TWI379829B - Triazole substituted aminobenzophenone compounds - Google Patents

Description

1379829 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel type of dis-substituted amino group, a guanidine, and its use in therapy. [Prior Art] Aminobenzophenone is known from the scientific literature as well as the patent literature. By way of example, WO 98/32730, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/05744 and WO 01/05745 all disclose compounds having the following core structures:

Among them, the benzene ring C is substituted with an amine derivative. Furthermore, WO 01/42189 and WO 02/076447 disclose compounds having a similar structure but which do not have a nitrogen substituent in the benzene ring C. Finally, WO 01/90074 and WO 02/083622 disclose compounds in which the phenyl rings A and C are respectively substituted by a heterocyclic ring. The compounds disclosed in these patent applications refer to inhibitors of in vitro secretion of interleukin 1 p (IL-1 β) and tumor necrosis factor ct (TNF-a), which makes these compounds suitable for therapeutic cells. An inflammatory disease associated with the pathogenesis of hormones. It is claimed that the aminobis acetophenone exerts its action by inhibiting p38 MAP kinase, which in turn inhibits the production of IL-Ιβ and TNF-a. The preparation of structurally related aminobenzophenones for use as textile dyes is disclosed in Man-Made Text. India (1987), 106609.doc 8 1379829

3〇(6), 275-6 ' Man-Made Text. India (1986), 29(5), 224-30 and Man-Made Text· India (1985), 28(1 1), 425,427-9 , 431. [Summary of the Invention]

Surprisingly, it was found that the novel triazole-substituted aminobenzophenone derivatives are effective inhibitors of in vitro and in vivo secretion of interleukin-1β (α-1β) and tumor necrosis factor a (TNF-a), suggesting In the treatment and/or prevention of inflammatory diseases and other conditions, the secretion and modulation of pre-inflammatory cytokines in these conditions are related to the pathogenesis. It has been found that the triazole-substituted aminodibenzophenone derivative of the present invention exerts its anti-inflammatory action by inhibiting or negatively regulating MAP kinase, more specifically p38MAp kinase (a stress/lingual protein). The kinase system is an important factor in the signal transduction pathway leading to the production of pro-inflammatory cytokines. Further, the diazole-substituted aminobenzoquinone derivative of the present invention can be suitably used for the treatment of cancer or an ophthalmic disease or condition. Accordingly, the present invention is directed to a compound of the formula 1 & or 113:

106609.doc «4 R1 is fluorenyl, chloro, bromo or methoxy; R2 is a gas or f group; R3 represents Cw alkyl, C2.6 alkenyl, C2.6 alkynyl, Cw hydroxyalkyl, Cw Burning group, Cl.6 decyloxy, Cl.6 oxo group, Cl.6 amine group, glandular 'thioglycine group, CK6 alkylcarbonyloxy group, Cw alkylcarbonyl group, Cm alkoxycarbonyloxy group ,

a Cl-6 alkoxysulfonyloxy group, a Cw alkoxyamine indenyl group or a Cw aminocarbonyl group, each of which is optionally selected from the group consisting of one or more of the following groups, the same or Different substituent substitutions: i, hydroxy, decyl, tri-I methyl, cyano, carboxy, conh2, nitro, keto, -S(0)2NH2, Cl-4 alkyl, C2_4 alkenyl, C2 -4 alkynyl, Cw hydroxyalkyl, Ci-6 haloalkyl, Cl_4 alkoxy, CN4 alkoxycarbonyl, ureido, thiourea, Cm alkylcarbonyloxy, CN4 alkoxycarbonyloxy, CN4 Alkoxysulfonyloxy, Cm alkoxyamine, mercaptocarbonyl, Cw aminocarbonyl, Cw alkylthio, c3-6 cycloalkyl, C3-6 cycloalkenyl, amine, imine, Cw amine Sulfosyl group, Cm aminocarbonyloxy group, Cw alkylsulfonylamino group, Cw alkoxyimino group, Cm alkylcarbonylamino group, Cw alkylsulfonyl group, CK6 heteroaryl group, Cw heterocyclic ring An alkyl group or a C2_6 heterocyclic group, wherein the Cm alkyl group, C2.4 alkenyl group, c2.4 alkynyl group, Cm hydroxyalkyl group, q.6 haloalkyl group, Cm alkoxy group, CN4 alkoxycarbonyl group, urea , thioureido-Cb4 alkylcarbonyloxy, Cm alkoxycarbonyloxy, ¢^4 alkoxysulfonyloxy, C!·4 alkane Oxyaminoguanidino, cN4 aminocarbonyl, Cw alkylthio, C3.6 cycloalkyl, C3-6 cycloalkenyl, amine, imine, Cm aminosulfonyl, CK4 106609.doc 1379829 amine Alkoxy group, Cw alkyl group, aryl amino group 'Cl_4 alkoxyimino group, Ci < alkylamino group, Cw alkyl group, Ci aryl group, Cl. 6 heterocycloalkyl group Or a C2.6 heterocycloalkenyl group, optionally substituted with one or more, the same or different substituents selected from the group consisting of dentate, hydroxyl, _NH 2 , fluorenyl, trifluoro f, a cyano group, a carboxyl group, a CONH 2 , a nitro group, a keto group, a _s(〇) 2NH 2 , a C 1.4 alkyl group or a Cu thiol group; or R 3 represents a hydrogen group, a hydroxyl group or a carboxyl group;

