-N 153 Me OH human H OMe H OMe H Et N 〇OMe 3-N 154 Me OH II Me H Me H · Me N 〇OMe 3-N 155 Me \ OH 乂 H OMe H OMe H Me N 〇OMe 3-N 156 Me \ OH \ X II Me H Me H Me N. 〇OMe 13-N j 157 Me 0CH-, human H OMe H OMe H Me N 〇1 OMe 3-N 158〆Me Vinyl H OMe H OMe H Me N 〇OMe 3-NI 159 Me Vinyl H Me H Me H Me N 〇OMe -1 3 -N 160 Me Vinyl H OMe H OMe H Et N 〇OMe 3-N 161 Me human H OMe H OMe H Me N 〇OMe 3-N 162 Me human H Me H Me H Me N 〇OMe 3-N 163 Me Ac II OMe H OMe H 0 CH? T'〇Et N 〇 'OMe 3-N 164 Me Ac II Me H Me H 0 CH? F〇Et N 〇1— OMe 3-N 165 Me Ac H OMe H OMe H 0 CH2i'〇HN 〇OMe 3-N 166 Me OH II OMe H OMe H 0 CH? F〇E 1 N 〇OMe 3-N 167 Me H OMe H OMe H 0 CH ^ 'OH N 〇OMe 3-N 168 Me OH H Me H Me H 0 CH2t' 〇Et N 〇OMe 3-N 169 Me H Me, H Me H 0 ch / oh N 〇OMe 3-N -86 (Please read the precautions on the back before filling out this page) This paper size applies to Chinese national standards (CNS ) A4 specification (210X 297 mm) 575564 A7 B7 Five 'invention description (82 Example 132) 1- [N- (5,6-dimethyl_2-methoxypyridine_3_fluorenyl) -N _Methylaminojiroyl] _4_ (3,5_dimethoxyphenyl) pyrazine 1-[(5,6-dimethyl_2_methoxypyridine_3_fluorenyl) amino Carbonyl group] -4- (3,5-dimethoxyphenyl) brittle (100 mg, 0-25 mmol), dissolved in dimethylformamide (15 ml), and sodium hydride was added (6.0 mg, 0.25 mmol), and then stirred at room temperature for 5 minutes, then add moth tofu (35 mg, 0.25 mmol), and stir at room temperature for 16 hours ^. Then, the dimethyl dimethylformate was removed by concentration under reduced pressure, and then the column was subjected to column chromatography (ethyl acetate · hexane = 丨: 2), and the compound was obtained after separation and purification. Yield: 94% Melting point: Oily matter NMR (CDCl3) (5: 2.17 (3H, s), 2.38 (3H, s), 2.92 (4H, t), 3.04 (3H5S), 3.29 (4H , T), 3.74 (6H, S), 3.96 (3H, S), 6.00 (3H, m), 7.08 (1H9s)? Example 133) l- [N- (5,6-dimethyl-2- Methoxypyridine-3 · fluorenyl) -N-ethylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine [(5,6-monofluorenyl-2-fluorene Oxygen-specific bite _3-St-based) Amine-based printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(Please read the precautions on the back before filling in this hundred C d group] -4- (3,5-dimethoxyphenyl) Lvkou Qin (10011 ^, 0.25 mmol), bath Dissolve in diamidinofluorene (15ml), add sodium sulfide (60mg, 0.25mmol), and stir at room temperature for 15 minutes, then add iodide iodide: 1: wood (39.211) ^, 0.25 millimoles), and stirred at room temperature for 16 hours. Then dichloromethane was removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane) was used. Alkane = 丨: 2), for separation of private paper. Applicable to China National Redundancy (CNS) -87- 575564 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs. 5. Description of the Invention (M) 83 The above compounds can be obtained after purification. Yield: 86% Melting point: oily! H NMR (CDC13) δ: 1.08 (3H? T)? 2.04 (3H? S)? 2.38 (3H? S) 5 2.90 (4H, t), 3.26 (4H, t), 3.52 (2H, q), 3.74 (6H, s), 5.99 (3H, m), 7.06 (1H, s) Example 134) 1- [1 ^-(5,6- 二Methyl-2-methoxypyridin-3-yl) -N-propylaminocarbonyl] -4- (3,5-dioxophenyl) piperazine 1-[(5,6- Dimethyl 2-methoxypyridin-3-fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) hydrazone (100 mg, 0.25 mmol), dissolved in Dimethylfluorenamine (15 ml) was added with sodium hydride (6.0 mg, 0.25 mmol), and the mixture was stirred at room temperature for 15 minutes and then at room temperature for 16 hours. Then, dimethylformamide is removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane = 1: 2) is used for separation and purification to obtain the above compound. Yield: 78% Melting point: oily matter W NMR (CDCl3) 6: 1.13 (6H, d), 2.19 (3H, s), 2.38 (3H, s), 2.82 (4H, t), 3.26 (4H, t), 3.74 (6H, s), 3.89 (3H, s), 4.27 (lH, m), 6.06 (lH, s), 6.10 (2H, d), 7.07 (lH, s), 8.14 (lH, s )

Mass (EI) m / z: 442.2538 (MH, C24H34N404 Calculated: 442.2580) Example 135) [N- (5,6-dimethyl-2-methoxyeta ratio fluoren-3-acid group) _N_Methylaminocarbonyl] _4- (3,5-dimethylphenyl) neazine-88- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back first Please fill in this page for more information) ^^ 衣 · —. 575564 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1. Description of the invention (84) Will be 1-[(5,6-dimethyl-2-methoxy The pyridine-3-amidino) aminocarbonyl] -4- (3,5-dimethylphenyl) piperidine was reacted in the same manner as in Example 132 above to obtain the above compound. Yield: 97% Melting point: Oily 1H NMR (CDC13) Occupation: 2-15 (6H, S), 2.23 (3H, S), 2.37 (3H, s), 2.89 (4H, t), 3.04 (3H, s), 3.30 (4H, t), 3.97 (3H, s), 6.46 (3H, m), 7.08 (1H, s) (Example 136) WN- (5,6-diamidino-2-methoxy Pyridin-3-amidino) -N-methylaminocarbonyl] -4_ (3,5-dimethoxyphenyl) travelazine 1-[(5,6-dimethyl-2-methoxy The pyridine_3_fluorenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) trazine can be reacted in the same manner as in Example 132 above to obtain the above compound. Yield: 94% Melting point: 131 ~ 132 ° CH NMR (CDC13) 5: 2.16 (3H, s), 2.38 (3H, s), 2-80 (4H, t), 3-〇5 (3H? S) 53.05 ( 4H? T) 53.82 (3H? S) 53.97 (3H? S)? 6.83 (4H5m)? 7.08 (1H? S) Example 137) l- [N- (5,6-dimethyl_2-methoxy Pyridyl-3_fluorenyl) -N-ethylaminocarbonyl] -4_ (2-methoxybenzyl) piperidine 1-[(5,6-dimethyl-2-methoxypyridinyl) ) Aminocarbonyl] 4- (2-methoxyphenyl) pyridine, which can be reacted in the same manner as in Example us above to obtain the above compound. Yield: 87% -89- The paper size is suitable for wealth management (CNS) inspection (21 () > < 297 public envy) (Please read the precautions on the back before filling this page); d 575564 A7 B7 Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs and Ministry of Foreign Affairs 5. Description of the invention (85) Melting point: 112 ~ 113 ° C 4 NMR (CDC13) (5: 1.08 (3H, t), 2.16 (3H, s ), 2.38 (3H, s), 2.77 (3H, s), 3.31 (4H, t), 3.58 (2H, q), 3.81 (3H, s), 3.96 (3H, s), 6.88 (lH, m) , 7.06 (lH, s) Example 13 8) 1- [N-benzyl-N- (5,6-dimethyl-2-methoxypyridin-3-amidino) aminocarbonyl] -4- (2-methoxyphenyl) piperazine will be 1-[(5,6-dimethyl-2-methoxypyridinium-3-donyl) aminocarbanyl] -4- (2- (Methoxyphenyl) hydrazone (100 mg, 0-27 mmol), dissolved in dimethylformamide (15 ml), and sodium hydride (6.5 mg, 0.27 mmol) was added to the chamber. After stirring at room temperature for 16 hours, the solution was concentrated under reduced pressure, and column chromatography (ethyl acetate: hexane = 1: 2) was used for separation and purification to obtain the above compound. Yield: 93% Melting point: Oily substance 'H NMR (CDC13) (5: 2.08 (3H5s) 52.35 (3H? S)? 2.85 (4H? T)? 3.32 (4H, t), 3.8 1 (3H, s ), 3.96 (3H, s), 4.76 (2H, s), 6.96 (4H, m), 7.41 (5H, m) Example 139) 1- [N-cyclopropylfluorenyl-N- (5,6 -Difluorenyl imethoxypyridin-3-fluorenyl) aminocarbonyl] -4- (2-fluorenylphenyl) piperazine will be 1-[(5,6-monomethyl-2-fluorenyloxy. Titanium-3-acid) aminoamino] -4- (2-methoxyphenyl) amidine (100 mg, 026 mmol), dissolved in dimethylformamide (15 ml ), Sodium hydride (6.2 mg, 0.20 mmol) was added, and after stirring at room temperature for 15 minutes, bromomethylcyclopropane (21.8 mg, 0.26 mmol) was added, and at room temperature Stir 16 (Please read the precautions on the back before filling in this page): Binding and ordering 4 -90- 575564 A7 B7 5. Description of the invention (86) hours. Then, the dimethylformamide is removed by concentration under reduced pressure, and then column chromatography (ethyl acetate: hexane = 1: 2) is used for separation and purification to obtain the above compound. Yield: 78% Melting point: oily substance iH NMR (CDCl3) 5: 0.34 (2H, m), 0.49 (2H, m), 1.35 (lH, m), 2.85 (4H, t), 3.28 (4H, t ), 3.40 (2H, S), 3-89 (3H, S), 3.97 (3H, S), 6.97 (4H, m), 7.11 (lH, s) Example 140) 1- [N- (5,6- Difluorenyl-2-methoxypyridin-3-fluorenyl) -N-methylaminocarbonyl > 4- (5-Methoxy-2_fluorenylphenyl) piperazine 1-[(5 , 6-Dimethyl-2-methoxystilbidine-3-amidino) amido] -4- (5-methoxy-2-methylphenyl) piperazine, as described above The reaction was carried out in the same manner as in Example 132 to obtain the above-mentioned compound. Yield: 74%

Melting point: 91 ~ 93 ° C iH NMR (CDC13) 5: 2.15 (3H, S), 2.18 (3H, s), 2.39 (3H, S), 2.67 (4H, t), 3.05 (3H, s), 3.30 (4H, t), 3.75 (3H, s), 3.97 (3H, s), 6.48 (3H, m), 7.10 (lH, s) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the Note: Please fill in this page again) Example 141) l- [N- (5,6-Difluorenyl-2-methoxypyridin-3-amidino) -N-ethylaminocarbonyl] -4- ( 5-Methoxy-2-methylphenyl) piperazine will be 1-[(5,6- ^ —methyl-2-methoxy-stilbidine —3-carbyl) aminocarbanyl]- 4- (5-methoxy-2-methylphenyl) piperazine was reacted in the same manner as in Example 133 described above to obtain the above compound. Yield: 94% -91-This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 male iT "-575564 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, A7 B7 i, Invention Note (87) Wengu Dian · Oil! H NMR (GDCl3) (5: 1.09 (3H? T) 52.15 (3H? S)? 2.18 (3H? S) 9 2.39 (3H, S), 2.60 (4H, t), 3.27 (4H, t), 3.59 (2H, q), 3.75 (3H, S), 3.96 (3H, s), 6.45 (3H, m), 7.08 (lH, s) Example 142) 1- [N-benzyl-N -(5,6-dimethyl-2_methoxypyridin-3-fluorenyl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine 1-[(5,6- Difluorenyl-2-methoxymethyl-3--3-yl) aminopropyl] -4- (5-methoxy-2-fluorenylphenyl), which is the same as that used in Example 138 above. The above-mentioned compound can be obtained by carrying out the reaction in the following manner. Yield: 97% Melting point: Oily iH NMR (CDC13) 5: 1.25 (3H, t), 2.08 (3H, S), 2.14 (3H, S), 2.35 ( 3H, s), 2.60 (4H, t), 3.32 (4H, t), 3.74 (3H, s), 3.95 (3H, s), 4.66 (2H, s), 6.44 (4H, m), 6.96 (5H , M), 7.12 (lH, s) Example 143) 1- [N- (5 · ethyl-2-methoxy-6-methylpyridin-3-fluorenyl) -N-formyl Aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperidine 1-[(5-ethyl-2-methoxy-6-methylpyridin-3-amidino) amino The carbamoyl] -4- (3,5-dimethoxyphenyl) group was reacted in the same manner as in Example 132 above to obtain the above compound. Yield: 87%

Melting point: 78 ~ 79 ° C NMR (CDC13) 5: 1.14 (3H, t), 2.41 (3H, S), 2.52 (2H, q), 2.91 (4H, t), 3.02 (3H, s), 3.28 ( 4H, t), 3.74 (6H, s), 3.98 (3H, S), 5.98 (3H, m), 7.11 (lHG, s) -92- This paper size applies to China National Standard (CNS) A4 specification (210X 297 (Mm) (Please read the precautions on the back before filling this page.) 575564 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (88) Example 144) 1-[N- (5-Ethyl-2-methoxy-6-fluorenylpyridine-3_fluorenyl) -N-methylaminocarbonyl] -4- (3,5-dimethylphenyl) piperazine will be 1- [(5-ethyl-2-methoxy-6-methylpyridin_3_fluorenyl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was implemented as described above The reaction was carried out in the same manner as in Example 132 to obtain the above-mentioned compound. Yield: 84% Melting point: 86 ~ 87 ° CH NMR (CDC13) (5: 1.14 (3H, t), 2.23 (6H, s), 2.45 (3H, s), 2_58 (2H, q), 2.87 (4H , T), 3.05 (3H, s), 3.30 (4H, t), 3.98 (3H, s), 6.46 (3H, m), 7.11 (lH, s) Mass (EI) m / z: 396.2575 (MH, C23H32N402 Calculated: 396.2525) Example 145) l- [N- (5-ethyl-2-methoxy-6-methyl, pyridin-3-fluorenyl) -N-ethylaminocarbonyl] -4- (3,5-Dimethylphenyl) piperazine will be 1-[(5-ethyl-2-fluorenyloxy-6-fluorenylsulfonyl-2-3-granyl) aminoweiyl ] -4- (3,5-dimethylphenyl) hydrazone was reacted in the same manner as in Example 133 above to obtain the above compound. Yield: 86% Melting point: 84 ~ 85 ° CW NMR (CDC13) 5: 1.13 (6H, m), 2.23 (6H, s), 2.41 (3H, s), 2.58 (2H, q), 2_85 (4H, t), 3.26 (4H, t), 3.46 (2H, q), 3.96 (3H, s), 6.45 (3H, m), 7_08 (lH, s) (Example 146) 1-[! ^-(2 -Methoxy-6-fluorenyl-5-propyl. Ratio of n-Methyl (fluorenyl) -N-fluorenylaminocarbonyl] -4- (3,5-diamidinophenyl) piperazine-93 -(Please read the precautions on the back before filling this page) • Binding-Order XI_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) 575564 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (89) 1-[(2-methoxy-6-methyl-5-propylpyridin-3-amidino) aminocarbonyl] -4- (3,5-dimethylphenyl ) Piperazine was reacted in the same manner as in Example 132 to obtain the above compound. Yield: 89% Melting point: Oily W NMR (CDC13) (5: 1.0 (3H, t), 1.78 (2H, s), 2.21 (3H, s), 2.78 (2H, t), 3.87 ( 6H, s), 3.86 (4H, t), 3.99 (3H, s), 4.00 (3H, s), 4.22 (4H, t), 6.01 (3H, m), 7.02 (lH, s) Example 147) l- [N- (6-ethyl-2-methoxy-5-fluorenylpyridine-3_fluorenyl: methylaminocarbonyl group ζμ (3,5-dimethylphenyl) piperazine will be 1- [(6-Ethyl-2-methoxy-5-methylpyridin-3-amidino) aminopyridinyl] -4- (3,5-monomethylphenyl) σbase, adopted The reaction was performed in the same manner as in Example 132 above to obtain the above compound. Yield: 85% Melting point · Oily! H NMR (CDC13) (5: 2.21 (3H? T) 52.21 (3H5s) 52.45 (2H5q) ? 3.21 (4H, t), 3.40 (3H, s), 3.67 (4H, t), 3_67 (4H, t), 3.77 (6H, s), 4.01 (3H, s), 6.07 (3H, m), 6.96 (lH, s), 8.07 (lH, s) Example 148) l- [N- (2-methoxy · 5-fluorenylpropylpyridin-3_fluorenyl) -N-fluorenylaminocarbonyl ] _4_ (3,5-Difluorenylphenyl) piperazine 1-[(2-methoxy-5-methyl-6-propylpyridin-3-amidino) aminocarbonyl] -4- (3,5-Dimethylphenyl) piperazine, as described above The above compound was obtained by reacting in the same manner as in Example 132. Yield: 86% -94- (Please read the precautions on the back before filling this page)

