TW200413343A - Benzofuran and benzothiophene derivatives useful in the treatment of hyper-proliferative disorders - Google Patents

Abstract

This invention relates to novel benzofuran and benzothiophene derivatives of the general formula, and their use for the treatment of hyper-proliferative disorders.

Description

200413343 A7 B7 V. Description of the Invention (1) Technical Field The present invention relates to a novel benzofuran and benzothiophene compound, a pharmaceutical composition containing these compounds and their compounds and / compositions for the treatment of hyperproliferative diseases. use. 5 Summary of the invention Compounds of the invention A specific embodiment of the invention relates to compounds of formula (I)

R2 10 where 15 X is selected from: 0 and S; R1 is selected from: H, (Ci-C6) alkyl, C (0) (Ci-C6) alkyl, and phenylfluorenyl; R2 is selected from : The phenyl and naphthyl groups are printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, and each can be replaced by 1, 2 or 3 substituents independently selected from the following: OH, CN, No2, (Ci-C6 ) Alkyl, (CrC6) alkoxy, halo, halo (Ci-C6) alkyl, halo (OCs) alkoxy, C (0) RA, C (0) NRBRB, NBRRB, Li [( CrC6) alkyl] 〇-{(0) 21 ^, leg [(CrC6) alkyl] (mC (0) Ra, and NH [(CrC6)

This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 92381A 200413343 A7 B7 V. Description of the invention (2) Alkyl] (mC (0) 0Rb, heterocyclic ring, selected from: 6 member miscellaneous Ring, 5-membered heterocyclic ring and fused bicyclic heterocyclic ring, each heterocyclic ring may be substituted with 1, 2 or 3 substituents independently selected from the following: 5 OH, CN, No2, (CrCO alkyl, (CrCe) alkoxy, halo, halo (Ci-C6) alkyl, i- (Ci-Ce) alkoxy, C (0) RA, C (0) NRBRB, NBRRB, NH [(CrC6) Alkyl] (MS (0) 2RB, NHKCrCe) alkyl] (mC (0) Ra, and NHKCrC6) Alkyl] (mC (0) 0Rb, 10 RA are independently H, (Ci-α ) Alkyl, (Ci-c6) alkoxy, NRBRB, or (C-C6) alkyl, this alkyl can be optionally passed through OH, C (0) RB, halo, (CrG) alkoxy, and NRbRb Substitute; RB is independently fluorene, (C3-C6) cycloalkyl, and (CrCe) alkyl in each case. The alkynyl group may be subjected to 0H, = 0, halo, (Ci-Cs) oxygen 15 if necessary. Base, NH (CrG) alkyl, N [(CrC3) alkyl] 2 and NC (0) (CrG) alkyl radicals, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, where rb is used as its When N atom is attached, in each case it is (G-C4) alkyl, then 2 (Ci-C4) alkyl and its attached N atom can form a saturated ring together, 20 and 1 ^ and RB and The attached N atoms can jointly form a morpholinyl ring or a hexahydro ° specific σ well-based ring. The available N atoms can be optionally substituted with (G-C6) alkyl groups, and the alkyl groups can be optionally substituted with 0, = 0, ΝΗ2, (G-C6) alkoxy, NH (Ci-C3) alkyl or Ν [(0G) alkyl] 2 substitution, -4- This paper size applies Chinese National Standard (CNS) A4 specifications ( 210x297 mm) 200413343 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of Invention (3), but the restriction is that when RB is attached to S (0) or S (0) 2, it cannot be Η R3 is selected from: Η, OH, CN, (CrCs) alkyl, (CrG) alkoxy, halo, halo (OC3) alkyl, and halo (GG) alkoxy; 5 R4 is selected From: piperonyl, Y, where Y is a heterocyclic ring, optionally substituted with 1, 2, or 3 substituents independently selected from the following: 10 = 0, N-oxide, hydrazone, CN, No2, Halo, halo (CrC6) alkyl, 0H, halo (Ci-Cs) alkoxy, C ( 0) 0RB, C (NH) NRbRb, NBRRB, S (0) 〇-2RB, s (o) 2nrbrb, (c ^ a) alkoxy group, which may optionally be selected from 1 or 2 selected from the following Substituent substitution: OH, NBRRB, and (Cl-15 C3) alkoxy, NReRe, where

Rc is selected from: RB, (: (0) [^ and S (0) 2RB, C (0) RD, where RD is selected from: RA, (C3-C6) cycloalkyl, Z and 20 NKCrG) alkane Group] Z, where Z is a heterocyclic ring in each case, which is independently substituted with the following substituents as necessary: CN, = 0, OH, N-oxide, No2, halo, (OCd alkoxy, Halo

This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 200413343 A7 B7 5. Description of the invention (4) c3) alkoxy, i-based (〇C3) alkyl, S (0) 2RB, S (0) 2NRBRB, nrbrb, c (o) ra, and (〇α) alkyl, which may optionally be substituted with OH, 5 C (0) RB, (OC3) alkoxy and NBRRB; NRBR £, Wherein RE is selected from the group consisting of: C (0) RA, C (0) RB, S (0) 2RB, 3 (0), and C (0) [(CrC6) alkyl] Z, among which 10 Z may be selected as required As described above, the substituted ((Ci-Cs) alkyl group may be substituted with the following substituents as required: CN, 0H, = 0, halo, (CrC6) alkoxy, C (0) RA, NRY, NRf , NRBRE, 15 C (NH) NRBRB, S (0) 〇-2RB, S (〇MRBRB, C (0) RBC (0) 0RB, Z, C (0) Z and C (0) N [(Ci- C3) Alkyl] z, where z in each case is independently replaced as needed as described above. The phenyl and naphthyl groups printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs can be independently selected by 1, 2, or 3, as required. Substitute from the following 20 columns: OH, CN, No2, halo, halo (Ci-C6) halo, halo (Ci ~ C6) alkoxy, C (0) 0RB, C (NH ) NRBRB, NRV, S (〇V2RB, S (0) 2NRBRB, Z, C (0) Z, where z in each case can be replaced as needed as described above, -6- sheet scale applies the National Standard (CNS) A4 Specifications (210x297 mm) " " '200413343

(Cl ~ C6) alkoxy group ′ This alkoxy group may be optionally substituted with 1 or 2 substituents selected from the group consisting of: OH, NBRRB, and (Ci-C3) alkoxy group, ′ where

Rc is selected from: RB, C (〇) RB and S (0) 2Rb, CC〇) RD, where RD is selected from: RA, (c3-α) cycloalkyl and NKG-c3) alkyl] Z, Where Z may be replaced as required as above: 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 'where R £ is selected from: C (0) RA, C (0) RB, S (0) 2RB, S⑻2NRY and C (0) [(C "C6) alkyl] z, where z may optionally be substituted as described above, (Cl-Cs) alkyl, which may optionally be substituted with the following substituents: CN, 0H, = 〇, Halo, (gG) alkoxy, C (0) RA, NBRRB, NRBRE, (: (ΝΗ) ΜΥ, S (0) 〇-2, S (0) 2NRBRB, c (o) rbc (o) orb , Z, c (o) z

And CCOHKG-C3) alkyl] z, where Z in each case is independently substituted as necessary as described above; R and R6 are independently selected from ·, 0H, CN, (Ci-C3 Deki, (Ci- (3) Burned oxy, halo, halo (CrC3) alkyl, and halo (OC3) alkoxy; or pharmaceutically acceptable salts or esters thereof. -7- This paper applies Chinese national standards (CN ^ A # specifications (21 × 297 mm) 200413343 A7 ______ B7 V. Description of the invention (6) The above terms are defined throughout the text t as follows: Technically substituted as necessary "means that the part of the group that is modified may not have a substituent to May have the highest number of substituents specified. When there are 2 or more substituents on any part of the group, the definition of each substituent is independent of the definition of any other 5 substituents, so they may be the same or different The term 'l (Cl-C6) alkyl, which may be substituted if necessary "means in the alkyl as defined below, where each carbon atom, if appropriate, is bonded to 0 or 2 or 3 hydrogen atoms and any hydrogen atom Up to all hydrogen atoms may be replaced by the listed substituents, but the restrictions are The combination of the listed substituents should yield a chemically stable compound. The term (Ci-c6) alkenyl n '" (Ci-c4) alkenyl "and " (CrC3) alkenyl" each have about 1 Straight-chain or branched saturated stone anti-groups of about 3, 4 or 6 carbon atoms. These groups include (but are not limited to): methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, second butyl, tertiary butyl, etc. 15 etc. The term printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (Cl-C6) and quotations (Ci-G) "Group" means an oxygen atom attached to a straight or branched saturated carbon group having from about 1 to about 6 or 3 carbon atoms, respectively. This oxygen atom is the point of attachment of the alkoxy substituent. These groups Including (but not limited to): fluorenyloxy, ethoxy, n-propoxy, 20-isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy, etc. The term "C3-acycloalkyl" refers to a saturated monocyclic alkyl group of 3 to about 8 carbon atoms, including groups such as cyclopropyl, cyclopentyl, cyclohexyl, and the like. Terminology "Halo" means selected from: Cl, Atoms of Br, F and I, of which the Chinese national standard (CNS) A4 specification (210x297 mm) is applied at the paper size 13343

(7) 5 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 n, Br # F is better, Cl and F are the best. There are about ^ self radicals (Cl-fluorenyl u and "i group (CrC3) alkyl" refers to a linear or branched saturated carbon group of M, 1 to about 6 or 3 carbon atoms, respectively, via at least one p 1 _4_, r or F atom substitution, up to completely Cl or F atom take my choice of ^, 蚪, each carbon atom is replaced by up to 3 halo groups), each attack \ or F atom in each case and any other C1 or F respectively includes groups such as dagger, but is not limited to: trifluoromethyl, trichloromethyl, pentamethyl, fluorobutyl, 6-chlorohexyl, and the like. Self-base (GH: 6) ^ m group (Gi_⑸remain group), respectively, or a straight or branched saturated carbon group of 3 carbon atoms, is completely substituted with C1 or F less than one G1 or F atom, up to ^ q, J Atomic substitution (that is, if appropriate, each carbon atom and at most other C1 or F atoms selected each time are independent of Ren or F in each case. These groups include (but are not limited to): trioxyl i and so on! 'chloromethoxy, pentaethoxy, fluorobutoxy, 6-chlorohex The term "6 heterocyclic ring" refers to an aromatic ring composed of 6 atoms, which can be a nitrogen atom, and the rest are Carbon, in which the heterocycle is connected via any stone as a molecule, and may be substituted with any available substituents such as λ and Γ! These groups include η ratio bit, _θ well, and Ergen All possible isomeric forms. The term "5-membered heterocyclic ring" refers to an aromatic ring composed of 5 atoms, 2 or 3 heteroatoms independently selected from 0, N, and S, and the remaining [山 atoms' but its _The condition is that the number of oxygen atoms in the heterocyclic ring should not exceed 2, -9-200413343 A7 B7 5. When the invention explains that there are 2 oxygen atoms, they must not be adjacent. An available carbon atom is attached to the core molecule and may be substituted with any of the enumerated substituents as necessary on any available atom or lice atom. These groups include pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, pyrene Oxazole, isoxazole, isothiazole, three wows, slogan two. All possible isomer types of sitting, stilbene, and tetrasial. 10 15 Order the printed term "condensation" of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. "Bicyclic heterocyclic ring" refers to a group having 9 atoms and 2 atoms divided into two rings, in which adjacent carbon atoms are used to join together, and the rest of the work, 2 or 3 atoms are separated and selected from: N, GW Atom. The heteroatom can be located at any available position on the part of the fused bicyclic ring system, but its limit = provided that the number of oxygen atoms in any fused bicyclic heterocyclic ring cannot exceed 2 and there are 2 on the right The oxygen atom must not be adjacent. At least one of the two fused rings must be aromatic. If the other ring is not fused with the aromatic ring, it can be = fragrant, partially saturated or saturated. Aromatic The ring is always attached to the core molecule via any available anti-atom. A bicyclic heterocyclic ring may optionally be substituted with any of the listed substituents on any available carbon atom. These groups include 5 ^ 5, 5-6, and 6 fused bicyclic rings, one of which is one of the above-mentioned hybrids The first J exhibition is benzene or another heterocyclic ring, including (but not limited to) ... Samantine, chromene, benzofuran, benzothiophene, oxoline, isoquinine, phthaloline, Cai bite, Ru Lin , Throat, ten flowers, called Bu sit, different ten flowers, ten flowers Lin, phoenix phoenix butterfly, different α bow and flower " sedine and squeak, taste spitting and spitting, second sale of naphthalene, stupid and啐 、, piperonyl, etc. ^ Υ is a heterocyclic ring "refers to a saturated, partial and or aromatic ring containing about 5 or 6 atoms, wherein 1, 2 or 3 atoms are independently selected from N, 〇 and S, the rest are carbon atoms, but the limiting condition is the oxygen in any heterocycle. -10- V. Description of the invention (9) A7 B7 10 15 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 Atoms must not exceed 2. _ Adjacent. When this heterocyclic ring is through any available gas atom, it must be attached to the core molecule if the heterocyclic ring is pyridyl, or it can be attached to any available nitrogen atom if necessary. When the heterocyclic ring is pyridyl, the ^ atom is substituted with the enumerated substituents. This heterocyclic ring includes furan: pyridine, rhizine, pyrene, pyridine, pyridine, pyridine, isodecyl, pyroline, pyrazoline, hexahydropyridine, J on any available nitrogen atom. Pyridine, imidazolidine, and imidazolium nitrogen dithiol = thiol = two, ..., hexa-i3L 丨 丨 7 4 south monothiol ', etc. Unsaturated == Contains: ^ N, 〇 and I My // // Atoms are separated from each other and must not be more than 2 adjacent. = When the ring is attached to the Ld: group via any available carbon atom, it is attached via any available nitrogen atom. The visibility is to be on any available carbon. It is expected to be substituted with the substituents described above, but when the heterocyclic ring is a fluorenyl group, it may be substituted on any available nitrogen atom. This heterocyclic ring includes squeaks. South " Bilo, Misal "Bi 嗤, different slogans, pyridine, roar, shoot" 啡 _ " Fuzan "Bilo bite " Miwa bite, sialoline, pyrazoline 'hexahydropyridine , Morpholine,% f thiagenol, cultivation 'three-cultivation, hexahydropyridine, dimorphazole, oxythiol, pyran, dithiol, etc. The term Π-oxide " refers to heterocyclic additional An unsubstituted sp2 N atom, the N atom may carry a covalently bonded oxygen atom, that is, -N (-> ⑴. Examples of such N-oxide substituted heterocycles include pyridyl N-oxide, Pyrimidine-11-This paper size applies to China Standard (CNS) A4 (210 x 297 mm) 4 Order 200413343 A7 _ B7 V. Description of the invention (10) " " ~~ Basic N-oxide N-oxide and pyrazolyl N-oxide. The term πpiperidinylπ refers to a fluorenyldioxybenzyl ring of the following structural formula, and its attachment point may be any available aromatic carbon atom. 5 Disclosed below Representative compounds of formula I. Compounds of formula I may contain one or more asymmetric centers, depending on the position and nature of the various different substituents required. Asymmetric broken atoms may be (R ) Or (S) configuration or (R, S) configuration. In some cases, it may also be caused by a bond around the specified 10 (for example, the center bond of two substituted aromatic rings connecting the specified compound). The rotation is restricted to produce asymmetry. The substituents on the ring can also be cis or trans, and the substituents on the double bond can be Z or e. All such configurations (including enantiomers) Or diastereomers) are included within the scope of the present invention. Preferred compounds are compounds of the present invention whose absolute configuration can produce a higher biological activity of 15. The isolated purified or part of the compounds of the present invention Purified isomers or racemic mixtures are also included within the scope of the present invention. The printing by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs and the printing of the present invention also includes the use of the pharmaceutically acceptable salts of the compounds of the present invention. " Salt " refers to an inorganic or organic acid or base salt of a compound of the present invention that is relatively non-toxic with a medically acceptable quality of 20 (see, for example, SM Berge et al., &Quot; Pharmaceutical Salts ", J. Pharm · Sci · 66: Bu 19, 1977). Representative compounds of the compounds of the present invention include conventional non-toxic salts formed from, for example, inorganic or organic owes or tests according to methods known in the relevant art, and -12-

200413343 A7 B7 V. Description of the invention (11) Quaternary ammonium salt. For example: these acid addition salts include acetate, adipic acid, alginate, ascorbate, aspartate, benzoate, benzoate, hydrogen sulfate, butyrate, citric acid Salt, camphor salt, camphor sulfonate, cinnamate, cyclopentane propionate, digluconate, dodecylsulfate 5 salt, ethanesulfonate, fumarate, glucoheptose Acid salt, glyceryl phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, argonate, 2-acetylacetate, itaconic acid, lactate , Maleate, mandelate, sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, paraben, pectate 'persulfate, 3- Phenyl 10 propionate, picrate, pivalate, propionate, succinate, tartarate, tartrate, thiocyanate, toluene sulfonate, and undecyl carbonate The term acid addition salt also includes the hydrates and solvents that can be formed by the compounds of the present invention. Examples of these types are, for example, hydrates, alkoxides, and the like. Alkaline salts printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as · 15 calcium salts and magnesium salts, and organic bases such as dicyclohexylamine and N- Ammonium salt of fluorenyl-D-glucosamine. In addition, test nitrogen-containing groups can be quaternized by the following formulations: low-carbon alkyl halides such as: fluorenyl, ethyl, propyl and butyl gaseous, bromide and iodide; dioxane sulfate Base esters such as: dimethyl vinegar, diethyl and dibutyl esters; and dipentyl sulfate, long chain compounds such as: decyl, 20 lauryl, myristyl and stearyl vapors, bromides And iodide; aralkyl iides such as: phenyl amidino and phenethyl bromide, and so on. The esters of suitable compounds of the present invention are pharmaceutically acceptable vinegars, such as: alkyl esters, including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, and the like . Other esters can also be used, for example: θphenyl-13-200413343 A7 B7 12 V. Description of the invention (Cl-co alkyl ester, but fluorene ester is preferred. Unless otherwise stated, the terms used herein " The compound π of the present invention, etc. includes chemically feasible pharmaceutically acceptable salts and / or esters and all stereoisomeric forms of the specified compounds. Method M of the compounds 10 15 Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs Preparation 20 In general, the compounds of the present invention can be prepared according to standard techniques known in the relevant art, similar known production methods, and / or production methods disclosed below, using commercially available standard raw materials, according to routine general chemical methods, or methods described herein. Preparation of synthetic starting materials. The specific method for preparing the compounds of the present invention depends on the specific compound required. These factors are whether the amine is substituted, the specific substituents selected may be located at different positions on the molecule, etc., respectively. Will affect the path followed. These factors are understood by those who are familiar with this technology. The general method for the preparation of benzofuran and benzothiophene derivatives is: (All are not limited to) The methods shown in the following reaction schemes 1 and 2. In the reaction scheme 1, the benzofuran or benzofuran product of which R1 is pyrene in formula (I) can be directly substituted by the appropriately substituted 2-cyano Phenol (formula (II), where X = 0) or 2-cyanothiophenol (formula (π), where x = s) and the appropriate formula (ΙΠ) 1 -aryl-2-haloethyl ketone (in ) Condensation. This reaction is usually suitable for testing, such as: carbonic acid planer, potassium carbonate, sodium carbonate or DBU, in a solvent such as · DMF or MeCN, at room temperature to 100 ° C, resulting in -14- This paper size applies the Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (13) Reaction Figure 1 Synthesis method of the starting material (II): R0

R

XH

10 Synthesis of starting material (III): 1. MeMgBr

NBS, NCS -or--Ph (Me) 3N + Βγ3 PyBOP heating 〇 Λ

Br. Or Cl (III) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 Synthesis from (II) and (III) (I) Synthesis: 20

(II) r2J ^ base / solvent 5 f Hn-R1 rvV A Br or CI, XR: 3 R3 (ΠΙ) (1), where R1 is hydrogen ... Or, when a phenol or thiophenol starting material cannot be obtained, it may be Adopt the reaction • 15- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200413343 A7

The method shown in FIG. 2, in which a benzo ° furan and benzothiophene intermediate of formula (IV) or (V) is first prepared in a similar manner, and then converted to an end product (IzP eling reaction) using Suzuki eQuPling reactions ). Therefore, halogenated benzofuran or benzobenzothiophene (IV) can be reacted with a dihydroxyborate of formula (VI) in the presence of a Pd catalyst and a base, or converted into a dihydroxyboron of formula (v) After the acid ester, the compound with the formula (VII) i-based compound is prepared under similar conditions. The starting material =, ⑽-η can usually be prepared from the fresh method known in the quotient technique and the method of the preparation example section below. Response to Consumer Co-operation and Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs

-16- 200413343 A7 B7 V. Explanation of the invention (15) In the formula (1) prepared according to the reaction diagram 1 or the reaction diagram 2! ^ Compounds that are H can be converted into other compounds of formula (where R is not Η in 0, as shown in the reaction diagram 3. For example: treatment with a base and an alkylating agent (such as methyl iodide or methyl sulfate) produces In the formula (0, R is a calcined compound. Similarly, treatment with a base and a brewing agent (such as ethyl chloride or benzyl chloride) can produce formula (!) In which ρ is ethyl or benzene Amidino compounds. Scheme 3

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. It is understood that sensitive or reactive substituents on intermediates or compounds of formula I may need to be protected and removed during the aforementioned manufacturing method. Protective groups can usually be added and removed according to methods known in the relevant art (see, for example: τ · 20 W. Greene and P.G. M. Wuts, Protective Groups in

Organic Synthesis; Wiley, New York, (1999)). The different compounds of the present invention can be easily prepared using the above-mentioned preparation method and the method described below, or other standard chemical preparation methods known in the relevant art, using appropriate starting materials or intermediate compounds that are readily available and / or described herein. -17- This paper size is in accordance with Chinese National Standards (CNs) A4 size x 297 1 Chu) 200413343 A7 ------------- B7 V. Description of the invention (16) Salts can usually be prepared in situ from the compound in a manner that is known to the relevant art during the final single release of the compound. For example, the so-called ^^ 'and the wind can be formed by the compound in its free base form or free 5 ^ appropriate organic or inorganic acid, or a suitable organic or inorganic base, and separate the formed salt. If it is a basic compound, for example, it can be treated with anhydrous HC1 in an appropriate solvent (such as THF), and the salt can be isolated. If it is an acidic compound, the preparation method of its salt is, for example, treating the free acid with anhydrous ammonia in a suitable solvent (such as ether), and then the ammonium salt can be isolated. These methods are general methods, and those who are familiar with the related skills. β Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs The compound of the present invention can be esterified by a variety of conventional methods, including the reaction of an appropriate acid, carboxylic acid, or fluorenyl chloride with the alcohol group of the compound of the present invention. Appropriate acid anhydrides can be reacted with alcohols in the presence of tests that can promote tritiation (eg, 1,8-bis [dimethylamino] naphthalene or N, N-dimethylaminopyridine). Alternatively, an appropriate carboxylic acid 15 may be used with an alcohol in a dehydrating agent (such as dicyclohexylcarbodiimide, 1- [3-dimethylaminepropyl] -3-ethylcarbodiimide, which can be used to exclude water to drive the reaction Amine), or other water-soluble dehydrating agents, and if necessary, a tritiated catalyst is used for the reaction. Esterification can also be performed using an appropriate carboxylic acid, in the presence of trifluoroacetic anhydride, and optionally in the presence of pyridine, or in the presence of N, N-carbonyldiimidazole and pyrimidine. The reaction between fluorenyl chloride and alcohol can be carried out using a tritiated catalyst (such as 4-DMAP or π-ratio). Those skilled in the art know how to successfully perform these esterification methods of alcohol and other known esterification methods. Purification method of isomers of the compound of formula (I) and the fraction of the isomer mixture -18- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (n The separation method can be completed using standard techniques known in the relevant art. The following examples further illustrate the compounds of the present invention and their preparation methods, but do not in any way constitute the limited scope of the present invention. 5 Beizi (Η) nuclear magnetic resonance (NMR) spectroscopy uses General

Electric GN-Omega 300 (300 MHz) spectrometer, used

Me4Sl (50 · 00) or residual protonated solvents (CHC13 5 7.26; MeOH 5 3.30; DMSO 5 2.49) were determined as standards. Carbon (13NMR spectrum system 10 was measured using a General Electric GN-Omega 300 (75MHz) spectrometer using a solvent (CDCls 6 77 · 0;; -MeOD; (5 49.0; d6-DMSO 5 39 · 5) as a standard. For the palm separation method, a commercial ChiracelRAD HPLC column was used to dissolve a gradient of hexane solution (1% to 15%) 15 containing 0.1% trifluoroacetic acid in isopropanol. Abbreviations The abbreviations used in this article are defined as follows: Economy Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau, ADDP 1, Γ- (azodicarbonyl) di-hexahydropyridine 20 DBU 1,8-diazobicyclo [5 · 4 · 0] undec-7-ene DMF N , N-Dimethylformamidine DMS0 Disulfoxide EA Elemental Analysis ES Electrospray-19- ^ Paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 Employees of Intellectual Property Bureau, Ministry of Economic Affairs Printed by a consumer cooperative V. Description of the invention (18) Ethyl ether ethyl acetate gas chromatography-mass spectrometry Hexane liquid chromatography-mass spectrometry Methylacetonitrile methanol Alcohol medium pressure liquid chromatography N -Aerosuccinimide Nuclear Magnetic Resonance Spectroscopy Pd (dppf) 2Cl2 [1,1bis (diphenylphosphino) -di Ferrocene] Dichloro-feline (II) phenylbenzotrisalyl-1-yl-oxy-shen-σbilohexyl-squatium hexahydrate salt retention time (HPLC) TLC retention factor room temperature tetrahydrofuran thin Layer chromatography

Et Et2〇 EtOAc GC-MS 5 HEX LC-MS Me MeCN MeOH 10 MPLC NCS NMR

15 Ph PyBOP 20

RTRf rtTHFTLC Preparation of starting materials and intermediates -20- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (I9 General method A: 2-halobenzoaryl ketone ( III) Compounds of formula (III) are commercially available or can be prepared according to the method shown in the reaction scheme of General Method A, which is illustrated in one or more of the following examples. Reaction Scheme of General Method A 10

NBS, NCS -or- Ph (Me) 3N + Βγ3- PyBOP heating 〇 ^ R2 ^]

Br or Cl (m) Example 1 Method A-l 15 Preparation of 2-bromo-1- (2,4,6-trichlorobenzyl) ethanone ci.

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 Take 1,3,5-trichlorobenzene (10.0 Og, 55.1 mmol), 2-bromoacetum (5.0 mL, 57.8 mmol, 1.05 eq) and A mixture of chloramine (7.7 g, 57.8 mmol, 1.05 eq) was heated in a solvent-free condition at 80 ° C and argon for 17 hours until a black precipitate formed. The reaction was cooled to room temperature and the resulting black material was dissolved in ethyl acetate (500 mL). Slow at 0 ° C-21- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200413343 Α7 __ Β7 V. Description of the invention (20) Ten Aiga water (200 mL) to stop the reaction and separate the two phases . The organic layer was washed with water (2 x 150 mL) and brine (1 x 150 mL), dehydrated (MgS04), filtered and evaporated in vacuo. Recrystallization from hexane gave 11.5 (69.3%) 2-bromo-1- (2,4,6-trichloro-5phenyl) monoethyl ketone as a flocculent white solid. W-NMR (DMSO-d6) 57.86 (3,211), 4.78 (3,21〇: 1 = 0.28,2 ° /. Ethyl acetate-hexane. Straight phenyl) ethyl ketone flocculation method Example 2 Method A -2a 10 B

15 Consumption cooperation by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the company under 20 argon argon, in an anhydrous tetrahydrofuran (53 mL) solution containing 2,5-dichloroacetamidine (5.0 · Ca 〇1) Tim I 芏 一一 == 9.94 one machine layer two (2 hours, concentrated and re-dissolved in ethyl acetate. Οι ς \ × 250 mL) washed with brine (lx150 mL), de-g 4 'filtered and evaporated in vacuo . Using MPLC, analytically pure 10 age), yielding 3 47g (52_5%) 2-bromo-bu (2, Bu-ethyl ketone, 焱 $-gas version);

It is a transparent oil. 1H-NMR (DMSO-d6) 5 7 r T = 9 1 u * · U • Ηζ, 0.9 Hz, 1Η), 7.61 to 7.60 (Ώ 2Η ,, (S, 2Η) 〇5 2ΗΧ 4 · -22- 200413343 A7 ______ _B7 V. Description of the Invention (21) Example 3 Method A-2b -2 (2 ^ 2 ^ fluoro-benzyl) -B

This compound is composed of 1- (2-bromo-4-fluoro-phenyl) -ethanone (2.5 · 10 g, 11.52 mmol), and 2-bromo-1- (2,5-difluorophenyl) ) -Ethyl ketone production method (Example A-2), yielding 2.14 g (63%) of 2-bromo_1- (2-bromo-4-fluoro-phenyl) -ethanone as a transparent oil. iH-NMR (CD2Cl2) (57.57 (dd, J = 9, 6 Hz, 1H), 7.44 (dd, J = 8, 2Hz, 1H), 7. 21 (m, 7.21-7 · 14, 1H) , 4.51 (s, 2H); TLC Rf = 0.38, 15% ethyl 15-acetate-hexane. Example printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 20

Ketone I ethyl pyridine ratio prepared by the radical-based method The paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (22)

ch3 5 Take anhydrous THF (3-glycetyl) specific bite (100 g, 0.82 mol), dimethylsulfide (400 mL, 5.4 mol), and copper (1) (7.94 g, 0.041 mol). 2 L) The solution was stirred at room temperature under argon. Adding phenyl chloroformate (0.4 mL, 0.82 mol) produced a dark brown precipitate. After 30 minutes, the mixture was cooled to below -21 ° C, and fluorenylmagnesium bromide (1.4 10 M in 3: 1 toluene-THF solution, 586 mL, 0.82 mol) was added over 50 minutes, keeping the reaction temperature at- Below 15 ° C. When the mixture forms a solution, the color becomes lighter; that is, a lime green precipitate will form at the end of the addition, but it will dissolve again when the addition is complete. 8 ° C。 Stir the mixture to slowly warm it; after 2 hours, rise back to 8.8 ° C. Add a saturated aqueous ammonium chloride solution (500 mL); after stirring for 10 minutes, pour the mixture into a water-containing (500 mL) separatory funnel. The organic phase was separated, washed with brine (500 mL), dehydrated (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a hexane-EtOAc gradient to yield 134.3 g (63.7%) of the dihydropyridine intermediate. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Dichloromethane (100 20 mL) solution of the intermediate (0.52 mol) was added to a stirred suspension of decalin containing sulfur (16.67 g, 0.52 mol), and slowly heated to reflux under argon flushing. After refluxing for 1 hour, the mixture was cooled to room temperature and then filtered through a silica gel pad. After dissolving the decalin solution in hexane, it was dissolved in a hexane-diethyl ether gradient to produce 49.4 g (70.3%) of the desired 1- (4-methyl-3-σ than fluorenyl) ethanone as a red-brown oil. Object: TLC Rf -24- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (23) 0.19 (ether); TLC Rf 0 · 14 (1 ·· 1 Hexane-EtOAc); NMR (CD2CI2) 5 8. 9 (s, 1H), 8.5 (d, 1H), 7.2 (dd, 1H), 2.6 (s, 3H), 2.51 (s, 3H) · GC MS 135 (M +). 5 Step 2: Preparation of 2-chloro-1- (4-methyl-3-pyridyl) ethanone hydrochloride

