TWI255266B - Benzodiazepine derivatives - Google Patents

Abstract

The present invention relates to compounds of general formula, wherein X is a single bond or an ethynediyl group, wherein, in case X is single bond, R1 is halogen or phenyl which is optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, or cyano; in case X is an ethynediyl group, R1 is phenyl, optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy; R2 is halogen; hydroxy; lower alkyl; lower halo-alkyl; lower alkoxy; hydroxymethyl; hydroxyethoxy; lower alkoxy-(ethoxy)n (n=1 to 4); lower alkoxymethyl; cyanomethoxy; morpholine-4-yl; thiomorpholine-4-yl; 1-oxothiomorpholine-4-yl; 1,1-dioxothiomorpholine-4-yl; 4-oxo-piperidine-1-yl; 4-alkoxy-piperidine-1-yl; 4-hydroxy-piperidine-1-yl; 4-hydroxyethoxy-piperidine-1-yl; 4-lower alkyl-piperazine-1-yl; alkoxycarbonyl; 2-dialkylamino-ethylsulfanyl-; N,N-bis lower alkylamino lower alkyl; carbamoylmethyl; alkylsulfonyl; lower alkoxycarbonyl-lower alkyl; alkylcarboxy-lower alkyl; carboxy-lower alkyl; alkoxycarbonylmethylsulfanyl; carboxymethylsulfanyl; 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl; carboxy-lower alkoxy; cyano-lower alkyl; 2,3-dihydroxy-lower alkoxy; carbamoylmethoxy; 2-oxo-[1,3]-dioxolan-4-yl-lower alkoxy; (2-hydroxy-lower alkyl)-lower alkyl amino; hydroxycarbamoyl-lower alkoxy; 2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5c]-pyrrol-5-yl; lower alkoxy-carbamoyl-lower alkoxy; 3R-hydroxy-pyrrolidin-1-yl; 3,4-dihydroxy-pyrrolidin-1-yl; 2-oxo-oxazolidin-3-yl; lower alkyl-carbamoylmethoxy; or aminocarbamoyl-lower alkoxy; R3 is a 5 or 6 membered aryl or heteroaryl which are optionally substituted by halogen; cyano; nitro; azido; hydroxy; carboxy; morpholine-4-carbonyl; carbamoyl; thiocarbamoyl; N-hydroxycarbamoyl; trimethylsilyl-ethynyl; or lower alkyl; lower alkoxy; halo-lower alkyl; 4-lower alkyl-piperazine-l-carbonyl; lower alkylcarbamoyl which are optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated; or an optionally substituted five-membered aromatic heterocycle, which may be optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated, or lower alkyl which is optionally substituted by halogen, amino, lower alkylamino, acylamino, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkenoyl, lower alkylsulfinyl, lower alkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, alkoxyimino, carboxy which is optionally esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl which is optionally substituted by lower alkyl, or amidino which is optionally substituted by lower alkyl, -C(NRR')=NR"" (where R, R' and R"" are hydrogen or lower alkyl) and their pharmaceutically acceptable addition salts. The compounds according to the present invention can be used for treating or preventing acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.

Description

1255266 A7 B7 V. INSTRUCTIONS (1) The present invention relates to a compound of the formula I, r1, 乂------------- (please read the notes on the back and then ^1^4) Wherein X is a single bond or an ethylenic diyl group, wherein if X is a single bond, R1 is a dentate or a phenyl group, which is optionally a ruthenium, a lower alkyl group, a decyl lower alkyl group, and a lower Alkalkoxy, halo lower alkoxy or cyano substituted; if X is acetylene diyl, then R1 is phenyl, optionally _, lower alkyl, decyl lower alkyl, lower carbon Cycloalkyl, lower alkoxy or fluorenyl lower alkoxy substituted; .R 2 is a self group; hydroxy; lower alkyl; lower _alkyl; lower alkoxy; hydroxymethyl; Ethoxy; lower alkoxy-(ethoxy)n (n = 1 to 4); alkoxymethyl; cyanomethoxy; Trolopinyl; thiolofosfolininyl, 1-mercaptothionorfos-4-yl; 1,1-dimercaptothiopheneline-4*•yl; 4-anthracene - hexahydro ρ-pred-1-yl; 4-alkoxy-hexahydrop-p-but-1-yl; 4-light-hexahydro-p-pred-l-yl; 4-3⁄4 ethoxy- 7ΤNitrogen ρ than precipitate-1-yl; 4-lower calcinyl-7Τchloropyrene than -1-yl; alkoxycarbonyl; 2-dialkylamino-ethylthio-; Ν, Ν-double low carbon Alkylamino-based lower alkyl; amine-mercaptomethyl; alkylsulfonyl; lower alkoxycarbonyl-low carbon: group; nucleyl-low carbon: fe-based; rebel-low carbon Calcination; oxycarbonylmethylthio; carboxymethylthio; 1,4-dioxo-8.nitro-spiro[4.5]dec-8-yl; alkyl-lowstone anti-pitoxy; gas-low Carbon: 13⁄4 base; 2,j-one per base-low carbon pit oxygen; amine-4 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees' Consumption Cooperatives Printed 5, Inventions (2) Mercaptomethoxy; 2-keto-[1,3]-dioxosyl-4-yl-lower alkoxy; (2-based Low carbon alkyl)-low carbon amine group; light amine amine methyl ketone-low carbon oxy group; 2,2-dimethyl-tetrahydro-[1,3] dioxo oxime [4,5 cp Bilo-5-yl; lower alkoxy alkoxy-amine-mercapto-lower carbon oxy; 3R-#i-yl-tetrahydrop-pyrrolidyl; 3,4-di-light-tetrahydropyrrole- 1-yl; 2-keto-J-oxazolidin-3-yl; lower alkyl-amine-methyl fluorenyl An oxy group; or an aminoamine carbaryl-lower alkoxy group; R.5 is a 5 or 6 membered aryl or heteroaryl group, which is optionally halogen, cyano, nitro, azide or hydroxy. , a carboxyl group, a phenanthroline-4.carbonyl group, an amine carbaryl group, an amine thioglycolyl group, an N-alkylamine sulfhydryl group, a trimethyl sulphate-ethyl group; or a lower alkyl group; Carboalkoxy; fluorenyl-lower alkyl; 4-lower alkyl-7T hydrogen? a low-carboyl amine-based base, which is optionally subjected to an amine group, a lower alkylamino group, a mercaptoamine group, a ketone group, a hydroxyl group, a lower alkoxy group, a lower alkane. Substituted by a thio or carboxy group which is optionally esterified or amided; or a optionally substituted five membered aromatic heterocyclic ring which may optionally be an amine group, a lower alkylamino group or a decylamino group. a keto group, a hydroxy group, a lower alkoxy group, a low carbon thiol group or a complex or a low carbon alkyl group which is optionally esterified or aminated, and the low carbon alkyl group is sucrose, Amine group, low carbon amine group, mercaptoamine group, hydroxyl group, lower alkoxy group, lower alkyl alkyl group, decyloxy group, lower carbenyl group, low carbon alkyl group, Si group, low carbon burning A ketone group, a cyclization base, a cyclization base, an oxyalkylene group, an alkylene group, an alkyloxy group, a carboxyl group which is optionally esterified or amided, a low carbon sulfhydryl group, a ketone group. , cyano, carbamoyloxy, optionally substituted with a sulfonyl group or a fluorenyl group substituted with a low alkyl group, which is optionally a lower alkyl group, -C(NRR') = NRn (wherein R, R, and Rn are hydrogen or low carbon burned) Substitute, -5- (Please read the notes on the back and then install the page); Line · This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Cooperatives Print 5, Invention Notes (3) and its pharmaceutically acceptable addition salts. It has surprisingly been found that the compounds of formula I are metabolically shifted glutamate receptor antagonists. The compounds of formula I are characterized by the therapeutic properties of valuable quinones. In the central nervous system (CNS), the transmission of stimulation is performed by the interaction of neurotransmitters and neuroreceptors delivered by neurons. L-glutamic acid is the most frequently occurring neurotransmitter in the CNS and plays an important role in a large number of physiological processes. Relying on the stimulating receptor for the transaminic acid g, it is divided into two main groups. The first major group constitutes the ion channel controlled by the ligand. The metabolic shifting glutamate receptor (mGluR) constitutes the second major group and is further assigned to the group of G-protein coupled receptors. Currently, eight different members of these mGluRs are known, and one of them has even subtypes. Based on the different influences on the synthesis of secondary metabolic products and the structural parameters such as the different affinities of low molecular weight chemical compounds, the eight receptors can be subdivided into three subgroups: mGluRl and mGluR5 belong to the group I group. mGluR2 and mGluR3 belong to the group II group, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to the group III. A ligand belonging to the metabolically shifting glutamate receptor of Group II, which can be used to treat or prevent acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders And lack of memory. Other treatable indications at this point are limited brain function due to shunt surgery or grafts, poor blood supply to the brain, spinal cord injury, head injury, hypoxia due to pregnancy, Cardiac arrest and hypoglycemia. Other treatable indications are chronic and acute pain, Huntington's disease, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS-6- (please read the back note and reload the page) ) _ . Line _ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266

V. Description of invention (4) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 'eye wounds' 'retinopathy, primary Bajinsheng's syndrome or Bajinsheng's syndrome caused by drugs, and will lead to glutamine Acid esters lack symptoms of function such as muscle spasms, convulsions, migraine, urinary incontinence, cravings, opioid addiction, anxiety, vomiting, difficulty in movement, and depression. The object of the present invention is a compound of the formula I and a pharmaceutically acceptable salt thereof, and a pharmaceutically active substance, which is produced, a medicament based on the compound according to the invention and a process for its manufacture, and a compound according to the invention for controlling or preventing The use of the type of disease and the manufacture of the corresponding agent. Preferred compounds of formula I within the scope of the invention are those wherein R3 is phenyl, the phenyl group is substituted at the meta position, the substituent is cyano, self-primed, or optionally lower thiol or a Thio-substituted imidazolyl, 1,2, oxatriazole, anthracene, 2,4-distenyl' or an isoxazolyl group optionally substituted by a lower alkyl group. The following are examples of such compounds: 3-(8-Chloro-4-keto-7-phenylethynyl-4,5-dihydro-3indole-benzo[b][l,4]dioxane 4-yl)-benzonitrile; 3-[8-(4-methyl-hexahydropyridyl)yl ketone: phenylethynyl-4,5-dihydro_3h_benzo[b ][l,4]dioxagenin:yl]_benzonitrile; 3-(cardochloroketo)-7-phenyl-4,5-dihydro-3H-benzoquinone[b][l,4 Dioxagen-2-yl)-benzonitrile; ^[4-(3-cyano-phenyl)-2-oneylphenylethyl-2,3-dihydro-1H-benzene And [b][l,4] hexylglycine-7-ylthio]-acetic acid formazan; 2-[4-(3-cyano-phenyl)-2- ketophenylphenylethynyl- 2,3-Dihydro-benzoquinone (1)4] Dioxepin-7-yl]-acetamide; 3-(8-methoxy-4-keto-7-phenylethynyl-4,5 -Dihydro-3H-benzoquinone [b][i,4]Two 丫-7 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back first) Page) set · ί line - 1255266 A7

V. Description of the invention (5) Glycine-2-yl)-benzonitrile; 3-(8-cyanomethyl+keto-7-phenylethylidene-4,5-dihydro-infrared_benzene幷 [to] dioxin-2-yl)-benzonitrile; '4_(3_ phenylene) 7-(2. methoxy-ethoxy)-8-phenylethynyl- 1,3-Dihydrobenzo[b][l,4]dioxapyrene_2·酉; 4-(3-imidazolium-i-yl-phenyl)7_(2_methoxy_ Ethoxy>8-phenylethylidene-丨,3_dihydrophenylhydrazine[b][l,4]dioxepin-2-one; [RS]each [4-keto-based winter (2) -keto-[I,3]dioxosyloxy-yloxyphenylethynyl-4,5-dihydro-3H-benzoquinone [b][l,4]dioxine j-based]- Benzoonitrile; 7-hydroxymethyl-4-(3-imidazolyl-phenyl)phenylphenylethynyl],3-dihydrophenylhydrazone [b][l,4]dioxine-2- Ketone; [4-(3-imidazol-1-yl-phenyl)-2-ketophenylphenylethynyl-2,3-dihydro-ih-benzoquinone[b][l,4]dioxin Insyloxy]-acetonitrile; 8-(4-fluorophenylethynylhydroxymethyl ice (3_imidazole small group_phenyl p,3_dihydrophenylhydrazone [b][l,4]diσ丫Heptinone; 7-(2-3⁄4-yl-ethoxy) ice (3_imidazol-1-yl-phenyl) phenyl ethynyl 丨, 3_dihydrobenzo[b][l,4 ] Dioxin 2 -1 ketone; 8-(4-fluorophenyl)-7-[4-(2-trans)-ethoxy)-hexahydropyridine small base printed by the Intellectual Property Office of the Ministry of Economic Affairs ]_4_(3"Mizozol+yl-phenyl)-1,3-dihydrophenylhydrazine[b][1,4]dioxine-1-one; 8-(4-fluorophenyl)-7-hydroxyl -4-(3-imidazolyl-phenyl)-i,3-dihydrobenzo[b][l,4]dioxan-2-one; H2-fluorophenyl)-7-methoxy 4-[3-(2-methyl-imidazolyl)-phenyl; μ,3-dihydrophenylhydrazone [b][l,4]dioxine-2-one; 8-(2 -Fluorophenyl)-7-hydroxy ice (3-[1,2,3]triazole+yl-phenylhydrazine" dihydrophenylhydrazine-8- This paper scale applies to China National Standard (CNS) A4 specification (21 〇X 297 public))"""

I 255266

V. DESCRIPTION OF THE INVENTION (6 [b][l,4] Dioxepin-2-one; 8-(2-fluorophenyl>7_hydroxy_4_[3_(2-methyl-imidazole_丨_) Base)_stupyl]_丨,3_dihydrophenylhydrazine[b][l,4]dioxine-2,; 8-(2-fluorophenyl>7, base ice [3-(2) -methylthio-imidazole small group), stupid base, dihydrophenylhydrazine [b][l,4]dioxine-2-one; 1 (2,5-difluorophenylmethoxy winter (h1,2,3)triazole small group_phenyl p,3_dihydrophenylhydrazine[b][l,4]dioxepin-2-one; 8-(2-fluorophenyl>7 _hydroxy winter [3_(3_methyl_isoxazole_5_yl)_styl]_丨, 3_dihydrophenylhydrazine [b][l,4]dioxepin-2-one; 3 -[7-(2,5-difluorophenyl)each hydroxy-4-ylketo group_4>dihydro_3H_ stupid and dioxin-2-yl]-benzonitrile; 8-(4 - phenylphenyl group) _7_ carbyl o-imidazolyl phenyl phenyl phenyl hydrazine [b] [l, 4] dioxin-2-one; and = 4-fluorophenyl acetylene Base >7_#基邻似3]三峻]_yl-phenyl)dichlorophenylhydrazine [b][l,4]dioxin "heptinone. Compound of formula I, which is a thiophene group, Preferably, it is substituted by a cyano group or a halogen; or the ruler 3 is a bite base, preferably a bite_4_ base, It is also preferred to be substituted at the 2-position with a cyano group or a cyano group, or wherein R3 is a carbazolyl group, which is optionally substituted with an imidazolyl group or a 4-methylimidazolyl group at the 2-position. The following compounds are particularly preferred: 5 fluoro fluorophenyl > 8 methoxy. 4 keto 4,5 · dihydro spectroscopy _, 4] dioxepin-2-yl]- Phen-2-carbonitrile; 2-[7-(2-fluorophenyl)-8-hydroxylketo- 4,5-dihydro-m_benzoquinone[b][i,4]dioxine - ___ ·9-I paper size applies to China National Standard (CNS) A4 specification (210 X 297 cc - ------------- installed - (please read the back note first page) • Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention (7) 2-Based] <Cenphene-3-carbonitrile; ------------ --Install i I (please read the note on the back first? Click again) '[Η2·Fluorophenylmethoxy-4-keto-4,5-dihydro-3H-benzoquinone[b][l , 4] 2, azepine-2-yl]-pyridinecaricillin; 4·!>(4-fluorophenyl)-8-3⁄4yl-4-keto-4,5-dihydro-3H -benzoquinone [b][l,4]dioxine-2-yl]-pyridine-2-carbonitrile; 4_[7-(2-fluorophenyl)-hydroxy-4-keto-4,5 -dihydro-3 H-benzoquinone [b][l,4]dioxine-2-yl]-pyridine-2-carbonitrile; and 8-(2-fluorophenyl)_4-[2-(4-methyl- Imidazol-1-yl)-indazole 4-yl]_1,3-dihydrophenylhydrazone [bB,4]dioxine-2-one. All tautomeric forms of the compounds of the invention are also included herein. The term "lower alkyl" as used in this specification, denotes a straight or branched saturated hydrocarbon residue having from 1 to 7 carbon atoms, preferably having from 1 to 4 carbon atoms, such as methyl. , ethyl, n-propyl, iso-propyl and the like. The term "lower cycloalkyl" as used in this specification means that the cyclic saturated hydrocarbon residue has 3-5 carbon atoms, preferably 3 carbon atoms, such as cyclopropyl. Carbon alkoxy, the term, means a lower alkyl residue which has the meaning defined above and is bonded via an oxygen atom. The Ministry of Economic Intelligence's Intellectual Property Office employee consumption cooperative prints halogen halogen. The term contains fluorine, gas, Bromine and iodine. The term "5 or 6 membered aryl or heteroaryl" includes phenyl, thienyl, pyridine, and hydrazine. The wording of the five-membered aromatic heterocyclic ring '' includes 吱 、, Ρ Ρ sit, σ 坐 sit, Ρ azole, 1,3-0 stopper, 1, 3 _ _ _ _ _ _ _ _ _ Sitting, ι, 2 〇 oxazole, l52, 3-sanjun, 1,2,4-dioxime, ι, 2,4-oxadiazole, iota, 2,3-oxadiazole, ι, 2, 4 -thiadiazole, 1,2,3- -10 ΜΆ - , * public 97 2 X 10 2 /V Grid A4 S) N (C ί保1255266 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing _____ B7_ ____ V. INSTRUCTIONS (8) Oral sputum and Sijun. The compound of formula I and its pharmaceutically acceptable salt can be prepared according to the following method: Figure A 2 + r3^^〇〇r r3 ^c〇2r F^/^^NHBoc reflux IVa , > R = Et, Bu« FA Γ 苯 benzoic acid under normal procedure General procedure Ρ According to the diagram A, a compound of formula I, where X, ri, r2 and R3 As described above, it can be prepared from a general oxime compound via a deuteration-deprotection-cyclization sequence: for example, a compound of the formula II is reacted with dioxostrenone IV, wherein r3 is as described above, in an inert solvent. For example, toluene or xylene is obtained at a high temperature, preferably at 80 C and 160 C, to give a compound of the formula. Alternatively, the oxime compound of the formula can also be prepared, for example, by reacting a compound of the formula π with a ketone ester (Formula IVa), wherein R3 is as described above, using the same as described for the reaction with dioxanthine Conditions are carried out. The BOC protecting group in the compound of formula III is then cleaved and the cyclization of the compound which has been removed is accompanied to produce the desired compound of the formula 。. Alternatively, any other suitable amine protecting group, such as Fm〇c or 芊oxycarbonyl (Z), may be substituted for the BOC group. This deprotection-cyclization step can be carried out by treating the formula 冚-11 with, for example, a bronzee acid such as trifluoroacetic acid in an inert solvent such as di-methane (DCM) - the paper size is applicable to the Chinese national standard (CNS) ) A4 size (210 X 297 mil) ---:----

-------------Installation - (Please read the notes on the back and then 15^4 pages) 0 Line · 1255266 A7 B7 Five Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

DESCRIPTION OF THE INVENTION (9) Compounds are carried out. The reaction is preferably carried out at a temperature between 0 ° C and 50 ° C. It is advantageously also possible to use toluene ether or 1,3-dimethoxybenzene as a carbocation scavenger in this reaction mixture. Figure TJT B ΛΑ

NHBoc V

According to the formula B, a compound of the formula II, wherein R1 is as described above for a compound wherein X is a single bond, and R2 is as defined above, which may be derived from a different route, depending on the nature of R1, from the formula V Iodine compounds, of which R2 is as above -12- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------Installation --- Please read the back first Precautions (page 2) · 丨 line - 1255266 A7 V. Description of invention (10). As shown in Figure B, the main step is a coupling reaction of Suzuki_ with a Stiue_ type, carried out in the presence or absence of carbon monoxide. For the correct conditions for individual π compounds, see the experimental section. Compounds of the general formula V, wherein R2 is as defined above, may be prepared via various routes depending on the individual residue R2:

ΓΥΝαr2 human 〆Ν XI

NaOAc/ HOAc - General procedure A R2

ΧΠ Picture C no2 NK ·

General procedure B

R

No2 NHBoc Va (please read the notes on the back and then install 1

GP B, method a: diphosgene, EtOAc, 77 ° C; then t-BuOH

GP B, method b: Boc2 0, Cs2 C03, 2-butanone, 52 ° C

GP B, Method c: i) b〇c2 〇, DMAP, THF; ii) TFA, DCM, 0 °C As shown in Figure C, a compound of the formula Va wherein R2 is lower alkyl, halogen or alkane An oxycarbonyl group which can be prepared by iodination from a known general formula, and a subsequent protection of a synthetic intermediate of the formula XII. This iodination step can be carried out, for example, by using iodine chloride in acetic acid in the presence of sodium acetate. This reaction can be carried out, for example, at a temperature between 2 (rc and 8 (rrc) to protect the amine group, which can be carried out, for example, by reaction of a compound of the formula XJJ with di-tert-butyl carbonate, in the presence of a base such as carbonic acid. This reaction can be carried out in a polar solvent such as acetone or methyl ethyl ketone, etc., at 2 (rc and 6 (temperature between rc. As shown in Figure D, the compound of the formula Vb and %, where R2 Each is linked via sulfur or a nitrogen atom (R2 represents, for example, morphine porphyrin; thiomorphine: line · Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing - 13 - 1255266 A7 B7 V. Inventions (11) Base group; dialkylamino group; carboxymethylthio group, etc., which can be prepared from the intermediate XIII by nucleophilic substitution reaction with a specific amine or thiol in the presence of a suitable base. ---------装--- (Please read the precautions on the back and then ^1^4 pages) · Figure D Nitrogen nucleophile q|A^Anhb〇c RR, NH does not contain solvents or 1 丫γΝ〇2 DIPEA/PhMe Δ RFTN^^^NHBoc ΧΠΙ General procedure C Vb Sulfur nucleophile Cl Human 〆 NHBoc RSH NaOMe DMF Ji 1 RS^^NHBoc ΧΠΙ General procedure D Vc This reaction is preferably carried out in a polar aprotic solvent such as dimethylformamide, N-methyl-tetrahydropyrrolidone or dimethyl hydrazine, etc. It may be selected from sterically hindered amines such as Hunig's base, alkoxides such as sodium methoxide and sodium tributoxide, or hydrides such as sodium hydride. The reaction may be between 20 ° C and 110 ° C. The temperature is carried out depending on the individual compound to be synthesized. The compound of the formula Vd wherein R2 is bonded via an oxygen atom (R2 represents, for example, a lower alkoxy group, a lower alkoxy alkoxy group, a lower alkoxy alkoxy group, Lower alkoxy-lower alkoxy, etc.), which can be made, for example, as shown in Figure E: -14. - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 1255266 A7 B7 V. Description of invention (12) Oxygen nucleophile

CI XX. 2

ROH KOH

Illustration E.N0o

XIV

DMSO General Procedure E

R〇, ^, NhL XV

General procedure B R〇 v 'NHBoc Yd

GP B, Method a: diphosgene, EtOAc, 77 ° C; then t-Bu〇H GP B, Method b: Boc2 〇, Cs2 C〇3, 2-butanone, 52 ° C GP B, Method c : i) Boc2 0, DMAP, THF ; ii) TFA, DCM, 0 ° C oxyalkylation

(PPh^RhCI DABCO NO. R-X KHCO, ------------- Pack--- (Please read the notes on the back page again) NHBOC EtOH General procedure

HO NHBoc

XIX

XX DMF general procedure s

Rcr

Vd .no2 "NHBoc · The reaction with a nucleophilic aromatic substitution with an individual alcohol in the presence of a suitable base, followed by protection of the amine functional group. The base may be selected from the group consisting of bronzee bases such as potassium hydroxide and the like. Preferably, the reaction is carried out in a polar aprotic solvent such as dimethylformamide, N-methyl-tetrahydropyrrolidone or dimethyl sulphur, at temperatures between 20 ° C and 100 ° C. get on. The protection of the amine functional group can be achieved by reacting, for example, a compound of the formula XV with di-tertiary-butoxycarbonate in the presence of a base such as cesium carbonate. This reaction can be carried out in a polar solvent such as acetone or methyl ethyl ketone at a temperature between 20 ° C and 60 ° C. Another way to achieve this protection step is to first convert the amine functional group in the compound of formula XV to an isocyanate by reacting it with phosgene or phosgene equivalent in the presence of a suitable base, and then It applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on the third-D-15-sheet scale: Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print Economy Ministry Intellectual Property Bureau Staff Consumption Cooperative Print 1255266 A7 _B7_ V. Description of the invention (13) Alcohol treatment to obtain the desired compound of the formula Vd. Another suitable method for achieving this protection step is to first convert the amine functional group of the compound of formula XV to its corresponding bis-Boc compound by the presence of 4-dimethylaminopyridine (DMAP). The reaction is carried out with an excess of di-tertiary-butoxyl carbonate and then treated with 2 equivalents of TFA in dichloromethane to give the desired compound of formula Vd. The reversal of this step means that the nucleophilic aromatic substitution and the second protection of the amine functional group are first carried out on the main intermediate XIV, as shown in the synthetic scheme E, and can also be applied to have the general formula Vb and Compound of Vc (Synthesis Figure D). Yet another method of preparing the compound of formula Vd is to use the oxime-allyl compound XIX, and to carry out the deallylation-alkylation sequence, as outlined in Figure E. Deallylation is preferably via a transition metal catalytic isomerization such as a ruthenium (I) salt, such as a Wilkinson's catalyst [(PPh3)3 RhCl], or an Ib (II)-salt, such as The reaction is carried out in the presence of [(PPh3)2PdCl2] followed by aqueous acid hydrolysis of the vinyl ether formed. An example of such a procedure can be found in J. Org. Chem. 1973, 38, 3224. Alkylation of phenol XX to the desired compound of formula Vd can be carried out in the presence of a base in the presence of a base in the presence of a base, wherein R has a lower alkyl group, a lower alkenyl group, an alkyl acetate group. The meaning of an ester or a thiol group, and X represents a cleavage group such as valerate, bromide, decanoate or toluene. Preferably, the reaction is carried out in a polar aprotic solvent such as a gasifying solvent such as dichloromethane, gas or dichloroethane, or a guanamine such as dimethylformamide or dimethylacetamide. And N-methyl-tetrahydropyrrolidone, or argon, such as dimethyl hydrazine. The base may be selected from sterically hindered amines such as Hunig's test, calcined oxides such as sodium methoxide and sodium terbutyrate, hydrogen-16-. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297). ----) I 1--------· II (Please read the notes on the back page again) Order · _ -·丨线· 1255266 A7 B7 V. Description of invention (14) For example, sodium hydride, hydroxide, such as potassium hydroxide, carbonate, such as potassium carbonate, or hydrogen carbonate, such as potassium hydrogencarbonate. This reaction can be carried out at a temperature between -20 ° C and 80 ° C depending on the individual compound to be synthesized. For the synthesis of a ruthenium-tertiary-butyl compound of the formula Vd, the phenol XX can be treated with DMF-di-tertiary-butyl acetal in toluene or benzene at 80 ° C, as in the synthesis journal Said in 1983, 135. According to the composite map, F ’

Figure F Carbon nucleophile ------------- Install i I (please read the notes on the back first page)

丨' •nhfT

R-ch2co2r, KOBu1 DMSO 100 °C

RO, C

N〇2 NHR R R”=H XVII R"=BocXVI

LiCI

DMSO H20 100 0C

No2 NHR RM=H Vf RM= Boc Ve R”=H R,,= Boc

XIV XIII ”|gpb

Cl-moiety

MeQ2C, 〇c

No2 NhU ICI NaOAc

HOAc GP A 3-Amino-4-mercaptobenzoic acid methyl ester

Me〇2C R = H XXI

,n〇2 "NHR

Ubh4 MeOH

THF 0eC

No2 NHBoc X X = OH X = OTHP -X = C1 Vk—I Χ = ΝΜ^ : Line · R:L?f

Vh —] Vi Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives prints compounds of the general formulas Ve and Vf, in which R2 is linked via a carbon atom (R2 represents, for example, lower alkoxy-carbonyl-methyl; cyano-methyl, etc.) It can be prepared from compound XIII or XIV by, for example, reacting with a malonate or a malonic acid half ester in the presence of a base, followed by removal of one of the alkyl carboxylates via decarboxylation. The correct reaction conditions vary with the identity of the individual compounds and are described in the examples. -17- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 _B7_ V. Description of invention (15) The main intermediates XIII and XIV can be as described in Figure C. production. For compounds of the formula Vh to VI having a carbon moiety, the synthesis begins with the known methyl 3-amino-4-nitrobenzoate. As described in the standard iodination described in Scheme C, the iodide XXI is obtained, which in turn can be protected by a Boc-group. The reduction of the oxime ester can be carried out, for example, by treatment with lithium borohydride, hydroborated steel or diisobutyl hydride in an aprotic solvent such as THF, ether or toluene. The presence of an alcohol, such as methanol, ethanol or isopropanol, is advantageous. This reduction is preferably carried out at a temperature between -20 ° C and 0 ° C. Further functionalization of the formed benzyl alcohol Vh, e.g., conversion to a vapor (Vk), is carried out according to standard procedures known to those skilled in the art. The correct reaction conditions vary with the identity of the individual compounds and are described in the examples.

Illustration G --------------I (Please read the notes on the back and then ^!^ page) - R2〆

V , no2 , NHBoc

Aj~= PdCyPPhg)^ PPh3 Cul, EtjN THF 60 eC General procedure R1, X, ^N〇2 SnC!2%H20, NHB〇c R\v

EtOH 70 eC mh2 , NHBoc ! Line - General procedure U method b Π Φ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Me3Si—= PdCI^PPhg)^ PPh3 Cul, E^N THF, 50 eC General procedure K

Then NaOH, MeOH

Ar-X PdCI2(PPh3)2, PPh3 Cul, EtgN THF 60 eC General procedure κ

R2〃 ▽ 'NHBoc ΧΥΠΙ According to the formula G, a compound of the formula II, wherein R1 is as described above for a compound wherein X is an acetylenediyl group, which can be prepared from iodide-18-sheet by different routes Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 1255266 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing Instructions (16) Compound V, depending on the nature of R1 and R2. As shown in Figure G, this transformation can be carried out, for example, in the following manner: a) via a Sonogashira type coupling, the R1 - alkynediyl substituent is directly attached to the compound of formula V, followed by reduction of the nitro group, or b) By a two-step Sonogashira type coupling, in which a trimethyl sulphate-ethyl block is first coupled to a compound of the formula V, after deprotection with sodium hydroxide in methanol, an intermediate XVIII is produced, which can then be carried out a second time. Sonogashira type coupling, using the appropriate reactants R1 -I, R1 -Br or R1 -0S02CF3, and reducing the nitro group to convert it to the desired oxime compound. See the experimental section for the correct conditions for individual compounds. Graphic

A method a) κ"〇'

MgClj, Et3N C02R* ch3cn Et. But 丄-------------- Install i I (please read the notes on the back and then 15|^4 pages) ·- R = Cl, OH, OMe, OEt on C〇, R, IVa R, = H, But method b) Method c) Λ

LDA, LiOBut OBut THF,,78 eC c〇2r, Vila R* = H, Et, But

Me3Si02C, ^C02SiMe3 1.) LiBr. Et3N, CH3CN 3 2 ^ 2 3 or 2.) BuLi, Etp General procedure Method a> Isopropyl acetate _Concentration H2S04 Method b) TFAA, TFA, acetone

General procedure N : line ·

IV. According to the diagram, dioxin ketene and ketone of formula IV and IVa; I ester structural unit, which can be prepared from the corresponding acid derivative R3 -COR by the method known to the artist. That is, free acid, methyl or ethyl ester and SI chloride. See the experimental section for the correct conditions for the corresponding compounds. -19 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 V. Inventive Note (17) After the synthesis of the compound of formula I, Ri, R2 and X have the same The above meaning, and R3 is a general formula C(0)NR4R5 urea, wherein R4 and R5 are hydrogen, lower alkyl, or R4 and R5 together form a morpholinyl residue or N-methyl-hexahydropyrrole , which is summarized in Figure I: Figure I R1, v > Η /P R4R5NH. CO Pd (OAc>2, PPh3 or dppp

La

DMF • General procedure Q

Please read the notes on δ first and then install the page. For the correct conditions for individual compounds, please refer to the experimental section. The pharmaceutically acceptable salts can be readily prepared according to methods known per se and by considering the nature of the compound to be converted into a salt. Inorganic or organic acids, such as hydrochloric acid, argonic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, enedic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methylation = acid, p-toluene Acids and the like are suitable for the salt of the pharmaceutically acceptable salt of the compound of the formula I. a compound and a pharmaceutically acceptable salt thereof, which are metabolic private glutamate receptor antagonists and are useful for treating or preventing if and/or spastic neurological disorders such as psychosis, schizophrenia, A "•, canine disease, tolerance to illness and lack of memory. Other treatable adaptations, 'systemic shunt surgery or grafts to limit brain function, = good I blood supply to the brain, spinal cord injury, head injury, oxygenation due to pregnancy and hypoglycemia . Other treatable indications are chronic and acute pain 'Hendington's disease, ALS, dementia caused by Inna' eye damage, retinopathy, primary Parkinson's syndrome - 20-297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention (18) or Bajinsheng's syndrome caused by medicinal agents, ^ Blowing and symptoms that may cause glutamate deficiency, such as muscle spasm , don't ^ horse, migraine, urinary incontinence, addiction, mental illness, opioid addiction, worry, middle

At ‘ heart vomiting, difficulty in movement and depression. formula! The compound and a pharmaceutically acceptable salt thereof can be used as a medicament, for example, in the form of a pharmaceutical preparation. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft silicone gelatin capsules, tablets, emulsions or suspensions. However, (iv) may also be achieved rectally, for example in the form of a suppository, or parenterally, for example in the form of an injection solution. The compounds of formula I and pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable pharmaceutical preparations. Λ ^ y Ν sugar, corn starch or its derivatives, talc, stearic acid or its salts, etc., j for tablets, coated tablets, sugar-coated tablets and hard gelatin capsules for the carrier,,,, Λ N 1 is more useful. The appropriate carrier for soft gelatin capsules is, for example, vegetable oil, lyophilized fat, semi-solid sputum liquid polyol, etc.; however, depending on the nature of the active substance 、', shellfish and oysters, in soft gelatin capsules Ih / In the brothers, there is no need for carriers. It is used to make wood, botanical, and yoghurt, such as water, polyol, sucrose, ^ wild sugar, grape for botanical. Adjuvants, such as alcohols, polyols, Glycerin, "I by the temple, can be used to inject the aqueous solution of the compound water-soluble salt, but usually 3 benefits, ., necessary for the chastity. For the Ministry of Economic Affairs, the Intellectual Property Office staff consumption cooperatives to use the appropriate carrier, For example, it is natural or hardened, <, 'jing, sample, fat, semi-liquid or liquid polyol, etc. In addition, the pharmaceutical preparation may contain a preservative, a core, a heart, a stabilizer, a wetting agent. Emulsifiers, sweeteners, colorants, flavors are used to change the salt, buffer, masking agent or antioxidant. His people have a pricey substance. σ σ有其他治-21 - 1255266 A7 B7 V. INSTRUCTIONS (19) As mentioned above, a medicament containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient is also a A method of making such an agent, for example, comprising administering one or more compounds of formula I, or a pharmaceutically acceptable salt thereof, and, if desired, one or more other therapeutically valuable substances, Formulated in a wide range with one or more therapeutically inert carriers. This dosage can vary over a wide range and, in each particular case, will of course be matched to the individual requirements. In general, for oral or non-administrative The effective dose for enteral administration is between 0 01-20 mg/kg/day, with a dose of 01_10 mg/kg/day, which is preferred for all of the indications described. The daily dose of a 70 kg adult is between 0.7 and 1400 mg per day, preferably between 7 and 700 g per day. The invention also relates to a compound of formula I and a pharmaceutically acceptable salt thereof. Manufacturing use In particular for the control or prevention of acute and/or chronic neurological disorders of the aforementioned classes. The compounds of the invention are mGhl receptor antagonists of the steroidal group. These compounds exhibit activity of 5 when measured in the assays described below. 〇 or lower 'typically 3 aM or lower, and ideally 〇·5 or lower. In -------------- loading --- C please read the back Precautions and then page) Order: Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 4 KKimGlu2 (uM) 3: (8-chloro-4-keto-7-phenylethynyl-4,5 -dihydro-3H-benzo[b][l,4]dioxine:yl)-benzonitrile 0.028 3-[8-(4-methyl-hexahydropyrrol-1-yl)-4 -keto-7-phenylethynyl-4,5-dihydro-3H-benzoquinone[b][l,4]dioxan-2-yl]-benzonitrile 0.305 22- 本Λ张尺度Applicable to China National Standard (CNS) A4 Specification (21〇χ 297 mm 1255266 A7 B7 V. Invention Description (20) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 3-(8-Alkyl-4-keto-7 -phenyl-4,5-dihydro-3H-benzoquinone [b][l,4]dioxan-2-yl)-benzonitrile 0.120 [4-(3-Nitentyl-Winter)- 2-i homo--8-winter Block B: yl-2,3-diaza 1H-benzoquinone [b][l,4]dioxine-7-ylthio]-acetic acid methyl ketone 0.051 2-[4-(3-propyl-冬基)-2-S synthyl-8-winteryl-yl-2,3-dihydro-1H-benzoquinone[b][l,4]dioxepin-7-yl]-acetamide 0.037 3-(8-Methoxy-4-keto-7-phenylethynyl-4,5-dihydro-3H-benzoquinone [b][l,4]dioxan-2-yl) -benzonitrile 0.046 3-(8-Cyanomethyl-4-keto-7-phenylethynyl)-4,5-dihydro-3H-benzo[b][l,4]dioxin In-2-yl)-benzalamide 0.016 4-(3-Drosyl)-7-(2-methyllacylethoxy)-8-benylethylidene-1,3-dihydrobenzene幷[b][l,4]dioxine-2-one 0.021 4-(3-flavor-1-yl-winter)-7-(2-methoxyi-yl-ethoxy)-8 -epi-ethynyl-1,3-dihydrobenzo[b][l,4]dioxepin-2-one 0.012 [RS]-3-[4-keto-8-(2-keto -[1,3]dioxoindol-4-ylmethoxy)-7-phenylethynyl-4,5-dihydro-3H-benzoquinone[b][l,4]dioxapene- 2-yl]-benzonitrile 0.035 7-3⁄4 methyl-4-(3-flavor. -1--1-yl-phenyl)-8-phenylethylidene _ 1,3-dihydrophenylhydrazine [b][l,4]dioxine-2-one 0.018 [4-(3-imidazole) Small base-phenyl>2-keto-8-phenylethynyl-2,3-dihydro-1H-benzoquinone [b][l,4]dioxine-7-yloxy]- Acetonitrile 0.009(8-(4-fluorophenylethynyl)-7-hydroxymethyl-4-(3-imidazolyl-phenyl)-1,3-dihydrophenylhydrazone [b][l,4] Azepine-2-one 0.009 7-(2-hydroxy-ethoxy)-4-(3-imidazol-1-yl-phenyl)-8-phenylethynyl-1,3-dihydrophenylhydrazine [b][l,4] Dioxepin-2-one 0.032 8-(4-Gaolyl)-7-[4-(2-N-yl-ethyl lactyl p-Pent-1-yl) 4-(3-imidazol-1-yl-phenyl)-1,3-dihydrobenzo[b][l,4]dioxepin-2-one 0.100 8-(4-fluorophenyl) -7-Hydroxy-4-(3-imidazolyl-phenyl)-1,3-dihydrophenylhydrazone [b][l,4]dioxine-2-one 0.007 -23- This paper size applies China National Standard (CNS) A4 specification (210 X 297 mm) -----------------Installation--- (Please read the back note before this page). ί Line _ 1255266 A7 B7 V. Description of invention (21