575564 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (90) Melting point: 105 ~ 107 ° CW NMR (CDC13) Heart 0.98 (3H, t), 1.73 (2H, q), 2.18 (3H, s), 2.63 (2H, t), 2.92 (4H, t), 3.05 (3H, s), 3.29 (4H, t), 3.74 (6H, s), 3.96 (3H, s), 6.00 (3H, m ), 7.11 (lH, s) Mass (EI) m / z: 442.2543 (MH, C24H34N404 Calculated: 442.2580) Example 149) 1-[N- (5-Ethyl-2-methoxy-6 -Methyl. More than σ- 3-Methyl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine will be 1-[(5 -ethonyl- 2-Methoxy-6-methylsulfan-3-yl) aminoweiyl] -4- (3,5-dimethoxyphenyl) pyridine, which is the same as that used in Example 132 above. The reaction is carried out by the method to obtain the above-mentioned compound. Yield: 89% Low valley point oily iH NMR (CDC13) 5: 2.50 (3H, s), 2.70 (3H, s), 2.97 (4H, t), 3.09 (3H, s), 3.33 (4H, t), 3.75 (6H, s), 4.06 (3H, S), 6.03 (3H, m), 7.72 (1H5s) Mass (EI) m / z: 442.2229 (MH, C23H3 () N405 Calculated value: 442.2516) Implementation Example 150) l- [N- (5-Ethylfluorenyl-2 · fluorenyloxy-6-methyl, ratio, n--3-fluorenyl) -N-ethylaminocarbonyl]] 4- (3,5 -Dimethoxyphenyl) piperidine 1-[(5-acetic acid-2-methoxy-6-methyl σ to fluoren-3-fluorenyl) aminodecdecyl] -4- ( 3,5-^-methoxyphenyl), which can be reacted in the same manner as in Example 133, to obtain the above compound. Yield: 87% -95-

(Please read the precautions on the back before filling in this page)-Binding and ordering k 575564 A7 B7 V. Description of the invention (91) Melting point: oily iH NMR (CDC13) (5: 1.09 (3H, t), 2.49 (3H , S), 2.70 (3H, S), 3.00 (4H, t), 3.32 (4H, t), 3.77 (6H, s), 4.01 (3H, S), 4.09 (2H, q), 5.98 (3H, m), 7.76 (lH, s) Example 151) l- [N- (5-Ethyl-2-methoxy-6-methylpyridin-3-yl) -N-methylaminocarbonyl ] -4_ (3,5-Dimethylphenyl) travelazine 1-[(5-ethylfluorenyl-2-methoxy-6-methylpyridin-3-amidino) aminopropyl]- 4- (3,5-Difluorenylphenyl) pyrene can be reacted in the same manner as in Example 132 above to obtain the above compound. Yield: 88% Melting point: Oily 1H NMR (CDC13) (^ 2.24 (6H, S), 2.50 (3H, S), 2.70 (3H, s), 2.93 (4H, t), 3.09 (3H, s) , 3.28 (4H, t), 4.06 (3H, S), 6.46 (3H, m), 7.73 (1H? S) Example 152) 1- [N- (5- (1-¾ethyl) -2 -Methoxy-6-Methylpyridyl-3-pyridyl) _N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) Employees of the Central Standards Bureau of Piqin Economy Printed by the Consumer Cooperative (please read the precautions on the back before filling out this page) will be 1-[(5- (1-methylethyl) -2 -fluorenyl-6-fluorenyl σ than sulfanyl-3-fluorenyl ) Aminocarbonyl] _4- (3,5-dimethoxyphenyl) piperazine (0.47 mmol), dissolved in absolute ethanol (15 ml), and added sodium borohydride (17.3 mg), After stirring at room temperature for 2 hours, the solution was concentrated under reduced pressure, and the above compound was obtained after separation and purification by column chromatography (ethyl acetate: hexane = 2: 1). Yield: 97% -96- This paper size applies to Chinese National Standard (CNS) A4 (210 X297 mm) 575564 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (92) Melting point: oily W NMR (CDC13) 6: 1.14 (3H, d), 2.44 (3H, s), 2.93 (4H, t), 3.06 (3H, s), 3.30 (4H, t), 3.74 (6H, s), 3.98 (3H, s), 5.03 (lH, q), 6.02 (3H, m), 7.05 (lH, s) (Example 153) 1 ** {N-ethyl-N- [5- (1-B ) -2-Amino-6-methylpyridine-3-amidino] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine 1- [N- (5- Ethyl-2-methoxy-6-methylmethyl-3-methyl) · N-ethylaminoweiyl] -4- (3,5-dimethoxyphenyl) pyridine, The reaction was carried out in the same manner as in the above-mentioned Example 152 to obtain the above-mentioned compound. Yield: 96% Melting point: Oily 1H NMR (CDC13) 5: 1.09 (3H, t), 1.41 (3H, d), 2.44 (3H, s), 2.91 (4H, t), 3.27 (4H, t) , 3.54 (lH, q), 3.74 (6H, s), 3.96 (3H, s), 5.03 (lH, q), 6.02 (3H, m), 8.46 (lH, s) Example 154) 1- {N -[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridine-3-fluorenyl] -N-methylaminocarbonyl}} __ 4_ (3,5-difluorenylphenyl) Piperazine will be 1- [N- (5-ethylfluorenyl-2 · fluorenyloxy-6 · fluorenyl. Specific to fluorenyl) _n_ methylaminocarbonyl] -4- (3,5-dimethylbenzene (Meth) piperazine. The same method as in Example 152 was used to perform the reaction to obtain the above compound. Yield: 97% Melting point: Oily -97-

(Please read the precautions on the back before filling in this page) • Binding and binding ¾ 575564 Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 Β7 V. Description of the invention (93) 'H NMR (CDC13) (5: 1.41 (3H ? d) 52.42 (6H? s) 52.44 (3H5s) 5 2.91 (4H, t), 3.06 (3H, s), 3.26 (4H, t), 3.99 (3H, s), 5_03 (lH, q), 6.49 (3H, m), 7.50 (lH, s) Example 155) 1-{> ^ [5- (1-hydroxyethyl-1-methylethyl) _2-methoxy-6-methylpyridine- 3-fluorenyl] -N-methylaminocarbonyl} -4- (3,5-dimethylphenyl) σ Chen Hei 1- [N- (5-Ethyl-2-methoxymethoxy) Methylpyridine-3-fluorenyl) -N-fluorenylaminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (221 mg, 0.50 mmol) was slowly added, and the mixture was stirred under reflux. After 15 minutes, the solvent was removed by concentration under reduced pressure, and then extracted with ethyl acetate, dried and filtered, and then separated and purified by column chromatography (ethyl acetate · hexane = 1: 2). After that, the above compounds can be obtained. Yield: 92% Melting point: Oily β NMR (CDC13) 5: 1.59 (6H, s), 2.66 (3H, s), 2.93 (4H, t), 3.〇6 (3H, s), 3.30 ( 4H, t), 3.74 (6H, S), 3.99 (3H, s), 6.03 (3H, m), 7.45 (lH, s) Example 156) 1- {1 ^ [5- (1-hydroxy-1 -Methylpropyl) _2-fluorenyl-6-fluorenyl group Bibitan; -3-acid group] -N-methylaminopentyl} -4_ (3,5-dimethylphenyl) 17 substrate Add 1 _ [N- (5-Ethyl-2-yloxy-6-methyl sigma bideno-3 · acid group) -N- fluorenyltrisylcarbonyl] -4_ (3,5 · di Methylphenyl) Luhe (2 i3mg, 0.50 mmol) was dissolved in tetrahydro. Bran (10ml), and gradually add boron and magnesium sintered (0.50ml, 1.50 millimoles), and then stir for 15 minutes, and then use a reduced pressure concentration -98- This paper scale applies Chinese national standards (CNS) Α4 specification (210X297 mm)! 丨 丨 丨 _ (Please read the precautions on the back before filling out this page) Equipment, 1T 575564 Α7 Β7 V. Description of the invention (94) After removing the solvent, use Ethyl acetate is extracted, dried and filtered, and then column chromatography (ethyl acetate: hexane = 2: 1) is used for separation and purification to obtain the above compound. Yield: 88% Melting point: Oily NMR (CDC13) 5: 0.079 (3H5t) 51.58 (3H5s)? 1.85 (2H? Q) 5 2.61 (3H, s), 2.99 (4H, t), 3.07 ( 3H, s), 3.30 (4H, t), 3.76 (6H, s), 6.12 (3H, m), 7.47 (lH, s) Example 157) 1- {N- [2-methoxy-5- (1-methoxyethyl-6-methylpyrimidin-3-amidino] -N-fluorenylaminocarbonyl} _4- (3,5-dimethoxyphenyl) σ Chen Hei 1- {N- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridine_3_fluorenyl] -aminocarbonyl} -4- (3,5-dimethoxyphenyl ) Piperazine, which was reacted in the same manner as in Example 132 above to obtain the above compound. Yield: 95%

Melting point: 117 ~ 119 ° C 1H NMR (CDC13) ά: 1.34 (3H, t), 2.43 (3H, s), 2.94 (4H, t), 3.06 (3H, S), 3.18 (3H, S), 3.30 (4H, t), 3.74 (6H, S), 3.99 (3H, S), 4.44 (1H, q), 6.02 (3H, m), 7.37 (lH, s) Example 158) 1-[N- (2-Methoxy-6-vinylpyridin-3-amidino) -N-methyl-molylmethyl} _4- (3,5-dimethyllactylphenyl) ρ Chen Hei 1- [ (2-Methoxy-6-methyl-5-ethoxymethyl-3-amino) aminoamino} -4- (3,5-dimethoxyphenyl) The reaction was carried out in the same manner as in the above-mentioned Example 132 to obtain the above-mentioned compound. -99- This paper size is in accordance with Chinese National Standard (CNS) Α4 size (210X297 mm) (Please read the precautions on the back before filling in this page). · 1T Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives 575564 A7 B7 V. Description of the invention (95) Yield: 94% Melting point: Oily 1H NMR (CDC13) 3: 2.46 (3H, s), 2.93 (4H, t), 3.07 (3H, s), 3.30 (4H, t ), 3.73 (6H, s), 3.99 (3H, s), 5.25 (lH, d), 5.48 (lH, d), 6_01 (3H, m), 6-78 (lH, s), 7.43 (lH, s) s) Example 159) l- [N- (2-methoxy-6-fluorenyl-5-vinylpyridin-3-yl) -N-methylaminocarbonyl} -4- (3,5 _Dimethylphenyl) piperazine 1-[(2-methoxy-6_methyl-5-ethenylfluorenyl) aminoweilyl} -4- (3,5-dimethylbenzene Based on the method described above, the same method as in the above-mentioned Example [32] was used for the reaction to obtain the above compound. Yield: 89% Melting point: Oily 1H NMR (CDC13) δ: 2.24 (6H, S), 2.43 (3H, s), 2.90 (4H, t), 3.04 (3H, S), 3.27 (4H, t) , 3_99 (3H, S), 5.23 (lH, d), 5.45 (lH, d), 6.05 (3H, m), 6.77 (lH, s), 7.40 (lH, s) Example 160) l- [N -(2-methoxy-6-methyl-5-vinylpyridine-3-amino) -N-methylaminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine The 1-[(2-methoxy-6-fluorenyl-5-vinylpyridin-3-fluorenyl) aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine is The reaction was carried out in the same manner as in the above-mentioned Example 132 to obtain the above-mentioned compound. Yield: 92% Melting point: oily! H NMR (CDC13) 6: 1.09 (3H, t), 2.43 (3H, s), 2.94 (4H, t), 3.28 (4H, t), 3.77 ( 6H, s), 4.01 (3H, s), 4.11 (2H, q), 5.25 (lH, d) 5 -100- This paper size applies to China National Standard (CNS) A4 (21 × 297 mm) ·- i -i--I -I ill am «•. Jm (Please read the notes on the back before filling out this page) Preparation A7 B7 V. Description of the invention (96) 5.49 (lH, d), 5.98 (3H, m), 6.77 (lH, s), 7.44 (lH, s) Example 161) 1- [N- (5-iso Propylphenyl-2-methoxy-6-methylpyridin-3-fluorenyl) -N · fluorenylaminocarbonyl}} 4- (3,5-dimethoxyphenyl) piperazine 1- [ (5-Isopropyl-2-methoxy-6-fluorenylpyridine_3-fluorenyl) aminorozinyl} -4- (3,5-monomethoxyphenyl dihexyl, adopted as The above compound was obtained by reacting in the same manner as in Example 132 above. Yield: 92% Melting point: Oily iH NMR (CDC13) 5: 1.98 (3H, s), 2.43 (3H, s), 2.92 (4H , T), 3.06 (3H, S ), 3.29 (4H, t), 3.74 (6H, S), 3.99 (3H, S), 4.84 (lH, S), 5.30 (lH, s), 6.01 (3H, m), 7.10 (lH, s) Example 162) [N- (5-Isopropyl-2-methoxy-6-methylpyridin-3-fluorenyl) -N-methylaminocarbonyl} -4- (3, 5-dimethylphenyl) piperidine 1-[(5-isopropylphenyl-2-methoxy-6-methylpyridine_3_fluorenyl) aminocarbonyl} -4- (3,5 -Dimethyphenyl, which can be reacted in the same manner as in Example 132 above. Yield ·· 9 1% Melting point: oily NMR (CDC13) δ: 1.98 (3H5s)? 2.24 (6H? S)? 2.43 (3H? S)? 2.90 (4H, t), 3.06 (3H, S), 3.28 (4H, t), 4.00 (3H, S), 4.84 (lH, S), 5.19 ( lH, s), 6.46 (3H, m), 7.10 (lH, s) Example 163) Ethyl-2-({[4- (3,5-dimethoxyphenyl) piperazine] carbonyl} ( 5-Ethyl-2-yloxy-6-methylpyridin-3-fluorenyl) acetate -g basket-based] amine-101-this scale is applicable to China National Standard (CNS) A4 (210 X 297 mm) '^ ~' 'I -------- 0 ^-( (Please read the notes on the back before filling out this page)