Halogen, -ΝΗ2, acetamyl, acetamidine R4, R5, R6, 117 and r8 independently of each other represent a hydrogen hydroxy group, a trifluoroF group, a methoxy group, an ethoxy group, a cyanoamino group, a methyl group or Ethyl; 'There is a limitation that the compound is not [4·(2-aminophenyl)amino]]oxyphenyl]-[2_methyl-5-[1-[2-[(tetrahydro-2-indole) _piperan-2-yl)oxy]ethyl]-, 2,3-tris-saltyl]-phenyl]-methyl(tetra)[4_[(2_aminophenylamine)

Base]_2·gasphenyl]_[5·[1-(2·ethyl)-1Η-1,2,3-tris-7.yl]_2.methylbenzyl]-formal steel; or A pharmaceutically acceptable salt, solvate or ester. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula la or lb, or a pharmaceutically acceptable salt, solvate or vinegar thereof, and a pharmaceutically acceptable excipient Or vehicle. The invention is directed to a method of preventing, treating or ameliorating a disease or condition or an ophthalmic disease or condition. The method comprises administering to a patient in need thereof an effective amount of a compound of formula la or lb. In another aspect, the invention is directed to a method of treating or ameliorating cancer, 106609. doc 1379829, which method comprises administering to a patient in need thereof an effective amount of a compound of the formula "or Ib. In another aspect The present invention relates to the use of a compound of formula 13 or Ib for the manufacture of a medicament for the prophylaxis, treatment or amelioration of an inflammatory disease or condition or an ophthalmic disease or condition. In another aspect, the invention relates to the manufacture of a compound of formula 13 or 115. A medicament for treating or ameliorating cancer. [Embodiment] Definitions As used herein, the term "alkyl" is used to mean a group obtained when a hydrogen atom is removed from a hydrocarbon t. The alkyl group contains 丨_6 Preferably, i_4 (such as 2_3) carbon atoms. The term includes sub-type n-alkyl (n-alkyl), second alkyl and third alkyl, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, t-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl. The term "cycloalkyl" is used to denote a saturated cycloalkyl group, which comprises 3 • 6 carbon atoms, such as 4-5 carbon atoms, such as cyclopropyl, cyclobutane Base, cyclopentyl and cyclohexyl. The term "cycloalkenyl" is used to denote a mono- or di-unsaturated non-aromatic cyclic hydrocarbon group containing from 3 to 6 carbon atoms, such as 4 to 5 carbon atoms, such as cyclopropenyl, cyclobutadienyl, ring. Pentenyl or cyclohexenyl. The term "heteroaryl" is intended to include heterocyclic aromatic rings which contain 丨4 heteroatoms (selected from 〇, S and Νβκ carbon atoms, such as 3 heteroatoms and 16 carbon atoms' such as a hetero atom and 5 carbon atoms, such as 2 heteroatoms and 4 carbon atoms, especially having a hetero atom selected from 〇, s& n or 106609.doc 1:2 heteroatoms 5 Or a 6-membered ring, for example: anthracenyl, tetras-sulphate, (tetra)yl, carbazolyl, oxazolyl, oxadiazolyl, thi〇phenyl, ′′ '4-oxazolyl, iso-α Orythracene, pyrrolidinylthiophenylpyridinium yl, hydrazone 1,2,3]trimethyl or isoindolyl. The term "cycloalkyl" is used to mean a cyclyl group as defined above, especially a di- or 6-membered ring comprising a polycyclic group comprising 4 hetero's selected from the group consisting of hydrazine, s and n, preferably 1 to 3 heteroatoms, such as tetrahydropyranyl, morpholine, imidazole , dioxolanyl or piperidinyl. = 浯"heterocycloalkenyl" is used to denote a cycloalkenyl group as defined above, which includes a oxiranyl group, including 〇4 selected from 〇, S&N Preferably, the heteroatoms are U heteroatoms For example, i, 6 • dichloro 0 is more than a bite group, 4, 5 dinitrogen-out-formal trifle. Sitrate 4,5-hydro-oxazolyl, 1-H-pyrazolyl or 5-dihydro- Isoxazolyl is used to denote a mono-, di- or tri-unsaturated hydrocarbon group containing from 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, such as 2 to 3 carbon atoms, such as vinyl , allyl, butenyl, pentenyl or hexenyl. The radical is used to represent a hydrocarbon group, which contains 1 - 5 CC bonds, for example 2 or 3 reference bonds and 2-6 a carbon atom, which usually contains 2 to 5 carbon atoms, especially 2 to 4 carbon atoms, such as 2 to 3 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl. 'Bermoid' is used to denote a substituent from the seventh main group of the Periodic Table of the Elements, preferably fluoro, chloro and fluoro. The term "alkyl group" is used to mean an alkyl group as defined above. Wherein one or more hydrogen atoms are replaced by a trans group. The term "haloalkyl" is used to denote an alkyl group as defined above, wherein one or 106,609.doc of a plurality of hydrogen atoms are the same or different halogens ( Substituted as bromine, iodine, chlorine and/or fluorine. The term "amino" is used to denote a radical of the formula -NR2, wherein each R independently represents a hydrogen, alkyl, alkenyl or ring as indicated above. An alkyl group such as -NH2, decylamino, diethylamino, cyclohexylamino, tert-butylamino or ethylamino. The term "imino" is used to denote the formula = NR a group wherein R represents a hydrogen or a hospital group as indicated above. The term "alkoxy" is used to denote a group of the formula -OR, wherein R is an alkyl or alkenyl group as indicated above, for example, a methoxy group. , ethoxy, n-propoxy, isopropoxy, butoxy, and the like. The term "alkylthio" is used to denote a group of the formula -S-R, wherein R represents an alkyl group as indicated above. The term "alkoxycarbonyl" is used to denote a group of the formula -C(0)-0-R, wherein R is an alkyl group as shown above, for example, methoxy, ethoxycarbonyl, n-propoxy oxide , isopropoxycarbonyl, etc. The term "alkylcarbonyloxy" is used to denote a group of the formula -0-C(0)-R, wherein R is alkyl as defined above, for example, decylcarbonyloxy , ethyl carbonyloxy. The term "alkoxycarbonyloxyindole" is used to denote a group of the formula -0-C(0)-0-R, wherein R is an alkyl group as indicated above. The term "alkylcarbonyl" is used to mean a group of -C(0)-R, wherein R is a court base as shown above, for example, an acetamino group. The term "ureido" is used to denote the formula -NR'-C(0)-NH-R a group wherein R1 is hydrogen or alkyl as shown above, and R is hydrogen, alkyl, dilute 106609.doc 11 1379829, alkynyl or cycloalkyl, such as -nh-c(o) as indicated above -nh2, guanylureido, ethylureido, tert-butylureido, cyclohexylureido, methylthiourea, isopropylureido or n-propylurea. The term "thiourea" is used to denote a group of the formula "-NR/-C(S)-NH-R, wherein R' is hydrogen or a court base as indicated above, and R is as shown above Hydrogen, alkyl or cycloalkyl, such as -NH-C(S)-NH2. The term "alkoxysulfonyloxy" is used to denote a group of the formula -0-S(0)2-0-R wherein R is an alkyl group as indicated above. The term "aminosulfonate The base " is used to denote a group of the formula -S(0)2-NR2, wherein each R independently represents hydrogen or alkyl as indicated above. The term "aminocarbonyloxy" is used to mean A group of NR'-C(0)-0-R, wherein R' is hydrogen or an alkyl group as shown above, and R is an alkyl group as shown above, for example, an aminocarbonyl-t-butoxy group. The term "alkylsulfonylamino" is used to denote a radical of the formula -NR'-S(0)2-R wherein R is alkyl as defined above and R' is hydrogen as indicated above Or an alkyl group such as methylsulfonylamino. The term "alkoxyimino" is used to denote a group of the formula: N-0-R, wherein R represents a hydrogen or a burnt group as indicated above, for example, a methoxyimino group. The term '• alkoxy group Amine thiol" is used to denote a group of the formula -C(0)NR'-0-R, wherein R' is hydrogen or alkyl as shown above, and R is an alkyl group as shown above. "Aminocarbonyl" is used to denote a group of the formula -C(0)-NR'2, wherein each R' independently represents a hydrogen, alkyl or alkenyl group as indicated above, eg, an amine fluorenyl group, a Aminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl or butylaminocarbonyl. 106609.doc 1379829 The term "alkylcarbonylamino" is used to denote a radical of the formula -NIV-C(0)-R, wherein R' is hydrogen or alkyl as indicated above, and R is as above An alkyl group such as an acetamino group.