10 In a 500 mL round-bottomed flask, put 90 mL Εΐ20 containing 1- (4-methyl-3-pyridyl) ethanone (10.0 g, 74.1 mmol). To this solution was added 88.9 mL of 1M HCl / Et20 (1.2 eq, 88.9 mmol), and the solution was stirred at room temperature for 1 hour. At this time, the precipitate was filtered and washed with Et20. The solid was dried under vacuum at about 60 ° C. This HC1 salt (12. g, 70.0 mmol) was dissolved in 15 70 · 0 mL 1M HC1 / acetic acid, and 9. 34 g (l eq, 70. 0 mmol) was added. N-chlorine printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Succinimide (NCS) was stirred overnight at room temperature under an argon atmosphere. At this time, 300 mL of Et20 was added, resulting in an off-white precipitate. After stirring for 1 hour, the solid was filtered and rinsed with Et20 to give 12.0 g (83%) of the desired 2-chloro-1- (4-fluorenyl-3-pyridyl) ethanone hydrochloride. GC / MS RT = 6.60 for 20 minutes; Li R (DMS0-d6) 5 2.51 (s, 3H), 5.15 (s, 2H), 7.68 (d, 1H), 8.68 (d, 1H), 9.06 (s , 1H); [ΜΓ169 (95%). Example 5 -25- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (24 Method A-4 _l_ [4 · 一 (二 惠 上 基) —3—p Specific method

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Step 1 In a 250 mL round-bottomed flask, place a 100 mL THF solution containing 30 g of 4-trifluoronicotinic acid (15.7 ramol, 1 eq). Add 5.3 mL (38 g, 10 37 · 7 mmol, 2.4 eq) of triethylamine and 9.8 g (18.8 mm 〇1, L2 eq)

PyBOP. Stir at room temperature for 0 minutes. At this time, 2.7 g of Meldrum s acid (18.8 mmol, 1.2 eq) was added, and the reaction was stirred at room temperature overnight (18 hours). At this time, 30 mL of 1M HC1 (aqueous solution) was added, and the reaction immediately changed from orange to purple. It was then heated for 18 hours and slowly turned from purple to yellow. The reaction was tested with saturated NaHCCb and extracted with EtOAc (3 X 200 mL). The combined organic phases are dehydrated, filtered and evaporated. The residue was purified by BIOTAGE (35% EtOAc / hexane) to give the desired product, 4-trifluorofluorenyl nicotinic acid ethyl ester, 1.84 g (62%) as a colorless oil. TLC Rf 20 0.57 (50% EtOAc-Hexane). Step 2 In a 100 mL flask, put 1.84 g (9.7 mmol, 1 eq) of methyl 4-trifluorofluorenyl nicotinate in 25 mL of 1M HC1 in CHs (CDOH). Add -26- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 --- B7 V. Description of the invention (25) 1 · 3 g NCS (9 · 7 mmol, 1 eq), stir Response overnight (18 hours). The reaction was then transferred to a 500 mL Erlenmeyer flask, and 300 mL of a 2 M solution of HC1 in EhO was added with stirring. A white precipitate was produced. After filtration, 1.2 g (49%) of the desired 2-gas-1-[4- (trifluoromethyl) -3-pyridyl] ethanone 5 ketone hydrochloride was obtained as a white solid. . iH-NMR (DMS0-d6) 5 9 · 21 (s, 1H), 9.02 (d, 1H), 7.94 (d, 1H), 5.19 (s, 2H). Example 6 Method Aj 10 Inflammation of dioxin to Jiao-4-yl-2-bromo-ethanone

15 Pan Li starters 丨 benzo Π, 31 ilJMf pentene-4 diyl-ethyl ketone production method

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 Dilute with MeMgBr in THF (1 M, 50 mL, 50 mmol, 15 mL) by adding 50 mL of THF and cool to -10 ° C. A 50 mL solution of THF containing benz [1,3] -dioxolene-4-carboxyaldehyde (50 g, 33.3 g mol) was slowly added, and the reaction was stirred for 1 hour. The reaction mixture was poured to 500 mL of ice-cold saturated chlorinated solution to stop the reaction, and the mixture was extracted with ether. Organic-27- 200413343 A7B7 V. Description of the invention (26 layers are dehydrated with sodium sulfate, filtered through a silica gel packing material, and concentrated in vacuo to produce 4.9 g of white solid. Vigorous stirring contains this solid C2 · 0 g, 12. 〇 _1) Benzene compound with 5 g of Mn, 5 g, 120.4, 1q.q, 48 hours. The reaction mixture was first passed through a gluing filler, then transitioned through a G 4 "m glass filler, and then concentrated in vacuo to produce a 2々 off-white solid. Purified by Guo Xingqing using gradient gradient separation, yielding 1.47 g (74%) ) l-Benzo [1,3] -dioxane series_4 ethyl acetate as a white solid. 1H-NMR (CDCL ·) δ 7%. τ / • of (d, J = 8 Hz, 1 Η) 6.97 (dm, J = 8 Ηζ, 1 Η), 6.87 W τ. '10 f ⑽, J = 8 Hz 1 6.08 (s, 2 H), 2.59 (s, 3H) · Τ Γ D Λ, , Ethyl acetate-hexane. TLC Rf 15 steps-intermediates-Benzene fluorenone M method M

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. ~ Base, prepared by the method (example A_2), which produces 15 dilactyl groups) Ethylenedioxolene_4_yl_2_bromo_Ethylpyridine β [benzyl] [1, (CD2Cl2) d : 7.41 (dd, j = 8 > 1 Ηζ human colored solid. 1Η ~ Ν = 8-1 Hz, 1H), 6.94 (dd, 1 = 8, 3 * '· 05 Z, 1H), 6. · 3 (- 28- The scale is applicable, the country is W ^ S) A4 specification (210X2_97_public fy 200413343 A7 B7 V. Description of the invention (27) 2H), 4.55 (s, 2H). TLC Rf = 0.28, 15%, ethyl acetate-hexane. Example 7 5 Method A-6 Preparation of 2-Mo-1- "3- (Third-Butyl-Diphenyl-Shioxanoxy) -phenyl] ethanone

Step 1: Preparation of 1- [3- (third-butyl-diphenylsilyloxy) phenyl] ethanone

The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed at 0 ° C, containing 1- (3-hydroxy-phenyl) ethyl ketone (3.3 g, 24.2 — 〇1) and a third butyl chlorodiphenyl silane ( 7.3 g, 26.7 mmol, 1.1 eq) was added to a solution of anhydrous digas scorch (50 mL) to add diamine amino ° ratio 唆 (296 -29- This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297 (Mm) 200413343 A7 B7 V. Description of the invention (28) mg, 2.42 mmol, 0.1 eq) and triethylamine (2.69 g, 26.7 mm, 1.1 eq). The reaction mixture was mixed with argon at room temperature. Stir under air for 16 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with water and brine, and dehydrated with magnesium sulfate. The solvent was evaporated under reduced pressure to yield 8.7 g (95.8%) of crude product 5. 1H-NMR (acetone-d〇5 7.78 (m, 5H), 7.56-7.38 (m, 7H), 7.22 (m, 1H), 7.00 (m, 1H), 2.38 (s , 3H), 1 · 12 (s, 9H); MS ES (MH + two 375); Rf = 0.90 (30% ethyl acetate-hexane). Step 2 2-2--1--1- (Third-Butyl-Diphenyl-Shixiyanyloxy) Preparation Method of Benzoyl 1 Ethyl Ketone 巳 Γ

15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. This compound is made from 1- [3- (third-butyl-diphenyl-shixiuyanoxy) phenyl] -acetamidine (8.7 g, 23.23 mmol) According to the preparation method of 2-mo-1- (2,5-dichlorobenzene 20-yl) ethyl ketone, 10.2 g (96 · 8%) of transparent oil was produced. W-NMR (acetone 46) (5 7.78 (111,411), 7.60 (111,111), 7.50-7.40 (m, 7H), 7.22 (m, 1H), 7.05 (m, 1H), 4.56 (s, 2H), 1 · 13 (s, 9H); Rf 0.92 (30% ethyl acetate-hexane). This material is used in the protection of Synthesis Example 104; in the formation of -30- this paper size applies Chinese national standards (CNS) A4 specification (210 X 297 mm) 200413343 A7 B7 V. Description of the invention 29 The desulfurization reaction (VI) Auye 2 _ ^^ used in the preparation of the formula of the invention (1) Compounds such as radicals or aryls are based on sulfonium disulfide (); (synthetic deletion), formulas 0, D, and G) can be prepared by quotient σ ^ ^ $ See the following method B method. Imitation; Langzhong :? And the following examples are mentioned-one or more can be connected: = used: the aryl halide (VII) 10 prepared by the method, or can be based on the start of Example C-2 Ridge 2 + step V h and D-3 Dihydroxyborate of formula (VI) and used in general methods. Example 8 Method Η-1 Ιζϋ-3-Methylthiomethyl—Smiling

Printed by the Intellectual Property Office of the Ministry of Economic Affairs and Consumer Affairs Co., Ltd. 20 Add sodium thiomethanol (0.616 §, 8.8_〇1) to the cold (8), and cool to rc. To this solution was added methylbenzene (2 g 8 υυ). The mixture was warmed to room temperature, ㈣1M, h. Mix ㈣ into cold water (50 mL), and extracted with EtoAc (3 X 2G mL). The organic phases were combined and dehydrated with sodium sulfate. The solution was concentrated in vacuo to produce a crude product, which was sharp-31-This paper size is in accordance with Chinese National Standard (CNS) A4 specifications (210x297 male p 200413343 A7 ___ B7 V. Description of the invention (30 ) Chromatographic purification (5% ethyl acetate-hexane) to produce ι · 3 g (68.5%) 1 monobromo-3 ~ methylsulfanylmethyl monobenzene as a pure product. Methane Yishan) 6 7 · 48-7.47 (m, 1H), 7.392 (dt, > 7.9, 1.5 Hz, 1H), 7.28-7.207 (m, 2H), 3.64 (s, 2H ), 1.99 (s, 3H); 5 LC-MS RT: 3. 70, [Μ + ΗΓ: 354 · 1. Example 9 Method H-2 Preparation method of a thioether with a aryl group 10 Production method of a certain sulfane 〇rBr

H3C Y S ch3 15 Add 3- > stinkthiol (ig, 5.3 mmol) to acetone (25 niL). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Then potassium carbonate (1.46 g, 10.58 — 〇1) and 2-iodopropane (1.17 g, 6.88 mmol) were added. Reflux for 5 hours. The reaction was then cooled to room temperature and filtered through Yin's salt packing. The organic phase was concentrated in vacuo and dissolved in ether, at which time a white 20 precipitated. The organic phase was filtered through the same yin salt filler and concentrated in vacuo to give 1.14 g (93.17%) of 1-benz-3-isopropylsulfanylbenzene as an oil. 111 a serving (dichloromethane- ^ 2) 5 7.54 (3,111), 7.37-7.31 (111,211), 7.18 (t, J = 7.9 Hz, 1H), 3.50-3.36 (m, 1H), 1.31 (d, J = 6.1Hz, 6H): LC-MS RT: 4.15, [M + H] +: 233.2. -32- This paper is a family standard (° ^) 8 4 size (210x297 mm) 200413343 A7 B7 V. Description of the invention (31) Example 10 Method H-3 1-bromo-3-fluorenylsulfonyl-molybdenum Preparation of 淦 gBr h3c, s ,, 〇Step 1 · 1- > Stinky 曱 曱 sub-green brewing of a certain-this foot production method

Production of 3-Bromothiophenyl phenyl ether (0.5 g, 2.46 mmol) was added to 15 methylene chloride (12 mL) and cooled to 0 ° C. Add 3-chloroperoxybenzoic acid (0.467 g, 2.71 mmol printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs). m-CPBA was not completely dissolved. Stir the mixture overnight. The reaction was stopped with a saturated sodium thiosulfate solution (30 mL). The product was extracted with EtOAc (3 × 20 mL). The organic phases were combined, and the bars were washed with brine (20 mL) and dehydrated over sodium sulphate. The organic phase was concentrated to give 0.912 g (81%) of 1- > sulphonyl ~ 20-sulfanylbenzene. 111 Li 1? (Dichloromethane- (12) (5 7.83 (1 :, > 2.〇112 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.3 jj2 1H ), 7.44 (t, J: 7.9 Ηζ, 1Η), 2.77 (s, 3H); LC, MS RT 1.28, [M + H] +: 219.0. -33- This paper size applies to Chinese national standards (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (32) Step 2: Preparation method of 1-bromo-3-mesoflavinate prBr H3crs, 〇5 added 3-bromothiobenzene Methyl ether (8.7 g, 43 mmol) into dichloromethane (125 mL) and cooled to 0 ° C. 3-chloroperoxybenzoic acid (22.2 g, 129 mmol) was added. M-CPBA was not completely dissolved. Disturbance The mixture was stirred overnight. The reaction was quenched with saturated sodium thiosulfate solution (150 mL). The product was extracted with EtOAc 10 (3 × 100 mL). The organic phases were combined, washed with brine (75 mL), dried over sodium sulfate. The organic phase was concentrated to give 9.89g (97%) 1-bromo-3-fluorenylsulfonylbenzene. Lili 1? (Dichloromethane-free) 58 · 09 (s, 1H), 7.85 (dd, J = 19.2? 7.8 Hz, 2H ), 7.50 (t, J = 8.2 Hz, 1H), 3.06 (s, 3H); GC-MS RT: 6.49, [H + H] +: 236.0. 15 Example 11 Method Amine amine prepared by the method of H-4 based toluene Sulfuric acid Printed by the Consumer Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs 20

This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 ------ B7 V. Description of the invention (33 10 Take 3-motamphetamine (1.0 g, 4.29 _〇 1) Stir with anhydrous pyridine (2.1 mL) with methanesulfonyl chloride (0.35 mL '4.51 mmo1, 1.05 eq) at 50 ° C under argon for 3 days. The reaction was cooled and stopped by IN HC1 'Diluted with ethyl acetate. The ethyl acetate layer was washed with water, brine, and dehydrated over sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by MPLC (Biotage), and was isolated with 25% ethyl acetate-hexane. Crystallization from methane-ether-hexane yielded 307 g (97 · 9 phantom product) of NMR (DMSO-de) 5 7.68 (s, 1H), 7.60 (ddd, J-7.8 Hz, 1.8 Hz, 1.2 Hz, 1H), 7.55 (t, J = 6.3 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H)? 7.80 (t, J = 7.8 Hz, 1H), 4.09 (d, J = 6.6 Hz, 2H), 2.85 (d, J = 1.8 Hz, 3H); LC-MS (ES MH + = 264, RT = 2.39 minutes); Rf = 0.48 (50% ethyl acetate-hexane). 15 Example 12 Method H-5 1- (3-iodine-jasmine) -3-methyl-urea production method Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20

〇 丫 NH .NH HX Anhydrous N, N-difluorene containing 3-antaniline (! · 〇g, 4.57 mmol) and methyl isocyanate (0.29 mL, 5.02mmmol, 1.1 eq) Methylamine-35- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 public love) 200413343 A7 B7 V. Description of the invention (34) (3.0 mL) Mixture at 100 ° C with argon Stir in the air for 16 hours. The reaction was diluted with acetic acid, the strips were washed with water and brine, and dehydrated with sodium sulfate. The solvent was removed under reduced pressure, and the crude oily product crystallized from ether-hexane, yielding 732.5 mg (58.1%) of the product. W-NMR (DMSO-d6) 5 8.60 (s, 1H), 7.93 5 (t, J = 1.8 Ηζ, 1Η), 7.25 (ddd, J = 8 · 1 Ηζ, 2.1

Hz, 0.9 Hz, 1H), 7.20 (ddd, J = 8.1 Hz, 2.1 Hz, 0.9 Hz, lH), 6.98 (t, J = 8.1Hz, lH), 6.04 (ld, J = 4.8 Hz, 1H ), 2.60 (d, J-5.4 Hz, 3H); Rf = 0.23 (50% ethyl acetate-hexane). 10 Example 13 Method IX-6 (R) -3- (3-bromo-benzyloxy) -propane-1,2-diol, gBr

The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed 3_ > Benzene (1.0 g, 5.78 mmol) and (R)-(+)-glycidol 20 (428 mg, 5. 78 mmol, 1.0 eq) Triethylamine (29 mg, 0.29 mmol, 0.05 eq) was added to ethanol (50 mL), and the reaction mixture was refluxed under argon for 3 hours. The reaction mixture was cooled and poured into ethyl acetate and water. The organic layer was washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by MPLC (Biotage) with 30% ethyl acetate-hexane burned-36-. This paper size is in accordance with China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 Ministry of Economy Wisdom Printed by the Consumer Cooperative of the Property Bureau V. Description of the Invention (35) The diol is produced, which is a white solid (1.20 g, 84.0%). Li R (acetone-d6) (5 7.23 (t, J = 8.4 Hz, 1H), 7.11 (m, 2H), 6.95 (m, 1H), 4.12 (m, 2H), 3.98 (m, 2H) , 3.80 (m, 1H), 3.65 (m, 2H): Rf = 0.12 (30% ethyl acetate-hexane). 5 Example 14 Method H-7 Preparation of 2-fluoro-3-moth-pyridine

Add diisopropylamine (6.5 g, 64.2 mmol, 1.0 eq.) In a hexane solution (40.14 mL, 1.6 M) containing n-butyllithium under argon and -78 ° C. . After 30 minutes of incubation at -78 ° C, an anhydrous THF (50 mL) solution containing 2-fluoro 15 ° specific bite (6.23 g, 64.2_〇1, 1.0 eq) was added. The reaction mixture was stirred at -78 ° C for 4 hours. Add iodine (16.3 g, 64.2 mmol, 1.0 eq) and stir the reaction mixture at -78 ° C for another 30 minutes. The reaction was hydrolyzed with 10% water-THF and diluted with ethyl acetate and water. The organic layer was washed with water, brine, and dehydrated. The solvent was evaporated under reduced pressure, and the product was purified by MPLC 20 (Biotage), and dissolved with 20/80 v / v ethyl acetate-hexane, resulting in 2-fluoro-3-broken-σ ratio, as a yellow oil (8.50 g , 59.4%). 4-NMR (acetone-d6) 58.14 (m, 2H), 6.94 (m, 1H); GC-MS (M + = 223, RT = 9.50 minutes); Rf = 0.70 (30% ethyl acetate-hexane). -37- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200413343 A7 B7 V. Explanation of the invention (36) Example 15 Method H-8 Preparation of 3-iodo-2-methoxy-pyridine

To a solution of methanol (60 mL) containing sodium alcohol (8.0 mL, 35.9 mmol, 4.0 eq, 25% methanol solution) was added 2-fluoro-3-iodo-pyridine (2.0 g, 10 8. 97 mmol) . The reaction mixture was refluxed under argon for 1 hour. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to give 1.8 g (85. 4%) of the crude product as a yellow oil. 1H-R (acetone-d6) (58.16 (m, 2H), 6.78 (m, 1H), 3.93 (s, 3H); LC-MS (ES MH + = 236.2); Rf -15 0 · 75 (30% Ethyl acetate-hexane) Example 16 Method Η-9 Production method of (3-iodo-pyridin-2-yl) -fluorenylamine printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

Η 20 To a 40% aqueous solution of amidine (60 mL) was added 2-fluoro-3-moth-. Specific bite (2.0 g, 8.97 mmol), the reaction mixture refluxed under argon 4 -38- This paper size applies Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (37) Time. The cooled reaction was diluted with ethyl acetate and water. The organic layer was washed with water and brine, and dehydrated. The solvent was removed under reduced pressure, yielding 1.70 g (81.0%) of the crude product. 1H-NMR (acetone-d6) 58.06 (dd, J = 4.8, 1.5 Hz, 1H), 7.89 (dd, J 7.2, 1.8 Hz, 1H), 6.34 (m, 1 H), 5 5.60 (wide , S, 1H), 2.94 (d, J = 4.5 Hz, 3H): Rf = 0.68 (30% ethyl acetate-hexane). Example 17 Method H-10 10 Preparation method of cyclopropanecarboxylic acid (3-bromobenzyl) fluorenamine 〇γΝΗ 'Δ 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs containing 3-bromoaniline (1.0 g, 5.81 mmol), Cyclopropane-Weiyl chloride (0.61 g, 5.81 mmol, 1.0 eq) and triethylamine (L17 g, 11.6 mmol, 2.0 eq) in dry THF (20 mL) at room temperature under argon Stir for 16 hours. The reaction mixture was diluted with ethyl acetate and water. The organic 20 layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 1.052 (75.2 ° / 〇 crude product. 111-Li 1? (Acetone- (16) (5 8.60 (width 3, 1H), 8.07 (dd, J-3.6, 2.1 Hz, 1H), 7.52 (m, 1 Η), 7.22 (m, 2H), 1.73 (m 1H), 0.90 (m5 2H), 0.80 (m, 2H); MS ES (MH + = 242); = 0.46 (30% ethyl acetate -Ji-39- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) _ 200413343 Α7 Β7 V. Description of the invention (38 ° C) Example 18 Method H-11 5 3-Bromo-N- (2- Method for preparing ethoxy-ethyl) -benzene diazine

Br ~ 〇, call 10 take 3-bromobenzenesulfonyl chloride (1.0 g, 3.72 mmol), 2-methoxyethylamine (0.84 g, 11.15 mmol, 3.0 eq), carbon dioxide (2.57 g A solution of 18.59ramol, 5.0 eq) in acetone (10.0 mL) was stirred at 40 ° C for 4 hours. The reaction was diluted with ethyl acetate, washed with water, brine and dehydrated with sulfuric acid. The solvent was removed under reduced pressure, purified by MPLC (Biotage), and dissociated with 20-15 25% ethyl acetate-hexane, yielding 1.05 g (96%) of the product. Rf = 0.33 (silica, ethyl acetate: hexane, 3: 7); Lai R (DMS0-d6) 5 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 7.94 to 7.76 (m, 4H), 7.54 ( t, J = 7 · 9Ηζ, 1H), 3.27 (t, J = 5 · 6 Ηζ, 2Η), 3.13 (s, 3Η), 2.93 (q, J 2: 5.6 Ηζ, 2Η). 20 Example 19 Method Η-12 Diethyl- (3-moth-phenylfluorenyl) -amine production method -40- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 5 , Description of invention (39)

ch3 5 take 3-bromobenzylmethyl bromide (1.0 g, 3.20 mmol), diethylamine (0.70 g, 9.60 mmol, 3.0 eq), potassium carbonate (1.33 g, 9.60 mmol, A 3.0 eq) solution of acetone (1.0 mL) was stirred at 40 ° C for 4 hours. The reaction was diluted with ethyl acetate, washed with water, brine and dehydrated with magnesium sulfate. The solvent was removed under reduced pressure, purified by MPLC (Biotage), and dissolved with 5-8% 10 ethyl acetate-hexane to give 0.92 g (99 ° /.) Of the product. Rf = 0. 28 (silica, ethyl acetate: hexane, 1: 9); W-NMR (DMS0-d6) 57.66 (bs, 1H), 7.59 to 7.55 (m, 1H), 7.33 to 7 29 (m, 1Η), 7.10 (t, J = 7.8Hz, 1H), 3.47 (s, 2H), 2.42 (q, J = 7.1 Hz, 4H), 0.95 (t, J = 6.9, 6H ). 15 Example 20 Method H-13 3-Bromo, fluorenyl-benzylamine

Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, anhydrous dichloromethane (10-containing methylamine hydrochloride (0.9 g, 13.40 mmol, 3.0 eq) and triethylamine (2.26 g, 22.33 mmol, 5.0 eq)) 41- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 V. Description of the invention (40) mL) The suspension is cooled to 0 ° C. The cooled suspension was treated with 3 ... stink (1.0 g, 4.47 mmol), and the reaction was diluted at room temperature with 4 ethyl ethyl fluoroacetate, and the reaction was washed with water, brine and magnesium sulfate. The solvent was removed with ethyl acetate, purified by MPLC (Biotage), and dissolved under reduced pressure with 35% to 45% water and 5 hexane to produce 0.60 g (63%) of the product. Rf = 〇 28 (. Ethyl diacid ~ ethyl ester: hexane, 2: 3); NMR (DMSO-d6) 5 8 55 ^ stone, acetic acid 7-99 (t, J = 1.7 Hz, ^), 7.835.7.79 (,, 1H ^ to 7.69 (111, 111), 7.42 (1 :, < 1 = 8.〇112, 111), 2; 7.J = 6.7 Hz, 3H). ′ · (D, 10 Example 21 Method Η-14 L (3-Bromo-Mosyl) -Ethylamine Method

The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed a solution containing 3-bromophenylacetonitrile (1.0 g, 5.10 mmol) in acetic acid (25 mL) and water (15 mL), and treated with sodium persulfate. . The reaction was stirred at 6 ° C for 20 nights. The organic solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate and water. The layers were separated, the organic phase was washed with brine, and dehydrated with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was Diethyl ether-hexane (1/1, v / v) was washed to give 0.65 g of the product (60%) as a white solid. Rf = 0.18 (silica, ethyl acetate: hexane, 3: 2); Li R (DMS0-d6) 6 7. 50 (bs, 1H), 7.46 to 7.39 -42- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 ----- B7 V. Description of the invention (41) (m, 2H), 7.26 to 7.22 (m, 2H), 6.93 (bs.lH), 3.37 (s, 2H). Example 22 5 Method for the preparation of propan-2-ol

Uch3 Η0 ^ Γμ 10 CH3 Take a solution of 3N fluorenylmagnesium bromide (6.53 mL, 19.59 mmol, 3 eq) in an ethyl bond solution and cool to "C, hydrazine 3-benzylbenzene (1.3 g, 6. 53 mmol). The reaction was stirred at room temperature for 4 hours. The reaction was diluted with ethyl acetate and water. The layered 'organic phase was washed with saturated sodium bicarbonate, 2N HC1, brine, and dehydrated with 15''acid. Subtract the solvent, purify by MPLC (Biotage), and dissociate with 5-10% ethyl acetate-hexane to produce 1.2 g (90%) of the product. Rf = 0.22 (Shi Xishi, ethyl acetate: hexane, 1: 9); 1hjMR (MS〇-d6) 57.63 (t, J = L8 hz, 1Η), 7.45 to 7.35 (m, 2H), printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 7.25 (t, J: = 7 7, ih), 5.15 (s, 1H), 1.39 (s, 20 6H). Preparation of phenol and cyanothiophenol and formation of compounds of formula (i) In these methods, the preparation of cyanophenol or cyanothiophenol (π) can be easily performed. -43- This paper is in accordance with China's national standard (〇vjS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (42) The benzene or sulfur obtained is coupled with (III) to produce the product of formula (I), such as the reaction diagram of general method B and the following clear examples of the present invention It is shown when X = 0. General Method B-1 Reaction Figure 5

(|) Example printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 23 20 Method B-1 3-Amino-6-benzyl-1-benzylfuran-2-yl) (2, 4-dichlorobenzyl) Production method of fluorenone-44- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (43)

Step 1: Preparation of 2-cyano-5-jasmonol as starting material

10 To a stirred solution of anhydrous tetrahydrofuran (50 mL) and anhydrous dichloroethane (50 mL) containing 3-phenylphosphonium (10.0 g, 58.75 mmol) at 0 ° C was added 1.0 M trigas. After a solution of boron chloride in dichloromethane (64.6 mL, 64.6 mmol, 1.1 eq), ethyl thiocyanate (4.4 mL, 64.6 mmol, 1.115 eq) and a chlorinated chain (7.83 g , 58. 75 mmol, 1.0 eq). Reaction mixture Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

After stirring at room temperature for 2 days, it was cooled to 0 ° C. To this dark brown reaction mixture was added 50% aqueous sodium hydroxide solution (150 mL) until the pH reached 10 or more. After the resulting yellow two-phase layer was stirred at reflux for 1 hour, it was cooled to room temperature. The two phases were separated and the aqueous layer was dried. (^ The solution was adjusted to pH 3 with 2. on hydrogen chloride solution (about 20 300 mL). The acidified aqueous mixture was extracted with ethyl acetate (3 X 400 mL), and the combined organic layers were dehydrated (MgS04), filtered and reduced. Concentrate under pressure. Crystallize from ether-hexane (150 mL) to give 2-cyano-5-phenylphenol as a white solid (5.81 g, (DMS〇-d6) ά 11.20 (s, 1H), 7. · 66 (d, J = 8.7 Hz, 1H), 7.62-7.59 (m, -45-) This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (44 ) 2H), 7.51-7.42 (m, 3H), 7.22-7.19 (m, 2H), Rf-0.08, 25% ethyl acetate-hexane. Step 2: The title compound 3-amino-6-phenyl -1-Benzosulfan-2-5yl) (2, 4-dichlorobenzyl) fluorenone production method Intellectual Property Bureau of the Ministry of Economic Affairs Employee Cooperative Cooperative printed on 2-cyano-5- containing step 1 Anhydrous N, N of phenylphenol (5. 71 g, 29. 25 mmol) and 2-gas-1- (2, 4-dichlorophenyl) ethanone (7.19 g, 32.17 mmol, 1.1 eq) -To a stirred solution of dimethylformamide (50 mL) was added potassium carbonate (4.85 g, 35.1 mmol, 1.2 eq), and the orange reaction mixture was stirred at 90 ° C. Stir for 17 hours. The resulting dark wine red reaction is poured into ethyl acetate (500 mL) and water (300 mL). The ethyl acetate layer is washed with a saturated aqueous ammonium chloride solution, water and brine. The organic layer is dehydrated (MgS04), Filtration and evaporation in vacuo. The crude product was purified by silica gel (flash column chromatography), and was sequentially separated with 10% ethyl acetate-hexane and 20% ethyl acetate-hexane. 15 crystals were formed from ether-hexane. The benzofuran product was produced as a yellow solid (7.56 g, 67.6%). NMR (DMS0-ds) 5 8 · 10 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 3.6 Hz, 1H), 7.74 (d, J = 3.0 Hz, 1H), 7.71 (m, 2H), 7.62 to 7.53 (m, 5H), 7.47 to 7.35 (m, 3H); MS LOMS (MH + = 382 ); Analysis C21H13Cl2N〇2: 65.99% H 20 3.43% N 3.66%, measured value C 65.70% H 3.40% N 3. 72%; melting point (uncorrected) 144 to 146.5 ° C. General method B-2 Reaction Diagram-46- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 Α7 Β7 V. Description of the invention (45 10 R6 RR (

OH (CH2〇) n MgCI2 〇 R ° 〇

P6 alkali / solvent heating

CN OH Example 24 15 Method B-2a "3-Amino-6- (2-methyl-isopropyl-4-yl) -benzyl-oxan- 2-ylpyridine- (2-methoxybenzyl Base)-Method for the production of acetophenone Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperatives 20 ΝΗ0

Step 1: Intermediate 4- (3-fluorenyl-benzyl) -2-fluorenyl-oxazole production method-47- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Invention Description (46)

HX 5 in 2-Mo-3′-methoxy-acetic acid benzene (1.9 g, 8.1 mmol)