1T -1¾ 575564 A7 B7 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the invention (97) carbonylcarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (20011 ^ 50.5 mmol), dissolved in dimethylfluorenamine (15 ml) +, and sodium hydride (185 mg, 0.5 mmol) was added, followed by stirring at room temperature for 15 minutes. Further ethyl acetate (83.5 mg, 0.5 mmol) was added and stirred at room temperature for 3 hours. Then, the solvent was removed by concentration under reduced pressure, and column chromatography (ethyl acetate: hexane = 1: 2) was used for separation and purification to obtain the above compound. Yield: 84% Melting point: Oily H NMR (CDC13) 5: 1.26 (3H, t), 2.51 (3H, s), 2.69 (3H, s), 3.04 (4H, t), 3.43 (4H, t) , 3.75 (6H, S), 4.05 (3H, S), 4.15 (2H, q), 4.19 (2H, s), 6.08 (3H, m), 7.96 (lH, s) Example 164) ethyl-2 -({[4- (3,5-Difluorenylphenyl) piperazine] carbonyl} (5-ethoxy-2-methoxy-6-methyl-4-methyl-3-donyl) acetate will 1-[(5-Ethylfluorenyl-2-methoxy-6-methylsulfonyl. Benzene-3_acidyl] amino-rodonyl] -4- (3,5-monomethylphenyl) σ Chen He, the same method as described in Example 163 was used for the reaction to obtain the above compound. Yield: 80% Melting point: oily ln NMR (CDC13) 5: 1.25 (3H, t), 2. 56 (3H, s), 2. 69 (3H, s), 3. 00 (4H, t), 3. 29 (4H, t), 3. 78 (6H, s) 4. 06 (3H, s), 4.18 (2H, s), 5.99 (3H, m), 7.98 (1H, s) Example 165) 2-({[4- (3,5-dimethylphenyl) piperazine ] Carbonyl} (5_ Ethyl-2-methoxy-6-methylpyridin-3-amidino) ethyl ethyl acetate-102- This paper size is applicable to China National Standard (CNS) A4 size (210X 297) %) (Please read the notes on the back before filling (Write this page)

1T 4 575564 A7 B7 V. Description of the invention

The ({[4- (3,5-dimethoxyphenyl) piperazine; | carbonylacetamido-2methoxy-6-methyl ° specificity-3-vinyl) aminoacetate ( 200 mg, 0.38 mmol), dissolved in dioxane: distilled water = 4: 1 (15 ml), and bell hydrate (48.1 mg 51.14 mmol) was added at room temperature After stirring for 3 hours, 1N hydrochloric acid was added to acidify the mixture, followed by extraction with ethyl acetate and drying and filtering. Then, the solvent was removed by concentration under reduced pressure, and column chromatography (ethyl acetate: hexane = 丨: 2) was used for separation and purification to obtain the above compound. Yield: 94% Melting point: 135 ~ 137QC 1HNMR (CDC13) 5: 2.52 (3H, s), 2.69 (3H, s), 3.11 (4H, t), 3. 49 (411, t), 3. 74 ( 6H, s), 4.05 (3H, s), 4.24 (2H, s), 6-15 (3H, m), 7.83 (1H, s) Example 166) ethyl-2-(((4- (355-Dioxophenyl) piperazine] carbonyl} (5- (l-hydroxyethyl) -2-methoxy-6-fluorenyltoxylpyridinyl) amino] acetate 2-({[4_ (3,5-Dioxophenyl) piperazine] carbonyl} (5_ethlyl-2-methoxy-6-methylpyridin-3-fluorenyl) amino] Acetic acid esters can be reacted in the same manner as in Example 152 above, and the above compounds can be obtained. Yield: 97% Melting point: 125 ~ 127 ° C -103 This paper applies the Chinese National Standard (CNS) a4 specification ( 210X 297mm (please read the notes on the back before filling this page), 11 d 575564 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, i. Description of the invention (99)! H NMR (CDC13) (5: 1.26 (3H5t)? 1.42 (3H5d)? 2.44 (3H? S)? 3.04 (4H, t,), 3.31 (4H, t), 3.75 (6H, s), 3.97 (3H, s), 4.16 (2H, q ), 4.19 (2H, s), 6.15 (3H, m), 7.69 (lH, s) Example I67) 2 _ ({[4- (3,5-dimethyl Oxyphenyl) piperazine] carbonyl) (5- (1-¾ethyl) -2 -methoxy-6-methylηβ-3-yl) amino] acetate ethyl-2 -({[4_ (3,5-Dioxophenyl) pyrazine] Jinyl} (5_ (1-Ethyl) -2-methoxy-6-methyl. Titanium-3-vinyl The above compound was obtained by the same method as in Example 165 above to obtain the above compound. Yield: 92% Melting point: Oily 4 NMR (CDC13) (5: 1.41 (3H.d ), 2.44 (3H, s), 2.98 (4H, t), 3.36 (4H, t), 3.74 (6H, s), 3.98 (3H, s), 4.40 (2H, s), 5.00 (lH, q) , 6.08 (3H, m), 7.69 (lH, s) Example 168) Ethyl 2-({[4- (3,5-Difluorenylphenyl) yl] quinyl} (5- (1- Hydroxyethyl) -2-methoxy-6-methyl. Pyridin-3-amidino) amino] acetate ethyl-2-({[4- (3,5-dimethylphenyl ) Travel] carbonyl} (5-ethynyl-2-methoxy-6-methylpyridin-3-amidino) amino] acetate, which was reacted in the same manner as in Example 15 2 above, The above compounds can be obtained. Yield: 94% Melting point 68 ~ 70 ° C -104- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)-Packing ·, 11 d 575564 A7 _______ B7 V. Description of the invention (100)! H NMR (CDC13) 5: 1.13 (3H, t) 1.47 (3H, d), 2. 33 (6H, s), 2.44 (3H, s ), 2.95 (4H, t), 3. 30 (4H, t), 3. 98 (3H, s), 4.10 (2H, q), 5.01 (lH, q), 6. 46 (3H, m), 7. 71 (1H, s) Example 169) 2-({[4- (3,5-Difluorenylphenyl) pyrazine] Weiji} (5_ (1-Ethyl) -2-form Oxy-6-methyl-2-methyl-3-amino) amino] acetate ethyl-2-({[4- (3,5-dimethylphenyl) piperazine] carbonyl} (5- Ethyl-2-methoxy-6-methyllazin-3-amidino) amino] acetate was reacted in the same manner as in Example 165 above to obtain the above compound. Yield: 92%

Melting point: 114 ~ 116 ° C β NMR (CDC13) 5: 1.440 (3H, d), 2.23 (6H, s), 2. 40 (3H, s), 2. 91 (4H, t), 3.21 (4H, t), 3.98 (3H, s), 4.〇6 (2H, s), 4.90 (lH, q), 6.50 (3H, m) 6. 5i (iH , S) (Please read the notes on the back before filling this page), I'll print the standard I family-Guo Guo I in a standard-size I sheet of paper 05 I Cm 575564 A7 B7

Invention Description (101)

Example number Ri R-2 H3 R4 R5 R6 R? P ^ 8 AX z • Y 170 Me Me HHHHHH CH 〇OMe 3-N 171 Me Me H OMe H OMe HH CH 〇OMe 3-N 172 Me Me H Me H Me HH CH 〇OMe 3-N 173 Me Me Me HHHH CH 〇OMe 3-N 174 Me Me Me H Me Me H CH 〇OMe 3-N 175 Me Me HFHFHH CH 〇OMe 3-N 176 Me Me Cl HHHHH CH 〇OMe 3-N 177 Me Me H Cl HHHH CH 〇OMe 3-N 178 Me Me OH HHHH. H CH 〇OMe 3-N 179 Me Me H OH HHHH CH 〇OMe 3-N ί j 180 Me Me H SH HHHH CH 〇OMe 3-N 181 Me Me 〇Ac HHHHH CH 〇OMe 3-Ni I 182 Me Me H 〇Ac HHHH CH 〇OMe 3-N 183 Me Me OMe HHHHH CH 〇OMe 3-N 184 Me Me H Me HH OMe H CH 〇OMe 丨 1 | 3-N! 1 1 185 Me Me H OMe HH Me H CH 〇OMe 3-N 186 Me Me H OMe HH Ph H CH 〇OMe 3-N 187 Me Me human HHHHH CH 〇 OMe 3-N 188 Me Me Benzo HHHH CH 〇OMe 3-N 189 Me Me Naphto HHHH CH 0 OMe 3-N __________j 190 Me Me H OMe H OMe H Me CH 〇OMe 3-N 1 191 Me Me H Me H Me H Me CH 〇OMe ---- 1 3-N 192 Me Me HFH FH Me CH 〇'OMe 3-N 193 Me Me H OMe H OMe H Et CH 〇OMe 3-N 194 Me Me H Me H Me H Et CH 〇OMe 3-N -106-I standard is applicable to Chinese national standards (CNS ) A4 specification (21〇 '乂 297mm) (Please read the precautions on the back before filling out this page) V. Invention Description (102)

AB Consumer Council of the Central Standards Bureau, Ministry of Economic Affairs, printed the serial number of the embodiment, ― 'I τ ~ \ Κ} j Κ2 j Rs R4 Rs Rv jj P ^ 8 1 A! Xl! Z .η 1 195 Me Me HFHFH Et CH 〇 OMe 3-N 196 Me Me HFHH iPr CH 〇OMe 3-N 197 Me Me H OMe H OMe HH CH s OMe 3-N 198 Me Me H Me H Me HH CH s OMe 3-N 199 Me Me Me Me .HHHH CH s OMe 3-N 200 Me Me HFHFHH CH s OMe 3-N 201 Me Me H Cl H! Cl HH CI-I s OMe 3-N 202 Me Me FHHHHH CH s OMe 3-N 203 Me Me Cl HHHHH CH s OMe 3-N 204 Me Me OMe HHHHH CH s OMe 3-N 205 Me Me SMe HHHH · H CH s OMe 3-N 1 206 Me Me H OH HHHH CH s OMe 3-N- 207 Me Me 〇Ph HHHHH CH s OMe 3-N j 208 Me Me Human HHH Ή H CH s! OMe 1 3-N | 1 209 'Me Me H OMe HH Me H CH s ---- j --- j OMe | 3-N 1 i 210 Me Me Benzo HHHH CH s OMe 3-N | 211 Me Acetyl H OMe H OMe HH CH 〇OMe 3-N 1 _j 212 Me Acetyl H Me H Me HH CH 〇OMe 3-N 213 Me Acetyl H Cl H Cl HH CH 〇OMe 3-N 214 Me 'OH H OMe H OMe HH CH 〇ONie 1 3-NI 215 Me OH H Me H Me HH CH 〇OMe! I Pn!!; I_____ 216 Me Vinyl H OMe H OMe HH CH 〇OMe 3-N 217 Me Vinyl H Me H Me HH CH 〇OMe 3-N 218 Me Acetyl H OMe H OMe HH CH s OMe 3 -N 219 Me Acetyl H Me H Me HH CH s OMe 3-N 220 Me Acetyl H Cl H Cl HH CH s OMe 3-N 221 Me OH H OMe H OMe H 1 H CH s OMe 3-N! -107- (Please read the notes on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 575564

A

7 B V. Description of invention (103)%

Example number Ri .μ R5 Re R7 Kg A x | 1!!! Z ^ YI 丨 丨 .1 i 222 Me H Me H Me H 1 H 1 CH s 1 OMe 3-N 223 Me OH H Cl H Cl HH CH s OMe 3-N 224 Me Me H 〇Me H ϊ 〇Me H 0 CH ^ OEt CH 〇OMe 3-N 225 Me Me H Me H Me H 0 CH ^ 'oEt CH 〇OMe 3-N 226 Me Me H 〇Me H 〇Me H 0 CH ^ OH CH 〇OMe 3-N j 227 Me Me H Me H Me H 0 CH ^ OH CH 〇OMe 3-N 228 Me Me H 〇Me H 〇Me HH CH 〇OH 3- N 229 Me Me H Me H Me HH CH 〇OH 3-N 230 '^ Me Me HFHFHH CH 〇OH 3-N 231 Me Me H Cl H Cl HH CH 〇OH 3-NI! 丨 丨 " (Please first Read the notes on the back and fill out this page), tr 4 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -108- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 575564 A7 Printed by the Bureau of Consumers of the Bureau of Standards (104) Example 170) H (4,5dimethyljmethoxyphenyl) aminocarbonyl] -4 -phenylpyridine) 3,4-dimethyl Fennel_ 3,4-Difluorenylbenzene (19.3 ^ 0.16 mmol), add methanol (150 ml), and add Potassium hydroxide (9.65g, 0.25 mmol), a reflux for 2 hours. Methane iodide (36e5g, 0.25 millimoles) was then added and allowed to flow for 3 hours. The above compound can be obtained by adding water (1501011), extracting with ethyl acetate, and then separating and purifying by column chromatography. Yield: 81%! H NMR (500MHz5CDC13) ά: 2.20 (3H? S)? 2.24 (3H? S)? 3.77 (3H, s), 6.71 (2H, m), 6.97 (lH, s) b) 4 , 5-< Monosyl-2 · Schizophyllum spp. 3,4-Difluorenyl anisole (17.lg, 0.13 millimoles), trifluoroacetic acid (25〇1111) was added, and slowly Sodium nitrite (16.6 & mmol) was added and stirred at room temperature for 14 hours. After removing trifluoroacetic acid, water (150 ml) was added, extraction was performed with diethyl ether, and then column chromatography was used for separation and purification to obtain the above compound. Yield: 55% 4 NMR (500MHz, CDC13) (5: 2.25 (3H, s), 2.32 (3fl, s), 3.94 (3H, s), 6.85 (1H, s), 7.70 (1H, s) e ) 4,5 *-fluorenyl-2-methoxyindocyanine bond 4,5-Difluorenyl-2-stone scent base (7.80g, 0.0043 moles), add tetrapyran (100ml) ) And ethanol (40ml), and slowly add the surface -109- This paper size applies the Chinese National Standard (CNS) a4 specifications (210X 297 mm) (Please read the precautions on the back first and fill in this page) · Order 4 575564 A7 Description of the Invention 105 / activated carbon (0.57 g), hydrogenation reaction is performed for 5 hours. After the completion of the reaction by the same method, separation and purification by column chromatography can obtain the above compounds. Yield: 82% Ή NMR (500MHz, CDC13) 5: 2.23 (3H, s), 2.27 (3H, s), 3.90 (3H, s), 6.80 (lH, s), 7.68 (lH, s) d) Phenyl N- (4,5-dimethyl-2-methoxyphenyl) formate in 4,5-dimethyl-2-methoxyanisole (4.50 g, 0.3 Mole) Dichloroethane (100ml) was added, and phenyl chloride (4.80g, 0.03 mole) was slowly added while stirring. After stirring for 2 hours, dichlorofane was used for extraction. After separation and purification by column chromatography, the above compounds can be obtained. Yield: 98% 1H NMR (500MHz? CDC13) 5: 2.24 (3H, s), 2. 27 (3H, s), 3.89 (3H5 s), 6. 85 (1H, s ), 7. 20 (5H, in), 7. 90 (1H, s) e) 1 [(4,5-Dimethyl-2-methoxyphenyl) aminojipinylpyrazine (please (Please read the notes on the back before filling in this page.) Printed by 1 消费 Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs

Phenyl N- (4,5-dimethylmethoxyphenyl) formate 2g'.002mol) and 1-phenylσ-diazine (344g, 002mol), / Combined in tetrahydro, biran (10ml), and added DBU (304g, 0 M Mol), and then stirred at room temperature for 2 hours, the reaction was concentrated, and then separated and purified by column chromatography. After that, the above compound can be obtained. Yield: 85% • Bn I -i m 丨 -110- ▲ Zhang Rulen II--g-- Printed by the Employees' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 575564 A7 ________ B7 V. Description of the invention (106)

Melting point: 143 ~ 144 ° C lR NMR (500MHz? CDC13): 2. 20 (3H, s), 2. 21 (3H, s), 3. 25 (4H, t), 3.67 (4H, t) , 3.85 (3H, s), 6.64 (1H, s), 6.94 (3H, m), 6.99 (lH, s) 'Example 171) l-[(4,5-dimethyl- 2 · methoxyphenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine will be the base N- (4,5-monomethyl-2-methoxyphenyl ) The formate and di (3,5-dioxophenyl) piperazine can be reacted in the same manner as in Example 170 above to obtain the above compound. Yield · 85%

Melting point: 119 ~ 120 ° C ^ NMR (500MHz5CDC13) d: 2.20 (3H, s), 2. 21 (3H, s), 3.27 (4H, t), 3.70 (4H, t), 3.79 (6H, s), 3.85 (3H, s), 6.65 (1H, s), 6.98 (1H, s), 7.90 (1H, S)

Mass (EI) m / z: 399.2168 (MH, C22H2GN3104 calculated: 399.2158) Example 172) M (4,5-diamidino-2-methoxyphenyl) aminocarbonyl] -4- (3,5-Dimethylphenyl) piperazinePhenyl N- (4,5-dimethyl-2-methoxyphenyl) formate and i_ (3,5-dimethylphenyl ) Chen Chen, the same method as in Example 170 above was used to perform the reaction to obtain the above compound. Yield: 88%

Melting point: 177 ~ 178 ° C -111-(Please read the precautions on the back before filling this page)

， 1T — This paper is applicable to the national standard (CNS) A4 size of the paper country (210X297mm) 575564 A7 B7 V. Description of the invention (107 Printed by ln NMR (500MHz5CDC13) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 20 (3H, s), 2. 21 (3H, s), 2.29 (6H, s), 3.23 (4H, t), 3.66 (4H, t), 3.85 (3H, s), 6. 58 (2H , m), 6. 65 (1H, s), 6. 99 (1H, s), 7. 92 (1H, s) Mass (EI) m / z: 367.2290 (MH, C22H29N302 calculated value 367.2259) Implementation Example 173) l-[(4,5-Dimethyl-2-methoxyphenyl) aminocarbonyl] -4- (2,3-dimethylphenyl) piperazine and phenyl N- (4 , 5-Dimethyl-2-methoxyphenyl) formate and di (2,3-dimethylphenyl) piperazine can be reacted in the same manner as in Example 17 above, but can The above compound is obtained. Yield: 95% Melting point: 140 ~ 142 ° C lHNMR (500MHz, CDCl3H: 2.21 (3H, S), 2 22 (3H, S) 2.27 (3H, s), 2.29 (3H, s), 2.95 (4H, t), 3.67 (4H, t), 325 (3H, s), 6.65 (lH, s), 7.01 (3H, m), 7.93 (lH, s) Example 174 ) l-[(4,5-dimethyl-2-methoxyphenyl) aminocarbonyl] -4_ (2,3,5,6-tetramethylphenyl Qin used benzylic N- (4,5-diamidino-2-methoxyphenyl) acetate and 1- (2,3,5,6-tetramethylphenyl) piperazine as follows The above-mentioned compound was reacted in the same manner as in Example 170 to obtain the above-mentioned compound. Yield: 93%.

--------- ^^ 装-(Please read the precautions on the back before filling out this page) Order d Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 ____ B7 V. Description of Invention (108) lH NMR (500MHz5CDC13) 5: 2. 20 (9H, s), 2.21 (9H, s), 3.17 (4H, t), 3.63 (4H, t), 3.84 (3H, s), 6.64 (1H, s) , 6.84 (1H, s), 7.95 (lH, s) Example 175) l-[(4,5-Dimethyl-2-methoxyphenyl) aminocarbonyl] 4- (3,5-di Fluorinated phenyl) piperazinePhenyl N- (4,5-difluorenyl-2-methoxyphenyl) formate and 1- (3,5-difluorinated phenyl) piperazine The reaction was carried out in the same manner as in the above Example 17 to obtain the above compound. Yield: 89%

Melting point: 102 ~ 103 ° C 4 NMR (500MHz, CDC13) 6: 2.20 (3H, s), 2.22 (3H, s), 3.29 (4H, t), 3.68 (4H, t), 3.85 ( 3H, s), 6.65 (lH, s), 6.97 (3H, m), 7.89 (lH, s) Example 176) l-[(4,5-dimethyl-2-methoxyphenyl) amine Carbonyl] -4- (2-chlorinated phenyl) σ bottom phenyl phenyl N- (4,5-dimethyl-2-methoxyphenyl) phosphonate and (2-chlorinated Phenyl chenchi was reacted in the same manner as in Example 17 above to obtain the above compound. Yield: 90%

Melting point: 176 ~ 177 ° C 'H NMR (500MHz? CDC13) δ: 2. 21 (3Η, s), 2. 22 (3Η, s), 3.10 (4H, t, J = 5.0 Ηζ), 3.69 (4H, t, J = 5.0Hz), 3.85 (3H, S), 6.65 (lH, s), 7.02 (2H, m), 7.24 (ΐΗ, ιη), 7.39 (IH, d , J = 4.0Hz), 7.92 (lH, s) This paper size is applicable to Chinese National Standard (CNS) M specifications (210X297mm j I. c.ir (Please read the precautions on the back before filling this page) Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 575564 A7 B7 V. Description of the invention (109) — '— · 一 " 化 化 例 177) 1-[(4,5-Difluorenyl_2-methoxybenzene (Amino) aminocarbonyl] -4- (3-gasified phenyl) morphazine ^ Phenyl N- (4,5-diamidino_2-methoxyphenyl) formate and (3- The phenyl) piperidine chloride was reacted in the same manner as in Example i70 above to obtain the above compound. Yield · 84%

Melting point: 75 ~ 76 ° C'H NMR (500MHz5CDC13) 5: 2.20 (3H, s), 2.22 (3H, s), 3.27 (4H, L, J = S.0HZ), 3.68 (4H, t, J = 5.0 Hz), 3.85 (3H, s), 6.65 (lH, s), 6.90 (3H, m), 7.21 (lH, t), 7.90 (1H, s)

Mass (EI) m / z: 373.1590 (MH, C2GH24N302 Cl calculated: 373.1557) Example 178) l-[(4,5-dimethyl-2-methoxyphenyl) aminocarbonyl] -4- (2-Vinyl) Lv Hei uses phenyl N- (4,5-dimethyl-2-methoxyphenyl) formate and 1- (2-hydroxyphenyl) piperazine 'as The reaction was carried out in the same manner as in Example 1 to obtain the compound. Yield: 87%

Melting point: 197 ~ 199 ° C! H NMR (500MHz? CDC13) 5: 2. 20 (3H, s), 2. 21 (3H, s), 2.98 (4H, t), 3.72C4H, t), 3. 84 (3H, s), 6.65 (1H, s), 6. 89 (1 H, t), 7. 00 (2H, m), 7. 1. 3 (2H, m), 7. 89 (1H, s) Example 179) 1 _ [(4,5-Dimethyl-2-methoxyphenyl) aminocarbonyl-114- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please Read the precautions on the back before filling out this page); install ·, tr Description of invention (n〇) group] · 4- (3-Transphenyl) Send phenyl N- (4,5-dimethyl_ The 2-methoxyphenyl) formate was reacted with 1 (3-.phenyl) to carry out the reaction in the same manner as in Example 1.7 above to obtain the above compound. Yield: 88% Melting point: 177 ~ 178. (:! H NMR (500MHz? CDC13) 5: 2.19 (3H, s), 2.21 (3H, s) 3.24 (4H, t), 3.68 (4H, t), 3.85 (3H, s), 6.41 ( 3H, m), 6.65 (1H, s), 6.98 (lH, s) 7.13 (lH, t), 7.88 (lH, s) Example 180) l-[(4,5-dimethyl-2-methyl Oxyphenyl) aminocarbonyl] -4- (3-thiophenyl) σsubstituted phenyl N- (4,5-dimethyl-2-methoxyphenyl) formate with κ (3-thiophenyl) piperazine can be reacted in the same manner as in Example 170 above to obtain the above compound. Yield: 79%

Melting point: 108 ~ 110 ° C ^ NMR (500MHz? CDC13) 5: 2.20 (3H, s), 2. 21. (3H, s) 3.26 (4H, t,), 3.65 (4H, t), 3.84 (3H, s), 6.64 (1H, S) 6.97 (4H, m), 7.05 (lH, s), 7.89 (lH, s) Example 181) l-[(4,5-Difluorenyl-2- Methoxyphenyl) aminocarbonyl] -4- (2-ethoxyphenyl) trazine is a phenyl N- (4,5-dimethyl-2-methoxyphenyl) formate with κ (2-ethoxyphenyl) piperazine can be reacted in the same manner as in Example 170 above to obtain the above compound. -115- 575564 Consumption cooperation by employees of the Central Bureau of Standards, Ministry of Economic Affairs, Du printed A7 —______ _ B7 V. Description of the invention ~ ^ ~~~~ Yield · 84% Melting point: 129 ~ 131 ° C ), 5: 2. 2 (3H, s), 2. 21 (3H, s) 2.32 (3H, s), 3.05 (4H, t), 3.63 (41f, t), 3. 85 (3H, s ), 6.64 (1H, s), 6.99 (1H, s), 7.〇4 (lH, m), 7.17 (2H, m), 7.22 (lH, m), 7.90 (1H, s) '' Example 182) WW: methyl_2_methoxyphenyl) aminochiridyl] -4- (3-ethoxyphenyl) piperazine phenyl N- (4,5-dimethyl The methoxyphenyl) carboxylic acid vinegar and kappa (3-ethoxyphenyl) piperazine were reacted in the same manner as in Example 170 above to obtain the above compound. Yield: 87% Melting point: 154 ~ 156 ° C! H NMR (500MHz, CDC13) 5: 2. 20 (3H, s), 2. 21 (3H, s) 2.29 (3H, s), 3.27 (4H, t), 3. 68 (4H, t), 3. 85 (3H, s), 6.64 (1H, s), 6.66 (2H, m), 6.82 (lH, m), 6.98 (lH, s) '7 90 (1H, s) 'Example 183) 1 _ [(4,5-Difluorenyl-2-fluorenylphenyl) aminocarbonyl] 4- (2-fluorenylphenyl) piperazine N- (4,5-dimethyl-2-methoxyphenyl) formate and κ (2-methoxyphenyl) piperazine were carried out in the same manner as in the above-mentioned Example 丨 70. Reaction to obtain the above compound. Yield: 90% Melting point: 144 ~ 145 ° C -116- This paper size is applicable to China National Standard (CNS) A4 specifications (210 公 297cm ^ ~~ ^-(Please read the precautions on the back before filling this page) -装--Order_ 4 575564 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (112) NMR (500MHz, CDC13) 5: 2. 20 (3H, s), 2. 22 (3H, s), 2. 26 (3H, s), 2. 95 (4H, t, J = 5. OHz), 3. 65 (4H, t, J = 5.0 Hz), 3.78 (3H, s), 3 85 (3H, s), 6.59 (1H, s), 6.65 (lH, s), 6.65 (1H, s), 7.00 (1H, s), 7.11 (1H, s), 7.93 (1H, s ) Example m) 1-[(4,5-Dimethylimethoxyphenyl) aminocarbonyl] -4- (5-methoxy-2-methylphenyl) piperazine -(4,5-dimethyl-2-methoxyphenyl) formate and ^ (5-methoxy-2-fluorenylphenyl) piperazine were used in the same manner as in Example 17 above. The reaction is carried out by the method to obtain the above-mentioned compound. Yield: 88%

Shao point · 140 ~ 141 C! H NMR (500MHz? CDC13) 5: 2.20 (3H, s), 2. 22 (3H? S), 2. 26 (3H, s), 2. 95 (4H , T, J = 5.0 Hz), 3. 65 (4H, t, J: 5.0 Hz), 3.78 (3H, s), 3.85 (3H, s), 6.59 (1H, s), 6.65 (lH, s), 7.0 (lH, s), 7.11 (1H, s), 7.93 (1H, s) Example 185) l-[(4,5-Difluorenyl-2-methoxy Phenyl) aminocarbonyl] -4- (2-methoxy-5_fluorenylphenyl) piperazinePhenyl N- (4,5-difluorenyl-2-fluorenylphenyl) methyl The above-mentioned compound can be obtained by reacting the acid ester with 1- (2-methoxy-2-methylphenyl) piperazine in the same manner as in Example 170 above. Yield: 88%

Melting point: 107 ~ 108 ° C ln NMR (500MHz? CDCl3) 5: 2.20 (3H, s), 2. 21 (3H, s), 2.29 (3H, s), 3. · 10 (4H, t, J = 5.0 Hz), 3. 69 (4H, t, J = 5.0 Hz), -117- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) • < * · ΜΗΜΜΙ ΗΒΗΜΜν · Η · ΗΜ · ι · I i m_i —m — · 1Ηϋ · ϋϋ iml mr tMK§Mt amfi (Please read the precautions on the back before filling out this page) 575564 Employee Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printed A7 invention description (_ — 3. 85 (3H, s), 3. 86 (3H, s), 6. 55 (1Η, s), 6. 79 (2H, m), 7.01 (1H, s) , 9.94 (lH, s) only Example 186) ^ Ιχ4,5-dimethyl-2-methoxyphenyl) aminocarbonyl] -4- (2-methoxy-5-phenylphenyl) Piperazine The benzyl N- (4,5-difluorenyl-2-methoxyphenyl) phosphonate and (2-fluorenyl-5-phenylphenyl) piperazine were implemented as described above. The reaction was carried out in the same manner as in Example 170 to obtain the above compound. Yield: 91%

Melting point: 139 ~ 140 ° C 4 NMR (500MHz, CDC13) heart 2.21 (3H, s), 2.22 (3H, s), 2.22 (3H, s), 3.20 (4H, t) , 3.74 (4H, t), 3.85 (1H, s), 3.94 (3H, s), 6.65 (lH, s), 7.02 (2H, m), 7.32 (2H, m), 7.49 (2H , T), 7.55 (2H, d), 7.93 (lH, s) Example 187) l-[(4,5-dimethyl_2-methoxyphenyl) aminocarbonyl] -4- (2 -Isopropylphenyl) piperazine The phenyl N- (4,5-dimethyl-2-methoxyphenyl) formate and 1- (2-cumyl) piperazine were used as The reaction was carried out in the same manner as in Example 170 above to obtain the above compound. Yield: 80%