The term "pharmaceutically acceptable salt" is used to denote a salt prepared by reacting a compound of formula I with a suitable inorganic or organic acid such as hydrogen acid or hydrobromic acid. , hydriodic acid, sulfuric acid, nitric acid, dish acid, formic acid, acetic acid, 2, 2 diacetic acid, adipic acid, ascorbic acid, ascorbic acid, L- face acid, galactose diacid, lactic acid, maleic acid , L-malic acid, phthalic acid, citric acid, propionic acid, benzoic acid, glutaric acid, gluconic acid, D-glucuronic acid, methanesulfonic acid, salicylic acid, succinic acid, propylene Acid, tartaric acid, benzenesulfonic acid, ethylene 4,2-disulfonic acid, 2-hydroxyethanesulfonic acid, terephthalic acid, aminesulfonic acid or fumaric acid. The pharmaceutically acceptable salts of the compounds can also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, or a suitable non-toxic amine.虱, a suitable non-toxic amine such as a lower alkylamine (eg, triethylamine hydroxy-lower alkylamine (eg, 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine), naphthenic a base amine (for example, dicyclohexylamine) or a benzene f amine (for example, N,N,-diphenylmethyl-ethylenediamine and dimercaptomethylamine) or L-arginine or L-isoamine. The term " "Solvate" is used to mean a substance formed by the interaction between a compound (for example, a compound of the formula) and a solvent (for example, an alcohol, glycerin or water), wherein the substance is in a solid form. When water is a solvent When the substance is called the term "pharmaceutically acceptable, it is used to indicate that it is not easily hydrolyzable" such as yttrium oxy sylvestre gti, sputum sputum saponin, stil , aryl oxime 106609.doc 8 • 13- 1379829 alkyl esters, such as ethoxylated methyl ester, p-pentyloxymethyl ester, stupid a quinone ester and the corresponding 1,-mercaptoethyl ester derivative; or an alkoxycarbonyloxyalkyl vinegar such as f-oxycarbonyloxymethyl ester and ethoxycarbonyloxymethyl ester and corresponding 1' - an oxyethyl ester derivative; or a lactone such as a decyl ester; or a dialkylamino leucoyl ester such as dimethylaminoethyl ester. An easily hydrolyzable ester comprising an in vivo hydrolysable ester of a compound of formula j Such esters can be prepared by conventional methods known to those skilled in the art, such as those disclosed in British Patent No. 490 852, which is incorporated herein by reference. The compounds include compounds la and lb. "p38 MAP kinase" is a stress-activated protein kinase that exists in several isoforms (p38tx, ρ3 8β, ρ3 8β2, ρ38γ, and ρ38δ). The p38 MAP kinase is stimulated by different stimuli. To activate, including heat, chemical, osmotic, pH and oxidative stress, growth factor regression, high or low glucose and ultraviolet radiation. p3 8 is also stimulated by agents that mediate initial physiological responses to injury, infection, and inflammation, such as LPS and pro-inflammatory cytokine IL-Ιβ, TNFtx, FasL, CD40L, and TGF-β 〇 are similar to other MAP kinases, and P38 is a kinase on tyrosine and tyrosine in the activation loop (Thr-Xaa-Tyr) near the ATP-substrate binding site. Phosphorylation (including MKK3, MEK6, and MKK6). Next, P38 phosphorylates and activates serine-breast protein kinase MAPKAP 敫2, MAPKAP kinase-3, MAPKAP kinase-5, MNK-1, and MSK- 1. It has been determined that activation of P38 in many cell types is directly by phosphorylation and activation of transcription factors involved in the expression of cytokines, or indirectly by phosphorylation of MSK-1 (which activates transcription factor CREB after activation). To regulate cytokine biosynthesis. Certain pyridyl imidazoles (e.g., SB203580) that inhibit p38 _9.d〇C · 14 8 1379829 have also been shown to inhibit IL-β and TNFa production by LPS-treated human monocytes. It is therefore concluded that p38 constitutes a target for the development of anti-inflammatory compounds that may be of high concern (cf. JC Lee et al, Immunopharmacology 47, 2000 'pp. 185-201 and the literature reviewed therein; PR Young, "Specific Inhibitors of p38 MAP Kinase" in