To 15 mL of toluene solution was added amine acetate (1.2 g, 20.3 mmol, 2.5 eq). The reaction was stirred at 110 ° C for 40 hours. The white solid was filtered off and washed with ethyl acetate. Evaporate the filtrate in vacuo (add some methanol to lower the boiling point) and wash. Purification by MPLC (Biotage) yielded 1.1 g (72%) of 4- (3-10 methoxy-phenyl > -2-methyl-oxazolazole as a pale yellow liquid. 1H-NMR (CHsOH- ~ d4) 5 8. 11 (s, 1H), 7.25-7.28 (m, 3H), 6. 83- 6.86 (m, 1H), 3.82 (s, 3H), 2.49 (s, 3H); Rf = 0.36, 25% ethyl acetate-hexane. 15 Step 2: Method for preparing intermediate 3- (2-fluorenyl-humazol-4-yl) -phenol

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20

H, C In an ice bath, add to a solution of 4_ (3-methoxy-phenyl) -2-fluorenyl-σ number 嗤 (1.1 g, 5.8 mmol) in anhydrous DCM (5 mL) in step 1 in an ice bath. 1M tribromide in DCM (18 mL, 17.4 mmol, 3 eq). The reaction mixture was stirred at room temperature for 2 hours. Pour the mixture into ice and ethyl acetate. -48- The paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of Invention (47). After adding about 50 mL of 1 N NaOH, a saturated aqueous sodium bicarbonate solution was added until pH 8. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The organic layer was combined and evaporated in vacuo. 88.88 g (87%) of 3- (2-fluorenyl-sigmaquatyl) was obtained as a yellow solid. 1H-NMR (CH3〇H-d4) 5 8. 07 (s, 5 1H), 7.22-7.15 (m, 3H), 6.78-6.75 (m, 1H), 2.52 (s, 3H); MS LC -MS (ΜΗ + = 176.3): TLC Rf 0.15, 25%

EtOAc-hexane. Intermediate 2-hydroxy-4- (2-fluorenyl-oxazolyl-4-yl) -jasminaldehyde 10

h3c 15 To a solution of 3- (2-methyl-humazol-4-yl) -phenol (0.88 g, 5.0 mmol) in step 2 in anhydrous acetonitrile (20 mL) was added magnesium chloride (14 g, 15 mmol, 3 eq), triethylamine (2.8 mL, 20 mmol, 4 eq), and Juyingjun (0.6 g, 20 mmol, 4 eq) were printed with the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The reaction mixture was refluxed for 7 days and the starting material was completely consumed. Add some water and saturated aqueous chloride solution until pH = 7. Some solids precipitated at this point. The red solid was filtered off and the filtrate was extracted 3 times with EtOAc. Most of the red solid was dissolved in MeOH. The EtOAc extracts were combined with the Me0H filtrate and dried over magnesium sulfate. Evaporate in vacuum to produce 2-hydroxy-4- (2-fluorenyl-oxazolyl-4-yl) -benzaldehyde formaldehyde 1.0g (98%), which is yellow-49. This paper size applies to Chinese National Standards (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (48) Color solid. 1H-NMR (CH3〇H-d4) 510.0 (s, 1H), 8.3 (s, 1H), 7.73 (d, J = 8 Hz 1H), 7.4 (dd, J = 8 Hz, 1.6 Hz, 1H), 7.34 (d, J = 1.6Hz, 1H), 2.54 (s, 3H); TLC Rf. 0.24, 25% EtOAc-hexane. 5 Step 4: Intermediate 2-Ethyl-4- (2-methylfluorene-4--4-)-benzyl

h3c To a solution of 2-hydroxy-4- (2-methyl-oxazol-4-yl) -benzaldehyde (1 g, 4.9 mmol) in acetic acid (5 mL) of step 3 was added nitroethane (〇. 74 15 g, 9.8 mmol, 2 eq) and sodium acetate (0.8 g, 9.8 — 〇1,2, printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, printed eq). The reaction mixture was refluxed for 17 hours. Starter completely > Shaw. Add some * water and neutralize with saturated aqueous sodium bicarbonate until pH = 7. Extracted 3 times with EtOAc. The extracts were combined and evaporated in vacuo. Purification by MPLC (Biotage) yielded 0.2 g (20%) of 2-hydroxy-4- (2-fluorenyl-oxazol-4-yl) -benzene 20-nitrile as a pale yellow solid. 1H-NMR (CH3〇H-d4) 5 8. 2 (s, I Η), 7.51 (d, J = 8 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 8 Hz, 1.6 Hz, 1H), 2.51 (s, 3H). Step 5: "3-Amino-6- (2-fluorenyl-oxazole-4-some) -benzofuran-2- -50- This paper size applies to China National Standard (CNS) A4 (210x297 mm) ) 200413343 A7 _ B7 V. Description of the invention (49) Method for the production of (2-methyloxy-2-jasmine) -methanone ^

In step 4 containing 2-hydroxy-4- (2-methyl-oxazol-4-yl) -phenylcyanide (25 mg, 0.12 mmol) and 2-methoxybenzylmethyl bromide (31 mg, 0.14 L.O. 1, 1.1 eq) in an anhydrous n, N-dimethylformamide (2 mL) solution was added 10 potassium carbonate (34 mg, 0.25 mmol, 2 eq). The reaction mixture was shaken at 90 ° C for 17 hours. The mixture was cooled to room temperature and poured into ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and evaporated in vacuo. Purification by HPLC yielded 19 mg (43 ° /.) [3-amino-6- (2-methyl-oxazol-4-yl) -benzofuran-2-yl]-(2-methoxy -Phenyl) -methanone as a yellow 15-color solid. 1H-NMR (CH3〇H-d4) 5 8.23 (s, 1H), 7.86 (d, J = 8 Hz, 1H), 7.65 to 7.39 (m, 4H), 7.13 (d, J = 8 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 3.82 (s, 3H), 2.51 (s, 3H). MS LC-MS (MH + = 349.2); Rf = 0.33 , 50% EtOAc-printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 Example 25 Method B-2b "3-Amino-6- (2-methyl" yl-thiazol-4-yl) -benzylfuran-2-yl 1- (2, 4-diaza-mosyl)- Production method of fluorenone-51- This paper size is applicable to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7

Step 1 ·· 中 ·. 物 物 2- 曱 某 _ 喽. Insect t

〇ch3 10 In a 10 mL absolute ethanol solution containing 2-mo-3'-methoxy-ethylbenzene benzene (10g, "ugly, i 2 eq) was added thioacetamide (〇27 ^ 3 6 mmol, 1 eq). Some solids were formed immediately. The reaction was stirred at 80 ° T. Working hours. After cooling the reaction to room temperature, it was placed in an ice bath for a short period of time. The white 15-color solid was filtered off and hexane was used. Washing and drying under vacuum yielded 0.67 § (90%) 4- (3-methoxy-phenyl) -2-fluorenyl-thiazole. 沱 -NMR (CH3OH-d4 and a small amount of DMS0-d6) ( 7.53 (s, 1H), 7.39 (m, 1H), 7 · 29 ~ 7 · 26 (m, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 1Η), 7 · 18 (m, 1Η), 6.78 (ra, 1Η), 3.74 (s, 3Η): 2.91 (s, 3H); MS LC-MS MH + = 206.3; Rf-〇.i3? 2% 20 EtOAc-hexane. Panlin 2: intermediate 3- [2-fluorenyl-thiazol-4-yl) -benzol-52- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7-B7 V. Description of the invention (51)

h3c was prepared in the same manner as 3- (2-methyl-humazol-4-yl) -phenol in Example 24 above. Yield: 74%. Qi-Li !? (CH3〇H-d4) 5 7.54 (s, 1Η), 7.32-7 · 19 (m, 3Η), 6.77-6. 74 (m, 1Η), 2.76 (s, 3H): TLC 0.57, 50% EtOAc-hexane. 10 Preparation method of 2-amidino-4- (2-methyl-thiazol-4-yl) -benzaldehyde of Aili intermediate 〇

h3c uses the same printing method as that of 2-Ethyl-4- (2-methyl-oxazole-4-yl) -benzaldehyde from the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. TLC Rf 0.71, 50 ° /. EtOAc-hexane. The crude product was used in step 4 without further purification. Actually, the intermediate 2- by H (2-methyl-oxazolyl-4-yl V-benzyl cyanide method, which is used for -53- National Standard (CNS) A4 specification mm of this paper size) 200413343 A7 ___ B7 V. Description of Invention (52)

Using the same method as 2-hydroxy-4- (2-methyl-oxazole_4-yl) -phenylcyanide. The total yield of the two steps was 83%. iH-NMR (CH30H-dJ 57 · 75 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 1.6 Hz 1H), 7.42 (dd, J = 8.2 Hz, 1.6 Hz , 1H), 2.75 (s, 3H). 10 MS LC-MS ΜΗ + = 217 · 2; 0 · 18, 30% Eto-Ac-hexane. Huangfa 5: 2 "3 diamino-6- ( 2-methyl 3 azole 4 4 a) a benzofuran 2 2

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs The same method as in Step 5 of Example 24 is used. The yield was 33%. R20 (DMSO-d6) δ 8.09 (s, 1H), 8.06 (dd, J = 8 2 Hz 〇8 · ζ, 1Η), 7.94 (m, 1H), 7.89 (dd, J = 8.2 Hz, 1.2Hz, 1H), 7.75 (dd, J = 2 Hz, 0.4Hz, 1H) 5 7.59 (dd, 8 · 2Ηζ, 0.4Ηζ, 1H), 7.55 (dd, J = 8.2Hz, UHz, 1H ), 2.71 (s, 3H). MS LC-MS (MH = 403. 2/405. 2) * Rf = 0 57, -54- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (53) 50% EtOAc-hexane. Example 26 Method B-2c 5 3-"Amine-6- (1-fluorenyl-1Η ~~ ρ is more than 17-seat ~~ 3 -yl) -benzognathion-2 -yl]-(2, 4 -Dichloro-benzyl) fluorenone

NK

Step 1: Method for preparing 3- (1-fluorenyl-1H-pyrazol-3-yl) -benzol

15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 3-Hydroxy-acetophenone (1 g, 7.3 mmol) and N, N-Dimethylamidamine-dimethyl shrink disk (2.6 g, 22 mmol, 3 eq) in a 40 mL vial and shake at room temperature for 17 hours. The mixture was evaporated in vacuo to give the phenol product and 20 methyl ether. To a solution of this mixture in 10 mL of absolute ethanol was added hydrazine (1 g, 22 mmol, 3 eq). The reaction mixture was shaken at 80 ° C for 2 hours. The mixture was evaporated in vacuo. Following the procedure of Example 24, step 2, the methyl ether of methyl ether was removed using a dichloromethane solution of boron tribromide (3 eq). Some methyl ether was still contained and this mixture was used in step 2 without further purification. -55- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 04 200 13343

V. Description of the Invention (54 Intermediate 2-Hydroxycyanine Production Method)-Benzene H3C, n

OH was prepared in the same manner as in step 3 and step 4 of Example 24. 10 2-Cyclo-6-U-methylmethyl (3-yl) _phenylcyanide, ㈣ = isomer. The mixture was used for ㈣3 without further purification. MS m TLC Rf = 0.16, 50% EtOAc-hexane. 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 l-3 ..: [3_amino-6-Π di ^ -3-yl) -moprofuran-2-yl]-(2 '4: One gas phenyl) methamine production method NH.

Using the same method as in Step 5 of Example 24: [3-Amino-6- (1-methyl-1H-pyrazol-3-yl) -benzofuran-2-yl]-(2, 4-dichloro -Phenyl) -fluorenone as a pale yellow solid. Yield: 12%. j-NMR (CDC13) 57.7-7-8 (m, 2H), 7.60 (d, J = i0.8 Hz, 1H), 7.51-7.48 -56- This paper size applies to Chinese national standards ( CNS) A4 specification (210x297 public love) 200413343 Α7 Β7 V. Description of the invention (55) (m, 2H), 7.38 -7.33 (m, 2H), 6.55 (d, J = 3.2 Hz, 1H), 5.99 (wide, s, 2H); 3.94 (s, 3H). MS LC-MS MH + di 386.22 / 388.2; TLC Rf = 0.3, 50% EtOAc-hexane. 5 Reaction Diagram for General Method B-3

R Br or 5 R6 1 R—B (OR) 2 R6 (V!) R5, rVCN R3 Coupling reaction of media R4 ^ V- R3 (II) 〇 Test / Solvent / R2 ^^ B oror 10 (III) Heating R5 'NH 15 A Λ- R4〆V R3 〇 (丨) Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 27 20 Method B-3 (3 ~~ amine group 6—σ ratio bite 3-group Yiben sigma scent—2-based—mono (2-methoxy-phenyl) fluorenone production method-57- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 ____ B7 V. Description of Invention (56) NH.

Step 丄 Two start-up 丄 2-benzyl arginine 3 a pyrimidine cyanide production method

This compound is prepared from 2-benzyloxyiodo-phenyl cyanide (20 g, 5.97_ο1), according to [3-amino-6- (σ than 3--3-yl) -1-benzo Cranan-2-yl] (2,4-difluorophenyl) methanone was prepared in the same manner, yielding 1.42 as (83%) 15 tan solid. NMR (DMS0-d6) 5 8.98 (d, J = i 8 Ηζ ° 1Η), 8.64 (dd, J = 5 · 1 Ηζ, 1.5 Ηζ, 1Η), 8.18 (dt J = 8 · Η Ηζ, 2 · 1 Ηζ, 1Η), 8.86 (d, J = 7.8 Hz 1Η) 7.68 (d, J = 1.2 Hz, 1H), 7.56- 7.32 (m, 7H) 5 42 Intellectual Property Office, Ministry of Economic Affairs Printed by employee consumer cooperative (s, 2H); LC-MS (ES MH + 287, RT = 2.39 minutes): Rf = 20 0.08 (25% ethyl acetate-hexane). Wei 2: Harrow starter: 2-hydroxy-4- (° specific bite 3-base) Benjizhen -58- This paper size is applicable to Chinese national standards (3) (Magic Eight 4 specifications (210x297)) 200413343 A7 _— _B7 V. Description of Invention (57)

5 In a dry flask containing 10% Pd / C (160 · 0 mg, 0.56 mmol, 0.2 eq), add 2-benzyloxy-4-. A solution of pyridin-3-yl-phenylcyanide (800. 0 mg, 2.79 mmol) in 1: 1 v / v ethyl acetate-ethanol (28.0%). The reaction mixture was hydrogenated under the hydrogen blanket provided by the attached balloon for 16 hours. The reaction was filtered through a Yin's salt pad, and the filtrate was concentrated to give 536.4 mg 10 (97.8%) of a white solid. 111-Li 8 (^ 30- (16) (5 11.21 (width 5, 1 H), 8.82 (dd, J = 2.4 Ηζ, 0.6 0ζ, 1 Η), 8.61 (dd, J = 5.1 Hz , 1.8 Hz, 1H), 8.02 (ddd, J = 7.8 Hz, 2.1 Hz,

1.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.50 (ddd, J = 8.1 Hz, 4.5 Hz, 0.6 Hz, 1H), 7.27-7.22 (m, 2H); 15 LC-MS (ES MH + = 197, RT = 0.97 minutes); Rf = 0.16 (75% ethyl acetate-hexane). Physicochemical standard 3 ¾¾ Step Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 2 I Furanyl benzyl I 3 I Amine I 6 Amine I 3

Method | 1 嗣 methyl benzene I yl oxymethyl I 2 κίν I group I

CH 9 5 This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (58 In the 2-hydroxy-4- (methidin-3-yl) phenyl cyanide (6 〇mg (0.31 mmol) and 2-bromo-2'-methoxyethoxybenzene (70 · ι mg, 0.31 — 〇1, 1.0 eq) in anhydrous N, N-dimethylformaldehyde Potassium carbonate (84 · 5 mg, 0.62 mmol, 2.0 eq) was added to the stirring solution of amidine (5.0 mL), and the orange reaction mixture was stirred at 80 ° C for 5 hours. The obtained dark wine red reaction was poured to Ethyl acetate (100 mL) and water (50 mL). The ethyl acetate layer was washed with a saturated aqueous solution of ammonium hydroxide, water and brine. The organic layer was dehydrated with sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to MPLC (Biotage ) Purified with 50% ethyl acetate-hexane. Crystallized from ether-hexane to give benzofuran as a yellow solid (24 · 4 mg, 23.2%). Η-NMR (acetone -d6) 5 8.8 (d, J = 1.5 Hz, 1H), 8.60 (dd, J = 7. 2, 1.5 Hz, 1H), 8.12 (m, 2H), 7.70 (d, J = 1.5 Hz, 1H), 7.65 (dd, J = 6.3, 0.9 Ηζ, ΙΗ), 7.52- 7.41 (m, 3H), 7.17 (d, J = 7.5 Hz, 1H) 7.06 (t, J = 6.6 Hz, 1H), 6.84 (wide, 15 s, 2H), 2.85 (s, 3H); LC-MS (ES MH + = 345, RT = 1.97 minutes). Intellectual Property of the Ministry of Economic Affairs Example 28 printed by the Bureau's Consumer Cooperatives Method B-4 20 N- {3- "3-Amino-2- (2, 4-diaza-benzylidene) -benzylopano-6-yl] -Pyridine-1-ylpromazine production method-60 " This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (59)

Step 1: Method for preparing 3′-amino-3-benzyloxy-biben-4-carbonitrile

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs to obtain a solution containing 2- (benzyloxy) -4-iodophenylcyanide (6.20 g, 18.5 mmol) in 1,2-dimethoxyethane using argon Degas for 30 minutes. At this time, after adding triphenylphosphine (0) (2.13 g, 1.85 mmol, 0.1 eq), 3-aminophenyldihydroxyboric acid (2.53 mg, 18 5 mmol, 1.0 eq) and 2M Na2CO3 aqueous solution (4.0 mL). After argon was passed through the reaction for 10 minutes, it was heated to 80 ° C overnight. (18 hours). The reaction was diluted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, purified by MPLC (Biotage), and dissolved in 30% ethyl acetate-hexane to give 3.33 g (59.9%) of a yellow solid product. 1H-NMR (acetone) 5 7.71 (d, J = 8.1 Hz, 1H), 7.58 (m, 2H), 7.48-7.30 (m, 5 Η), 7.18 (m, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.76 (m, 1H), 5.44 (s, 2H), 4.81 (width, s, 2H); -61- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) %) 200413343 A7 B7 V. Description of the invention (60)

Rf 0.32 (30% ethyl acetate-hexane). Step 2 »Method for preparing N- (3, -benzyloxy-4, -amino-earthyl-3-yl) -N-propanyl-propanilamine 5

10 Add dropwise to a solution of 3'-amino-3-benzyloxy-biphenyl-4-nitrile (800 mg, 2. 66 mmol) in dichloropyrene (100 mL) at 0 ° C. After propyl chloride (370 mg, 4.00 mmol, 1.5 eq), triethylamine (405 mg, 4.00 mmol, 1.5 eq) was added. Stir the reaction at 0 ° C with argon for 1 hour and 15 hours. The reaction was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and purified by MPLC (Biotage) and isolated with 30% ethyl acetate-hexane to give 980 mg (89.2%) of the product as a yellow solid. 1H-Li R (acetone-d6) 5 7. 76 (m, 2H), printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs

7.69 (m, lH), 7.64-7.55 (m, 4H), 7.48-7 · 36 (m, 5H), 20 5 · 45 (s, 2Η), 2.61 (q, J = 6.9 Hz, 4Η), 1.05 (t, J = 6.6 Hz, 6H); Rf 0.42 (30% ethyl acetate-hexane). Step 3: Preparation method of N- (4'-cyano-3'-hydroxy-bibenz-3-yl) -N-propanyl-propanilamine-62- This paper standard applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (61)

Add 10% PWC (124 · 0 mg, 0.13 eq) to a dry flask containing N- (3'-benzyloxy-4'-cyano-biphenyl-3-yl) -N-propanyl -A solution of propylamine (980 mg, 2.38 mmol) in 1: 1 v / v ethyl acetate-ethanol (10 10 mL). The reaction mixture was hydrogenated under a hydrogen blanket provided by the attached balloons for 24 hours. The reaction was filtered through a Yin's salt pad, and the filtrate was concentrated. Purified by MPLC (Biotage) and isolated with 30% ethyl acetate-hexane to give 332 mg (43.4%) of the product. W-NMR (acetone-d6) 59 · 95 (width s, 1H), 7.75 -7.58 (m, 4H), 7.35 (m, 3H), 2.61 (q, 1 = 1.2 15 Hz, 4H), 1.05 (t , J-7.2 Hz, 6H); LC-MS (ES MH + = 323) Rf = 0.20 (30% ethyl acetate-hexane). N-material center oral standard 4 Step-based amines Benzene I Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Furan benzene IX)-Benzyl benzene I I-1 amines propyl I propyl propyl Legal paper size is applicable to Chinese National Standard (CNS) A4 (210 x 297 mm) 200413343 A7 B7 V. Description of Invention (62)

In N- (4'-cyano-3'-hydroxy-biphenyl-3-yl) -N-propionyl-propionamine (70.0 mg, 0.22ππηο1) and 2,2 ', 4'- Trichloro-benzene acetate (48.5 mg, 0.22 mmol, 1.0 eq) in anhydrous N, N-dimethylformamide (5 mL) 10 was added potassium carbonate (60.0 mg, 0.43 mmol, 2.0 eq). The reaction mixture was stirred under an argon atmosphere at 80 ° C for 16 hours. The brown reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of chloride, water, and brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by MPLC (Biotage) and dissolved in 20% ethyl acetate with ethyl acetate to yield 15 39.6 mg (35.8%) of the product. iH-NMR (acetone-d6) 58.10 (d, J printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economy 8.4 Hz, 1H), 7.83 (d, J = 6.3 Hz, 1H), 7.72-7.53 (m, 7 H ), 7.30 (m, 1H), 7.08 (width, s, 2H), 2.63 (q, J = 7.2 Hz, 4H), 1.04 (t, J = 7.2 Hz, 6H); MS ES (MH + two 509); Rf = 0.25 (30% ethyl acetate-hexane). 20 Step 5 · · N- {3- [3-Amino-2- (2, 4-dichloro-phenylhydrazone) -benzoxan-6-yl 1-pyridin-1-ylpropanamide Making method-64- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200413343 Α7 Β7 V. Description of invention (63)

Printed on N- {3- [3-Amino-2- (2, 4-dichloro-benzyl) -benzobenzoan-6-yl] -benzene To a solution of N-propionyl-propionamine (230 mg, 0.45 mmol) in anhydrous THF (5 mL) was added 2 N aq · NaOH (0.46 mL, 10 0.90 mmol, 2.0 eq). The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with a saturated aqueous ammonium chloride solution, water, and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by MPLC (Biotage) and isolated with 20% ethyl acetate-hexane to give 161 mg (78.4%) of a yellow solid. 1H-Li R (acetone-d6) 5 15 9.02 (width s, 1H), 8.00 (m, 1H), 7.95 (d, J = 6.9Ηζ, 1 Η), 7.53-7 · 40 ( m, 6Η), 7 · 28 (m, 2Η), 6.96 (width s, 2Η), 2.26 (q, J = 7 · 8 Ηζ, 2Η), 1.04 (t, J = 4 · 5 Ηζ , 3Η) · MS ES (ΜΗ + = 453); Rf = 0.28 (30% ethyl acetate-hexane). 20 Example 29 Method B-5 [3-Amino-6- (4-fluorenyl-.seden-3-yl) -benzyl-brown sigma-2-yl]-(2, 4-dichlorobenzyl Base)-Method for producing fluorenone-65- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (64)

Step 1: 2-Chrysyl-4- (4-fluorenyl-0 moin-3-yl) -molybdenum

CN OH 10 was dissolved in DMF (25 mL) containing 4-bromo-2-methoxy-phenylcyanide (2.4 g, 11.32 mmol). To this solution was added bis (tetramethylethylenedioxanyl) dioxane (3 g, 11.88 mmol), acetic acid (11) (0.76 g, 0.34 mmol), and potassium acetate (3.3 g, 34 mmol). ). This mixture was degassed by Ar flushing for 15 15 minutes and heated to 80 ° C for 5 hours. Add 3-bromo-4-methyl-methylphene (1.8 g, 10.2 mmol) and cesium carbonate (5.53 g, 17 mmol) to the mixture. (Triphenylphosphine) Palladium (0). The solution was stirred at 80 ° C for 18 hours. The reaction mixture was poured into a system of ethyl acetate: water (1: 1,200: 200 mL). The organic phase was separated and the product was extracted with EtOAc (3 X 200 mL). The organic 20 layers were combined, washed with brine (100 mL), and dried over sodium sulfate. The organic layer was concentrated in vacuo and the crude product was dissolved in dichloromethane (2.5 mL) and cooled to 0 ° C. Chlorine (0.726 g, 5.45 mmol) was added, and the solution was stirred for 5 minutes. Ethyl mercaptan (0.333 g, 5.45 mmol) was added, and the solution was stirred at room temperature for 2 hours. The reaction was stopped by adding water (10 mL), and the aqueous layer was extracted with methane (3X20 mL). -66- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (65 ). The organic phases were combined and dried over sodium sulfate. The organic solution was concentrated in vacuo. Purified by flash chromatography (10% EtOAc · Kiyain-> 30% EtOAc: hexane) to give 0.231 g (9.75%) of 2-acetyl-4- (4-fluorenyl-σ-phene- 3-yl) -phenylcyanine. 1HNMR (digas methane- 丄) (57.56 (d, J = 8.5 Ηζ, 5 1Η), 7.31 (d, J = 4.2 Ηζ, 1Η), 7.25—7.03 (m, 4Η), 2 · 29 (s, 3H) · LC-MSRT: 3.34 minutes, [μ + ΗΓ: 216.1. Step 2: [3-Amino-6 (4-methyl-thiophen-3-yl) -benzene; ^ furan Method for mono-2-yl 1- (2,4-dichloro-phenyl) fluorenone

Employees' cooperation in the Intellectual Property Bureau of the Ministry of Economic Affairs, co-printed by the agency 15 In the step 1 containing 2-hydroxy-4- (4-fluorenyl-thiophen-3-yl) _phenylcyanide (0.050 g, 0.23 mmol) and A stirred solution of 2-bromo-1- (2-gas-4-fluoro-phenyl) -ethanone (0.071 g, 0.28 mmol, 1.2 eq) in anhydrous N, N-dimethylformamide (2 mL) To this was added potassium carbonate (0.048 g, 0.35 mmol, 1.5 eq), and the orange reaction mixture was stirred at 80 ° C. for 18 hours. The resulting deep 20 burgundy reaction was poured into ethyl acetate (5 mL) and water (5 mL). The ethyl acetate layer was washed with water and brine. The organic layer was dehydrated (MgS04), filtered and evaporated in vacuo. The crude product was dissolved in acetonitrile (2 mL) and purified by HPLC (10% acetonitrile: water-> 90% acetonitrile: water). The benzofuran product was collected as a yellow solid (0.066g, (CD2Cl2) 5 7_72 (d, J = 7. 6 -67- Hsi (CNS) A4 specification (210x297 mm) applicable to this standard.)-Description of the invention ν 6 & lt 0 A7 B7 ΗZ, 1Η), 7.e L18-7.09 (Π1, Ms LC-MS (Mr shown in Table 1 and / or can be prepared according to this method A and / or g. K) 3-7 r η ^ 584 (m, 1H), 7.38-7.30 (m, 4 H), 2H), 6.05 (s, 2 H), 2.30 (s, 3 H): > 386.2), RT II 4. 12 minute. Other compounds can be prepared according to the above methods, using appropriate starting materials that are easily available and synthesized by Hu Jinhe method, and prepared by other standard chemical manufacturing methods known above or related technologies.