4-[7-(2-fluorophenyl) methoxy 4-keto 5 gas-3]9_ awkward [b][M]dioxeine|yl]-pyridine 1 acetonitrile 0.033 ?12: Gas production 3 on 7-side base ice (3-[1,2,3]three"sitting small base-phenyl)-1,3-anthracenequinone [b][i,4]吖gyne: ketone 0.028 8-(2-fluorophenyl)-7-monoyl_4-[3-(2-methyl-imidazolium)-based phenyl]-1,3-dihydrophenylhydrazine [b][1,4] Dioxetanone 0.108 ----------------- (Please read the notes on the back page again) 1 (2-fluorobenzene) Base)_7 side group _4-[3-(2-methylthio-imidazol-1-yl)-phenyl H,3-dihydrophenylhydrazine [b][丨,4]二.丫庚因-2 -ketone 0.021

3-[7·(2,5-Difluoro-phenyl)-8-hydroxy-4-keto-4,5-dihydro 3H-benzoquinone [b][l,4]dioxine-2 -yl]-benzonitrile 0.006 8-(4-fluorophenylethynyl)-7-hydroxyl (3-imidazol-1-yl-phenyl)-1,3-dihydrophenylhydrazine [b][l, 4] Dioxepin-2-one 8-(4-fluorophenylethynyl)-7-hydroxy-4_(3-[indol, 2,3]triazol-1-yl-phenyl)-1,3 -Dihydrophenylhydrazine [b][l,4]Dioxeine·2-ketone 0.013 0.010 : Line 'Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed J^-|j[]-LY354740 combined with mGlu2 transfection CHO cell membrane transfer infection and cell culture The mouse mGlu2 receptor protein encoded by cDNA in pBluescript II was obtained from S. Nakanishi (Sakamoto Kyoto) and obtained from Invitr〇gen (Leek, Netherlands). The nucleated cell expression vector pcDNA I-amp was used for secondary generation asexual plague. Using the modified calcium citrate method described by Chen & Okayama (1988), the vector construct (pcDlmGR2) and the psvNeo plasmid encoding the new serotonin #药-24- This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) A7 1255266 B7_ V. Invention description (22) -------------- Pack--- (Please read the notes on the back and then 5^| |4 pages)

The gene was co-transfected into CHO cells. These cells were maintained in Dulbecco's denatured Eagle medium with reduced L-glutamate (2 mM final concentration) and 1 〇 °. Dialyzed bovine fetal serum obtained from Gibco BRL (Basel, Switzerland). The selection was made in the presence of G-418 (final 1000 micrograms per milliliter). The clonal propagation line was confirmed by a total of 5 micrograms of RNA reverse transcription followed by PCR using the mGlu2 receptor-specific primer 5'-atcactgcttgggtttctggcactg-3' and 5'-agcatcactgtgggtggcataggagc-3' at 60 mM Tris HC1 ( pH 10), 15 mM (NH4)2S〇4, 2mMMgCl2, 25 units/ml Taq polymerase, 30 cycles of annealing at 60 ° C for 1 minute, 72 ° C for 30 seconds, and 1 minute Denaturation at 95 °C. Cell membrane preparation line • Cells cultured as described above were collected and washed three times with cold PBS and cold at -80 °C. The pellet was resuspended in cold 20 mM HEPES-Na〇H buffer (pH 7.4) containing 10 mM EDTA and homogenized with a polytron (Kinematica, AG, Littau, Switzerland) at 10,000 rpm for 10 seconds 0 to 4 After centrifugation for 30 minutes at ° C, the pellets were washed once with the same buffer and once with cold 20 mM HEPES-NaOH buffer (pH 7.4) containing 0.1 mM EDTA. The protein content was measured using the Pierce method (Socochim, Lausanne, Switzerland) using bovine serum albumin as a standard. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative Printed [3H]-LY354740 After thawing, resuspend the cell membrane in cold 50 mM Tris-HCl buffer (pH 7) containing 2 mM MgCl2 and 2 mM CaCl2 (binding buffer) in. The final concentration of the cell membrane in the assay was 25 μg protein/ml. The inhibition test was performed using a cell membrane that had been cultured at 10 nM [3 H]-LY354740 at room temperature, -25- This paper scale was applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Bureau employee consumption cooperative printed 1255266 A7 _B7_5, invention description (23) carried out in the presence of different concentrations of the test compound for 1 hour. After the incubation, the cell membrane was filtered on a Whatmann GF/C glass fiber filter and washed 5 times with a cold binding buffer. Non-specific binding was measured in the presence of 10 β M DCG IV. After the device was transferred to a plastic vial containing 10 ml of Ultima-gold scintillation fluid (Packard, Zurich, Switzerland), the radiation was measured by liquid scintillation in a Tri-Carb 2500 TR counter (Packard, Zurich, Switzerland). active. Data analysis The inhibition curve was consistent with the four-parameter calculation equation to obtain IC5 〇 H and Hill coefficient. EXAMPLES The following examples relate to the preparation of (4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl vinegar (Synthesis Scheme C): General Procedure A by 2-nitroaniline Iodination to prepare 4-iodohexylnitroanilide [according to Wilson, J. Gerald; Hunt, Frederick C. Aust. J. Chem. 1983, 36, 2317-25] to 2-nitroaniline (1.0 mol) Adding a single gas of iodine in H〇Ac (300 ml) in a stirred solution of anhydrous NaOAc (93-103 g, 1 J25-1.25 mol) in HOAc (500 mL) -66 ml, 1.125-1.25 m). The reaction mixture is heated to a specific temperature until thin layer chromatography (TLC) shows complete conversion of the starting material, stirring at 23 ° C for another 30 minutes, then slowly diluting with H20 (1000 ml), which causes crystallinity The product was isolated. Stirring was continued for 1 hour, and the product was filtered off, washed with HOAc and dried at room temperature at 60 ° C. Example A1 -26- -------------- Install i I (please read the note on the back and then page 41k) _ : Line · This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. INSTRUCTIONS (24) &quot; A 5-chloro-4-yl-yl-2-yl-aniline according to the general procedure A (8(TC), at H0Ac/ In Na0Ac, dry emulsified hydrazine was prepared from 5-chloro-2-nitroaniline by foot and hydration to obtain an orange solid. MS (EI) 298 (M+) and 300 [(M+2) +]; melting point 202-203 ° C (decomposition). Example A2 4-iodo-5-methyl-2-nitro-aniline according to the general procedure A (80 ° C), in HOAc / NaOAc, monochloro Iodine was prepared from 5-methyl-2-nitroaniline by iodination to give a red solid. 曰MS (EI) 278 (M+); mp 154 ° C (decomposition). Example A3 5-Amino- Methyl 2-iodo-4-nitrobenzoate was prepared from 3-amino-4-nitrate according to the general procedure A (35 ° C) in HOAc/NaOAc with iodine monochloride by iodination. Methyl benzoate (22.25 g { CAS-No. [99512-09-1]; made in two steps as follows: 3-hydroxyindole nitrobenzoic acid (30 g, 164 mmol) , cis 4 〇 (21, 91 g, 410 mmol) in 25 ° '. NH3 aqueous solution (180 ml), in steel hot-pressed steel, heated at 16 〇 under the armpit for 7 hours (internal pressure: 23 The mixture was cooled to 23 ° C and evaporated to dryness. EtOAc EtOAc (EtOAc) (EtOAc) The organic layer was dried over <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The material was suspended in MeOH (500 mL). EtOAc (EtOAc)EtOAc. Saturated NaHC〇3 solution and brine, then -27- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------- Μ - (please Read the precautions on the back page again) Η^τ ·_ Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266

Dehydrated and dried with MgS04. The solvent was removed leaving a sufficiently pure I-amino ice nitrobenzoic acid methyl acetonate (22.25 g, 93%) as an orange solid. }Get orange (29.38 grams, 80%). MS (EI) 322 (M+); mp 168 (dec.). General procedure B · · Preparation of nitroaniline (2_nitro-phenyl)-amine methyl acid third-butyl ester method a · in diphosgene (41 ml, 341 mmol) in the section (10) In a solution of 4 liters, in (TC), add a solution of 'iodo-based winter in hemp (ml), and mix the mixture (four) to the 18-day temple. Remove the solvent in the air, leaving The product was triturated with EtOAc (EtOAc)EtOAc.EtOAc. This was refluxed for a period of 25 hours in excess of a mixture of the second-BuOH and CH2 (3⁄4). The solvent was removed to leave an orange solid which was purified by column chromatography using hexane / EtOAc. 4-iodo-2-nitro-phenylamine methyl acid tert-butyl ester as a yellow solid. Method b: 4-iodo-2-nitroaniline (142 mmol) with cesium carbonate ( 55 5 g, Π 0 mmol) in a mixture of 2-butanone (740 ml), Β〇(:2〇(37.8 g, 173 mmol) in 2-butanone (170 ml) Solution in the solution The mixture was stirred for 26 hours at 52 ° C. The solvent was removed in the sputum and the residue was taken up in a mixture of H.sub.2 (240 mL) and MeOH (240 mL). The combined burned layers were washed with brine (200 ml) and all the aqueous layers were re-extracted with hexanes (3 liters), and all the combined layers were dehydrated and dried with MgS〇4. , too, and in the air 28 paper standards apply to the Chinese National Standard (CNS) A4 specifications (210 X 297 mm) — (please read the precautions on the back and then ^||^4 pages), · ·· · Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

1255266 V. Description of the invention (26) Evaporation of the solvent to give an orange solid, which was purified by chromatography eluting with hexane / EtOAc to give (4-diyl-2-nitro-phenyl) Amino-methyl 3-butyrate is a yellow solid. Method C: in a solution of 'iodo-1-nitroaniline (550 mmol) and DMAP (1.22 g, 1 mM mmol) in THF (1000 mL) at 23 χ: A solution of B〇C2〇 (246 g, 1128 mmol) in THF (5 mL) was added dropwise. (Stirring was continued for 75 minutes. The whole mixture was evaporated to dryness and dried <RTI ID=0.0></RTI> to </RTI> <RTI ID=0.0> TFA (84 ml, 1100 mmol) was added dropwise. The mixture was stirred in EtOAc. EtOAc (EtOAc m.). The solvent was removed in the sputum, leaving a dark brown solid (199.71 g), which was applied to silica gel and purified by column chromatography using hexane / EtOAc -Nitro-phenyl)-amino acid tert-butyl ester as a yellow solid. Example B1 (5-chloro-4-pyridyl-2-nitro-phenyl)-amine methyl acid _Butyl ester according to the general procedure B (method a), from 5-chloro-bromoiodo-2-nitro-phenylamine (example Α1) (7·0 g ' 23.45 mmol) and diphosgene (2.12 ml, This isocyanate was prepared in EtOAc (3 mL) EtOAc (3 mL) 6%) 〇MS (EI) 398 (M+) and 400 [(M+2)+ ]; melting point 82-84Ό. Example B2 -29- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 Love) -------------^ · 11 (Please read the notes on the back and then ^||^ page) Order: Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed A7 V. Description of invention (27 (4-Alkyl-5-methyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester according to the general procedure B ( Method a), from 4-iodo-5-methyl-2-nitro-phenylamine (Example Α 2) (13. 51 g, 48.6 mmol) with diphosgene (4.4 mL, 36.4 mmol) This isocyanate was prepared by treatment with EtOAc (50 mL) EtOAc (EtOAc) (EtOAc) M+); melting point 99-l 〇〇 DC. Example B3 5-tris-butoxycarbonylamino 2 -iodoyl nitro-benzoic acid methyl ester according to the general procedure B (method a), from 5-amino Methyl 2-iodo-4-nitro-benzoate (Example A3) (5.5 g, 17 mmol) with diphosgene (155 mL, 1 This isocyanate was prepared by treatment with EtOAc (135 mL) EtOAc (EtOAc:EtOAc) Obtained as a yellow solid (5 2 g, 72%). MS (ISP) 440 [(M+NH4)+]; melting point i26 °C. Example B4 (5-allyloxy-4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl ester according to General Procedure B (Method a) from 5-Allyloxy- 4-iodo-2-nitro-aniline (Example Ε1) (9·0 g, 28.2 mmol) with diphosgene (2.6 mL, 212 mmol) in KOAc (150 mL), then This isocyanate was prepared by treatment with a third _Bu 〇 H (8 mL) and CH 2 C 丨 2 (80 mL). Obtained a yellow solid (9.16 g, 77%) 〇 MS (ISP) 421 [(M+H)+] and 438 [(M+NH4)+]; melting point 93-95 Ό. Example B5 I----丨 11丨1丨! — II (Please read the precautions on the back page again) · · : Line. -30- 1255266 A7 B7 V. Description of invention (28) (4-Qi-5-methoxy-2-nitro-phenyl - Aminomethyl 3-butyrate according to General Procedure B (Method a), from 4-iodo-5-methoxy-2-nitro-phenylamine (Example E2) (2.85 g, 9.69 mmol) Isocyanate was prepared by treatment with diphosgene (0.88 mL, 7.27 mmol) in EtOAc (EtOAc) (EtOAc) Obtained as a yellow solid (3.0 g, 79%). MS (EI) 394 (M+); mp. Example B6 [4-Butyl-5-(2-methoxy-ethoxy)-2-nitro-phenyl]-amine methyl acid tert-butyl ester according to General Procedure B (Method a), 4-iodo-5-(2-decyloxy-ethoxy)-2-nitro-phenylamine (Example E3) (2.73 g, 8.08 mmol) with diphosgene (0.8 mL, 6.06 mmol) The isocyanate was prepared by treatment with EtOAc (50 mL) eluting EtOAc (EtOAc) Obtained a yellow solid (3.0 g, 86%). MS (ISP) 439 [(Μ+Η). ],456 [(Μ+ΝΗ4)+] and 461 [(M+Na)+]; melting point 109- lire 〇Example B7 [4-硪基-5-( 2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy) 2-nitro-phenyl]-amine methyl acid - 酉 酉 according to the general procedure B (method a), from 4-iodo-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy} -ethoxy)-2-nitro-phenylamine (Example E4) (8.0 g, 17 mmol) with diphosgene (1 - 54 mL, 13 mmol) in EtOAc (100 mL) This isocyanate was prepared by treatment with -BuOH (25 mL) and CH2C12 (25 mL). Obtained yellow oil (8.6 g, 890 /.). MS(ISP) 588 [(M+NH4)+] 〇-31 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) (please read the notes on the back and then 13^4 pages) 40 Γ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Invention Description (29) Example B8 -------------- Installation - (Please read the notes on the back first) 13^This page) (RS)-[5-(2,2-Dimethyl-[1,3]dioxosyl glacial methoxy)! Nitro-t-phenylphenyl-phenyl-phenyl]-amine methyl acid, the third-butyr, according to the general procedure B (method b), at 52 ° C, from (RS)-5-(2,2- Dimethyl-[1,3]dioxoindol-4-ylmethoxy)-2-nitro- ice phenylethynyl-aniline (Example K14) (2.678 g, 5.7 mmol), Cs2C〇3 (2.23 g, 6.8 mmol) and Boh 0 (1.52 g, 7.0 mmol) in 2-butanone (36.5 mL). Obtained yellow foam (2.0 g, 75%). MS (ISP) 469 [(M+H).] and 486 [(M+NH4)+]; melting point 32 °C. Example B9 fVe (R=CN; R,,=Boc)| (5-Cyanomethyl-4-iodo-2-nitro-phenyl&gt; Aminomethyl acid tert-butyl ester-line·According to General Procedure B (Method a) from (5-Amino-2-iodopiperidinyl-phenyl)-acetonitrile (Example Vf (R=CN; R"=H)) (5.15 g, 17 mmol) Prepared with diphosgene (2〇5 ml, 17 mmol) in EtOAc (150 mL) followed by a third _Bu〇H (25 L) and CH2 (3⁄4 (25 L) Isocyanate. Obtained as a yellow solid (4.0 g, 58%). MS (ISN) 402 [(Μ-ΗΠ; melting point 124-126. (:. Example B10 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed [5-(2- Tertiary-butoxy-ethoxy)methanol iodide: nitro-phenylamine methyl acid tert-butyl ester according to the general procedure B (method c), from 5-(2-tri-butoxy) _Ethoxy) ice iodo nitro-aniline (Example Ε 6) (13·9 g, 36.6 mmol) and Β〇〇2 〇 (16.35 g, 75 mmol) followed by 2 equivalents of TFA Processed in CH2%, prepared two

Boc-compound. Obtained as a yellow solid (14.96 g, 85%). -32- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public Chu) 1255266 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (3Q) MS (ISP) 481 [(M +H)+]; melting point 113-116T:. Example B11 [4-Alkyl-5-(4-methoxyoxy)-2-nitro-phenyl]-amine methyl acid third-butyl vinegar according to General Procedure B (Method c), from 'Iodine 5-O-(4-methoxy-l-oxy)_2-nitro-aniline (Example E7) (2.88 g, 7.20 mmol) with BoC 2 〇 (3·3 g, 15.12 mmol), The di-Boc-compound is then prepared by treatment with 2 equivalents of TFA in CH2C12. An ant yellow solid (1·4 g) was obtained. MS (ISN) 499 [(M-H)-]. The following procedure pertains to the preparation of (4-pyridylnitro-phenyl)-amine methyl acid tert-butyl ester with a nitrogen substituent at the 5-position (Figure D). General procedure C: Preparation of 5-N-substituted-(4-picyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester: Method a: from (5-chloro-4-pyrene Benzyl-2-nitro-phenyl)-amine methyl acid, the third-butyl phthalate (Example β1) With the desired amine, optionally with toluene or DMSO and/or DIPEA, stir at a temperature of 23 ° C to 100-130 C; mix until tic shows complete disappearance of the chloride. The reaction was cooled to 23 ° C, poured into ice water, and the precipitate was filtered, washed with water and dried in the air. In the case where the product did not precipitate, the mixture was extracted with EtOAc, washed with water and brine, and dried over Na 2 s. Filtration and removal of the solvent in EtOAc (EtOAc m. Method b: 5-Alkyl-4-mercapto-2-nitro-phenylamine (Example Al) from 5-chloro-4-iodo-2-nitro-phenylamine (1.49 g, 5.0 mmol) Ear) 'The desired limb (6-25 Amor) and appropriate test, such as NaHCO;, Κ2 CC^, -33- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -- ------------装--- (Please read the notes on the back and then 1^114 pages) Order: • 丨 line - 1255266 A7 --- B7__ V. Invention description (31)

A mixture of Ey N or DIPEA (10-15 mmol) was stirred at 60-130 ° C in DMS oxime, DMF or toluene (20-50 liters) until tlc showed that the gas disappeared completely. The reaction was cooled to 23. (:, pour into ice water, neutralize with in HC1, filter out the precipitate, wash with water and dry in the sputum. In the product will not be / redundant, extract the mixture with Et〇Ac, with water And brine washing, dehydration and drying with Na]SO4. The solvent is removed in the hydrazine and the crude product is obtained, which is purified by column chromatography using hexane / Et. The protection of the amine group was achieved according to the general procedure B. Example C1 [4-iodo-5-(4-methyl-hexahydropyrazine + yl)-2_nitro-phenylamine methyl acid _酉 酉 according to the general procedure C (method a), prepared from (5-chloro- ice-iodoyl winter nitro-phenyl) amine methyl acid third-butyl ester (example Bl) (2.39 g, 6.0 mmol) ) with μMethyl hexahydropropane (1.60 ml, 15 mmol) in toluene (4.5 ml) for 18 hours to give a yellow solid (2.2 g). MS (ISP) 463 [(Μ+Η) )]]; melting point i34-136 ° C. Example C2 (4-ceptyl-2-nitro-5-thiofenoflavin-4-yl-phenyl)-amine methyl acid third_丁酉General Procedure C (Method a), prepared from (5_ gas base iodine: nitro-phenylamine A Acidic tri-butyl ester (Example Β1) (2·〇克, 5·〇 mmol) and thiomorpholine (2.6 ml) in toluene (3.8 ml), DIPEA (1.7 ml) at H5° 48 hours under C. Obtained a yellow solid (1·1g) MS (ISP) 466 [(M+H)+]; melting point 132-134 ° C. Example C3 -34- This paper scale applies to the Chinese National Standard (CNS) )A4 size (210 X 297 mm) -------------Installation - (Please read the notes on the back and then 1!^^ page) Order: :Line. Ministry of Economics intellectual property Bureau employee consumption cooperative printing 1255266 A7 B7 V. Description of invention (32) (4-Bulk-5-iflupreo-4-yl-2-decyl-phenyl)-amine methyl acid third_丁酉According to the general procedure C (method a), from (5-chloro-bromoiodo-2-nitro-phenyl)-amine methyl acid, third-butyl vinegar (consistent example B1) (2.0 g, 5.0 mmol) Ears with holphaline (1 ml), refluxed for 3 hours to give a yellow solid (0. 805 g) MS (ESI) 450 [(Μ+Η)+]; melting point 43-44 ° C. C4 [5-(1,4-Dioxo-8-nitro-spiro[4.5]dec-8-yl&gt; 4-iodo-2-nitro-phenyl]-amine methyl acid tert-butyl ester According to the general procedure C (method a) Made from (5-gas-based iodine-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example Β 1) (3.00 g, 7.53 mmol), ι, 4- Dioxo-8-aza-spiro(4,5) oxime (4.82 mL, 37.63 mmol) and DIPEA (2.58 mL, 15.0 mmol) in toluene (4 mL). Obtained an orange solid (4.0 g). MS (ISP) 506 [(Μ+Η)+]; melting point 132-134 °C. Example C5 [4-Mothyl-5-(4-methoxy-7T hydrogen p ratio-1-yl)-2-nitro-phenyl]-amine methyl acid tert-butyl ester according to the general procedure C (Method b), prepared from 5-oxyl-4-picyl-2-nitro-phenylamine (example Α) (6.91 g, 23.15 mmol), 4-methoxy pyridine (4 〇) Gram, 34.73 mM) and NaHC03 (5.83 g, 69.45 mmol) in DMSO (230 mL) at 100 °C. The obtained brown solid (7.95 g) was converted to the title compound according to General procedure B (Method C). Obtained a yellow solid (6 55 g). MS (ISP) 478 [(M+H)+]; mp. Example C6 -35- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ 1 I (Please read the notes on the back and then 1?^ 4 pages) Order · Line _ Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Ministry of Printing and Economy Ministry Intellectual Property Bureau Employees Consumption Cooperatives Printed 1255266 A7 B7 V. Description of Invention (33) {5-[(2-Hydroxy-ethyl) -Methyl-amino]-4-iodo-butyryl-phenyl-p-methylamino acid tert-butyl ester according to the general procedure C (method a) 'made from (5-chloro-4-pyryl-2 -Nitro-phenyl)-Aminomethyl-tert-butyl ester (Example B1X 1.99 g, 5.0 mmol) with 2-methylaminoethanol (2.00 liters, 25.0 mmol) in DMSO (2.5 In ml), at 23 ° C. Obtained yellow gum (1.88 g). MS(ISP) 438 [(M+H)+] 0 Example C7 [5-(4-#-based-hexahydro-p-pred-1-yl)-4-bromo-2-nitro-phenyl] -Aminomethyl acid third-butyl ester according to the general procedure C (method a), from (5-chloropiperidinyl iodide-phenyl) &gt; amine methyl acid tert-butyl ester (example Β 1) (1·99 g, 5 mmol) and 4_light hexahydropyridine (2.53 g, 25 mmol) in DMSO (2.5 mL). EI) 463 (M+); m.p. 58-60 ° C. Example C8 {5-[4-(2-hydroxy-ethoxy)-hexahydropyridin-1-yl] ice iodoyl 1 nitro-phenyl} -Aminomethyl acid tert-butyl ester according to the general procedure C (method a), from (5-chloro-4-homyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example Β 1) (2.2 g, 5.5 mmol), 4-(2_ethoxylated) hexahydropyridine {CAS-number [40256-14_2]} (800 mg, 55 mmol) and Et3N (2.3 ml, 16.5 mmol) in DMSO (2.3 mL) EtOAc (EtOAc: EtOAc) The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) -------- ------Installation--- (Please read the notes on the back and then 1^4 pages) Order: -•丨线·1255266 A7 B7 V. Invention description (34) tjHC9 [5-(cis-3 , 4-dihydroxy-tetrahydropyrrolidyl)-4-iodo-2-nitro-phenyl]-amine methyl acid tert-butyl ester

Made in two steps as follows: according to the general procedure C (method a), (5-chloro-4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl ester ( Example Bl) (8.73 g '21.9 mmol) with 3-pyrroline (2.0 mL, 26.3 mmol, 70% pure, containing 30% tetrahydropyrrole), Et3N (9.12 mL, 65_7 mmol) The reaction was carried out in DMSO (14 ml) and EtOH (5 ml) at 23 ° C to give [5-(2,5-dihydrotol-l-yl)-4-ironyl-2-nitro a 7:3 mixture of 3-phenyl]-aminomethyl acid tert-butyl ester and (4-iodo-2-nitro-5-tetrahydropyrrole small-phenylamine methyl acid tert-butyl ester) Obtained as a yellow solid (8·57 g). A portion (4.31 g) of this material was dihydroxylated by &gt; 〇^〇 (1.28 g, 11.0 mmol), 2.5% 〇 S〇4 in t-BuOH (1 ml, 0.1 mmol), and K2〇s〇4 (40 mg, 0.1 mmol) in acetone (250 ml) and H2 0 (100 ml), at 23 The reaction was carried out for 6 days at <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt;

Instance CIO

[5-(2-Hydroxy-ethylamino) gladonyl-2-nitro-phenyl]-amine methyl acid, third-butyl vinegar, according to the general procedure C (method a), from (5-gas base) 4--4-bromo-2-nitro-phenyl)-aminomethyl acid tert-butyl ester (Example Bl) (3_99 g, 1 mol) with ethanolamine (3.01 mL, 50 mmol) In DMSO (20 ml) at 2 yC. Obtained a yellow solid (4.5.3 g). MS (ISP) 424 [(M+H)+]; mp. 130-148.

Example CU -37 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----I---. 1 1 (Please read the note on the back and then 13^4 pages) -- Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7 V. Invention description (35) [5-((R)-3-j% base-four Mouse p-pyridin-1-yl)-4-bromo-2-nitro-phenyl]-amine methyl acid tert-butyl ester according to the general procedure C (method a), from (5-gas-based 4-Butyl-2-nitro-phenyl)-aminomethyl acid tert-butyl ester (Example Bl), (R)-3-hydroxytetrahydropyrrole hydrochloride and Et3 N in DMSO, At 23 ° C. Obtained a yellow solid (3 · 153 g). MS (ISP) 450 [(M+H)+]; mp 158 (dec.). The following procedure pertains to the preparation of (4-framo-j-nitro-heyl)-amine methyl acid tert-butyl vinegar with a sulfur substituent at the 5-position (Synthesis Figure D): General Procedure D : Preparation of 5_s_substituted-(4-Ethyl-2-nitro-phenyl) from (3-(yl)-4-iodo-2-nitro-phenyl)-amine methyl acid, third butyl ester -Aminomethyl acid tert-butyl ester in a solution of thiol (2.2 mmol) in DMF, Na 〇Me solution (5.4 M in MeOH, 0.41 mL, 2.2 mmol), followed by Chloro- 4-cyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example Bi) (797 mg, 2.0 Torr), and stirring was continued at 23 ° C until Tlc showed that the chloride completely disappeared, poured into ice-cold 5% citric acid, extracted with Et〇Ac, washed with saturated NaHC〇3, brine, and dried with MgS〇4. The solvent was removed to leave an orange oil, which was purified by column chromatography eluting with hexane / Et. Example D1 [5-(2-Methylamino-ethylthio) 4-degraded nitro-phenyl]-amino acid tert-butyl ester according to the general procedure D, from (5_ gas base + Iodoethyl j nitro-phenyl)-amine methyl acid third-butyl ester (Example Bl) (399 mg, 1. 〇 millimol), 2-dimethylaminoethyl-38- Guanjia Standard (CNS) A4 specification (21〇X 297 public) --------------Installation--- (Please read the notes on the back and then 1^114 pages) Line · 1255266 A7 B7 V. Description of the invention (36) § Ethyl mercaptan hydrochloride (312 mg, 2.2 mmol) and Na〇Me solution (5 4M, ------------ --- Pack--- (Please read the notes on the back and then 1311^) in MeOH (0.8 ml '8.8 mmol) in DMF (2 mL). Obtained a yellow solid (306 mg). MS (ISP) 468 [(M+H)+]; mp. Example D2 (5-Second-butoxycarbonylamino-2-iodoylnitroso-phenylthio]&gt; Methyl acetate was prepared according to the general procedure D from (5-carbyl-4-iodobutyryl) _Phenyl)-Aminomethyl acid No. 3 - butyl g (Example Bl) (797 mg, 2.0 mmol), methyl thioglycolate (0.2 liters '2.2 mmol) and NaOMe solution (5.4 M, in MeOH (0.41 liters &lt;RTI ID=0.0&gt;>&&&&&&&&&&&&&&&&&&&& The procedure for the preparation of (4-cyl-2-bromophenyl)-amine methyl acid tert-butyl ester with an oxygen substituent at the 5-position (Figure E): General procedure E : :Line · From 5-Gasyl-4-bromo-2-propenyl-aniline, Preparation of 5-0-Substituted-4-Mercapto-2-nitro-phenylamine in KOH (85 % ' 3.62- 7.96 g, 55-121 mmol) In a suspension of DMSO (50 ml) printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative, add alcohol (125-500 mmol) and mix the mixture at 23. : Stir under until all KOH has dissolved. Add 5_ gas-based 4-iodo-2-nitro-benzene in small portions Amine (Example Al) (15.0 g, 50 mmol), and the resulting dark red transparent solution was stirred at 23-60 ° C until tic showed complete disappearance of the gas. Pour into ice-cold INHCr or ice-cold saturated NH4C1 In solution, extract with EtOAc or CHC13, with 1NHC1 or saturated NH4C1 solution and salt-39- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 V. Description of invention (37 Washing Service' Drying with MgS〇4, removing the solvent, leaving a dark red solid, which was purified by column chromatography to give a pure compound. Example E1 allyloxy-4-iodo-2-nitro - Aniline according to the general procedure E, prepared from 5-chloropiperidinyl nitro-aniline (Example A1) (15.0 g, 50 耄 Mo Er)' 晞propanol (5 〇 ml) and K〇H (7.96 g) , 121 mM in DMSO (50 ml). Obtained an orange solid (9·38 g). MS (ΕΙ) 320 (Μ+); melting point 74 ° C. Example E2 4-iodo-5-A Oxy-2-nitro-aniline was prepared according to the general procedure E from 5-chloropiped iodo-2-nitro-phenylamine (Example A1) (2.98 g of &lt;RTI ID=0.0&gt; And K〇 H (145 g, 22 mmol) in DMSO (10 mL) afforded an orange solid (2·9 g) MS (ISP) 295 [(Μ+ΗΠ and 312 [(Μ+ΝΗ4)+]; Melting point i 89χ:. Example E3 4-iodo-5-(2-methoxy-ethoxy)-2-nitro-aniline according to the general procedure E from 5-chloro-4-iodo-2-nitro-aniline (Example A1) (2·98 g, 10 mmol), 2-methoxyethanol (7.9 liters, ι〇〇mole) and Κ〇Η (1·45 g, 22 Amol) In DMSO (8 ml). Obtained an orange solid (2.8 g). &quot; MS (ISN) 337 [(M-Η)-]; melting point 121-122 ° C. Example E4 4-Alkyl-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy ethoxy) 2-nitro-aniline -40- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). Please read the notes on the back and then I#. Page Binding Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of the invention (38) According to the general private sequence E, from 5-chloro-bromoiodo-2-nitro-phenylamine (Example A1) (9.48 g, 323⁄4 mol), tetraethylene glycol monomethyl ether (1) g , % mM) and K〇H (2.31 g, 35 mM) in DMS 亳 (25 liters) at 6 。. Obtained red oil (8.4 g). MS (ISP) 471 [(Μ+Η)+]. Example Ε5 (RS)-5-(2,2-_^methyl-[1,3]dioxoindolylmethoxy)- ice iodo-nitro-aniline according to the general procedure E 'from 5-gas 4-iodo-2-nitro-phenylamine (Example A1) (4.48 g '15 耄 Moel), D, L-α, /?-isopropylidene-glycerol (1 〇 ml, μ mmol) And ΚΟΗ (1.01 g '18 mmol) in DMSO (10 ml) at 23 °C. A yellow solid (4.9 g) was obtained. MS (ISN) 393 [(M-H).], m.p. Example E6 5-(2-Terti-butoxy-ethoxy)-4-bromo-2-nitro-phenylamine was prepared according to the general private order E' from 5-carbyl-4-bromo-2- Nitro-aniline (Example A1) (14.9 g, 50 mmol), 2-tris-butoxyethanol (29.5 g, 250 mmol) and KOH (3.99 g, 60 mmol) in DMSO ( 25 ml) at 23 °C. A yellow solid (14.3 g) was obtained. MS (ISP) 381 [(M+H)+]; mp 144-146. Example E7 4-Alkyl-5-(4-methoxyoxy)-2-nitro-phenylamine was prepared according to the general private order E' from 5-carbyl-4-bromo-2-nitro-phenylamine ( Example A1) (5.97 g, 20 mmol), 4-methoxybenzyl alcohol (4.98 ml, 40 mmol) -41 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) --------------S--- (Please read the precautions on the back and then ^® this page) · .丨线· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention instructions (39 and Κ〇Η (1 · 58 g, 24 mmol) in DMS 〇 (30 ml), at 23 ° C. Obtained a tan Solid (2.94 g) MS (ISN) 399 [(M - Η)·]; mp 183 ° C. The following example relates to (5-tris-butoxycarbonylamino iodo-4-nitro-phenyl ) · Preparation of vinegar acetate and (5-cyanomethyl_4_iodo-2-nitro-phenyl)-amine methyl acid III · Dingzhi (Synthesis Figure F): - Example XVI ( R=C〇iMe ; R&gt;Me ; R,,=Boc, 2-(5-tris-butoxycarbonylamino-t-butyryl glacial nitro-phenylmalonic acid dimethyl ester in K OBut (0.56 g, 5.02 mmol) in DMSO (3 mL), add dimethyl malonate (0·58 mL, 5 〇 2 mmol), followed by (5-gas-based) 4-Butyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example Β1) (1 gram, 2.51 耄mol) and the dark red transparent solution formed in 丨(8). C. Stir down until tic shows that the chloride has completely disappeared. Pour into ice-cold 5/min. (100 ml), extract with Et0Ac (2 χ 1 〇〇 ml), wash with brine, with MgS The residue was dried <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; ISP) 512 [(M+NH4)+] and 517 [(M+Na)+]. Example XVII (R=CN; R&gt;Et; Rn=H) (RS&gt;(5-Amino-2-iodo) 4-Nitro-phenyl&gt;Cyano-acetic acid ethyl ester was prepared as described in Shell XVI from 5-chloro-4-pyridyl-2-nitro-phenylamine (example μ) (14.9 g, 50 Millol), ethyl cyanoacetate (14.7 ml, 1 mmol) and KOBut (11.2 g, 100 mmol) in DMSO ( In 60 ml), at 1 〇 (rc for 2 hours) to obtain a dark brown gum. -------------- Pack --- (Please read the note on the back first) · , - Line - 42 1255266

V. Description of the invention (4Q) MS (EI) 375 (M+). Example Ve (RCO? Me; R丨丨=Boc) -------------- Pack--- (Please read the notes on the back page again) (5-Third-butoxy Talk to arylamino-2-iodyl nitro-phenyl)-methyl acetate to 2-(5-tris-butoxycarbonylamino-2-iodo-4-phenyl-phenyl)-propyl Diacid diacetate (example XVI (R=C02Mr R'=Me H〇c)) (3.34 g, 6 76 mmol), LiCl (573 mg, 13.52 mmol) & h2〇 (〇122 ml) The mixture was stirred at EtOAc (46 mL) over EtOAc (EtOAc)EtOAc. The title compound was obtained as a yellow solid ( 1.37 g, 470 / EtOAc). (M+); melting point 93 ° C. Example Vf (R=CN; Rn-H) (5-Amino-2-iodo-4-nitrophenyl)-acetonitrile: s. 'Manufactured from (RS)-(5-Amino-2-pyridyl-4-nitro-phenyl)-cyano-succinic acid ethyl ester (Example XVII (R=CN; R'HEt; R&quot;=H )) (20.62 grams, 55 millimoles) with LiCl (9 33 g, 220 mM) in 〇?^〇 (370 ml) and 112 〇 (4.4 ml) at 2.5 ° C for 2.5 hours. Obtained a green-brown solid. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Consumer Cooperatives MS (EI) 303 (M+); melting point 145-183X: The following example relates to (5-hydroxymethyl-4-iodo-2-nitro-phenylyaminemethyl acid second-butyl vinegar, Preparation of the corresponding THP-acid, and (5-dimethylaminomethyl-glycolyl nitro-phenyl)-amine methyl acid tert-butyl ester via an intermediate vapor (Synthesis Figure F): Example Vh - 43- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 -----SI_____ V. Invention Description (41) (5- &amp;methyl-4-iodo-2-nitro-phenyl)-aminomethyl acid tert-butyl ester LlBH4 (〇.32 g, 14.78亳莫耳) is added to the 〇. Tri-butoxymethylamino-2-iodopiperidine nitro-benzoic acid methyl ester (Example B3) (3 i2 g, 1% mmol) with MeOH (0.6 mL, 14.78 mmol) in THF ( In a solution of 44 ml), the reaction mixture was stirred at (TC for 15 minutes, It was poured into 5% citric acid, extracted twice with EtOAc, washed with aq. The solvent was removed, EtOAc (EtOAc m. MS (ISP) 412 [(M+NH4)+]; mp. &lt;25 〇 °C. Example Vi (RS)-[4-iodo-2-nitro-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl&gt; Aminomethyl 3-butyrate (5-Hydroxymethyl-4·iodo-2-nitro-phenyl)-amine methyl acid third-butyl ester (Example Vh) (394 see gram ' 1. 〇 millimol) and 3, 4 _Dihydro-2H-furan (0.11 ml, 1 2 mol) in a mixture of DCM (5 ml), add _Ts〇H · Η2〇 (about 5 mg) at 〇 ° C, and The reaction was stirred at 〇 ° c for 1 hour. Dilute with Duan 〇 &amp;, wash with saturated NaHC〇3 solution and brine, and dry with MgS〇4. The solvent was removed in vacuo, EtOAc (EtOAc)EtOAc. ~MS (ISN) 477 [(M-H)-]. Example VI (5-monomethylaminomethyl-4-indol-2-nitro-benyl)-amine methyl acid 3rd-butyryl-44-