Signaling Networks and Cell Cycle Control: The Molecular

Basis of Cancer and Other Diseases, JS Gutkind (ed.),

Humana Press, Inc., Totowa, NJ, and the literature reviewed therein). There are several reports regarding p38 MAP kinase and inflammatory cytokines associated with cell growth and dying (such as tumor growth and cancer metastasis). Although the exact mechanism by which MAP kinase mediates cell growth regulation is not known, is it reasonable? 38 MAP kinase constitutes a target for the development of anticancer drugs that may be of high concern (s

Nakada, Anticancer Research 21 (1A), 2001, pp. 167-171 and references cited therein; C Denkert et al. 'Cancer Letters 195(1), 2003, pages 101-109 and references cited therein). The compound of formula la or lb may comprise an asymmetric substitution (pivot) of a carbon atom and a carbon-carbon double bond which may cause the presence of isomeric forms (eg, enantiomers, diastereomers, and geometric isomers). . The present invention is directed to all such isomers in pure form or as such compositions. The pure stereoisomeric forms of such compounds and the intermediates of the invention can be obtained by the use of procedures known in the art. The diastereomer, the conformation can be separated by physical separation methods, such as selective crystallization and chromatographic techniques, such as the use of a liquid phase layer # of the palmitic stationary phase. Enantiomeric = can be separated from each other by selective crystallisation of diastereomeric salts with optically active acids or 'enantiomers can be obtained by chromatography using a palmitic stationary phase 106609.doc -15- 1379829 Technology to separate. Such pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, with the proviso that the reaction occurs stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is desired, the compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ a palmitic pure starting material. Likewise, pure geometric isomers can be obtained from the corresponding pure geometric isomers of the appropriate starting materials. Mixtures of geometric isomers will typically exhibit different physical properties, and thus can be separated by standard chromatographic techniques well known in the art. The triazole moiety can be regarded as the isoster of the indoleamine, but is not easily hydrolyzed by the enzymatic hydrolysis of the prolinease. Therefore, the salty la or lb compound is more stable than its corresponding indoleamine derivative. Preferred Embodiments of the Compounds of Formula la and lb In the presently preferred embodiment of the compound of formula la or lb, Κ·3 represents C, -6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Cw hydroxyalkane a group, a Cw alkoxycarbonyl group, a Cw alkyl group, a gland group or a Ci_6 amino group, each of which is optionally one or more, the same or different substituents selected from the group consisting of the following groups; Substitution: dentate, thiol, sulfhydryl, trifluoromethyl, cyano, carboxy, CONH2, nitro, keto, -S(0)2NH2, Cm alkyl, C2-4 alkenyl, C2_4 alkynyl, Cw hydroxyalkyl, Cm alkoxy, Cw alkoxycarbonyl 'ureido, thiourea, Cy alkylcarbonyl fluorenyl, Cm alkoxy oxy, Cl. 4 alkoxy ethoxy, Cl .4 alkoxyamine oxime, Cw aminocarbonyl, Cm alkylthio, C3-6 cycloalkyl, C3.6 cycloalkenyl, amine 106609.doc 1379829, imine, Cm amine sulfonate Stuffed base, Ci.4 amino methoxy group, cl 4 systemic amine group, Ci-4 alkoxyimine group, Ci.4 alkyl group & amine group, q «μ» 1·4 pit base Sulfonyl, Cw heteroaryl, Cw heterocycloalkyl or C2-6 heterocycloalkenyl, wherein the last 27 are optionally selected from the following Groups of groups consisting of _ or multiple, identical or different substituent substitutions: halogen, thiol, Wei, trimethyl, gas, ruthenium, CONH2, nitro, steel-S(0) 2NH2, Cw alkyl or Ci-4 hydroxyalkyl; or R3 represents hydrogen, a trans group or a slow group;