Rf = 0.50 [30% EtOAc / HEX] -68- (210x297 mm)

Rf (TLC solvent) or RT (minutes) * Rf = 0.41 [25% EtOAc / HEX] Rf = 0.45 [30% EtOAc / HEX] Rf = 0.30 [30% EtOAc / HEX] LC / MS ([M + H] +) (III) Synthesis ** (ij Synthesis 416.0 A-1 j B-1 i I ----! 374.0 comm I B-1 II 342.0 comm B-1 357.0 A-4 巳 -1 200413343 A7 B7 V. Description of the invention (67) Example of the printed structure of the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 丨 Rf (TLC solvent) or RT (minutes) * LC / MS ([M + H] +) (III) Synthesis method ** (I) Synthesis method 34 nh2 h3c Rf = 0.14 @N 50/50 EtOAc / HEX 348.2 comm B-2 35 f ^ Ynh c, 〇Rf = 0.43, HEX / EtOAc = 70/30 525.0 comm B -4 36 f ^ Ynh f 0 Rf = 0.42, HEX / EtOAc = 70/30 509.0 comm 巳 -4 37 4170% FfrNH F 0 Rf = 0.28, HEX / EtOAc = 70/30 505.0 comm B-4 38 RT = 3.91 378.2 A-5 B-5 39 nh2 F RT = 4.09 430/432 A-2 B-5 40 nh2〇h3c Rf = 0.51 [50% EtOAc / HEX] 380 comm B-2 -69- 4. Order. This Paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 Ming (68) Side T— 4 42 43

5 IX Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 Dagger: 1 description of LCMS conditions: HPLC-Electrospray Mass Spectrometry (HPLC ES-MS) is used to install two Gilson 306 pumps and one Gilson 215. Measured by an automatic sampler, a Gilson diode detector, a YMC Pro 018 column (x 23 mm, 120 A), a Gilson HPLC system, and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Scan the spectrum of 120-1000 amu in 2 seconds. ELSD (Evaporative Light Scattering Detector) data was also obtained on analog channels. Using buffer A (aqueous solution containing 2% acetonitrile in 0.02% TFA) and buffer B (acetonitrile solution containing 0.02% TFA in 2% water), perform ladders at 1.5 mL / min • 70- This paper Standards are applicable to China National Standard (CNS) A4 specifications (210x297 mm) 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (69)

Degree of dissociation. The sample rolls off and soil L rises to 3.5% in 3.5 minutes. After 90 minutes of A operation, 0.5 minutes later, the column is in U minutes and 95% B in 0.5 minutes, and then the initial conditions are set. The total operating time is 4.8 minutes. General Method H (i) Compound Preparation Method via 6 * Benzene Cleavage v) The reaction scheme of General Method c below illustrates the method by formula (IV) and (v) present compounds / formula VII compounds. Appropriately substituted 2-amino-5-iodine-benzine (11) and aryl aryl 2: 2: acetamidine]) under experimental conditions (such as: field acid, potassium potassium, carbonic acid steel, _, under For example, the condensation of the buoyant in the feet and at room temperature to loot will produce 6-benzobenzouran (IV) UV) and aryl dihydroxyboronic acid or dihydroxy borate (VI). Coupling reactions between palladium forces can produce the desired compounds. Alternatively, the desired compound is prepared by converting 6 ~ iodo-benzopyran (iv) to di-saccharic acid ester (v), and then performing a coupling reaction between the medium and the aryl halide (VII). Reaction Diagram for General Method C 20

Br or Cl (VIII) (IN) test / solvent heating

-71- This paper size is in accordance with China National Standard (CNS) A4 (210x297) # Γ 200413343 Α7 Β7 5. Description of the invention (70

Example 44 10 Method (Ma_L_3 diamino-6-M-pyridyl) -l-benzyfuran-2-yl 1 (2, 4-digasmidine) _ Method for preparing methylone

15 Step 1: Starting material: 2-cyano_5_ iodojamol production method

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 20 At 0 ° C, add 1.0 M 3 to a solution of 3-dibenzidine (20.0 g, 90.9 mmol) in anhydrous dichloroethane (60 mL) Chlorinated shed dichloroamidine-72- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (71 10 alkanes (100 mL, 100 · 0 mmol, 1.1 eq) After the solution, ethyl thiocyanate (6.85 mL, 100.0 ramol, l.leq) and aluminum vaporization (12.1 g, 90.9 mmol, 1.0 eq) were added. The reaction mixture was at room temperature. After 3 days of incubation, cool to 0 ° C. Add a 50% aqueous sodium hydroxide solution (150 mL) to the dark brown reaction mixture until pH 11. The resulting yellow two-phase layer was allowed to incubate under reflux for 3 hours and then cooled to At room temperature. The two phases were separated, and the aqueous layer was adjusted to pH 1 with a 50% aqueous hydrochloric acid solution at 0 ° C. The acidified aqueous mixture was extracted with ethyl acetate (3 X 400 mL), and the combined organic layers were dehydrated (Na2S04). Filtration and concentration under reduced pressure. Crystallization from ether-hexane (200 mL) yielded 2-cyano-5-phenol as a white solid (14.8 g, 66.4%). W-NMR (DMS0-d6) 5 11 . 43 (s, 1 Η), 7.38-7.36 (m, 2Η), 7.29 (dd? J = 8.4, 1,5 Hz, 1 H): MS GC-MS (M + = 245: RT = 7.45 minutes) : Rf 0.16, 25% ethyl acetate-hexane. Order 15 Step 2: Intermediate: (3-Amino-6-iodo-1-penofuran-2, a method for preparing dikisperyl) fluorenone Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20

In 2-cyano-5-iodophenol (3.68 g, 15.0 mmOl) and 2,2 ', 4'-trichloroethylbenzene (4.02 g, 18 Add potassium carbonate (3 · n -73-) to the anhydrous N, N-dimethylformamide (15 mL) stirring solution of e (1) (this paper size is applicable to China National Standard (CNS) A4 size (210x297 mm) 200413343 A7 B7 V. Description of the invention (72) g, 22.5 mmol, 1.5 eq), the orange reaction mixture was stirred at 80 ° C for 16 hours. The resulting dark wine red reaction was poured into ethyl acetate (500 mL) And water (300 mL). The ethyl acetate layer was washed with a saturated aqueous solution of chloroform, water and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure. The crude product 5 was passed through MPLC (Biotage). Purify and elute with 20% ethyl acetate-hexane. Crystallize from dichloromethane-hexane to give benzofuran as a yellow solid (6.16 g, 95.0 ° / °. R (DMS0-d6) c5 7.88 (d, J = 1.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 1.5, 0.9 Hz, 1 H), 7.61 (dd, J = 8.4, 1 , 5 Hz, 1H), 7.55- 7.51 10 (m, 4H); LC-MS (ES MH + = 432/434). Step 3: The title compound: "3 -Amino-6- (3-pyridyl M-jasmine H ran-2-yl 1 (2,4-diamosyl) methanone

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, containing (3-amino-6-iodo-1-benzofuran-2_yl) (2, 4-dichlorophenyl) 20 ketones (2.0 g , 4.63 mmol) in toluene (10 mL) and ethanol (10 mL) was degassed with argon for 10 minutes. At this time, pyridine-3-dihydroxy rotten acid (740 mg, 6.02 mmol, 1.3 eq), [1, Γ-bis (diphenylphosphino) -ferrocene] dichloro-palladium (II ) And dichloromethane (1: 1) (378 11 ^, 0.46 111111〇1, 0.169) and 2% such as 2 (: 03 aqueous solution (11.6 -74- this paper size is suitable for Chinese national standards) (CNS) A4 specification (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (73)

mL). After argon was bubbled through the reaction for 10 minutes, it was heated to 80 ° C overnight. The reaction was diluted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, purified by MPLC (Biotage), and eluted with 45-65% ethyl acetate-hexane to give 1.69 g (95.3%) of a yellow solid product. 1H-5 Bandit R (DMS0-d〇 (5 8.95 (d, J 2 2. 4Ηζ, 1H), 8.56 (dd, > 4.5, 1.5 Hz, 1H), 8.14 (d, J 2 8. 4Ηζ , 2Η), 7.83 (s, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.1, L2 Hz, 1H), 7.58—7.53 (m, 4H), 7.47 (dd, J = 8.4, 4.8 Hz, 1H): LC-MS (ES MH + = 383/385, RT = 2.58 minutes). 10 Analytical C 62 · 68% Η 3.16% N 7.31%, measured C 62.41% Η 3.18% N 7.230 / 00 Example 45a method Olb 15 (3-amino-5-fluoro-6-pyridin-3-yl-benzofuran-2-yl)-(2, 4-di Chloro-benzyl) -fluorenone

This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (74)

5 Take 4-amino-2,5-diphenyl cyanide (500 mg, 3.24 mmol), benzyl alcohol (385. 9 mg, 3.57 mmol, 1.1 eq), potassium carbohydrate (896. 2 A mixture of mg, 6.49 mmol, 2.0 eq) and 4 angstrom molecular sieves (500 mg) in anhydrous N, N-dimethylformamide (6.5 mL) was stirred at 100 ° C for 24 hours under argon. The reaction was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by MPLC (Biotage) and dissolved in 15% ethyl acetate-hexane, yielding 155.0 mg (19.7%) of the product. iH-NMR (DMS0-d6) 5 7.42-7.32 (m, 6H), 6.49 (d, J = 7.5 Hz, 1Η), 6.27 (width s, 2Η), 5.09 (s, 2H); LC-MS (ES MH + = 243, RT = 2.75 minutes); Rf = 0.27 (25% 15 ethyl acetate-hexane). Step 2: Starting material: 5-Fluoro-2-Ethyl-4-Ephenylphenylcyanide

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs at 0 ° C in a concentrated HC1 aqueous solution (2.6 mL) containing 4-amino-2-phenylfluorenyl-5-fluorophenylcyanide (155.0 mg, 0.64 mmol) ) Sodium lithochonate (66. 2 mg, 0.96 mmol, -76-) dissolved in water (1.0 mL) is added to this paper. The size of the paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200413343 5 Description of the invention (75) A7 B7 L5eq). After stirring at Ot for 1 hour, acetic acid (159 · 3 mg, 0.96 mmol, 1.5 eq) dissolved in water (5.1 raL) was added, and the reaction mixture was stirred at room temperature for 3 days. The reaction was diluted with ethyl acetate and washed with water and brine 'and dehydrated over sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by MPLC 5 (B10tage) and isolated with 25% ethyl acetate-hexane to give 63.0 mg (37_4%) of the product. NMR (DMSO-d6) (Π0.20 (width s, 1H), 7.54 (d, J = 5.1 Hz, 1H), 7.47 (d, J = 7.2 Hz, 0.16 ( 25% ethyl acetate-hexane). 10 products: 3-amino-6-iodo-1-moscouran-2-yl) (2,4-diplex I) fluorenone 15

Printed by the Consumers 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the People's Republic of China containing 20 ~ 5-2-benzyl-4-mothenyl fl (60 mg, 0.23 mmol) and 2,2', 4'-trichloroacetophenone ( 76.5 11 ^, 0.34 111111〇1, 1.5 69) anhydrous N, N-dimethylamidamine (3.3 mL) was added to a stirred solution of potassium carbonate (47.3 mg, 0.34 mmol, 1.5eq), the orange reaction The mixture was stirred at 80 ° C for 16 hours. The resulting dark wine red reaction was poured into ethyl acetate (100 mL) and water (50 mL). The ethyl acetate layer was washed with a saturated aqueous solution of ammonium hydroxide, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by MPLC (Biotage), and dissolved in 15% ethyl acetate-hexane. -77- This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of the invention ( 76) 41.0 mg (39.9%) of the product was produced. Li R (acetone-d6) (57 · 95 (d, J = 4.5 Hz, 1H), 7.83 (d, J = 7. 5 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H ), 7.61 (s, lH), 7.56 (d, J = 1.8 Hz, 1H), 7.00 (width s, 2H): LC-MS (ES MH + = 450, RT = 5 3.78 minutes) Rf = 0.39 (25% ethyl acetate-hexane). Step 4: The title compound: (3-amino-5-fluoro-6-ammonium-3-yl-benzocoll-2-yl )-(2, 4-Digas-benzyl) -methanone

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, this compound is composed of (3-amino-6-moth-1-benzoσfuran-2-yl) (2, 4-15 diphenylphenyl) methanone ( 38.0 mg, 0.08 mmol), as described above [3-Amino-6- (pyridin-3-yl) -1-benzofuran-2-yl] (2, 4-dichlorobenzyl) methyl Ketone was prepared in the same manner, yielding 13.0 mg (38.4%) of the product. NMR (acetone-ds) 5 8.84 (t, J = 1.8 Hz, 1H), 8.64 (dd, J = 4 · 8Ηζ, 1.5 Hz, 1H), 8.06- 8.01 (m, 1H), 7.92 ( d, J 20 = 10.2 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.63 (s, 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.56 (dd, J = 8. 1 Hz, 2.1 Hz, 1H), 7.45 (ddd, J = 7 · 2Ηζ, 4.8 Hz, 0.9 Hz, 1H), 7.05 (width s, 2H); LOMS (ES MH + = 401, RT = 2. 66 minutes) . -78- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200413343 A7 _ B7 V. Description of the invention (77) The palladium used in the coupling reaction of palladium medium in the process of step 3 above may be used There are some changes in the catalyst, as shown in the following example: ii! 45b 5 1 Amine-6- (2-fluorenyl-benzium) -moprofuran-2-some 1- (2,4-dihelium- Pen base)-Method for preparing fluorenone

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Add 75 mg (0.17 mmol, 1 eQ) (3-amino-6-iodo-1-benzofuran-2-yl) (2, 4-dichlorophenyl) methanone in a 7 mL vial. 2.5 mL of DME degassed with argon. 10 mg (0.01 mmol, 15 0.05 eq) Pd (PPh3) 4 was added, and the vial was shaken for 5 minutes. At this time, 29.1 mg (0.21 mmol, 1.2 eq) of 2-methylphenyldihydroxyboronic acid and 0.43 mL (0.43 mmol, 2.5 eq) of 1 M Na were added, and the reaction was carried out at 80 ° C with It was shaken overnight under argon. The volatiles were eliminated and the residue was purified by preparative DLC (25% EtOAc / hexane) to give 42.9 mg (62%) of the desired product, 20 as a yellow solid.沱 -legs !? (DMS0-d6) 57.91 (d, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.49 (dd, 1H), 7.34-7.24 (m, 8H), 2.28 (s, 3H), LC -MS (+ esi MH + = 396.3, RT = 3. 86 minutes), TLC Rf = 0.48 (25% EtOAc / hexane). -79- This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 ______ B7 V. Description of the invention (78 Example 46 Method C-2: [3'- 暴: 6—RAN-2-a 1 (2 '4-Difluorobenzyl) fluorenone ^

10 steps ": Initial detection of L3-amino-6- (4 · 4HTOmethyl-L · 2 · 2 · 2 pentamyl-2-yl) -1-benzyl. Husband drinking—2-based 1 (2 · 4-diqibenzyl) methanone f method

15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Take (3-amino-6-iodo-1-benzofuran-2-yl) (2, 4-difluorophenyl) fluorenone (225 mg, A solution of 0.52 mmol) of 1,4-di-moxa alkane (2.6 mL) was degassed with argon for 30 minutes. At this time, [1,1, -bis (diphenylphosphino) -ferrocene] digas-palladium (II) complex with dichloromethane (1: 1) (12.8 mg, 0.02 mmol, 0.03 eq), triethylamine (0.22 mL, 1.56 mmol, 3.0 eq) and o-di-tert-ol borane (0.13 mL, 0.89 riol, 1. 7 eq). After argon was passed in the reaction for 10 minutes, it was heated to 80 -80- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (79) ° c overnight . The reaction was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, purified by MPLC (Biotage), and eluted with 15% ethyl acetate-hexane to give 154.5 mg (68.7%) of an orange foam. 1H-NMR (DMS0-d6) (5 8.05 (d, J = 7.8 Hz, 1H), 5 7.76 (d, J = 2.4 Hz, 1H), 7.58-7.48 (in, 6 H), 1.28 (s , 12H); LC-MS (ES MH + = 432/434, RT = 3.97 minutes). Step 2: The title compound: "3-Amino-6- (2-methylsome-3- also pyrimidine)- Preparation method of 1 -10 benzofuran-2-yl 1 (2, 4-diazabenzene fluorenone

Take [3-Amino-6- (4, 4, 5, 5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1-benzofuran-2-yl] (2,4-Difluorophenyl) methanone (65 mg, 0.15 mmol) in toluene (1.0 mL) and ethanol (10 times) was printed using the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Degas for 30 minutes. At this time, after adding 3-bromo-2-fluorenylpyridine (33.6 mg, 20 0.20 mmol, 1.3eq), [1, ι, -bis (diphenylphosphino) -ferrocenyl iron] di The complex of chloro-palladium (II) with dioxane (1: 1. 2 mg, 0.02 mmol, 0.1 eq) and 2M Na2CO3 aqueous solution (0.38 mL). After argon was passed through the reaction for 15 minutes, it was heated to 8 ° C—night. The reaction was diluted with ethyl acetate, washed with water and brine, and dehydrated with magnesium sulfate. The solvent was removed under reduced pressure-81- National Standard (CNS) A4 specification (210x 297 mm) 200413343 A7

On the other hand, MPLC (Biotage) was used to purify it with 45-65% ethyl acetate-hexane to produce 23 mg (38.5%) of a yellow solid product.沱 -NMR (DMS〇- 丄) 58 · 46 (dd, J = 4.5, 1.5 Ηζ, 1Η), 8.11 (d, J = 8 · 4 Ηζ, ^), 7.75 (d, J = 2 · 1 Ηζ, 1 Η), 7.64-7 · 56 (m, 5Η), 46 (s, 1Η), 7.31-7.27 (m, 2Η), 2.41 (s, 3Η) · LC-

ms (eSmh +: 397/399, κτ = 2.34 minutes). ) 'LC ^ Other compounds shown in Table 2 below can be prepared according to the above method, using appropriate starting materials that are easy to extract and / or can be synthesized according to the method shown herein, and prepared using the above method or other standard chemical methods known in related art . Example of compound of formula (I) synthesized by Method C. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs.

-82- This paper is suitable for CJNS A4 (21G X 297).

AB Consumer Intellectual Property Bureau of the Ministry of Economic Affairs, printed the structural formula of Rf (TLC solvent) or RT (minutes) * LC / MS ([_] +) (ΠΙ) synthesis method * wood (VI) or (VII) Synthesis method # (I) 的 合成 方法 48 nh2 C! Rf = 0.14 [25% EtOAc / HEX] 401/403 comm comm C-1 49 nh2 〇 乂. C, Rf = 0.14 {25% EtOAc / HEX) 427/429 comm comm C-1 50 nh2 C! Rf = 0.35 (25% EtOAc / HEX) 388/390 comm comm C-1 51 Rf = 0.245 (25% EtOAc / HEX) 426.0 comm comm C-1 52 NH2 C! Rf = 0.34 (50% EtOAc / HEX) 397.0 comm comm .C-1 53 nh2 110¾1 Cl Rf = 0.25 (25% Et〇Ac / HEX) 388/390 comm comm C-1 54 nh2 c Rf = 0.13 (25% EtOAc / HEX) 430/432 comm comm C-1 55 nh2 H3 (T〇C 丨 Rf = 0.30 (25% EtOAc / HEX) 412/414 comm comm C- 1 56 nh2 CN Cl Rf = 0.08 (25% EtOAc / HEX) 407/409 comm comm C-1 -83-

This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (82) Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economics Example structural formula Rf (TLC solvent) or RT (minutes r LC / MS ([M + H] +) (Synthesis of IEO * Synthesis of Wood (VI) or (VII) ** Synthesis of Tritium 57 nh2 F Rf = 0.10, HEX / EtOAc = 50/50 347.0 A -3 comm C-1 58 ch3 Cl Rf = 0.21 (25% EtOAc / HEX) RT = 3.45 424.3 comm comm C-1 59 nh2 α?% Cl Rf 2 0.15 (25% EtOAc / HEX) RT = 3.25 397.3 comm comm C-1 60 nh2 of% C! Rp0.48 (25% EtOAc / HEX) RT = 3.86 396.3 comm. Comm C-1 61 02¾1 Cl Rf = 0.35 (25% EtOAc / HEX) RT = 3.69 412.3 comm C-1 62 nh2 F Cl Rf = 0.75 [50% EtOAc / HEX] 400/402 comm comm C-1 63 nh2 h3cX ^ Rf = 0.65 [50% EtOAc / HEX] 424/426 comm comm C-1 64 〇NH bl h3c 〇 Rf II 0.35 [50% EtOAc / HEX] 475/477 comm comm .C-1 -84- This paper size applies to China National Standard (CNS) A4 (210x297) 200413343 A7 B7 V. Description of the invention (83) Economy Printed by the Consumer Property Cooperative of the Ministry of Intellectual Property Bureau Structural formula Rf (TLC solvent) or rt (minutes) * LC / MS, + H] +) I (in) synthesis method ** (VI) or (vn) synthesis method ** (I) synthesis method 65 FC! Rf = 0.75 [50% EtOAc / HEX] 418/420 comm comm C-1 66 nh2 C! Cl Rf = 0.75 [50% EtOAc / HEX] 416/418 comm comm C-1 67 nh2 CH, C! Rf = 0.75 [50% EtOAc / HEX] 396/398 comm comm C-1 68 nh2 OEt n Rf = 0.75 [50% EtOAc / HEX] 426/428 comm comm C-1 69 nh2 ςτ0% 4 nh2 Rf = 0.27 (50 % EtOAc / HEX) RT = 2.13 398.0 A-4 comm C-1 70 pr € c% F CN F Rf = 0.33 [30% EtOAc / HEX] 375.0 comm comm C-1 71 H3cX H Rf = 0.25, HEX / EtOAc = 70/30 392.0 comm comm C-1 72 OMe F Rf = 0.33, HEX / EtOAc = 70/30 380.0 comm comm C-1 -85- 4. Order · This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 Μ B7 V. Description of the invention (84) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, the structural formula Rf (TLC solvent) or RT (minutes r I LC / MS ([M + H] +) Synthetic method of (m) * Synthetic method of wood (VI) or (VII) ** Synthetic method of tritium 73 ch3 f Rf = 0.40 [30% EtOAc / HEX] 364.0 comm comm C-1 74 nh2 Rf = 0.46 (50% EtOAc / HEX) RT = 3.12 373.4 A-4 comm C-1 75 nh2 Rf = 0.51 (50% EtOAc / HEX) RT = 3.25 389.4 A > 4 comm C-1 76 nh2 Rf = 0.46 (50 % EtOAc / HEX) RT = 3.26 389.4 A-4 comm C-1 77 V, b Rf = 0.15, HEX / EtOAc = 50/50 443.0 comm comm C-1 78 g0% 〇 NH C! Ch3 Rf = 0.14 [ 50% EtOAc / HEX] 439/441 comm comm C-1 79 nh2 170¾ n〇2 Rf = 0.43 (75% EtOAc / HEX) RT = 2.26 374.1 A-4 comm C-1 80 nh2 ch3 Rf = 0.10 [30% EtOAc / HEX] 343.0 comm comm C-1 -86- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of invention (85) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Example Structural formula Rf (TLC solvent) or RT (Minute LC / MS ([_] +) Synthesis method of (m) ** Synthesis method of (VI) or (VII) ** 合成 Synthesis method 81 n〇 2 ch3 Rf = 0.45 [30% EtOAc / HEX] 387.0 comm comm C-1 82 nh2 CN ^ CH3 Rf = 0.43 [30% EtOAc / HEX] 367.0 comm comm C-1 83 nh2 0 < ^ nh one ch3 ch3 Rf = 0.10 [30% EtOAc / HEX] 399.0 comm comm C-1 84 nh2 HN CH3 〇? 'Ch3 Rf = 0.15 [30% EtOAc / HEX] 435.0 comm comm C-1 85 nh2 F CH3 Rf = 0.50 [30% EtOAc / HEX] 360.0 comm comm C-1 86 nh2 Cl ^ ch3 Rf = 0.50 [30% EtOAc / HEX] 376.0 comm comm C-1 87 nh2 K, C ^ O ChLj Rf = 0.35 [30% EtOAc / HEX] 384.0 comm comm C-1 88 nh2 fO € c% H3 CH3 Rf = 0.46 [30% EtOAc / HEX] 410.0 comm comm C-1 -87- Applicable to this paper size China National Standard (CNS) A4 Specification (210x297 mm) 200413343 A7 B7 V. Invention Description (86) Employees' Cooperatives of Intellectual Property Bureau of the Ministry of Economic Affairs printed examples of structural formula Rf (TLC solvent) or RT (minutes r LC / MS ( [M + H] +) (IU) Synthesis ** (VI) or (VII) Synthesis ** ① Synthesis 89 89 〇Me CH3 Rf = 0.40 [30% EtOAc / HEX] 372.0 comm comm C- 1 90 nh2 FY ° f CH3 F Rf = 0.45 [30% EtOAc / HEX] 426.0 comm comm C-1 91 nh2 F Rf = 0.05, HEX / EtOAc = 70/30 367.0 A-4 comm C-1 92 nh2 n〇 2 f Rf = 0.28, HEX / ET) AC = 70/30, 411.0 A-4 comm C-1 93 nh2 CN F Rf = 0.28, HEX / EtOAc = 70/30 391.0 A-4 comm C-1 94 nh2 〇 Ah NH f ch3 Rf = 0.10, HEX / EtOAc = 70/30 423.0 A-4 comm C-1 95 nh2 Rf = 0.08, HEX / EtOAc = 70/30 349.0 A-2 comm C -1 96 HN P ~ F 〇..ch3 Rf = 0.05, HEX / EtOAc = 70/30 459.0 A-4 comm C-1 -88- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 V. Description of the invention (87) Example of printing the structural formula of Rf (TLC solvent) or RT (minutes) * LC / MS ([M + H] +) (ΙΠ) synthesis method by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ** (VI) or (vn) synthesis ** (I) synthesis 97 nh2 Rf = 0.30, HEX / EtOAc = 70/30 384.0 A-4 comm C-1 98 nh2 Rf = 0.08, HEX / EtOAc = 70/30 381.0 A-4 comm C-1 99 nh2 pr °% CN Rf = 0.30, HEX / EtOAc = 70/30 373.0 A-2 comm C-1 100 nh2 O NH \ Rf = 0.05, HEX / EtOAc = 70/30 405.0 A-2 comm C-1 101 nh2 HN., 0 o 'ch3 Rf = 0.05 ,: HEX / EtOAc = 70/30 441.0 A-2 comm C-1 102 nh2 9 ^%' NH? Rf = 0.10, HEX / EtOAc = 70/30 363.0 A-2 comm C-1 103 nh2 σ0% F RpO.14 (50% EtOAc / HEX) RT = 2.50 363.4 A-2 comm C-1 104 nh2 HN., 〇〇 ·, Ch3 Rf = 0.10, HEX / EtOAc = 50/50 423.0 A-6 comm C-1 -89- 4. Order · This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 5 Description of the Invention (80) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, the structural formula Rf (TLC solvent) or RT (minutes) * LC / MS ([M + H] +) (in) Synthesis ** (VI ) Or (VII), ** ⑴ ⑴ 105 C Rf = 0.11 (100% EtOAc) 426.0 comm comm C-2 106 00¾1 CI Rf = 0.10 (25% EtOAc / HEX) 383.0 comm comm C-2 107 nh2 0f, NH2.丨 Rf = 0.15 (SILICA, EtOAc: HEX, 4: 6) 461.0 comm comm C-2 108 Η〇 ^ Rf = 0.13 (SILICA, EtOAc / HEX, 3/7) 412.0 comm comm C-2 109 νη2 η2ν Rf = 0.11 (SILICA, MeOH / CH2CI2, 6/94) 435 comm comm C-2 110 νη2 〇Η Rf = 0.09 (SILICA, EtOAc / HEX, 3/7) 426.0 comm comm C-2 111 HO 丄 CH3 C 丨 Rf = 0.26 (SILICA, EtOAc / HEX, 3/7) 426.0 comm comm C-2 -90- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (89) Ministry of Economic Affairs Intellectual Property Bureau employee consumer cooperative printed examples of structural formula Rf (TLC solvent) or RT (minute r LC / MS ([M + H] +) (1¾ synthesis method ** (VI) or (vn) synthesis method * * 〇〇 的 合成 方法 112 nh2 Rf = 0.23 (SILICA, EtOAc / HEX, 3/7) 421.0 comm comm C-2 113 nh2 (/ ¾ p, ~, α Rf = 0.29 (SILICA, EtOAc / HEX, 3 / 7) 519.0 comm H-11 C-2 114 CI (^ OH OH Rf = 0.55, 100% EtOAc 472/474 comm H-6 C-2 115 nh2 (7 ° ¾1 穸, ~. H Cl Rf = 0.18 (SILICA , EtOAc / HEX, 6/4) 505.0 comm H-11 C-2 116 nh2 0 'Cl Rf = 0.15 (10% MeOH / EtOAc) 399.0 comm comm C- 2 117 〇 < y.NH Cl Δ Rf = 0.23, HEX / EtOAc = 70/30 465/467 comm H-10 f 118 nh2 00¾1 k ^ Cl N CH3, ch3 Rf = 0.14 (SILICA, EtOAc / HEX, 1 / 1) 467.0 comm H-12 C-2 -91- This paper size is applicable to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of invention (90) Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Preparation Example Structural formula Rf (TLC solvent) or RT (minutes Γ LC / MS ([M + H] +) (m) Synthesis; Synthesis of method ** (VI) or (VII) ** 〇〇 Synthesis Method 119 nh2 9r〇:% 0 丄 N, Cl Η Rf = 0.24 (SILICA, EtOAc / HEX, 3/2) 439.0 comm H-13 C-2 120 νη2 {if% 3 Cl Rf = 0.33 (100% EtOAc) 386.0 comm comm C-2 121 νη2 h3c Cl Rf = 0.32 (100% EtOAc) 386.0 comm comm C-2 122 nh2 OH F Rf = 0.12, HEX / EtOAc = 70/30 382.0 A-4 comm C-2 123 nh2 OH Cl Rf = 0.14, HEX / EtOAc = 70/30 398/400 comm comm C-2 124 C, Rf = 0.30 (SILICA, MeOH / CH2CI2, 8/92) 494.0 comm H-12 C-2 125 nh2 00¾01 L / NH2 Cl 〇Rf = 0.17 (SILICA, EtOAc / HEX, 4/1) 439.0 comm H-14 C-2 126 00¾1 lo c, Rf = 0.07 (SILICA, EtOAc / HEX, 7/3) 465.0 comm H-12 C-2 -92- 4. • Order · This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343

AB 5. Description of the invention (91) Synthesis of structural formula Rf (TLC solvent) or RT (min. F LC / MS ([M + H] +) (ΙΠ)) by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs; * Synthesis method of (VI) or (VII) ** Synthesis method of ⑴ 127 lo c, Rf = 0.30 (SILICA, MeOH / CH2CI2 > 6/94) 462.0 comm H-12 C-2 128 CN Cl Rf = 0.32, HEX / EtOAc = 70/30 425/427 comm comm C-2 129 nh2 0 丄 NH C, A Rf = 0.13 (SILICA, EtOAc / HEX, 4/6) 465.0 comm H-13 C-2 130 00¾1 O 丄 NH C, * ^ ch3 Rf = 0.24 (SILICA, EtOAc / HEX, 4/6) 453.0 comm H-13 C-2 131 Rf = 0.10 (SILICA, EtOAc / HEX, 6/4) 453.0 comm H-4 C-2 132 nh2 H〇 ^ C1 Rf = 0.35 (SILICA, EtOAc / HEX, 4/6) 440.0 comm H-15 C-2 133 nh2 a °% '〇 丄 hn ~ ⑶c, Rf = 0.17 (SILICA, EtOAc / HEX, 8/1) 469.0 comm H-13 C-2 -93- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343

A

7 B Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (92) Examples of structural formula Rf (TLC solvent) or RT (minutes r LC / MS ([_] +) (in) synthesis method **. Synthesis method of (VI) or (VII) ** Synthesis method of 00 134.0 C! OH Rf = 0.55t 100% EtOAc 472/474 comm H-6 C-2 135 nh2 N〇2 C! Rf = 0.45, HEX / EtOAc = 70/30 445/447 comm comm C-2 136 nh2 Rf = 0.14 (SILICA, EtOAc / HEX, 1/1) 483.0 comm H-13 C-2 0 丄 'N 八' ^ 〇Me C 丨H 137 nh2 00¾ ° L ^ o Cl Rf = 0.17 (SILICA, EtOAc / HEX, 7/3) 453.0 comm H-13 C-2 hn'ch3 138 pr ^% 0 ^ S'NH C, ππ3 Rf = 0.10 ( SILICA, EtOAc / HEX, 3/7) 475.0 comm H-11 C-2 139 〇; S, N ~ C, U Rf = 0.15 (SILICA, EtOAc / HEX, 3/7) 489,0 comm H-11 C -2 140 nh2 Rf = 0.23, HEX / EtOAc = 401/403 comm H-7 C-2 kN ^ F \ = (Cl 70/30 141 nh2 a?% 1 n Rf = 0.30, HEX / EtOAc = 70/30 413.0 comm H-8 C-2 -94- nv

Gage 4) AM No. 97 2 X o 200413343 A7 ___ B7 V. Description of the invention (93) Example Structural formula Rf (TLC solvent) or RT (minutes LC / MS ([M + H] +) (ΙΠ) Synthesis method ** Each component of (VI) or (VII) ** 合成 Synthesis of i (I) 142 nh2 Human CH3 F Η Rf = 0.26 (SILICA, EtOAc / HEX, 3/2) 423.0 A-2 H-13 C-2 143 νη2 〇0% 'UNH2 I Rf = 0.12 (SILICA, EtOAc / HEX, 4/1) 453.0 Comm H-14 C-2 144 νη2 cci?% Η Vi Rf = 0.33, HEX / EtOAc = 70/30 412/414 comm H-9 C-2 145 νη2 〇c?% Cl Rf = 0.29 (40% EtOAc / HEX) 419.0 comm comm C-2 Note field: * The following describes the LCMS conditions: HPLC-electrospray mass spectrometry (HPLC ES-MS) is printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. It uses two Gilson 306 pumps, one Gilson 215 to take 20 prototypes, one Gilson diode detector, and one YMC Pro C-18 column Measured by a Gilson HPLC system with 23 mm, 120 A) and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. The spectrum of 120-1000 amu was scanned in 2 seconds. The analog channel was also used Obtain ELSD (evaporative light scattering detector) data. Buffer solution-95- This paper size applies Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (94 0.02% TFA in 2% acetonitrile in water) and buffer B (containing = 2 Hidden 2% water in acetonitrile solution), separate the ladder f in 15 minutes. ^ The secretion of the sample is as follows: _A After 0.5 minutes, it rises to 95% B in the clock, and holds β β for 5 minutes. , And then make & 1 knife clock _ to the initial conditions. The total operating time is 4.8 minutes. ** comm refers to available from the commodity. MD. Side dibenzofuran intermediate 10 H11) and dicarboxyl ester (V Method f) and (VI) Another method for preparing compounds of formula (I) is illustrated in the following reaction schemes of general methods D-1 and D-2 and the reaction scheme of general method D-3. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs on Consumer Consumption Cooperatives. 20 General methods D-1 and D-2 use common intermediates [(3-monoamino-6-bromo-benzofuran-2-yl)-( 2,4-Dichloro-phenyl) -methanone (νπι) 15 to prepare a 6-substituted benzofuran analog of formula (I). The compound (yin) was synthesized from 4- > stin-2-fluoro-phenylcyanide using three simple chemical conversion reactions (see the experimental section) shown in the following reaction scheme. (VIII) and aryl dihydroxyboronic acid or dihydroxy borate (VI) are coupled by a palladium medium to produce the desired compound (L). Alternatively, 6-bromo-benzofuran (VIII) can be converted to form The dihydroxy pendant ester (V) is then prepared via the coupling reaction of the palladium medium with the aryl halide (VII) to prepare the desired compound. General method D-1 and D-2 reaction chart -96- This paper is applicable to the standard China National Standard (CNS) A4 specification (210 X 297 mm) 200413343 A7 B7 V. Description of invention (95)