--------I--- (Please read the notes on the back page again) · ·. Line. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 5. Description of the invention (42) Tris-butyl (5-hydroxymethyl-4-iodo-2-nitro-phenyl)-amine methylate (Example Vh), LiCl (3 equivalents) and pyridine (2 eq.) In a mixture of DMF, methanesulfonyl chloride (1.5 equivalents) was added at 0 °C, and the reaction was stirred at 23 ° C for 24 hours. Me2NH (10 equivalents) in EtOH was added and stirring was continued for 24 hours. It was diluted with EtOAc, washed with aq. The solvent was removed in hydrazine 2 to leave a yellow oil which was purified by EtOAc EtOAc EtOAc EtOAc EtOAc MS (ISP) 422 [(M+H)+ ]. The following examples relate to the preparation of (2-amino-4-aryl-phenyl)-amine mercapto acid tert-butyl ester, [2-amino-based ice (1-alkenyl) in a pure manner on a regioisomeric basis. Base &gt;Phenyl&gt; Amino acid tert-butyl ester and (2.Amino-4-arylindenyl-phenyl)-amine mercapto acid tert-butyl ester (Synthesis Figure B): General Procedure F: Preparation of (4-aryl-2) by direct Suzuki coupling of (4-c-yl-2-nitro-phenyl)-amine methyl acid tert-butyl ester with aryl dilight borane -nitro-phenyl)-amine methyl acid, third-butyl ester, (4-iodo-2-nitrophenyl)-amine methyl acid, third-butyl ester (3. 〇 millimolar) , Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperatives, printing ------------------- (Please read the notes on the back and then 6 pages): Line · Aryl dihydroxyborane (4.5 mmol) and a mixture of PdCl2(PPh3)2 (2 mol.,.) was refluxed in 1,4-dioxane (25 ml) with 2M Na2 C03 solution (7.5 mL). Use 1M NaHC03 solution (7.5 ml), LiCl (6·0 mmol) and (Ph3 P)4 Pd (3 mol%) in DME (3 mL); also use ν (9.0 mmol) ), Pd(〇Ac) 2 (3 mol.), pph3 (6 mol./.) in DMF (10 ml) 'at 100 ° C] until tic shows complete conversion of iodide. Mixed-45- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Inventive Note (43) The compound is transferred to a separatory funnel, H20 (25 ml) is added, and The product was extracted with ether or EtOAc (3.times.30 mL). The combined organic layer was washed with brine (5 EtOAc) and dried over Na. Purify by column chromatography on EtOAc EtOAc EtOAc (EtOAc) Amino-methyl 3-butyrate was prepared according to the general procedure F from (3-chloro-4-indolyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example Bl) L2 gram, 3.00 mmol, and phenyldihydroxyboron (0.62 g, 3.30 mmol). Obtained a yellow oil (843 mg). MS (ΕΙ) 348 (Μ+) and 350 [(Μ +2)+]. Example F2 (2·methyl-5-nitro-biphenyl bucket --Aminomethyl 3-butyrate was prepared according to the general procedure F from (4-iodo-5-methyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example B2) (L135 g, 3 mmol) with phenyl dihydroxyborane (630 mg, 3.3 mmol). Obtained yellow oil (971 mg). MS(EI) 328(M+) 〇Example F3(RS)-{4'_Fluoro-5-nitro-2-[4-(tetrahydro-pyran-2-yloxy)-hexahydrop ratio淀-1-yl]-bimethylidene-4-ylindole-amine methyl acid second-butyryl is prepared according to the general procedure F, from (RS)-{4-iodo-2-nitro-5-[ 4-(tetrahydro-piperidin-2-yloxy)-hexahydrop-biti-1-yl]-phenyl}-amine methyl acid tert-butyl ester [RO-69-4319/000, made From [5-(4-hydroxy-hexahydropyridinyl)-t-iodo-2-nitro-phenyl]-amine methyl acid to the third-butyl ester (Example C7) via 3,4-dihydro- 2H-pyran and catalyst-46 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) -------------Installation --- Please read the back first Precautions on this page) · · ί线· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 ---------B7__ V. Invention description (44)

TsOH · H20 is treated in DCM under οχ: (1 〇 9 g, 2 〇 mmol) with 4-fluorophenyl dihydroxyborane. Obtained an orange solid (894 mg). MS (ISP) 516 [(M+H)+]; mp. Example F4 (RS)-(4,-Fluorobutyryl-2-{4-[2-(tetrahydro-bran-2-yloxy)-ethoxy]-hexahydrophyllin-l -Based on the basis of the general procedure F, from (rs)-(4-iodo-2-nitro-5-{4-[2- (tetrahydro-pyran-2-yloxy)-ethoxy]-hexahydropyridine small phenyl)-amine methyl acid third-butane vinegar [RO-69-4355/000 'made from { 5-[4_(2-hydroxy-ethoxy)-hexahydropyridine small group]_ 4-c-yl-2-nitro-phenylamine methyl acid tert-butyl ester (example C8), via 3 , 4-Dihydro-2H-pyran and catalyst TsOH · H2〇, in DCM, at 0. (:Under treatment) (950 Aike ' 1.87 mmol) with 4-fluorophenyl dihydroxyborane (314 mg, 2.25 mmol). Obtained a thick orange oil (93 mg). MS (ISP) 560 [(M+H)+]; melting point 144-146 Ό. Example F5 (RS)-[4L-fluoro-5-nitro-2-(tetrahydro-guaran-2-yloxymethyl)-linked Phenyl glayl]_Aminomethyl acid third-butyl ester according to a general procedure F 'made from (RS)-[4- deradyl-2-nitro-5-(tetrachloro-♦-an-2 -Phenoxymethyl)-phenyl]-amine methyl acid, third-butyl ester (Example Vi) and 4-fluorophenyldihydroxyborane. An orange oil (1.24 g) was obtained. Example F6 (2- Cyano-methoxy-4-'-fluoro-5-nitro-biphenyl-4-yl)-amine mercapto acid tert-butyl ester according to the general procedure F, from (5-cyanomethoxy) 4-iodo:nitro-phenyl)-amine methyl acid third-butyl ester (example S2) (838 mg, 2.0 mmol) and 'fluorobenzene-47- this paper scale applies to Chinese national standards ( CNS)A4 specification (210 X 297 mil) &quot; ^ · II (Please read the note on the back and then 13||^4 pages) - : Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 B7 five , invention description (45 Dihydroxyborane (392 mg, 2.8 mmol) afforded a yellow solid (333 mg). MS (ESI) 405 [(M+NH4)+]; mp 148. Aminomethyl-4'-fluoro-5-nitro-biphenyl phenyl)-amine methyl acid 3 - butyl hydrazine according to the general procedure F, prepared from (5-dimethylaminomethyl ice iodine) 3-Chloro-phenyl)-amine methyl acid tert-butyl ester (Example VI) and 4-fluorophenyl dihydroxyborane. Obtained a yellow solid (1·1 g). Example F8 [2] -(2,2-dimethyl-tetrahydro-[1,3]dioxoindolyl[4,5-c>pyr-5-yl)-4f-fluoro-5-nitro-linked Phenyl-4-yl]-amine methyl acid tert-butyl ester was prepared from [5-(cis-2,2-dimethyl-tetrahydro-[1,3]dioxane according to the general procedure F. Terpenyl [4,5-c]pyrrole-5-yl)-4-mercapto-2-nitro-phenyl]-amine methyl acid tert-butyl ester [RO-69-4741/000, made From [5-(cis-3,4-dihydroxy-tetrahydropyrrole-1-yl)_4-石典-2-nitro-phenyl]-amine methyl acid third_丁@旨(Example C9 ), treated with 2,2-dimethoxypropane and catalyst butyl sOH · Η2 Ο in DMF at 23 ° C] (845 mg, 1.67 mmol) and 4- Phenyl dihydroxyborane (327 mg, 2.34 mmol). Obtained as a yellow solid (643 mg). MS (ISP) 474 [(M+H)+]; mp. Example F9 (4'-Fluoro-2-methoxy-5-nitro-biphenyl-4-yl)-amine methyl acid, the third group, according to the general procedure F, from (4-iodo) -5-Methoxy-2-nitro-phenylamine methyl acid Third-butyr S (Example B5) (3.68 g, 9.34 mmol) and 4-fluorophenyl di 48- This paper scale applies China National Standard (CNS) A4 Specification (210 X 297 mm) Please read the notes on the back first and then install the page. Order the Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 ______B7___ V. Invention Description (46) Hydroxyl boron Alkane (3.61 g, 25.8 mmol) afforded a yellow solid (2.69 g). MS (ISN) 361 [(MH)·]; melting point 25 (TC). Example F10 [2-(1,4-dioxo-8) -Nitro-spiro[4.5]dec-8-yl)t-fluoro-5-nitro-biphenyl-4-yl]-amine methyl acid tert-butyl ester according to the general procedure F, manufactured from [5- (1,4-Dioxo-8-nitro-spiro[4.5]dec-8-yl)-4-iodo-2-nitro-phenyl]-amine methyl acid third-butyr (example ¢ 4) (4.0 g, 7.02 mmol) and 4-fluorophenyldihydroxyalkane (1.33 g, 9.5 mmol) afforded a yellow solid (2.43 g). Example F11 (4L fluoro-2-methyl-5-nitro-biphenyl-4-yl)-amine methyl acid, third-butyr, according to the general procedure F, from (4-iodo) -5-Methyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example B2) (756 mg, 2.0 mmol) and 4-fluorophenyl dihydroxyborane (420 mg) , 3.0 mmol; obtained amorphous yellow material (611 mg). MS (ISN) 345 [(M-Η)·]. Example F12 (4-T-butoxycarboxyamino-4'-fluoro 3--5-nitro-biphenyl-2-yloxy)-acetic acid tert-butyl ester according to the general procedure F, from (5-tris-butoxycarbonylamino-2-iodo-4- Nitro-phenoxy)-acetic acid tert-butyl ester (Example Sl) (2.14 g, 4.33 mmol) and 4-fluorophenyldihydroxyborane (728 mg, 5.2 mmol). Solid (1.80 g). -49- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------------- Install i I (please read the back first) Note: page _ : Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 B7 ^; __ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing invention Ming (47) MS (ISN) 461 [(M-H) -]; mp 92-93X :. Example F13 -------------- Install _! (Please read the notes on the back and then on this page) (2-Chloro-4'-fluoro-5-nitro-biphenyl Alkyl-based amino acid tert-butyl ester according to the general procedure F, from (5-chloro + iodo-2-nitro-phenyl)-amine methyl acid, third-butyl ester (example B1) with 4-fluorophenyldihydroxyborane. A yellow solid (625 mg) was obtained. MS (EI) 366 (M+) 〇 Example F14 [I-fluoro-2-(2-methoxy-ethoxy)_5-nitro-biphenyl]-amine methyl acid tert-butyl ester According to the general procedure F, from [4-iodo-5-(2-decyloxy-ethoxy)-2-nitro-phenyl]-amine methyl acid tert-butyl ester (example B6) 4-fluorophenyl dihydroxyborane. Obtained a yellow solid (1.833 g). MS (EI) 406 (M+). Example F15 ·-Line·[2-(2-Terti-butoxy-ethoxy)-4'-fluoro-5-nitro-biphenyl-4-yl]-amine methyl acid -Butyl ester according to the general procedure F, from [5-(2-tris-butoxy-ethoxy) ice iodo-2-nitro-phenyl]-amine methyl acid tert-butyl ester ( Example B10) with 4-fluorophenyldihydroxyborane. Obtained a yellow solid (735 mg). MS (ISP) 449 [(M+H)+ ]. Example F16 [4'-Fluoro-5-nitro-2-(2-keto-dip-3-yl)-biphenyl-4-yl]-amine methyl acid tert-butyl ester-50 -This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (48) According to the general procedure F, from [4_ Iodo-2-nitro-5-(2-keto-4-oxazolidin-3-yl)-phenyl]-amine methyl acid tert-butyl ester [r〇_69-6758/000, manufactured from [ 3-(2-hydroxy-ethylamino)-4. keto-2-nitrophenyl]-amine methyl acid tert-butyl ester (example cl〇) via 1, fluorene-carbonyldiimidazole In dioxane, then in pyridine, treated with catalyst DMAP, each at i〇〇°C] (503 mg, 1.12 mmol) and 4-fluorophenyl biszepine (235 mg, 1.68 millimoles). Obtained a yellow solid (31 mg). MS (ISN) 416 [(M-H).]. (:. Example F17 (4L fluoro-2-bromo-2f-methyl-5-nitro-biphenyl-4-yl)-amine methyl acid third _ vinegar according to the general procedure F, From (4-iodo-5-methoxy-2-nitro-phenyl)-amine methyl acid to the third-butyl ester (Example B5) and 4-fluoro-2-methyl-phenyl dihydroxyl Borane. Obtained as a yellow solid ( 699 mg). MS (EI) 376 (M+). Example F18 (2-2-butoxy-4'-fluoro-5-nitro-biphenyl-4-yl )-Aminomethyl acid third _ 酉 酉 according to the general procedure F, made from (5-tris-butoxy-4-iodo-2-nitro-phenyl)_amine methyl acid third-butyl Ester (Example S4) (1.4 g, 3.21 mmol) and 4-fluorophenyldihydroxyborane (0.67 g, 4.42 mmol). Obtained amorphous yellow material (12 g). MS (EI) 404 (M+). Example F19 (2-second-butoxy-2f-fluoro-5-nitro-biindyl-4-yl)-amine methyl acid third_ 酉 酉-51 - paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -------------- Packing - (Please read the notes on the back page again) -.-Line_ 1255266 A7 ____ B7__ Five Ministry of Economic Affairs Intellectual Property Bureau staff consumption Instructions for printing the invention (49) ------------- Loading ·-- (Please read the notes on the back and then 1^ this page) According to the general procedure F, from (5- Third-butoxy-4-carbenyl-2-nitro-phenyl)-amine methyl acid, third-butyl ester (Example S4) (1.4 g, 3.21 mmol) and 2-fluorophenyl di Hydroxyborane (0.67 g, 4.83 mmol). Obtained amorphous yellow material (960 mg). MS (EI) 404 (M+). Example F20 (RS)-{4-Fluoro-5-nitro- 2-[(11)-3-(tetrahydro-m-butan-2-yloxy)-tetrahydrop ratio p each small group]-biphenyl-4-yl}-amine methyl acid third-butyl The ester is prepared according to the general procedure F from (RS)-{4_bromo-2-nitro-5-[(R)-3-(tetrahydro-pyran-2-yloxy)-tetrahydropyrrole Benzyl-p-phenylamine methyl acid, third-butyl ester [r〇-69_ 6376/000 'from [5-((R)-3-#i-yl-tetrahydro-p-l-l-yl) _4_ _ _ _ nitro-phenyl]-amine methyl acid third-butyl ester (example C11), via 3,4-dihydro-2H- snoring and catalyst TsOH · called 0, in In DCM, under (TC) and 4-fluorophenyldihydroxyborane. Obtained as a yellow solid ( </ </ </ /> Fluoro-2-methyl 5--5-nitro-biphenylyl ice-based amino acid tert-butyl ester according to the general procedure F, prepared from (4-iodo-5-methoxy-2-nitro-phenyl) - Aminomethyl acid third-butyl vinegar (Example B5) (L gram, 2.54 mmol) and 2-fluorophenyl di-barrium boron (0.60 g ' 4.32 mmol). Obtained an amorphous yellow material (687 mg). MS (EI) 362 (M+). Example F22 [2-(1,4-Dioxo-8-nitro-spiro[4.5]fluorenyl)_2'-fluoro-5-nitro-biphenyl-4-yl]-amine-52- Paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 public Chu) 1255266 A7 B7 V. Invention description (50) Methyl acid third-butyl ester according to the general procedure F, made from [5-(1.4 -Dioxo-8-nitro-spiro[4.5]dec-8-yl)-4-bromo-2-nitro-phenyl]-amine methyl acid, third-butyl (example C4) (1.89 g, 3.47 millimolar) with 2-fluorophenyl di-base shed (〇·63 g, 4.49 mmol). Obtained as a yellow solid (1.46 g). MS (ISP) 474 [(Μ+Η)+]; mp 164 ° C. Example F23 (2', Difluoro-2-methoxy-5-nitro-biphenyl-4-yl)-amine methyl acid, tert-butyl ester, according to the general procedure F, from 4-iodo -5-decyloxy-2-nitro-phenyl)-amine methyl acid tert-butyl ester (example Β5) (3·94 g, 10 mmol) and 2,5-difluorophenyl di Hydroxyborane (2.21 g, 14 mmol). Obtained an amorphous yellow material (丨.05 g). MS (ISN) 379 [(Μ-ΗΠ. Example F24 [2L fluoro-2-(2-methoxy-ethoxy)-5-nitrophenyl "4-yl]-amine methyl acid third -Butyl ester Ministry of Economics Intellectual Property Bureau employee consumption cooperative printing ------------- loading --- (please read the back note before this page) • Line _ according to the general procedure F, From [4-iodo-5-(2-methoxy-ethoxy)_2_nitro-phenyl]-amine methyl acid, third-butyl vinegar (example B6) and 2-fluorophenyl two Hydroxyboron. Obtained as a yellow solid (3.63g). MS (ISN) 405 [(MH)·]. Example F25 (RS)-[2'-Fluoro-nitro-(tetrahydro-glyoxymethyl) Biphenyl butyl]-aminomethyl acid tert-butyl ester according to the general procedure F, prepared from (RSH4-iodo! nitro ice (tetrahydro-pyrano: yl-53-

1255266 A7 B7

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (51) Oxymethyl)-phenyl]amine methyl acid, third-butyl ester (example Vi) and 2-phenylphenyl diborane borane . Obtained a yellow liquid (2.606 g). MS (ISN) 445 [(Μ-Η)- ] 〇 Example F26-based 2-(4-methoxyoxy)-5-nitro-biphenyl-4-yl]-amine methyl acid -Butyl ester is prepared according to the general procedure F' from [4-pyridyl-5-(4-methoxy-l-yloxy)_2-nitro-m-yl]-amine methyl-di-di-di- Example B11) (1.69 g, 3.38 mmol) with 2-fluorophenyldihydroxyborane (0.61 g, 4.39 mmol). A yellow blister (940 mg) was obtained. MS (ISP) 469 [(M+H)+ ]. Example F27 (2-Terti-butoxy-2,5,-difluoro-5-nitro-biphenyl-4-yl)-amine methyl acid _ _ _ _ _ _ _ _ From (5-T-butoxy-4-iodohexylnitro-phenyl)· Amidinoic acid tert-butyl ester (Example S4) (3.00 g, 6.88 mmol) and 2,5- Difluorophenyl dihydroxyborane (2.23 g, 14.1 mmol). Obtained an amorphous yellow material (2.30 g). MS (ISN) 421 [(Μ-Η)-]. General procedure G: Suzuki coupling with (4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl ester and bis(dimethylbutyric acid) diboron, and then with aromatic Preparation of (4-aryl-2-nitrophenyl)-amine methyl acid, third-butyr, (4-mercapto-2-nitro-phenyl)-amine A Base acid - Ding G (2.0 ^: Moer), -54 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ --Install i I (please read the notes on the back and then 6 pages) ιδι·- :Line · 1255266 A7 V. Description of invention (52 ) Bis(dimethylbutyric acid) diboron (2 2 mmol) ) 'K〇Ac (6 〇 millimolar) and Pd 〇 2 (PPh3 ) 2 (3 mol %) in a mixture of 二, 'dioxane (25 ml), mix under loo c' until Tlc shows complete conversion of iodide [see

Teti*· Lett· 1997, 38, 3841-3844]. Adding an aryl halide (4 毫 millimolar),

After PdCl2(PPh3)2 (3 mol%) and 2M c〇3 solution (7.5 ml), the mixture was stirred under loo c until tlc showed complete conversion of the intermediate dihydroxyborane ester. The mixture was transferred to a sep. funnel, EtOAc (3 mL). The combined organic layers were washed with water (100 liters) and dehydrated with 2 s 〇4. The solvent was removed, and the title compound was obtained from EtOAc EtOAc. General procedure Η : Preparation of (4_aryl fluorenyl nitroso) by carbonyl Suzuki coupling of (4-iodo:nitro-phenyl)-amine methyl acid to the carbonyl group of aryl dihydroxyborane -phenyl)-amine methyl acid, third-butyl ester, (4-transyl-2-nitro-phenyl)-amine methyl acid, third-butyl ester, 〇〇 millimolar, square dihydroxy Borane (U millimolar), heart (7) old force millimolar) and PdCL (PPh3 &amp; (3 moles / /) in a mixture of decyl ether (6 ml), at 8 〇t and CO atmosphere Stir under until the thin layer chromatography shows complete conversion of the iodide [see Tetr· Lett 1993, 34, 7595-7598]. Transfer the mixture to a separatory funnel, add Ηρ (30 ml), and Et〇Ac extraction χ 1〇〇 ml). The combined organic layers were washed with brine (50 mL) and dried with EtOAc. The solvent was removed, the title compound was purified eluting elut elut elut elut --------------装--- (Please read the note on the back and then this page): Line 'Ministry of Economics Intellectual Property Bureau employee consumption cooperative printing 55- 1255266

V. DESCRIPTION OF THE INVENTION (53) II_^ Procedure J: by (2-nitro-4-tributylstannyl-phenyl)-amine methyl acid tert-butyl ester with aryl halide or trifluoromethane Preparation of Styrene Coupling of StiUe Coupling of Vinyl Sulfonate or Stme Coupling of Tri-Butyl Ester Methylate with Trialkyl Arylstannane (4-Aryl-2- Nitro-phenyl)-amine methyl acid third-butyl ester or (4-mercapto, cyclodecyl- or heterocyclic)}-2-nitro-phenyl)-amine methyl acid third_ Ding Yuzhi (2-nitro-4-tributylstannyl-phenyl)-amine methyl acid, third butyl ester (525 mg '1.0 mmol; according to Bull.Chem. Soc. Jpn.l983, 56 , 3855-3856, prepared from its corresponding (4-ceptyl-2-nitro-phenyl)-amine methyl acid, the third _ butyl g (example b) (10 millimolar), via with six butyl Base distannane (7.5 ml, 15 mmol) and Pd(PPh3) 4 (116 mg, 0.1 mmol) in toluene (20 ml) at 6 °τ for 5 days), aryl halide Or trifluorodecane vinyl acetate (〇·95_6 〇 millimolar), anhydrous LiCl (126 mg, 3.0 mmol) and Pd(PPh3) 4 (5 mol.) in DME (3) The mixture liter) and the mixture was stirred at 100 ° C for an argon atmosphere, until the display until the complete consumption of the stannane. The reaction was cooled to 23 ° C, stirred with a saturated aqueous solution of kf (5 liters) for 45 minutes, filtered over celite, washed with acid, and the filtrate was dried with EtOAc. The solvent was removed in the sputum, and the title compound was obtained eluting with EtOAc EtOAc. The following example is for the preparation of amino-4-tetraethethynyl-phenyl)-amine methyl acid tert-butyl ester as a homogeneous on a regioisomer (Synthesis Scheme G): General Procedure K : Sonogashira coupling with (4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl ester and acetylene compound; -56- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) hi—·------------ (Please read the notes on the back and then on this page) .- Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266

5. Description of the invention (also by Sonogashira coupling of (3-ethynyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester with aryl complex; and 8-iodo-4-aryl Preparation of (4-alkynyl-2-nitro-phenyl)-aminomethyl group by coupling Sonogashira of keto-l,3-dihydrophenylhydrazone [b][l,4]dioxanone with acetylene compound Acidic third-butyl ester. Halide (3.0-4.5 millimolar), acetylene compound (3.0-4.5 millimolar),

Et3N (13.5 millimolar), PdCl2 (PPh3) 2 (5 moles / /) and pph3 (2.5 moles / oxime) in THF (12 ml) [where a very non-falling substance dmp can be added (up to 12) The mixture in ML) was stirred at 23 ° C for 20 minutes while scrubbing with argon. Cul (1.2 mol%) was added and stirring was continued at 60 ° C under argon until a small amount of the component was completely converted [see j. 0rg. Chem 1998, 63, 8551]. The mixture was transferred to a sep. funnel, 5% citric acid (5 mL) was added and the product was extracted with EtOAc (2 X 100 mL). The combined organic layers were washed with aq. NaHC.sub.3 (50 mL) and brine (50 mL). The solvent was removed to give a yellow residue which was purified eluting eluting eluting eluting eluting Example K1 (5-muro-2-nitro-4-phenylethyl block: phenyl-phenyl)-amine methyl acid third _ 酉 酉 according to the general private order K 'made from (5-gas base-4 -transyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (example Β1) (1.2 g, 3.0 mmol) and phenyl bromide (ο" ml, 4.5 mmol ). Obtained as a yellow solid (944 mg). MS (ISN) 371 [(Μ-ΗΠ with 373 [(Μ-Η+2Π ; melting point 166-167 ° C. Example K2 -57- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) -------------- Install i I (please read the note on the back and then this page) Order _ · -_线_ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266

V. Description of the invention (55) (5-Methyl-2-nitro-4-phenylethynyl-phenyl)-amine methyl acid terpyl ester according to the general procedure K, prepared from (4-iodo) Methyl: nitro-phenyl)-amine methyl acid third-butyl ester (Example B2) (1.13 g, 3. 〇 millimol) and phenylacetylene (〇 5 mL, 4.5 Torr). A greenish yellow solid (794 mg) was obtained. MS (EI) 352 (M+); m.p. Example K3 [5-(4-Methyl-hexahydropyrylene-1-yl)-t-nitro-t-phenylphenylethynyl-phenyl]-aminomethyl acid tert-butyl ester according to the general procedure K, manufactured from [ 4-iodo- 5 benzylidene hexahydropyrazine small base)-2-nitro-phenyl]-amine hydrazinoic acid tert-butyl ester (Example C1) (134 g, 3 〇 mmol) Block with benzene (0.5 ml, 4.5 mmol). Obtained a greenish yellow solid (u). MS (ISP) 437 [(M+H)+]; mp. 170. Example K4 (5-morpholine-4-yl-2-nitro-4-phenylethynyl-phenyl)-amine methyl acid tert-butyl ester according to the general procedure K, from 4-iodo 5-5-fosfosin-2-yl-phenyl)-amine methyl acid tert-butyl ester (example C3) (890 mg, 2.0 mmol) and phenylacetylene (0.33 ml, 3.0 mmol) ear). Obtained an orange solid (58 mg). MS (ISP) 424 [(M+H)+]; mp 190-191. Example K5 (2-nitro-4-phenylethylidene-5-thiofenofin-4-yl-phenyl)-amine methyl acid third-butyl vinegar according to the general procedure K, manufactured from (4 - mercapto-2-nitro-5-thiofenofo-4-yl-phenyl)-amine methyl acid tert-butyl ester (example C2) (1.0 g, 2.15 mmol) and stupid acetylene (0.36 ml, 3.22 mmol). Obtained an orange solid (62 mg). -58- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -------------Installation--- (Please read the back note first. ) - Line Ministry of Economics Intellectual Property Office Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention (56) MS (ISP) 440 [(M+H)+ ] and 462 [(M+Na)+]; Melting Point 2〇rc (decomposed). Example K6 [5-(1,1-dione-thio-fosfosin bucket base&gt;2_nitro-phenylphenyl-phenyl) phenylmethyl-tert-butyl ester in two steps Made as follows: (4-iodo-2-nitroj thiomorpholine-phenyl)-amine decyl methacrylate (Example C2) (465 mg, 1 mmol) In a drop of acetone (25 ml) and Η2〇 (1 liter), add 〇·3Μ ammonium molybdate solution (9) 3 ml and 33% Η2〇2 (2.3 ml) in 〇 °C, and The mixture was stirred at 23 °: for 1 hour. Obtained [5 (1,1 - ligand, dyfosin-4-yl)-4-indolyl-2-nitro-phenyl]-amine methyl acid Di-butyl ester (497 mg, 1. 〇 millimol), an amorphous yellow material which was reacted with benzene b (0·17 mL, 15 mmol) according to the general procedure κ. (245 mg) MS (ISP) 472 [(Μ+Η)+]; m.p. 217-22IX:. Example K7 〇(1,4-dioxo-8-nitro-spiro[4.5]癸-8-yl] ; 2-nitro-4-phenylethynyl-phenyl]-amino acid tert-butyl ester according to the general procedure K, prepared from [5-(1,4-dioxo-8-nitrogen-spiro[ 4.5]癸-8-yl)-4-bromo nitro-phenyl]- Methyl acid tert-butyl ester (Example C4) (3.80 g, 7.53 mmol) and phenyl b. (1.24 mL, 11.3 mmol). Obtained orange solid (18 g). MS (ISN) 478 [ (Μ-ΗΠ; melting point 179-180X: Example K8 [5-(2-Methylamino-ethylthio)-2-nitro-4-phenylethyl-phenyl]-amine methyl acid -59 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----r---------Installation--- (Please read the notes on the back first) 6 Page) Book · · 丨-line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Α7 Β7 1255266 V. Invention description (57) Third-butyl ester according to the general procedure K, from [5-(2- two Methylamino-ethylthio) bromoiodo-2-nitro-phenyl]-amine methyl acid tert-butyl ester (Example Dl) (721 mg, 1.54 mmol) with phenylacetylene (0.25 mL, 2.31 mmol) Obtained amorphous yellow material (595 mg) MS (ISP) 442 [(M+H)+]; mp 179-180 ° C. Example K9 (5-tris-butoxycarbonylamine Methyl 4-nitro-2-phenylethynyl-phenylsulfanyl)-acetate is prepared according to the general procedure K from (5-tris-butoxycarbonylamino-2- Iodophenyl-4-nitro-phenylthio)-acetic acid methyl ester (Example D2) (780 mg, 1.67 mmol) and phenylacetylene (0. 27 mL, 2.5 mM). Obtained an orange solid (700 mg). MS (ISP) 460 [(Μ+ΝΗ4)+]; mp. 125-127. Example K10 [5-(2-Methoxy-ethoxy)-2-nitro-4-phenylethynylphenyl]-amine methyl acid tert-butyl ester according to the general procedure K, manufactured from [ 3-iodo-5-(2methoxy-ethoxy)-2-nitro-phenyl]-amine methyl acid tert-butyl ester (Example B6) (876 mg, 2 mmol) and Phenylene block (0.33 ml, 3 mmol). A yellow solid (569 mg) was obtained. MS (ISP) 413 [(M+H)+] and 430 [(M+NH4)+]; mp. (:. Example K11 (5-methoxy-2-nitro-4-phenylethynyl-phenylamine methyl acid tert-butyl ester according to the general procedure K, from (4-iodo-5-) Methoxy-2-nitro-phenyl)-amine methyl benzoate di-butyl ester (example Β 5) (1·18 g, 3.00 mmol) and phenylacetate (ο % 毫升, 4·5 毫Moer). Obtained a yellow solid (Ug). -60- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) L丨-卜---------Installation-- - (Please read the notes on the back and then the page) · Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention (58) MS (EI) 368 (M+); Melting point 129 °C. Example K12 [5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy]_2_nitro-4-phenylene Benzyl-phenyl]-amine methyl acid _ 酉 酉 according to the general procedure K, from [4_iodomethoxy-ethoxy] ethoxy]-ethoxy}-ethoxy )-2-nitro-phenyl]-amine methyl acid third-butyl ester (conventional Β7) (5·7 g '10.0 耄m) and phenyl bromide ([Μ亳升,Μ毫莫耳Obtained yellow oil (5.2 g). MS (ISN) 543 [(M-Η)·]. Example K13 (5-Terti-butoxycarbonylamino-4-nitro-2-phenylethynyl-phenoxy)·T-butyl acetate According to the general procedure K, from (5-tris-butoxycarbonylamino-2-iodo-4-nitro-phenoxy)-acetic acid tert-butyl ester (Example Sl) (1.46 g, 2.99 m) Mole) and phenylacetylene (0.49 ml, 4.49 mmol). Obtained a yellow solid (1·4 g) MS (ISP) 486 [(Μ+ΝΗ4)+]; melting point 130 ° C. Example K14 (RS) -5-(2,2-dimethyl-[1,3]dioxoindol-4-ylmethoxy)-2-nitro-4-phenylethylidene-aniline according to the general procedure K From (RS)-5-(2,2-dimethyl-[1,3]dioxoindol-4-ylmethoxy)-4-pyridyl-2-nitro-phenylamine (Example Ε5) 4·5 g, 11.4 mmol, and phenylacetylene (1·88 ml, 17.1 mmol). Obtained an orange solid (5.4 g). MS (ISN) 367 [(MH)·]; melting point 147-149 °C. Example K15 -61 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -----r-------I-install--- (please read first Precautions on the back ^►►) - 丨线 - Ministry of Economic Affairs Intellectual Property Bureau employee consumption Printed by the Society 1255266 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Inventions (59) (5-di-di-butyl sylvestreyl-4-nitro-2-phenylethylidene) Benzoic acid methacrylate is prepared according to the general procedure K' from 5-second-butoxycarbylamino-based thioglycol-methyl benzoate (Example Β3) (1·22 g, 2.89 mmol) and benzene Acetylene (〇 48 ml, 4.34 mmol). A yellow solid (793 mg) was obtained. MS (ISP) 397 [(Μ+Η)+ ] and 414 [(Μ+ΝΗ4)+ ]; melting point 173Χ:. Example Κ16 (5-Terti-butoxymethylamino-4-nitro-2-phenylethynyl-phenyl)·methyl acetate was prepared according to the general procedure from (5-tri-butoxycarbonyl) Amino iodohydridyl nitro-phenyl)-methyl acetate (Example Ve (R=C02Me; R&quot;=Boc)) (1.32 g, 3.03 mmol) with phenyl bromide (0.5 mL, 4.55 mmol) ). Obtained a yellow solid (i.i gram). MS (ISP) 411 [(M+H)+], 428 [(M+NH4)+] and 433 [(M+Na)+]; mp. Example K17 (5-Cyanomethyl-2-nitro-4-phenylethynyl-phenyl)-amine methyl acid tert-butyl ester according to the general procedure K, from (5-cyanomethyl- 4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example B9 [Ve (R=CN; R"=Boc)]) (3.97 g, 9.85 mmol) and Phenyl bromide (3.24 ml, 29-56 mmol). Obtained olive solid (1.6 g) MS (ESI) 395 [(M+NH4)+]; mp 166 ° C. Example K18 (RS)-[5- (2,3-Dihydroxy-propoxy)-2-nitro-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester according to the general procedure K, from (RS)-[ 5-(2,3-dihydroxy-propoxy)-4-bromo-2-nitro-phenyl]-amine methyl acid tert-butyl ester (RO-68-5451/000 (3.23 g, 7.11 毫-62- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------------- Good ^--- (Please read the notes on the back first) 15 more on this page)

1255266 A7 B7 V. INSTRUCTIONS (6(}) Moer)·'made from (5-fluorenyloxy-4-c--2-nitro-phenyl)-amine methyl acid tert-butyl ester ( Example Β 4) (4·20 g, 1〇·〇 mmol), via NM〇 (128 g, 11〇 mmol), 〇s〇42.5% in t-BuOH (1 ^: liter, 〇. ; [mole] and k2〇s〇4 (40 mg, 0.1 mmol) in acetone (250 ml) and h20 (1 ml), reacted at 23 ° C for 6 days) with phenylacetylene (1.17 ml, 10.67 mmol). Obtained a yellow solid (2.74 g). MS (ISP) 429 [(M+H)+]; mp. 157 (dec.). Example K19 (5-# to methyl-2-nitro-4-phenylethynyl-phenyl)amine methyl acid tert-butyl ester according to the general procedure K, from (5-hydroxymethyl-4- Iodo-2-nitro-phenyl)-amine mercapto acid tert-butyl ester (Example Vh) (2.61 g, 6.62 mmol) and phenyl b. (1.10 mL, 9.93 mmol). A yellow solid (176 g) was obtained. MS (ISP) 386 [(M+NH4)+]; mp 177 (dec.). Example K20 [5-(4-methoxy-hexahydrop-pred-1-yl)-2-nitro-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester according to general Procedure K, prepared from [4-iodo-5-(4-methoxy-hexahydropyridine small) 2-nitro-phenyl]-amine methyl acid tert-butyl ester (example C5x1 gram , 21 mM) with phenylacetylene (0.35 ml, 3.15 mmol). A yellow solid (799 mg) was obtained. Melting point 147-150 ° C. Example K21 (5-Cyanomethoxy-2-nitro-4-phenylethyl-phenyl)-amine methyl acid tert-butyl ester according to the general procedure K, from (5-cyanomethyl) Oxy-4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example S2) (605 mg, 1.44 mmol) and phenylethyl-63- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the note on the back and then mr page) Binding--------^-Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (61) Alkyne (0.24 ml, 2.16 mmol). Obtained a yellow solid (5 〇 8 mg). MS (EI) 393 (M+); mp. 170. Example K22 [4-(4-Fluoro-butyryl)-5-3⁄4 methyl·2-nitro-phenyl]-amine methyl acid _ _ 酉 根据 根据 根据 根据 根据 根据 根据 根据Hydroxymethyl-4-iodo-2-nitro-phenyl)-amine methyl acid tert-butyl ester (Example Vh) (2.00 g, 5.07 mmol) and 4-fluorophenylacetylene (0.91 g) , 7.61 millimoles). A yellow solid (155 g) was obtained. MS (ISN) 385 [(M-H)-]; mp. Example K23 (RS)-(4-(4-Fluorophenylethyl)-5-{indolyl-[2-(tetrahydrofuran-2-yloxy)-ethyl]-amino-1 2-Nitro-phenyl)-amine methyl acid tert-butyl ester according to the general procedure K, from (RS)-(4-iodo-5-{methyl-[2-(tetrahydro-pyran) -2-yloxy)-ethyl]-aminonitro-phenyl)-amine methyl acid tert-butyl ester [R〇_69_ 3820/000, manufactured from {5-[(2-yl) -ethyl)-methyl-amino]-based nitro-phenyl}-aminomethyl acid tert-butyl ester (example C6) via 3,4-dihydro-2-indole and catalyst TsOH · Η2 Ο, treated in DCM at 〇 ° C (2·〇9 g, 4.01 mmol) and 4-fluorophenylacetylene (0.72 g, 6.02 mmol). Obtained a tan solid (1.84 g). MS (ISP) 514 [(M+H)+]; mp. Example K24 (RS)-{2-Nitro-4-phenylethynyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenylh-amine methyl acid The third-butyl ester is prepared according to the general procedure K from (RS &gt; {4-picyl-2_nitro-5-[2-(tetrahydro-indol-2-yloxy)-ethoxy] Private base}-Aminomethyl acid third-buty g (Example 83) (743 mA-64- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -- (Please read the back first Precautions again @ this page) Packing: Line _ 1255266 A7 V, invention description (62) grams, 1.46 millimoles) and phenylacetylene (〇 · 24 ml, 219 millimoles). Obtained brown cohesive oil ( 429 mg) MS (EI) 393 (M+). </RTI> </RTI> <RTI ID=0.0></RTI> Amino-methyl 3-butyrate (Example B1) (144 g, 3 mmol) and 4-fluorophenylacetylene (541 mg, 4.5 mmol) afforded a yellow solid (777 mg). (EI) 472 (M+); m.p. 96-98 ° C. Example K26 [5-Se-butoxy-4-(4-fluorophenylethylidene-phenyl)-amine methyl acid Tri-butyl ester according to the general course K, produced from (5-tris-butoxysuccinyl-2-nitro-phenyl)-aminomethyl-tert-butyl ester (example S4) (i.4 gram, 3.21 mil Mole) with 'fluorophenylacetylene (0.66 g, 5.46 mmol). Obtained a brown solid (52 g). MS (El) 428 (Μ+); melting point 201 ° C. General procedure L : Preparation of (^-aminophenyl)-amine methyl acid third-butyl ester by reduction of (2-nitro-phenyl)-amine methyl acid tert-butyl ester; also by 3- Preparation of 4-aryl-1,3-dihydrobenzoquinone dioxime by reduction of aryl-N-(2-nitro-phenyl)-3-g-iso-propionamide and concomitant cyclization Catalytic hydrogenation of the nitro compound (1.0 mmol) in MeOH or EtOH with THF (1:1, approximately 20 mL), and 10% palladium/carbon (20 mg) or hydrazine Ni _Ni (2 〇 mg) of mixed LIIU---------- Pack--- (Please read the back of the note before this page) · Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266