Melting point: 134 ~ 135 ° C 4 NMR (500MHz, CDC13) 5 — · 2 · 20 (3H, s), 2.21 (6H, s), 3-l0 (4H, t), 3.64 (4H, t ), 3.85 (3H, s), 5.08 (lH, s), 5.14 (1H, s), 6.64 (lH, s), 7.05 (3H, m), 7.70 (1Η, π), 7.92 ( 1H, s) -118- (Please read the notes on the back before filling out this page) k-pack ·-The size of the paper is applicable to Chinese National Standards (CNs) A4 (210X297 mm 575564 A7

Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, Example 188) l-[(4,5-dimethyl-2-methoxyphenyl) aminocarbonyl] -4- (1-naphthyl) pyrazine Phenyl N- (4,5-dimethyl-2-methoxyphenyl) phosphonate and ^ (1-naphthyl) pyrazine were reacted in the same manner as in Example 17 above, and The above compounds can be obtained. Yield: 92%

Melting point: 160 ~ 162 ° C 'H NMR (500MHz? CDC13) 5: 2.20 (3H, s), 2. 24 (3H, s), 3.31 (4H, t., J = 5.0ffz), 3.83 ( 3H, s), 4.04 (4fl, t), 6.39 (2H, m), 6.69 (lH, s), 7.13 (lH, t), 7.30 (lH, s), 7.46 (1H, s) Examples 189) 1 _ [(4,5-Dimethyl-2-methoxyphenyl) aminocarbonylo-aminobenzyl) piperazine will be N- (4,5-dimethyl_2_methyl The oxyphenyl) formate and (1-o-aminophenylphenyl) piperazine were reacted in the same manner as in Example 170 above to obtain the above compound. Yield: 94%

Melting point: 74 ~ 75 ° C 3.24 (4H, t), 3.70 (4H, t), 3. 86 (3H, s) / 6. 70 (1H, s) / U5 (3H, m), 7.45 (5H , M), 8.00 (2H, m) yoke example 190) 1- [N_ (4,5-dimethyl-2-methoxyphenyl) aminocarbonyl] -4_ (3,5-dimethoxy Phenyl) piperazine-119- This paper size is applicable to China National Standard (CNS) 8-4 (2lOx ^ 97mm) (Please read the precautions on the back before filling this page) -5 4 575564 A7

L-[(4,5-dimethyl-2_methoxyphenyl) aminoweiyl] _4 ', 5-dimethoxyphenyl) pyrazine (0.2 g, 0.5 mmol), It was dissolved in dimethylformamide (15 ml), and sodium hydride (12 mg, 0.05 mmol) was slowly added, followed by stirring at room temperature for 15 minutes. Then, decomposed methane (71 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The above compound can be obtained by concentrating under reduced pressure to remove the solvent and extracting it with dichloromethane, extracting, drying, filtering, and then separating and purifying it by column chromatography. Yield: 92%

Melting point: 86 ~ 88 ° C ^ HNMRCSOOMHz ^ CDCU ^: 2.21 (3H, S), 2. 24 (3H, s), 2.92C4H, t), 3.06 (3H, s), 3.31 (4H, t), 3 75 (6H, s)} 3.83 (3H, s), 6.00 (lH, m), 6.71 (1H, s), 6.83 (1H, S)

Mass (EI) m / z: 413.2293 (MH, C23H31N304 calculated: 413.2314) Example 191) MN- (4,5-dimethyl_2_methoxyphenyl) _N_fluorenylaminocarbonyl]- 4- (3,5-dimethylphenyl) piperazine will be 1-[(4,5-dimethyl-2-methoxyphenyl) aminocarbonyl] _4_ (3 $ dimethylphenyl) Piperazine was reacted in the same manner as in Example 190 above to obtain the above compound. Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page} 、 = 口 Yield: 90%

Melting point: 137 ~ 138 ° C lHNMR (500MHz? CDCl3) (J: 2.15 (3H, s), 2. 24 (3H, s) 2.88 (4H, t), 3.06 (3H, s), 3.29 (4H, t ), 3.83 (3H, S) '6.45 (3H, s), 6.71 (lH, m), 6.83 (lH, s)' -120- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 575564 A7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of Invention (116)

Mass (EI) m / z: 381.2436 (MH, C23H29N302 Calculated: 381.2416) Example 192) Dimethyl benzyloxyphenylmethylaminoweilyl] -4- (3,5-difluorobenzene Group) The 1-[(4,5-dimethyl-2-methoxyphenyl) aminocarbonyl group;] _ 4_ (3,5_difluorinated phenyl) piperazine was used as in the examples The above-mentioned compound can be obtained by performing the reaction in the same manner as in the above. Yield: 87%

Melting point: 98 ~ 100 ° C! H NMR (500MHz5CDC13) 5: 2.16 (3H, s), 2. 25 (3H, s), 2.92 (4H, t), 3.06 (3H, s), 3. 29 (4H , t), 3.83 (3H, s), 6. 23 (3H, m), 6. 72 (1H, s), 6. 83 (1H, s) Example 193) 1_ (N-ethyl-N- (4,5-Dimethyl-2-methoxyphenyl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine 1-[(4,5-difluorenyl -2 · methoxyphenyl) aminocarbonyl> 4- (3,5_dimethoxyphenyl) piperazine (0.2§, 0.5mmol) dissolved in dimethylformamidine A female (15 ml) was added with sodium hydride (12 mg, 0.05 mmol) slowly, followed by stirring at room temperature for 15 minutes. Then, ethane iodide (78 mg, 0.5: mole) was added, and the mixture was stirred at room temperature for 6 hours. The above-mentioned compound can be obtained after concentration removal under reduced pressure, extraction with methylene chloride, drying, filtration, and separation and purification by column chromatography. Yield · 89% Refining point: oily (please read the precautions on the back before filling out this page) Pack. Order 121-575564 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (117)! H NMR (500MHz5CDC13) ^: 1. 09 (3H, t), 2. 16 (3H, s), 2.24 (3H, s), 2.75 (4H, t), 3.28 (4 H, t), 3.52 (2H , Q) 3.75 (6H, s), 3.81 (3H, s), 5.98 (3H, m), 6.70 (1H, s), 6.80 (1H, s) 'Example 194) l- [N- (4,5_dimethyl_2_methoxyphenyl) _N_ethylaminocarbonyl] -4_ (3,5-difluorenylphenyl) piperidine 1-[( 4,5-dimethyl-2-methoxyphenyl) aminocarbonyl] -4_ (3,5_dimethylphenyl) piperazine was reacted in the same manner as in Example 193 above, but The above compound is obtained. Yield: 93% Melting point: 80 ~ 82 ° C! H NMR (500MHz? CDC13) 5: 1. 21 (3H, t), 2. 15 (3H, s), 2.23 (9H, s), 2.90 (4H , T), 3.25 (4H, t), 3.59 (lH, q), 3.81 (3H, s), 6.45 (3H, m), 6.69 (lH, s), 6.81 (1H, S) Example 195) l -[N- (4,5-Dimethyl-2-methoxyphenyl) _N-ethylaminoquinyl] -4- (3,5-difluorinated phenyl) [(4,5-Difluorenyl-2-methoxyphenyl) aminocarbonyl] Difluorophenyl) piperidine was reacted in the same manner as in Example 193 above to obtain the above compound. Yield: 87% Melting point: Oily ^ NMRCSOOMHz ^ DC ^) ^: 1.09 (3H, t), 2.16 (3H, s) 2.25 (3H, s), 2.90 (4H, t), 3.27 (4H, t) ， 3.52 (2H, q) '3.81 (3H, s), 6.24 (3H, m)' -122- This paper size applies to China National Standard (CNS) M specification (2 丨 0 > < 297 public shame) (please Read the note I # on the back before filling. Install-: Write this page) 4 575564 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ---------------- B7 V. Description of the invention (118) Example 196) 1- [N- (4,5-dimethyl-2-methoxyphenyl) -N-isopropylaminocarbonyl] -4- (3, 5-difluorophenyl) piperazine 1-[(4,5-dimethyl_2_methoxyphenyl) aminocarbonyl > 4- (3,5_difluorophenyl) Piperazine (0.2 g, 0.2 mmol) was dissolved in dimethylformamide (1 ml), and sodium hydride (12.48 mg, 0.52 mmol) was slowly added, followed by stirring at room temperature for 15 minutes. . Isopropane iodide (87.88 mg, 0.52 moles) was added thereto, followed by stirring at room temperature for 2 hours. The above compound can be obtained by concentrating under reduced pressure to remove the solvent, subdividing with dichloromethane, extracting, drying, filtering, and then separating and refining the product by column chromatography. Yield · 84% Melting point 1 Oily lH NMR (500MHz, CDCl3H: 1.10 (3H, s), L 26 (now s), 2.20 (3H, s), 2.25 (3H, s), 2. 86 (4H , t), 3. 26 (4H, t), 3.77 (3H, s), 4.25 (lH, m), 6.17 (3H, m) > 6. 68 (1H, s), 6.82 (1H, s) Example of lambda bismuth 197) SIX4,5 · dimethyl-2-methoxyphenyl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine a) phenyl N- (4,5-: methyl-2-methoxyphenyl) thioformate in 4,5--fluorenyl-2-methoxyaniline (450 g, 〇03mol ), Add Erqijiayuan (100ml) 'while mixing, and slowly add phenyl chloride thioformic acid (5.16g, 0.03 mole). After being taught for 2 hours, water (15_) was added, and extraction was performed with dichloro f, followed by separation and purification by column chromatography to obtain the above compounds. Yield: 92% (Please read the precautions on the back before filling this page)

、 1T 4 -123- The paper ruler of the financial institution ^ TcNS) Α4 size （210X29iJ7 575564

1H NMR (500MHz? CDC13) 5: 2.21 (3H, s), 2. 25 (3H, s), 6.80 (1H, s), 6.93 (5H, m) , 7.31 (lH, s) b) l- (4,5 · Difluorenyl-2-methoxyphenyl) aminothiocarbonyl] -4_ (3,5 _- '' methoxyphenyl). Di Hei made phenyl N- (4,5-difluorenyl-2-methoxyoxyphenyl) thioformate (0.2 g, 0.7 mmol) and 1_ (3,5_difluorene) Oxyphenyl) piperazine (〇16g, 0.7mmol), dissolved in tetrahydropyran (101111), and added DBU (0.11g, 0.7mmol) Stir at warm for 2 hours. After concentrating the reaction mixture with the reaction mixture and then separating and purifying it by column chromatography ', the above compound can be obtained. Yield: 84%

Melting point: 128 ~ 129 ° C 'HNMRCSOOMHz ^ DC ^) ^: 2.20 (3H) S), 2.24 (3H, s), 2.32 (6H, s), 3.37 (4H, t), 3. 83 (3H, s ), 4. 08 (4H, t), 6.69 (3H, m), 7.39 (lH, m), 7.47 (lH, s)

Mass (EI) m / z: 415.1912 (MH, C22H29N303 Si Calculated: 415.1929) Example 198) ^ [(bucket, ^ dimethyl-2-methoxyoxyphenyl) aminothiocarbonyl] -4 -(3,5-Difluorenylphenyl) piperazinePhenyl N-[(4,5-Difluorenyl-2-methoxyphenyl) thioformate with 1- (3,5- Dimethylphenyl) piperazine can be reacted in the same manner as in Example 197 above to obtain the above compound. Yield: 90%

Melting point: 164 ~ 165 ° C -124- This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) I ------- ^ Packing ------ Order (please read the first Note: Please fill in this page again) 575564 Printed by A7, Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (12) 'H NMR (500MHz? CDC13) 5: 2.20 (3H, s), 2. 24 (3H, s), 2.32 (6H, s), 3.37 (4H, t), 3.83 (3H, s), 4. 08 (4H, t), 6.69 (3H, m), 7.39 (lH, m), 7.47 (lH, s)

Mass (EI) m / z: 383.2086 Calculated: 383.2031) Example 199) l-[(4,5-dimethyl-2-methoxyphenyl) aminothiocarbonyl] -4- (2, 3_Difluorenylphenyl) Lui Hei Phenyl N-[(4,5-dimethyl-2-methoxyphenyl) thioformate and 1- (2,3-dimethylbenzene (Meth) piperazine, which was reacted in the same manner as in Example 197 above, to obtain the above compound. Yield: 89%

Melting point 15 1 ~ 15 2 ° C 'H NMR (500MHz? CDC13) (5: 2.21 (3H, s), 2. 24 (3H, s), 2.29 (6H, s), 3.03 (4H, t) , 3. 83 (3H, s), 4.10 (4H, t), 6.69 (1H, s), 6.97 (2H, m), 7.11 (lH, t) t Example 200) l-[(4,5- Dimethyl-2-methoxyphenyl) aminothio-chipinyl] -4- (3,5-difluorophenyl) piperazine Phenyl N-[(4,5-dimethyl- The 2-methoxyphenyl) thioformate and 1- (3,5-difluorinated phenyl) were slightly reacted in the same manner as in Example 197 above to obtain the above compound. Yield: 92%

Melting point: 167 ~ 168 ° C Ή NMR (500MHz, CDC13) 5: 2. 20 (3H, s), 2. 24 (3H, s), 2.27 (3ll, s), 2.32 (3H, s) , 3.39 (4H, t, J = 5.0Hz), 3.83 --------- ^ install-(Please read the precautions on the back before filling this page)

, 1T it -125- 575564 A7 B7 V. Description of the invention (121) (3H, s), 4.14 (4H, t), 6.70 (1H, s), 6.80 (2H, m), 7.36 (lH, s), 7.44 (lH, s) Example 201) 1 _ [(4,5-Dimethyl-2-methoxyphenyl) aminothiocarbanyl] -4- (3,5-dichlorophenyl ) Σ 辰 嗔 Phenyl N-[(4,5-dimethyl_2_methoxyphenyl) thioformate and 1- (3,5-monofluorinated phenyl) The reaction was performed in the same manner as in the above-mentioned Example 197 to obtain the above-mentioned compound. Yield · 85%

Melting point: 188 ~ 189 ° C XH NMR (500MHz? CDC13) (J: 2.21 (3H, s) 2. 24 (3H, s), 3. 40 (4H, t), 3. 83 (3H, s) , 4. 25 (4H, t), 6. 70 (1H, s), 7. 13 (3H, m), 7.37 (2H, m)

Mass (EI) m / z: 423.0956 Calculated: 423.0938) Example 202) l-[(4,5-dimethyl-2-methoxyoxyphenyl) aminothioM] -4- (2 -Fluorinated phenyl) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 丨 • Approval-- (Please read the precautions on the back before filling this page) The methyl-2-methoxyphenyl) thioformate and 1 (2-fluorinated phenyl) piperazine were reacted in the same manner as in Example 197 above to obtain the above compound. Yield: 85%

Melting point: 139 ~ 140 ° C NMR (500MHz5CDC13) 5: 2.21 (3H, s), 2. 24 (3H, s), 3.40 (4H, t), 3.83 (3H, s), 4. 25 (4H, t), 6.70 (lH, s), 7. 13 (3H, m), 7. 37 (2H, m) -126- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 (Mm) 575564 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (122) _ Implementation Example 203) 1-[(4,5-dimethyl_2-methoxyphenyl) amine Thiocarbonyl] -4- (2-chlorophenyl) piperazine connects phenyl N-[(4,5-diamidino-2-methoxyphenyl) thioformate with 1- ( 2-Chlorophenyl) piperazine was reacted in the same manner as in Example 197 above to obtain the above compound. Yield: 85%