Br V, F

XN K2C03 / Me0H / DMF-> Heating CN 〇Me

AICI3 / DCM heating

CN Λ

Br or Cl (HI) Λ test / solvent heating

15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. In formula (I), when Rf is a low-carbon alkyl group, it can be prepared according to the general method D-3. Intermediate (VIII) is tritiated by a general method, and then reduced by calorimetry to form intermediate (IX). After the coupling reaction of palladium medium between (IX) and aryldihydroxyboronic acid or dihydroxyborate (VI), the desired compound of formula (I) is produced. General Method D-3 Reaction Diagram Method D-3 -97- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7

200413343 A7 B7 V. Description of the invention (97) Take 4- > stinky-2-gas-base gas (15.0 g, 75.0 minol), formazan (30.4 mL, 350 mmol) and potassium carbonate ( 31.ig, 225 mmol) of DMF (150 mL) was stirred overnight under argon and 55 ° C. At this point, TLC (100% dichloromethane) showed no starting material, and the reaction mixture was poured into ether (300 mL) and water (150 mL). The layers were separated, and the organic layer was washed with water (150 mL) and brine (50 mL), dehydrated with magnesium sulfate, filtered and decompressed to produce (15.2 g, 95.5%) 4- > Odor-2 ~ 曱Phenyl-phenyl nitrogen as a white solid. 1H-NMR (CDC13) 5 7 · 41 (d, J = 8.1 Hz, 1H) 7.16 (dd, J = 8. 1, 1, 6 Hz, 1H), 7.13 (d, J = 1, 6Hz 10 1H), 3.93 (s, 3H); MS GC-MS (M + = 211; RT = 6.15 minutes). Step 2: Intermediate: 4-bromo-2-hydroxy-benzyl cyanide

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. To a solution containing 4-mo-2-methoxy-phenylcyanide (4.60 g, 21.7 dioxane (20 mL) was added aluminum chloride (14.5 g, ι (08 20 mmol). After stirring under argon for 10 minutes, dichloromethane was added and the mixture was refluxed overnight under argon. The reaction was diluted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give (4.09 g / 95 · 2%) 4-bromo-2-hydroxy-phenylcyanide as a light gray product. Li R (CDCl3) 5 7.35 (d, J = 8. · 4Ηζ, 1Η), 7.19 (d, j: -99-) This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (98) 1.4 Hz, 1H), 7.14 (dd, J = 8.4, 1, 4 Hz, 1H), 6. 15 (s, 1H); TLC Rf = 0.88 (50% ethyl acetate -Hexane). Step _1 · "(3-amino group ~~ 6- > odor-benzyl 17-furan-2-yl)-(2,4-dichloro-benzyl 5-yl) -fluorenone

10 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs This compound is composed of 4-bromo-2-hydroxy-phenylcyanide (4.0 g, 20.3 mmol) 'Similar to [(3-Amino-6-moth-benzo-smell -2-yl)-(2,4-digas-phenyl) -methanone (Example C-1 step 2) was prepared by the method of producing 6.lg (78%) [(3-amino-6-bromo -Benzocran-2-yl)-(2,4-dichloro-phenyl) -methyl 15 ketone as a yellow solid. 1H-NMR (DMS〇-d6) < 5 7.96 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 1.7 Hz, 1.0 Hz, 1H), 7.56-7.49 (m, 4H), 7.44, (dd, J = 8.5 Hz, 1.7 Hz, 1H). MS LC-MS (MH + = 386.1), LC MS RT: 3.68 minutes. 20 Example 147 Method D-1: 113-Amino-6-fluorene-benzyl. Palladium-2-yl)-(2,4-diazepine-jasmine V methyl ketone and aryl dihydroxyboronic acid to form a diboron ester coupling between palladium-mediated coupling reaction -100-This paper size applies to China National Standard (CNS) A4 specification (21 × 297 mm) 200413343 A7 B7 V. Description of the invention (99) According to the process described in Example C ~ 1 step 3, but use [(3-amino-6-bromo -Benzofuran ~ 2-yl) — (2,4-digas-phenyl) -fluorenone (VIII) instead of [(3-amino-6-iodine ~ benzofuran-2 2-yl) — (2 , 4-Digas-phenyl) monomethanone (IV) ° is also used in the example!)-3 A similar reaction is performed in step 2. Example 148 Method D-20 Amine-6-Ethyl-Benzene) Monobenzyl-2-N-yl-1_ (2,4-dichlorodibenzyl) -fluorenone

15 Step 1: `` 3-Amino-(^ (4.4.5. 5-tetramethyl-``1,3,21 dioxorane 1 10 cyclo-2-some benzofuran-2-yl- (2, 4-dichloro-phenyl) -methanone

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the People's Republic of China 20 g, 6.5 mmol), potassium acetate (1.97 g, 19.5 -101- This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (lGG) mmol), An anhydrous DMS0 mixture of bis (tetramethylethylenedifluorenyl) diboron (1.99 g, 7.79 mmol) was degassed under Ar for 30 minutes. Then Pd (dppf) 2Cl2 (0.53 g, 0.65 mmol) was added and the mixture was degassed again for 10 minutes. The reaction was heated to 100 ° C for 3.5 hours. The reaction mixture was poured into 5 ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on a silica column and dissolved in 25% ethyl acetate-hexane to give 1.2 g (43%) of 3-amino-6- (4,4,5,5-tetramethyl- [1 , 3,2] dioxoborolan-2-yl) -benzofluoran-2-yl]-(2,4-dichloro-phenyl) -methanone as a brown solid. 1Η-Li R (CDC13) c? 7.81 (s, 1Η), 7.67 (d, J 10 2 7 Hz, 1H), 7.60 (d, J = 7 Hz, 1H), 7.55-7 · 46 (m , 2H), 7.34, (dd, J = 8.2 Hz, 2.0 Hz, 1H), 5.93 (bs, 2H), 1.33 (3, 12 H). MS LC-MS (mT = 432.3, 434.2), LC MS RT: 3. 95 minutes. 15 Step 2: "Method for preparing 3-amino-6- (3-ethylbenzyl) -benzyfuran-2-yl M2, 4-dichloro-benzyl) -fluorenone

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs This compound is made from 1-mo-3-ethyl-benzene (0.06 g, 0.30 mmol) using [3-amino-6- (2-methyl-pyridyl)- 1-benzofuran-2-yl] (2,4-dichlorophenyl) methanone (Example C-2, step 2), produced -102- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (101) Health 35.1mg (37%) [3-amino-6- (3-ethyl-phenyl) -benzofuran-2-yl ^^ -Dichloro-phenylbupropionone 'is a yellow solid. ) 5 7 · 67 (dd, J — 8, 1 Hz, 1H), 7.56-7, 53 (m, 1H), 7.55-7.49 (m, 3H), 7.45-7.34 (m, 4H), 7.25 -7.21 (dm, 5 J = 4 Hz, 1H), 6.04 (bs, 2H), 2.72 (q, J = 6 Hz, 2H), 1 · 28 (t, J = 6 Hz, 3H) · MS LC-MS (MH + = 410.3, 412.1), LC MS RT: 4.17 minutes. Example 149 10 Method D-3 N- (3- "2- (2,4-Digas-benzylidene V3-methylamino-benzyfuran-6-a certain benzylacetamide

H3Cv.NH Cl Y 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Step 1: Intermediate (6-bromo-3-fluorenylamino-benzocrean-2 _-- yl) di C_2, 4-20 di Chloro-benzyl) -methanone

25 -103- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (102) Prepare acetic acid formic anhydride according to the following method: dropwise formic acid (L 5 mL (39 mmol) to acetic anhydride (3 mL, 32 jnmol) in a 250 raL flask in an ice bath, and then gently heated at 60 ° C for 2 hours. In a cooled flask containing acetic acid acetic anhydride (2.5 eq), add (3-amino-β-mo-benzobenzofuran-2-5)-(2, 4-dichloro-phenyl) -Fluorenone (prepared according to Method D) (5 g, 13 mmol, 1 eq) in 20 mL of anhydrous THF. The reaction was refluxed at 70 ° C for 40 hours. As the reaction cooled, many solids precipitated. The white solid was filtered off, washed with THF, and dried in a vacuum oven. The resulting product was suspended in 40 mL of THF printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, and methylborane methyl sulfur (3, 32 10 mmol, 2.5 eq) was added dropwise in an ice bath. The reaction mixture was stirred in an ice bath for 3 hours, 10 mL of methanol was added, and the mixture was stirred for another 30 minutes. The reaction mixture was evaporated to give a green sticky substance. When EtOAc was added to the mixture, a white solid formed, and the solid was filtered off. The filtrate was concentrated and the residue was purified by MPLC (Biotage). 700 mg (14 ° / 0) of 6-bromo-3-methylamino-benzofuran-2-yl)-(2,4-15 dichloro-phenyl) -methanone was obtained as a yellow solid. 1H-NMR (CDC13) 57. 98 (width, m, 1H), 7.82 (d, J = 8 Hz, 1H), 7.52 (d, > 2 Hz, 1H), 7.48 (d, 1 = 2 Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 7.35 (t, J = 2 Hz, 1H)? 7.33 (t, J = 2 Hz, 1H), 2.40 (s, 3H). MS LC-MS MH + = 398/400/402; Rf = 0.72, 50% EtOAc- 20 hexane. Step 2: Preparation method of N- {3- "2- (2,4-diargon-benzylidene) -3-fluorenylamine-moprofuran-6-some1 molybamine -This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (103)

Take ethyl containing (6-bromo-3-fluorenylamino-benzofuran-2-yl)-(2,4-dichloro-phenyl) -methanone (100 mg, 0.25 mm〇i) Glycol dimethyl ether (1 mL) was degassed with argon for 10 minutes. At this time, a solution of degassed 3-acetamido 10-ylbenzenedihydroxyboronic acid (49 mg, 0.28 mm, 1.1 eQ) in ethylene glycol dimethyl ether (4 mL) was sequentially added with [1, 1, ~ Bis (diphenylphosphino) -ferrocene iron] dichloro-palladium (II) complex (20mg, (K〇3mm〇1, 〇leqL) and 2M sodium carbonate aqueous solution (0_63mL, 1.25 〇〇ι, 5eq). Argon was passed into the reaction for 10 minutes, and heated to 80 ° C for 5 hours. The reaction was diluted with EtoAc: washed with water and 15 brine. The organic layer was dried under vacuum. Preparative TLC was used. Purification yielded 66.4 mg (59%) of N- {3- [2- (2,4-dichloro-benzylidene) -3-methylamino-benzyl-6-yl] -benzyl Gibacetamide is a yellow solid. Ijj-plane r (CDCl0d8.0 (broad, q, j = 56 Hz, 1H), 7 91 (d, j = 8 4 employees' consumption by the Intellectual Property Bureau of the Ministry of Economic Affairs) Printed by a cooperative

Hz, 1H), 7.63 (wide, s, 1H), 7.50-7.33 (m, 8H), 20 3.42 (d, J = 5.6 Hz, 3H), 2.21 (s, 3H). MS LC-MS MH-453.2 2 / 455.2; Rf = 0.13, 50% EtOAc-hexane. The other compounds shown in Table 3 below can be prepared according to the method described above, using appropriate starting materials that are readily available and / or synthesizable by the methods shown herein, using the methods described above or other standard chemical methods known in the relevant art. -105- 200413343 A7 B7 V. Description of the invention (104) Table 3 Example of synthesis using method D Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economics Structure example Rf (TLC solvent) or RT (minutes) * LC / MS ((M + H) +) (m) synthesis ** (VI) or (VII): 150 nh2, ch3 c 丨 RT = 4.17 410.3 comm comm D-2 151 n- ch3 H3Cv.NH Ci Ϊ Rf = 0.13 @ 50/50 EtOAc / HEX 453.2 / 455.2 comm comm D-3 152 of1% '0 Cl RT = 3.94 416.1 comm comm D-1 153 00¾ ° C, O ^ ro rf ^ CH3 Rf = 0.09 (50% EtOAc / HEX) 489.0 comm H-4 D-2 154 〇 丫 NH Cl h3 (TNH Rf = 0.19 (75% EtOAc / HEX) 454.0 comm H-5 D-2 155 nh2 C! RT = 4.33 402.1 comm comm D-2 -106- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (105) -107- This paper size is applicable to Chinese countries Standard (CNS) A4 size (210x297 mm)

Examples Structural formula Rf (TLC solvent) or RT (minutes r LC / MS ([M + HH (ΙΠ) synthesis method ** (VI) or (VII) synthesis method ** (I) synthesis method 156 〇J 'CH3 Cl RT = 3.54 444.1 comm H-3 D-2 157 nh2 g0% s, ch3 c, RT = 4.41 428.2 comm comm D-2 158 nh2 〇 = S = 〇Cl ch3 RT = 3.78 460.1 comm H-3 D -2 159 nh2 s〇2nh2 f RT = 2.96 445.1 A-2 comm D-2 160 nh2 00¾01 0 K to F RT = 3.58 437.2 A-2 comm D-2 161 nh2, coonh2 RT = 2.89 423.2 A-2 comm D-2 162 H RT = 3.00 437.2 A-2 comm D-2 163 nh2 RT = 3.82 405.2 A-2 comm D-2

AB 5. Description of the invention (106) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, an example of the structural formula Rf (TLC solvent) or RT (min r LC / MS ([M + H] +) (m) synthesis ** Synthesis of (VI) or (vn) ** Synthesis of 00 164 HN | 〇Cl Rf = 0.21 (50% EtOAc / HEX); Contains -5% impurity (double adduct D) 489.0 comm H- 4 D-2 165 9, NH Cl h3? -Ch3 Rf = 0.3 (50% EtOAc / HEX); containing ~ 5% diadduct D 504.0 comm H-4 D-2 166 nh2 of% Cl RT = 4.37 402.1 comm comm D-2 167 nh2 ksXH3 C! 0 RT = 3.06 458.0 comm H-1, H-3 D-2 168 nh2 f,% F Rf = 0.08 (50% EtOAc / HEX) 473.0 A-2 H-4 D-2 169 nh2 pr ^^ c, yam 〇c 丨 ch3 ° RT = 4.03 488.2 comm H-2, H-3 D-2 170 nh2 Cl 0 CH3 RT = 3.91 474.1 comm H-2, H-3 D -2 -108- d. Order. The paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (107) Example structural formula Rf (TLC solvent) or RT (minutes) LC / MS ([M + H] +) (ΙΠ) Synthesis ** (VI) or (vn) Synthesis ** 00 Synthesis 171 N-CH3 〆〇α Rf 0.59 @ 50/50 EtOAc / HEX 441.1 / 443.1 com m comm D-3 172 n-ch3 op% ch3 Cl RfO.70 @ 50/50 EtOAc / HEX 426.2 / 428.2 comm comm D-3 173 β-CH3 H3C, sCNH Cl 〇Rf = 0.28 @ 50/50 EtOAc / HEX 489.1 / 491.1 comm comm D-3 174 CH3 C! Rf = 0.76 @ 50/50 EtOAc / HEX 410.1 / 412.1 comm comm D-3 175 N-CH3 fff C 丨 Rf = 0.74 @ 50/50 EtOAc / HEX 464.1 / 466.1 comm comm D-3 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Automatic sampler, a Gilson diode detector, a YMC Pro C-18 column (2 X 23 mm, 120 A) and a Gilson HPLC system with Z-Spray-109- This paper is sized to Chinese National Standards (CNS) A4 size (210x297 mm) 200413343

10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 Micromass LCZ single quadrupole mass spectrometer for ionization by private spraying. Sweep the spectrum from 1210 to 1000 in 2 seconds h. ELSD (Evaporative Light Scattering Detector) data was also obtained from analog channels. Buffer A (aqueous solution containing 2% acetonitrile in 0.02% TFA) and buffer B (acetonitrile solution containing 0.02% TFA in 2% water) were used to perform gradient dissolution at mL / min. The dissolution method of the sample is as follows: After operating at 90% A for 0.5 minutes, it rises to 95% B within 3.5 minutes, maintains 95% B for 0.5 minutes, and then returns the column to the original within 0.5 minutes. condition. The total operating time is 4.8 minutes. ** comm means available from merchandise. Two methods E: N-heterocyclic-substituted benzofuran method. The methods E-i to e-4 shown in the following general reaction scheme are used to prepare the examples of the present invention, in which the R4 substituent is attached to the Benzofuran on the core. Examples E-1 to E-4 illustrate various methods for preparing appropriately substituted 2-cyanophenol (intermediate XI or XIII). (乂 1) or (and 111) with i-aryl-2-haloethyl ketone (ΙΠ) under experimental conditions (such as · carbonate, potassium carbonate, sodium carbonate, DBU), such as · DMF, MeCN Condensation is performed in a solvent at a temperature between room temperature and iq0 ° C to produce the desired product of formula (I). The reaction diagrams of the two general methods El, E-2, and E-4 -110- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 \ 297 Gongchu_20042004343 A7 B7 V. Description of the invention (109). CN BnBr / K2CO. Χτ — ~-

MeCN / Heating, ΧοΙ 10 15 (XI)

Η2 / Pd-C 〇

R—Η Metal medium rxcN R4> ^ -V〇Bn (X) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 〇 Reaction method of general method E-3

COOMe OH (XII)

(Ml) -111- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (lio)

(I) 5 Example 176 Method E-1 3- "3-Amino-2- (2,4-difluorobenzyl) -1-benzylfuran-6-yl1- 1,3-oxazole Preparation method of pyridin-2-one νη2 10 〇 °° VJ Q Cl Step 1: Starter: Preparation method of 2- (benzylmethoxy) -4-iodobenzyl cyanide 15 / N Γτ,. ^ 0 Ministry of Economic Affairs wisdom Printed by the Consumer Cooperative of the Property Bureau, containing 2-cyano-5-iodophenol (963 mg, 3. 93 mmol), benzyl 20 bromide (0.51mL · 4.32 mmol, 1.1 eq) and carbonic acid An anhydrous acetonitrile mixture of potassium (597 · 5 mg, 4.32 mmol, 1.1 eq) was stirred under reflux for 17 hours under argon. The reaction was poured into ethyl acetate (300 mL) and water (150 mL). The ethyl acetate layer Washed with saturated aqueous ammonium chloride solution, water and brine. The organic layer was dehydrated with sodium sulfate, evaporated and evaporated under reduced pressure to produce a white solid. -112- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 _ B7 V. Description of the invention (111) (1.31 g, 99.5%). GC-MS (ES MH + = 336); TLC Rf = 0.27 (5% ethyl acetate-hexane). Step 2_ .. _: Bis (benzyl-Hexyl-L 3-oxazolidin-3-yl) -molybdenum 5 Manufacturing method

Take 2- (benzyloxy) -4-iodophenyl cyanide (400 mg, 1.19 111111〇1), 2-oxazolidone (519.6 1 ^, 5.97 111111〇1, 5.0 called), copper (14 〇3 11 ^, 2.21111111〇1, 1.85 09), carbon dioxide (24.08 111, 1.74 mmol, 1.46 eq) and potassium iodide (309 · 丨, 1.86 mmol, 15 1.56 eq ) Of anhydrous N, N-dimethylformamide (4.8 mL) solution was printed at 150 ° C, printed by 150 employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, and stirred for 19 hours. The resulting orange reaction was diluted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, purified by MPLC (Biotage), and dissolved with 4: 1: 5 v / v ethyl acetate-digasmethane-hexane to give 142.6 mg (40.6%) of the product. j-NMR (DMS0-d6) 5 20 7.73 (d, J = 9Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.49-7.34 (m, 5 H), 7.25 (dd , J = 8. 7 Hz, 2.1 Hz, 1H), 5.27 (s, 2H), 4.45 (t, J = 8. 1 Hz, 2H), 4.07 (t, J-8. 7 Hz, 2H); LC -MS (ES MH !, = 294.9, RT-2.82 minutes). -113- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297). 200413343 A7 B7 V. Description of the invention (m) Bu Shou J: 2-jingji-4- (2-oxo-1, 3 -Oxazolidine-3-yl) fish made from benzyl cyanide

Put 10% Pd / C (14.0 mg, 0.05 mmol, 0.1 eq) in the dry flask. 'Add 2- (benzyloxy) -4- (2-oxo-1,3- 啐 嗤Yodo-10 3-based) solution of the basic chaos (140 mg, 0_48 mmol) in 1: 1 v / v tetrahydro ° furan-ethanol (16 mL). The reaction mixture was hydrogenated under a hydrogen blanket provided by an attached balloon for 16 hours. The reaction was filtered through Yin's salt packing, and the filtrate was concentrated to give 90.5 mg (93%) of a white solid. 1H-NMR (DMS0-d6) (5 7.53 (d, J = 8.4 Hz, 1 Η), 7.31 (s, 1 Η), 6.95 (dd, 15 J = 8.7 Hz, 1.8 Hz, 1 H), 4.40 (t, J = 8.7 Hz, 2H), 4.00 (t, J = 8.4 Hz, 2H), 3:25 (width s, ih); TLC Rf = 0.14 (75% ethyl acetate -Hexane). Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Step 4 · 3- [3-Amino-2- (2,4-《— Gabonyl Brewing Group) -1-Benzene 20 6-based 1-1, 3-p search. Production method of sitting lake 2-_

-114- This paper size is in accordance with China National Standard (CNS) A4 (210x297). 200413343 A7 _________ B7 V. Description of the invention (113) Amidazol-3-yl) phenyl cyanide (62 11 ^, 0.30 111111〇1) and 2,2 ', 4'-trichloroacetanilide (101.8 11 ^, 0.46 — 〇1, 1.5 eq) To a stirred solution of anhydrous n, N-dimethylformamide (3.0 mL) was added potassium carbonate (63.0 mg, 0.46 mmol, 1.5 eq), and the colored 5 reaction mixture was stirred at 8 (TC for 16 hours. The resulting The dark wine red reaction was poured into ethyl acetate (100 mL) and water (50 mL). The ethyl acetate layer was washed with a saturated aqueous solution of chloride, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by MPLC (Biotage) and dissolved in 60% ethyl acetate-hexane. Crystallized from dichloromethane-hexane to give a benzofuran 10 as a light-colored solid (43 mg, 36.2%). Tun-Li !? (DMS0-d6) 5 8 · 01 (d, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.73 (dd, J = 1.8, 0.9 Hz, 1 H) , 7.63 (dd, J = 8.7, 1.8 Hz, 1H), 7.55 to 7.52 (m, 4H), 4. 43 (t, J = 8.7 Hz, 2H), 4.07 (t, J = 8.7 Hz, 2H): LC-MS (ES MH +-391/393, 15 RT = 3.0 minutes). Example 177 Method E -2 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ~ 歴 -6-Meta-4-yl-benzyl-2-yl)-(2, 4-diaza-benzene 20-yl) -methanone System of law

CI 〇0 -115- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (110) Step 1: 2- (Benzyloxy) -4- (? (Phenyl-4-yl) phenyl cyanide

Take 2- (benzyloxy) -4-iodophenyl cyanide (350 mg, 1.04 mmol), ginseng (diphenylene acetone) two (0) (95. 6 mg, 0.1 mg, 0.1 eq), tricresyl gallate (95.3 mg, 0.31 mmol, 0.3 eq), potassium tert-butoxide (281.0 mg, 2.92 mmol, 2 · 8 eq) 10 anhydrous di The Sakizaki (5.2 mL) solution was degassed under argon. After 20 minutes, morphine (0.22 mL, 2.51 mmol, 2.4 eq) was added, and the reaction mixture was stirred at 90 ° C for 4 hours. The reaction was diluted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by MPLC (Biotage) and isolated with 30% ethyl acetate / hexane to give 220-5 15 11 ^ (71.7 ° /.) Product. 111-Li 1 ^ (0% 30- (16) 5 7.48- 7.33 (111, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 6H), 6.70 (d, J = 2.1 Hz, 1H), 6.59 (dd , J = 8. 7 Hz, 2.1 Hz, 1H), 5.24 (s, 2H), 3. 70 (t, J-5.1Hz, 4H), 3.29 (t, J = 5. 1 Hz, 4H): LC -MS (ES MH +-295, RT = 3.09 minutes); = 0.17 (30% ethyl acetate-hexane). 20 Step 2: 2—Cyclo-4— (Gamalin 4—Cyl) benzyl Atmosphere

oO 25 -116- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 ___ B7 V. Description of the invention (115) Put 10% Pd / c (25.0 mg, 0.08 mmol) in a dry flask , 〇 · 1 eq), add i: iv / v ethyl acetate-ethanol (2- (benzyloxy) -4- (morpholin-4-yl) phenyl cyanide (250 mg, 0.85 mmol)) ( 8 · 5 mL) solution. The reaction mixture was hydrogenated under an argon blanket provided by an attached balloon for 16 5 hours. The reaction was filtered through a Yin's salt pad, and the filtrate was concentrated. Crystallization from dichloromethane-hexane gave 164.2 mg (94.7%) of a white solid. 1H-NMR (DMS0-d6) (? 10.64 (width s, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.49 (dd, J = 9. 0 Ηζ, 2.1 Hz, 1H) , 6.34 (d, J = 2.1 Hz, 1H), 3.68 (t, J = 5. 1 Hz, 4H), 3.15 (t, 10 J = 5. · 1 H, 4H); LC-MS (ES MH + = 205, RT = 2.01 minutes); Rf = 0.21 (50% ethyl acetate-hexane).

Step 3 · (3-Amino-6 ~ Moryl-4-yl-benzo bite ~~ 2-yl)-(2,4-diamino-phenyl) -fluorenone method 15 00 Printed by the Intellectual Property Bureau of the Ministry of Consumers 'Cooperatives in 20 containing 2-hydroxy-4- (morpholin-4-yl) phenyl cyanide (75 mg, 0.37 mmol) and 2,2', 4'-trifluoroacetamidine To a stirred solution of benzene (123.1 mg, 0.55 mmol, 1.5 ed) in anhydrous N, N-dimethylphosphonium amine (3.7 mL) was added thorium carbonate (76 · 1 mg, 0.46 mmol, 1.5 · eq), the orange reaction mixture was stirred at 80 ° C for 17 hours. The obtained dark wine red reaction is poured into ethyl acetate 〇00-117- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (116) mL) and water ( 50 mL). The ethyl acetate layer was washed with a saturated aqueous ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by MPLC (Biotage) and dissolved in 30% ethyl acetate-hexane. Crystallized from ether-hexane to give benzofuran as a yellow solid (37 5 tn, 25.8%). W-NMR (DMSO-d6) 5 7 · 80 (d, J = 9. 3 Hz IH), 7.70 (m, 1H), 7.75 (m, 2 H), 7.43 (width s, 2H), '6.98 (dd, J = 9 Hz, 1.8 Hz, IH), 6.78 (d, J = 1.8Hz, IH), 3.69 (t, J = 4.5 Hz, 4H), 3.18 (t , J = 4.5 Hz, 10 4H): LC-MS (ES MH + = 391/393, RT = 3.11 minutes). Example 178: Method E-3: Method for preparing 1-biyl-6-romo-1-yl-benzofurandi-2-yl)-(2,4-yl) -methanone 15

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Step 1: Starter: 2-Jingji-4- (1Η-ρΗ: υ 一 基) Benji atmosphere method

CN -118- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 Gong -------- 200413343 A7 _-_____ B7 V. Description of invention (117)

In a sealed test tube, add 2-hydroxy-4- (1H-pyrrole-1-yl) benzenecarboxylic acid vinegar (960 mg, 4.42 mmol), 1M sodium bis (trimethylsilyl) amine in THF (7.1 mL) , 7.1 mmi, 16 eq) and 1,3-dimethylimidazolinone (1.77 mL) 'reaction mixture was heated to 185 hours. The reaction on cooling should be stopped by HC1 aqueous solution and poured into ethyl acetate (200 and water (100 mL). The ethyl acetate layer was washed with water and brine, dehydrated with sodium sulfate, filtered and evaporated under reduced pressure. Crude The product was purified by MPLC (Biotage) and was isolated with 25% ethyl acetate-hexane to give a white solid (585 mg, 71.9%). 1H-NMR (DMSO-de) 5 11.36 (s, 1H), 7.66 (d, = 10 8 · 4 Hz, 1H), 7.34 (t, J = 2.4 Hz, 2H), 7 · 16 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.29 (t, J = 2.4 Hz, 2H); Rf 0.18 (25% ethyl acetate-hexane). 15 Step 2: The title compound: (3-amino-6-pyrrole-1-yl -Benzofuran-2-yl)-(2,4-dichloromonazine V-methanone)

Printed on the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs containing 2-Chrysyl-4- (1H-π to 17- each-1-yl) phenyl cyanide (60 mg, 0.33111111〇1) and 2,2 ', 4' -Carbon is added to an anhydrous n, N-dimethylformamide (3 · 2 mL) solution of trichloroacetanilide (109.2 11 ^, 0.49 111111〇1, 1.5 eq) -119- This paper is for China National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (118) Potassium acid (67 · 5 mg, 0 · 49 πιηο1, 1 · 5), the orange reaction mixture was disturbed at 80 ° C Stir for 16 hours. The resulting dark wine red reaction was poured into ethyl acetate (100 mL) and water (50 mL). The ethyl acetate layer was washed with a saturated aqueous solution of ammonium hydroxide, water and brine. The organic layer was dehydrated with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by MPLC (Biotage) and was isolated with 25% ethyl acetate-hexane. Crystallization from dichloropyrene-hexanoic acid yielded benzofonamine as a yellow solid (89 · 0 mg, 73.6%). NMR (DMS0-Free) 5 8 · 08 (d, J = 8. 7Ηζ, 1H), 7.73 (d, J = 10.0 Hz, 2H), 7.60- 7.53 (m, 5H), 7.48 (t, J = 2.4 Hz, 2H), 6.26 (t, 10 J = 2.1 Hz, 2H); LC-MS (ES MH + = 371, RT = 3.74 minutes). Example 179 Method E-4 15 (3-Amino-6-17 m ps ~~ 1 ~~ yl-benzyl and bite-2-yl)-(2, 4-digas-phenyl) -methanone System of law

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Step 1: Starter: Preparation of 2-benzylmethoxy-4- (imidazol-1-yl) phenyl cyanide -120- Zhang scale applicable to Chinese National Standard (CNS) A4 specifications (210x297 mm y 200413343 A7 B7 V. Description of the invention (119)