V. INSTRUCTIONS (63) 3, vigorously stirred at 23 ° C under a hydrogen atmosphere until tic shows complete conversion. The catalyst was filtered off and the strip was washed well with Me 〇H or Et 〇H and hexanes HF (1:1) and solvent was removed from the hexane to give the title compound which was substantially pure enough for further conversion. Method b: a mixture of a nitro compound (1.0 mmol) and SnCl 2 · 2H20 (5.0 mmol) in the reduction of SnCl 2 · 2H 2 0 in EtOH (30 ml), at 70-80 T: Or, in 咐 &lt;(3 ml) and DMF (12 ml), stir at 23 ° C under argon atmosphere until tic shows complete conversion [see Ding Xue [Hung 1984, 25, 839]. The reaction mixture was brought to pH 8 and then extracted with EtOAc (2×1······ The combined organic layers were washed with brine and dried with EtOAc EtOAc. The solvent is removed, leaving a yellow solid which can be purified by chromatography on silica gel column if necessary. Method c: reduction of Zn and NH4 C1 to a mixture of this nitro compound (1.0 mmol) in EtOH / THF / saturated NH4 C1 solution (1:1: 1, 30 ml), zinc powder added ( 3 〇 mmol; and the mixture was stirred at 70 Torr and argon atmosphere until tlc showed complete conversion. The aqueous solution treatment was carried out as described in Method B. Method d: reduction of Fe and HOAc to a mixture of this nitro compound (1.0 mmol) in THF/I^O (4: 丨, 10-50 ml), Fe powder (6.0 mmol), And the mixture was at 7 〇. 〇 Stir to the atmosphere until tic shows a redundant conversion. The aqueous solution treatment was carried out as described in Method b. Example L1 -66- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) —.----------Installation - (Please read the back note first. · -* Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention (64) (2 Amino-4-keken-5-thiofenofin 4-yl-phenyl) -Aminomethyl acid tert-butyl ester was prepared according to the general procedure L (Method b) by reduction with SnCl 2 · 2H 2 〇 (2·54 g, 11.3 mmol) from (4) iodine-2-nitro _5-Thiofosolin-4-yl-phenyl)-amine methyl acid tert-butyl ester (Example C2) (1 〇 5 g, 2 25 mmol). Obtained as a pale yellow solid (993 mg). MS (ISP) 436 [(M+H)+]; mp. Example L2 (2-Amino-4-iodo-5-morpholine-4-yl-phenyl)-amine methyl acid tert-butyl ester according to the general procedure L (Method b), via SnCl2 · 2H2 Reduction of 0 (1.9 g, 8.27 mmol) from (4-iodo-5-morphobordol-2-nitro-phenyl)-amine methyl acid tert-butyl ester (example) C3) (753 grams, 1.65 millimoles). Obtained a yellow solid (696 mg). MS (ISP) 420 [(M+H)+]; melting point Π9-143Χ:. Example L3 (2-Amino-5-chloro-4-phenylethynyl-phenylaminemethyl acid tert-butyl ester according to the general procedure L (Method b), via SnCl 2 · 2 Η 2 Ο (2.245 g, Reduction of 10 mM) from (3-chloro-2-nitro-4-phenylethynyl-phenyl)-amine methyl acid tert-butyl ester (Example Kl) (742 mg, 2.0 mmol. Obtained an orange solid (483 mg). MS (ESI) 343 [(M+H)+] and 345 [(M+2+H)+]. Example L4 (2-Amino-5) -Methyl-4-phenylethylidene-phenyl)-aminomethyl acid tert-butyl ester according to the general procedure L (method b), via reduction with SnCl2 · 2H20 (2.37 g, 10.3 mmol) Function, made from (5-methyl-2-nitrophenylphenylethynyl-phenyl) -67- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----- --------装--- (Please read the back note before this page). • Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1255266

V. INSTRUCTIONS (65) - Aminomethyl 3-butyrate (Example K2) (741 mg, 21 mmol). Obtained as a pale brown solid (419 mg). MS (ISP) 323 [(M+H)+]; melting point 172-173 °C. Example L5 [2-Amino-5-(4-methyl-hexahydropyridinyl)-4-phenylethynyl-phenyl]-amino acid tert-butyl ester according to the general procedure L (method b ), by reduction with SnCl 2 ·2Η2Ο (2,820 g, 12.4 mmol), from [5_(4-methyl-hexahydropyrazine)&gt;2_nitro-4-phenylethynyl- Phenyl]-amine methyl acid, third butyl ester (example Κ3χ1〇8 g, 2.48 mmol). Obtained an orange solid (1 g) MS (ISP) 407 [(M+H)+]; Melting point 81-85 Ό. Example L6 (5-Amino-2-chloro-biphenyl-4-yl)-amine methyl acid tert-butyl ester according to the general procedure L (method b), via SnCl2 · 2H2 0 Reduction of (2.53 g, 11.2 mmol) from (2-chloro-5-nitro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example Fl) (783 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 2-Methyl-biphenyl-4-yl)-amine mercapto acid tert-butyl ester according to the general procedure L (method a), via catalytic hydrogenation with Pd/C, from (2-methyl-5) -nitro-biphenyl-4-yl)-aminomethyl Third-butyl ester (Example F2) (921 mg, 2.8 mmol) obtained as a white solid (796 mg). MS ( s) 298 ( Μ+); melting point 122 ° C. -68- Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ----U----------Install i I (please read the precautions on the back page again) · --Line _ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention (66) Example L8 [2-Amino-5-(2-diamino-ethylthio)_'phenylethynyl- Phenyl]-aminomethyl acid tert-butyl ester was prepared according to the general procedure L (method b) by reduction with SnCl 2 · 2H 2 0 (1.41 g, 6.25 mmol) from [5-(2-) Methylamino-ethylthio)-2-nitro-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester (Example K8) (551 mg, 1.25 mmol). Color foam (51 mg) MS (ISP) 412 [(M+H)+]; mp. 115-117 ° C. Example L9 (4-amino-5-tri-butoxycarbonylamino-2- _Phenylethynyl-phenylthio)-acetic acid methyl ester according to the general procedure L (method b), via SnCl2 · 2Η2 Ο (1.62 g, 7.16 mmol) Effect, prepared from (5-tertiary - butoxycarbonyl-amino-4-nitro-2-phenyl-ethynyl - phenylthio) acetate (Example Κ9) (634 mg, 1.43 mmol). Obtained orange gum (590 mg). MS (ISP) 413 [(Μ+Η)+ ], 435 [(M+Na)+ ] and 451 [(Μ+Κ)+ ]. Example L10 (4-Amino-5-tris-butoxyamino-2-phenylethylidene-phenyl)-acetic acid methyl hydrazine according to the general procedure L (Method b), via SnCl2 · 2Η2 Reduction of hydrazine (3.00 g, 13.28 mmol) from (5-tris-butoxycarbonylamino-4-nitro-2-phenylethynyl-phenyl)-decyl acetate (example K16) ) (1.09 g, 2.66 mmol). Obtained as a pale yellow solid (900 mg). MS (ISP) 381 [(M+H)+] and 403 [(M+Na)+]; (:. Example L11 [2-Amino-5-(2-methoxy-ethoxy]&lt;4-phenylethynyl-phenyl]-amine methyl acid No. -69- This paper scale applies to China Standard (CNS) A4 specification (210 X 297 mm) ----K----------Install--- (Please read the note on the back again - this page) Order - : Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. INSTRUCTIONS (67) Tri-butyl ester was reduced according to the general procedure L (method b) by SnCl2 · 2H2 〇 (3.88 g, 17.2 mmol) Effect, prepared from [5-(2-methoxy-ethoxy)-2-nitro-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester (Example Κ 10) (1.417克, 3·44 mmol. Obtained as an off-white solid (1.04 g). MS (El) 382 ( Μ+); mp l -5-l 〇 7 ° C. Example L12 (2-Amino-5-? Folinac-4-yl-4-phenylethynyl-phenyl)-amine methyl acid, the third-butyr, according to the general procedure L (method b), via SnCl2 · 2Η2 Ο (1.5 g, 6.65 mmol) Reducing effect, prepared from (5-morpholine)-2-amino-phenylphenylethynyl-phenyl)-aminomethyl acid tert-butyl ester (example K4) (563 mg , </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 4-Phenylethynyl-phenyl)-amine methyl acid tert-butyl ester was prepared according to the general procedure L (Method b) by reduction with SnCl 2 · 2Η2 Ο (3.06 g, 13.57 mmol). From (5-methoxy-2-nitro-4-phenylethynyl-phenyl)-amine methyl acid tert-butyl ester (Example Κ 11) (1·00 g, 2.71 mmol). Yellow solid (870 mg) MS (EI) 338 (M+); mp 158 ° C. Example L14 4-amino-5-tris-butyl- succinylamino-2-ethylidene-benzoic acid The hydrazine was prepared according to the general procedure L (method b) by reduction with SnCl 2 · 2H 2 0 (2.15 g, 9.51 mmol) from (5-tris-butoxycarbonylamino-4-nitro- 2-Benzene-70- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------- Pack--- (Please read the back of the note first) Matters again page) π·! Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 _____B7__ V. Invention description (68) Ethynylidene-benzoic acid methyl ester (Example K15) (754 mg, 丨·^ mmol). A pink solid (431 mg) was obtained. MS (EI) 366 (M+); mp. 164. Example L15 [2-Amino-5-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy ethoxy]&gt; 4-phenylethynyl Phenyl]-aminomethyl acid tert-butyl ester was prepared according to the general procedure L (method b) by reduction with SnCl 2 · 2H 2 0 (6.2 g, 27.54 mmol) from [5-(2-{ 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylidyl}-ethoxy)-2-nitro-4-phenylethylidene-phenyl]-amine Methyl acid tert-butyl ester (Example K12) (3.0 g, 5.51 mmol). Obtained brown oil (2·9 g). MS (ISP) 515 [(Μ+Η)+]. Example L16 (4) -Amino-5-tris-butoxycarbonylamino-2-phenylethynyl-phenoxy)-acetic acid tert-butyl ester according to the general procedure L (method b), via SnCl2 · 2Η2 0 (3.18克, 14.10 mmol, reduction from (5-tris-butoxycarbonylamino-4-nitro-2-phenylethynyl-phenoxy)-acetic acid tert-butyl ester (Example Κ13 (1.32 g, 2.82 mmol). Obtained amorphous orange material (1.2 g) MS (ISP) 439 [(Μ+Η)+] and 461 [(M+Na)+]. Example L17 ( 2-amino-5-cyanomethyl-4-phenylethynyl-phenyl)-amine methyl acid -Butyl ester was prepared according to the general procedure L (Method b) by reduction with SnCl2 · 2H20 (1.13 g, 5.0 mmol) from (5-cyanomethyl-2-nitro-4-phenylacetylene) Base _ phenyl)-amine methyl acid third-butyl ester (Example K17) (377 mg, 1 〇 millimolar) -71 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) ----)---------- II (Please read the notes on the back and then 6 pages) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 B7 V. Invention description (69 Obtained an orange solid (338 mg) MS (ISP) 348 [(M+H)+] and 37 〇[(M+Na)+];,]: 143 ° C. Example L18 [2-amine 5-(1,4.dioxa-8-nitrospiro[4.5]dec-8-yl)-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester and [2 -Amino-5-(4,4-diethoxy-hexahydropyridine small)-4-phenylethynyl-phenyl]-amine mercapto acid tert-butyl ester according to the general procedure L (Method b ), by reduction with SnCl 2 · 2H 2 0 (4.0 g, 18.0 mmol), in EtOH, from [5-(1,4-dioxo-8-nitro-spiro[4.5] 癸-8- 2-nitro-4-phenylacetylene - phenyl] _ acid tert Butyl (Examples Κ7) (1 · 73 g, 3.6 mmol). Individually obtained brown solid (418 mg) and dark brown solid (379 mg). MS (ISP) 450 [(Μ+Η)+]; m.p. 79-82°C; MS (ISP) 480 [(Μ+Η)+]. Example L19 [2-amino-5-(1,1-dione-6-thiomorpholine-4-yl)-4-phenylethynyl-phenyl]-amine methyl acid third- Butyl ester is prepared according to the general procedure L (method 1)) from [5_(丨,1_二格同基- by the action of 311 &lt;1;12*2112〇(564 mg, 2.5 mmol) Thiofuron-4-yl)-2-nitro-4-phenylethylidene-phenyl]-amine methyl acid tert-butyl ester (Example Κ6) (235 mg, 0.5 mmol) . Obtained as a brown solid (418 mg, imp., used directly in Example 6 without purification and characterization). Example L20 [2-Amino-5-(2,2-dimethyl-[1,3]dioxoindolylmethoxy)-4-phenylethynyl-phenyl]-aminemethyl acid The three-buter g is based on the general procedure L (method b), via SnCl2 · 2Η2 Ο (4.6 g, 20.32 -72- this paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 public meals) J.II . Bu---------Install--- (Please read the notes on the back and then on this page) Printed by the Department of Intellectual Property of the Intellectual Property Department of the Ministry of Economic Affairs

1255266 V. Description of invention (70) Amol's reduction, produced from (called [5 like 曱 曱 仰]: Oxygen 斗 曱 曱 曱) oxy) 2-nitro phenyl ethynyl benzene Base]-Aminomethyl-tert-butyl ester (Example Β8) (1·90 g, 4.06 mmol). The crude product was reprotected by stirring with 2,2-dimethoxypropane (5 mL) and _Ts s H H2 (U eq.) in DMF (5 mL) at EtOAc. A brown solid (11 g) was obtained. MS (ISP) 439 [(M+H)+ ], 461 [(M+Na)+ ] and 477 [(M+K)+ ]. Example L21 4-Amino-5-t-butoxycarbonylamino-2-iodo-benzoic acid formazan according to the general procedure L (Method b), via SnCl2 · 2Η2 Ο (8_02 g, 35.55 Amor The reduction was carried out from methyl 5-tris-butoxycarbonylaminoiodo-4-nitro-benzoate (Example Β3) (3.00 g, 7.11 mmol). A light red bubble (1.9 g) was obtained. MS (ISP) 393 [(Μ+Η)+]; mp 60-78 °C. Example L22 [RS]-[2-Amino-5-(2-keto-[1,3]dioxoindol-4-ylmethoxy)-4-phenylethyl-phenyl]- Aminomethyl acid tert-butyl ester was prepared from [RS]-[2-nitro-5 by reduction with SnCl2 · 2Η2 Ο (1.02 g, 4.5 mmol) according to the general procedure L (Method b) -(2-keto-[1,3]dioxoindol-4-ylmethoxy)-phenylphenylethynyl-phenyl]-amine methyl acid tert-butyl ester [RO-68-8108/ 000 (411 mg, 0.9 mmol), prepared from (rs)-[5-(2,3-dihydroxy) by treatment with 1, fluorene-carbonyldiimidazole in THF at 0 to 23 °C. -propoxy)-2-nitro-4-phenylethylidene-phenyl]-amine methyl acid tert-butyl ester (Example K18)]. Obtained an amber solid (370 mg). MS (ISP) 425 [(M+H)+]; mp. -73- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ----^---------Installation--- (Please read the back note first. ) · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (71) Example L23 (2-Amino-5-ethoxymethyl- 4-Phenylethynylphenyl)-amino acid tert-butyl ester was prepared from the 5-carbonate-butoxycarbonyl group by reduction with snCl 2 · 2H 2 oxime according to the general procedure L (method b). Amino-4-nitro-2-phenylethylidene-yl ester methyl ester [RO-68-8481/000, made from (5-mole methyl-2-nitro-4-phenylethynyl- Phenyl)-aminomethyl acid tert-butyl ester (Example K19) was treated with methyl formate and Et3N in THF at 0 °C. Amorphous brown material (139 mg) was obtained. MS (ISP) 367 [(M+H)+]. Example L24 2,2-Dimethyl-propionic acid 4-Amino-5-tris-butoxycarbonylaminophenylethynyl-monodecyl ester according to the general procedure L (Method b), via SnCl 2 · 2H 2 0 Reduction, from 2,2-dimethyl-propionic acid 5-tris-butoxycarbonylamine-based nitro-2-phenylethylidene-yl ester [RO-68-9779/000, made from (5-#methyl-2-nitro-4-phenylethylidene-phenyl)-amine methyl acid third-buty@ (example K19), via trichlorinated chloride The media DMAP was treated at p to 23 ° C in p-precipitate. A non-crystalline yellow material (182 mg) was obtained. MS (ISN) 421 [(M-Η)-]. Example L25 (RS)-[2-Amino-4-phenylethynyl-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-aminomethyl acid tert-butyl ester According to the general procedure L (method b), from (RS)-[2-nitro-4-phenylethynyl-5-(tetrahydro-pyran-2-) via reduction with SnCl2 · 2H,0氧基oxymethyl)_ -74- ----^---------- Pack--- (Please read the back note on this page first) Φ Order: --Line - Paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (72)

Phenyl]-aminomethyl acid tert-butyl ester [RO-69-2829/000, made from (5-hydroxymethyl-2-nitro-4-phenylethynyl-phenylamine methyl acid) Tri-butyl ester (Example K19) was treated with 3,4-dihydro-2H-pyran and catalyst Ts 〇 H.H.sub.2 in DCM in DCC. MS (ISN) 421 [(Μ-ΗΠ ; mp 158 ° C. Example L26 [2-amino-5-(4-methoxy-hexahydropyridinyl) phenylphenylethynyl-phenyl]-amine The third-butyl methacrylate was prepared from [5-(4-methoxy-hexahydropyridin-1-yl)-2- via the reduction of SnCl 2 · 2H 2 0 according to the general procedure L (Method b). Tri-butyl nitro-4-phenylethynyl-phenyl]-aminemethyl acid (Example K20) (727 mg, 1.61 mmol). [(M+H)+]; melting point 173-176 ° C. Example L27 (2-amino-5-cyanomethoxy-4-phenylethynyl-phenyl)-amine methyl acid third - Butyl ester is prepared according to the general procedure L (method b) from (5-cyanomethoxy-2-nitro-4-phenylethylidene-phenyl)-amine via reduction with SnCl 2 · 2H 2 0 Methyl acid third-butyl ester (example K21) (395 mil , 0.91 mmol, obtained amorphous yellow material (219 mg). MS (ISP) 364 [(M+H)+] 〇 Example L28 (RS)-[2-Amino-4-(4-fluoro Phenylethyl)-5-(tetrahydro^chen-2-yloxymethyl)-phenyl]aminomethyl acid tert-butyl ester according to the general procedure L (method b), via SnCl2 2Η2 还原Reduction -75- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ---3^. (Please read the back note before this page)

1255266 A7 B7 V. Invention description (73) ----Γ---------Install i I (please read the precautions on the back and then ^r page) 'Manufactured from (RSH4-(4· Fluorophenylethyl)-2-nitro-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-amine methyl acid third-butyl ester [R〇_69_3877/ 〇〇〇, made from [heart (I fluorophenylethyl)-5-methyl-methyl nitro-phenyl]-amine methyl acid, third butyl ester (real

Example K22) was treated with 3,4-dihydro-2H-pyran and catalyst TsOH.H2 oxime in DCM at EtOAc. An amorphous light brown material (99 mg) was obtained. MS (ISP) 441 [(M+H)+ ]. Example L29 (RSM2-Amino-4-(4-fluorophenylethynyl)_5_{methyl-[2_(tetrahydro-pyranoyloxy)ethyl]-amino}-phenyl)-amine The third-butyl methyl methate is prepared from (RS)-(4-(4-fluoromethylene-yl)-5-{A via the reduction of SnCl2 · 2H2 0 according to the general procedure L (method b) Base-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-amino}-2-nitro-phenyl)-amine methyl acid tert-butyl ester (example K23) 1.79 grams, 3.49 millimoles). Amorphous light brown material (12 g) was obtained. MS (ISP) 484 [(M+H)+]. Example L30 -·Line-(RS)-{2-Amino-4-phenylethynyl-5-indole (tetrahydrotetrayloxy)-ethoxy]-phenyl}-amine hydrazinoic acid 3. Ding Ding, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, printed according to the general procedure L (method b), via the reduction of SnCl2 · 2H2〇, from (RS)-{2-nitro-4-phenyl Block base_5-[2-(tetrahydrotetram-2-yloxy)-ethoxy]-phenyl-p-methylamino acid tert-butyl ester (example K24) (42 〇 mg, 〇87 毫Moore). Obtained as a pale brown solid (346 mg). MS (ISP) 453 [(Μ+Η)+]. Example L31 (RS)-{5-Amino-4'-orbito-2-[4-(tetrahydro-pyran-2-yloxy)-hexahydrop-butyl-1-yl]_-76 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Description of invention (74) Biphenyl-4-yl]-amine methyl acid third-butyl ester according to general Procedure L (Method a), via catalytic hydrogenation with Pd/C, from (RS)-{4f-fluoro-5-nitro-2-[4-(tetrahydro-l-butan-2-yloxy) Base)-hexahydrop to butyl-1-yl]-biphenylyl yl}-amine methyl acid third-butyl vinegar (Example F3) (845 mg, 1.64 mmol). Obtained as a light green solid (758 mg). MS (ISP) 486 [(M+H)+]; mp 157-161. Example L32 [2-Amino-5-(2-tris-butoxy-ethoxy)-4-(4-fluorophenylethynyl)-phenyl]-aminomethyl acid tert-butyl ester According to the general procedure L (method b), from [5-(2-tris-butoxy-ethoxy)_4_(4-fluorophenylethylidene) by reduction with SnCl 2 · 2H 2 0 2-Nitro-phenyl]-aminocarbamic acid tert-butyl ester (Example K25) (744 mg, 1.57 mmol). Obtained as a pale yellow solid (575 mg). MS (ISP) 443 [(M+ H)+]; melting point 149-15CTC 〇 Example L33 (RS)-(5-Amino-4'-fluoro-2-{4-indole (tetrahydrotetram-2-yloxy)-ethoxy • • hexahydro p-but-1-yl}-biphenyl-4-yl)-amine methyl acid tert-butyl ester according to the general procedure L (method a), via catalytic hydrogenation with Pd/C, From (RS)-(4f-Fluorosylnitro-2_{4-[2-(tetrahydrofuranyloxy) ethoxy] 7T Hydrogen p-l-yl}-biphenyl Base ice base &gt; Amino acid tert-butyl ester (Example F4) (9 mg, 1.61 mmol). Obtained a pale brown foam (779 mg). MS (ISP) 530 [(M+H +]; melting point 56-58 ° C. Example L34 (RS)-[5-Amino group | Fluoryl winter (tetrahydrotetram-2-yloxymethyl)_ Biphenyl _4_yl]- -77- This Λ 尺度 week uses the T National Standard (CNS) A4 specification (210 X 297 mm) ——!/---------- —— (Please read the note on the back page first) · • Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1255266 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of invention (75) Aminomethyl The acid tert-butyl ester is prepared from (RS)-[4'-fluoro-5-nitro-2-(tetrahydro-) by reduction with SnCl 2 · 2H? 根据 according to the general procedure L (method b). Triamyl-2-yloxymethyl)-biphenyl-4-yl]-amine methyl acid (Example F5). Obtained an orange solid (1.15 g). mp 139-142. Example L35 (5-Amino-2-cyanomethoxy-4'-fluoro-biphenyl-4-yl)-amine methyl acid, the third-butyr, according to the general procedure L (method b), Reduction of SnCl2 · 2H2 0' from (2-oxymethoxy-4^fluoro-5-nitro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (example) F6) (310 mg, 0.8 mmol). m. m. (:. Example L36 (5-Amino-2-dimethylaminomethyl-4f-fluoro-biphenyl-4-yl)-amine methyl acid tert-butyl ester according to the general procedure L (method b ), from (2-dimethylaminomethyl-4'-fluoro-5-nitro-biphenylmethylene)-amine methyl acid tert-butyl ester by reduction with SnCl 2 · 2Η 2 Ο (Example F7) Obtained as a yellow solid (9·························· Oxygen oxime [4,5-c]p is more than 5-(5-yl)-4f-gas-linked keto-4-yl]-amine methyl benzoate-tert- ing according to the general procedure L (method a) By catalytic hydrogenation with pd/c, from [2-(2,2-dimethyl-tetrahydro-[1,3]dioxosyl[4,5-c]pyrrolylfluoro-78- This paper scale applies to the national standard (CNS) A4 specification (210 X 297 mm) ----,----------Install i I (please read the back note on this page first) : -- Line · 1255266 A7 B7 V. Description of the invention (76) Benz-5-nitrobiphenyl yl]-amine methyl acid third butyl ester (example F8^1 〇 mg ' 1.29 耄 Mo Er) Obtain an off-white foam (578 mg). (Please read the back first) Note on this page) MS (ISP) 444 [(M+H)+]. Example L38 (5-Amino-4'-fluoro-2-methoxy-biphenylyl)-aminomethyl The acid tert-butyl ester is prepared according to the general procedure L (method a) by catalytic hydrogenation with pd/c from (4-fluoro-2-methoxy-5-stone schottyl-biphenyl-4-yl) - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ C (decomposition). Example L39 Amidino-2-(l,4-dioxo-8-nitro-spiro[4.5]indole)-4,-fluoro-biphenyl-4-yl]-amine A The tert-butyl ester of the acid is prepared from [2-(1,4-dioxo-8-nitro-spiro[4.5]癸-8 by catalytic hydrogenation with Pd/C according to the general procedure L (method a)). -yl)-4'-fluoro-5-nitro-biphenyl-4-yl]-amine methyl acid tert-butyl ester (Example F10) (2.4 g, 5.00 mmol). Green solid (2.37 g) MS (ISP) 444 [(M+H)+]. Example L40 Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative (5-Amino-4'-fluoro-2-methyl- Biphenyl)-amine methyl acid third _ 酉 酉 according to the general procedure L (method a), From the catalytic hydrogenation with Pd/C, from (4'-fluoro-2-methyl-5-nitro-biphenyl-4-yl)-amine methyl acid, the third-butanthene (example Fll) ) (560 mg, 1.62 mmol). Obtained as a pale brown solid (512 mg). MS (ISP) 317 [(M+H)+]; mp. Example L41 -79- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Inventive Note (77) (5-Amino-4-tris-butoxycarbonylamino group -4,-Fluoro-biphenyl-2-yloxy)-acetic acid tert-butyl ester according to the general procedure L (method a), via catalytic hydrogenation with Pd/C, from 4-tetra- Butoxycarbonylamino-cardiofluoro-5-nitro-biphenyl-2-yloxy)-acetic acid tert-butyl ester (Example F12) (2.29 g, 4.95 mmol). Obtained a dark blue solid (2.14 g). MS (ISP) 433 [(M+H)+]; mp. 30-33. Example L42 (5-Amino-2-carbenyl-fluoro-biphenyl-4-yl)-amine methyl acid tert-butyl ester according to the general procedure L (method b), via SnCl 2 · 2H 2 0 Reduction, from (2-carbyl-4'-fluoro-5-nitro-biphenylyl)-amine methyl acid tert-butyl ester (Example F13). A pale red solid (544 mg) was obtained. MS (ISP) 337 [(M+H)+]. Example L43 [5-Amino-4'-fluoro-2-(2-methoxy-ethoxy)-biphenyl-4-yl]-amine methyl acid tert-butyl ester according to the general procedure L ( Process a), by catalytic hydrogenation with pd/c, from [4'-fluoro-2-(2-methoxy-ethoxy)-5-decyl-biphenyl-4-yl] - Aminomethyl-tert-butyl ester (Example F14). Obtained as a pale brown solid (1.652 g). MS (ISP) 377 [(M+H)+]. Example L44 [5-Amino-2-(2-tris-butoxy-ethoxy] 4'-fluoro-biphenyl-4-yl]-amine methyl acid butyl butyl ester according to General procedure L (method a), via catalytic hydrogenation with pd/c, -80- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----r----- ----装--- (Please read the notes on the back and then this page) · • Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 B7 V. Invention description (78) ----P- -I--- - - II (Please read the following note on the back page) Prepared from [2-(2-Terti-butoxy-ethoxy) flupros-5-nitro-biphenyl _ 4-Methoxy]-amino acid tert-butyl ester (Example F15). Obtained as a purple solid (547 mg). MS (ESI) 419 [(M+H)+]; Example L45 [5-Amino-41-fluoro-2-(2-keto-oxazolyl-3-yl)-biphenyl-4-yl]-aminomethyl acid tert-butyl ester according to the general procedure L (Method a), via catalytic hydrogenation with Pd/c, from [4^Fluoro-5-nitro-2_(2-keto-j-dis--3-yl)-biphenyl-4 -yl]-aminomethyl acid tert-butyl ester (example F16) (280 mg 67·67 mmol. Obtained as a yellow solid (277 mg). MS (ESI) 388 [(M+H)+]; mp. 210 ° C. Example L46 (5-amino-4'-fluoro-2 -Methoxy-2'-methyl-biphenyl-4-yl)-amine methyl acid _ _ 酉 - - line _ according to the general procedure L (method a), via catalytic hydrogenation with Pd / C The effect was prepared from (4f-fluoro-2-methoxy-2'-methyl-5-nitro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example FH). Obtained a brown solid (588 mg) MS (ISP) 347 [(M+H)+]. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Example L47 (5-Amino-2-tris-butoxy-4f -Fluoro-biphenyl-4-yl)-amine methyl acid, third, butyl, according to the general procedure L (method a), via Pd/C hydrogenation, from (2-second - Butoxy-4'-fluoro-5-nitro-biphenyl-4-yl)-amine methyl acid tricate-butyl ester (Example F18) (1.15 g, 2.84 mmol). Pink solid (747 mg) -81 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Description of invention (79) MS (ISP) 375 [(M+H )]]; melting point 1 39 ° C. Example L48 ----:----------Installation - (Please read the back note on this page first) (5-Amino-2-tris-butoxy-2,-fluoro -biphenyl-4-yl)-amine methyl acid tert-butyl ester according to the general procedure L (method a), via catalytic hydrogenation with Pd/C, from (2-tris-butoxy- 2'-Fluoro-5-nitro-biphenyl-4-yl)-amine methyl acid second-butyl ester (Example F19) (930 mg, 2.3 mmol). Obtained a pink solid (649 mg). MS (ISP) 375 [(M+H)+]; m.p. 13 (TC). </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Piperidine-2-yloxy)-tetrahydropyrrole small group]-biphenylyl yl}}-aminomethyl acid tert-butyl ester according to the general procedure L (method a), via catalytic hydrogenation with Pd/C Function, from (RS)-{4,-fluoro-5-nitro-2-[(R)-3_(W-hydro-m--2-yloxy)-tetrahydropyrrole small group]-linked Phenyl-4-yl}-amine methyl acid tert-butyl ester (Example F20). Obtained a dark green solid (852 mg).---MS (ESI) 472 [(M+H)+]. L50 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed (5-Aminofluoro-2-methoxy-biphenyl-4-yl)-amine methyl acid tert-butyl ester according to the general procedure L (Method a ), by catalytic hydrogenation with Pd/C, from (2'-fluoro-2-methoxy-5-nitro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example F21) (649 mg, 1.79 mmol). m. m. m. Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 ----- B 7 _ V. Description of the invention (80) [5-Amino-2-(1,4-dioxo-8-nitro-spiro) oxime)_2,_fluoroindole phenyl phenyl]-aminomethyl The acid tert-butyl ester is prepared according to the general procedure L (method a) by catalytic hydrogenation with pd/c from 〇(1,4-dioxo-8-nitro-spiro[4.5]癸-cardoyl)_2L Fluoryl J nitro, phenyl phenyl] amino acid tert-butyl ester (Example F22) (U9 g, 2.94 mmol). Obtained pale beige solid (1.01 g). MS (ISP) 444 [(Μ+Η)+ ]; melting point 198. (:. Example L52 (5-month female base-2', 5f-difluoro-2-methoxy-biphenylyl ylaminomethyl acid third -butyl ester according to the general procedure L (method a), via catalytic hydrogenation with pd/c, from (2',5'-difluoro-2-methoxy-5-nitro-biphenylyl yl _ Amino acid methyl butyl butyl ester (C3) (1.05 g, 2.76 mmol). Obtained as a beige solid (618 mg). MS (ISN) 349 [(Μ-ΗΠ; melting point 144 ° C Example L53 [5-Amino-2'-fluoro-2-(2-methoxy-ethoxy)-biphenyl-4-yl]-amino acid tert-butyl ester according to the general procedure L (method a), via catalytic hydrogenation with Pd/C, From [2f-Fluoro-2-(2-methoxy-ethoxy)-nitro-biphenylmethylene]-amine methyl acid tert-butyl ester (Example F24). Obtained a purple solid (2·581 g). Example L54 (RS)-Amidino-2'-fluoro-2-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yl]-amine methyl acid - Butyl ester according to the general procedure L· (Method b), via the reduction of SnCl2 · 2Η2 - -83- This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the back note first) Matters again on this page) - Packing ------ Order -------: Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 ------- - B7_____ V. Invention Description (81) 'Prepared from (RS)-[2'_fluoro-5-nitro-2-(tetrahydro-ttan-2-yloxymethyl)-biphenylyl]-aminomethyl Acidic third-butyl ester (Example F25). Obtain a yellow liquid g). MS (ISP) 439 [(M+Na)+ ]. Example L55 [5-feyl-2-fluoro-2-(4-methoxy-yloxy)-biphenyl]-amino-methyl-acid tri-butyl ester according to the general procedure L (method b ), by the reduction of SnCl 2 · 2H 2 0 'from [2f-fluoro-2-(4-methoxyoxy)-5-nitro-biphenylyl)-m-methyl acid - Butyl ester (Example F25) (0.90 g, 1.92 mmol). Obtained a beige solid (719 mg). MS (ISP) 439 [(M+H)+]. Example L56 (5-Amino-2-tris-butoxy-2,5,-difluoro-biphenyl-4-yl)-amine methyl acid third_ 酉 酉 according to the general procedure L (method a) from (2-tris-butoxydifluoro-5-nitro-biphenylyl)-amine methyl acid tert-butyl ester via catalytic hydrogenation with Pd/C (example) F27). Amorphous gray-blue material (2 37 g) was obtained. MS (ISP) 393 [(M+H)+]. Example L57 [2-Amino-5-t-butoxy-4-(4-fluorophenylethynyl)-phenyl]-amine methyl acid tert-butyl ester according to the general procedure L (Method b) , by [5-tris-butoxy-4-(4-fluorophenylethynyl)-2-nitro-phenyl]-amine A-84-benz by reduction with SnCl2 · 2H20 The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) -----·---------Install--- (Please read the notes on the back and then 6 pages) Order··-Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (82) Acid-terminated third-butyl ester (example K26) (649 Mg, 1.51 millimoles). Obtained as a pale yellow solid (410 mg). MS (ISP) 399 [(M+H)+] ; J: Tolerance point 183. (: The following examples are for 3-aryl-3-keto-propionic acid ethyl ester or third-butyl vinegar (general formula

Preparation of Vila), which is the structural unit for the synthesis of the compound as a standard (Synthesis Scheme H): General Procedure Μ Method a) Preparation of 3-aryl keto-ethyl propionate or tert-butyl ester 3 - aryl-3·-keto-ethyl propionate or tri-butyl ester, according to the Synthetic Journal 1993, 290 'automated aromatized aromatic and malonate or third-butyric acid unsalted salt [ CAS-numbers 6148-64-7 and 75486-33-8] with Et3N and MgCl2, in CH3 CN 'at 0 C to 23 C. The free aryl carboxylic acid is used in this reaction, and it is activated by treatment with ethyl chloroformate in THF/C H3 CN at 0 ° C before reaction with malonic acid salt. Process b) Preparation of 3-aryl-3-keto-propionic acid tert-butyl ester, or 3-aryl-3-keto-propionic acid tert-butyl ester, according to the Synthetic Journal 1985, 45, Prepared in the presence of a third-butyric acid oxide via a third-butyl acetate surface [via a third-butyl vinegar acetate treated with diisopropylamine in THF at -78 ° C in THF Processing, from aryl methyl ester or ethyl ester. If the product contains residual starting material after treatment, it can be removed by selective saponification using THF/Me〇H/ Η2〇 at 23 Torr. Process c) Preparation of 3-aryl-3-keto-propionic acid 3-aryl-3-keto-propionic acid, according to Synth·c〇mmun·1985, 15, 1〇39 (Method cl) 'Use E1:3 N with LiBr in CH; 3 CN, at 〇 °C, or according to Synthetic-85- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) ---- K----------装--- (Please read the note on the back page first.) - Line · 1255266 A7 B7 I, invention description (83) Journal 1979, 787 (method c2), use n-BuLi, in the ether, at 40 ° C to 〇 ° C, from the gasification of lanthanum and bis(trimethyldecyl) malonate. Example Ml 3-keto-3-(3-[l,2,4]di-p--4-yl-phenyl)-propionic acid ethyl hydrazine R0-71-2790/000 Ο

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, 0~ according to the general procedure 方法 (method a), activated by ethyl chloroformate / Et3 oxime, and using Et3N and MgCl2, in CH3 CN, with ethyl malonate Potassium salt reaction from 3-[1,2,4]triazol-4-ylbenzoic acid [r〇7i] 432/000 in acetic acid at 120 ° C via 3-aminophenylhydrazine The acid is prepared by reacting with hydrazine hydrate and triethyl orthoformate]. Obtained as a white solid (5.74 g). MS(EI) 259 (M+) 〇 Example M2 3-keto-3-(3-[1,2,3]3.sodium-1-yl-phenyl)-propionic acid B. Method a) is carried out by reacting with ethyl chloroantimonate / Et3N, and using Et3N and MgCl2 in CH3CN, reacting with potassium malonate potassium salt, from 3-[1,2,3]triazole Base-benzoic acid [RO-71-3703/000, via 3-azidobenzoic acid methyl ester [CAS-No. 93066-93-4] in trimethyldecyl acetylene reflux followed by aqueous NaOH in reflux Made by saponification in EtOH]. Obtained as a pale yellow solid (2.22 g). MS (EI) 259 (M+); mp. Example M3 3-(3-cyano-phenyl)-3-keto-propionic acid tert-butyl ester----b---------- loaded i I (please read the back Precautions on this page) ·. --Line - -86- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Invention description (according to the general procedure Μ (Method b) Obtained from methyl 3-cyanobenzoate [CAS-No. 13531-48-1] by treatment with lithium tri-butyl acetate. Obtained as a pale brown oily semi-solid. MS (EI) 245 (M+) 〇 Example M4 3-(3-tert-l-yl-phenyl-phenyl)-3-i-iso-propionic acid, third, butyl, according to the general procedure 方法 (method b), via treatment with lithium tributyl-butyl acetate Prepared from 3-(1H-imidazolyl)benzoic acid methyl [from 3-(1]9-imidazolyl)benzoic acid (J. Med. Chem. 1987, 30, 1342; CAS-No. [108035] -47-8], obtained by refluxing in concentrated H2S04/Me0H]. Obtained tan oil. MS (ISP) 287 [(M+H)+] 〇 Example M5 3-(2-flavor. -ρ 咬-4-yl)-3-mercapto-propionic acid _ 酉 酉 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据-Base - different from the test Hydrochloride [via 2-gas group is different from acid-testing third-butyl ester with imidazole and NaH in DMF at 8 〇. (: lower reaction, treatment with formic acid at 50 °c, and with two gas Ruthenium sulfoxide was reacted in toluene at 1 ° C to prepare a potassium salt of tert-butyl malonate. A brown solid (1 〇 · 8 g) was obtained. MS (EI) 287 ( M+); melting point 80 ° C (decomposition). tjH M6 3-indolyl-3-(3-[1,2,4]dident-1-yl-phenyl)-propionic acid General Procedure Μ (Method b), prepared by treatment with a third-butyl acetate clock, from 3-[1,2,4]triazole-based-benzoic acid-methyl [CAS-No. 167626_27-9]. 87- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ----»---------^ - II (Please read the notes on the back page again) 1 ·················································································································· 〇 Example M7 3-[3-(4-Methyl-myin-1-yl)-phenyl]-3-indolyl-propionic acid Third-butyr Procedure Μ (Method b), prepared from 3-(4-methyl-imidazolyl)-benzoic acid methyl ester [RO-69-6483/000, via J. Med Chem. 1987, 30, 1342, from 3-isothiocyanabenzoic acid and 2-aminopropionaldehyde dimethyl acetal, followed by reflux in concentrated H2S04/Me0H from the corresponding acid]. Obtained a tan oil (10.69 g). MS (EI) 300 (M+). Example M8 3-[3-(2-Methyl-imidazol-1-yl)-phenyl]-3-keto-propionic acid tert-butyl ester according to the general procedure 方法 (Method b), via the third- Treatment with lithium butyl acetate from ethyl 3-(2-methyl-imidazolyl)-benzoate [RO-69-7480/000 via ethyl 3-aminobenzoate and acetimidate Ethyl ester hydrochloride, reacted in EtOH at 0 ° C, with amino acetaldehyde diethyl acetal, directly treated in EtOH at 23 ° C, followed by addition of concentrated H 2 S04 and reflux ]. Obtained brown oil (9.66 g). MS (ISN) 299 [(MH:T]. Example M9 3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl] keto-propionic acid tert-butyl ester according to General procedure Μ (Method b), prepared from 3-(2,4-dimercapto-imidazol-1-yl)-benzoic acid ethyl ester [RO-71-0583/ 000, via ethyl 3-aminobenzoate and ethyl acetimidate hydrochloride, reacted in EtOH at 0 ° C with 2-aminopropionic acid dimethyl acetal in EtOH , -88- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ----l·---------Installation - (Please read the note on the back first) Page) · _ -- Line · 1255266 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Β 7 Β 7 V. Inventive Note (86) Directly treated at 23 ° C, followed by adding concentrated h2S04 &amp; reflux to make]. Obtained a tan Oil (6.00 g) MS (ISN) 313 [(MH: T]. Example M10 3-(2-Cyano-pyridin-4-yl)-3-one-propionic acid tert-butyl ester according to the general procedure Μ (Method b), prepared from ethyl 2-cyano-isonicotinate [CAS-No. 58481-14-4] by treatment with lithium-tert-butyl acetate. Solid (7.70 g) MS (ISN) 245 [(MH)-] 〇 M M M M M M 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- Propionic acid third-butyr is prepared according to the general procedure 方法 (method b), by treatment with tri-butyllithium acetate, from 3-[1,2,4]triazol-4-yl-benzoic acid methyl ester [ Obtained by 3- 3 -aminobenzoic acid with hydrazine hydrate and triethyl orthoformate in acetic acid at 12 ° C, followed by concentration in S 〇 4, esterified in refluxing MeOH. Light yellow gum (870 mg) MS (ISN) 286 [(M-Η)-]. Example M12 3-[3-(2-methoxymethylglycosyl-sodium-1-yl)·木基]_3 _mercapto-propionic acid third-butyr is prepared according to the general procedure 方法 (method b), by treatment with tri-butyllithium acetate, from 3-(2-methoxysulfonylthio-small-small base) _benzoic acid ethyl ester [ester-transfer H2S〇4, in EtOH, 3-(2-methoxymethylthio-imidazolyl)-benzoic acid [CAS-No. 108035-46-7], Then, it was prepared by treating with methyl methyl ether and NaH in THF/DMF. Obtained orange oil (1.82 g). ----r--------- (Please read the notes on the back first) This page) = I - Line -89-