Melting point: 115 ~ 116DC Η R (500MHz, CDC13) (5: 2.21 (3H, s), 2.24 (3H, s), 3.18 (4H, t), 3.83 (3H, s), 4. 09 (4H, t), 6.69 (lH, s), 7.05 (2H, m), 7.33 (1H, s), 7. 41 (2H, m) Example 204) 1 _ [(4,5- Dimethyl-2-methoxyphenyl) aminothioalkyl] -4- (2-methoxyphenyl) piperazine The phenyl group N-[(4,5_diamidino-2 -Methoxyphenyl) thioformate and 1- (2-methoxyphenyl) piperazine can be reacted in the same manner as in the above Example 97 to obtain the above compound. Yield: 90% Melting point: oily! H NMR (500MHz5CDC13) 5: 2. 2 0 (3H, s), 2. 23 (3H, s), 3. 14 (4H, t, J = 5. 0Hz) , 3. 82 (3H, s), 3.88 (3H, s), 4. 06 (4H, t, J = 5.0Hz), 6.94 (3H, m), 7.30 (lH, s), 7.40 (lH, s Example 205) l-[(4,5-Dimethyl-2-fluorenyloxyphenyl) aminothiocarbonyl] -4- (2-fluorenylthiophenyl) piperazine -[(4,5-dimethyl-2-methoxyphenyl) thioformate with! -(2_fluorenylthiophenyl), which is used in the same way as in the above Example 197 -127--Approval-(Please read the precautions on the back before filling this page) Order it This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 575564 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (123) The same method can be used to obtain the above compounds. Yield: 93%

Melting point: 136 ~ 137 ° C NMR (500MHz5CDC13) 5: 2.20 (3H, s), 2. 26 (3H, s), 2.45 (3H, s), 3.33 (4H, t), 4. 39 (4H, t), 6.74 (lH, s), 7.16 (3H, m), 7.47 (2H, m) Example 206) l-[(4,5-dimethyl-2-fluorenyloxy Phenyl) aminothiocarbamoyl] -4- (3-Phenyl) trazinePhenyl N-[(4,5-dimethyl-2-methoxyphenyl) thiocarboxylic acid The ester was reacted with 1- (3-hydroxyphenyl) piperidine in the same manner as in Example 197 above to obtain the above compound. Yield: 77% Melting point: Decomposed (200 ° C)! Η NMR (500MHz, CDC13) 5: 2.17 (3H, s), 2.23 (3H, s), 3.31 (4H, t), 3.82 (3H, s ), 4.03 (3H, t), 6.37 (2H, m), 6.47 (lH, d), 7.13 (lH, t), 7.45 (lH, s) Example 207) 1. ((4,5-dimethyl -2-methyloxyphenyl) aminothio

Ik-based] -4- (2-oxophenylphenyl) π Chenhe converts phenyl N-[(4,5-diamidino-2-methoxyphenyl) thioformate to 1- ( The 2-oxyphenylphenyl) piperidine was reacted in the same manner as in Example 197 above to obtain the above compound. Yield: 86% Melting point: Oily -128- ί The paper size applies the Zhongguanjia Standard (CNS) M specification (: Runs 297 kilometers-丨 binding (please read the precautions on the back before filling this page) 575564 Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau A 7 —_____ B7 ____ 5. Description of the Invention (124)! H NMR (500MHz, CDC13) 5: 2.17 (3H, s), 2.24 (3H, s), 3.19 (4H, t), 3.89 (3H, s), 3. 85 (4H, t), 6.66 (lH, s), 6.91 (2H, m), 6.98 (lH, m), 7.05 (3H, m), 7.13 (lH, m) , 7.23 (lH, m), 7.31 (2H, m), 7.36 (1H, s) Example 208) [(4,5-Difluorenyl-2-methoxyphenyl) aminothiochi ] -4- (2-Isopropylphenylbenzene) sends phenyl N-[(4,5-dimethyl-2-methoxyphenyl) thioformate to 1_ (2_isopropyl The above compound can be obtained by carrying out the reaction in the same manner as in Example 197 described above. Yield: 75% Melting point: 157 ~ 158 ° C NMR (500MHz, CDC13) 5: 2.20 (3H, s), 2.21 (3H, s), 2.24 (3H, s), 3.19 (4H, t), 3.82 ( 3H, s), 4. 05 (4H, t), 5.07 (lH, s), 5.16 (lH, s), 6.69 (lH, s), 7. 11 (33H, m), 7.33 (1H, s) 7.45 (1H, s) Example 209) l-[(4,5-dimethyl-2-methoxyphenyl) aminothiocarbonyl] -4- (2-methoxyfluorenyl Phenyl) piperazine Phenyl N-[(4,5-dimethyl-2-methoxyphenyl) thioformate and 1- (2-methoxymethylphenyl) piperazine, The reaction was carried out in the same manner as in Example 197 above to obtain the above compound. Yield: 87% Melting point: Oily NMR (500MHz, CDC13) 5: 2. 20 (3H, s), 2. 23 (3H, s), 2.29 (3H, s), 3.13 (4H, t), 3.8 3 (3H, s), 3.85 (3H, s), -129- This paper size is applicable to towel standard (CNS) A4 specification (210X297 mm) — '— "-(Please read the note on the back first 4 items to refill-Pack —: Write this page)

、 1T 575564 A7 --____ B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy s), 7.40 (1H, s) Example 210) l-[(4,5-Dimethylmethoxyphenyl) aminothio-kisyl] -4- (1-naphthyl) The reaction of phenyl N _ [(4,5-dimethyl_2_methoxyphenyl) thiophosphonate with (1-naphthyl) piperazine was carried out in the same manner as in Example 197 above. The above compounds can be obtained. Yield: 87% Melting point: 139 ~ 140 ° C IfJMIKSOOMI ^ CDClW: 2.23 (3H, s), 2.24 (3H, s), 3.2K4H, t), 3.84 (4H, s), 4. 09 (4H, t ), 6. 70 (1H, s), 7.10 (lH, d), 7.48 (5H, m), 7.85 (lH, m), 8.22 (lH, d) Example 211) l-[(5-acetamidine Methyl-2-methoxy-4-methylphenyl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine Phenyl N- (5-ethylfluorenyl- 2-methoxy-4-methylphenyl) formate and 1- (3,5-methoxyphenyl) pyrazine can be reacted in the same manner as in Example 17 above to obtain The above compounds. Yield: 91% Melting point: 103 ~ 105 ° C 'H NMR (500MHz, CDC13) (5: 2.54 (3H, s), 2.59 (3H, s), 3.27 (4H, t), 3.70 (4H, t ), 3.79 (6H, s), 3.94 (3H, s), 7.05 (lH, s), 8.72 (lH, s) Example 212) [(5-Ethyl-2- 2-fluorenylphenyl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine-130- (Please read the notes on the back before filling this page) 4 items The size of this paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 575564

、 Explanation of the invention (126) (Please read the precautions on the back before filling in this page) Phenyl N- (5-ethylfluorenyl-2-methoxy-2-methylphenyl) formate and ^ Methylphenyl) piperazine can be reacted in the same manner as in Example 170 above to obtain the above compound. Yield: 88%

Melting point: 140 ~ 142 ° CH NMR (500MHz, CDC13) (5: 2. 30 (3H, s), 2.54 (3H, s), 2.59 (3H, s), 3.26 (4H, t), 3.70 (4H, t), 3.97 (3H, s), 6.61 (3H, m), 6.70 (lH, s), 7.06 (lH, s), 8.72 (lH, s) (Example 212) l-[(5_ 乙醯Methyl-2-methoxy-2-methylphenyl) aminothiocarbonyl] -4- (3,5-dichlorophenyl) piperazine Phenyl N- (5-ethylfluorenyl-2 -Methoxy-2-methylphenyl) phosphonate and 1- (3,5-dichlorophenyl) pyridine were reacted in the same manner as in Example 170 above to obtain the above compound. . Yield: 78%

Melting point: 170 ~ 172 ° C NMR (500MHz, CDC13) 5: 2. 54 (3H, s), 2. 59 (3H, s), 3.32 (4H, t), 3.74 (4H, t), 3.94 (3H , s), 6.69 (lH, s), 6.86 (3H, m), 7.04 (lH, s), 8.69 (lH, s) Example 214 printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, Example 214) 1-{(5 · (1-Hydroxyethyl) _2-methoxy-4-fluorenylphenyl] aminocarbonyl} _4- (3,5-dimethoxyphenyl) piperazine 2--2-methoxy-4-methylphenyl) aminocarbonyl] -4 · (3,5-dimethoxyphenyl) pyrazine (0.2 g, 0.47 mmol), dissolved After adding sodium borohydride (17-3 mg) to anhydrous ethanol (1 ml), the mixture was stirred at room temperature for 2 hours. After the ethanol was removed by concentration under reduced pressure, the column layer was 131-This paper size is applicable to the Chinese National Standard (CNS) A4 (210X29? Mm). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 ^ ______ 5. Description of the invention (127) The above compound can be obtained after separation and purification (ethyl acetate since hexane · hexyl = 1: 2). Yield: 96%

Melting point: 152 ~ 154 ° C 1H NMR (500MHz, CDC13) 5: 1.4l (3H, d)? 2. 32 (3H, s), 3.27 (4H, t), 3.71 (4H, t), 3.79 (6H , S), 3.87 (3H, s), 5.04 (lH, q), 6.10 (3H, m), 6.63 (1H, s), 8.22 (lH, s)? Example 215) Hydroxyethyl) -2 _Methoxy-4-methylphenyl] aminocarbonyl} -4- (3,5-difluorenylbenzyl)? 1-[(5-ethylfluorenyl-2-methoxy-4 The methyl compound) 4- (3,5-difluorenylphenyl) can be reacted in the same manner as in Example 214 above to obtain the above compound. Yield: 96%

Melting point: 140 ~ 142 ° C NMR (500MHz, CDC13) 5: 1,48 (3H, d), 2.33 (3H, s), 3.26 (4H, t), 3. 68 (4H, t), 3. 87 (3H, s), 5.06 (1H, q), 6.61 (3H, m), 6.64 (lH, s), 7.01 (1H, S), 8.22 (lH, s) Example 216) M ( 2-Methoxy-4-methyl-5styryl) aminoweiyl] -4- (3,5-dimethoxyphenyl) piperazine will be 1-{[5- (1-hydroxy Ethyl) -2-methoxyfluorenylphenyl] aminocarbonyl 4- (3,5-monomethoxyphenyl) pyrazine (0.2 g, 0.47 mmol), dissolved in chloroform (15ml), and then added pyrimide p-toluenesulfonate (0.12g, 0.47mmol), and then column chromatography (ethyl acetate-132- this paper size (CNS) A4 Specifications (-—---- | 丨 _; ——.--- f I— C Please read the notes on the back to fill in this form fo Order 575564 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____________ B7 5 Explanation of the invention (128) One bone; L ·: Hexyl = 1: 2) After separation and purification, the above compounds can be obtained. Yield: 84% Melting point: 163 ~ 165 ° CNMR (500MHz, CDC13) 5: 2.31 (3H, s), 3. 23 (4H, t), 3. 58 (4H, t), 3. 77 (6H, s), 3. 87 (3H, s), 5.20 (1H, d), 5.62 (lH, d), 6.59 (3H, m), 6.63 (1H, s), 6.88 (lH, t), 6.99 (1H, s), 8.32 (1H, s) Example 217) K (2-A Oxy_4-fluorenyl-5_styryl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperidine 1-{[5- (1-hydroxyethyl) -2 -Methoxy_4_fluorenylphenyl] aminocarbonyl} -4- (3,5-difluorenylphenyl) piperazine can be reacted in the same manner as in Example 216 above to obtain the above-mentioned Compounds. Yield: 82% Melting point: 201 ~ 203 ° C 'H NMR (500MHz, CDC13) (?: 2. 29 (6H, s), 2. 34 (3H, s), 3.24 (4H, t), 3.68 ( 4H, t), 3.87 (3H, s), 5.22 (lH, d), 5.66 (lH, d), 6.59 (3H, m), 6.63 (ll, s), 6.86 (lH, t), 7. 2 (1H, s), 8.32 (1H, s) Example 218) l-[(5-ethylfluorenyl-2_methoxy-4-methylphenyl) aminoquinyl] -4- (3 Phenyl N- (5-ethylfluorenyl-2-methoxy-4-methylphenyl) thioformate with 1- (3,5-di The methoxyphenyl) piperazine was reacted in the same manner as in Example 197 above to obtain the above compound. Yield: 82% -133- This paper size applies to towel family standards (CNS) A4 ^^ Gx297 public director) '" (Please read the precautions on the back before filling out this page) I # then fill in > · Order it printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 B7 _ "------- ------. —— V. Description of the invention (129)

Melting point: 163 ~ 165 ° C! H NMR (500MHz, CDC13) 5: 2.16 (3H, s), 2. 56 (3H, s), 3.35C4H, t), 3.9K6H, s), 4. 03 (3H , s), 4.13 (4H, t), 0.606 (3H, m), 6.73 (1H, s), 8.62 (1H, s) Example 219) l-[(5_ethy -2-Methoxy-4-methylphenyl) aminothioquinoyl] -4- (3,5-dimethylphenyl) -Methoxy_4-methylphenyl) thioformate and 1- (3,5-dimethylphenyl) piperazine can be reacted in the same manner as in Example 197 above to obtain The above compounds. Yield: 79%

Melting point: 180 ~ 182 ° C NMR (500MHz, CDCI3) 5: 2. 29 (6H, s), 2. 57 (6H, s), 3.32 (4H, 4t,), 3.92 (3H, s), 4.12 ( 4H, t), 6.56 (3H, m), 6.72 (lH, s), 7.39 (lH, s) (% of Example 220) -Acetyl-2-methoxymethylphenyl) aminothiochi ] -4- (3,5_dichlorophenyl) travelazine Phenyl N- (5-ethylamido-2-methoxy-4_fluorenylphenyl) thioformate with dichloro The phenyl) piperidine was reacted in the same manner as in Example 197 above to obtain the above compound. Yield: 79%

Melting point: 201 ~ 203 ° C NMR (500MHz, CDC13) 5: 2. 20 (3H, s), 2. 57 (3H? S) 3.46 (4H5t), 3.92C3H, s), 4. 25 (4H, t ), 6.64 (1H s) 6.88 (3H, m), 7.72 (lH, s), 8.57 (1H, S) '' -134- The paper size of Shicai County (CNS) M specifications (21GX297 public shame) —- —- I ^ 批 衣-(Please read the notes on the back before filling in this page)

1T i # Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 B7 V. Description of the invention (130) Example 221) 1-{[5- (1-hydroxyethyl) -2-methoxy-4- Methylphenyl] aminothiocarbonyl 4- (3,5-dimethoxyphenyl) piperazine 1 _ [(5-ethylamido-2-methoxy_4_methylphenyl) Aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) was reacted in the same manner as in Example 214 above to obtain the above compound. Yield: 94%

Melting point: 146 ~ 148 ° C 'H NMR (500MHz, CDC13) 5: 1.44 (3H, d), 2. 32 (3H, s), 3.35 (4H, t), 3.78 (6H, s), 3.84 (3H , S), 4.11 (4H, t), 5.06 (1H, q), 6.13 (3H, m), 6.66 (1H, s), 7.41 (1H, s), 7. 77 (1H, s) Example 222) l-{[5- (l-hydroxyethyl) -2-methoxy-4-methylphenyl] aminothiocarbonyl} -4- (3,5- Dimethylphenyl) piperazine 1-[(5-ethylfluorenyl-2-methoxy-4-methylphenyl) aminothiocarbonyl] -4- (3,5-dimethylbenzene Group), the same method as in Example 214 was used for the reaction to obtain the above compound. Yield: 93%