The limitation is that the compound is not [4-(2-amino-phenylamino)·2·gas·phenyl]_(2-indolyl_5_{1_[2_(tetrahydro-pyran-2-) Benzyl)-ethyl]-1H-[1,2,3]triazol-4-yl}-phenyl)-carboxamidine, fluorene [4-(2-amino-phenylamino)-2 - gas-phenyl]-{5-[1_(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-2-indolyl-phenylmethanone. In another presently preferred embodiment of the compound of formula la or lb,

Re, R·7 and Rs independently of each other represent hydrogen, dentate, hydroxy, trifluoromethyl, methoxy, ethyl fluorenyl, fluorenyl or ethyl. In another embodiment of the present invention, R·5, I and the ruler 7 independently of each other represent hydrogen, halogen, —nh2, hydroxy group, ethyl sulfonyl group, acetaminophen base, hydrogen, dentate, via group, and B. Anthracenyl, acetamidodifluoromethyl, methoxy, ethoxy, cyanomethyl or ethyl' and is independently of each other, difluoromethyl, methoxy, ethoxy, cyanomethyl or Ethyl. In the case of the formula la or lb compound - R4, R5, R6, R7 and

Re represents hydrogen, gas or gas independently of each other. In another vigilant example of a compound of formula la or lb, R4, r5, r6, ruler 7, or 106609.doc