I255266 A7 _B7____ V. INSTRUCTIONS (87) MS(EI) 362 (M+). Example M13 3-[3·(2-Methylthio-taste.sodium-1-yl)-mungyl]-3-mercapto-propionic acid 2nd-butylpyridine according to the general procedure 方法 (Method b) Treatment with lithium tris-butyl acetate from 3-(2-methylthio-imidazol-1-yl)-benzoic acid ethyl ester [via concentrated H2 S04 in EtOH, 3-(2-methoxy) Methylthio-imidazolium)-benzoic acid [CAS-No. 108035-46-7] was esterified, followed by treatment with methane iodide and NaH in THF/DMF]. Obtained light brown oil (4.41 g). MS (ISP) 333 [(M+H)+] 〇 Example M14 3-[3-(3-Methyl-isoxazol-5-yl)-phenyl]-3- keto-propionic acid - Butyl ester is prepared according to the general procedure 方法 (Method b) from 3-(3-methyl-isoxazol-5-yl)-benzoic acid ethyl ester via a third-butyl acetate clock [according to Tetrahedron 1984, 40, 2985-2988, via a mixture of ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] with NCS, cesium acetate, Et3 N and a catalytic amount of π-pyridine, in CHC13 at 50° Made under the reaction of C]. Obtained as a yellow solid (2.54 g). MS (ISP) 302 [(M+H)+]; mp. 50-56. Example M15 3-keto-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl hydrazine according to the general procedure 方法 (method a), via ethyl chloroformate / called n, and using Et3 N and MgCl2 'in CH3 CN, reacted with ethyl malonate potassium salt' from 3-tetrapyridin-1-yl-benzoic acid [CAS-No. 204196-80-5]. Obtained as a pale yellow solid (211 mg). MS (EI) 260 (M+). -90- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 public f - -----.--------- loaded--- (please read the notes on the back first) On this page) · : Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 Invention Description (88) Example M16 3-(3-Chloro-thiophen-2-yl) Ethyl-3-keto-propionate is prepared according to the general procedure 方法 (Method a) using Et3N and MgCl2 in CH3CN via a reaction with potassium malonate to form 3-chloro-2 - thiophene guanidine [CAS-No. 86427-02-3]. Obtained brown oil (6.84 g) MS (EI) 232 (M+) and 234 [(M+2f]. Example M17 3-(5-Cyano- The tert-butyl-2-yl)-3-keto-propionic acid tert-butyl ester was prepared from 5-cyano-2-thiophene according to the general procedure 方法 (Method b) by treatment with lithium-tert-butyl acetate. Ethyl carboxylate [CAS-No. 67808-35-9] Obtained as a yellow solid (6-66 g). MS (EI) 251 (M+); mp. 78 ° C. Example M18 3-(5-冬基)-3-酉同基-丙乙酉 According to the general procedure 方法 (Method a), using Et3N and MgCl2, in CH3 CN, via Ethyl diacid ethyl ester reaction, prepared from 5-cyano-2-fluoro-benzhydryl chloride [via S〇C12, catalyst DMF in toluene, treated at 80 ° C, from its corresponding Acid [CAS-No. 146328-87-2]] gave a pale-yellow solid (3.85 g). MS (EI) 235 (M+); mp. 55-60 ° C. Example M19 3-(2- 1-Base-p tomb σ all-4-yl)-3-indolyl-propionyl-di-pyrene is prepared according to the general procedure 方法 (method b) by treatment with a third-butyl lithium acetate from 2-imidazole Small base-carbazole-4-carboxylic acid ethyl ester [CAS-No. 256420-32-3]. Obtained orange oil (12.0 g) -91 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----^----------Install i I (please read the note on the back page first) Order 1255266 A7 _ B7__ V. Invention description (89) Example M20 3- [2-(4-Methyl-mithio-1-yl)-Farunary 4-yl]_3·keto-propionic acid Third-Dining is based on the general procedure 方法 (Method b), via the third _ Lithium acetate-based treatment, prepared from 2-(4-methyl-imidazolidinyl)-thiazole carboxylic acid ethyl ester [by the following synthesis sequence. 1·) NaH, 2-isosulfuryl-i, i-di Methoxy _ propyl, d Mf, 23 ° C; 2.) H2S04 aqueous solution, reflux; 3.) Et0H, concentrated h2S〇4, 23χ: ; 4) 3〇0〇Η: 〇2, HOAc, 23 C, from 2_amine plug π 坐 酸 酸 酉 酉 酉 [256420-32-3])]. Obtained brown oil (8.73 g). MS(EI) 307 (M+) 〇 Example M21 3-[3-(1-Methyl-1H-miso-2-yl)-phenyl]-3-keto-propionic acid Third-butyr Procedure Μ (Method b), prepared by treatment with a third-butyl acetate clock, from ethyl 3-(1-methyl-1H-imidazol-2-yl)benzoate [CAS-No. 168422-44-4] . A pale yellow liquid (1.26 g) was obtained. MS (ISP) 301.3 [(M+H)+]. The following examples relate to the preparation of 6-aryl-2,2-dimethyl-[1,3]dioxanthene (Formula VII) as a structural unit for the synthesis of the compound Composite illustration H):

General procedure for the preparation of N 6-aryl-2,2-dimethyl-[1,3]dioxanthene-4-one a) 6-aryl-2,2-dimethyl-[1 , 3] Dioxordecene-4-one, according to Chem. Pharm. Bull. 1983, 31, 1896, at 23 ° C in isopropyl acetate, from 3-aryl-3- The keto-propionic acid is in a concentrated amount of h2S04 or trifluoroacetic acid (TFA). Apply the most -92 - paper size to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). I--1 II (please read the back note first on this page) -ir-ά. --Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 V. Inventive Note (9Q) The product was purified by column chromatography using hexane / Et〇Ac. Method b) 6-aryl-2,2-dimethyl-[1,3]dioxanthene ketone, according to Lett. 1998, 39, 2253, at 23 C, a mixture of tfa and acetone The third-butyl ester of 3-aryl keto-propionic acid was prepared by treatment with difluoroacetic anhydride (TFAA). If necessary, the final product was purified by column chromatography using hexane / EtOAc. Example N1 2,2-Dimethyl-6-thiophen-2-yl-[1,3]dioxanthene ketone 3·keto-3-thiophen-2-yl-propionic acid, according to the general procedure M (method c2), using n-BuLi (1.6 M in hexane, 62. 5 ml) in ether, said. c to 〇. The oxime was prepared from thiophene-2-carbonyl chloride (5.3 ml, 50 mmol) with bis(trimethyldecyl) oxalate (25.6 ml, 1 mM millimolar). According to the general procedure 方 (method a), the crude material (78 g) was transferred to the oxime compound by stirring in isopropenyl acetate and TFA. Obtained a yellow solid (4 09 g). MS (EI) 210 (M+); mp 42 (dec.). Example N2 6-(3-Chloro-pyrimidin-2-yl)-2,2-dimethyl-[U]dioxolene oxime 3-(3-chloro-pyrimen-2-yl) G-iso-propionic acid, according to the general procedure M (method cl) 'Use Ey N (12.65 ml, 90.7 mmol) and LiBr (3 53 g, 47·5 mmol) in CH3 CN, in 〇 . (: Manufactured from 3-gas-cetobutanyl carbonyl (7.82 g, 43. 2 mmol) and bis(trimethyldecyl) oxalate (ι 6 ml, 45 4 mmol). According to the general procedure 方法 (Method a), the crude material (5.69 g) was converted to the title compound by stirring in isopropyl acetate and concentrated. ____-93- This paper scale applies to the _ home standard (CNS) A4 specification ( 21Q χχ公发) ----^----------装--- (Please read the back note on this page first) _ Line · 1255266 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7__ V. Inventive Note (91) Obtained an orange solid (2.3 g) MS (EI) 244 (M+) and 246 [(M+2)+]; mp 88-89 ° C (decomposition). Example N3 6 -(3-cyano-soul-2-yl)-2,2·dimethyl-[1,3]dioxanthrone-ketone 3-(3-cyano-p-cephen-2-yl) )-3-keto-propionic acid, according to the general procedure μ (method cl) 'Use Et3N (413⁄4: liter, 295.4 millimoles) with LiBr (13.5 grams, 154.7 millimoles) in CH3 CN 'at 0 Made from 3-cyano-farophene-2-carbonyl chloride (24.33 g, 140.6 mmol) and bis(trimethyldecane) malonate at °C ) g (38 ml, 147.7 mol). According to the general procedure n (method a), the crude material (24·8 g) was changed to the title by stirring in the wrong acid isopropenyl ester and concentrated H^SO4. Compound: Obtained as an orange solid (5.6 g). MS ( s) 235 ( Μ+); melting point 116-12 CTC (decomposition). Example N4 3-(2,2-dimethyl-6-keto-6H-[ 1,3]dioxantemene-4·«yl)-benzonitrile 3-(3-cyano-phenyl)-3-keto-propionic acid, according to the general procedure M (method c2) n-BuLi (1.6M in hexane, 6.25 ml) in ether, _6 (rc to below) self-gasification 3-cyanobenzoic (828 mg, 5 mmol) with malonic acid Bis(trimethyldecyl) vinegar (2.56 ml, 10 mmol). The crude material (1.04 g) was converted to the title compound by stirring in EtOAc (EtOAc) Obtained as a pale-yellow solid (m.p. 8g). MS (ESI) 229 (M+); mp. )+,3]dioxanthene ketone 3-keto oxime-(3-di-methyl-phenyl)-propionic acid, according to general Order μ (square-94- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----Ρ---------装--- (Please read the back Note this page) Order: :Line - 1255266

V. Description of the invention (92) Method cl), using Et3N (20 ml, 142 mmol) and LiBr (646 g, 744 亳 Mo) in CHsCN, at 〇 ° C, self-gasification Benzobenzidine (ω pen liter, 67.6 moles) and bis(trimethylsulfonyl) malonate (丨8·2 ml, 71 mmol). The crude material (7 g of the obtained 154 g) was converted to the title compound by stirring in EtOAc (EtOAc). Obtained as a pale yellow solid (5 3 g). MS (EI) 272 (M+); mp. 77-78 (dec.). Example N6 6-(3-Phenylphenyl)-2,2-dimethyl-[1,3]dioxolene-4-ylketone 3-(3-phenylphenyl)-3-keto-propanyl Acid, according to the general procedure μ (method ci), using EtsN (25 ml, 180 mmol) and LiBr (8.19 g, 94·3 mmol) in C^CN, at 〇 ° C 3_ gas-based benzamidine (11 ml, 85·7 mmol) and bis(trimethyldecyl) malonate (23. 〇 ml, 9 〇〇 millimolar). The crude material (17.1 g) was converted to the title compound by stirring in EtOAc EtOAc (EtOAc). A tan solid (8.0 g) was obtained. MS (EI) 238 (M+) and 240 [(M+2)+]; mp. 87-88 ° C (dec.). Example N7 6-(3-iodophenyl)-2,2-dimethyl-[1,3]dioxolene-4-one 3-(3-iodophenyl) keto-propionic acid, According to the general procedure 方法 (method cl), using Et3N (23 ml, 165.5 mmol) and LiBr (7.54 g, 86.7 mmol) in CH3 CN, self-gasification 3-iodo group at 〇 ° C Benzoquinone (21.0 g, 78.8 mmol) with bis(trimethyldecyl)malonate (21.0 mL, 82.8 mmol). According to the general procedure N (method a)., apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm) via the isopropenyl acetate and concentrated-95- paper scales I-------- ----装--- (Please read the notes on the back and then this page). Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266

V. INSTRUCTION INSTRUCTION (93) Stir in ΗΘ〇4 to convert the crude material (2i.9 g) to the title compound. A yellow solid (9.6 g) was obtained. ----:----------Installation—(Please read the note on the back page first) MS (EI) 330 (M+); Melting point 79-80°C (decomposition). Example N8 2,2-Dimethyl(3-trifluoromethoxy-phenyl)^]dioxanthine scorpion with 3-keto-3-(3-difluoromethoxy-phenyl - propionic acid, according to the general procedure method cl), using with LiBr, in 〇 ^ (^, here from chlorinated 3-difluoromethoxybenzopyrene and malonic acid bis (trimethyl decane) The base was converted to the title compound by stirring in EtOAc EtOAc (EtOAc) EtOAc (EtOAc) Melting point 49-54 ° C (decomposition). Example N9 2,2·-methyl each p than phospho-4-yl-[1,3]dioxanthone-line · according to the general procedure N (method b ), prepared by treatment with acetone, TFA and TFAA, from 3-keto-3-pyridin-4-yl-propionic acid [according to antibiotic journal 1978, 31, 1245 'in DMF, at 120 C from 4-C) B. 咐 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . -1-yl-phenyl)-2,2-dimethyl-[1,3]dioxolene-4-one 3-(3-imidazol-1-yl-phenyl)-3-one -propionic acid, according to the general procedure 方法 (method cl), using Et3N and LiBr, in CH3 CN, at 〇 ° C, self-vaporizing Η 1Η-imidazol-1-yl) benzamidine hydrochloride [via SOCl·^ treatment of 3-(1Η-imidazole small group) benzoic acid (J· Med·Chem· 1987, 30, 1342; CAS·No. [108035-47-8]] -96 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) '

1255266 V. Description of the invention (94) with bis(trimethyldecyl) vinegar. According to the general procedure! ^(Method a), the crude material was converted to the title compound by stirring in isopropyl acetate and concentrated H.sub.2. Obtained an orange semi-solid (617 mg). MS (EI) 270 (M+). Example Nil 2.2-Dimethyl-6-(3-methoxy-phenyl)-[ι,3]dioxolene-4-butanone 3-(3-methoxy-phenyl)-3- Keto-propionic acid, according to the general procedure % (method cl), using Et3N (17.7 ml, 127 mmol) and UBr (5.77 g, 66·4 mmol) in CHfN at 〇 ° C Self-gasification of 3-methoxybenzothymidine (1 〇·3 g, 60.4 Amol) and bis(trimethyldecyl) malonate (16. 2 ml, 63.4 mmol). The crude material (6.38 g) was converted to the title compound by stirring in EtOAc EtOAc (EtOAc). Obtained yellow oil (640 mg). MS (ISP) 235 [(M+H)+] and 252 [(M+NH4)+]. Example N12 2.2-Dimethyl-6·(3-nitro-phenyl)-[ι,3]dioxolene-4-one 3-(3-nitro-phenyl) keto-propyl Acidic third-butyl ester, according to the general procedure 方法 (method a), using Et3N (4.5 ml, 32.2 mmol) and MgCl2 (3.48 g, 36.52 mmol) in CH3 CN from chlorinated 3-nitrate Benzobenzamide (2.71 g, 14.6 mmol). Potassium tert-butylate malonate (6 g, 3 〇〇 millimolar). The crude material (3.88 g) was converted to the title compound by stirring in TFA /EtOAc and EtOAc. Obtained a yellow solid (2.76 g). MS (EI) 249 (M+); m.p. - -97- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 public) ---J----------Install i I (please read the back note first) Page) · Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Invention Description (95) Example N13 ----l·---------Installation - (Please read the back first Precautions on this page) 2.2-Dimethyl-6-(3-[1,2,4]tris-l-yl-phenyl)_[丨,3]dioxene decyl ketone 3- Ketopropyl-3-(3-[1,2,4]triazole small-phenyl)-propionic acid tert-butyl vinegar [r〇_69_ 3506/000] according to the general procedure 方法 (method b), It was prepared from 3-[1,2,4]triazol-1-yl-benzoic acid methyl ester [CAS-No. 167626_27_9] by treatment with a third butyl acetate. According to the general procedure N (Method b), it was prepared by stirring in TFA / acetone and TFAA (Example M6). Obtained a yellow solid (539 mg). MS (EI) 271 (M+) 〇 Example N14 6-(2-Min-1-yl-p-preo-4-yl)-2,2-dimethyl-[1,3]dioxane The ketone was prepared according to the general procedure N (Method b) by stirring in TFA/acetone and butyl FAA from 3-(2-flavor.spin-1-yl-p-pred-4-yl)-3-indenyl - Propionic acid third - butyl g (example M5). A brown solid (10.8 g) was obtained. MS (EI) 271 (M+); m.p. · _ line - Example N15 2.2-Dimethyl-6-[3-(2-methyl-imidazolyl)-phenyl]-[1,3]dioxolene-4-one according to the general procedure N (Method b), printed in TFA / Acetone and TFAA, Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives, printed, produced from 3-[3-(2.methyl-flavor. sit-1-yl)-wood base ]-3-mercapto-propionic acid third-butyr (example M8). Obtained as a beige solid (2.13 g). MS (EI) 284 (M+); mp. Example N16 4-(2,2,Dimethylhexanyl-6H-[1,3]dioxolyn-4-yl)-pyridine-2-carbonitrile according to General Procedure N (Method b) Stirring in TFA / acetone and TFAA from 3-(2-cyano-pyridin-4-yl)-3-keto-propionic acid tert-butyl ester (Example M10) -98- This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) 1255266 A7

V. Description of invention (96). A brown solid (3.30 g) was obtained. MS (EI) 230 (M+); mp. The following examples relate to the preparation of 4, bistriaryl-1,3-dihydrophenylhydrazone [bHM]dioxepin-2-one in a pure manner on a regioisomer, individually 4 aryl aryl Ethyl ethynyl-1,3-dihydrophenylhydrazine [b][1,4]dioxanone and 8•arylindoleyl aryldihydrophenylhydrazine[b][l,4]dioxin Gyne-2-one (Synthesis Scheme: General Procedure 经由 via (2. Amino '^aryl-phenyl)-Amino-Mercaptoic Acid Tri-Butyl Ester with 3-Aryl-3-keto-Pro Preparation of {2-[3-aryl-3-keto, propyl ketone) by the reaction of ethyl acetate or 6-aryl-2,2-dimethyl-[1,3]dioxanthene Amino]+aryl-phenyl-b-aminomethyl-tert-butyl ester; also via 2-nitropanearyl-phenylamine and aryl-2,2-dimethyl-[[,3] Preparation of aryl-indole-(2-nitro-4-yl-phenyl)-3-keto-propanamide to give 2-amino-4-aryl- Phenyl)-amine methyl acid third-butyl ester or 2-nitrohaaryl-aniline (1_0 t-mole) with excess (1·2-15 mmol) aryl aryl ketone-propionic acid B Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -----:--------- loaded--- (please read the back of the note first) @@)): Line ester [According to Synthetic Journal 1993, 290, using Et3 Ν and MgCl2, in CH3 CN, at 23 C, self-gasification of lanthanum and ethyl malonate potassium salt] or 6-fang a mixture of benzyl-2,2-dimethyl-[1,3]dioxanthene ketone, refluxed in toluene (8 ml) until tlc showed complete consumption of the amine. The solution was cooled to 23 Torr, then the product It is substantially crystallized (in the case where crystallization does not appear, by adding pits to cause &lt;). The solid is filtered, washed with ether or ether/hexane mixture 'and dried in the air, and {2- [3-aryl keto-propionylamino]-4-aryl-phenylamine methyl acid tert-butyl ester or aryl (2-nitro-t-arylphenyl) ___ 99- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public) &quot; !255266

^ Female, it is used directly in the next step, or if necessary, it is recrystallized or purified by column chromatography. /, tjH 01 {2 ano-cyano-phenyl>3, kefosylamine 破•cracking _5_thiofenofin _ 4-yl-phenyl}-amine methyl acid third- Ding vinegar according to the general procedure 〇, u (2m Qiji _5_ 代代福福 &lt;_4_ phenyl phenylamine methyl acid third-butyl vinegar (example L1) (653 mg, 15 millimoles) ^ 3 · (2,2^methyl_6-keto-- 1,3): oxoquinone-benzonitrile (example N4) (690 g, 2.25 mmol). Obtained a yellow solid ( 629 mg) MS (ISP) 607 [(M+H)+] 〇 Example 02 {2-[3·(3-Cyano-phenyl keto-propionylamino) ice iodophorronate ice The base _ phenyl}-amine methyl acid third _ 酉 酉 according to the general procedure 0, from (2_amino-4-iodo-5-morpholine ice-phenyl)-amine methyl acid Tri-butyl ester (Example L2) (690 mg, 165 mmol) and hydrazine (2,2-monomethyl-6-keto-6H-[1,3]dioxol-4-yl)- Benzoonitrile (Example N4) (566 mg, 2.47 mmol) afforded an orange solid (523 mg). MS (ESI) 591 [(M+H)+] and 613 [(M+Na)+]. Example 〇3 {2-Alkyl-5-[3-(3-cyano-phenyl)-3-keto-propyl-arylamino]-biphenyl-4-yl}-amine methyl acid three- Butyl ester was prepared according to the general procedure from (3-amino-2-methyl-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example L6) (652 mg, 2.05 mmol) With 3-(2,2-dimethylglycosyl-6H-[1,3]dioxanthene)-benzonitrile (Example N4) (564 mg, 2.46 100- this paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) -----I I------ Install i I (Please read the back note before this page) -Jr-a· :Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Invention Description (98) Miller) Obtained off-white solid (725 mg). -----1--------- -- (Please read the notes on the back and then on this page) MS (ISN) 488 [(M-Η)· ] 〇Example〇4 [2-[3-(3-Cyano-phenyl)-3 Base-propionylamino]-5-(2-dimethylamino-ethylthio)-4-phenylethyl-phenyl]-aminomethyl acid tert-butyl ester according to the general procedure 0, Made from [2-amino-5-(2-dimethylamino-ethylthio)-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester (Example L8) (206 mg , 0.5 mM) and 3-(2,2-dimethyl-6-keto-6H-[1,3] Lu won oxygen-4-yl) - benzoic months cream (Example N4) (138 mg, 0.6 mmol). Obtained a yellow solid (210 mg). MS (ISP) 583 [(M+H)+]; mp. Example 05 {5-Terti-butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3-keto-propionylamino]- 2-phenylethylidene-benzene Thio]-methyl acetate: line - according to the general procedure, from (4-amino-5-tris-butoxycarbonylamino-2-phenylethynyl-phenylthio)-methyl acetate ( Example L9) (534 mg, 1.3 mmol) with 3-(2,2-dimethyl-6-keto-6H-[1,3]dioxol-4-yl)-benzonitrile (Example N4) (358 mg, 1.56 mmol). Yellow foam (457 mg) was obtained. MS (ISP) 584 [(M+H)+ ], 601[(M+NH4)+ ] and 605 [(M+Na)+ ]; Melting Point 69-73 °C ° Example 06 {5-Terti-butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3-keto-propenylamino]-2-phenylethynyl-benzene Methyl acetate - methyl acetate (4-amino-5-tris-butoxycarbonylamino-2-phenylethynylphenyl)-methyl acetate (Example L10) (721) Mg, 2.0 millimoles) and -101 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) J255266 A7 V. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Description (99) 3 -(2,2-Dimethyl-6-keto-6H-[1,3]dioxol-4-yl)-benzonitrile (Example N4) (550 mg, 2.4 mmol). Obtained as a pale yellow solid (886 mg). MS (ISP) 552 [(M+H)+] and 569 [(M+NH4) dec. Example 07 [2-[3-(3-Cyano-phenyl) keto-propionylamino]-5-(2-methoxy-ethoxy)tolylethynyl-phenyl] -Aminomethyl 3-butyrate is prepared according to the general procedure 0, from guanamido-5-(2-methoxy-ethoxy)-4-phenylethylidene-phenyl]-aminomethyl Acid tri-butyl ester (Example L11) (415 mg, 1.09 mmol) and 3·(2,2-dimethyl-6-keto-6H-[1,3]dioxane-4 -yl)-benzonitrile (Example N4) (373 mg, 1.63 mmol). Obtained as a pale yellow solid (137 mg). MS (ISP) 554 [(M+H)+], 571 [(M+NH4)+] and 576 [(M+Na)+]; mp 175-176 〇C 〇 Example 08 {2-[3-( 3-cyano-phenyl)-3-g-iso-propionylamino]5-methoxy-4-phenylethynylphenyl}-aminomethyl-tert-butyl ester Procedure 0, made from (2-amino-5-nonoxyphenylphenylethynyl-phenyl)-amine methyl acid tert-butyl ester (Example L12) (338 mg, 1·〇 mmol) With 3_(2,2-dimethyl-6-keto-6Η-[1,3]dioxanthene-4-yl)-benzonitrile (Example Ν4) (252 mg, U mmol) . Obtained as a yellow solid (388 mg). MS (ISP) 510 [(Μ+Η)+ ], 527 [(Μ+ΝΗ4)+ ] and 532 [(M+Na)+]; melting point 169. (:. Example 〇9 5-Terve-butoxycarbonylamino-4-[3-(3-cyano-phenyl)oxanyl-propionylamino]_ 2-phenylethynyl-benzene Methyl formate is prepared according to the general procedure 4- 'from 4-amino-5-t-butoxycarbonylaminophenyl 102- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -- --l·---------Install i — (Please read the back note on this page first) Order: 1255266 A7 B7 V. Invention description (100) -----:----- -----装--- (Please read the back of the note before this page) ethynyl-benzoic acid methyl ester (example L14X396 mg, 1.08 millimolar) and 3-(2,2-monomethyl- 6-keto-6H-[1,3]dioxanthyl)-benzonitrile (Example N4) (273 mg, 1.19 mmol).

MS (ISP) 538 [(M+H)+], 555 [(M+NH4)+] and 560 [(M+Na)+]; melting 158 ° C (decomposition). Example 010 {2-[3-(3-Cyano-phenyl) keto-propionylamino]-5-morpholine _4-yl phenyl phenylethynyl-phenyl-p-aminomethyl acid The third-butyl ester was prepared according to the general procedure from (2-amino-5-morpholine-4-ylphenylphenylethyl-phenyl)-amine methyl acid tert-butyl ester (example L12) (483 mg, 1.23 mmol) with 3-(2,2-dimethyl keto ketone-6H-[1,3]dioxolysinyl)-benzonitrile (Example N4) (422 Mg., 1.84 millimoles). Obtained an amorphous orange material (375 mg). MS (ISP) 565 [(M+H)+ ] and 587 [(M+Na)+]. Example Oil [2-[3-(3-Cyano-phenyl)-3-keto-propenylamino]-5-(2-{2-〇(2-methoxy-B; Oxy)-ethoxy]-ethoxy}••ethoxy)-4-phenylethylidene-phenyl]-amine methyl acid third-butyl ester Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative According to the general procedure, prepared from [2-amino-5-(2-{2-[2-(2-methoxy-ethoxy)·ethyllacto]-ethylidyl}-ethoxyl -4-phenylethylidene-phenyl]-amine methyl acid tert-butyl ester (example L15) (514 mg, 1. 〇 millimol) and 3_(2,2-dimethylbutanone Base-6H-[1,3]dioxanthene-4-yl)-benzonitrile (Example N4) (344 mg, 1.5 mmol). Obtained as a pale yellow solid (353 mg). MS (ISP) 686 [(M+H)+] and 703 [(M+NH4)+]; mp 135-136. Example 012 -103- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 __B7 V. Description of invention (101) {5-Second-butoxyprokiol-4-[ 3-(3-Cyano-phenyl)-3-keto-propionylamino]-2-phenylethynyl-phenoxy}-acetic acid tert-butyl ester according to the general procedure, 4-Amino-5-tertiary-butoxycarbonylamino 1phenylethyl-phenoxy)-acetic acid tert-butyl ester (Example L16) (877 mg, 2.0 mmol) and 3-( 2,2-Dimethyl-6-keto-6H-[1,3]dioxolene-4-yl)benzonitrile (Example N4) (504 mg, 2.2 mmol). Obtained as a yellow solid (723 mg). MS (ISP) 610 [(M+H)+], 627 [(M+NH4)+] and 632 [(M+Na)+]; Example 013 {5-Cyanomethyl-2-[3-(3)cyano-phenyl)-3-keto-propionylamino; μ-phenylethynyl-phenyl}-aminomethyl The acid tert-butyl ester was prepared according to the general procedure from (2-amino-5-cyanomethyl-4-phenylethynyl-phenyl)-amine methyl acid to the third-butyr (example L17) ) (298 mg, 〇·86 mmol) with 3-(2,2-dimethyl-6-keto-6Η-[1,3]dioxol-4-yl)-benzonitrile (Example Ν 4) (218 mg, 0.95 mmol). Obtained as a yellow solid (299 mg). MS (ISP) 519 [(Μ+Η)+ ], 536 [(Μ+ΝΗ4)+ ] and 541 [(M+Na)+ ] ·, mp 98 °C. Example 014 [2-0 (3-cyano-phenyl&gt; 3-keto-propionylamino]-5-(1,4-dioxonitro-spiro[4.5]decyl)-4 -Phenylethynyl-phenyl]-amine methyl acid tert-butyl ester according to the general procedure 0 'from [2-amino-5-(1,4-dioxo-8-nitro-spiro[4.5]癸))-4-phenylethyl. Block-phenyl]-amine methyl acid third-butyl ester (Example L18) (393 mg, 0.87 mmol) and 3-(2,2-dimethyl Benzyl-6-keto-6H-[1,3]dioxolysine)-benzonitrile (Example N4) (301 mg, 1.31 mmol). Obtained amorphous orange material ( 268 mg). MS (ISP) 621 [(M+H)+]. -104 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -----Γ----- ------ (Please read the phonetic transcription on the back? This page is the first page) Order · Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives! 255266 V. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing Instructions (102) tExample 015 (Please read the phonetic transcription on the back side and then on this page) [2-[3-(3-Butyl)-3-keto-propyl arylamino]-5-(2-methoxy -ethoxymethyl-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester According to the general procedure 0, from [2-amino-5-(2-methoxy-ethoxy] 4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester (example ul ) (84 〇 mg, 2.2 亳 Mo) and 6-(3-iodophenyl) 2,2-dimethyl-[1,3]dioxolene-4·one (Example N7) (780 mg) , 2·36亳莫耳). Obtained a white solid (1.3 g) MS (ISP) 655 [(Μ+Η)+ ],672 [(Μ+ΝΗ4)+ ],677 [(M+Na) + ] and 693 [(Μ+Κ)+ ] ; melting point 172 ° C. Example 016 [2-[3-(3-Cyano-phenyl)-3-keto-propenylamino]-5- (2,2-Dimercapto-[1,3]dioxoindol-4-ylmethoxy)-4-phenylethynyl-phenyl]-aminemethyl acid tert-butyl ester according to the general procedure 0, produced from [2-amino-5-(2,2-dimethyl-[1,3]dioxoin-4-ylmethoxy)-4-phenylethynyl-phenyl]- Aminomethyl 3-butyrate (Example L20) (439 mg, 1.00 mmol) and 3-(2,2-dimethyl-6-S-iso-6-[1,3] Oxylyzin-4-yl)-benzonitrile (Example Ν 4) (345 mg, 1.5 mmol) afforded a yellow solid (275 mg). MS (ISP) 610 [(Μ+Η)+], 627 [(Μ+ΝΗ4)+ ] and 632 [(M+Na)+ ]; melting point 132- 134 C 〇 Example 017 5- Third-butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3pyridyl-propionylamino]_ 2-iodo-benzoic acid methyl ester according to General procedure 0, prepared from 4-amino-5-tertiary-butoxycarbonylamino 1 iodine-benzoic acid methyl ester (Example L21) (395 mg, 1·〇 mmol) and M2,2-dimethyl Based on the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 5. Inventive Note (103) Keto-6H-[1,3] Dioxetene-4 -yl)-benzonitrile (example N4) (254 mg, 1.1 mmol). Obtained an amber solid (435 mg). MS (ISP) 564 [(M+H)+], 581 [(M+NH4)+] and 586 [(M+Na)+]; mp 162-166 〇C 〇 Example 018 [[2-[3- (3-imidazol-1-yl-phenyl)-3-keto-propionylamino]-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenyl]- Aminomethyl acid tert-butyl ester according to the general procedure, prepared from [2-amino-5-(2-decyloxy-ethoxy)-4-phenylethylidene-phenyl]-amine A Tri-butyl ester (example L11) (191 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-diindolyl-[1,3] Oxadecene-4-one (Example N10) (135 mg, 0.5 mmol). Obtained as a pale brown waxy solid (206 mg). MS (ISN) 593 [(Μ-ΗΠ; m.p. 122-129X: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> [2-[3-(3-cyano-phenyl) 3- keto-propenylamino] -5-(2-keto-[1,3]dioxoindol-4-ylmethoxy)-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester according to the general procedure K, made from [RS]-[2-amino-5-(2-keto-[1,3]dioxoin-4-ylmethoxy)-4-phenylethylidene-phenyl ]-Aminomethyl 3-butyrate (Example L22) (346 mg, 0.82 mmol) and 3-(2,2-dimethyl-6-keto-6H-[1,3]dioxo Tert-en-4-yl)-benzonitrile (Example N4) (206 mg, 0.9 mmol) afforded a pale yellow solid ( 433 mg). MS (ISP) 594 [(MH)+]; C. Example 020 {2-[3·(3-Alkyl-phenyl)-3-keto-propionylamino]-5-ethoxymethyl-4-phenylethynyl-phenyl} -Aminomethyl acid third- butyl---- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----^---------Install i — ( Please read the note on the back of this page.) ······· -------装--- (Please read the notes on the back page again) According to the general procedure K, from (2-amino-5-ethoxymethyl-4-phenylethynyl- Phenyl&gt; Amino acid tert-butyl ester (Example L23) (130 mg, 0.35 mmol) with 3-(2,2-dimethyl-6-keto-6H-[1,3] Dioxol-4-yl)-benzonitrile (Example N4) (80 mg, 0.35 mmol). Obtained amorphous yellow material (148 g) MS (ISP) 538 [(MH)+ Example 021 2,2-Dimethyl-propionic acid 5-tris-butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3-indenyl-propenylamine Ethyl-2-phenylethynyl; ester according to the general procedure K, from 2,2-dimercapto-propionic acid 4-amino-5-tris-butoxycarbonylamino-2-phenyl Block base-Ye g (Example L24) (l55 mg, 0.37 mmol) with 3-(2,2-dimethyl-6-keto-6H-[1,3]dioxene terpene-4 -benzonitrile-benzonitrile (Example N4) (94 mg, 0.41 mmol). Obs. (yield: 184 mg). (MS) 611 [(M+NH4)+].线_(RS)-[2-[3-(3-Min-1-yl-phenyl)-3-keto-propionylamino]-4-phenylethynyl-5-(tetrahydro) -峰喃-2- Oxymethyl)-phenyl]-amine methyl acid third-butyl ester Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed according to the general procedure 制, from (RS)-[2-amino-4-phenyl Ethynyl-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-amine methyl acid tert-butyl ester (example L25) and 6-(3-imidazolyl-phenyl &gt; 2,2-Dimethyl-[1,3]dioxanthene-4-one (Example N10). An amorphous yellow substance (267 mg) was obtained. MS (ISP) 635 [(M+H)+]. Example 023 [2-[3-(3-Imidazol-1-yl-phenyl)-3-keto-propenylamino]-5-(4-methoxy-hexahydrop-precipitate-1- Base)-4-phenylethyl-phenyl]-amine methyl acid third-butyr-107- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) &quot; 1255266 Α7 Β7 V. Description of the invention (105) According to the general procedure 0, from [2_Aminos (4-methoxy-hexahydropyridine + yl) 4-phenylethynyl-phenyl]-amine methyl acid Third-butyl ester (Example L26) (236 mg, 0.56 moles) and 6-(3-imipo-i-yl-phenyl)_2,2-dimethyl-[ι,3] dioxane Terpene-4-one (Example N10) (151 mg, 0.56 mmol). Obtained amorphous yellow material (253 mg). MS (ISP) 634 [(M+H)+] 〇 Example 024 [2- [3-(3-Cyano-phenyl)-3-keto-propionylamino]_5-(4-methoxy-hexahydropyridin-1-yl)-4-phenylethynyl-benzene ]--aminomethyl acid tert-butyl ester according to the general procedure, prepared from [2-aminomethoxy-hexahydropyridin-1-yl)-4-phenylethylidene-phenyl]-amine Tri-butyl methacrylate (Example L26) (224 mg, 0.53 mmol) and 3-(2,2-dimethyl ketone-6H-[1 , 3] Dioxetene-4-ylbenzonitrile (Example N4) (125 mg, 〇·53 mmol). Obtained yellow foam (274 mg). MS (ISN) 591 [(MH)· Melting point: 97_100 χ:. Example 025 {5-oxymethoxy-2-[3-(3)m-but-1-yl-phenyl) keto-propionylamino]-4-phenyl乙基基-phenyl}-amine hydrazinoic acid _ _ @ @ According to the general procedure 0, from (2-aminocyanomethoxy Iphenylethynyl-phenyl)-amine methyl acid Tri-butyl ester (Example L27) is the same as 6-(3-imidazolyl-phenyl)-2,2-monomethyl-[1,j]oxoxaindole-4-S (Example N10). Obtained amorphous yellow material (169 mg) MS (ISP) 576 [(M+H)+]. Example 〇26 -108- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Please read the notes on the back first. έ έ 衣 订 订 经济 经济 经济 经济 经济 经济 经济 1 1 1 1 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 255 3-乱基**冬基)-3-§同基-propylaminoamino]-4-phenylethynyl-phenyl}-amine mercapto acid tert-butyl ester according to the general procedure〇 From (2-amino; cyanomethoxy phenyl ethynyl-phenyl)-amine methyl acid tert-butyl ester (example L27) (80 mg, 0.22 mmol) and 3-(2 2,Dimethyl-6-keto-6H-[1,3]dioxolyn-4-yl)benzonitrile (Example N4) (55 mg, 0.24 mmol). Obtained an amorphous yellow material (96 mg). MS (ISN) 533 [(Μ-ΗΠ. Example 027 (RS)-[4-(4-Fluorophenylethylidene)-2-[3-(3-M..-1-yl-phenyl)) -3. propyl-propyl decylamino]-5-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-amine methyl acid third _ 酉 酉 according to the general procedure 制, from (RS)-[2-Amino-4-(4-fluorophenylethynyl)-5-(tetrahydrofuran-2-yloxymethyl)-phenyl]-amine hydrazinoic acid - Butyl ester (Example L28) with 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxolene-4-one (Example N10). Amorphous yellow material (990 mg) MS (ISN) 651 [(M-Η)-]. Example 028 (RS)-(4-4-fluorophenylethynyl)-2-[3-(3- Imidazol-1-yl-phenyl)-3-ketopropionylamino]-5-{methyl-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-amino }·Phenyl)-Aminomethyl 3-butyrate was prepared according to the general procedure from (RS)-(2-amino-4-(4-fluorophenylethylidene)-5-{methyl -[2-(tetrahydro-pyran-2-yloxy)-ethyl]-amino}-phenyl)-amine methyl acid tert-butyl ester (Example L29) (242 mg, 0.5 mmol) Ear) with 6-(3-imidazolyl-phenyl)-2,2-dimethyl-[1,3]dioxanthene (Example N10) (135 mg, 〇·5 mmol). An amorphous yellow material (198 mg) was obtained. -109- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -------------- Pack--- (Please read the back note on this page first) Line. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 Invention Description (107) MS(ISN) 694 [(MH)—]. Example 〇29 {5-(4,4-Diethoxy-hexahydropyridin-1-yl)-2-[3-(3-imidazolyl-phenyl)-3-keto-propionylamine Tert-butyl 4-phenylethynyl-phenyl}-amine methyl acid, according to the general procedure, from [2-amino-5-(4,4-diethoxy-hexahydro) Pyridin-1-yl)-4-phenylethylidene-phenyl]-amine methyl acid tert-butyl ester (Example L18) (321 mg, 0.67 mmol) and 6·(3-imidazole-1 -yl-phenyl)-2,2-dimethyl-[1,3]dioxolene-4-one (Example Ν10) (240 mg, 0.89 mmol). Obtained orange foam (295 Mg) MS (ISP) 692 [(M+H)+]. Example 030 (RS)-{2-[3-(3-Miso-1-yl-phenyl)-3-indolyl-propyl Triamino--4-phenylethylidene-5-[2-(tetrahydro-piperidin-2-yloxy)-ethoxy]-phenyl}-amine methyl acid tert-butyl ester According to the general procedure, from (RS)-{2-amino-4-phenylethynyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl }-Aminomethyl 3-butyrate (Example L30) (346 mg, 0.76 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1 , 3] Dioxolene-4-one (Example N10) (300 mg, 1.11 mmol). Obtained as a yellow foam (196 mg). MS (ESI) 665 [(M+H)+]. Example 031 (RS)-{4·-fluoro-5-[3-(3-imsin-1-yl) -phenyl)-3-keto-propionylamino]-2-[4-(tetrahydro-pyran-2-yloxy)-hexahydropyridine small group]-biphenyl-4-yl Tert-butyl methacrylate is prepared according to the general procedure 0, from (RS>[2-amino-4-(4-fluorophenylethynyl)-5-(-110-) Standard (CNS) A4 specification (210 X 297 mm) ---:----------Installation--- (Please read the back note on this page first) - 1255266 Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Printing A7 B7 V. INSTRUCTIONS (108) Tetra-Butyl-Chan-2-yloxymethyl)-phenyl]-Aminomethyl Acid Tri-Butyl Ester (Example L28) and 6-(3) -Imidazolyl-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxolene-4-one (Example N10) afforded a yellow solid (282 mg). MS (ISP) 698 [(M+H)+]; mp 129-132X: </RTI> </RTI> 032 {5-(2-tri-butoxy-ethoxy)-4-(4-fluorophenylethynyl)-2- [3-(3-Imidazolyl-phenyl)-3-keto-propionylamino]-phenyl}-amine methyl acid, third-butyl ester Private sequence 〇 'made from [2-amino-5-(2-tris-butoxyethoxy)-4_(4-fluorophenylethynyl)-phenyl]-amine methyl acid -Butyl ester (Example L32) (560 mg, 1.27 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxene terpene 4- Ketone (Example N10) (413 mg, 1.53 mmol). Obtained a yellow solid (507 mg). MS (ISP) 655 [(M+H)+]; mp. 62-65. Example 033 (RS)-(4'-Fluoro-5-[3-(3-amido-1-yl-phenyl)-3-§-iso-propionylamino]-2-{4- [2_(tetrahydro-peak-n-yl-2-yloxy)-ethoxy]-hexahydropyridine small-base diphenyl phenyl)-aminomethyl acid tert-butyl ester according to the general procedure 0, (RS)-(5-Amino-4,-fluoro-2-{4-[2-(tetrahydro-piperidin-2-yloxy)-ethoxy]-hexahydropyridin-1-yl丨_biphenyl|yl group&gt; Amino-mercaptoic acid third-butyl ester (Example L33) and 6-(3-imidazolyl-phenyl)_2,2-diindolyl-[1,3]dioxo圜晞 酮 ketone (Example N10). Obtained as a yellow solid (473 mg). MS (ESI) 742 [(M+H)+]; mp. 57-58 ° C. Example 034 (RS)-[4 Base-5-[3-(3Hl-yl-phenylyl-propenylamine group (four-111 - this paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) • 11111 -- --- 1--. II (Please read the notes on the back and then ϋβ► this page)