Melting point: 150 ~ 152 ° C! H NMR (500MHz, CDC13) 5: 1.44 (3H, d), 2. 29 (6H, s), 2.32 (3H, s), 3.30C4H, t), 3.84 (3H, s), 4.07 (4H, t), 5.〇6 (lH, q), 6.61 (3H, m), 6.66 (1H, s), 7.38 (1H, s), 7 · 79 (1H, s) Example 223) l-{[5- (1-Ethyl) -2-methoxyoxy-4-fluorenylphenyl] aminothiocarbonyl} -4- (3 , 5-Digasified phenyl) piperazine-135- This paper size applies to Chinese National Standard (CNS) A4 (210 X297 mm) ^^ Pack. Order. (Please read the precautions on the back before filling this page ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 ----------- B7 V. Description of the invention (131) The phenyl) aminothiocarbonyl] -4- (3,5-dichlorinated phenyl) was reacted in the same manner as in Example 214 above to obtain the above compound. Yield · 77%

Melting point: 166 ~ 168 ° C NMR (500MHz, CDC13) (5: 1.45 (3H, d), 2. 33 (3H, s), 3-35 (4H, t), 3.84 (3H, s), 4. 03 (4H, t), 5.07 (lH, q), 6.68 (3H, m), 6.83 (lH, s), 7.37 (lH, s), 7.82 (lH, s) Example 224) Ethyl 2- ( {[4- (3,5-Dimethoxyphenyl) piperidinium] quinyl} -2-methoxy-4,5-dimethylaniline) acetate will be 1-[(4,5-di Methyl-2 · methoxyphenyl) aminopropyl] -4_ (3,5_dimethoxyphenyl) piperidine (0.2g, 0.5mmol), dissolved in dimethylformamide (15ml ), And after adding sodium hydride (I8.5mg, 0.5mmol), it was expanded at room temperature for 3 hours. The solvent was removed under reduced pressure, and the compound was separated and purified by column chromatography (ethyl acetate: hexane = 1: 2). Yield: 79% Melting point: oily ^ NMR (500MHz, CDC13) 5: 1.36 (3H, t), 2. 15 (3H, s), 2.23 (3H, s), 2.9K4H, t), 3. 22 (4H, t), 3.82 (6h / s), 4.12 (3H, s), 4.18 (2H, s), 5.98 (3H, m), 6.69 (1H, S) '7. 03 (1H, s) '' Example 225) Ethyl 2-({[4- (3,5-«— methylbenzyl)] [Carbonyl] -2-carboxy-4,5-dimethylaniline ) Acetate 136-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). Binding (please read the precautions on the back before filling this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 ----- B7 V. Description of the invention (132) The 1-[(4,5-dimethyl-2-methoxyphenyl) aminocarbonyl group] _4_ (3,5_ —methylphenyl) is slightly Alas, the same method as in Example 224 was used for the reaction to obtain the above compound. Yield: 78% Melting point: oily! H NMR (500MHz, CDC13) 5: 1.26 (3H, t), 1.56 (6H, s), 2. 24 (3H, s), 3. 32 (4H, t) , 3.52 (411, t), 3.82 (3H, S) 4.15 (2H, q), 4.18 (2H, s), 6.70 (3H, m), 6.94 (1H, S) '7. 46 (1H, s) 'Example 226) 2-({[4- (3,5-Dioxophenyl) piperazine] carbonyl} _ 2-methoxy-4,5-difluorenylaniline) acetate 2-({[4- (3,5-Dimethoxyphenyl) piperazine] carbonyl} _2_methoxy_4,5-dimethylaniline) acetate (200mg, 0 41 mmol) , Dissolved in dioxane: distilled water = 4: 1 (15ml), and added lithiated gas hydrate (50.7mg, 1.23mmol), stirred at room temperature for 3 hours, and then added 1N hydrochloric acid to acidify Extraction with ethyl acetate and drying filtration. Then, the solvent was removed by concentration under reduced pressure, and column chromatography (ethyl acetate: hexane = 丨: 2) was used for purification by eight-step separation to obtain the above compound. Knife Yield: 80%

Melting point: 188 ~ 189 ° C 4 Li R (500MHz, CDC13) 6: 2.14 (3H, s), 2.23 (3H, S) 2.93 (4H, t), 3.35 (4H, t), 3.75 (6H, s) , 3.87 (31 s) 4.18 (2H, s), 5.96 (3H, m), 6.71 (lH, s), 7.71 (ih, 's)' -137- This paper standard applies to China National Standard (CNS) 8-4 Specifications (210X297 mm) I —-----— 9 ^ ------ Order ------ (Please read the notes on the back before filling this page "575564 A7 B7 Central Ministry of Economic Affairs 榡Printed by the Consumer Bureau of the Prospective Bureau. 5. Description of the Invention (133) Implementation Example 227) 2-({[4- (3,5-dimethylphenyl) piperazine] carbonyl group 2_methoxy-4,5 -Dimethylaniline) acetate Ethyl 2-({[4- (3,5-dimethylphenyl) british] mine-based methoxy-4,5-dimethylaniline) acetate The reaction was carried out in the same manner as in Example 226 above to obtain the above compound. Yield: 78% Melting point 170 ~ 171 ° C JH NMR (500MHz, CDC13) (5: 2.13 (3H, s), 2. 24 (9H, s), 2.91 (4H, t), 3.35 (4H, t), 3.83 (3H, s), 4.18 (2H, s), 6.45 (3H, m), 6.70 (2H, s), 6.80 (1H, s) Example 228) l-[(2-hydroxy-4 , 5-dimethylphenyl) aminocarbonyl] _ 4- (3,5-dimethylaniline) piperazine a) 4,5-dimethyl-2-nitrobenzene 3,4-dimethyl Benzene (12.1§, 0.1 mole), trifluoroacetic acid (250 ml) was added, and sodium nitrite (124 g, 0.018 mole) was slowly added in a water tank 'and stirred at room temperature for 14 hours. The trifluoroacetic acid was removed by concentration under reduced pressure, and then water (150 mi) was added, followed by extraction with ether, followed by separation and purification by column chromatography to obtain the above compound. Yield: 80% iH NMR (500MHz, CDC13) (5: 2.17 (6H, s), 6.74 (lH, s), 7.15 (5H, m), 7.31 (lH, s) b) 4,5 -— ， -2-4,5-dimethyl-2-nitrophenyl (ll_7g, 0.07 mole) via amine benzene, add -138- (Please read the notes on the back J # first, then fill in -Install-: Write this page)

, 1T

Jt This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 575564 A7 ___________ B7 __ 5. Description of the invention (134) Tetrahydrofuran (100ml) and ethanol ( 40 ml), and palladium / activated carbon (0.57 g) was slowly added, and a hydrogenation reaction was performed for 5 hours. After completion of the reaction by the same method, separation and purification by column chromatography can obtain the above compounds. Yield: 77% 4 NMR (500MHz, CDCl3M: 2.11 (6H, s), 6.56 (2H, s) c) Phenyl N- (4,5-dimethyl_2-phenylphenyl) formate in Dichloromethane (100 ml) was added to 4,5-difluorenyl-2-methoxyaniline (6.80§, 5 mol), and phenylchloroformate (8.0) was slowly added while stirring. g, 0.05 mol), after stirring for 2 hours, water (150 ml) was added, and extracted with dichloromethane, and separated and purified by column chromatography to obtain the above compound. Yield: 92% NMR (500MHz5CDC13) 5: 2. 17 (6H, s), 6. 74 (1H, s), 7.15 (5H, m), 7.31 (1H, S) d) Phenyl N- [2 -(t-butyldiethylsilyloxy) -4,5-difluorenylphenyl] phosphonate in phenyl N- (4,5-dimethyl-2-hydroxyphenyl) phosphonic acid Diethyl methane (100 ml) was added to the ester (7.72 g, 0.03 mol) and flavor saliva (2.2 g, 33 mmol). Slowly add t-butyldimethylsilyl chloride (5 〇g, 33 millimoles), after stirring for 2 hours, water (150 ml) was added, and extracted with dichloromethane, dried and concentrated under reduced pressure, and performed by official column chromatography After separation and purification, the above compounds can be obtained. ○ -139- i Paper size is applicable to China's CNS) A4 specifications I --------------, order ------ 0 (please Read the notes on the back before filling this page) 575564 Printed A7 B7 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (135) ~ " Yield: 83% 'H NMR (500MHz5CDC13) (5: 0. 27 (6H, s), 0.98 (9H, s), 2.17 (6H, s), 7.12 (5H, m), 7. 30 (2H, s) e) 1-[(2_ Hydroxy_4,5-difluorenylphenyl) amine Carbonyl] _4_ (3,5_dimethoxyphenyl) piperazine Phenyl N- [2- (t-butyldimethylphosphosilyloxy) _4,5_difluorenylphenyl] formate (0.17g, 0.5 mmol) and ^ (3, ^ dimethoxybenzene) piperazine (0.13 g, 0.6 mmol), dissolved in tetrahydropyrane (1000 ml), and added DBU (0.09 g, 0.6 mmol) and stirred for 2 hours. After concentrating the reaction product and separating and purifying it by column chromatography, the above compound can be obtained. Yield: 87% H NMR (500MHz? CDC13) (5: 2.14 (3H, s), 2.18 (3H, s), 3.26 (4H, t), 3.67 (4H, t), 3. 79 (6H, s ), 6.07 (3H, m), 6.40 (3H, m), 6.67 (lH, s), 6.82 (1H, s), 8.87 (lH, s) Through Target Example 229) ^ [(2-hydroxy-4, 5-Difluorenylphenyl) aminocarbonyl]-4- (3,5-dimethylphenyl) piperazine Phenyl N- [2-hydroxy-4,5-dimethylphenyl) formate With ^ (3,5 " -methylbenzene) piperidine, the same method as described in Example 228 was used for the reaction to obtain the above compound. Yield · 84%

Melting point: 160 ~ 162 ° C -140- This paper is suitable for Standards ® Standard (CNS) A4 specification (binding (please read the precautions on the back before filling this page) 575564 A7 .....----- ---- D / V. Description of the invention (136) Printed by H ™ (500MHz) CDCl3) 5: 2.13 (3Η) 5), 2. 17 (3Η, s), 2.31 ( 6H, s), 3.26 (4H, t), 3.75 (4H, t), 6.73 (3H, m), 6.81 (1H, s), 8.86 (1H, s) (Example 230) 1 _ ((2 -Hydroxy · 4,5-dimethylphenyl) aminocarbonyl]-(4-, 3,6-di-I-phenyl) pyrazine Phenyl N_ [2-hydroxy_4,5_difluorenylbenzene The above-mentioned compound can be obtained by the same method as in Example 228 above for the reaction of the phosphonium ester with di (3,6-difluorobenzene) piperazine. Yield: 80% Melting point: 152 ~ 154 ° CH NMR (500MHz, CDC13) ά: 2.17 (3H, S), 2.20 (3H, s), 3.30 (4H, t), 3.70 (4H, t), 6.40 ( 3H, m), 6.70 (lH, s), 6.82 (1H, s), 6.98 (1H, s) Example 231) 1 _ [(2-hydroxy-4,5-dimethylphenyl) aminocarbonyl] _ 4- (3,5-dichlorophenyl) piperazine combines phenyl N- [2-hydroxy-4,5-difluorenylphenyl) phosphonate with "(3,5-dichlorobenzene ) Piperazine, which was reacted in the same manner as in Example 228 above to obtain the above compound. Yield: 77% Melting point: oily! H NMR (500 MHz, CDC13) 5: 2.15 (3H, s), 2. 20 (3H, s), 3.32 (4H, t), 3.69 (4 H, t), 6.29 (3H, m), 6.69 (1H, S), 6-81 (1H, s), 8.65 (1H, s) -141-This paper size is applicable to Chinese National Standard (CNS) a4 specification (210X297mm) I -------^^ installed-C Please read and read the notes on the back first (Buy this) Order 4 575564 A7 B7 V. Description of the invention (137) The following is a test of the anti-cancer pharmacological activity of the compound of the present invention prepared as described above. The anti-cancer activity of the compound of the present invention is in accordance with the in vitro method using 5 kinds Human tumor cell lines and two leukemia tumor cell lines The results are shown in the following table. The so-called in vitro method is performed in the following manner. Experimental Example 1) ★ In vitro anticancer effect on human tumor cell lines 1. Tumor cell line: A549 (human non -small lung cell) SKOV-3 (Human ovary) HCT-15 (Human rectum) XF-498 (Human CNS) SKMEL-2 (Human melanocytes) 2. Test method a. Use A549 containing human tumor cell line (Human non-small lung cell), SKOV-3 (human ovary), HCT-15 (human rectum), XF_498 (human CNS), SKMEL-2 (human melanocytes) and other 10% FBS in RPMI 1640 medium, at 37 Cultivate with C02 and an incubator at ° C. The breeding system is performed once or twice a week. When cells are detached from the attachment surface, a solution dissolved in 0.5% trypsin and 3 mM CDTA PBS㈠ is used. B_ 于 96 5 X 103 ~ 2X 104 cells were added to each well of a well plate (Nunc), and cultured at 37 ° C for 24 hours in a 5% CO 2 incubator. -142- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling _: write this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 575564 Α7 Β7 Five Explanation of the invention (138) c. Dissolve various reagents in a small amount of DMSO, adjust to the appropriate concentration for the test, and dilute with the experimental medium to make the final DMSO concentration below 0.5%. d. After absorbing and removing the culture medium in each well of 4 亍 2 for 4 hours in item b. above, add the medicines prepared in item c. 2 and 1 respectively, and then proceed. 48 hours of culture. At the time of drug addition, Tz (Time zero) plates were collected. e. Tz plates and plates at the end of each culture medium were fixed by SRB analysis in accordance with TCA, cells were stained with 0.4% solution, and OD values were measured at 520 nm. 3. Result calculation a. Collect the time when the drug is added and start culturing, and obtain the value of the SBR protein mass as Time Zero (Tz). b. The OD value of the wells with only no cells is called the control value (C). c. The OD value of the wells with drug treatment is called the drug treatment test value (T). d. From Tz. C and T, the effect of the drug can be judged by growth stimulation, net growth inhibition, and net killing. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) e. When T ^ Τζ, the cell response formula is lOOX (T-Tz) / (C-Tz), When T < Tz, it is 100X (T-Tz) / Tz. The results are shown in the following table. ★ References -143-This paper size applies to China National Standard (CNS) Α4 size (210X 297 mm) 575564

and M * R. β〇yd .;

A7 B7 V. Description of the invention (139) 1) P. Skehan, R. Strong / ^ cudiero, A. Monks, J. B. ficaiahan, H. Vistica, J. Warren, H. Bokesch, S. Renney, and MRBoyd ; Froc.AK,

Assoc. Cancer Res., 30, 612 (1989). 2) LV Rubinstein, R, H. Shoemaker, KD ^ Faull, RMSiroon, S. Tosini, P. Skehan, D. Scudiero, A. Ko! J. Natl Cancer Inst., 82, 1113 (1990). 3) P. Skehan, R. Strong, D. Scud iero, A. Monks, J \ B. Mcmahan, DTVistica, J. Warreπ, H. Bokesch, S. .Kenney and SR Boyd.: J.Natl. Cancer Inst., 8! Shown on human solid cancer. From all the compounds, in human solid cancer, it is observed that it has an anticancer effect more than equal to that of adriamycin. --------------- IT ------ Φ (Please read the notes on the back before filling out this page} Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