· 17· 1379829 At least three of r8 represent hydrogen. In another presently preferred formula la or lb compound, and Re represents hydrogen. In another presently preferred embodiment of the compound of formula la or lb, R5, R6, R7 and Rg represent no hydrogen. In another presently preferred embodiment of the compound of formula la or lb, R4, R5, R7 and Rg represent hydrogen. In another embodiment of the compound of formula la or lb, wherein R and R6, R7 &R8' or R4, R6, R7AR8' or ruler 4, heart and heart, or heart, R_6 and represent hydrogen. In another presently preferred embodiment of the compound of formula la or lb, Ri is a fluorenyl group and R is a gas. In another presently preferred embodiment of the compound of formula la or lb, & represents a Cu alkyl group, a Cm alkenyl group or a Cm hydroxyalkyl group, each of which is optionally selected from the group consisting of the following groups; Substituted by multiple, identical or different substituents. halogen, thiol, fluorenyl, -NH2, fluorenyl, c〇NH2, nitro, keto, -s(o)2nh2, Cw hydroxyalkyl, cN2 alkoxy Base, Cl 2 alkoxycarbonyl, Cw gland, Cw thiourea, Ci. 2 carbonyloxy, oxycarbonyloxy, C, 2 alkoxysulfonicoxy, Cw alkoxy Aminomethyl sulfhydryl, Cl 2 aminocarbonyl, Cw thiol, Cw amine, Cw imine, Cl 2 aminosulfonyl, Ci. 2 aminocarbonyloxy, C.. 2 alkyl sulfonamide a group, a C 2 alkoxyimino group, a C, a 2 alkyl group, a Cw alkylsulfonyl group, a c 2_5 heteroaryl group, a c2.5 heterocycloalkyl group or a C 3_5 heterocycloalkenyl group, of which the last 22 Further substituted with one or more, identical or different substituents selected from the group consisting of: 106609.doc.jg 8 1379829: hydroxy, _NH2, carboxy, CONH2, keto or Cw alkyl, optionally The restriction is that the compound is not [4-(2- --phenylamino)_2_chloro-phenyl]·(2_methyl·5_{卜[2·(四气,派兔-2-yloxyethyl]·1Η_[ι,2,3 Triazol-4-ylphenyl)-indole, or [4-(2-aminophenyl)amino-2-phenyl-phenylhydroxyhexyl)-1Η-[1,2,3] Zin-4-yl]-2-methyl-phenyl}-fluorenone. In another presently preferred embodiment of the compound of formula la or lb, it is meant a Cu alkyl group, a Cw alkenyl group or a Cw hydroxyalkyl group, each of which is optionally selected from one or more of the group consisting of the following groups: Substituted by the same or different substituents: hydroxy, -NH2, carboxyl, gas, c〇NH2, nitro, fluorenyl, -S(0)2NH2, Cm hydroxyalkyl, Cu alkoxy, Cu alkoxycarbonyl , C0.2 gland, C!.2 aminocarbonyl, Cw amine, C! 2 alkylsulfonylamino, (: 2 · 5 heterocycloalkyl) wherein the last 8 are further selected from argon or argon Substituting one or more, the same or different substituents of the group consisting of alkyl groups, with the proviso that the compound is not [4-(2-aminophenyl)phenyl)-2 gas-phenyl]-( 2-mercapto-5-{1-[2-(tetrahydro-°-decano-2-yloxy)-ethyl]_1Η-[1,2,3]triazol-4-yl}-phenyl )--ketone, or [4-(2-amino-phenylamino)-2_qi-phenylhydroxy-ethyl)-1Η-[1,2,3]triazol-4-yl]- 2-methyl-phenyl}-methanone. In another presently preferred embodiment of the compound of formula la or lb, r3 represents methyl, ethyl, propyl, propenyl, wherein all groups are selected from one or both of the group consisting of the following groups: Substituted by three or four, identical or different substituents: hydroxy, CONH2, keto, diethylamino, ethylamine 106609.doc • 19- 81 1379829 carbonyl, methyl, hydroxymethyl, pyrrolidine , morpholinyl, gas, h2n-c(o)-nh-, methoxycarbonyl, methoxy, -NH2, ethoxycarbonyl, ethoxy, methylsulfonylamino, -S(〇)2NH2 , tetrahydropyranyl, [1,3]-dioxolanyl, ethylamino, piperazinyl, and the last four are optionally selected from one or two of the group consisting of methyl or ethyl. Three or four, identical or different substituents are substituted. In another presently preferred embodiment of the compound of formula la or lb, R3 is 2-hydroxyethyl, 3-hydroxypropyl, amine-methylmethyl, 2,3-dihydroxypropyl, 2-(曱Ethylsulfonyl)ethyl, sulfonylaminopropyl, 2,2-dimercapto-[1,3]dioxolan-4-ylindenyl, 2-(tetrahydropyran-2- Ethyloxy)ethyl, 3-(tetrahydro-bunda-2-yloxy)-propyl, ethoxycarbonylmethyl, carbonylmethyl, ethylaminocarbonylmethyl, (2-hydroxyl) -1,1-dimethyl-ethyl)aminocarbonylmethyl, 1-pyrrolidin-1-yl-acetamidine, 1-norphin-4-yl-acetamidine, 2-oxyethyl, 1- Benzyl-1-methyl-ethyl, ethenyl, 1-amino-1-indenyl-ethyl, methoxycarbonyl, carboxy, hydroxymethyl, 3-hydroxy-propenyl, 2-amino- Ethyl, methylurea, 2-morpholin-4-yl-ethyl, (4-methyl-α-indol-1-yl)-ethyl, 2-ethylaminoethyl-ethyl, 2 - (2 · thiol ethylamino)-ethyl, propylaminoethyl or diethylamine. Specific examples of compounds of formula I may be selected from the group consisting of: [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl]-(2-indolyl-5-{ 1-[2-(Tetrazo-Nang-Nan-2-yloxy)-ethyl]-1Η-[1,2,3]diox-4-yl}-phenyl)-carboxamidine