Jrd-line · 1255266 A7 B7 V. INSTRUCTION DESCRIPTION (109) Hydrogen-systemane-2-yloxymethyl)-biphenyl phenyl]-amino acid tert-butyl ester according to the general procedure From (RS)-[5-Amino-hydrofluoro-2-(tetrahydro-pyranyloxymethyl)-biphenyl-4-yl]-amine methyl acid tert-butyl ester (example) L34) with 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxolene-4-one (Example N10). Obtained as a pale yellow solid (330 mg). Example 〇35 {2-Cyanomethoxyfluoro-5-[3-(3-imidazol-1-yl-phenyl)-3-keto-propenylamino]-biphenyl-4- }--aminomethyl acid tert-butyl ester according to the general procedure 0, from (5-amino-2-cyanomethoxyfluoro-biphenyl-4-yl)-amine methyl acid third - Butyl ester (Example L35) (190 mg, 0.53 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxene terpene- 4-ketone (Example N10) (164 mg, 0.61 mmol). Obtained yellow gum (90 mg). MS (ISP) 570 [(M+H)+]. Example 036 {2-Dimethylaminomethyl|Fluoro-5-[3-(3-imidazol-1-yl-phenyl)-3-keto-propenyl)-biphenyl-4 - Aminomethyl acid, third-butyl hydrazine, according to the general procedure 0, prepared from 5-amino-2-dimethylaminomethyl Ifluoro-biphenyl-4-yl)-amine methyl acid - Butyl ester (Example L36) and 6-(3-imidazol-1-yl-phenyl). 2,2-dimethyl-[1,3]dioxanthene ketone (Example N10). Obtained as a pale yellow solid (329 mg). Example 〇37 {2-(2,2-Dimethyl-tetrahydro-[1,3]dioxos(4,5-c]pyrrole-5-ylfluoro-5-[3-(3) ··Imidazole small group-phenyl) keto-propionylamino]-biphenyl-4-yl-b-methylamino acid tert-butyl ester-112· This paper scale applies to China National Standard (CNS) A4 size (210 X 297 mm) ------------- Pack--- (Please read the note on the back page first. ) -- Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of the invention (110) According to the general procedure, it is prepared from [5-amino-2-(2,2-dimethyl-tetrahydro 41,3]dioxosole [4, 5-cH-rho-5-yl)_4,-fluoro-biphenyl+yl&gt;amine methyl acid third·butyl vinegar (example L37) (465 mg, 1.05 mmol) and 6-(3·imidazole +yl-phenyl&gt;2,2-dimethyl-[1,3]oxoxaindole-4-one (Example N10) (314 mg, ι·ΐ6 mmol). Obtained amorphous yellow Substance (540 mg) MS (ISN) 654 [(MH)-]. Example 038 K-Fluoro-5-[3-(3-M. Aminoamino-biphenyl-4-yl}-amine methyl acid third-butyr is based on the general procedure, from (5- Base-4,-fluoro-2-methoxy-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example L38) (332 mg, 1.0 mmol) and 6-(3 -methanol-1-yl-phenyl)_2,2-dimethyl-[1,3]dioxanthene-4-one (Example N10) (270 mg, 1.0 mmol). Obtained amorphous Brown substance (328 mg) MS (ISN) 543 [(M-Η)-]. Example 039 {2-(1,4-dioxo-8-nitro-spiro[4.5]癸-8-yl)- 4,-Fluoro-5-[3-(3-imidazolyl-1-yl-phenyl)-3-keto-propionylamino]-biphenylyl yl}-amine methyl acid third- Butyl ester is prepared according to the general procedure from [5-amino-2-(l,4-dioxo-nitro-spiro[4.5]indole);-fluoro-biphenyl-4-yl]-amine A Tri-butyl ester (example L39) (444 mg, 1·〇 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1, 3] Dioxonone ketone (Example N10) (321 mg, 1.19 mmol). Obtained brown solid (457 mg). MS (ISN) 654 [(MH)-]; melting point 1 ίο] 15 ° C (Decomposition) Example 040 -113- This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 public) -----.---------装--- (Please Read the back first Precautions on this page) -Jr-d· Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Invention Description (111) {4,-Fluoro-5-[3-(3·imidazole small Base-styl)-3-keto-propionylamino]methyl-biphenyl-4-yl}-amine methyl acid tert-butyl ester according to the general procedure 0, from (5-amino group _4,-Fluoro-2-methyl-biphenyl-4-yl)-amine methyl acid, third-butyl ester (example L40) (316 mg, 1.0 mmol) and 6-(3_m) Biting 1-yl-phenyl)-2,2-dimethyl[1,3]dioxolone ketone (example Ν1〇χ297 mg '1.1 Love: Moer). An amorphous yellow material (361 mg) was obtained. MS (ISP) 529 [(M+H)+]. Example 041 {4-Terti-butoxycarbonylamino-4f-fluoro-5-[3-(3-imidazol-1-yl-phenyl)-3.yl-propenylamino]-biphenyl Benzyl-2-yloxy}-acetic acid _ 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Base)-acetic acid third-butyl ester (Example L41) (14 g, 3.24 mmol) and 6-(3-imidazolyl-phenyl) 2,2-dimethyl-[1,3] Oxalindole-4-one (Example N10) (885 mg, 3.27 mmol) afforded a pale brown solid ( s s s s s s s s s s s s s s s s s s C. Example 042 {2-Chloro-4f-fluoro-5-[3-(3-amido-1-yl-phenyl)-3-keto-propenylamino]-biphenyl- 4-Butyl-aminomethyl acid tert-butyl ester according to the general procedure 0, prepared from (5-amino-2-yl-l-fluoro-biphenylyl)-amine methyl acid tert-butyl ester (Example L42) (168 mg, 0.5 mmol) with 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxolene-4- Ketone (Example N10) (252 mg, 0.93 mmol) afforded a pale-yellow solid (156 mg). MS (ISN) 547 [(M-Η). Example 043 -114- Use Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----r- -------- Install i I (please read the precautions on the back and then 13||^4 pages) : ί线· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention ( 112 ) [4'-Fluoro-5-[3-(3-imidazol-1-yl-phenyl)-3 -keto-propionylamino]-2-(2-methoxy-ethoxy)-biphenyl-4-yl]-amine methyl acid, third butyl ester, according to the general procedure, [5-Amino-4,-fluoro-2-(2-methoxy-ethoxy)-biphenylylidyl]-amine methyl acid tert-butyl ester (Example L43) (188 mg, 0.5 mM) with 6-(3-imidazolyl-phenyl)-2,2-dimethyl-[1,3]dioxolene-4-one (Example N10) (260 mg, 0.96) Obtained an orange solid (218 mg). MS (ESI) 589 [(M+H)+]; mp 61-63T: Oxy)·4,_fluoro-5-[3-(3-imidazolyl-phenyl) keto-propyl arylamino]-biphenyl-4-yl 1-amine methyl acid Tri-butyl ester is prepared according to the general procedure from [5-amino-2-(2-tris-butoxy-ethoxy)-4,-fluoro-biphenyl- Tetra-butyl 4-amino]-aminomethyl acid (Example L44) (209 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl -[1,3] Dioxanedecene ketone (Example N10) (135 mg, 0.5 mmol). Obtained a beige solid (194 mg). MS (ISP) 631 [(M+H)+]; m.p. Example 045 [Heartylfluoro-5-[3-(3-imidazol-1-yl-phenyl) keto-propionylamino]-2-(2-keto-oxazolidine-3-yl) )-biphenyl-4-yl]-aminomethyl acid tert-butyl ester according to the general procedure, prepared from [5-amino-4,-fluoro-2-(2-keto-sodium oxazide) -3-yl)-biphenyl-4-yl]-amine methyl acid tert-butyl ester (Example L45) (130 mg, 0.34 mmol) and 6-(3-imidazolyl-phenyl) -2,2-Dimethyl-[1,3]dioxolene-4-one (Example N10) (92 mg, 0.34 mmol). Obtained an amorphous yellow material (86 mg). -115- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) illl·---------Installation - (Please read the back note on this page first) .- •丨线· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 B7 V. Invention description (113) MS (ISP) 600 [(M+H)+]. Example 046 -----,---------Install--- (Please read the phonetic on the back? Matters again page) {4·-说基-5-[3-(3-咪峻Small base-phenyl)-3-keto-propyl arylamino]-2-methoxy-2-phenyl-co-brenyl-4-yl 1-amine methyl acid third-butyl@ Procedure 0, prepared from (5-amino-4f-fluoro-2-methoxy-2,-methyl-biphenyl-4-yl)-amine methyl acid, third-butyr (example L46) (173 mg, 〇·5 mmol) and 6-(3-imidazolyl-phenyl)_2,2-dimethyl-[1,3]dioxanthone|ketone (Example N10) 199 mg, 1.47 mmol.) Obtained an orange solid (182 g). MS (ISP) 559 [(M+H)+], mp. 99-102. Example 047 {2-Terti-butoxy-4,-fluoro-5-[3-(3-imidazol-1-yl-phenyl)-3-g-iso-propionylamino]-linked Phenyl-4-yl]-amine methyl acid tert-butyl ester' fluorene line according to the general procedure 0, from (5-amino-2-tri-butoxy-4,-fluoro-biphenyl 4-Base)-Aminomethyl 3-butyrate (Example L47) (187 mg, 〇·5 mmol) and Bu (3-Imidazol-1-yl-phenyl)-2,2-di Methyl-[1,3]dioxanthene ketone (Example Nl〇) (135 mg, 0.5 mmol). An amorphous yellow material (237 mg) was obtained. MS (ISN) 585 [(M-H)_]. Example 048 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed {2-di-di-butanyl-2'-fluoro-5-[3-(3-flavor. sit-1-yl-phenyl)-3- Benzo-propyl arylamino]-biphenyl phenyl}-amino phthalic acid tert-butyl ester according to the general procedure 0, from (5-amino-2-tri-butoxy-2'- Fluorine-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example L48) (187 mg, 0.5 mmol) and Bu (3-imidazolylphenyl)-2,2-di Methyl [1,3]dioxanthene ketone (example Nl) (135 mg, 0.5 mmol). An amorphous yellow material (234 mg) was obtained. -116- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266

V. INSTRUCTIONS (114) MS(ISN) 585 [(M«H)-]. Example 049 Install i I (please read the back note on this page first) (RS)-K-Fluoro-5-[3-(3-imidazo-i-yl-phenyl)3-marine-propionate Aminoamino]_2·[(8)-3-(tetrahydro-methane-2-yloxy)·tetrahydropyrrole small group]-biphenylyl yl-p-aminomethyl acid tert-butyl ester according to general private order 0, made from (RS&gt;{5-aminolfluoro group [(8) each (tetrahydrotetram-2-yloxy)-tetrahydropyrrole+yl]-biphenyl] carbamide methyl acid third -Butyl ester (Example L49) (236 mg, 〇·5 mmol) and 6-carbazole small group _phenyl)_2,2-monomethyl-[1,3]monooxanthone (Example Ν10 (200 mg, 0.74 mmol). Obtained an orange solid (188 mg). MS (ISP) 684 [(M+H)+]; melting point 99-l 〇 3 ° C. Example 050 {2-Fluor 5-[3-(3-imidazol-1-yl-phenyl) keto-propionylamino]1 methoxy-biphenyl-4-yl}-amine methyl acid _ Ding Yu Line · According to the general procedure 0, from (5-amino-2'-fluoro-2-methoxy-biphenyl-4-yl)-amine methyl acid third-butyl ester (example L50 ) (159 mg, 0.5 mmol) and 6-(3-imiran-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxolene-4-one ( Instance N10) (135 mg, 0.5 mmol). Obtained amorphous yellow material (199 mg). Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed MS (ISN) 543 [(MH)-]. Example 051 {2- Di-butyl-butyryl-5-[3-(3-indolyl-winteryl)-3-S-yl-propyl-arylamino]-4'-^ ••biphenylyl yl}-amine A The third acid - butyl ester was prepared according to the general procedure 0 from (5-amino-2,t-butoxy-4'-fluoro-biphenyl-4-yl)-amine methyl acid - Butyl ester (Example L47) (187 mg, 0.5 mmol) -117- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Invention description (115) and 3 -(2,2-Dimethyl ketone-6H-[1,3]dioxol-4-yl)-benzonitrile (Example N4) (126 mg, 0.55 mmol). Crystal light pink material (196 mg) MS (ISP) 546 [(M+H)+]. Example 052 {2-T-butoxy-5-[3-(3-cyano-phenyl) )-3-keto-propionylamino]-2,-fluoro-biphenyl-4-yl}-amine methyl acid tert-butyl ester according to the general procedure, from (5-amino group - 2-tert-butoxy-2f-fluoro-biphenyl-4-yl)- Tri-butyl methacrylate (Example L48) (187 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-keto-6H-[1,3]dioxene terpene 4-yl)-benzonitrile (Example N4) (126 mg, 0.55 mmol). An amorphous pale pink material (丨97 mg) was obtained. MS (ISP) 546 [(M+H)+]. Example 053 {5-[3-(3-Cyano-phenyl)-3-keto•propanylamino]-2^·fluoro-2-methoxy-biphenylylidyl}-amine Third-butyl methacrylate was prepared according to the general procedure from (5-amino-fluoro-2-methoxy-biphenyl phenyl)-amine methyl acid tert-butyl ester (Example L50) (112 mg, 〇35 mmol) and 3_(2,2-dimethyl-6-keto-6H-[1,3]dioxol-4-yl)-benzonitrile (example) N4) (80 mg, 0.35 mmol). Yellow foam (131 mg) was obtained. MS (ISN) 502 [(Μ-Η:Γ]. Example 054 (2^·Fluoro-2-methoxy-5-{3-[3-(2-indolyl-imidazolyl)-phenyl) ]-3-keto-propyl arylamino}-biphenyl-4-yl)-amine methyl acid second-butyl hydrazine is prepared according to the general procedure, from 5-aminofluoro-2-yl Oxy-biphenyl ice-118- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ----^---------装--- (please first Read the notes on the back and then 1?^4 pages. . : Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266

V. INSTRUCTIONS (116) s-aminomethyl acid tert-butyl ester (example L50) (249 mg, 0.75 mmol) and 3-[3-(2-methyl-mipropionyl)- Phenyl]-3-keto-propionic acid tert-butyl ester (Example M8) (275 mg, 0.92 mmol). A yellow solid (312 mg) was obtained. MS (ISP) 559 [(M+H)+]; mp. Example 055 {5-[3-(5-Cyano-indol-2-yl)-3-one-propenylamino]-2,-fluoro-2-methoxy-biphenyl- 3-Benzyl-aminomethyl acid tert-butyl ester according to the general procedure 0, from (5-amino-2f-fluoro-2-methoxy-biphenylyl)-amino acid Tri-butyl ester (Example L50) (166 mg, 0.5 mmol) 3-(5-cyano-soul-phen-2-yl)-3-keto-propionic acid tert-butyl ester (Example M17) 138 mg, 0.55 mmol. Obtained as a pale yellow solid (244 mg). MS (ISP) 510 [(M+H)+], mp. 200 ° C (dec.). Example 056 {2,-Fluoro-2-methoxy-5-[3-keto-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamine Benzyl-terphenyl-4-yl}-amine methyl acid tert-butyl ester according to the general procedure, prepared from (5-amino-2,-fluoro-2-methoxy-biphenyl ice Amino acid tert-butyl ester (Example L50) (166 mg, 0.5 mmol) and 3-keto-3-(3-[1,2,4]triazol-4-yl- Phenyl)-propionic acid ethyl ester (Example M1) (260 mg, 1.03⁄4 mol). Obtained yellow gum (70 mg). MS (ISP) 546 [(M+H)+]. Example 057 {5-[3-(2-Cyano-pyridin-4-yl)-3-one-propenylamino]-2,-fluoro-2-methoxy-Limyl-4 -基}-Amino-based acid third _ 酉 酉 according to the general procedure 制, made from (5-amino-2,-fluoro-2-methoxy-biphenyl ice 119- this paper scale applies to China Standard (CNS) A4 specification (210 X 297 mm) ----1---------Installation--- (Please read the back note on this page first) Order: -Line - Ministry of Economics Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention (117) Base)-Aminomethyl 3-butyrate (Example L50) and 3-(2-Cyano-4-pyridin-4-yl)-3 - Keto-propionic acid tert-butyl ester (Example M10). A pale yellow solid (189 g) was obtained. MS (ISP) 522 [(M+NH4)+]. Example 058 (2-second-butoxy-4^-fluoro-5-{3-[3-(2-methyl-amido-1-yl)-phenyl]-3-oneyl-propane Tert-butylamino}-biphenyl-4-yl)-amine methyl acid tert-butyl ester according to the general procedure 0, from (5-amino-2-tris-butoxy-4,-fluoro -biphenyl-4-yl)-aminomethyl acid tert-butyl ester (example L47) (140 mg, 〇.37 亳mol) and 3-[3-(2.methyl-imidazole-1- Tris-phenyl]-3-keto-propionic acid tert-butyl ester (Example M8) (111 mg, 0.37 mmol). An amorphous yellow material (139 mg) was obtained. MS (ISP) 601 [(M+H)+]. Example 059 {5-[3-(5-Cyano-2-fluorophenyl)-3-one-propenylamino]-2'-fluoro-2-methoxy-biphenyl-4 -Based on the basis of the general procedure 0, from (5-aminofluoro-2-methoxy-biphenylyl)-amine methyl acid tert-butyl ester (Example L50) (166 mg, 0.5 mmol) and 3-(5-cyano-2-fluorophenyl)-3-S synthyl-propionic acid B g (Example M18) (141 mg, 0.6 m Moore). An amorphous yellow material (165 mg) was obtained. MS (ISP) 522 [(M+H)+ ] 〇 Example 060 {2-di-butyl-butyryl-5-[3-(2-ranyl-p-pred-4-yl)-3-indenyl - propylamino] 4-fluoro-biphenyl-4-yl}-amine methyl acid tert-butyl ester according to the general procedure, from (5-amino-2-tri-butoxy -4,-fluoro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (example L47) (140 mg, 〇_37 mmol) and -120- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) -------------- Pack --- (Please read the back note before this page) · Ministry of Economic Affairs Intellectual Property Bureau staff consumption Cooperatives printed 1255266 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed A7 B7___ V. Description of invention (118) 3- (2-cyano-pyridyl-4-yl)-3-keto-propionic acid third-butyl Ester (Example M10) (91 mg, 0.37 mmol). Obtained an amorphous yellow material (164 mg). MS (ISP) 547 [(M+H)+] 〇 Example 061 {2-T-butoxy-2'-fluoro-5-[3-keto-3-(3-[1,2, 3] Triazol-1-yl-phenyl)-propanylamino]-biphenyl-4-yl}-amine methyl acid _ 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉2-tert-butoxy-2'-fluoro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (example L48) (187 mg, 〇·5 mmol) and 3 Ethyl keto-3-(3-[1,2,3]triazol-1-yl-phenyl)propanoate (Example M2) (i.sup.8 mg, 0.69 mmol). Obtained as a pale yellow solid (257 mg). MS (ISP) 588 [(M+H)+]; mp. 47-50. Example 062 [5-[3-(3-Cyano-phenyl)-3-keto-propenylamino]_2-(l.,4-dioxo-8-nitro-spiro[4.5] The base -2f-fluoro-biphenyl-4-yl]-amine methyl acid tert-butyl ester was prepared according to the general procedure from [5-amino-2-(l,4-dioxo-8-). Nitrogen-spiro[4.5]decyl)-2'-fluoro-biphenyl-4-yl]aminemethyl acid tert-butyl ester (example L51) (222 mg, 0.5 mmol) and 3-( 3-Cyano-phenyl)-3-keto-propionic acid tert-butyl ester (Example M3) (182 mg, 0.8 mmol). An amorphous yellow material (258 mg) was obtained. MS (ISP) 615 [(M+H)+]. Example 063 {2-(1,4-Oxo-8-Aromatic-spiro[4.5]dec-8-yl)-2'-gas-5-[3-(3-flamo-1-yl-phenyl) -3-keto-propionylamino]-biphenyl-4-yl}-amine methyl acid tert-butyl ester according to the general procedure, from [5-amino-2-(l, 4 -Dioxo-8-nitro-spiro[4.5]dec-8-yl)-2^fluoro-biphenyl-4-yl]-amine methyl acid tert-butyl ester (Example L51) (222 mg-121 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --------------Installation --- (Please read the notes on the back page again). Line · 1255266 A7 B7 V. Description of invention (119), 0.5 Amor) and 6-(3·&quot;M..-1-yl-phenyl)-2,2-dimethyl-[ι,3 Dioxetene 4-copper (example N10) (135 g, 0.5 mmol). Obtained an amorphous yellow material (294 mg). MS (ISP) 656 [(M+H)+]. Example 064 (2-second-butoxy-2'-fluoroyl-5-{3-[3-(2-methyl-miquid-1-yl)-phenyl]_3-|isolated _ propyl Tert-butyl ester of arylamino}-biphenyl-4-yl)-amine methyl acid according to the general procedure 0, prepared from (5-amino-2-tris-butoxy-2l fluoro-linked Phenyl-4-yl)-amine methyl acid tert-butyl ester (Example L48) (187 mg, 〇·5 mmol) and 2,2-dimethyl-6-[3-(2-A) Methyl-i-but-1-yl)-phenyl]-[ι,3]dioxanthene 4-one (Example N15) (142 mg, 0.5 mmol). Obtained an amorphous yellow material (234 mg). MS (ISP) 601 [(M+H)+]. Example 065 {2-Terti-butoxy-5-[3-(2-cyanopyridin-4-yl)-3-keto-propionylamino]-2f-fluoro-biphenyl- Tetra-butyl 4-amino}-aminomethyl acid was prepared according to the general procedure 0 from (5-amino-2-tri-butoxy-2,-fluoro-biphenyl-4-yl)_ Aminomethyl 3-butyrate (Example L48) (187 mg, 0.5 mmol) and 4-(2,2-dimethyl-6-keto-6H-[1,3]dioxane Benzene)-pyridine-2-carbonitrile (Example N16) (115 mg., 0.5 mmol). Obtained an amorphous yellow material (216 mg). MS (ISP) 547 [(M+H)+]. Example 066 (2-Terti-butoxy-2'-fluoro-5-{3-[3-(2-methylthio-imidazol-1-yl)-phenyl]-3-one-propyl Mercaptoamine}-biphenyl-4-yl)-amine methyl acid tert-butyl ester-122- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) •--- ---------- Install i I (please read the notes on the back and then this page). Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1255266 A7 .......... ....B7_____ V. INSTRUCTIONS (120) According to the general procedure 0, from (5-amino i-t-butoxy-2,-fluoro-biphenyl-4-yl)-amine methyl acid Third-butyl ester (Example L48) (187 mg, 〇 5 mmol) and 3_ [3-(2-methylthio) imidol] phenyl] keto-propionic acid third-butyl Ester (Example M13) (211 mg, 0.63 mmol) afforded a pale-yellow solid (26 mg). MS (ISN) 631 [(MH)_]; mp. 59-62 ° C. Example 067 {5-[ 3-(3-Cyano-phenyl)-3-keto-propionylamino]-2',5'-difluoro-2-indolyl-biphenyl-4-yl}-amine A The third-butyl acrylate is prepared according to the general procedure from (5-amino-2',5'-difluoro-2-methoxy- Phenyl phenyl)-aminomethyl acid tert-butyl ester (example L52) (175 mg, 〇·5 mmol) and 3-(2,2-dimethyl ketone-6H-[1, 3] Dioxolene-4-yl)-benzonitrile (Example N4) (115 mg '0.5 mmol). Obtained amorphous yellow material (丨 36 mg). MS (ISP) 522 [(M +H)+] 〇Example 068 {2',5'-Difluoro-2-methoxy-5-[3-keto-3-(3-[1,2,3]triazole-based-benzene ))-propionylamino]-biphenyl-4-yl}-amine methyl acid, the third-butyr, according to the general procedure, is prepared from (5-amino-2',5'-difluoro- 2-methoxy-biphenylyl)-amine methyl acid tert-butyl ester (Example L52) (175 mg, 0.5 mmol) and 3-keto-3-(3-[1,2 , 3] triazol-1-yl-phenyl)-propionic acid ethyl ester (Example M2) (130 mg, 0.5 mmol). Obtained as a pale yellowish material (185 mg). MS (ISN) 562 [ (MH)·]. Example {69 {2-Terti-butoxy-5-[3-(3-cyano-thiophen-2-yl)-3-one-propenylamino]-2 ^ Fluorine-biphenyl-4-yl]-amine methyl acid tert-butyl ester-123- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------- - ------Install i I (please read the note on the back and then this page) Order: Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 B7 V. Invention description (121) According to the general procedure 0, (5-Amino-Tungsten-tert-butoxy-2,-fluoro-biphenyl-4-yl)-aminomethyl acid tert-butyl ester (Example l48) (187 mg, 0.5 mmol) and 6_(3-Cyano-soul-phen-2-yl)-2,2·dimethyl-#,3]dioxolene-4-one (Example N3) (130 mg, 0.55 mmol). Obtained yellow oil (278 mg). MS (ISN) 550 [(MH)-] 〇 Example 070 {2-T-butoxy-5-[3-(5-cyano-thiophen-2-yl)-3-one-propionyl-' Aminoamino-2,-fluoro-biphenyl-4-yl}-amine methyl acid, third butyl ester, according to the general procedure, prepared from (5-amino-1 tert-butoxy-21- Fluorine-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example L48) (187 mg, 0.5 mmol) and 3-(5-cyano-4 phen-2-yl)-3 - Keto-propionic acid tert-butyl ester (Example M17) (138 mg '0.55 Amor). Obtained an amorphous yellow material (268 mg). MS (ISN) 550 [(M-Hy]. Example 071 "2-di-*-butoxy-4-carbyl-5-[3-indolyl-3-(3-[1,2,3]] Diwax-1-yl-winteryl)-propionylamino]-biphenyl-4-yl}-amine methyl acid third-butyl ester Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing ----- r---------装--- (Please read the notes on the back and then on this page) ί线· According to the general procedure, from 5-amino-2-tri-butoxy -4'-Fluoro-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example L47) (187 mg, 0.5 mmol) and 3-keto-3-(3-[1, 2,3]triazole-p-phenyl)-propionic acid ethyl ester (Example M2) (156 mg, 〇·6 mmol). Obtained yellow gum (198 mg). MS (ISP) 588 [(M+ H) +]. Example 072 [5-[3-(3-Cyano-phenyl)-3-keto-propenylamino]-2'-fluoro-2-(2-methoxy- Ethoxy)-biphenyl-4-yl]-amine methyl acid tert-butyl ester-124- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1255266 ________B7_ V. Description of the invention (122) According to the general procedure 制'from 15-amino-2'-fluoro-2-(2-methoxy-ethoxy)-biphenyl-4- Amino acid-tert-butyl ester (Example L53) and 3·(2,2-dimethylglycosyl-6Η-[1,3]dioxolan-4-yl)-benzene Formonitrile (example Ν 4). A yellow solid (188 mg) was obtained. MS (ISP) 548 [(M+H)+]. Example 〇73 (RS)-[5-[3-(3-Cyano-phenyl)-3-keto-propyl-arylamino]-21-fluoro-2-(tetrahydro-pyro-2 - methoxymethyl)-biphenyl-4-yl]-amine methyl acid tert-butyl ester according to the general procedure 0, from (RS)-[5-amino-2,-fluoro-2 -(tetrahydro-pyran-2-yloxymethyl)-biphenyl-4-yl]-amine methyl acid, third-butyl vinegar (example L54) and 3-(2,2-dimethyl -6-keto-6H-[1,3]dioxolyl-4-yl)-benzonitrile (Example N4). A yellow solid (155 mg) was obtained. MS (ISP) 548 [(M+NH4)+]. Example 074 (2·-Fluoro-2-(4-methoxy-benzyloxy)-5-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]- 3-keto-propionylamino}-biphenylyl)-amine methyl acid tert-butyl ester according to the general procedure 0, from [5-amino-2,-fluoro-2-(4) -Methoxy-yloxy)-biphenylindolyl--aminomethyl acid tert-butyl ester (example L55) (438 mg, 1. 〇 millimol) and 3-[3-(3- Methyl-isoxazol-5-yl)-phenyl]-3-keto-propionic acid tert-butyl ester (Example M14) (301 mg, 1.0 mmol). Obtained an amorphous light yellow material (561 mg). MS (ISP) 666 [(M+H)+]. Example 075 {2-Terti-butoxy-5-[3-(3-cyano-phenyl)-3-one-propenylamino]-2,5,-di-125- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ------------- Install i I (please read the back note before this page) .- Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed 1255266 A7

V. Description of the invention (123) Gaso-biphenyl-4-yl]-amine methyl acid The third-butyr is based on the general private order 0, from (5-amino 1 3 -butoxy 2, ,5,-Difluoro-biphenyl-4-yl)-amine methyl acid, third-butyl ester (example ί 56 χ 1% mg, 〇 5 mmol) and 3-(2,2-dimethyl-6 -Ketyl-6Η-[1,3]dioxolyn-4-yl)benzonitrile (Example Ν4) (115 mg, 0.5 mmol). Obtained amorphous beige material (155 grams). MS (ISP) 564 [(M+H)+]. 1 m 076 {5-Terti-butoxy-4-(4-fluorophenylethynyl)&gt;2-[3-(3-imidazol-1-yl-phenyl)-3-keto-propionate The amino-amino]-phenyl}-amine methyl acid tert-butyl ester is prepared according to the general procedure from [2-amino-5-tris-butoxy-4-(4-fluorophenylethynyl). -Phenyl]-aminomethyl acid tert-butyl ester (Example L57) (160 mg, 0.4 mmol) and 3-(3-imidazol-1-yl-phenyl)-3-one - Tert-propionic acid tert-butyl ester (Example Μ 4) (115 mg, 0.4 mmol). Obtained amorphous yellow material (140 mg). MS (ISP) 611 [(M+H)+] 〇 Example 077 { 5-Terti-butoxy-4-(4-fluorophenylethynyl)-2-[3-keto(3-[1,2,3]triazol-1-yl-phenyl)- Propylamino]-phenyl-p-aminomethyl acid third-butyr is prepared according to the general procedure from [2-amino-5-tris-butoxy ice (4-fluorophenylethynyl) -Phenyl]-aminomethyl acid tert-butyl ester (Example L57) (160 mg, 0.4 mmol) and 3-keto-3-(3-[1,2,3]triazole-1 Ethyl-phenyl)-propionic acid ethyl ester (Example M2) (104 mg, 0.4 mmol) afforded yellow gum (150 mg) MS (ISP) 612 [(M+H)+]. : -126- _ this paper Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -------------- Installation — (Please read the back note before this page) Order: -丨· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing [255266 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7 V. Invention description (124) 4,8-diaryl-1,3-dihydrobenzoquinone [ 1,4] Dioxane: ketone, 4_aryl, aryl fluorenyl-1,3-dihydrophenylhydrazine [b][l,4]dioxine-2-one or 4-aryl Preparation of arylethynyl-1,3-dihydrophenylhydrazone [b][l,4]dioxepin-2-one {2-[3-aryl keto-propionylamino] Ice aryl phenyl amidinoic acid second-butyl ester or {2-[3-aryl-3-keto-propionylamino arylethynyl-phenyl-p-aminomethyl acid second -butyl ester (1.0 mmol) in CH2Cl2 (5 mL) [If necessary, add xylene or 1,3-dimethoxybenzene (5-15 mmol)] to TFA (0.5- 5.0 ml) was treated at 〇 ° C and stirring was continued at 2 yC until the tic cheek π starting material was completely consumed. The solvent was removed in the sputum and the residue was treated with a very small amount of ether. Then, it is crystallized. The solid is stirred up with a saturated NaHC〇3 solution, filtered, washed with a mixture of % hydrazine and ether or ether/hexane, and dried to give the title compound. / 03⁄43⁄4 /ether / hexane, purified by crystallization. General procedure 0: by 4-(3-iodophenyl)-8-phenylethynyl_i,3-dihydrophenylhydrazone [b][1,4]dioxine _ 2 as well as Pd- Catalyzing carbonyl amination to prepare 4_[3_(amino phenylcarbonyl)-phenyl]_8_phenylethynyl-1,3-dihydrophenylhydrazone [b][i,4]dioxine 1 ketone 4 -(3-iodophenyl)-8-phenylethynyl-indole, 3-dihydrophenylhydrazine [b][1,4]dioxine-2-one (1.0 mmol), secondary amine (5·〇毫莫耳), ppM6 Mo Er. 】) or dPPp (3 mole %), Pd (〇Ac) 2 (3 mole %) and Et3N (2 〇 millimolar) solution in DMF (4 liters), under 2yC and c〇 atmosphere Stir until ❿ shows complete consumption of iodide. After diluting with Et0Ac, it was washed with a saturated NaHc? Remove the solvent, leave a brown oil, and purify it by column chromatography, using hexane / hexane, ---il,---------^--- (please read the back first) Precautions on this page) . : Line. -127- I255266 A7 ----- B7____ V. Inventive Note (125) The title compound was obtained. Preparation of (5-hydroxy-2-) by catalytic allysylation of (5-allyloxy-2-nitro-phenyl)-amine methyl acid tert-butyl ester Nitro-phenyl)-amine methyl acid third-butyl ester according to J. 〇rg. Chem. 1973, 38, 3224, (5-fluorenyloxy-nitro-phenyl)-amino acid Mixture of second-butyl ester, (PPh3)3 RhCl (5 mol%) and DABCO (20 mol%) in EtOH, reflux for 2.5 hours. Add 5% citric acid and dial off at 23 C The mixture was extracted with EtOAc EtOAc (EtOAc m. Example R1 (5-hydroxy ice iodo-2-nitro·phenyl)-amine methyl acid tert-butyl ester according to the general procedure R, from (5-allyloxy_4·iodyl winter nitrate Base phenyl)-amino acid tert-butyl ester (Example B4), (PPh h RhCl (5 mol %) and DABC 〇 (20 mol %) in EtOH. Obtained a yellow solid. (ISN) 379 [(MH)·]; melting point 140 ° C. General procedure S: from (5-3⁄4yl-4-iodo-2-nitro-phenyl)-amine fluorenyl Acidic third-butyl ester, preparation of 5_〇_substituted-(4-diyl-2-nitro-phenyl)-amine methyl acid tert-butyl ester (5-hydroxy-4-iodo-2 a mixture of -nitro-phenyl)-amine methyl acid third-butyl ester (Example R1), KHC〇3 and a suitable alkylating agent, in DMF, stirred at 23 to 6 ° C until tic Show full conversion of 旯. Diluted with Et〇Ac, followed by aqueous solution with 5% citric acid, saturated NaHC〇3 solution, brine, and -128- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ----:---------Installation--- Please read the notes on the back of this page again) Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print A7 1255266 B7_____ Five , Inventive Note (126) Dehydrated with MgS04, the solvent was removed, and the crude material was purified, which was purified by column chromatography eluting with hexane / Et EtOAc to give the title compound. -butoxycarbonylamino-2-iodo-4-nitro-phenoxy)-acetic acid tert-butyl ester according to the general procedure S, from (5-hydroxy phenyl iodo-2-nitro-phenyl )-Aminomethyl acid third-butyl ester (example ρπχΐ .23 g, 3.24 mmol, KHC03 (0.39 g, 3.89 mmol) and tri-butyl bromoacetate (〇·59 ml, 3.89 mmol). Obtained a yellow solid (1.5 g, 94%) . MS (ISP) 495 [(M+H)+], 512 [(M+NH4)+] and 517 [(M+Na)+]; mp. Example S2 (5-Cyanomethoxy-4-bromo-2-nitro-phenyl)-amine methyl acid tert-butyl ester according to the general procedure S, from (5-hydroxy-4-iodo) 2-Nitro-phenyl)-aminomethyl acid tert-butyl ester (Example R1) (614 mg, 1.62 mmol), KHC03 (208 mg, 2.08 mmol) and bromoacetonitrile ( 〇·21 ml, 3.16 mmol.) Obtained as a yellow solid (574 mg, 85%). MS (ISN) 418 [(Μ-ΗΠ; melting point 125 ° C. Example S3 (RS)-{4-Bus-2-nitro-5-[2-(tetrahydro-peak-2-yloxy) --ethoxy]-phenyl-b-aminomethyl acid tert-butyl ester according to the general procedure S, prepared from (5. hydroxy-4-iodo-2-nitro-phenyl)-amine methyl acid Tri-butyl ester (Example Rl) (760 mg, 2 mmol), khcc^mo mg' 4 Amol) and 2-(2-&gt; odoryl ethoxy) tetrahydrofuran (0.6 mL, 2.6 Millions of ears). Obtained orange oil (804 mg, 79%). MS (EI) 508 (M+). -129- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----:---------Install i — (Please read the back note before you Page) Book · ί Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266