〇 5 Take 2-benzyloxy-4-iodine-phenylcyanide (500 mg, 1.49 mmol), indica spit (152.3 mg, 2.24 mmol, 1.5 eq), and cesium carboxylate (534.7 mg, 1.64 mmol, 1.1 eq), copper (II) trifluoroformate (75.0 mg, 0.15 mmol, 0.1 eq), 1,10-phenirolin (269 mg, 1.49 mmol, 1.Oeq) and trans A mixture of trans-dibenzylideneacetone (95.6 10 mg, 0.1 mmol, 0.1 eq) in anhydrous dibenzobenzene (6.0 mL) was subjected to ultrasonication for 2 minutes, and the reaction mixture was stirred at 110 ° C for 19 hours . The reaction was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by MPLC (Biotage), and was sequentially separated with 60% and 100% ethyl acetate. Crystallization from ethyl acetate-hexane yielded 15240.11 (58.4%) of the product. 111-Li 1 ^ (0% 30- (16) (5 8.47 (1 :, 1 = 0.9 Hz, 1H printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs), 1.93 (t, J = 1.5 Hz, 1H), 7.90 (d, 1 = 8.4 Hz, 1H), 7.65 (d5 J-2.1 Hz, 1H), 7.52 -7.36 (m, 6H), 7.15 (t, J = 1.5 Hz, 1H), 5.39 (s, 2H); LC-MS (ES MH + = 276, RT = 2.07 minutes); Rf = 0.13 (75% 20 ethyl acetate-hexane). Step 2: Starter: 2-hydroxy-4- (imidazole-1 -Base) Method for the production of benzyl cyanide-121- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 Description of invention (m)

Put 10% Pd / C (20.0 mg, 0.07 mmol, 0.1 eq) in a dry flask, and add 2-benzyloxy-4- (imidazole-}-yl) phenyl cyanide (2〇 (0,73 mmol) in a solution of i: iv / v ethyl acetate-ethanol (7-3 mL). The reaction mixture was hydrogenated under a hydrogen blanket provided by the attached balloon for 16 hours. The reaction was filtered through a Yin's salt pad, and the filtrate was concentrated. Crystallization from ethyl acetate-10 hexane gave 120 mg (89. 2 ° /.) Of a white solid. 1H-NMR (DMS〇-d6) (5 8. 23 (s, 1H), 7. 68 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.09 (s, 1H), 7.06- 6.98 (m, 3H): Rf = 0.13 (20% methanol-ethyl acetate). 15 Step 3 Dititled compound: amine-6-imidazol-1-yl-benzofuran-2-yl)-(2, 4-Digas-Mosyl) -methanone

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs on 2-Chloro-4- (Taste Sigma-I-Base) Phenyl Milk (60 mg, 0.32 mmol) and 2, 2 ', 4'-Trichloroethyl Carbon (122 · 6 mg, 0.49 mmol, 1. 5 eq) in anhydrous N, N-difluorenylhydrazine (3.2 mL) was added as a carbon-122- This paper size applies Chinese national standards (CNS) A4 specification (210 X 297 mm) 200413343 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 __ B7 V. Description of the invention (m) Potassium acid (67.2 11 ^, 0.49 111111〇1, 1.569), the orange color The reaction mixture was stirred at 80 ° C for 16 hours. The resulting dark wine red reaction was poured into ethyl acetate (100 mL) and water (50 mL). The ethyl acetate layer was washed with a saturated aqueous ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate, transitioned, and evaporated under reduced pressure 5. The crude product was purified by MPLC (Biotage), and was sequentially separated with 75% ethyl acetate-hexane and 100% ethyl acetate. Crystallization from dichloromethane—hexane, yielding a ranky orange solid (32.5 mg, 27.0%). 4-NMR (DMS0-d〇5 8.37 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.86 (d, J = ΐ · 8 Ηζ, 1Η), 7.84 (ΐ, J = ΐ · 3 Ηζ, 1Η), 10 7 · 76 ((1, > ι · 5 Ηζ, 1Η), 7.65 (dd, J = 8 · 4 Ηζ, J = 1.8 Hz, ιη) , 7.58-7.57 (m, 4Η), 7.11 (s, iH); LC ^ MS (ES MH + = 372, RT = 2.37 minutes). The other compounds shown in Table 4 below can be easily obtained and / Or suitable starting materials can be synthesized according to the method shown here, prepared by the above 15 methods or other standard chemical methods known in related techniques. -123- 200413343 A7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ) Table 4 Examples of Synthesis Using Method E Example Structural Formula Rf (TLC Solvent) · or RT (minutes) * LC / MS ([M + H] +) (ΙΠ) Synthesis Method ** R4-H Synthesis Method * * (I) Synthesis method 180 Rf = 0.41 (75% EtOAc / HEX) 355/357 A · 2 comm E-1 181 Cl Rf = 0.14 (50% EtOAc / HEX) 389/391 comm comm E-1 182 nh2 Cl Rf = 0.18 (75% EtOAc / HEX) 390/392 comm comm E-1 183 nh2 Rf = 0.16 (50% EtOAc / HEX) 404/406 comm comm E-1 184 nh2 H3 ^ F Rf = 0.23 (75% EtOAc / HEX) 384.0 A-2 comm E-1 185 nh2 Cl Rf = 0.16 (25% EtOAc / HEX) 375.0 comm comm E-2 -124- 4. Order this paper Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 200413343 A7 B7 V. Description of invention (l23) Printed by the Intellectual Property Bureau Employee Consumer Cooperative of the Ministry of Economic Affairs 1 Example structural formula Rf (TLC solvent) or RT (minutes) r LC / MS ([M + H] +) (in) Synthesis. Method ** 'R4-H Synthesis Method ** (I) Synthesis Method 186 Rf = 0.30 (50% EtOAc / HEX) 337.0 comm comm E-2 187 x = / CH3 Rf = 0.12 (25% EtOAc / HEX) 333.0 comm comm E-3 188 nh2 ο0%, Rf = 0.1 (25% EtOAc / HEX) 333.0 comm comm E-3 189 RT = 3.23 347.3 A-5 comm E-3 190 nh2 CT °% ch3 Rf = 0.26 (5% MeOH / EtOAc) 332.0 comm comm E-4 191 nh2 CH. Rf = 0.11 (25% EtOAc / HEX) 332.0 comm comm E-4 192 nh2 or0% 3 Rf = 0.17 (25% EtOAc / HEX) 334.0 comm comm E-4 193 W CH3 Rf = 0.08 (25% EtOAc / HEX) 334.0 comm comm E-4 194 Rf = 0.345 (50% EtOAc / HEX) 368.0 comm comm E-4 -125- • 4. Order · This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 ---- ^ _ B7 V. invention is described in (! 24) Footnotes: * LCMS conditions are described below: HPLC-Electrospray Mass Spectrometry (HPLC ES-MS) uses two Gilson 306 pumps, a Gilson 215 autosampler, a Gilson diode detector, and a YMC Pro C Measured on a Gilson HPLC system with -18 column 5 (2 x 23 mm, 120 A) and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. The spectrum of 120-1000 amu was scanned in 2 seconds. ELSD (Evaporative Light Scattering Detector) data was also obtained from analog channels. Buffer A (2% acetonitrile in water solution containing 0.02% TFA) and buffer β (acetonitrile solution containing 2% water in 10% TFA) were used for gradient dissolution at 1.5 mL / min. The sample dissolution method is as follows: After operating at 90% A for 0.5 minutes, it rises to 95% B within 3.5 minutes, maintains 95% β 0.5 minutes, and then returns the official column to the initial conditions within 0.1 minutes. . The total operating time is 4.8 minutes. Knife 15 ** co Lai refers to available from merchandise. General formula-every compound has been prepared (the compound of π compound Intellectual Property Bureau of the Ministry of Economic Affairs employee consumer cooperative printed below) Method Example 195 Method F-la

200413343 A7 ___ ___B7 V. Description of the invention (125)

CH

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Take (3-amino-6-phenyl-1-benzocrean-2-yl) (2,4-dichlorophenyl) methanone (129 mg, 0.333 mmol) and acetamidine chloride ( 0.0mL, 1.41 mmol, 4 · 2 eq), diisopropylethylamine polystyrene resin (loo, bearing 10 · load 3.75 Liol / g, 1.1 eq) of anhydrous dichloride The ethane mixture was shaken at 40 ° C for 4 days. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by MPLC (Biotage) and isolated with 10% ethyl acetate-hexane. Crystallization from ether-hexanes' yielded 86.8 mg (60.6%) of the product. j-NMR (DMSO-dO 5 10.36 (s, 1H), 8.03 (d, J = 8.7 Hz, 1 15 H), 7.95 (d, J = 1.0 Hz, 1 H), 7.83 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 6.9 Hz, 1H), 7. 72-7.62 (m, 4H), 7.49-7.39 (m, 3H), 2.12 (s, 3H); LC-MS (ES MH + = 423, RT = 4.01 minutes). 20 f Example 196 Method F-lb N- "6- (3-Ranyl-benzyl) -2- (2, 4-digas-benzyl (Base) -benzene # pfran — 3-yl 1-acetamidamine-127- The paper size Chinese National Standard (CNS) A4 (210 X 297 public love)-200413343 A7 B7 126)

CH3 ο 乂 u NH

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs on 3- [3-Amino-2- (2, 4-dichloro-benzoate) -benzocran-6-yl] -benzene To a solution of method C-1) (200 mg, 0.5 mmol) in anhydrous THF (2 mL) was added acetic anhydride (0.12 mL, 1.2 mmol, 2.5 10 eq) and sodium acetate (100 mg, 1.2 mmol, 2 5 eq). The reaction mixture was stirred at 60 ° C for 40 hours. Upon cooling to room temperature, some white solid precipitated and was filtered off. The filtrate was evaporated in vacuo and washed with water and EtOAc. After high vacuum pump drying, 120 mg (55%) of N- [6- (3-cyano-phenyl) -2- (2, 4-digas-phenylfluorenyl) -benzofuran-3 was produced -Yl] -acetamide 15 yellow solid. 1Η-Li R (CDC13) 510.36 (width, s, 1H), 8.67 (d, J-8.8 Hz, 1H), 7.89 -7.83 (m, 2H), 7.67-7.49 (m, 6H), 7.40 (dd, J = 8.8 Hz, 2 Hz, 1H), 2.40 (s, 3H). Rf = 0.62, 50% EtOAc-hexane. 20 Example 197 Method F-2 3- [3-Amino-2- (2, 4-dichloro-benzylidene) -benzyl-6-yl " I-benzylidene- 128- The size of this paper is applicable to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of invention (m)

Acetone containing 3-amino-6- (3'-cyanophenyl M-benzofuran-2-yl) (2,4-dichlorophenyl) methanone (36 mg, 0.09 mmol) (1 · 7 mL) and water (0.88 mL) was added sodium percarbonate (69.4 mg, 0.44 mmol, 5eq) containing 25% hydrogen peroxide. The reaction mixture was stirred at 60 ° C for 10 7 hours. The reaction mixture was cooled 'and the volatile solvent was evaporated. The residue was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the crude product was recrystallized from ethyl acetate-hexane to give 18.8 mg (50.0%) of the product. W-MR (DMS0-d6) (58 · 22 (t, J = 1.5 Hz, IH), 8 · 14 (d, J = 8.7 Hz, IH), 8.09 (s, IH), 7 · 92— 15 7.84 (m, 3H), 7.73 (d, J = 1.8 Hz, IH), 7.69 (dd, J = 8.1 Hz, 1.5 Hz, IH), 7.62 -7.51 (m, 5H), 7.44 (s, IH); LC-MS (ES MH + = 425, RT = 2.99 minutes). Example printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 198 20 Method F-3 N-Lli [3-amino-2- (2 , 4-Dichloro-phenylfluorenyl) -benzylfuran-6-p-phenyl} -2-methyl-gas acetamide-129- This paper size applies to China National Standard (CNS) A4 ( 210x297 Public Chu 200413343 A7 ------- B7 V. Description of the invention (128)

9 mg, containing ethoxyacetic acid (27. 2 mg, 0.30 mmol, 1.5 eq), 10-diamidopropylpropyl) -3-ethylcarbodiimide hydrochloride 10 〇 · 30 mmol, 1.5 eq), 1-hydroxybenzotriazole hydrate (40.8 mg, 0.30 mmol, 1.5 eq) and diisopropylethylamine (698 mg, 0.60 mmol, economical The Ministry of Intellectual Property Bureau employee consumer cooperative printed 3 eq) of anhydrous 1: 1 v / v THF-acetonitrile (5 mL) solution and stirred at room temperature under argon for 1 hour. Add [3-amino-6- (3-amino-benzyl) -benzofuran-2-yl]-(2,4-dichlorophenyl) methanone (80 mg, 0.20 mm) Of 15 anhydrous THF (5 mL) solution, the reaction mixture was stirred at 8 ° C for 18 hours. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was washed with water, brine, and dehydrated. The crude product was subjected to a preparative thin layer Analytical purification, separation using 50% ethyl acetate-hexane. Crystallization from ether-hexane, yielding 28.2 mg (29.9%) of the product. 111-Li 1? (Acetone- (16) 5 9.10 (width 3 , 111), 20 8.15 (m, 1H), 8.10 (dd, J = 8. 1 Hz, 1.8 Hz, 1 H), 7.83 (m, 1H), 7.65-7.41 (m, 7H), 7.11 ( Width, s, 2H), 4.03 (s, 2H), 3.47 (s, 3H); MS ES (MH + = 496); Rf = 28 (30% ethyl acetate-hexane). -130- This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 200413343 A7 B7___ V. Description of the invention (129) ^ JL199 Method Ezi Dusk-N- {3- 「3-Amino-2- (2 , 4-Dihelium-Methamidinyl) -benzofuranyl-fi-ylbenzyl 丨 acetamidine

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 10 Take N- {3- [3-amino-2- (2,4-dichlorobenzyl) -benzofuran-6-yl] -phenyl Trimethylamino} -methyl) carbamic acid third butyl ester (prepared according to Example 198 F-3) (80 mg, 0.14 mmol) was mixed with trifluoroacetic acid (20 mL) and anhydrous THF (40 mL) in argon. Stir at room temperature for 18 hours. 15 The reaction mixture was diluted with ethyl acetate and water, and the organic layer was washed with a saturated sodium carbonate aqueous solution, water, and brine, and then dehydrated with sulfuric acid. The solvent was removed under reduced pressure, and the crude product was purified by MPLC (Biotage) and isolated with 10% dichloromethane-methanol to give 21.3 Ing (32.5%) of the product. 1H- ^ IMR (I-d6) 5 9 96 (width s, 1H), 8.09 (m, 2H), 8.00-7 · 42 (m, 7Η), 7.27 20 (d, J = 7 · 8 Ηζ, 1Η), 7 · 10 (width s, 2Η), 4.00 (s, 2Η), 2.92 (width s, 2Η): MS ES (ΜΗ + = 454); Rf = 0.33 (10% dichloromethane-methanol). Example 200 This paper size applies Chinese national standard specifications (21 × 297 mm) 200413343 A7 B7 V. Description of the invention (no method F-5 {3-amino-6- "3-((10-2,3-II Jingji-Cingfai) Benji 1-xiao; Method for preparing lan-2-ylbu (2, 4-digas-mosyl) -methanone

Take 3-amino-6- (3'-aminophenyl) -1-benzopyran-2-yl) (2,4-dichlorophenyl) methanone (150.0 mg, 0.38 mmol) and A 2: 1 v / v dioxane-water mixture of (S)-(-)-glycidol (0.03 mL, 0.38 mmol, 1.0 eq) was stirred at 80 ° C for 16 hours. The reaction was diluted with ethyl acetate 15 and washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by MPLC (Biotage) and dissolved in 5% methanol-ethyl acetate. The product was printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, and produced 78.2 mg (43.9%) of the product. 4-Li R (acetone-d6) 5 8 · 03 (d, J = 8.4 Hz, 1H), 7.65-7.53 (m, 5H), 7 · 20 (t, J = 8 · 1 Ηζ, 1Η), 7.70 (width s, 2Η), 7.04 (t, 20J = 2.1 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.72 (dd , J = 7 · 8Ηζ, 2.4 Hz, 1H), 5.03 (width s, 1H), 3.96 (width 3, 111), 3.89 (1:,: [= 5.4 112, 11〇, 3.74 (Width 3, 1H), 3.66- 3.59 (m, 2H), 3.44-3.36 (m, 1H), 3.21-3.12 (m, 1H); LC-MS (ES MH + = 471, RT = 2.82 points- 132- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 --------- B7 V. Description of the invention (⑴) Clock) 〇XM201

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 々, add Pt (K4.0 mg, 〇018 mm 〇1) to a dry flask. After flushing the flask with argon: methanol (0.6 mL) and tetrahydrofuran-like hydrogenated gas (50 / zl, 2N dioxane solution) were added. Add (3-Amino-6-pyridyl-3 ~ benzofuran-2-yl)-(2,4-digas-phenyl) monomethanone (40 mg, mmol) to the flask under argon in. The solution was degassed in vacuum and refilled with argon to introduce hydrogen into the flask using a tritium bulb. The mixture was stirred under a hydrogen blanket with a chamber / HZL overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by 1 ^ [(: purification 'to give 155? (38.2%) of the title compound. 1} 1-leg 1 ^ 2〇 (CD〇D3) ^ 7.89 (d, J = 8.1 Hz, 1H) 7.58 (d, J-1.7 Hz, 1H), 7.47 (m, 2H), 7.29 (s, 1H), 7.23 (dd, J = 8 * 2 Hz, 1.7 Hz, 1H), 3.44 (m, 2H), 3.08 (m, 3H), 2 · 07 (t, 2H), 1.86 (m, 2H): MS LC-MS (MH +-389 · 6) 〇-133- This paper is applicable to the standard CNS A4 (21 × 297 public love 1 '-200413343 A7 B7 V. Description of the invention (132) 10 Example 2Q2 Method F-6b 1- {3-``3-Amino-2- (2, 4-dichloro-benzyl) ) -Benzofuran-6-yl 5 hexahydropyridin-1-yl} -3-diethylamino-propan-1-one

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, containing (3-amino-6-hexahydroσ than fluoren-3-yl-benzyl-2-nan)-(2, 4-dichloro-benzene ) -Formamidine (65 mg, 0.17 mmol), (3-dimethylamine 15-propyl) -ethyl-carbodiimide hydrochloride (35 mg, 0.18 mmol) and 1- The mixture of dichloromethane (1.5 mL) with dibenzotrifluorene (25 mg, 0.18 mmol) was stirred at room temperature for 10 minutes. Add triethylamine (70 # 1, 0.50 mmol) and 3-diethylamino-propionic acid (24 mg, 0.17 mmol) to the mixture. The solution was stirred at room temperature overnight. The solution was concentrated in vacuo and the resulting residue was purified by 20 HPLC to give .31 mg (42%) of the title compound. W-NMR (CDC13) 5 7.54 (d, J-8.8 Hz, 1H), 7.42 (m, 2H), 7.29 (m, 1H), 7.12 (d, J = 4. 9 Hz, 1H), 7.06 (d , J = 8.4 Hz, 1H), 6.04 (d, 2H), 4.67 (t, J = 14.5 Hz, 1H), 3.87 (m, 1H), 2.99 (t, J = 12.5 Hz, 1H), 2.76 (m , 3H), -134- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (133) 2.49 (m, 6H), 2.00 (m, lH ), Ϊ́ · 79 (m, 1H), 1.62 (m, 1Η), 1.54 (m, 1Η), 0.96 (m, 6H); MS LOMS (MΗ + = 516.9). 5 Example 203 Method F-6c [3-Amino-6- (1-isopropyl-hexaoxo-ratio_3-yl) -synthesis. Bianchuan-2-K2, 4-digas-benzyl) -fluorenone

Take (3-amino-6-hexahydropyridinium-3-yl-benzosweep-2-yl) -15 (2,4-dichloro-phenyl) -methanone (50 mg, 〇 · 13 mmol), acetone ((10 # L, 0.13 mmol), sodium triacetoxyborohydride (38 mg, 0.18 mmol), triethylamine (27 # 1, 0.19 mmol) and acetic acid (7 · 0 # 1, 0.13 mmol) of 1,2-digasethane (1.3 mL) was stirred overnight at room temperature. The solution was concentrated. The resulting residue was purified by HPLC to yield 18 mg of intellectual property of the Ministry of Economic Affairs 20 (32%) of the title compound was printed by the Bureau's Consumer Cooperative. W-NMR (CDC13) (5 7 · 53 (d, J = 8. · 4Ηζ, 1Η), 7.49 (s, 1Η), 7.48 (d, J = 4.6 Ηζ, 1Η), 7.35 (dd, J = 8.7, 2.2 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J = 8.7 Hz, IH), 6.02 ( s, 2H), 2.94 (m, 3H), 2.76 (m, 1H), 2.16 (m, 2H), 1-94 (m, 1H), 1.80 (m, -135-

This paper size applies to China National Standard (CNS) A4 specifications (21 × 297 male U 200413343 A7-B7 V. Description of the invention (134) 1H), 1.69 (m, 1H), 1.46 (m, 1H), 1.04 (d , J = 2.6

Hz, 3H), 1.02 (d, J = 2.6 Hz, 3H); MS LC-MS (MH + = 431.7). 5 Example 204 Method F-6d [3τ. Basket lid-Ul-butyl-hexa-hydropyridine-3—benzobenzofuran-2-yl μ (2,4-mono-benzyl) -methylamidine law

15 This compound is printed by (3-amino-6-hexahydropyridin-3-yl-benzofuran-2-yl)-(2,4-dichloro-phenyl) ) -Methanone (50 mg, 0.13 mmol) according to [3-Amino-6- (1-isopropyl-hexahydropyridin-3-yl) -benzofuran-2-yl]-(2, 4- Preparation of digas-phenyl) -methanone, yielding 27 mg (47%) of the title compound as a yellow solid. 1H-NMR (CDC13) 57.53 (d, J = 8.20 20 Ηζ, 1Η), 7.49 (d, J = 2 · 1 Ηζ, 1Η), 7.48 (d, J = 4.2 Hz, 1H) , 7.34 (dd, J- 8.5, 2.1Hz, 1H), 7.21 (s, 1H), 7.14 (dd, J = 8.5, 2.4 Hz, 1H), 6.01 (s, 2H), 2.97 (m, 3H), 2.33 (m, 2H), 1.94 (m, 3H), 1.75 (m, 2H), 1.46 (m, 3H), 1.29 (m, 2H), 0.89 (t , J = 7.3 Hz, -136- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of Invention 135 3H); MS LC-MS (MH + = 445.4) iiL205 Method F- 7pj

Production method of Alz benzofuran-6-dichloro1-dichloro 'acid 10

NhL

Take 3- [3-Amino-2-2- (2, 4-dichloro ~ benzyl) 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 6-based] —benzyl nitrogen (16mg, 38.0_ ), Saturated with hydrochloric acid gas, and at room temperature _mL) the solution was saturated with more hydrochloric acid gas, and stirred at room temperature. Then go to Bu. 1 hour 'until tlc shows = starting residue. The solvent was removed under reduced pressure. The obtained crude product 3_ [3_ soil2, 4-aqi—phenylfluorenyl) -benzofuran-6-yl] -benzimidate was treated with ammonia in methanol solution (7 N, 10mL) , And stirred overnight at room temperature. The solvent was removed under reduced pressure. After separation by HPLC, a white solid product (34.4 mg, 16.4%) was obtained. 2- {3_ [3_amino-2- (2, 4-digas-benzyl) -benzfuran-6- Phenyl] -phenylbuthyltrifluoro-acetic acid. lH—wake R (CD3〇D) (5 6.34 (d, J = 8.7 Hz, 1H), 6 07 (s 1H), 6.03 (d, J = 7.7 Hz, 1H), 5.94 (m, 3H), 5 -137- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 86 200413343 A7 V. Description of the invention (I36) (t, J = 8 · 0 Hz, 2H), 5.82 (s, 1H), 5.77 (t, J: 7.4 Hz, 1H), 2.23 (s, 2H); MS LC-MS (MH +. 438 3) LC MS RT: 2.42 minutes. ^, F Example 206 Method F-7b g- "3-Amino-2- (2, 4- & N-dimethyl-stupidity @ 屋 一 6 一 某 1 一 10

15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Add 3-[3-amino-2- (2, 4-dichloro-benzyl) -benzofuranyl] to anhydrous methanol (10 mL) —Phenylcyanine (1.0 & 2. mmol). The solution was saturated with HC1 gas. Stir at room temperature for i hours. The solution was concentrated in vacuo, and a part of the residue (Q._g, G. 16 mmol) was dissolved in anhydrous MeOH (2mL) under inert gas. Add dimethylamine (3ι§⑽ _υ. The solution was allowed to stir at room temperature for 72 hours. The solution was concentrated in vacuo and purified by HPLC to give 0.025 g (34.7%) of 3- [3 ~ amino-2— (2,4 -Dichloro-benzylidene) -benzocrean-6-yl] -N, N-dimethyl-benzyl vein. 1JINMR (Me0H-d4) (J7.99 (d, J = 9.3 Hz, 1H), d 7 · 78 (d, J = 8 Hz1H), d 7 · 69 (s, 1H), d 7.62-7.39 (m, 7H), d 2.98 -138- This paper size applies to the Chinese National Standard (CNS ) A4 size (21 × 297 mm) 200413343 A7

Take [3-Amino-6- (3-Amino-phenyl) -benzocrete-2-yl] -15 (2,4-dichloro-benzyl) -fluorenone (100 mg ， 0.25 mmol), formaldehyde (7.5 // printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, L, 0.26 mmol), sodium triethoxylate borohydride (75 mg, 0.35 mmol) and acetic acid A solution of 15 // L, 0.25 mmol) of 1,2-digasethane was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by MPLC (Biotage) and dissolved with 5% to 30% ethyl acetate-hexane to give 20 (13.7 mg, 13.2%) as a yellow solid. NMR (CDC13) 5 7.65 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.51 (m, 2H), 7.37 (dd, J = 8..2, 2.0 Hz, 1H), 7.27 ( t, J = 7.8 Hz, 1H), 7.26 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.82 (t, J -2.0 Hz, 1H)? 6.75 (dd, J = 8.2 Hz, 2.5 Hz, 1H), -139- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (138) 6.01 (s, 2H), 2.89 (s, 3H); MS LC-MS (MH + = 411.2), RT 2.37 minutes. Example 208 5 Method F-9 (3-Amino-6-. Hydroxy-3-yl-benzoan-2-yl)-(2,4-dichlorophenyl) fluorenone hydrochloride

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs on (3-Amino-6_ϋ Bidian_3-yl-benzopyridin-2-yl)-(2,4-dichlorophenyl) methanone ( 80 mg, 0.21 mmol) of hot ethanol (3 mL) was added 15 concentrated hydrochloric acid (0.16 mL, 5.22 mmol, 25 eq). The reaction mixture was stirred at room temperature for 18 hours and at 3 ° C for 24 hours until a crystalline solid was formed. The yellow precipitate was filtered and washed with cold ethanol to produce 37.5 11 ^ (42.8 ° / 〇hydrochloride. 111-Liz 0 ^ 130- (16) (5 9.19 (3, 11〇, 8.78 (d, J = 5.1 Hz , lH), 8.66 (d, J = 7.5 Hz, 1H), 8.22 20 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.90 (t, J = 6.6 Hz , 1H), 7.78-7.75 (m, 2H), 7.64-7.55 (m, 4H); ^^ £ 3 011+ = 383; residence time = 2.48 minutes). Other compounds in Table 5 can be similar to the above example 195 FI- The method of 208 F-9, which is easy to obtain and / or can be synthesized according to the method shown in this paper -140- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 Intellectual Property Bureau of the Ministry of Economic Affairs Printed by Employee Consumer Cooperatives. 5. Description of Invention (l39) The starting material was prepared by the above method or other standard chemical methods known in the related art. Table 5 Examples of Synthesis Using Method F Structural Formula Rf (TLC Solvent) or RT (minutes) ) * LC / MS ([M + H] +) (m) Synthesis ** (VI) or (VII) Synthesis ** (I) Synthesis 209 Cl Rf = 0.37 (75% EtOAc / HEX ) 425.0 comm comm C-1, F-1 210 nh2 〇 person nh2 f Rf = 0.29 (100% EtOAc / HEX ) 409.0 A-2 comm C-1, F-2 211 nh2 Yaguang CI Rf = 0.10, HEX / EtOAc = 50/50 496.0 comm comm C1, F-3 212 HNrA c, ch3 Rf = 0.08, HEX / EtOAc = 50/50, 90% PURE 519/521 comm comm C1, F-3 213 NH2 ° o ^ nh ~ a h3c into nh2 Rf = 0.30, CH2CI2 / MeOH = 90/10 468.0 comm comm C-1, F-3, F-4 214 nh2 ην ^ Λ ^ ci Rf = 0.22 (50% EtOAc / HEX) 455.0 comm comm C-1, F-5 215 nh2 ΗΝ, / Λ ^ 〇Η Cl Rf = 0.28 (100% EtOAc) 471.0 comm comm C-1, F-5 -141- 4. • Order · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of the Invention (HO) Example Structural Formula Rf ( TLC solvent) or RT (minutes) * LC / MS ([M + H] +) (ΙΠ) Synthesis ** (VI) or (VII) Synthesis ** (I) Synthesis 216 nh2 g? % HN 〜Λ ^ 〇Μθ Cl Rf = 0.13 (50% EtOAc / HEX) 485.0 comm comm C-1, F-5 217 nh2 00¾ h3c ^ n ^ nh < RT = 2.55 452.3 comm comm C-1, F- 7 218 people h2 c 丨 Rf = 0.10, HEX / EtOAc = 50/50 441 comm comm G, F-2 219 nh2 a0% 'o 丄 nh2 F Rf = 0.08, HEX / EtOAc = 50/50 425 A-4 comm G, F-2 220 HjN ^ P 00¾1 V Cl RF = 0.75 [25% EA / Hex] [Calculated by elemental analysis: c28h17ci2n 〇3:% C 69.15% H 3.52% N 2.88, found:% C 69.01% H 3.57% N 2.84] comm B-1, F-1 Ministry of Economic Affairs Printed footnotes for employees' cooperatives of the Intellectual Property Bureau: * The following explains the LCMS conditions: HPLC-Electrospray Mass Spectrometry (HPLC ES-MS) -142- This paper is in accordance with China National Standard (CNS) A4 (210x297 mm) 200413343 Printed by A7 B7 of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (141) Two Gilson 306 pumps, a Gilson 215 automatic sampler, a Gilson diode detector, and a YMC PrOc-18 tube are used. Measured by a Gilson HPLC system with a column (2 X 23 mm, 120 A) and a Micromass LCZ single quadrupole mass spectrometer with z-spray spray ionization. Scan the spectrum of 120-1000 amu in 2 seconds. ELSD (Evaporative Light Scattering Detector) data was also obtained from analog channels. Buffer A (2 ° /. Acetonitrile in water with 0.02% TFA) and buffer solution

0 · 02% TFA in 2% water in acetonitrile), dissolve at 15 mL / min. The sample dissolution method is as follows: 90% a operation 0.5 minutes after 10 to 95% B within 3.5 minutes, maintaining 95% β 0.5 minutes, the column returned to the original within 0.1 minutes condition. The total operating time is two clocks. t 8 points ** comm means available from the product. 15 Two general methods G: Formula (I) pyrenethioha The production method of the benzofluorene of the present invention is described in the following general reaction, which is clearly described in the production method of Example 221. , And 20, ΛΙ

CN (Me) 2NC (S) CI base

〇 Jiu hTCH3 ch3 1. Heating 2. Alkali, DMF -143- This paper size is applicable to the home standard (CNS) A4 specification (210x297 public reply 200413343 A7 B7 V. Description of the invention (I42

Br or Ci

CN SH Λ (Hi) base, ΙΪ R—B (OR) 2 (VI) test / solvent Pd catalyst

10 15

Example 221 Method G

[3-Amino-6- (3-Hydroxypyridyl) -1-benzyl-2-phene-2-yl1 (2,4-dichlorophenyl) Method for the production of fluorenone Employees at the Intellectual Property Bureau of the Ministry of Economy Cooperative print 20