Compound 101), [2-Ga-4(2,4-difluoro-phenylamino)-phenyl]-{5-[1-(2-trans-ethyl-ethyl)-1Η-[1, 2,3]triazol-4-yl]-2.methyl-phenyl ketone (Compound 102), [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl] -(2-indolyl-5-{1-[3-(four 106609.doc -20- 8 1379829 gas-Nymphaea 2_yloxypropyl)丨h_[12 3]triazole_4_yl }•Phenyl)-fluorenone (Compound 103), U-gas-4-(2,4-difluoro-phenylamino)-phenyl]hydroxy-propyl)-111-[1,2,3 Triazol-4-yl]-2-methyl-phenyl}-ketone (Compound 104), [2-Ga-4-(2,4-difluoro-phenylamino)phenyl] {5_[Bu(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)_1H-[1,2,3]triazol-4-yl]-2-methyl -phenyl}-methanone (compound 105), [2- gas-4-(2,4-difluoro-phenylamino)phenyl]-{5_[1_(2,3-dihydroxy-propyl Base)-1Η-[1,2,3]triazole·4·yl]-2-methyl-phenyl bromide (Compound 106), 2-(4-{3-[2-Ga-4-(2,4-difluoro-phenylamino)-phenylindenyl]-4-indolyl-phenyl}-[ 1,2,3]diin-1-yl)-ethanoamine (compound 1〇7), 3-(4-{3-[2-gas-4-(2,4-difluoro-phenylamine) ))-曱醯曱醯基]-4-mercapto-phenyl}-[1,2,3]triazol-1·yl)-propan-1-sulfonamide (Compound 108), N-[2- (4-{3-[2-Chloro-4-(2,4-difluoro-phenylamino)-benzylidenyl]·4-methyl-phenyl}-[1,2,3] Zin-1-yl)-ethyl]-methanesulfonamide (Compound 1〇9), (4-{ 3-[2-Ga-4-(2,4-difluoro-phenylamino))benzene Methyl hydrazide]_4-methyl-phenyl}_[1,2,3] bis. sit-1-yl)-acetic acid ethyl ester (compound 11 〇), (4-{3-[2- gas-4 -(2,4-difluoro-phenylamino)-benzylidenyl]_4-methyl-phenyl}-[1,2,3]triazol-1-yl)-acetic acid (compound 111}' 2-(4-{3·[2·Ga·4-(2,4-difluoro-phenylamino) aglylosinyl]_4_decyl·phenyl}-[1,2,3] Zin-1-yl)-indole-ethyl-acetamide (Compound 112), 2-(4-{3-[2-Ga-4-(2,4-difluoro-phenylamino)-benzene Methyl fluorenyl]_4_fluorenyl _ phenyl}-[1,2,3] bis-sodium-1-yl)-hydrazine-(2. thiol-l,i-dimethylethyl) Brewing I06609.doc - 21 - 8, 1379829 Amine (Compound 113), 2-(4-{3-[2-Ga-4-(2,4-Difluoro-phenylamino)-benzyl] -4 -decyl-phenyl}-[1,2,3]triazol-1-yl)-1-pyrrolidin-1-yl-ethanone (Compound 114), 2-(4-{3-[ 2-ox-4-(2,4-difluoro-phenylamino)-phenylindenyl]-4-methyl-phenyl}-[1,2,3]triazol-1-yl)- 1-morpholin-4-yl-ethanone (compound 115), [2-chloro-4-(4-trifluoromethyl-phenylamino)phenyl]-{5-[4-(2- Hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 116), (2-Chloro-4-o-phenylphenylamino) -phenyl)-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]_2-methyl-phenyl}-methanone (compound 117), [2-Ga-4-(2-Ga-4-fluoro-phenylamino)-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazole -1-yl]-2-methyl-phenyl}-methanone (Compound 118), [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl]-(2- Methoxy-5-{1-[2-(tetrahydro-piperidin-2-yloxy)-ethyl]-111-[1,2,3]triazol-4-yl}-phenyl) - anthrone (Compound 119), [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[1-(2-hydroxyethyl)- 1Η-[1,2,3]triazol-4-yl]-2-methoxy-styl}•anthrone (Compound 120), [2-Ga-4-(4-fluoro-phenylamino) )-phenyl]-(2-methyl-5.{1-[2-(tetrahydro-l-bran-2-yloxy)ethyl]-1Η-[1,2,3]tris- 4-yl}-phenyl)-methanone (compound 121), [2-chloro-4-(4-fluoro-phenylamino)-phenyl]-{5-[1-(2-hydroxy- Ethyl)·1Η-[1,2,3]triazol-4-yl]-2-methyl-phenyl}-methanone (Compound 122), [2-Ga-4-(4-Fluoro-Benzene) Amino))phenyl]-{5-[1-(2,2-dimercapto-[1,3]dioxolan-4-ylmethyl)-1Η-[1,2,3] Triazol-4-yl]-2-methyl-phenyl}- 106609.doc . 22 - 8 1379829 ketone (compound 123), [2-qi_4-(4-fluoro-phenylamino)- Phenyl]-{5-[1-(2,3-dihydroxy-propyl)·1Η-[1,2,3]triazole·4·yl]_2-methyl·phenyl ketone (compound) 124), 2-(4-{3-[2-Ga-4-(4-fluoro-phenylaminobenzimidyl)-4-methyl-phenyl}-[1,2,3]III Azole-1·yl)-acetamide (compound 125), gas_4_(2,4·difluoro-phenylamino)-phenyl]-{5-[1-(2-chloro-ethyl) -1Η-[1,2,3]triazol-4-yl]methyl-phenyl}-methanone (Compound 126) [2-Ga-4-(4-Fluoro-phenyl) Base)·phenyl]_{5_[4·(2·hydroxyethyl)-[1,2,3]triazol-1·yl]·2-methyl-phenyl fluorenone (compound 127), [2_Gas·4_(2,4·Difluoro-phenylamino)-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazole-1 -yl]_2-methyl-indolyl ketone (Compound 128), [2-Ga-4-(2,4-difluoro-phenylaminophenyl)hydroxy-methyl-ethyl)-[1, 2,3]triazol-1·yl]_2-methyl-phenyl}-methanone (compound 129), 1-(1-{3-[2- gas-4-(2,4-difluoro) Phenylamino)-benzylidene]-4-methyl-phenyl}-1Η-[1,2,3]triazol-4-yl)-ethanone (Compound 130), {5-[4 -(1-Amino-1-methyl-ethyltriazole-buyl]·2_fluorenylphenyl}-[2-chloro-4-(2,4-difluoro-phenylamino) Phenyl]-methanone (compound 131), 1-{3-[2-chloro-4-(2,4-difluoro-phenylamino)-benzhydryl;]_4-methyl-benzene }}-1Η-[1,2,3] triazole-4-carboxylic acid decyl ester (compound 132), 1-{3-[2-chloro-4-(2,4-difluoro-phenylamino) Benzyl hydrazino]_4_methyl-phenyl}-111-[1,2,3]triazole-4-carboxylic acid (compound 133), [2- gas-4-(2,4-di) Fluoro-phenylamino)phenyl]·[5_(cardiohydroxymethyltriazol-1-yl)-2-methyl -Phenyl]-methanone (Compound 134), • 23·106609.doc