V. INSTRUCTIONS (127) JL^1_S4 (5-Terti-butoxy-4-iodo-2-nitro-phenyl)-amine methyl acid, third-butyl ester, N,N-dimethyl Carbamide-di-tert-butyl acetal (19.2 ml, 8 Torr) was added dropwise to (5-3⁄4 bp-4····· Phenyl)· Aminomethyl 3-butyrate (Example R1) (7.60 g, 20 mmol) in toluene at 80 ° C and at 80. (: stirring was continued for 3 hours (see, Synthetic Journal 1983, 135). Obtained a yellow solid (5.97 g, 68%). MS (ISN) 435 [(Μ-ΗΠ; melting point 94 ° C. Example 1 3-(7 - Iodo- ketone-based thio-of-of-fosfosin-4,5-dihydro-3H-benzoquinone [b][i,4]dioxane-2-yl)-benzonitrile according to the general procedure P, prepared by treatment with TFA in CH2Cl2, from cyano-phenyl)-3-keto-propionylamino]-4-iodo-5-thioxofolin-4-yl-benzene Amino acid mono-butyl ester (Example 01) (629 mg, 1·4 亳 4 亳). Obtained an olive solid (437 mg). mp 227-228 ° C (decomposition). 3-(7-iodo-8-morpholine-4-yl-4-keto-4,5-dihydro-3H-benzoquinone [b][i,4]di,azepine-2- Benzo-benzonitrile was prepared according to the general procedure P by treatment with TFA in (:3⁄4% from {2-[3_(:&gt;-oxy-mungyl)-3-indolyl-propyl aryl amine Alkyl-4-pyrene-5-? 309 mg) MS (ΕΙ) 472 (Μ+); melting point 224Ό (decomposed). -130- paper ruler Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------------- Installation - (Please read the back note on this page first) Order • Line · Ministry of Economics Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (128) Example 3 3-(8-Chloro-4-keto-7-phenylethynyl) ,5-dihydro-3H-benzoquinone [b][i,4]dioxane-2-yl)-benzidine according to the general procedure 0, from (2-amino-5-chloro+benzene) Ethyl ethynyl-phenyl)·amine methyl second-butyl ester (conventional L3) (171 mg, 〇·5 mmol) and hiro (2 2·monomethyl-6-keto-6Η-[ 1,3]-oxoindole # -4-yl)-benzonitrile (example) (183 g, 〇·6 mmol). Obtained as a pale yellow solid (284 mg). Treatment with TFA in 03⁄43⁄4, this material was deprotected and cyclized. Obtained an orange solid (483 mg) MS (ISP) 343 [(Μ+ΗΠ and 345 [(M+2+Na)+ melting point 248-25ιχ : (decomposition). Example 4 3-(8-Methyl-4-carbazyl-7-phenylethynyl-4,5-dihydro-3Η-benzoquinone [b][l,4]dioxane Because-2 -yl)benzonitrile according to the general procedure 0, from (2-amino-5-methyl-phenylphenylethynyl-phenyl)-amine methyl acid, third-butyl ester (example L4) (161 mg, 5.5 millimolar) with 3_(2,2•dimethyl-6-keto-6H-[1,3]dioxolyn-4-yl)benzonitrile (Example N4) (23〇 Mg, 〇·75 pens, 75% pure). Obtained as a pale yellow solid (227 mg). This material is removed for protection and cyclization according to the general procedure P by treatment with butyl FA in 03⁄4⁄4. Obtained as a pale yellow solid (83 mg). MS (ISP) 375 (M+); mp 237-239 (dec.). Example 5 3-[8-(4-Methyl-hexahydropyrazine)-free ketone-based 7-phenylethynyldihydro-3H-benzoquinone [b][l,4]dioxine- 2-Based]-benzonitrile is prepared according to the general procedure 0, from [2-amino-based (4-methyl-hexahydropyrazine + base) ice-131 - This paper scale applies to China National Standard (CNS) A4 specifications. (210 X 297 mm) (Jing Xian read the phonetic transcription on the back? Matters again page) Gutter 1255266 A7 B7 V. Invention Description (129 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Phenyl Ethyl-Phenyl ]-Aminomethyl 3-butyrate (example L5x203 mg, 0.5 moles) and 3-(2,2-dimethyl ketodioxanthene)-benzonitrile (Example N4) (230 mg, 〇.75 mmol, 75% pure). Obtained orange oil (181 g) by chromatography. According to the general procedure p, the material was removed by treatment with TFA in ch2 ci2. Cyclization. Obtained an orange solid (82 mg). MS (ESI) 46 〇 _5 [(M+H)+]; melting point mMc (decomposition). Example 6 3- [8-(1,1-dione) -thio-fosfosin)-iceketo-t-phenylphenylethynyl-4,5-dihydro-3H-benzoquinone [b][l,4]dioxepin-2-yl]- The carbonitrile is prepared according to the general procedure from [2_Amino-based (Adenyl diketo-6·thionorfosolin-4-yl) ice phenylethynyl-phenyl]-amine methyl acid _ Butyl ester (Example l19) (22 〇 mg, 〇·5 mmol) and 3-(2,2-dimethyl-6-keto-6Η-[1,3]dioxane-4 -yl)-benzonitrile (Example Ν4) (172 mg, 0.75 mmol). The obtained material was deprotected and cyclized by treatment with TFA in CH2C12 according to the general procedure. 47 mg) MS (ISP) 495 [(M+H)+]; melting point &gt; 250 ° C (decomposition). Example 7 3-(8-chloro-4-keto-7-phenyl-4, 5-Dihydro-3H-benzoquinone [b][l,4]dioxan-2-yl)-benzonitrile was prepared according to the general procedure P by treatment with TFA in CH2C12 from {2- gas. -5-[3-(3-Cyano-phenyl)-3- keto-propyl arylamino]-biphenyl 4-yl}-aminomethyl acid tert-butyl ester (Example 03) 720 mg, 1.47 mol.) Obtained as an off-white solid (457 mg) MS (EI) 371 (M+) and 373 [(M+2)+]; mp 242-244 ° C (decomposition). Applicable to China National Standard (CNS) A4 specification (210 X 297厘) Please read the precautions of the back δ and then the binding line of this page 1255266 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Α7 Β7 V. Invention description (130) Example 8 3-(8-methyl-4-keto- 7-Phenyl-4,5-dihydro-3H-benzoquinone [b][l,4]dioxine:yl)-benzonitrile according to the general procedure, from (5-Amino-2- Methyl-biphenyl-4-yl)-amine methyl acid tert-butyl ester (Example L7) (298 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-keto) -6H-[1,3]dioxanthene,ylyl)-benzonitrile (Example N4) (460 mg, 1.5 t mole). The obtained material (351 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure. A pale yellow solid (206 mg) was obtained. MS (EI) 351 (M+); mp 236-239 (m.). Example 9 3-[8-(1,4-Dioxoxane-spiro[4.5]fluorene>&gt; 4-keto-7-phenylethynyl-4,5-dihydro-3H-benzoquinone [ b][l,4]dioxan-2-yl]-benzonitrile was prepared from [2-indole-3-cyano-phenyl)-3 by treatment with TFA in CH2C12 according to the general procedure P -keto-propionylamino]_5-(l,4-dioxa nitrogen-spiro[4.5]dec-8-yl)-4-phenylethylidene-phenyl]-amine methyl acid Tri-butyl ester (Example 〇 14) (265 mg, 0.43 mmol) afforded brown solid (121 mg). MS (ESI) 503 [(M+H)+]; mp 239-243. Example 10 3-(8-moffin-4-yl-4-keto-7-phenylethylidene-4,5-dihydro-3H-benzoquinone [b][l,4] Indole-2-yl)-benzonitrile was prepared from {2-[3_(3-cyano-phenyl)3-keto-propenyl) by treatment with TFA in CH2Cl2 according to the general procedure P Amino] morphine sulphate · 4 · phenylethynyl-phenyl}-amine methyl acid tert-butyl ester 010 (370 mg, 〇 · 66 mmol). Obtained -133- This paper size applies China National Standard (CNS) A4 Specification (210 x 297 mm) -----»---------Installation - (Please read the notes on the back and then on this page) -•线- 1255266 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 ____ B7___ V. Inventive Note (131) Obtained as a light brown solid (216 mg) MS (El) 446 (M+); mp 239-243 ° C ( Decomposition) Example 11 3-[8-(2-Dimethylamino-ethylthio)-4.keto-7-phenylethynyl-4,5-dihydro-3H-benzoquinone [b][ l,4]Dioxein-2-yl]-benzonitrile was prepared from [2-[3-(3-cyano-benzene) by treatment with TFA and toluene in CH2Cl2 according to the general procedure P. ))-3-keto-propionylamino]-5-(2-dimethylamino-ethylthio)-4-phenylethylidene-phenyl]-amine methyl acid third-butyl Ester (Example 〇 4) (166 mg, 0.28 mmol) afforded a pale-yellow solid (1 </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> MS (ISP) 465 [(M+H)+]; 12 [4-(3-Cyano-phenyl)-2-keto-8-phenylethynyl-2,3-dihydro-1H-benzoquinone[b][i,4]-one-leaf -7-thio]-succinic acid is prepared according to the general procedure P, by treatment with TFA and toluene in CH 2 Cl 2 'from {5-di-di-butoxyamino} 4-[3- (3-apo-phenyl)-3-mercaptopropylamino]-2-phenylethynyl-phenylthiob Methyl acetate (Example 〇 5) (421 mg, 0.72 mmol). A pale yellow solid (3 〇 9 mg) was obtained. MS (ISP) 465 [(M+H)+]; mp. (: (decomposition). Example 13 [4-(3-Cyano-phenyl)-2-keto-8-phenylethynyl-2,3-dihydro-1H-benzoquinone [b][l, 4] Azepin--7-ylthio]-acetic acid [4-(3-cyano-phenyl)-2-keto-8-phenylethynyl-2,3-dihydro-1H- Benzoquinone [b][l,4]dioxine-7-ylthio]-acetic acid methyl ester (Example 12) (265 mg, 0.57 mmol) with Li〇H · Η2 Ο (26 mg, 0.63) Millimeter) in THF (5 ml), -134- This paper scale applies Chinese National Standard (CNS) A4 specification (21〇X 297 mm) ----l·--------- —— (Please read the notes on the back and then the page) · Line · 1255266

V. Description of the invention (132)

A solution of MeOH (1 mL) and EtOAc (1 mL) was stirred at 23 °C for 24 hr. Obtained as a pale yellow solid (257 mg). MS (ISP) 452 [(M+H)+ ] ; capacitance 202 ° C (decomposition). Example 14 [4-(3-Cyano-phenyl)-2-g-iso-phenylphenylethynyl-2,3-dihydro-1H-benzoquinone [Tonne to] Dioxepin-7-yl] - Methyl acetate is prepared according to the general procedure P by treatment with TFA in CH2C12 from {5_tris-butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3-one -propenylamino group &gt; 2-phenylphenyl phenyl phenylacetate (Example 06) (846 mg, 153 Torr). Obtained as a pale yellow solid (557 mg). MS (EI) 433 (M+); mp 236 (dec.). Example 15 [4-(3-Cyano-epiyl)-2-|isopicophenylphenylethynyl-2,3-dihydro-1H-benzo[b][l,4] Dioxeine- 7-yl]-acetic acid A solution of LiOH·H2 (54 g, 1.28 mmol) in EtOAc (2 mL) [4-(3-Cyano-phenyl)-2-keto-8-phenylethynyl-2,3-dihydro-1H-benzoquinone[b][1,4]dioxine Methyl acetate (Example 14) (505 mg, U7 mmol), and the mixture was stirred at 23 C for 48 hours. Obtained as a pale yellow solid (62 mg). MS (ISP) 452 [(M+H)+]; mp 248 (dec.). Example 16 4-(3-Cyano, phenyl) each iodo group: keto-2,3-dihydro-1Η-phenylhydrazine [T (4) dioxetane-7-recovery A] According to the general procedure P , processed by TFA in CH2C12, manufactured from 5_第-135- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) -----:-------- - Packing - (Please read the notes on the back and then this page) Order: 1.·Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 ____B7__ V. Description of Invention (133) Tri-butoxycarbonylamino -4-[3-(3-Cyano-phenyl)-3-keto-propionylamino]_2-iodo-benzoic acid methyl ester (Example 〇17) (430 mg, 0.763 mmol). Obtained as a flesh-colored solid (199 mg). MS (El) 445 (M+); mp 247 - 248 C (dec.). Example 17 2-[4-(3-Cyano-phenyl)-2-one- 8-Phenylethynyl 2,3-dihydro-1H-benzoquinone [b][l,4] geninyl-7-yl]-ethinyl[4-(3-cyano-benzene) Yl)-2-keto-8-phenylethynyl-2,3-dihydro-benzo[b][l,4]dioxepin-7-yl]-acetic acid (Example 15) (48亳Gram, (U14 millimolar), with BcK2〇 (37 mg), cis 4 this 〇3 (13 mg) And pyridine (6 μL) was treated in dmf (0.6 liters) at 23 C for 24 hours [see Tetrahedron Letters 1995, 36, 7115] to obtain a pale yellow solid (14 mg). MS (ISN) 417 [ (M-Η)·]; melting point 250 ° C (decomposition). Example 18 3- [8-(2-methoxy-ethoxy)-4-keto-yl-7-phenylethylidene-4, 5_Dihydro-3H-benzoquinone [b][l,4]dioxan-2-yl]-benzonitrile was prepared according to the general procedure P by treatment with TFA in CH2Cl2 from [2-[ 3-(3-cyano-phenyl)-3-keto-propionylamino]-5-(2-methoxy-ethoxy)-4-phenylethynylphenyl]-amine A Third-butyl acrylate (Example 07) (135 mg, 0.251 mmol). mp. mp. mp. 4-(3-cyano-phenyl)-2-keto-8-phenylethynyl-2,3-dihydro·1Η-benzoquinone[b][l,4]dioxine-7 Methyl ester-136- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ----.---------Installation--- Please read the notes on the back first. @@)) • Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 V. Description of Invention (134) Install i I C Please read the phonetic transcription on the back first? Matters again on this page) According to the general procedure P, prepared by treatment with TFA in CH2% from 5-tris-butoxycarbonylamino-4-[3-(3-cyano-phenyl)-3-one Methyl-propenylamino] 2 -phenylethylidene-methyl benzoate (Example 09) (511 mg, EtOAc EtOAc) (m. Μ+); melting point &gt; 250 ° C. Example 20 3-(8-methoxy-4-keto-7-phenylethynyl 4,5-dihydro-3H-benzoquinone [b][l, 4] 2-oxoheptin-2-yl)-benzonitrile was prepared from {2-[3-(3-cyano-phenyl)-3 by treatment with TFA in CH2Cl2 according to the general procedure P. Base-propionylamino]methoxy-4-phenylethylidene-phenyl]-amine methyl acid tert-butyl ester (Example 08) (359 mg, 〇·7 mmol). Tawny solid (87 mg). MS (ESI) 391 (M+): mp. )-ethoxy]-ethoxy}-ethoxy)brydenyl-7-phenylethynyl-4,5-dihydro-3H-benzoquinone[b][l,4]dioxine- 2-Base]-benzonitrile Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed according to the general procedure P, via TFA in CH2 Cl2 Medium treatment, prepared from [2-[3-(3-cyano-phenyl)-3-keto-propenylamino]-5-(2-{2-[2-(2-methoxy) -ethoxy)-ethoxy]-ethoxy}-ethoxy)-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester (example 011) (300 mg, 0.437 Obtained a pale yellow solid (211 mg). MS (EI) 435 (M+); mp 140-141 ° C (decomposition). Example 22 -137- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1255266

V. Description of invention (135) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, [4-(3-cyano-private)-2-g-iso-yl-8-phenylethylidene-2,3-dihydro 1H-benzoquinone [b][l,4]dioxine-7-yloxy]-acetic acid was prepared from {5-second-butyl via TFA in CH2C12 with toluene according to the general procedure P Oxycarbonylamino 4-[3-(3-cyano-phenyl)-3-keto-propylamino]-2-phenylethynyl-phenoxyacetic acid tert-butyl ester (example) 〇 12) (698 mg 'U4 millimoles). Obtained as a yellow solid (265 mg). MS (ISN) 434 [(M-Η)-]; mp 257 ° C (dec.). Example 233-(8-Cyanomethyl-4-keto-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4]dioxan-2-yl Phenyl nitrile is treated according to the general procedure P via TFA in CH2Cl2 with decyl ether, I from {5-carbylmethyl-2-[3-(3-)-phenyl)-3-one Tert-butylamino-4-phenylethyl-phenyl}-amine methyl acid tert-butyl ester (Example 〇 13) (266 mg, 0.51 mmol). Obtained as a yellow solid (145 mg). MS (EI) 400 (M+); mp 262 (dec.). Example 24 3-[8-(2,3-Dihydroxy-propoxy)crallow-7-phenylethynyl-4,5-dihydro-3H-benzo[b][l,4]吖heptyl-2-yl]-benzonitrile is prepared from [2-[3-(3-cyano-phenyl)-3-) by treatment with TFA in CH2Cl2 and decyl ether according to the general procedure P Ketopropyl-propionylamino]-5-(2,2-dimercapto-[1,3]dioxoindol-4-ylmethoxy)-4-phenylethynyl-phenyl]- Aminomethyl 3-butyrate (Example 016) (265 mg, 0.435 mmol). Obtained as a yellow solid (62 mg). MS (ISP) 452 [(M+H)+] and 474 [(M+Na)+]; melting point 230-234 ° C (decomposition). Example 25 Please read the precautions of the back δ and then #PAGE binding line-138 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Invention Description (136) 4-( 3-iodophenyl)-7-(2-methoxy-ethoxy)phenylphenylethynyl]}dihydrophenylhydrazone [b][ 1,4]dioxane-2-one, please read first Precautions on the back side of this page) According to the general procedure P, by treatment with TFA in CH2Cl2 and toluene ether, [2-[3-(3-iodophenyl)-3-keto-propenylamino) ]-5-(2-methoxy-ethoxy)-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester (Example 〇 15) (124 g, 1.89 mmol) ear). Obtained as a yellow solid (517 mg). MS (ΕΙ) 536 (Μ+); melting point 192 ° C (decomposition). Example 26 2-[4-(3-Cyano-indenyl)-2-yl-1-ylphenylethynyl-2,3-dihydro-1H-benzoquinone[b][l,4] -7-yloxy]-ethonamine EDC (42 mg, 0.22 mmol) was added to [4-(3-cyano-phenyl)2-indolyl-8-form under 〇C Ethyl bromide-2,3-dihydro-1H·benzoquinone [b][l,4]di.azepine-7-yloxy]-acetic acid (Example 22) (50 mg, 0.11 mmol) , nh4C1 (18 mg, 〇·33 mmol) and NMM (56 mg, 0.55 mmol) in DMF (1.1 mL) and the mixture was stirred at 23 ° C for 2 hours to obtain a yellow solid ( 5 mg) MS (ISN) 417 [(M-Η)-]; melting point 250 ° C (decomposition). Example 27 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 4-(3-Mijun-1-yl- Phenyl)-7-(2-methoxy-ethoxy)-8-phenylethynyldihydrophenylhydrazone [b][l,4]dioxepin-2-one according to the general procedure P, TFA is treated with CH2C12 in toluene ether from [[[2-[3-(3-imidazol-1-yl-phenyl)-3-g]-yl-propenylamino]_5_(2-methoxy , ethoxy)-4-methylene-yl-branched-mungyl--amino acid, third _ 酉 酉 (example 〇 18) (200 Gram, 0.336 millimolar). Obtained a yellow solid (28 mg). -139 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Description of invention (137) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed MS (EI) 476 (M+); Melting Point 187-189 ° C. Example 28 [RS]_3_[4_keto-8-(2 Martyo 4U) Dioxetan Ice Base Methoxy)_7_phenylethynyl-4,5-dihydro-3H-benzoquinone [b][l,4]dioxine-2-yl]benzonitrile is passed according to the general procedure P TFA was treated in CH2Cl2 from [RS]-[2-[3-(3-)-yl-yl)-3-keto-propenylamino]-5-(2-keto-[ 1,3] Dioxin-4-ylmethoxy)-4-phenylethynyl-phenyl]-amine methyl acid, third butyl ester (Example 019) (400 mg, 〇·67 mmol) Obtained as a yellow solid (287 mg). MS ( s) 477 ( Μ+).; mp 222 ° C (decomposition). Example 29 3-(8-ethoxymethyl-4-keto-7- Phenylethylidene-4,5-dihydro-3H-benzoquinone [b][l,4] Dioxepin-2-yl)-benzonitrile according to the general procedure P, via TFA in CH2Cl2 Treatment, made from {2-[3-(3-cyano-phenyl)-3-keto- Propionylamino]-5-ethoxymethyl-4-phenylethynyl-phenyl}-amine methyl acid tert-butyl ester (Example 020) (140 mg, 0.26 mmol). Obtained as a yellow solid (93 mg). MS (EI) 419 (M+); mp. Example 30 2,2-Methyl-propyl 4-(3-cyano-phenyl)-2-keto-8-phenylethylidene-2,3-dihydro-1H-benzoquinone [b ] [lr4] Dioxepin-7-ylmethyl ester was prepared according to the general procedure P by treatment with TFA in CH2Cl2 from 2,2-dimethyl-propionic acid 5-tris-butoxycarbonylamino 4-[3-(3-Cyano-phenyl)-3-keto-propionylamino]-2-phenylethynyl-word ester (Example 021) (156 mg, 0.26 mmol) . Obtained as a pale yellow solid (75 mg). -140- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). Please read the back © Note Note Item #再页 装线 1255266

5. Description of the invention (138) MS (EI) 475 (M+); m.p. 218. Example 31 Please read the notes on the back side of this page again) 3- (8-3⁄4 methyl-4-keto-7-phenylethynyl-4,5-dihydro-3H-benzoquinone [b][l , 4] dioxin-2-yl)-benzazole from 2,2-monomethyl-propionic acid '(3-cyano-phenyl)-2-keto-l-phenylethynyl _ 2, 3-Dihydro-1H-benzoquinone [b][l,4]dioxine-7-ylmethyl ester (Example 3〇) (3〇mg, 〇·〇63 4mol) and LiOH · Η: 0 (8 gram, 〇. 289 mmol) in thf (2 mL), MeOH (0.4 mL) and H.sub.2 (0.4 mL). Obtained as a yellow solid (17 mg). MS (EI) 391 (M+); m.p. &gt; 255. Example 32 7-Hydroxymethyl-4-(3-imidazolyl-phenyl)phenylphenylethynyl '3-dihydrobenzoquinone [1,4]-portal f-gyne-2-pyrene Procedure P, prepared by treatment with TFA in CH2Cl2 from (RS)_[2-[3-(3-imifluor-1-yl-phenyl)butanyl-propionylamino]-4_ Phenylethylidene hexyl (tetrahydro^endan-2-yloxymethyl)-phenyl]-amine methyl acid tert-butyl ester (Example 〇 22). Obtained as a yellow solid (77 mg). MS (EI) 432 (M+); melting point 227 °C. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing Example 33 4- (3-Methoxy-1-yl-phenyl)-7-(4-decyloxy-hexahydropyridinium + yl) phenylethynyl _ 1,3 -Dihydrophenylhydrazine [b][i,4] Dioxanthone is prepared according to the general procedure P, by treatment with TFA in CH2Cl2, from [2-[3-] 3-keto-propionylamino]-5-(4-methoxy-hexahydropyridin-1-yl)-4-phenylethynyl-phenyl]-amine methyl acid tert-butyl ester (Example 〇 23). _ _ -141 - This paper size applies to China National Standard (CNS) A4 specification (21〇x 297 mm) 1255266 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7__ V. Invention Description (139) Yellow solid ( 159 mg). MS (ISP) 516 [(M+H).]; melting point 222 °C. Example 34 3-[8-(4-Methoxy-hexahydropyridine small group &gt; 4-keto-7-phenylethynyl-4,5-dihydro-3H-benzoquinone [b][l, 4] Dioxepyn-2-yl]-benzonitrile was prepared from [2-[3-(3-cyano-phenyl)-3-one by treatment with TFA in CH2Cl2 according to the general procedure P Base-propionylamino]methoxy-hexahydropyridin-1-yl)-4-phenylethynyl-phenyl]-aminocarbamic acid tert-butyl ester (Example 〇 24). Obtained a yellow solid (128 mg). MS (ISP) 475 [(M+H)+]; mp. 250-251. Example 35 [4-(3-Miso.Spin-1-yl-phenyl)-2-keto-8-phenylethynyl-2,3-dihydro-1H-benzoquinone [b] [1,4 Dioxepin-7-yloxy]-acetonitrile was prepared from {5-cyanomethoxy-2-indole (3-imidazol-1-yl) by treatment with TFA in CH.sub.2 Cl. -Phenyl)_3_keto-propionylamino]-4-phenylethynyl-phenyl-benzamidinoic acid tert-butyl ester (Example 〇 25). Obtained as a yellow solid (43 mg). MS (EI) 457 (M+); mp. Example 36 3-(8-Cyanomethoxylketo)-7-phenylethynyl-4,5-dihydro-3-indole benzoquinone [Qiu (4) Dioxe-2-yl)-benzonitrile Prepared from the cyanomethoxy-2-indole (3-cyano-phenyl)-3-keto-propenylamino]phenylethynyl group by treatment with TFA in CH2Cl2 according to the general procedure -Phenyl}-aminomethyl acid tert-butyl ester (Example 〇 26). Obtained a yellow solid (7][ -142- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) -----r---------Installation - (please first Read the precautions on the back ##页) tj·—·线- 1255266 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (140) mg). MS (EI) 416 (M+); mp. Example 37 8-(4-Fluorophenylethynyl)-7-hydroxymethyl-4-(3-imidazolyl-phenyl)-1,3-dihydrophenylhydrazone [b][l,4]dioxin Glycan-2-one is prepared according to the general procedure P by treatment with TFA in CH2C12 from (RS)-[4-(4-fluorophenylethynyl)_2-[3-(3-imidazol-1-yl) -Phenyl)-3-keto-propionylamino]-5-(tetrahydro-methane-2-yloxymethyl)-phenyl-p-methylamino acid tert-butyl ester (Example 027 ). Obtained as a yellow solid (462 mg). MS (EI) 450 (M+); mp. Example 38 8-(4-Fluorophenylethyl)-7-[(2-hydroxyethyl)-methyl-amino] Winter (3-imidazolyl-phenyl: fluorene, 3-dihydro Phenylhydrazone [b][l,4]dioxan-2-one was prepared from (RS)-(4-(4-fluorobutylidene) by treatment with TFA in CH2Cl2 according to the general procedure P. -2-[3-(3-benzophen-1-yl-phenyl)-3-keto-propionylamino]-5-{methyl-[2-(tetrahydro-pyran-2- (Ethyloxy)-ethyl]-amino}-phenylamine methyl acid, tert-butyl ester (Example 028), obtained as a yellow solid (yield: 73 mg). MS (EI) 493 (M+); Decomposition) Example 39 4-(3-Imidazol-1-yl-phenyl)-7-(4-keto-hexahydropyridine small)-8-phenylethylidene-1,3-dihydrobenzene幷[b][l,4] Dioxepin-2-one is prepared according to the general procedure P, by treatment with TFA in CH2Cl2, from {5-(4,4-E-emulsion-based mouse p-sense - 1-yl)-2-[3-(3-isophen-1-yl-phenyl)-3-indolyl-propenylamino]-4-phenylethynyl-phenyl-p-aminomethyl acid Third-Butyl Ester (Example 〇29) -143- (Please read the note on the back and then on this page) -Installation • II eaia ·βι·β ---订----线线Paper scale applies to Chinese national standards (CNS ) A4 specification (210 X 297 public)) 1255266 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 V. Inventive Note (141) Obtained a yellow solid (180 mg) MS (EI) 499 (M+); melting point 231° C (decomposition). Example 40 N-Terti-butyl-2-[4-(3-cyano-phenyl)-2-keto-phenylphenylethynyldihydro-1H-benzoquinone [b][l , 4] Dioxepin-7-yloxy]-acetamide via chlorinated grass mash (26 μl, 〇·3 mmol) in DMp (〇·6 ml), under 〇C After treatment for 1 hour, it was further treated with tri-butylamine (1 〇 6 μl, ι 〇 millimolar) at 0 C for 30 minutes from [4-(3-cyano·phenyl)_2_ Ketosylphenyl phenylethynyl-2,3-dihydro-1 fluorene-benzo[b][l,4]dioxine-7-yloxy]-acetic acid (Example 22) (87 g, 〇·································· -keto-8-phenylethynyl 2,3-dihydro-1H-benzo[b][l,4] diheptan-7-yloxy]·Ν-methoxy-acetamidine The amine is via EDC (38 g, 〇. 2 mmol), Me0NH2 HC1 (9 mg, 0.11 pen) Mole), NMM (0.021 ml, 〇·3 mmol) and h〇BT (15 mg '0.113⁄4 mol) in DMF (1 ml), treated at 〇 to 23 ° C for 20 hours. [4-(3-Cyano-phenyl)-2-keto-8-phenylethynyl-2,3-dihydro-1H-benzoquinone [b][l,4]-&lt;gine- 7-Alkyloxy]-acetic acid (Example 22) (44 mg, 〇. 1 mmol). Obtained as a yellow solid (36 mg). MS (ISP) 465 [(M+H)+]; mp. Example 42 1 (2-Light-ethoxy)-4-(3-imidazolyl-phenyl)-8-phenylethynyldihydrophenylhydrazone [b][l,4]dioxine- 2-ketone I · II (please read the precautions on the back page again) . -144 - 1255266

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing, V. Inventions (142) According to the general procedure P, by TFA in CH2C12, from (RS&gt; {2-[3-(3-imidazol-1-yl-) Phenyl)-3-keto-propionylamino] bromophenylethynyl_5_ [2-(tetrahydro-peak-2-yloxy)-ethoxy]-phenylamine methyl acid The third-butyl ester (Example 029) gave a pale-yellow solid (48 mg). MS (ESI) 462 (M+); 4-3⁄4 yl-hexahydro ton m ) _4_(3-imidinyl phenyl), 3-dihydrophenylhydrazine [b][l,4]dioxine-2-g is according to the general procedure P By treatment with TFA in CH2C12, (RS&gt;{4L fluoro-5-[3-(3-imidazol-1-yl-phenyl)-3-keto-propionylamino]ι[ 4_(tetrahydro-pyran-2-yloxy)-κhydropp-pred-1-yl]-biphenylwhenylamine methyl acid tert-butyl ester (Example 031). Solid (1 〇 9 mg) MS (ISP) 496 [(Μ+Η)+]; mp 238-240 ° C. Example 44 8-(4-fluorophenylethynyl)-7-(2-hydroxy- Ethoxy)-4-(3-imidazolyl-phenyl,)_1,3-dihydrophenylhydrazone [b][l,4]dioxepin-2-one Prepared from {5-(2-tris-butoxy-ethoxy)-4-(4-fluorophenylethynyl)-2-0 by treatment with TFA in CH2Cl2 according to the general procedure 3-Myryl-1-yl-phenyl)-3-keto-propyl-arylamino]-phenyl}-aminomethyl acid tert-butyl ester (Example 〇 32). Obtained pale yellow solid (83 mg) MS (EI) 480 (M+); mp. 220-222 ° C. Example 45 8-(4-fluorophenyl)-7-[4-(2-hydroxy-ethoxy)-hexahydro Pyridin-1-yl]-4-(3-imidazol-1-yl-phenyl H,3-dihydrophenylhydrazone [b][l,4]dioxepin-2-one-145- paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ----1---------Installation---1 (Please read the back note on this page first) Order--- ------- Line 1255266 A7 B7 V. INSTRUCTIONS (143) According to the general procedure P, by TFA in CH2C12, from (RS)-(4f-fluoro-5-[3-( 3-Miso.Spin-1-yl-phenyl)-3-keto-propionylamino]_2-{4-[2-(tetrahydrofuran-2-yloxy)-ethoxy] - Hexahydropyridine small base diphenyl phenylmethylene) - amine methyl second - butyl vinegar (Case 033). Obtained as a pale yellow solid (97 mg). MS (ISP) 540 [(M+H)+]; mp. Example 46 8-(4-Fluorophenyl)-7-hydroxymethyl-4-(3-imidazolyl-phenyl η,3^hydrobenzoquinone, 4] Dioxepin-2-one according to General Procedure P, prepared by treatment with TFA in 03⁄4⁄4, from [RS&gt;[4f-fluoro-5-[3-(3-imis-l-yl-phenyl)-3-keto-propenyl) Amino]-2-(tetrahydrofuran-2-yloxymethyl)-biphenyl-4-yl]-amine methyl acid tert-butyl ester (Example 〇 34). Obtained as a pale yellow solid ( 162 mg) MS (EI) 426 [(M)+]; mp. 180-195 ° C. Example 47 [8-(4-Fluorophenyl)-4-(3-Minyl-1-yl-phenyl) )-2-keto- 2,3-dioxaquinone [b] [1,4]-17 f-glycol-7-yl-lactyl]-ethyl acetoin according to the general procedure P, via TFA in CH' Processed in l2, made from {2_aminomethoxy-5-[3-(3-imipo-yl-phenyl)_3-keto-propenylamino]] Ministry of Economic Affairs Intellectual Property Office staff consumption Co-operative printing -----:---------Shang Yi I (please read the notes on the back #this page) • Line - biphenyl-4-yl}-amine methyl acid Tri-butyl vinegar (Example 035). Obtained as a yellow solid (11 mg). &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&& Phenyl -4-(3-imidazolium-stupyl H 3_bis[b][l,4]dioxine-2-ketone-146 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 嫠) 1255266 A7 B7 V. INSTRUCTIONS (144) According to the general procedure P, by treatment with TFA in CH2Cl2, from {2-dimethylaminomethyl.4^fluoro-5-[3 -(3-Imidazo-phenyl)-3-keto-propionylamino]-biphenyl-4-yl}-amine methyl acid #3 - butyl g (Example 〇 36). Obtained as a brown solid (180 mg). MS (ESI) 454 (M+H)+; mp s:::::::::::::: Dioxosulfon [4,5-c]ppirin-5-yl)(4-fluorophenyl)-4-(3-imtop-1-yl-phenyl)-1,3- Dihydrophenylhydrazine [1^][1,4]di-sigma-heptan-2-one is prepared according to the general procedure, by treatment with TFA in CH2Cl2, from {2_(2,2-didecyl-tetra Hydrogen-[1,3]dioxosin [4,5-c]ppylo-5-yl)-4,-fluoro-5-[3-(3-imifluor-1-yl-benzene) Benzyl-3-keto-propylaminoamino]-biphenyl-4-yl}-aminomethyl acid tert-butyl ester (Example 037). Obtained as a yellow solid (358 mg). MS (EI) 537 (M+); mp. 240 (dec.). Example 50 7-(cis-3,4-«-mono-yl-tetrazine p-l-l-yl)-8-(4-phenylphenyl)-4-(3- propyl-l-yl) Phenyl)-1,3-dihydrobenzo[b][l,4]dioxan-2-one via 13% HCl (15 ml) in THF (50 mL) at 23 ° C Treatment for 16 hours, from 7-(2,2-dimethyl-tetrahydro-[1,3]-dioxacillin [4,5-c]pyrrole-5-yl)-8-(4- Fluoro-phenyl)-4-(3_imistenyl-phenyl)-1,3-dihydrophenylhydrazone [b][l,4]dioxalyl-2-one (Example 49) 304 mg, 0.57 mmol. Obtained a yellow solid (209 mg). MS (ISP) 498 [(M+H)+]; mp. Example 51 8-(4-Fluorophenyl)-4-(3-imidazol-1-yl-phenyl)-7-methoxy-1,3-dihydrophenylhydrazone [b][l,4] - 147- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the back note on this page first) Pack------------ -: Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Description of Invention (145) Dioxane-2-one is processed according to the general procedure P' via TFA in CH2 C12, from {心气5-[3-(3-imith-1-yl-phenyl)-3-keto-propyl-arylamino]-2-methoxy-biphenyl-4-yl-b-aminomethyl Acidic third-butyl ester (Example 038). Obtained a yellow solid (182 mg). MS (EI) 426 (M+); mp 221 (dec.). Example 52 8-(4-Fluorophenyl)-4-(3-imidazol-1-yl-phenyl)-7-(4-keto-hexahydropyridine small group h,3-dihydrophenylhydrazine [b ][l,4] Dioxepin-2-one was prepared according to the general procedure P by treatment with TFA in 03⁄4 % from (1,4-oxo-8-nitro-spiro[4.5]癸-8- -4'-Fluoro-5-[3-(3-imiran-1-yl-phenyl) keto-yl-arylamino]-biphenyl-4-yl}-aminomethyl Acidic third-butyl ester (Example 〇 39) obtained Y in orange-brown solid (150 mg) MS (ESI) 494 [(M+H)+]; mp. 204 ° C. Example 53 8-(4-fluoro Phenyl)-4-(3-imidazol-1-yl-phenyl)-7-methyl-1,3-dihydrophenyl hydrazine dioxetane-2-one Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System----:---------Installation - (Please read the note on the back of this page first) - 丨 line _ according to the general procedure Ρ, by TFA in CH2 Cl2, from { 4,-Fluoro-5-[3-(3-imidazol-1-yl-phenyl)-3-keto-propionylamino]_2-methyl-biphenyl-4-yl}-amine Tri-butyl methacrylate (Example 〇 4 〇) gave a pale-yellow solid (216 mg). MS (EI) 410 (M+); mp 196 ° C. Example 54 [8-(4-fluorophenyl) Ice (3-imidazole-1- -Phenyl)_2-keto-2,3-dihydro-1H-benzoquinone [b] -148 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1255266 A7 Ministry of Economics Property Bureau employee consumption cooperative printing 5, invention description (146) [1,4] a leaf gem-7-yloxy]-acetic acid according to the general procedure P, by Ding from (3) 2%, from (4) Third-butoxysylamine-based oxy-5-[3-(3-m- ox+yl-phenyl); keto-propionylamino]-biphenyl-2-yloxy Tri-butyl acetate (Example 〇 41) gave a beige solid (570 mg). MS (ESI) 471 [(M+H)+]; mp 209 ° C (decomposition). Example 55 2-[8 -(4-fluorophenyl)-4-(3-imidazolyl-phenyl)-2-ylenyldihydromethane benzophenanyl[1,4]azepin-7-yloxy ]-N-radio-yl-bromoamine via hydrazine-tritylhydroxylamine (61 mg, 〇·22 亳 molar), h〇b butyl (9) mg, 0.22 mmol, (66 μl, 〇·6 mmol) and EDC (77 gram, 0.4 φ mol) in j)MF (2 ml), from 〇 to 23. The hydrazine reaction was carried out for 18 hours from [8-(4-fluorophenyl)-4-(3-imidazolyl·phenyl ketone-2-&gt;dihydro-1H-benzoquinone[b][l,4]吖gyne -7-yloxyacetic acid (Example 54) (94 mg, 〇·2 耄 Mo). According to the general procedure P, after extraction and chromatography, the formed orange solid fa and TFA in CH2 Stir in Cl2 to give a pale-yellow solid (7 mg). MS (ESI) 486 [(M+H)+]; melting point i47-157 ° C (decomposition). Example 56 7-Gas-8-(4- Fluorophenyl)-4-(3-micyl-phenyl)-1,3-dihydrophenylhydrazine [^[m]dioxan-2-one is treated according to the general procedure P via TFA in CH2Cl2 , from {2-chloro-1 fluoro-5-[3-(3-amido-1-yl-phenyl)-butanyl-propionylamino>&gt;biphenyl-4-ylpamine Third-butyl methacrylate (Example 〇 42). Obtained a pale yellow solid (7). Please read the notes on the back first. Binding-149- A paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 PCT 1255266 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventions ( 147 ) g ) MS (EI) 430 (M+); melting point 209-21 rC. Example 57 H4- Fluorophenyl)-4-(3-imidazolyl-phenyl)-7-(2-methoxy-ethoxy)&gt;: 1,3 dihydrophenylhydrazone [b][l,4]dioxine 2-ketone was prepared according to the general procedure P by treatment with TFA in 03⁄4 % from [4匕fluoro-5-[3_(3-imidazol-1-yl-phenyl)-3-yl-propyl) Aminomethoxy-ethoxy)-biphenyl-4-yl]-amine methyl acid tert-butyl ester (Example 〇 43). Obtained as a yellow solid (96 mg). MS (El) 470 (M+); mp 196-197. Example 58 8-(4-Fluorophenyl&gt;7-(2-hydroxy-ethoxy)-4-(3-imidazol-1-yl-phenylh,3-dihydrophenylhydrazine [b][l , 4] Dioxin-2-yl is prepared according to the general procedure P, by treatment with TFA in CH2%, from {2-(2·first-butoxy-ethoxy)-4f-fluoro -5-[3-(3-imifluoren-1-yl-phenyl)_3_g synthyl-propyl-ylamino]-binyl-4-yl}-amine methyl acid second-butyr Example 044). Obtained as a pale green solid (95 mg). MS (EI) 456 (M+); mp 225 C. Example 8 (4-fluorophenyl)-4-(3-imidazolyl-phenyl)- 7-(2-keto-oxazolidinyl-3-yl H,3-dihydrophenylhydrazone [b][l,4]dioxepin-2-one according to the general procedure P, via TFA in CH2 C Processed in !2, prepared from [4^ gas-based-5-[3-(3-imidazolyl-phenyl keto-propionylaminoketone ketone-3-yl)-3-biphenyl _ 4_基]_Amino acid tert-butyl ester (Example 〇 45). Obtained yellow __ -150- This paper scale applies to China National Standard (CNS) A4 specification (21〇χ 297 公^&quot;) ^ -----Γ 1 I--- II (Please read the notes on the back and then on this page) Order _ 1· _ Line·