Step 1: Preparation method of 2-cyano-5-iodobenzyl- (diamido) phosphonium thioester-144- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (143)

N

5 At 0C, argon oxidation (2. 52 g, 44.9 mmol, 1.1 eq. ) In water (60 mL). After 45 minutes of incubation, acetone (60 mL) containing dimethylthioaminomethyl chloride (5.55 g, 44.9 mmol, 1. 1 eq) was added at 0 ° C over 30 minutes. Solution. The resulting 10 brown reaction mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium hydroxide, water and brine. The aqueous washings were combined and extracted with ethyl acetate. The organic layer was dehydrated, filtered and evaporated under reduced pressure. The crude oily product was crystallized from ether / hexane to give 2-cyano-5-iodophenyl- (dimethylamino) phosphonium thioester (10.3 g, 76.0%) as a beige solid. 15 body: W -NMR (acetone-d6) 5 7.89 (dd, J = 8.4, 1.8 Hz, 1 Η), 7.79 (d, J-1.5 Hz, 1 H), 7.60 (dd, J = 8.1 Hz, 1 H), 3.44 (s, 6H); MS ES (MH + = 333); Rf = 0.70 (30% ethyl acetate-hexane). 20 Step 2: Preparation of S- (2-cyano-5-moth-phenyl) -dimethylthio-carbamic acid >

This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200413343 A7 B7 V. Description of the invention (144) Take 2-cyano-5-discphenyl- (dimethylamino) methylthio acid vinegar (100g, 30.1% 1) at 20 (TC and argon) It was heated for 6 hours under the atmosphere to dissolve. The reaction was cooled to 温: warm, and the resulting brown @body was purified by ΜΡχχ, which was dissolved with 20% ethyl acetate-hexane, to produce s_ (2_ 气 基 _5_Angle. _Phenyl) -Di-5methylthiocarbamic acid, as a white solid (8.3g; 83.0%); 1mmr (acetone-d6) < 5 8.12 (d'J = 1.8 Hz, 1 Η), 8 · 〇 5 (dd, J = 7.8, 1.5 Ηζ, 1Η), 7.66 (d, J = 8.1 Ηζ, 1Η), 3.11 (width s, 3H), 3.08 (width s, 3H); MS ES (MH + = 333.0), Rf = 0.53 (30% ethyl acetate-hexane) · 10 Step 3: 2-cyano-5-thiosulfanil test

15 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs at 0 ° C and argon in the presence of s- (2-cyano ~ 5-iodo-phenyl) -difluorenylthiocarbamic acid (3.0 g , 9 · 0 mmol) of anhydrous N, N-dimethylformamide (30 mL) was added dropwise to a 25% solution of sodium methoxide in methanol (61 mL, 27 j mmol, 3.0 eq). The resulting yellow reaction was stirred at room temperature for J hours. The reaction mixture was poured into cold 2N HCK (100 inL), and extracted with ethyl acetate. The combined organic layers were dehydrated, filtered, and evaporated under reduced pressure to produce the crude product 2-monocyano-5-epine. The obtained crude product was used without further purification. Step away from an intermediate --- "2-((2 ', 4'-dichloromethane) carbonyl group]-3-face-β- -146- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 Gongfaj 200413343 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (145) Method for the production of iodobenzothiophene

Anhydrous N, N-dimethyl group containing crude product 2-cyano-5-mothithione (3.0 mmol) and 2,2 ', 4'-trichloro-acetanilide (673 mg, 3.0 mmol) Potassium hydroxide (832 mg, 6.0 10 mmol, 2.0 eq) was added to amidine (10 mL). The reaction mixture was stirred under argon at 80 ° C for 16 hours. The brown reaction mixture was cooled and diluted with ethyl acetate and water. The organic layer was washed with a saturated aqueous ammonium chloride solution, water, and brine, and dehydrated. The solvent was evaporated under reduced pressure, and the crude product was purified by MPLC (Biotage), after dissolving with 20% ethyl acetate-hexane, and then triturating in hexane to give 1.012 g (75.0%) of benzothiazephene. 1Η-NMR (acetone-d6) 6 8 · 24 (d, J = 1.5 Hz, 1H), 8 · 05 (d, J = 8.4 Ηζ, 1Η), 7.94 (width, s, 2H), 7.79 (dd, J = 8.4, 1.5 Hz, 1 H), 7.65 (dd, J = 1.5, 0.9 Hz, 1H), 7.56 (m, 2H); MS ES (MH +-448/450); Rf- 0.58 (30% ethyl acetate-hexane). 20 Step 5: Heading 4 compound: [3-Amine-6- (3-Hydroxybenzyl)-1-benzog sphen-2-enyl 1 (2, 4-dichloro-benzyl) Method for the production of methyl ketone-147- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm)

200413343 A7 _ B7 V. Description of the invention (146)

Take (3-amino-6-iodo-1-benzythiophene-2-yl) (2,4-difluorophenyl) methanone (150 mg, 0.33 mmol); [, 2 one two The methoxyethane solution was degassed with argon for 30 minutes. At this time, (Q) (3g mg, 0.03 mmol, 0.1 eq), pyridine-3-dihydroxyboronic acid (41 mg, 0.33 10 mmol, 1.0 eq) were sequentially added. With 2M Na2CO3 aqueous solution (40 mL). After argon was passed through the reaction for 10 minutes, it was heated to 8 ° C—night (18 hours). The reaction was diluted with ethyl acetate, washed with water and brine, and dehydrated with magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was passed through MPLC. (Biotage) purification and dissociation with 45-65% ethyl acetate-hexane, yielding 37.5 mg (28.1%) of a yellow solid product. 1η- 15 NMR printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs -de) (5 8 · 84 (dd, J = 2 · 7, 〇6 Hz 1H) 8.49 (dd, J = 4.8, 1.8 Hz, 1H), 8 · 21 (dd, J = 8.4, 〇 · 6 Hz, 1 H), 8.00 (m, 2H), 7.87 (width, s, 2Η), 7.68 (dd, J = 8.4, 1.5 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H) , 7.46 (s, 1H); 7.44 (d, J = 1.8 Hz, 1H), 7.36 (m, 20 1H) LC-MS (ES MH + = 399, RT = 2.71 minutes) · Rf = 0 · 08 ( 50% ethyl acetate-hexane). For the other compounds shown in Table 6 below, appropriate starting materials that are easily obtained and / or can be synthesized according to the methods shown in this paper can be selected according to the methods described above. Prepared by other standard chemical methods. -148- 200413343 A7 V. Description of Invention (l47) Table 6 Synthesis by Method G Example: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, a real inverted structure Hf (TLC solvent) or RT (min Γ 'LC / MS ([M + H] +) 〇! 〇 Synthetic method **. (VI) or "VII): of. Synthesis of Synthesis Method 4 (I); Method 222 nh2 nhso2ch3 ci Rf = 0.08, HEX / EtOAc = 50/50 491/493 comm comm G 223 nh2 Ci C! Rf = 0.58, HEX / EtOAc = 70/30 434 comm comm G 224 nh2 F Rf = 0.08, HEX / EtOAc = 50/50 383 A-4 comm G 225 nh2 N〇? ^ C! Rf = 0.45, HEX / EtOAc = 70/30 443/445 comm comm G 226 nh2 Rf = 0.08, HEX / EtOAc = 60/40 361 comm comm G 227 CN Rf = 0.32, HEX / EtOAc = 70/30 385 comm comm G 228 nh2 ΗΎ Rf = 0.12, HEX7EtOAc = 60/40 417 comm comm G 229 nh2 nhso2ch3 Rf = 0.14, HEX / EtOAc = 60/40 453 comm comm G 230 nh2 ^%-Oe nh2 Rf = 0.10, HEX / EtOAc = 70/30 375 comm comm G -149- • 4. Order · This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 -----_ B7 V. Description of the invention (l48) Footnote: * The following explains the LCMS conditions: HPLC-electrospray mass spectrometry (HPLC ES -MS) is equipped with two Gilson 306 pumps , A Gilson 215 automatic sampler, a Gilson diode detector, a YMC PrOc-18 column 5 (2 X 23 _, 120 A), a Gilson HPLC system, and Micromass with z-spray electrospray ionization Measured by IXZ single quadrupole mass spectrometer. The spectrum of 120-10000 amu was scanned in 2 seconds. ELSD (Evaporative Light Scattering Detector) data was also obtained from analog channels. Buffer A (30% 02% TFA in 2% acetonitrile in water) and buffer β (0.22% 10 TFA in 2% water in acetonitrile) were used for gradient dissolution in 15 minutes. The sample dissolution method is as follows: _ A operation 0.5 minutes, rise to 95 / QB within 3.5 knife clocks, maintain 95% β Q 5 minutes, and then return the column to the original within 0.1 minutes condition. The total operating time is 48 minutes. Mumu comm is available from commodities. 15 Other compounds of formula (I) can be prepared according to the methods described herein, using appropriate starting materials that are readily available and / or synthesizable by the methods shown herein, using other standard chemical methods known in the relevant arts. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -150-

200413343 A7 B7 V. Description of the invention (l49) Table 7

(I) Example printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs X R1 R2 R3 R4 R5 R6 231 〇PhCO- σ Η H3C \ / ΝΗ Υ 〇 Η 232 〇Η 00 " Η H3C, / ΝΗ ϊ Η Η 233 S Η Ο 〇 " '^ nhcoch3 Η 234 234 〇Η ο5 Η 9 " S02Me Η 235 235 〇Η :: 〇〇 " Η 〇 " · ^ οονη2 Η 236 236 〇Η Me φο " · Me Η S02Me 237 Η Η S Η Η σ- ^ CN Η 151 -151- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of the invention (ISO) Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs system

Example X R1 R2 R3 R4 R5 R6 238 〇Η 4-CI-Ph- H S02Me HH 239 〇Η 3-N〇2Ph- H 9 " ^ CN HH 240 S Η 4-CN-Ph- H o " '^ ΝΗδ020Η3 HH 241 S Η 2,4,6-triCI-Ph- H N02 HH 242 〇Η 3,4,5-triMe-Ph H ^ conh2 OH H 243 '〇4- 4-CF3 ~ Ph- H (y · ^ νηοοοη3 HH 244 〇Η 3-CH3CO-Ph H 〇 " HN human, e) 2 HH 245 〇Η 4- (COOH) -Ph- H (^ 'CF3 HH 246 〇Et 3- (C02Et) -Ph- H 3 〇HH 247 〇Η 4- [CON (Me) 2] -Ph H N02 HH 248 〇Η 3- (NHCH2CH2S02Me)-Ph H ^ CN HH -152- 4. Order · This paper size applies Chinese National Standard (CNS ) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of invention (1S1) Printed example of employee consumer cooperative of Intellectual Property Bureau of Ministry of Economy X R1 R2 R3 R4 R5 R5 249 Me 4- (NHS02Me) -Ph Η 9 " CN Η Η 250 〇Η 3- (NHCOEt) -Ph Η 9 " ^ οονη2 Η Η 251 〇Η 4- (NH- (CH2) 4-C〇Me) -Ph Η ^ νηοοοη3 OMe Η 252 S Η Η ^ ^ ΝΗδΟ20Η3 Η Η 253 S Η Ν j Η CN Η Η 254 〇Η Corpse Ν Ν / > ί- Η 3 〇Η Η 255 〇Η Ν-Ν 'Η σ- ^ ο νη2 Η 256 256 〇Ac Η S02Me Η Η 257 〇Η Corpse Ν Ν-Ν 'Η 9 " ^ CN Me Η 258 〇Η Η〇 ~ < θ > ^ " Ν J Η (Τ' ^ conh2 Η Η 259 〇Η 〇2Ν— ~ / Η- Ν- ^ 'Η ¢ 7. Ν〇2 Η 153 -153- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention ( l52) Ministry of Economic Affairs and Smart Money ▲ Printed by Bureau Consumer Cooperatives

Example X R1 R2 R3 R4 R5 R6 260 〇Η Cl_ Ν j H Λ HH 261 S Η MeO-ζ Vi ~ Ν j · H CN Cl H 262 S Η Me Ν j H σ 'HN person n (_2 HH 263 〇 Η co ^ X / nh2 Μβ- ^ ~ H 9 " ^ NHSO〇CHn H OH 264 〇Me C〇2Me Me-ζ Vf- NJ 1 H 9 " ^ nhcoch3 HH 265 〇Η c (〇) ch3 H • N〇2 Me H 266 〇Η C (0) N (CH3) 2 H 〇 " ^ CN Cl H 267 〇Et 5 (Et) 2N H c ^ '^ conh2 cf3 H 268 〇Η 0 H CN OH H 269 〇Η NH (CH2) 4S02Me H S02Me FH -154 · This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of Invention (l53) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

Example X R1 R2 R3 R4 R5 R6 270 S Et S〇2Et H (T- ^ νηοοοη3 Et〇H 271 〇Et Et (OC) CN H HN ^ -N (Me) 2 C! H 272 〇Me Me (〇) C (H2C) 3N H 〇 " · ^ NΗδ〇2〇Η3 CF3〇H 273 〇Η H (T '^ conh2 ch3 H 274 〇Η H 〇 " · ^ CN HH 275 〇Η H CN HH 276 S Η if Me H HN ^ N (Me) 2 HH 277 S Η H (7 '. NHCOCH3 HH 278 〇Η N Me H 9 " ^ CN HH 279 S Η N, 2 HN〇2 H -155- This paper is for China National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of invention (1M) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

Example X R1 R2 R3 R4 R5 R6 280 S Η ς Τ. Η σ. ^ ΝΗ8〇2〇Η3 Cl H 281 〇Η Κ3Κ H3cHh3 Η σ- ^ -conh2 FH 282 〇Η Η3K C ) 2 Me H 283 〇Η Η CN H OMe 284 S Me χί Me02C ^ x〇 / ^ C02Me Η, nhc〇ch3 OH H 285 〇 H3Cr ^ Η pr- S02Me HH 286 〇 (Μβ) 2N ^ ζ > 〇 Η 9 " ^ CN HH 287 σ Et (Β) 2ν ^ χ Q Η N〇2 HH 288 〇Η HO-Ng Η 3 〇OH H 289 〇Me 、, Me02S / N '>-^ · Η C ^ · ^ nhso2ch3 HH -156- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of Invention (155) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Example X R1 R2 R3 R4 R5 R6 290 〇Η VH 9 " ^ nhcoch3 HH 291 〇Η Me N ^ \ s ^ Me H CN H Cl 292 S Η ch3 H3C ^ N / k ^^ CH3 H 9 " HN ^^ N (Me) 2 HH 293 S Η ch3 H3C4cc3 H ^ conh2 HH 294 〇Η H 9 " HN Human N (Me) 2 H cf3 295 〇Η 00 " HS〇2Me 〇Me H 296 〇Η oy〇H 〇 " ^ νηοοοη3 OH H 297 〇Et C〇2Et, so HC〇2Et H nhcoch3 Me H 298 〇 h3c H Cl H 299 〇Η (Me) 2NOC WH CN FH -157- -4. This paper size applies Chinese national standards ( CNS) A4 specification (210 X 297 mm) 200413343 A7 B7 V. Description of invention (l56) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

Example X R1 R2 R3 R4 R5 R6 300 〇Η 〇Χ3 H 9 "-nhc〇ch3 Et H 301 S 欢 Huan H (T- ^ νηοοοη3 CF30 H 302 S Me H ^ CN HH 303 〇Η ΓΝ) ΤΥ ′ Μ 〇 〇 H 9 " N02 HH 304 〇Η (/ Τ γ octa (rMe μ ιΐ H〇H 0 " '^ οονη2 Me H 305 〇 · Η ^ Ν 八 C〇N (Me) 2 H o "' HN 丄 N (Me ) 2 OH H 306 〇Η αχ 'i CH3 ch3 H 9 " no2 HH 307 〇Η 〇 ^^^ N, ^ S〇2Et Η H HsC ^ X ^ Ci 〇HH 308 〇Η F3C-〇2S ^ jT) s H nhc〇ch3 H OH 309 〇Η μΛ ^ υ〇〇〇H H3cJD " 'HH 310 〇Η cxt- H 9 " CN HH -158- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 V. Description of Invention (l57) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

Example X R1 R2 R3 R4 R5 R6 311 〇Η Η 9 " ^ CN OH H 312 S Η Cl (Τ '^ νηοοοη3 HF 313 〇Η (_2' Me nhcoch3 H Cl 314 〇Η ρ- H3C--S— '6 cf3 SC ^ Me HH 315 0 ΗMeO ^ / Η〆cf3o p " CN 〇Me H 316 〇Η Η3〇 ^ ° ^ Ν—S〇2 Η〆OH 〇 " ^ νηοοοη3 H 〇Me 317 〇Η OH (Τ '^ νηοοοη3 H Me 318 〇Η 〇Me ύΆ 〇Me NHCOCH3 HH 319 〇ΗMe—〇H CO " HH -159- 4. Revision · This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of Invention (l58) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs

Example X R1 R2 R3 R4 R5 R6 320 〇Η σ · H Me Me HH 321 〇Η H ci ^ y ^ ci Cl HH 322 〇Η H a ^ a Ci HH 323 〇Η H XY ^ h3c ^^ s Me H 324 〇Η H IV ^ HH 325 〇Η H / Me〇- Me 'HH 326 〇Η H 9 F3C HH 327 〇 〇 χ H ^ = NH Cl 328 〇Η XX H Me〇HH 329 〇Η H ^ (ch2) 2 ^-〇HH -160- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 V. Description of Invention (l59) Example printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs X R1 R2 R3 R4 R5 R6 330 〇Η j3: H Me02C HH 331 〇Η rr: H H3c H OH 332 〇 IT H (Me) 2N Me H 333 〇Η H (Et) 2N < f ~ V-^ = NHH 334 〇Η H Me02S ^ hn u HH 335 Η j3r: 'H ch3 H MeO 336 〇Η j3: · H HN r. ~~ λ (_ / 0 " HH 337 〇Η jCC H Me〇2S ^ N Me Me〇H 338 〇Η HHH 339 〇Η H 〇% repair HH -161- This paper size applies Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of invention (16) Intellectual property of the Ministry of Economic Affairs Bureau employee consumption Printed by

Example X R1 R2 R3 R4 R5 R6 340 Η. Double H Me Me— H Cl 341 〇Η H FXX 'F into N people FHH 342 〇Η 丨 H $ HH 343 〇Η H OH H 344 〇Η rc: H /-\ 〇Nx) wA-C HH 345 〇Η H / -Λ O ^ · Me—N N- \ / 〇HH 346 〇 XT H rr [less 〇HH 347 〇Η jy: H ro HH -162- This paper size is applicable to China National Standard (CNS) A4 specifications ( 210x297 mm) 200413343 A7 B7 V. Description of the invention (101) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

: Example X R1 R2 R3 R4 R5 R6 348 〇Η 丨 OH HH 349 〇Η 0, i2; c, H Or- H OH 350 〇Η double OH HH 351 〇Η OH p- h2n HH 352 〇Η nr: H h2n OH H 353 S Η H p- h2n H OH 354 〇Η IX · OH h2n OH H -163- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (I62) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Example X R1 R2 R3 R4 R5 R6 355 〇Η F h2n HH 356 〇 H H2n HF 357 〇 Λ F h2n HF 358 〇Η H-shaped HH 359 〇Η 〇, / 0: 〇, H QN- / HH 360 〇 Η HHH 361 S ϊ Χϊ HHH -164- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (l63)

Example X R1 R2 R3 R4 R5 R6 362 Η χχ · OH H H 363 〇 Η. Double H OH H 364 〇 x fx3: f H.彳 OH H 365 S Η HH OH • 4. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, the composition suitable for the method of the present invention. The compound of formula I is formulated into a pharmaceutically acceptable composition. In the method, the diseases described further herein are treated. A pharmaceutically acceptable composition is a mixture of a compound of formula I in a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and harmless to the patient at a concentration that is compatible with the effective activity of the active ingredient, so any side effects that the carrier may cause will not destroy the beneficial effects of the active ingredient. -165- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200413343 Description of the invention (M4) 10 It can be used for blending properly. The group of pharmaceutical ingredients for the required route of administration include:% + hanging acidification Agents, such as (but not limited to): acetic acid, citric acid, hydrochloric acid, nitric acid; field horseshoe crab, alkalizing agents, such as (but not limited to): ammonia solution, ammonium carbonate, monoamine, monoethanolamine, hydroxide Unloading, soda, carbitol triethanolamine, triethanolamine-ne); oxoweiner, adsorbent 'for example (but secret): powdered cellulose and active aerosol propellant, such as (but not limited to) : Two * = 'CC12F2, F2C1C-CC1F2, and CC1F3;-lice carbon, air replacement agents, such as (but not limited to): ammonia and argon; antifungal preservatives, such as (but not limited to): benzyl Jun, Paraben 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 20 Butyl Ester, Ethyl Paraben, Ethyl Paraben, Para ~~ Propyl Ester, Sodium Benzoate; This Formic Acid Antimicrobial preservatives, such as (but not limited to): Benzammonium ammonium, benzyl ammonium ethoxylate, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, benzyl, phenethyl alcohol, phenylmercury nitrate and ethylmercury sodium thiosalicylate; antioxidants, For example (but not limited to): ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypoandrosine, monothioglycerol, propyl gallate, sodium ascorbate, sulfurous acid Sodium hydrogen, sodium formaldehyde sulfoxylate, sodium metabisulfite; binding materials, such as (but not limited to): polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, Polysiloxane and styrene-butadiene copolymer; -166- Yizhang scale is applicable to China National Standard (CNS) A4 (21 × 297 mm) 200413343 A7 B7 V. Description of the invention (165) Buffering agent, such as (But not limited to): potassium metaborate, dipotassium phosphate, sodium acetate, anhydrous sodium citrate and sodium citrate dihydrate; carrier, such as (but not limited to) ·· acacia syrup, aromatic syrup, aromatic Tincture, cherry syrup, cocoa syrup, orange syrup, Sugar 5 syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride for injection and bacteriostatic water for injection; chelating agents, such as (but not limited to): disodium ethylenediamine tetraacetate and ethylenediamine Amine tetraacetic acid; colorants, such as (but not limited to): FD &amp; C Red 3, FD &amp; C Red 10 Color 20, FD &amp; C Yellow 6, FD &amp; C Blue 2, D &amp; C Green 5 No., D &amp; C orange No. 5, D & C red No. 8, caramel and red iron oxide; clarifying agents, such as (but not limited to): bentonite; emulsifiers, such as (but not limited to): acacia gum, Cetyl polyethylene glycol, threonyl alcohol, glyceryl monostearate S, egg fillings, sorbitan mono 15 oleate, polyoxyethylene 50 monostearate; embedding agents such as (But not limited to): gelatin and cellulose acetate phthalic acid m; flavours printed by consumer cooperatives of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, such as (but not limited to): anise oil, cinnamon oil, cocoa, menthol, orange Oil, spicy peppermint oil, and vanilla; 20 humectants, such as (but not limited to): glycerin, propylene glycol, and sorbitol Abrasives, such as (but not limited to): mineral oil and glycerin; oils, such as (but not limited to): peanut oil (arachis oil), mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil; -167- Standard for this paper Applicable to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (166) Ointment bases, such as (but not limited to) lanolin, hydrophilic ointment, polyethylene glycol ointment , Petroleum jelly, hydrophilic petroleum jelly, white ointment, yellow ointment, and rose water ointment; penetration enhancer (transdermal delivery), such as (but not limited to): monohydroxy 5 alcohol or polyhydric alcohol, monovalent or polyvalent Valent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phospholipid derivatives, cerebrophospholipids, terpenes, amines, ethers, ketones, and ureas; Plasticizers, such as (but not limited to): diethyl acetate and glycerol; solvents, such as (but not limited to): alcohol, corn oil, cottonseed oil, sugar 10 oil, isopropanol, mineral oil, oleic acid, Peanut oil, pure water, injection Water, sterile water for injection and sterile water for infusion; hardeners, such as (but not limited to): Lupinol, Lutenyl volcanic acid, microcrystalline vanillin, stone linden, stearyl alcohol, white tincture, and scutellaria baicalensis ; Suppository bases, such as (but not limited to): cocoa butter and polyethylene glycol 15 (mixture); surfactants, such as (but not limited to): ammonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80 、 Sodium lauryl sulfate and sorbitan monopalmitate; printed suspension agents, such as (but not limited to): agar, bentonite, polycarboxylate, Sodium methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl fluorenyl cellulose, kaolin, methyl cellulose, tragacanth, and magnesium aluminosilicate; sweeteners such as (but Not limited to): Aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose; -168- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (167) Loading agents such as (but not limited to): magnesium stearate and talc; lozenge binding agents such as (but not limited to): acacia gum, alginic acid, sodium methylcellulose, compressible sugar, ethyl cellulose, Gelatin, liquid glucose, methyl cellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized powder, tablets and capsule diluents, such as (but not limited to): dibasic calcium phosphate, kaolin, lactose, manna Sugar alcohols, microcrystalline cellulose, cellulose powder, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch; lozenge coatings such as (but not limited to): liquid glucose, hydroxyethyl 10 cellulose , Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate and shellac; tablets directly compressed excipients, such as (but not limited to) ): Dibasic calcium phosphate; Rotary disintegrating agents, such as (but not limited to) · alginic acid, methyl cellulose 15 # 5, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinyl pyrrolidone, alginic acid Sodium, starch sodium glycolate and starch; Slip agents, such as (but not limited to): colloidal silica, corn starch, and talc; printed lubricants for tablets printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, such as (but not limited to): calcium stearate, stearic acid 20 Magnesium, mineral oil, stearic acid and zinc stearate; pastilles / capsule opaque agents, such as (but not limited to): titanium dioxide; pastille polishers, such as (but not limited to): Brazilian palm wax and white wax ; Thickeners, such as (but not limited to): beeswax, cetyl alcohol, and paraffin; isotonicity agents, such as (but not limited to): dextrose and sodium chloride; -169- This paper size applies to China Standard (CNS) A4 specification (210x297 mm) 200413343 Economic Imprint 5. Description of the invention (Viscosity increasing agent 'for example (but not limited to): alginic acid, bentonite, polyvinyl ethylene preparation, sodium methylcellulose, methyl Cellulose, polyethylene. Biloba, sodium alginate, and tragacanth; and wetting agents, such as (but not limited to): heptadecylethoxyl, omega-5, sorbitol monooleate, polyoxyethylene Sorbitol monooleate, and polyoxyethylene stearate. It can be used for the treatment of this month's chemical products, which are known in the relevant arts, to make it more effective-general units, such as immediate release, sustained release or timed release preparations, including the following: Capsules for two The compound to be administered can be formulated into solid or liquid preparations such as: two ingredients, lozenges, dragees, oral tablets, melts, powders, and soluble groups, and can be used according to the relevant technology Used in the manufacture of pharmaceutical hard. The solid military dosage form can be a capsule, which can be a general capsule capsule type, which includes, for example, boundary lubrication, d, and inert fillers such as: lactose, flank, and silk_corn palace powder. In the UΛ detailed example, the compound of the present invention, such as: lactose, nucleus, and jade, and combined with gelatin, gallbladder, or gelatin; disintegrating agents that help to dissolve and dissolve after administration, such as potato curd powder, algae Acid, corn 20 starch, and guanhua bean gum, tragacanth gum and acacia gum; can improve the flow rate of keying agent in the granulation process, and prevent the tablet material from adhering to the surface of the key punch plate puncher Lubricants, such as: talc, stearic acid or stearic acid, stearic acid or stearic acid; and dyes, colorants, and flavoring agents that can enhance the aesthetic quality of tablets and improve patient accessibility substance. Applicable to oral liquid-170- 10 ·! 4 order 15 This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) 200413343 A7 B7 V. Description of the invention (169 excipients for body dosage forms include phosphoric acid Two types, such as: ethanol, benzyl alcohol, and diluent ... Water and alcohol plus pharmaceutically acceptable interfacial alcohols, which can be added or not added. Other different materials as coatings include 5 ：: Or, coating = 二 ， 性 # Agents and granules are suitable for the preparation of aqueous suspensions, formulations or wetting agents, suspensions, and intermediates. Suitable dispersants or wetting agents and suspensions It can also contain other agents, such as 10 coloring agents. 1 flavoring agent and 15 The pharmaceutical composition of the present invention can also be an oil-in-water emulsion. This can be a vegetable oil, such as a mixture of liquid stone or vegetable oil. . Suitable emulsification: can be converted into natural ingredients such as acacia gum and tragacanth, natural fats such as dadan and lecithin, (3) derived from fatty acid and hexitol anhydride esters or = parts of esters , Such as: sorbitan monooleate, and (4) the condensation product of this part ^ with% oxyethane For example: polyoxyethylene sorbitan monooleic acid vinegar. The emulsion can also contain sweeteners and flavoring agents. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 &gt; Ingredients are suspended in vegetable oils, such as' for example: peanut oil, olive oil, sesame oil, or coconut oil; or mineral oils such as liquid paraffin. Oily suspensions may contain thickeners such as, for example, bee stings, hard paraffin, or Cetyl alcohol. Suspensions may also contain one or more preservatives, such as ethyl or n-propyl paraben; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as : Sucrose or saccharin. -171- This paper size is applicable to China ¥ ^ ((5 ^^ _ (210χ29737 200413343 A7 --_ —_ B7___) V. Invention ^^ — Syrup or tincture can be formulated with sweeteners, such as For example: glycerol, glycerol, sorbitol or sucrose. These formulations may also contain a demulcent, and a preservative, flavoring and coloring agent. The compounds of the present invention can also be administered parenterally, that is, subcutaneously. , Jing 5 pulse, In the eye Intra-synovial, intramuscular, or intraperitoneal, it is a compound that is physiologically compatible with diluent, which forms a dosage form with a pharmaceutical carrier. The pharmaceutical carrier can be a sterile liquid or a mixture of liquids such as: Aqueous solutions of physiological saline, dextrose and related sugars; alcohols such as ethanol, isopropanol, or cetyl alcohol; glycols such as propylene glycol or polyethylene glycol; sweeteners, such as : 2,2-difluorenyl; 1-dioxolane-4-ol, ethers such as: poly (ethylene glycol) 400; oils; fatty acids; fatty acid esters or fatty warm glycerol; or Ethyl alcohol-based fatty acid glycerides, with or without the addition of pharmaceutically acceptable surfactants such as: soaps or detergents' suspending agents such as: pectin, polycarboxylates, methyl cellulose, hydroxypropyl methyl ester Cellulose, or 15-methyl cellulose, or emulsifiers and other medical adjuvants. The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs prints that the oils that can be used in the parenteral formulation of the present invention can come from petroleum, animal oil, vegetable oil or synthetic oil, such as: peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, Olive oil, vaseline and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and cinnamic acid. Suitable fats are fatty acid vinegars such as ethyl oleate and isopropyl sarcoate. Suitable species include fatty acid metal salts, ammonium salts, and triethanolamine salts, and suitable detergents include cationic detergents, such as: dimethyldicarbonate dentate, acetonide halide, and amines. Acetic acid salts; anionic detergents, such as: burned, aryl, and olefinic acids, fluorenyl, dilute smoke, bonded glycerin -172- 200413343 V. Description of the invention (m 10 15 Employees ’Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Printed 20 such as ester sulfates, copolymerized with sulfosuccinates; non-ionic cleaners such as: fatty amine oxides, fatty acid alkanolamines, and poly (oxyethylene-oxypropylene) or ethylene oxide or propylene oxide And ampholytic cleaners, such as: alkyl-m-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and mixtures thereof. The parenteral compositions of the present invention are typically in solution Contains about 05% to about 25% by weight of active ingredients. Preservatives and buffers can also be used. To minimize or eliminate irritation at the injection site, these compositions can include a hydrophilic-lipophilic balance Value (^ ⑶ 乂 about 12 to 17 nonionic surfactant. The amount of surfactant used in these formulations can range from about 5% to about 15% by weight. The surfactant can be a single component with the above Hyg, or it can be A mixture of two or more components of HLB is required. Examples of surfactants used in parenteral formulations are polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and epoxy High molecular weight adducts of ethane and a hydrophobic matrix (formed by the condensation of propylene oxide with propylene glycol). Pharmaceutical compositions can be in sterile aqueous suspensions for injection. These suspensions can be prepared according to known methods using a suitable dispersant or wet Formulating agents and suspending agents such as, for example: sodium carboxymethyl cellulose, fluorenyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone 'tragacanth and acacia gum; dispersing agent or wet Chemical agent, which can be a natural fat filling such as: the condensation products of lecithin, stilbene oxide and fatty acids such as: polyoxyethylene stearate, ethylene oxide and long chain fatty alcohols Products such as ... Glyoxysanol, -173- 4 The paper size of the edition is applicable to the Chinese National Standard (CNS) A4 χ 297 public meal) 5. Description of the invention 172 5 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Concentrated condensation products with part of hexitol, such as lactone sorbitan monooleate, or part of ethylene glycol fatty acid and hexitol anhydride. Purpose. H product, such as: polyoxyethylene or solvent; t shot :: can be contained in non-toxic parenterally acceptable diluent as an example i She's solution 4 · _. Can make the diluent and solubility Chlorinated solution and isotonicity (SGlutiQn), isotonicity is the solvent so that the class' includes synthetic mono- and di-acid glycerides. In addition, fatty acids such as oleic acid can be used to prepare injections. The other groups ==== suppositories are administered rectally. It is solid at this temperature, but liquid at the rectal temperature, so it can be straight. These substances are, for example, cocoa butter and polyethylene glycol. W = Another method used in the method—a skin-transport conveyor. These transdermal patches can be used for continuous or discontinuous delivery. The structure and usage of the transdermal patch for conveying medicaments are well-known (see, for example, U.S. Patent No. 5,5, 〇23, 252, the content of which has been cited as a dipper, μ xi, 1, 1 (Incorporated into this article with <10,000 styles). These patches can be used for tandem, pulse, or on-demand delivery. Controlled-release parenteral formulations include microlipids and polymerizable microfilament gel formulations known in the relevant art. -174 *