575564 V. Description of the invention (140)

AB Ministry of Economic Affairs ordered the printing of EDr by the Consumers' Cooperatives of the Jiaojiao Bureau. O Second / Knowledge / M Example No. A 549 SK-OV-3 SK-MEL-2 XF-498 HCT 15 4 0.007 0.022 0.007 0.94 0.093 5 0.71 0.96 0.60 > 10.0 0.96 9 0.15 0.07 0.21, 0.11 0.11 11 0.91 0.56. 0.62 0.73 0.71] 4 0.022 0Ό2-0.001 0.16 0Ό07 15 0.002- 0.05 0.052 0.035 0.038 16 0.008 0.04 0.038 0.005 0.061 17 0.018 0.01 0.021 0.077 0.008 22 0.0009 0.006 0.027 , 0.0053 0.01 23 0.09 0.04 0.09 0.092 0.05 24 0.03 0.006 0.01 0.234 0.01 27 0.02 0.11 0.01 0.046 0.165 is 0.06 0.07 0.001 0.41 0.05 46 0.21 0.12 0.08 0.14 0.16 47 0.92 0.62 0.47 0.64 0.81 53 0.47 0.47 0.64 0.67 0.71 56 0.017 0.0027 0.01 0.013 0.045 57 0.27 0.15 0.18 0.22 0.25 63 0.04 0.1 0.11 0.03 0.07 64 0.42 0.56 0.52 0.23 0.37 73 0.01 0.0054 1 0.02 0.013 0.012 74 0.016 0.0138 0.02 0.026 0.021 75 0.19 0.09 0Ό9 0.13 0.12 Shunbai 0.8184 0.7134 0.7147 0771 3.0381 Asian Guard 0.0168 0.0176 0.0108 0.0250 1.6689 (Please read the notes on the back before filling this page) -145- Paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 575564 A7 B7 V. Description of the invention (14ι) Solid square knee 丨 A 549 y SK-uV-3 SK-MEL-2 XF 438 HCT 15 81 0.0032 0.0007 0.0107 0.0097 0.0054 82 0.0676 0.0249 0.0754 0.0479 0.0346 8Γ] 0.048 0.117 0.039 0.104 0.10 88 0.014 0.043 0.02 0.009 0.011 99 0.43 0.41- 0.40 0.52 0.36 100 4.54 3.02 1 3.47 0.66 4.21 103 0.52 0.46 0.49 0.36 0.33 109 0.47 0.91 0.86 0.53 0.49 110 0.52 1.06 0.97 0.81 0.69 112 0.5G 6.43 0.222.07 0.61 128 0.40 0.37 0.42 0.44 0.51 Short article 0.8184 0.7134 0.7147 0.771 3.0381 Asian addiction dummy 0.0168 0.0176 0.0108 0.0250 1.6689 1 (In this page) The policy of employee consumer cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 146- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 575564 A7 B7 V. Description of the invention Printing implementation-^ Ά549 SK-OV-3 SK-MEL-2 1 XF-498 HCT15 132 0.03 0.01 0.03 0.04 0.04 133 0.57 0.94 0.53 0.61 0.57 134 0.0009 0.0091 0.0086 0.002 0.0065 135 0.056 0.092 0.102 0.06 0.06G 140 0.33 0.470.56 0.54 0.59 0.49 142 0.015 0.011; 0.021 0.026 0Ό17 143 0.0004 0.0095 0.0121 0.0009 0.0108 147 0.031 0.092 0.024 0.066 0.48 0.18 148 0.01 0.07 0.03 0.05 0.05 151 0.004 0.008 0.007 0.007 0.037 152 0.18 0.37 0.2 0.26 0.44 156 0.06 0.10 0.09 0.06 0.07 157 0.000002 0.000002 0.000043 0.000245 0.000245 0.000211 159 0.05 0.10 0.07 0.21 0.17 MMMiQ 0.8184 0.7134 0.7147 0.0771 3.0771 Asia Pacific Mute 0.0168 0.0176 0.0108 0.0250 1.6689 147 (Please first Read the notes on the reverse side and fill in this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 575564 A7 B7 V. Description of the invention (143) Implementation number SK-OV-3 SK-MEL -2 XF 498 HCT 15 171 0.000645 0.00372 0.003233 0.000572 0.001809 172 0Ό047 0.0097 0.0233 0.0086 0.0180 174 0.54 0.56 0.27 0.49 0.33 177 0.52 0.39 0.17 0.12 0.09 179 1.04 0.98 · 0.72 0.74 0.63 lcS3 0.42 2.27, 1.17 1.41 2.09 184 0.28 0.34 0.14 0.20 190 0.004 0.008 0.002 0.443 0.017 191 0.09 0.28 0.06 0.47 0.40 198 0.021 0Ό68 0.0080.072 0.56 200 0.50 0.53 0.26 1.01 0.44 201 0.014 0.053 0.049. 0.026 0.071 202 0.57 1.26 0.48 ^ 2.09 0.64 206 0.47 0.54 0.52 0.70 0.38 cis white 0.8184 0.7134 07147 0.7771 3.0381 Asian Guard 丨 "« 0.0168 0.0176 0.0108 0.0250 1.6689 (Please read the precautions on the back before filling out this page) 1 · * Fill in and fill out-Order it Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 575564 A7 B7_ _______ 5. Description of the Invention (144) " Experimental Example 2) ★ For animal leukemia cells Anti-cancer effect in vitro 1 · Experimental materials Tumor cell line: L1210 (mouse leukemia cells) P3 88 (lymph node neoplastic cells in mice) 2 · Experimental method (dye exclusion analysis) 1) L1210 and P388 cells cultured in RPMI 1640 medium were adjusted to a concentration of 1 × 10 5 cells / ml. 2) Add each concentration of drug diluted in logarithmic series, and measure the number of viable cells after incubation at 5% C02 for 48 hours at 37 ° C. This number of viable cells was tested by dye exclusion analysis using trypan blue. 3) The number of cells obtained from the measurement is compared with the control value, and the compound concentration (IC50) representing 50% cell growth inhibition is calculated. The results are shown in the following table. ㈣x 献 φ 1) P. Skehan R. str ong ^^^ Scud i er o A. Honks, J „B. Mcmahan, DTVistica, J.warren, H. Bokesch, S. Kenney and MRBoyd .; Proc Am. Assoc. Cancer Res., 30, 612 (1989). 2) LVRubinsteiii, R. H. Shoemaker, K. D. Pau] J, R # H. Sirion, S. Tosini, P. Skehan r D .Scudierot A.roonks, J'Natl. Cancer Inst., 82, 1113 (1990) 3) P. Skehan, R. Strong, D. Scudiero, JBMcMahan, DTVistica, J. Warren, H. Bokesch t S. Reηney, and M, R Λ Boyd; -149- ”This paper size is applicable to China National Standard (CNS) A4 (2l0x297 mm) --------- Installation ------ Order- ----- (Please read the precautions on the back before filling this page) 575564 A7 B7 Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (145) #' 1107 (1990) JN at]. Cancer [ ns t.3. Results The test results of the compounds of the present invention on antitumor effects of LI210, P3 88 mouse tumor cells show that they have an anticancer effect that is equal to or more than that of the control drug mitomycin C. -150- This paper size applies to Chinese National Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling in,: Write this page) 575564 A7

7 B V. Description of the invention 0.5 49 1,5-56 0.2 0.2 57 1.8 1.2 60 1.1-(53 0.5 0.3 64 1.9 1.4 69-0.5 71-0.07 72-0.9 73 0.2 0.04 74 0.5 0.4 7 (3-0.4 77-0.5 c L6 1.1 -151 -This paper size is applicable to China National Standard (CNS) A4 (210X297mm) I ------- — «t-shirt ------ IT ------ 0, Wei * (please first Read the notes on the back and fill out this page) 575564 A7 B7 V. Invention Description (147)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the U. 154-0.1 157 1.7 1.0 158 0.5 0.2 c 1.6, 1.1 Implementation Preparation L1210 P388 170 0.4 0.4 173 0.5 0.2 178 1.8 1.6 181 0.5 0.4 182 .1.2 0.5 186 1.6-187 1.0 0.6 190 0.3 0.3 195 1.7 1.0 196 0.5 0.2 $ / ¾¾¾¾¾ 1.6 1.1 ---------- Clothing-(Please read the precautions on the back before filling in this page)

、 1T -152- This paper size is applicable to Chinese National Standard (CNS) Α4 specification (210X 297mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 575564 A7 --- --- _B7 V. Description of the invention (148)- Experimental example 3) ★ In vivo anticancer effect on mouse P388 cells I Experimental material BDFI mice 2 · Experimental method υ 8 6-week-old BDFI mice were used as a group. P388 cells were transplanted in each mouse, and 1 × 106 cells / ml were transplanted into the lumen cavity. 2) The test drug was suspended in 0.5% Tween80, and the dye was injected into the abdominal cavity every 9 hours. 3) The mice were observed daily, the survival rate was measured, and the average survival day increase ratio (T / C%) relative to the administration group of the control group was calculated from the intermediate survival time of each experimental group to determine the anticancer effect. The results are shown in the following table. ★ References A. Goldin et al: Europ. J. Cancer, 17, 129 (1981) 3. Results In vivo experiments using P388 mouse tumor cells, No. 8 '15' 16, 20, 56, 73, 74 and other inventive substances Validity (T / C > 125%) 〇-153- This paper size applies the Chinese National Standard (CNS) A4 specifications (2ΐ〇χ: 297) (Please read the precautions on the back before filling this page)

575564 A7 B7 V. Description of the invention (149) Printed implementation code of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-Dose (mg / kg) ^ T / C (%) mmmm 8 200 140.9 100 every 1,5,9 days 104.5 15 25 150 every 9 days' 10 110 1 () 50 165 every 9 days 25 110 100 150 22 50 140 every 9 days 25 110 200 227.3 5 (5 100 140.9 every 1, 5, 9 50 118.2 50 165.0 5 (3 25 '145.0 every other day 10 140.0 50 180.0 73 25 150.0 every other day 10 140.0. 50 250.0 74 25 150.0 every other day 10 140.0 (Please read the notes on the back first (Fill in this page again) -154- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 575564 A7 B7 V. Description of the invention (150) __ Implementation of flat number Dose (mg / kg) ^ T / C (%) mmmm 1 200 218.2 -—— ~-— -1 81 100 145.5 every 1,5,9 days, 50 127.3 50 210.0 81 25 140.0 every other day 10 140.0 82 100 127.3 every 1,5,9 days . 100.0 100 150.0 50 110.0 Every other day 9 25 110.0 (Please read the precautions on the back before filling this page) Shifangna_ Do se (mg / kg) T / C (%) 100 150.0 i 135 50 110.0 Every other day every day 25 100.0 200 125.0 144 100 110.0 Every other day every day 50 110.0 155- This paper size applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, the Dose Code (Dose (mg / kg) T / C (%)) "100 140.0 171 50 100.0-every 1, 4, 8 days, 25 100.0 200 190.9 172 100 127.3 I, 4, 8 50 * 118.2 575564 V. Description of the invention (151) Continuing test example 4) ★ Acute toxicity test 1 · Experiment method: Purchase the 6-week-old | ^ a # Before the experiment, the two males were allowed to ingest freely under the conditions of 30, 2, and 3; :: =, humidity 6 ° ± 5% conditions ^ ^ The dried mash and water were taken. These experimenters were used again, and, in order not to administer drugs into the abdominal cavity, and the appearance status and death of κ during the 14th day, the dead animals were dissected and the condition was observed with the naked eye status. LD5 is calculated according to the Richfiled-Wilcon method. value. The results are shown in the following table. In the acute toxicity, the compounds of the present invention are superior to cisplatin or adriamycin in acute toxicity. With regard to dosage limits, toxicity, etc., it can be confirmed that the compounds have exceeded the conventional technology, which is sufficient to overcome the habit. Know the technical disadvantages. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -156 This paper size applies to the Chinese National Standard (CNS) A4 (21 × 297 mm) 575564 A7 B7 V. Description of the invention (152)

Table 4 Example No. LD50 (nig / kg) (i'p), ... 8 707 12 165 13 284.8 15 190 1G 282.8 22 > 2,000 28 > 2,000 56 4 410 57 455 73 250 74 361.4 Shun white 9.7 (Please read the precautions on the back before filling this page)

1T d Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs • 157- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 575564 A7 B7 V. Description of the invention (153 painted embodiment number LD5. (ingykg) (ip) 81 Ι, βΟΟ '82 700 Cis white 9.7 Example number, LD50 (mg / kg) 132 573.1 134 723.7 144. 348.9 146 309.6 148 > 2,000 149' 417.6, Cis white 9.7 Ministry of Economic Affairs t Central Standards Staff Consumers Cooperative Society Printing Example Number LD50 (nig / kg) 170 573 172 723 182 348 184 309 186 > 2,000 187 • 417.6 Shunbai 9.7 158 (Please read the precautions on the back before filling this page )

This paper size applies to China National Standard (CNS) A4 specification (2 丨 〇 '乂 297mm)

Claims (1)

575564 * U 4 Α8 Β8 J τ Ming Tu's application for amendments to the scope of patent application No. 861 12235 of this application Patent application dated July 4, 1992! A new hydrazone derivative and its pharmaceutically acceptable acid addition salt refer to the following general structural formula (1) As shown, (Please read the cautions on the back and fill in this page first) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ~ C6 alkyl, substituted or unsubstituted C2 ~ C6 unsaturated alkyl, phenyl, substituted or unsubstituted ( ^ ~ (: 4 alkoxy, ethanoyl, or &amp; and r2 simultaneously form a hydrocarbon 3 ~ 4 unsaturated or saturated ring; and r3, r4, r5, R6, and I represent a hydrogen atom, a halogen atom, and a hydroxyl group, respectively , Ci ~ C4 lower alkynyl, (^ ~ lower thioalkyl, substituted or unsubstituted Ci ~ c4 lower alkoxy, C〗 ~ C4 lower thioalkoxy, (^ ~ 0: 4 cycloalkane Oxygen, substituted or unsubstituted phenyl, or r3 and r4 combine with each other to form benzo or naphthyl; X means oxygen atom and sulfur atom; Y means -NRs · group (here r8 is η Or Ci ~ C4 alkyl), and Y is bound to the 3-position or 4-position of the aromatic ring to which γ is bonded in the compound of structural formula (1); Z refers to a hydrogen atom, a hydroxyl atom, and c 1 ~ C4 lower alkoxy group, ci ~ C 4 lower alkylamino group, σ base group, hydrazine group, σ sephenyl group; This paper size applies to China National Standard (CNS) A4 specification (210 X 29 ? ΠΤ-575564 A8 B8 C8 D8, the scope of patent application = refers to a nitrogen atom or a nitrogen atom (but when A is a gas atom, R1A is not <^ ~ (: 6 alkyl). 2 · a kind of new piperazine The second method for producing a derivative or an unacceptable acid addition salt thereof is a method for producing a compound represented by the general structural formula ⑴. In the presence of an organic solvent, it is reacted with a base-supplying reagent to produce a general compound represented by the general structural formula (b) and the compound shown in the general structural formula (b) Method for reacting with general structural formula _ compound to obtain compound represented by general structural formula (1), by R2 (please read the note on the back? Fill in the matter and write the tribute) (b) Order: In the formula, Ri, R2, R3, R4, R5, R6, R7, a, x, y, z are as defined above, and Liei means the same leaving group as the hydrogen atom. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -2. This paper size applies to China National Standard (CNS) A4 (2) 0 X 297