1255266 V. INSTRUCTIONS (148) Colour solid (35 mg). MS (EI) 481 (M+); m.p. 23 ( s. s. s. s s s s s s s s s s s s s s.基—I,···································································· [3-(3-Min-1-yl-phenyl)- each fluorenyl-propionylamino]_2-methoxymethyl-biphenyl-4-yl}-amine methyl acid _ Butyl ester (Example 〇 46). Obtained a beige solid (101 mg). ^ MS (EI) 440 (M+); melting point 225 ° C. Example 61 8-(4-Fluorophenyl)-7-hydroxy-4-(3-imidazolyl-phenyl)-indole, 3·dihydrophenylhydrazine [b][1,4]dioxine- 2-ketone was prepared according to the general procedure P from p- 2,4-butoxy-4'-fluoro-5-[3-(3-imidazol-1-yl-phenyl)- via TFA in CH2C12 3-keto-propionylamino]-biphenyl phenylaminomethyl acid tert-butyl ester (Example 047). Obtained a yellow solid (109 mg). MS (EI) 412 (M+); mp. Example 62 8-(2-Fluorophenyl)-7-hydroxy-4-(3-imidazol-1-yl-phenyl)-1,3-dihydrophenylhydrazone [b][l,4]dioxane In-2-ketone is prepared according to the general procedure P, by treatment with TFA in CH2C12, from {2-first butoxy-oxyl-5-[3-(3-flavor-1-yl-winter) -3-indolyl-propylaminomethyl]-biphenyl-4-yl}-amine methyl acid tert-butyl ester (Example 〇 48). Obtained a yellow solid -151 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) ^--- (Please read the back note before this page) '•Line - Ministry of Economics Intellectual Property Bureau employee consumption cooperative printing 1255266

V. Description of the invention (149) (132 mg). MS (EI) 412 (M+); mp. 220. -------------Installation--- (Please read the notes on the back and then 0) Example 63 8-(4-Fluorophenyl)-7-((R&gt;3- Hydroxy-tetrahydropyrrole+yl&gt;4-(3-imidazolyl-phenyl)·1,3-dihydrophenylhydrazone [b][l,4]dioxepin-2-one according to the general procedure p , by treatment with TFA in CH2Cl2, from (rs)-K-fluoro-5-[3-(3-imidazol-1-yl-phenyl) keto)-propionylamino]_2_[( Ιι) (tetrahydro-pyran-2-yloxy)-tetrahydropyrrole+yl]diphenyl- 4 benzylamine methyl acid tert-butyl ester (Example 049). Obtained a yellow solid ( 74 mg) MS (ΕΙ) 481 (Μ+); mp 155-158 ° C. Example 64 8-(2-fluorophenyl)-4-(3-imidazol-1-yl-phenyl)-7- Methoxy-oxime]dihydrophenylhydrazine [b][i,4] Dioxepin-2-one is prepared from {2,-fluoro-5-- via TFA in CH2Cl2 according to the general procedure P. [3-(3-imidazol-1-yl-phenyl)-3-keto-propionylamino group methoxy-biphenyl phenyl]-amine methyl acid tert-butyl ester (example 〇 5〇). Obtained a yellow solid (10) mg) MS (EI) 426 (M+); melting point 216 ° C (decomposition). Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative Example 65 3-[7-(4-Fluorophenyl)-8-hydroxy-4-keto-4,5-dihydro-3H-benzoquinone [b][l,4]dioxine- 2- Benzyl-benzonitrile was prepared from {2-tri-butoxy-5-indole (3-cyano-phenyl)-3.-propanyl via TFA in CH2Cl2 according to General Procedure Tert-Amino]_4,-fluoro-biphenylyl}-aminomethyl acid tert-butyl ester (Example 〇 51). Obtained a yellow solid (66 mg). -152 - The paper scale applies to the Chinese national standard ( CNS) A4 Specification (210 X 297 public) 1255266 A7 V. Description of the Invention (150) MS (EI) 371 (M+); Melting Point &gt; 250 ° C. Example 66 3-[7-(2-Fluorophenyl) -8-hydroxy-4-keto 4,5-dihydro-3H-benzoquinone [b][1,4p, azepine-2-yl]-benzonitrile' according to the general procedure P, via TFA ( :3⁄43⁄4 in the preparation, from {2_T-butoxy-5-[3-(3-cyano-phenyl)-3- keto-propyl arylamino]_2, _ fluoro__ Phenyl 4-yl}-aminomethyl acid tert-butyl ester (Example 〇 52). Obtained as a yellow solid (8 mg). MS (EI) 371 (M+); melting point &gt; 250 ° C. Example 67 3- [7-(2-Fluorophenyl)-8-indolyl-4-keto-4,5-dihydro-3H-benzoquinone [b][l,4]di-sigma-heptan-2-yl ]-benzene The nitrile was prepared according to the general procedure P from [5-[3-(3-cyano-phenyl)-3-indolyl-propenylamino]-2,-fluoro-2 via TFA in CH2C12. -Methoxy-biphenyl]-yl}-aminomethyl acid tert-butyl ester (Example 〇 53). Obtained as a pale yellow solid (51 mg). MS (EI) 385 (M+); mp 245-247. Example 68 8-(2-Fluorophenyl)-7-methoxy-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydrophenylhydrazine 0] [1,4] Dioxepin-2-one is prepared according to the general procedure P by treatment with TFA in CH2Cl2 from (2,-fluoro-2-bromo-5-{3-[3- (2-methyl-myroxy-1-yl)-phenyl]-3-§-yl-propyl-arylamino}-biphenyl-4-yl)-amine methyl acid tert-butyl ester ( Example 〇 54). Obtained a yellow solid (207 mg). MS (EI) 440 (M+); mp. 220-222. Example 69 -153 This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) -----r---------Install--- c Please read the back of the note first Matters again page) Order · Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266

V. INSTRUCTIONS INSTRUCTION (151) 5-[7-(2-Fluorophenyl)-methoxyl-keto- 4,5-dihydro·3Η•benzo[b][i,4]dioxine 2-yl]-p-cephen-2-ylcarbonitrile was prepared from G屮_(5-cyano-thiophen-2-yl)-3-one by treatment with TFA in (3) 2% according to the general procedure P -propenylamino] 2 L fluorojjmethoxy-biphenyl phenyl}-aminomethyl acid tert-butyl ester (Example 〇 55). Obtained a yellow solid (1 〇 3 mg). MS (EI) 391 (M+); mp. &lt; Example 70 8-(2-Fluorophenyl)-7-methoxy ketone (3-[1,2,4]triazol-4-yl-phenylindene dihydrobenzo[b][l,4 Dioxepin-2-one is prepared according to the general procedure P by treatment with TFA in CH^Cl2 from {2L-fluoro-2-methoxy-5-[3-keto-(3-[1 , 2,4]triazole_4_yl-phenyl)·propanylamino]_biphenyl-4·ylbuminic acid tri-butyl ester (Example 〇 56). Obtained a yellow solid ( &lt;2&gt; MS (EI) 427 (M+); mp 188 ° C (decomposition). Example 71 4-[7-(2-fluorophenyl)-8-methoxy-4-keto-4 ,5-dihydro-3H-benzo[b][i,4]dip丫heptin-2-yl]π ratio bite-2-曱 guess according to the general procedure P, by treatment with TFA in ¢:3⁄43⁄4 , from {5-(&gt;(2-cyano-4-pyridin-4-yl)-3.keto-propionylamino]-2f-fluoromethylmethoxy-biphenyl-4-yl }-Aminomethyl 3-butyrate (Example 〇 57). Obtained a yellow solid (10 mg). MS (EI) 386 (M+); mp. 240-242 ° C. Example 72 - 154 - National Standard (CNS) A4 Specification (210 X 297 mm) ———-----Install i— (Please read the note on the back and then on this page) Word: Line. Property Bureau employee consumption cooperative printed 1255266 A7 B7 V. Invention description (152) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 8-(4-fluorophenyl)7-hydroxy_4-[3-(2-A Base-imidazole small group)-phenyl H,3-dihydrophenylhydrazine [b][l,4]dioxeine-2-indole according to the general procedure P, by treatment with TFA in Cj^d2 Self-仏3 -butoxylfluoro-5-{3-[3-(2-methyl-imidazolyl)-phenyl]-3-ketopropenylamino}-biphenyl-4 -Based --Aminomethyl-tert-butyl ester (Example 〇 58). Obtained a yellow solid (49 g). & MS (ISP) 427 [(Μ+Η)+]; melting point 260 ° C. 73 4-fluoro-3-[7-(2-fluorophenyl)-8-methoxy-4-keto-4,5-dihydro-3H-benzo[b][l 4] diterpene Glycon-2-yl]-benzonitrile was prepared according to the general procedure P by treatment with butyl FA in CH2% from (5-methyl-2-fluoroundyl)-3-keto-propionylamine Base] 2'-Fluoro- 2 -methoxy-biphenyl-4-yl-b-methylamino acid, tert-butyl ester (Example 〇 59). Obtained a yellow solid (52 mg). MS (ISP) 404 [(M+H)+]; Melting Point &gt; 25〇Ό. Example 74 4-[7-(4-Fluorophenyl)fosyl-4-keto-4,5-dihydro-3Η-benzoquinone [b][i,4]di-p-heptane·2- ]] 淀-2-甲月青 according to the general procedure P, via TFA in CH2 (3⁄4, from {2_T-butoxy-5-[3-(2-cyano-p ratio) Pyridin-4-yl)-3-keto-propionylamino]-4,_qi_biphenyl-4-yl}-amine methyl acid tert-butyl ester (Example 〇 60). Obtained yellow Solid (24 mg) MS (EI) 372 (M+); mp 164 ° C. Example 75 - 155 - (Please read the back note on this page) Binding - _ - Line · This paper size applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1255266

V. Description of the invention (153) 8-(2-fluorophenyl)-7-hydroxy-4-(3-[l,2,3]triazol-1-yl-printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs Phenyl&gt;u-dihydrobenzo[M]dioxepin-2-one was prepared from {2_tris-butoxy-2, by treatment with TFA in 03⁄43 according to the general procedure P. Fluoro-5-[3-keto-(3-[1,2,3]triazol-1-yl-phenyl)-propylaminoamino]-biphenyl-4-yl}-amine A Third acid butyl acrylate (Example 〇 61). Yellow solid (6) mg). &quot;MS (ISP) 414 [(M+H)+]; melting point > 250 °C. Example 76 3-[8-(1,4-Dioxo-8-nitro--spiro[4.5]fluorenyl)-7-(2-fluorophenyl)-4-keto-4,5-dichloro _ 3H-benzoquinone [b][l,4]dioxan-2-yl]-benzonitrile was prepared from [5-[3· (3) by treatment with TFA in CH2Cl2 according to the general procedure P. -cyano-phenyl) keto-propionylamino]_2-(l,4-dioxil-spiro[4.5]dec-8-yl)-2f-fluoro-biphenyl-4- Alkyl--aminomethyl acid tert-butyl ester (Example 062). Obtained a yellow solid (132 mg). MS (ISP) 497 [(M+H)+]; mp. Example 77 7-(1,4-Dioxo-8·nitro-spiro[4.5]fluorenyl)-8-(2-fluorophenyl)-4-(3-imidazol-1-ylphenyl)_ 1 , 3-dihydrophenylhydrazine [b][l,4]dioxine-2-one is prepared according to the general procedure P by treatment with TFA in CH2Cl2 from {2·(1,4-dioxo- 8-Nitro-spiro[4.5]fluorenyl)-2,-fluoro-5-[3-(3-imidazol-1-yl-phenyl)oxanyl-propionylamino]-biphenyl Ice-based amino acid-tert-butyl ester (Example 063). Obtained as a yellow solid (133 mg). MS (ISP) 538 [(M+H).]; melting point 225 °C. Example 78 -156- This paper size applies to China National Standard (CNS) A4 specification (21〇 X 297 public) Please read the note on the back before this page) Binding* · Line·

1255266 V. INSTRUCTIONS (1&amp;4) 8_(2-Fluorophenyl)_4-(3-imidazole+yl-phenylketo-hexahydropyridine small group p,3_dihydrophenylhydrazine[b][l, 4] Two 丫 因 酉 酉 酉 酉 酉 酉 酉 酉 绖 IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN -8-nitro-spiro[4.5]癸j-yl)-8-(2-fluorophenyl)-4-(3-miso-1 phenyl)-1,3-monohydrophenylhydrazine [b][i , 4] Dioxenone (Example 77) (54 mg, 〇 1 mmol). Obsed a yellow solid (39 mg). MS (EI) 493 (M+); melting point 230. (3. 8-(2-Fluorophenyl)-7-hydroxy-4-l&gt;(2-methyl-imidazo-indenyl)-phenyldihydrophenylhydrazone [b][l,4]dioxine- The 2-ketone was prepared according to the general procedure P from (2) 2% by weighting from (2-second-butoxy-2'-fluoro-5-{3-[3-(2-methyl-) Imidazole + yl) phenyl] keto-propionylamino}-biphenyl-4-yl&gt; Amino acid tert-butyl ester (Example 〇 64). Obtained a yellow solid (111 mg) MS (ISN) 425 [(M-Η)·]; melting point &gt; 250 ° C. Example 80 4-[7-(2-fluorophenyl)-8-hydroxy-4-keto-4,5- Dihydro-3H-benzoquinone , 丫 因 _ 2- base 比 -2- -2- 猜 根据 according to the general procedure P, by TFA in 03⁄43⁄4, from {2 · second-butoxy-5-[3-(2-cyanide Base-pyridin-4-yl)-3-keto-propionylamino]-2,-fluoro-biphenyl-4-yl]-aminocarbamic acid tert-butyl ester (Example 〇 65). Obtained as a yellow solid (47 mg). MS (ISN) 371 [(M-Η)·]; melting point &gt; 250 ° C. Example 81 - 157 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 ----)J---------Installation - (Please read the note on the back of this page first) · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1255266 A7

V. INSTRUCTIONS (155) 8-(2-Fluorophenyl)-7-hydroxy-t-[3-(2-methylthio-mipropionyl)-phenyl]",3-dihydrophenylhydrazine [b ][l,4] Dioxephenone Please read the following notes on the back of this page. According to the general procedure P, by treatment with TFA in CH2^, (2 - 3 -butoxy-2,- Fluoro-5-{3-[3-(2-methylthio)mazole small group)-phenyl]_3•keto-propionylaminodiphenyl-4-yl)-aminomethyl Acidic third-butyl ester (Example 〇 66). A pale yellow solid (148 mg) was obtained. MS (ISN) 457 [(M-H)-]; mp. &lt;250. Example 82 3-[7-(2,5·F-Phenyl-phenyl)-t-methoxy-4-butanyl-4,5-dihydro-3H-benzoquinone[b][l,4]dioxine In-2-yl]-benzonitrile is prepared from {5_[3_(3-cyano-phenyl) keto-propionylamino]_2 by treatment with TFA in CH2Cl2 according to the general procedure P. , 5,-Difluoro-2-methoxy-biphenyl-4-yl}-aminomethyl acid tert-butyl ester (Example 〇 67). Obtained as a yellow solid (49 mg). MS (EI) 403 (M+); mp. Example 83 8-(2,5-Difluoro-phenyl)-7-methoxy-4-(3-[1,2,3]triazol-1-yl-phenyl)-l,3-di Hydrogen benzo[b][l,4] dioxin is produced according to the general procedure P, by TFA in CH2 Cl2, from {2,,5匕 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, printing of difluoride 2-methoxy-5-[3-keto(3-[1,2,3]triazol-1-yl-phenyl)-propenylamino]biphenyl-4-yl Aminomethyl 3-butyrate (Example 〇 68). Obtained a yellow solid (78 mg). MS (EI) 445 (M+); mp. Example 84 2-[7-(2-Fluorophenyl)hydroxy-4-ketone-4,5-dihydro-1H-benzo[b][l,4]dioxine·____-158- This paper scale applies to China National Standard (CNS) A4 specifications (10) 297 297 public meals) 1255266

2-yl]-thiophene-3-carbonitrile was prepared according to the general procedure P from (3) 2%, from (2·3 -butoxy-5-[3-(3-cyano-septene) :&gt; 3-keto-propionylamino group]·2,·Fluoro-biphenylindolylmethylamine tert-ester (Example 〇69). An orange solid (=mg) was obtained. MS (ISN) 376 [(Μ-Η)_]; m.p. 242 ° C. Example 85 5-[7-(2-fluorophenyl)-hydroxyl ketone 4,5-dihydrophenylhydrazine [b][1 , 4] Dioxepin-2-yl]-thiophene-2-carbonitrile was prepared from {2_second-butoxy-5-[3-( according to the general procedure P, by treatment with TFA in CH2Cl2. 5-cyano-farophen-2-yl)-3 marriage-propionylamino]_2,_fluoro-biphenylyl yl}-amine methyl acid tert-butyl ester (example 〇7〇) Obtained a yellow solid (126 mg) &amp; MS (EI) 377 (M+); mp. 86. 8- (4-fluorophenyl) 7-hydroxy-4-(3-[1,2,3] Oxazolyl-phenyl from [dihydrophenylhydrazine [b] [1,4] dioxepin-2-one according to the general procedure P, by treatment with TFA in CH2C12, from {2•third-butyl Oxy-4'-fluoro-5-[3-keto-3-(3-[1,2,3]triazole+ylphenyl)-propionylamino]-biphenyl-4 -yl}-amine Third-butyl acrylate (Example 〇 71). Obtained as a yellow solid (78 mg). MS (ESI) 414 [(M+H)+]; melting point &gt; 250 ° C. Example 87 3- [7-( 2-fluorophenyl)-8-(2-methoxy-ethoxy)-4-keto_4,5-dihydro-3H-benzoquinone [b] -159- This paper scale applies to Chinese national standards (CNS) A4 specification (210 X 297 mm) ------------- Installation - C Please read the notes on the back first page) J^T· Line · Ministry of Economic Affairs Intellectual Property Bureau Printed by employee consumption cooperatives

V. 255266 DESCRIPTION OF THE INVENTION (157 [1,4] Dioxephin-2-yl]-benzonitrile is prepared from [5_[3_(3-cyano) according to the general procedure P by treatment with TFA in CH2Cl2 -Phenyl)-3-keto-propionylamino]_2L fluoro 4(2-methoxy-ethoxy)-biphenyl phenyl]-aminomethyl acid tert-butyl ester (example) 〇 72). Obtained as a pale yellow solid (141 mg). MS (EI) 429 (M+); melting point 2 ii - 213 ° C. Example 88 3-[7-(2-fluorophenyl)-8-hydroxyindole Ice keto-4,5-dihydro-3H-benzo[b][l,4]dioxan-2-yl]-benzonitrile was prepared according to the general procedure P by TFA in CH2C12 From (RS)-[5-[3-(3-cyano-phenyl)-3-keto-propenylamino]_2l fluorotetrahydro-hydropyridyloxymethyl)-biphenyl -4-yl]-aminomethyl acid tert-butyl ester (Example 〇73). Obtained as a pale yellow solid (69 mg). MS (EI) 385 (M+); m.p. 9-9. Example 89 8-(2-Fluorophenyl)-7-hydroxy-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-indole] dihydrobenzo[b][ 1,4] Dioxepin-2-one is prepared according to the general procedure P by treatment with TFA in CH2Cl2 from (2,-fluoro-2-(4.methoxymethoxy)-5-{ 3-[3-(3-Methyl-isoxazol-5-yl)-phenyl]-indenyl-propanylamino}-biphenyl-4-yl)-amino acid - Butyl ester (Example 〇 74). Obtained as a yellow solid (278 mg). MS (ISP) 428 (M+H)?; mp. Example 90 3-[7-(2,5-Difluoro-phenyl)-8-3⁄4yl-4-keto-4,5-dihydro-3H-alum[b][l,4]丫-160- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----:---------Installation - (Please read the back note on this page first) ) - Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7

V. INSTRUCTIONS (158) Gyne-2-yl]-benzidine is prepared according to the general procedure P, by treatment with TFA in CH2%, from {2-second*butoxy-5-[3-( 3-cyano-phenyl)-3-keto-propylaminomethyl]_2,,5f-dier ############################### Obtained a yellow solid (56 mg). MS (ISP) 390 (M+H)+; melting point &gt; 250 °C. Example 91 8-(4-Fluorophenylethyl)-7-3⁄4yl-4-(3-miso.spin-1-yl-phenyl)-1,3-dihydrophenylhydrazine [b][l , 4] Dioxepin-2-one according to the general procedure Λ Λ by treatment with TFA in CH 2 Cl 2 , from the third · butoxy-4-(4-fluorophenylethynyl)-2-[ 3-(3-Imidazol-1-yl-phenyl)-t-yl-propenylamino]-phenyl}-amine decyl acid tert-butyl ester (Example 076). Obtained a yellow solid (55 mg). MS (EI) 436 (M+); mp. Example 92 8-(4-Fluorophenylethynyl)-7-hydroxy-4-(3-[1,2,3]triazole small-phenyl)·ι,3-dihydrophenylhydrazine [b] [l,4] Dioxepin-2-one was prepared according to the general procedure P, by treatment with TFA in CH2Cl2 from {5-Second-butyl-butyr-4- )-2-[3-mercapto-3-(3-[1,2,3]triammonium-phenyl)-propionylamino]-phenyl}-amine methyl acid third-butyl Ester (Example 〇 77). Obtained a yellow solid (56 mg). MS (EI) 437 (M+); mp. The following examples illustrate that 4-aryl iodo-1,3-dihydrophenylhydrazone [b][l,4]dioxepin-2-one can also be used as a starting material for Sonogashira coupling, such as Synthetic illustration -161 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mil) ------------- Pack--- Please read the notes on the back first This page) 0 I. Line. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255266 A7 B7 V. Invention Description (159) G is shown. Example 93 3-(4-keto-7-phenylethylidene-8-thiofifoxaline bucket base_4,5-dihydro·3h_benzo[b][l,4]dioxin In-2-yl)-benzonitrile is prepared according to the general procedure K from 3-(7-iodopiperidinyl thio-ofofolinine _ 4,5-monohydro-3H-benzoquinone [b] [l,4] Dioxane j base &gt; benzonitrile (Example 1) (437 g, 0.895 mol) and phenyl bromide (〇 15 ml, 134 mmol). Solid (334 mg) MS (EI) 391 (M+) · mp 234-235 ° C (decomposition). Example 94 (RS)-3-[4-keto-(1-keto-thio- phen Phenyl ethyl) phenyl ethynyl _4,5-dihydro-3H-benzoquinone [b][l,4]dioxepin-2-yl]-benzonitrile 3-(4-keto -7-phenylethynyl thiomorpholine _4_yl-4,5-dihydro-3H-benzoquinone 1&gt;][1,4]dioxan-2-yl)-benzonitrile (Example 27 χ 5 〇 mg, 〇 18 〇 mmol) and a mixture of Davis reagent (116 mg, 432· 432 mmol) in DCM (4.5 mL), and stirred for 1 hour at 23 ° C. Wash with 〇〇^ to give a pale yellow solid (16 mg). MS (ESI) 479 [(M+H)+] and 501 [(M+Na)+]; °C (decomposition) 4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydrophenylhydrazone [b][l,4]dioxepin-2-one, in the second The palladium-catalyzed carbonylation in the presence of a hydrazine directly leads to the corresponding guanamine as shown in the synthetic scheme I. Example 95 3-[8-(2-Methoxy-ethoxy)-4.one Benzyl-7-phenylethylidene-4,5-dihydro-3H-benzoquinone[b][l,4]dioxan-2-yl]-benzamide-162- This paper size applies China National Standard (CNS) A4 specification (210 X 297 mm) &quot; -------------- Pack--- (Please read the notes on the back and then ^|?) I - I-line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255266 A7 B7 V. Invention description (160) According to the general procedure Q 'from 4-(3-breaking winter base)-7-(2-A乳-乙乙基)-8_phenylethynyl-1,3-dihydrophenylhydrazone [b][l,4]dioxan-2-one (Example 25) (268 mg, 0.5 mmol) And hexamethyldioxane (0.52 ml, 2.5 mmol). Obtained as a yellow solid (102 mg). MS (EI) 453 (M+); mp 227-230 ° C (decomposition). The tablets are made in the usual way: mg /Tablet active ingredient 100 Powdered lactose 95 White corn starch 35 Polyvinyltetrahydropyrrolidone 8 Nacarboxymethyl starch 10 Magnesium stearate 2 Tablet weight 250 Example II Tablets of the following composition are prepared by conventional means成··mg/tablet (please read the note on the back page first) Binding - 1·丨线· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Active Ingredients 200 Powdered Lactose 100 White Corn Starch 64 Polyethylene Four Hydropyrrolidone 12 Na Methyl Starch 20 Magnesium Stearate ' 4 Tablets Weight 400 Γ -163- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1255266 A7 B7 V. Invention Description (161 capsules 50 60 34 5

EXAMPLE III Capsules of the following composition: mg active ingredient crystalline lactose microcrystalline cellulose talc magnesium stearate 1 capsule filling weight 150 active ingredient with appropriate particle size, crystalline lactose and microcrystalline cellulose, xiao The sentences are mixed with each other's sieves, and then mixed with talc and stearic acid. The final mixture is filled into an appropriate size, ~ j &lt; hard gelatin capsule. -----------------Γ (Please read the note on the back page first) Ericsson Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print 164 This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm)

Claims (1)

Patent application No. I255·9120913 Chinese patent application scope replacement (94 years 10) VI. Patent application scope A8 B8 C8 D8 94·ΐα _ A benzodioxine derivative of the formula (I), Wherein X is a single bond or an ethylenic diyl group, wherein if X is a single bond, the shell IJ 1^ is _ or phenyl' which is unsubstituted or substituted by a saccharin or a C&quot;alkyl group; if X is a block II Base, then R1 is phenyl, which is unsubstituted or passed! I substituted. R2 is dentate; hydroxyl; Cl-7 alkyl; Cl.7 alkoxy; hydroxymethyl; hydroxyethoxy; C丨-7 alkoxy _(ethoxy) η (η: =ι to 4); c]-7 alkoxymethyl; cyanomethoxy; whal-4-yl; thiofenoflavin _4_yl; dithiol thioporfosin; _diketothio-fosfosin bucket base; 4-keto group _ hexahydro-P ratio bite base; 4-C&quot;alkoxy-hexahydroindenyl; 4-thio-hexahydropyridyl-i- Base; 4-ethoxy-hexahydropyridyl small base; 4Χ]·7 pit base. Hexahydroxin well-base; Cm* oxygenated base; 2&lt;Ci-7 aromatine-ethylidene , N,N-double c ! . 7 alkylamino c - 7 alkyl; amine methyl hydrazino methyl; c ! · 7 alkoxycarbonyl-C &quot;alkyl; Cl · "charged carboxyl group _Ci 7 alkyl; carboxy-Cm alkyl; C]·7 alkoxycarbonylmethylthio; carboxymethylthio; dioxyl nitrogen-spiro[4.5]fluorenyl; carboxy-Cy alkoxy; cyano The Ci.7 alkane paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1255266, the scope of the patent application; 2,3-dihydroxyX]-7 alkoxy; amine mercaptomethoxy; 2•keto group. [1,3]-dioxoanthene ice-based Χι-7垸 oxygen (2. hydroxy Xl.7 alkyl) χΐ7 acrylamine; hydroxyamine-methane-C-.7 alkoxy; 2,2-dimethyl-tetrachloro[1,3]dioxo And [4,5〇μ 比罗士基; C]j alkoxy_amine 甲^^ _ C -7-7 alkoxy; 3R-hydroxy·tetrahydropyrrole+ group; 3,4•dihydroxy-four Hydropyridyl = small group; 2-keto-indanyl-3-yl; Cl_7 alkyl-amine-mercaptomethoxyl R3 is phenyl, thienyl or pyridyl, unsubstituted or via cyano Substituted by an amine or an aminomethyl group; ^ or via an imidazolyl group, H3-triazolyl, 〗 2, 4-triazolyl; isoxazolyl substituted, the substituents are unsubstituted or C] 7 alkyl or C 1 · 7 alkylsulfonyl substituted; 1 and its pharmaceutically acceptable addition salt. 2 · According to the patent scope of the scope of the derivative of the item, where r3 is in the meta position Substituted &lt; phenyl, the substituent is cyano, _ or imidazolyl (which is unsubstituted or substituted by C alkyl or methylthio), triazolyl, = wide triazolyl or isoxazole a group (which is unsubstituted or substituted by c ^ 7 alkane). 3. According to the derivative of claim 2, which is a chloro-4-keto-7- Phenylethynyl·4,5^Α.Benzo-,4]dioxaheptan-2-yl)-benzonitrile; 3-[8-(4-methyl-hexahydropyrazine)•yl) Benzenyl benzene|ethynyl·4,5-dihydro-3Η-benzo[b][l,4]dioxine-2-yl]benzonitrile; chloro-4-keto-7 · Phenyl dihydrogen benzo [, 4] two 丫 因 j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b --- Six, the scope of the patent application base) - benzonitrile; [4-(3-cyano-phenyl) 2-keto-8-phenylethylidene-y-dihydro-benzo[b ][l,4] A "gyne-7-ylthio"-acetic acid@@; 2 [4-(3-cyano-phenyl)_2_g homophenyl phenyl bromide_2,3_ Dihydrobenzo[b][M]-ephedos-7-yl]-acetic acid amine; 3-(cardiomethoxy-4-keto-7-phenylethynyl-4,5-dihydro- 3H-benzo[b][l,4]dipyridin-1-yl)-benzonitrile; 3-decanocyanomethylbutanyl-7-phenylethynyl-4,5-dihydro_ Benzene [ton^] dioxin-2-yl)-benzonitrile; 4 (3 phenyl)-7-(2-methoxy-ethoxyphenylethynyl 丨, 3 _Dihydrobenzo[b][l,4]dioxepin-2-one; 4-(3-imidazole+yl-benzene - 7-(2-methoxyethoxy) phenylethynyl·^ Dihydrobenzo[b][l,4]dioxepin-2-one; [RS]-3-[ 4-keto-8-(2-Langyl-[1,3]dioxoanthracene methoxy)-, phenylethynyl 4,5-dihydro-3H-benzo[b][l , 4] dioxin-2-yl]-benzonitrile; 7-hydroxymethyl ice (3-imidazole + phenyl-phenyl &gt; 8 phenyl ethynyl dihydro benzo[b][l, 4] Dioxepin-2-one; [4-(3-Min-1-yl-phenyl)-2-keto-phenylphenylethynyl-2,3-dihydro-iH_benzo[ b][l,4]dioxine π-yloxy&gt;acetonitrile; 8-(4-d-phenylphenyl)- 7-7-based thiol ice (3·»imiban-1-yl-phenyl )-i,3-dihydrobenzo[b][l,4]dioxepin-2-one; 7-(2-3⁄4-yl-ethoxy) ice (3-imidazol-1-yl-benzene _8_phenylethynyl-pyridyldihydrobenzo[b][l,4]dioxepin-2-copper; 8-(4-fluorophenyl)-7-[4-(2- Mercapto-ethoxy)-hexahydropyridyl]whenimidazole _ -3- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1255266 A BCD 1-yl-phenyl H,3-dihydrobenzo[b][M]dioxepin-2-one; phenyl)-7-redomyl-imidinyl-phenyl-dihydro Benzo-,4]-ylidene-2-anthracene; 8-(2-fluorophenylπmethoxy-o-methyl-methyl------------- [l,4]2ρ丫gine·2__ ; 8-(2-fluorophenyl)-7-hydroxy-4-(3-[1,2,3]tristiminyl-phenyl-dihydrobenzene And [b][l,4]dioxine-2-one; 8-(2-fluorophenyl&gt;7-hydroxy.4_[3_(2_methyl-imidazolium)-phenyl) Η}Dihydrobenzo[b][l,4]dioxine-2-one; 8-(2-fluorophenyl)-7-hydroxy ice [3·(2·methylthio-imidazole+yl) )·Phenyl 3_dihydrobenzo[b][l,4]dioxanone; heart (2,5-difluorophenylmethoxy-4-(3-[152,3]3 Azole]-yl-phenyldihydrobenzo[b][l,4]dioxepin-2-one; 8-(2-fluorophenyl)-7-hydroxy-4-[3-(3- Methyl-isoxazole_5_yl)-phenyl]dihydrobenzo[b][l,4]dioxepin-2-one; 3-[7-(2,5-difluorophenyl) )-8-hydroxycryl group-4&gt;dihydro-3-indole_benzo[b][14]di-f-h-hept-2-yl]-benzica; 8-(4-fluorophenylethynyl) Hydroxyl ice (3-imidazole + phenyl-phenyl) Η"Dihydrobenzo[b][l,4]dioxanone; and 5 8-(4-fluorophenylethyl)&gt;7-hydroxy-4_(3_[l52,3]triazole Small base-phenyl)^-dihydrobenzo[b][l,4]dioxan-2-one. 4. A derivative according to the first aspect of the patent application, wherein "is thiophene ( It is unsubstituted or substituted by cyano or genomic or pyridyl (unsubstituted at the 2 position or substituted with cyano or genomic). -4- This paper scale applies to Chinese national standards (CNS) A4 size (210X 297 mm) 1255266 A BCD Patent Application No. 5: A derivative according to item 4 of the patent application, which is 5-|&gt;(2-fluorophenyl) methoxy ketone base Dihydro-cation-benzo[Rigmentary (4) Dioxepyn-2-yl-p-phen-2-ylcarbonitrile; 2-[7-(2.fluorophenyl)-8-hydroxyecroleinyl_4&gt; Dihydrobenzo[b][14]dioxan-2-yl]-pyrimidine each carbonitrile; 4 [7-(2-fluorophenyl) methoxy ketone group _4,5-di Hydrogen-3H-benzo[b][l,4]dioxan-2-yl]-p is not-2-carbonitrile; 4-[&gt;(4-phenylene) thioglycolate 4--4,5-dihydro-3H-benzo[b][l,4]dioxan-2-yl]-pyridine-2-carbonitrile; 4-[7-(2-fluorophenyl)-8-hydroxyecrocarbyl-4,5-dihydro-3H-benzo[b][l,4]dioxan-2-yl]-p Than 2-acetonitrile. A pharmaceutical composition for treating an acute and/or chronic neurological condition, which comprises one or more derivatives according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient. 7. A pharmaceutical composition according to claim 6 wherein the acute and/or chronic neurological condition comprises psychosis, schizophrenia, Alzheimer's disease, cognitive condition and memory deficiency. 8. A method of preparing a benzodiazepine derivative according to the scope of the patent application, the method comprising -5- The paper size it is Η 家 家 家 家 家 家 家 家 家 家 家 Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ B B B B B B Or IVa compound reaction or CO.R IV IVa wherein R is ethyl or butyl, and becomes a hydrazine compound The deprotection of the amine group and the cyclization are carried out, and the formula of the scope of the application is obtained according to the scope of the application! The derivative, wherein the deprotection-cyclization step is carried out by reacting a compound of formula III with Brünnsted acid at a temperature between 〇 C and 50 °C. 9. According to the patents of the scope of the patents, from the fifth to the fifth, the derivatives are for the treatment of acute and / or chronic neurological disorders, including mental illness, mental knife disease, Alzheimer's disease, cognition Insufficient illness and memory. 10. Use of a derivative according to item liL5 of the scope of the patent application for the manufacture of a medicament for the treatment of acute and/or chronic neurological disorders, including psychosis, schizophrenia, Alzheimer Silent disease, cognitive illness and lack of memory. -6- The paper scale it financial rewards β^Ν8)Α4ϋ·(21〇χ2ϋ--------