200413343 A7 _ B7 V. Description of the invention (m) It may or may not be necessary to deliver the pharmaceutical composition to the patient via a mechanical transfer device. The construction and use of mechanical transfer devices for transferring medicaments are related to the art. For example, direct techniques for direct administration to the brain usually involve installing a drug delivery guide to the patient's ventricular system to bypass the blood-brain barrier. 5 Among them-an implantable delivery system for delivering a medicament to a specific anatomical region of the body is described in U.S. Patent No. 5,011,472 issued on April 30, 1991. The composition of the present invention may also contain other conventionally known pharmaceutically acceptable chemical ingredients, which generally refers to a carrier or diluent which is necessary or required. A general method for preparing these compositions in an appropriate dosage form can be used. These ingredients and processes include those described in the following references (the disclosures of which have been fully incorporated herein by reference, hPoweU, mf et al, Co in pend i uni of Excipients for Parenteral Formulations 11 PDA Journal of Pharmaceutical 15 Science &amp; Technology 1 998,52 (5), 238-31 1; Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs

Strickley, R. G &quot; Parenteral Formulations of Smal1 Molecule Therapeutics Marketed in the United States (1999) -Part-1 &quot; PDA Journal of Pharmaceutical Science &amp; Technology 20 1 999, 53 (6), 324-349; and Nema, S. et al,

Excipients and Their Use in Injectable Products’1 PDA Journal of Pharmaceutical

Science &amp; Technology, 1997, 51 (4), 166-171 o -175- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 __ B7 V. Description of Invention (l74) Learn about this Those skilled in the art understand that using the foregoing information can maximize the present invention. Nevertheless, the method of the present invention can use the following examples of pharmaceutical formulations. The following examples are merely illustrative of the present invention and should not limit the scope of the present invention in any way. 5 The medical music composition according to the present invention can be further explained as follows: 1) Bacteria IV / Valley fluid ● Use sterile> main injection water to prepare a 5rag / ml solution of the desired compound of the present invention. Adjust the pH if necessary. Dilute the solution with sterile 5% dextrose to 1-2 mg / ml, and administer IV round solution for 60 minutes. Freeze-drying: Aseptic preparations can use (i) 100-10 1000 freeze-dried powder of the compound of the present invention, (ii) 32-327 mg / mL sodium citrate and (iii) 300-3000 mg Dextran 4. preparation. This formulation uses sterile saline for injection or 5% dextrose in water to reconstitute a concentration of 10-20 mg / mL, and then it is diluted to 0.2-0.4 mg / mL with physiological saline or 5% dextrose in water. IV bolus or IV infusion for 15-60 minutes.

Ik intramedical suspension: Prepare the following intramuscular suspensions: Consumption cooperation by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, and the company printed 50mg / ml of the water-soluble compound of the invention 5mg / ml sodium carboxymethyl cellulose 4mg / ml TWEEN 80 20 9mg / ml sodium chloride 9mg / ml benzalcohol hard gelatin capsules each with 100mg active ingredient powder, 150mg lactose, 50% cellulose-176-

A7

5 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Gum 2 Hard inspection pure quasi-cut capsules, preparing a large number of units to prepare edible oils containing active ingredients Soybean oil, cottonseed oil or olive adult! N: Orthogonal injection pump is injected into molten gelatin to form soft gelatin capsules of active ingredients. Capsules are dried and silk. Live into a medical mixture that is miscible with water. A lot of tablets are prepared in the same way as usual, so that the peritectic fiber in the unit dose is removed, 5 mg magnesium stearate, 275 u microcellulose, llmg powder, and 98 ^ with a non-aqueous coating. Give 1 mouthful of 1 g of lactose. It can be coated with suitable water-absorbing properties. Improve appearance and stability or retarder / gum to prepare solid-state Xingqing by subtractive method according to known methods. These units = π drink without water, For immediate dissolution and delivery of medicines. The active ingredients are mixed in liquids containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified by freeze-drying and solid-state extraction techniques to form solid tablets or film-coated spins. .Pharmaceutical compounds can interact with viscoplastic and thermoplastic sugars and polymers The compound or foaming composition is compressed into a porous parent material, and the drug can be released immediately without the use of water. .177- This paper size is applicable to the national standard (cns) a4 specification (〇χ297 公 爱) 200413343 A7 5 Description of the invention (176) The compounds and compositions described in this article printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs can be used to treat or prevent overgrowth disease. Patients with this need can be administered an effective amount of the invention into: Or compound to achieve the desired medicinal effect. Patients suitable for this purpose ^^ Diseases that are specifically described herein need treatment (including preventive treatment): 5 animals, including humans. A pharmaceutically effective amount of a compound or composition Dosage for hyperproliferative diseases that can be buried in two places. Hyperproliferative diseases include (but are not limited to): solid tumor room, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eyes, etiquette Cancers of the skin, head and neck, thyroid, parathyroid, etc., are far away from 10 cancers. They also include lymphoma, sarcoma, and leukemia. Examples of breast cancer include (but not Yu): Invasive Ductal Carcinoma, Sexual Lobular Carcinoma, Ductal Carcinoma in Situ, and Lobular Carcinoma in Situ. Examples of polyclonal respiratory cancers include (but are not limited to) small cell and non-famous carcinomas' and bronchial glands. Tumors and pleural lung germ cell tumors. Examples of lung, brain, and lung cancer include (but are not limited to) brainstem and hypothalamus glia: cerebellum and cerebral astrocytoma, neural tube forming cell cytoma, two, tumor, And neuroectodermal and pineal tumors. Male genital tumors include (but are not limited to) prostate and bile. Female genital tumors include (but are not limited to) endometrial papillary carcinoma of the ovary, vagina, and vulva. Cancer, and uterine fibroids. Zilu gastrointestinal tumors include (but are not limited to): anus, colon ^ esophagus, gallbladder, stomach, tense, rectum, small intestine and salivary glands :: intestinal rectum urinary tract tumors including (but not limited to) ): Bladder, 昤 #. Cancers of Bali, kidney, ureter and urethra. Month 15 20 Symptoms Cervical Bowel -178- This paper size applies to China National Standard (CNS) A4 (210x297 mm) · Order

I 200413343 A7 B7 V. Description of the invention (177) Eye cancers include (but are not limited to): intraocular melanoma and retinoblastoma. Examples of liver cancer include (but are not limited to): hepatocellular carcinoma (hepatocellular carcinoma with or without changes in the fibrous layer), bile duct carcinoma (intrahepatic cholangiocarcinoma) 5 and mixed hepatocellular cholangiocarcinoma. Skin cancers include (but are not limited to) squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer and non-melanoma skin cancer. Head and neck cancers, including (but not limited to): throat / hypopharyngeal / nasopharyngeal 10 / oropharyngeal cancer, and lips and oral cancer. Lymphomas include, but are not limited to, AIDS-related lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Hodgkin's disease, and lymphomas of the central nervous system. 15 Sarcomas, including (but not limited to) soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytoma, lymphosarcoma and rhabdomyosarcoma. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Leukemia, including (but not limited to) acute bone marrow: leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, and hairy cell leukemia. 20 The characteristics of these diseases in humans are well understood, but there are some similarities in other mammals. Therefore, the method of the present invention can be administered to mammals, including humans, in need of treatment for diseases related to angiogenesis and / or hyperproliferation. The use of the compound of the present invention can be achieved by, for example, the following -179- This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413343 A7 B7 V. Description of the invention (178) In vivo and in vivo The activity of the tumor cell proliferative assay was confirmed. The relationship between the activity of the in vitro tumor cell proliferation assay and the anti-tumor activity in clinical trials has been confirmed in detail in related techniques. For example: Yew Fen (Silvestrini et al. Stem Cells 1993, 11 (6), 5 528-35), taxotere (Bissery et el · Anti

Cancer Drugs 1995, 6 (3), 339) and Topoisomerase Inhibition 1996, 37 (5), 385-93) have been confirmed for medical use in vitro tumor proliferation analysis. 10 The compounds and compositions (including their salts and esters) described herein have anti-hyperproliferative activity and are therefore suitable for use in the prevention or treatment of diseases associated with hyperproliferation. The following assay is one way to determine the activity of a compound in treating the diseases described herein. 15 In Vitro Tumor Cell Proliferative Score; I: Method for Testing the Adhesive Tumor Cell Proliferative Assay of the Compounds of the Invention Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, which involves the development of the "cell titer (" Ce 11 Titre) -Glo〃 Analysis (Cunningham, BA &quot; A Growing Issue: Cell Proliferation Assays. 20 Modern kits ease quantification of cell growth'1 The Scientist 200 1, 15 (13), 26, and Crouch, SP et al., 丨 丨 The use of ATP bi o1um i nescence as a measure of cell proliferation and cytotoxicity "Journal 〇f -180- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 --- ---- B7 V. Description of Invention (179)

Immunological Methods 1993, 160, 8b 88). H46O cells (lung cancer, purchased from ATCC) were coated on a 96-well assay plate, 3000 cells / well, and contained in a complete culture medium containing 10% fetal bovine serum 'and cultured at 37 C for 24 hours. After 24 hours of coating, the test 5 compound was added. After a series of dilutions, the final concentration range was from 10 nM to 20 # M, and the final DMS0 concentration was 0.2%. After adding the test compound, the cells were cultured in a complete growth medium and cultured at 37 ° C for 72 hours.

At day 4 ', the cells were lysed using a promamega ceu Titer Glo LuminescentR analysis kit, and 100 microliters of the buffer 10 mixture was added to each well, mixed, and incubated at room temperature for 8 minutes. Read this data on a luminometer to determine the ATP content of lysate in each well, which is equivalent to the number of live cells in the well. The data obtained after deducting the culture for 24 hours is the data of the Q day. When measuring IC50, linear regression analysis can be used to determine the concentration of the drug when this analysis mode is used to inhibit 50% of cell proliferation. The compounds of the present invention have been shown to significantly inhibit tumor cell proliferation in this assay. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs based on the above tests and other conventional methods used to analyze other standard laboratory techniques applicable to the prevention and / or treatment of the above-mentioned diseases or lesions, determined by standard toxicology and standard medical analysis methods The effectiveness of preventing and / or treating the above mentioned conditions in mammals, and comparing these results with the results of medicines known to treat these 20 conditions, it is easy to determine the prevention and / or treatment of each of the required treatment conditions Effective compound dose at the time. The amount of active ingredient used in the prevention and / or treatment of one of these conditions can be based on, for example, the specific compound and dosage unit used, the mode of administration, the period of treatment (including prophylactic treatment), the age and sex of the patient being treated, and the Prevention and / or treatment of disease -181 · Applicable to B scale-200413343 A7 B7 V. Description of the invention (丨 80) The nature and extent of the disease and other factors have changed greatly. The total amount of active ingredients administered is usually in the range of about 0.001 mg / kg to about 300 mg / kg body weight per day, and preferably about 0.00 mg / kg to about 150 mg / kg body weight. A unit dose may contain from about 0.5 mg to about 5 1500 mg of active ingredient, and may be administered one or more times per day. The daily dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral) and infusion techniques may be about 0.001 to about 200 mg / kg, and the overall weight is better. The daily dose of rectal therapy may be from 0.01 to 200 mg / kg, and the overall weight is better. The daily dose of vaginal therapy can be from 0.001 to 200 mg / kg and the overall weight is better than 10. The daily dose of local dose therapy may be from 0.1 to 200 mg / kg, and it is administered 1-4 times a day. Percutaneous administration may be required to maintain a daily dose of 0.01 to about 200 mg / kg. The daily dose of inhalation therapy may be from 0.01 to 100 mg / kg overall weight is better. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Of course, each patient's clear initial dose and subsequent dose course will be determined by the participating physicians based on the nature and severity of the disease, the activity of the clear compound used, the patient's age and general condition, and medication Time, route of administration, rate of drug excretion, combination of drugs, and so on. The treatment mode and number of doses required for the compound of the present invention or a pharmaceutically acceptable salt or ester thereof can be confirmed by those skilled in the art using conventional preventive and / or therapeutic test methods. 20 The compounds of the present invention can be administered as a single agent or in combination with one or more other agents, and the combination must not cause unacceptable side effects. For example, the present invention can be used in combination with other anti-hyperproliferative or other indication agents, etc., as well as in mixtures and combinations thereof. For example: anti-hyperproliferative agent that can be added to the composition as required -182- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A7 B7 V. Description of the invention (181) Ministry of Economic Affairs Property Bureau employee consumer cooperatives print compounds including (but not limited to) the 11th edition of the Merck Index (1996) compounds for cancer chemotherapy (the disclosures of which are fully incorporated herein by reference), such as: Asparagus Asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, asparaginase ( colaspase), cyclolinamine, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), Epirubicin, 10 etoposide, 5-fluorouracil, hexafluorenylmelamine, hydroxyurea, ifosfamide, irinotecan, formamidine tetrahydrofolate (Leucovorin), Lomos (Lomustine), mechlorethamine, 6-hydrothiopurine, mesna, metotrexate, mitomycin C, mitoxantrone, Prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thiobird , Topotecan, vinblastine, vincristine, and vindesine 〇 Other anti-hyperproliferative agents suitable for use in combination with the composition of the present invention include (but are not limited to) They are known to be useful compounds for the treatment and / or prevention of neoplastic neoplasia, which are described in The Pharmacological Basis of Therapeutics &quot; (9th Edition) by Goodman and Gilman. ) A4 size (210x297 mm) 200413343 A7 B7 V. Description of the invention (182)

Edited by Molinoff et al., Published by McGraw-Hill, p. 1225-1287, printed by the Employee Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (1996), the disclosures of which have been fully incorporated herein by reference, such as: aminophenylethyl Aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol ((^ 6 ^ 13 &quot; ^ 15631:]: 〇1), 2 ', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethynyl estradiol, 5 -Fludeoxyurinary bitter, 5-fluorodeoxyurin, single filling acid, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone Caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, o-p-dichlorobenzene dichloroethane ( mitotane), paclitaxel 15, pentosestat, pentoistatin, N-Asia Dendrol acetamidine-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate , Thiotepa, trimethylmelamine, urinary bite and vinorelbine. 20 Other anti-hyperproliferative agents suitable for use in combination with the composition of the invention include, but are not limited to, other anticancer agents , Such as: epothilone, irinotecan, raloxifen, and topotecan 〇 Those who are acquainted with this technology can use the aforementioned information and self-related technology -184 -This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200413343 A7 B7 Invention Description (I83) Information obtained from the printing art of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, the use of the invention to the maximum Those who are skilled in this art understand that the present invention can be changed and modified without departing from the scope set in this article. 185- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

Claims (1)

200413343 A8 B8 C8 D8, patent application scope 1. A compound of formula I Wherein X is selected from: 0 and S; R1 is selected from: fluorene, (CrCe) alkyl, (: (0) (〇C6) alkyl, and benzene10 fluorenyl); R2 is selected from: phenyl and Naphthyl, each optionally substituted with 1, 2 or 3 substituents independently selected from the following: OH, CN, No2, (CrC6) alkyl, (CrCOalkoxy, 15-yl, halo ( Cl-C6) alkyl, halo (Cl-C6) alkyl, C (0) RA, C (0) NRBRB, NBRRB, Li [(CrC6) alkyl] 0-say 0) this, NH [( CrC6) alkyl] (mC (0) Ra, and NH [(CrC6) alkyl] hC (0) 0Rb, a heterocyclic ring printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy Member heterocycles and fused bicyclic system 20 heterocycles, each heterocycle may be substituted with 1, 2 or 3 substituents independently selected from the following: OH, CN, No2, (G-CO alkyl, ( CrC6) alkoxy, halo, halo (ocoalkyl, halo (α-α) alkoxy, C (0) RA, C (0) NRBRB, NBRRB, NH [(CrC6) alkyl] Η -186-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 92381B 200413343 A8 B8 C8 D8 Employee Cooperatives of Intellectual Property Bureau, Ministry of Economic Affairs Print τ, patent application scope S (0) 2RB, leg [(Ci-C〇 alkyl) (mC (0) Ra, and NH [(CrC6) alkyl] (mC (0) 0Rb, RA in each case Are independently H, (Ci-C6) alkyl, (G-C6) alkoxy, NBRRB, or (OCO alkyl, and the alkyl can be optionally passed through 5 OH, C (0) RB, halo, ( CrCO alkoxy and NBRRB are substituted; RB is independently H, (G-C6) cycloalkyl, and (CrC6) alkyl in each case, and this alkyl can be optionally replaced by 0H, = 0, halo, ( CrC6) alkoxy, M (CrG) alkyl, NKG-G) alkyl] 2 and NC (0) (G-C3) alkyl are 10 generations, and 1 ^ when it is attached to N atom, in each When the example is a (Cr-C4) alkyl group, then two (Ci-C4) alkyl groups and the N atom to which they are attached can form a saturated ring together, and 1 ^ and the N atom to which they are attached can form together. Mo 15 Phenyl ring or hexahydropyridyl ring, the available N atom can be optionally substituted with (Ci-C0 alkyl group, the alkyl group can be optionally substituted with 0H, = 0, leg 2, (CrC6) alkoxy Group, NH (CrG) alkyl or N [(Cr C3) alkyl] 2, but the limitation is that when S (0) or S (0) 2 is attached, then 20 cannot be Η; R3 is From Rhenium, OH, CN, (CrG) alkyl, (CrG) alkoxy, halo, halo (Cl-C3) halo, and halo (C1-C3) halo; R4 is selected from:- 187-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A8 B8 C8 D8 τ, the scope of patent application piperonyl, Υ, where Υ is a heterocyclic ring, which may be substituted with 1, 2 or 3 substituents independently selected from the following: 5 2 0, N-oxide, Η, CN, NO2, halo, halo (CrC6) alkyl, 0Η, halo (CrC6) alkoxy, C (0) ORB, C (NH) NRBRB, NBRRB, S (〇V2RB, S (0) 2MBRB, (CrCO alkoxy group, the alkoxy group may be optionally substituted with 1 or 2 10 substituents selected from the group consisting of: 0H, NRY, and (C-G) alkoxy, NReRe, where Rc is Selected from: RB, (: (0) ^ and S (0) 2RB, C (0) RD, where 15 RD is selected from: RA, (C3-C6) cycloalkyl, Z and N [(C 「C3 ) Alkyl] Z, where Z printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics is heterocyclic in each case, and it can be independently substituted with the following substituents as required: 20 CN, = 0, OH, N-oxide, No.2, halo, (CrC6) alkoxy, halo (C1-C3) alkyl, halo (GG) alkyl, S (0) 2Rb, S (0 &gt; NRBRB, NRY, C (0 ) RA, -188-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200413343 A8 B8 C8 ___ D8 6. The scope of patent application and (G-Ce) alkyl group, this alkyl group can be optionally substituted with OH, C (0) RB, (OC3) alkoxy group and NBRRB; 5 NRBRE, where R £ Is selected from the group consisting of: C (0) RA, C (0) RB, S (0) 2Rb, S (0) 2NRBRB, and C (0) [(CrC6) alkyl] Z, where Z may be substituted as described above, if necessary, (G-C6) alkyl, which can be optionally substituted with the following substituents 10: CN, 0H, = 0,-, (Ci-C6) alkyloxy, C (0) RA, NRY, NRCRC, NRBRE , C (NH) NRBRB, S (0) 〇-2RB, S (0) 2NRY, C (0) RbC (0) 0Rb, Z, C (0) Z and alkyl] z, where z in each case If necessary, they can be substituted as described above, and phenyl and naphthyl can be substituted with 1, 2, or 3 substituents independently selected from the following: Employees ’cooperation with the Intellectual Property Bureau of the Ministry of Economic Affairs, printed OH, CN, No. 02, halo, halo (Ci-C6) alkyl, halo 20 (CrCO alkoxy, C (0) ORB, C (NH) NRY, NRY, S (〇V2RB, S (〇MRBRB, Z, C (0) Z, where Z in each case is optionally substituted as described above, (Ci-C6) alkoxy, the alkoxy may be optionally The following substituents are substituted: OH, NBRRB, and -189-This paper size applies to the Chinese national standard (⑶㊉84 4 specifications (210x297 mm) 200413343 A8 B8 C8 D8 VI. Patent application scope (Cl-C3) oxo, NRT, where is selected from: 1 ^, (: (0) {^ and 3 (0) #, C (0) RD, where RD is selected from: RA, (C3-C6) cycloalkyl and N [( 〇C3) alkyl] Z, where Z may be substituted as described above as required: NRBRE, where RE is selected from: C (0) RA, C (0) RB, S (0) 2RB, S (0) 2NRbRb and C (0) [(Ci-C6) alkyl] Z, where Z is optionally substituted as described above, (Cl—Cd alkyl, this alkyl may optionally be substituted with the following substituents: CN, 0H, = 0, halo , (〇 (: 6) carboxy, 15 C (〇) RA, NBRRB, NRBRE, C (NH) NRBRB, S (〇V2RB, S (0) 2NRbRb, C (0) RBC (〇) 〇RB, z, C (0) Z and (: (0) ^ (0c3) alkyl] z, z in each case printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs may be independently replaced as described above; 20 R6 Are independently selected from the group consisting of: Η, OH, CN, (c "c3) alkyl, (Cl-C3) alkoxy, Halo (Ci-C3) alkyl, with the tooth group% - alkoxy; or a pharmaceutically acceptable salt or ester thereof. 2. The compound according to item 1 of the scope of patent application, wherein 1 is 0. -190-This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200413343 Αδ Β8 C8 5 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 3. According to the scope of patent application! Of compounds of the formula, wherein xgS. 4. According to the compound in the scope of patent application No. 2, Lizhong R2 is selected from: phenyl, 6-membered heterocyclic ring and 5-membered heterocyclic ring, each of which may be substituted as necessary. 5. The compound according to item 2 of the scope of patent application, wherein r4 is selected from: Y and phenyl, each of which may be substituted as necessary. 6. = According to the compound in item 2 of the claim, wherein r2 is selected from: phenyl / 6-membered heterocycle and 5-membered heterocycle, each of which may be substituted as necessary, and R is selected from, γ and Phenyl, each of which is optionally substituted. 7. = According to the compound in the patent claim 5, wherein r4_ is from: phenyl and Y ', where γ is selected from the group consisting of 5-membered heterocyclic groups. Specific bite, each ring group may be substituted as needed. ^ 8. The compound according to item 6 of the scope of patent application, which is substituted by 1 or 2 substituents as needed, and R3 and i R are each independently selected from: Η, 〇ίίη η "CF secret. 0H, c1 , F ,, ch3, 0CH3, 9 · According to the application materials, the compound of item 8 is Η and (0 · C6) alkyl. The eight K is selected from: 10. The compound of item 3 of the patent scope, M-phenyl, 6-heterocyclic and 5-membered heterocyclic rings, each of which can be substituted for k as needed · Special: Compounds in the third item of the range, among which: Y and base are selected, and each can be substituted as necessary. The compound of the third item of the patent scope, phenyl, 6-membered heterocycle and 5-membered heterocycle, each ^ K is selected from the group consisting of: γ and phenyl, each of which can be substituted as needed. The paper size is suitable for wealth and family-order -191-A8 B8 C8 丄 ----- D8 VI. Application for patents ^ --- 13. According to the compounds in the u range of the patent, where r4 is selected from : Phenyl and Y, where Y is selected from: 5-membered heterocyclic ring and fluorene, each cyclic moiety may be substituted as required. 14. Compound according to item 12 of the patent claim, in which ^ 2 and chi 4 5 each Independently, if necessary, m is substituted by 1 or 2 substituents to be independently selected from mcum ·, CF3, and 0CF3. 15. According to the compound in the scope of application for item 14, r1 is selected from: Η and (G-C6) Alkyl. 10 16 · —a compound selected from: (3-amino-6-phenyl-benzofuran_2-yl) — (2, 4-dichloro-phenyl) monomethanone, (3-Amino-6-pyridin-3-yl-benzofuran-2-yl)-(2,4-dichloro-phenylmethane, 15 [3-amino-6- (3-nitro -Phenyl) -benzofuran-2-yl]-(2,4-dichloro-benzyl) -methyl, [3-amino-6- (3-amino-phenyl) -benzofuran— 2-Base]-(2, 4-Digas, one base) -A Gang, printed by 3- [3-Amino-2- (2, 4-dichloro-benzyl) Fluorenyl) -benzofuran-6-yl] -20 phenylcyano, N- {3- [3-amino-2- (2, 4-dichloro-benzylidene) -benzofuran-6 —Yl] -phenyl} -methyxanthanamine, N- {3- [3-amino-2- (2, 4-dichloro-benzylidene) -benzofuran-6-yl] -benzene Based} -acetamidine, -192-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 20 0413343 Α8 Β8 C8 _________________ D8 6. Scope of patent application [3-Amino-6- (2-methyl than fluoren-3-yl) -benzo bite sigma nan-2-yl] — (2, 4-dichloro -Phenyl) -methanone, 5- [3-Amino-2- (2, dichloro-benzylidene) -benzoanan-6-yl] -amidine, 5 3- [3- Amino-2- (2,4-dichloro-benzylidene) -benzocrean-6-yl] -Benzylamine, (3-Amino-5-fluoro-6-sucking-3 -Yl-benzocrean-2-yl)-(2,4-digas-phenyl) -fluorenone, {3-amino-6- [3-((S) -2, 3-dihydroquinone -Propylamino) -phenyl] -benzene10 benzo ° furan-2-yl}-(2,4-dichloro-phenyl) -pyrene 1,3- [3-amino-2- (2,4-dichloro-benzyl) -benzyl-6-yl] -N-fluorenyl-benzylamine, [3-amino-6- (1-fluorenyl-lΗ- Sial-4-yl) -benzopyran-2-yl]-(2,4-digas-phenyl) -methanone, 15 3- [3-amino-2- (2-chloro- 4-Gas-benzyl) -benzophenanthrene-6-yl] -benzidine, 2- {3- [3-amino-2- (2, 4-digas-benzyl) -Benzene-6-yl] -phenyl} -acetamide, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs [3-amino-6- ( 2-methyl-thiazol-4-yl) -benzofuran-2-yl] -20 (2,4-digas-phenyl) -fluorenone, N- {3- [3-amino-2- (2,4-《— Gas-benzyl group) -benzyl benzoyl-6-yl] -benzyl} -methanesulfonylamine, Ν- {3- [3-amino-2- ( 2, 4-digas-phenylfluorenyl) -benzofuran ~ yl] -benzyl} -acetamidamine '-193-This paper size applies to the Chinese national standard (3). 200413343 AB c D t, patent application scope [3-amino-6- (2-fluorenyl-. boast. Sit-4-yl) -benzon ° South-2-yl]-(2-methoxy-phenyl) -methanone, [3-amino-6- (3-fluoro-5-nitro- Phenyl) -benzoσfuran-2-yl]-(2,4-digas-phenyl) -methanone, 5 [3-amino-6- (3-methylsulfonyl-phenyl) -Benzofuran-2-yl]-(2,4-dichloro-phenyl) -methyl-, [3-amino-6- (2-fluoro-pyridin-3-yl) -benzofuran- 2-yl]-(2,4-dichloro-phenyl) -fluorenone, and [3-amino-6- (2-fluorenylamino-pyridin-3-yl) -benzofuran-2- 10-based]-(2,4-dichloro-phenyl) -methanone. 17. A composition comprising a compound of formula I. 18. The composition according to item 17 of the scope of patent application, wherein X is 0. 19. A composition according to item 17 of the scope of patent application, wherein X is S. 20. The composition according to item 18 of the scope of patent application, in which R2 is selected from 15: phenyl, 6-membered heterocyclic ring and 5-membered heterocyclic ring, each of which may be substituted as necessary. R4 is selected from: Y and phenyl, Each of them can be replaced if necessary. Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 21. According to the composition in the scope of patent application No. 19, where R2 is selected from the group consisting of phenyl, 6-membered heterocycles and 5-membered heterocycles, each of which may be substituted as required, R4 It is selected from: Y and phenyl, each of which may be substituted as necessary. 20 22. A method of treating or preventing a hyperproliferative disease comprising administering to a patient in need thereof an effective amount of a compound of formula I. 23. The method according to item 22 of the scope of patent application, wherein X is 0. 24. The method according to item 22 of the scope of patent application, wherein X is S. 25. The method according to item 23 of the scope of patent application, where R2 is selected from ... -194-This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 200413343 A8 B8 C8 _D8_ VI. Patent Application The range phenyl, 6-membered heterocyclic ring and 5-membered heterocyclic ring may be substituted as needed, and R4 is selected from: Y and phenyl, each of which may be substituted as necessary. 26. The method according to item 24 of the scope of patent application, wherein R2 is selected from the group consisting of phenyl, 6-membered heterocycles and 5-membered heterocycles, each of which may be optionally substituted, and R4 5 is selected from: fluorene and phenyl, Each of them can be replaced if necessary. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 9 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200413343 2.) Brief description of the representative symbols of the components in this representative map: Page 2-1