1379829 [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[4-(3-hydroxy-propenyl)-[1,2,3]triazole -1-yl]-2-mercapto-phenyl}-methanone (compound 135), {5-[4-(2-amino-ethyl)-[1,2,3]triazole-1- 2-methyl-phenyl}-[2-chloro.4.(2,4-di-p-stylamino)-phenyl]-carboxamidine (Compound 136), ([-•^- [之-乳-斗-^心二敦-Phenylamine Benzyl Benzyl ketone - thiol-phenyl}-11€-[1,2,3]triazol-4-ylmethyl) -urea (compound 137), [2-chloro-4-(2,4-difluoro-phenylamino)phenyl]_{2_methyl-5-[4-(2-morpholin-4 -yl-ethyl)-[1,2,3]triazol-1-yl]-phenyl}-methanone (Compound 138), [2-Ga-4-(2,4-difluoro-phenyl) Amino)-phenyl]-(2-methyl-5-{4-[2-(4-methyl-p-but-1-yl)-ethyl]-[1,2,3]triazine- 1-yl}-phenyl)-methanone (Compound 139), [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl]_{5-[4-(2- Dihexylamino-ethyl)-[1,2,3]triazol-1-yl]-2-indenyl-phenyl}-methanone (Compound 140), [2-Ga-4-(2, 4-Difluoro-phenylamino)-phenyl]-(5-{4-[2-(2-hydroxy-ethylamino)-ethyl]-[1,2,3]triazole-1 -基}-2-A -Phenyl)-methanone (Compound 14 1), [2-Ga-4-(2,4-difluoro-phenylamino)-phenylmethyl-5-[4-(2-propylamino) -ethyl)-[1,2,3]triazol-1-yl]-phenyl}-fluorenone (Compound 142), [2-Chloro-4-(4-fluoro-2-indolyl-phenyl) Amino)-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2.indolyl-styl}•anthrone ( Compound 143), [2-Ga-4-(2-methoxy-phenylamino)-phenyl]-{5_[4-(2-hydroxy-ethyl)-[1,2,3] Zin-1-yl]-2-methyl-phenyl}-methanone (compound 144), [2·gas-4-(4-carb-2-indolyl·phenylaminophenyl]_{5 -[4-(2·hydroxyethyl)-[1,2,3]triazol-1-yl]-2-indolyl-phenyl- phenone (Compound 145), 106609.doc •24· 1379829 [2-Ga-4-(4-decyloxy-phenylamino)-phenyl]_{5-[4-(2-hydroxy-ethyl)-indole, 2,3]triazole-1- 2-methyl-phenyl}-methanone (compound 146), [2-chloro-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[4- (2. Ethylamino-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenylmethanone (Compound 147), [4-(2,4- Difluoro-phenylamino)-2-methyl-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1 , 2,3]triazol-1-yl]-2-methyl-phenyl ketone (Compound 148), [4-(3-Ga-4-fluoro-phenylamino)-2-methyl -phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenylmethanone (compound 149), {5-[4-(2-Hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-(2-indolyl-4-phenylamine -Phenyl)-methanone (Compound 150), 1_[3-(4-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]- 2-methyl·benzyl}-3-methylphenylamino)-phenyl]-ethanone (compound 151), 3·(4-{5-[4-(2-hydroxy-ethyl) )-[1,2,3]triazol-1-yl]-2-methyl-benzoyldibu 3-methyl-phenylamino)-benzonitrile (Compound 152), (5·[ 4-(2-hydroxy-ethyl)-[1,2,3]triazol-l-yl]-2-indenylphenyl}-[2-methyl·4·(3-trifluoromethyl)- Phenylamino)-phenyl]-fluorenone (Compound 153), [(3,4-Pro-phenylamino)-2-methyl-phenyl]-{5-[4-(2- Light-ethyl-hnhnd]triazole-yl]. -methyl-phenyl ketone (compound 154), [4_(3,4-dimethyl-phenylamino)-2-methyl-phenyl]-{5·[4-(2-hydroxy- Ethyl Hi,2,3]triazol-1-yl]-2-methyl-phenylphenone (Compound 155), [4-(3-Gas-2-methyl-phenylamino)- 2-mercapto-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazole-i-yl]_2-methyl-phenyl-indole (compound) 156), [4_(3,4-dioxa-phenylamino)-2-indolyl-phenyl]-{5-[4-(2-hydroxy-ethylHH3]triazole-bubub, Methyl·Phenyl ketone (Compound 157), l〇6609.d〇c -25· 1379829 1^-[3-(4-{5-[4-(2-hydroxy-ethyl)-[1 , 2,3]triazol-1-yl]-2-mercapto-benzylidenyl}-3-methyl-phenylamino)-phenyl]-acetamide (Compound 158), [2- Gas-4-(2,4-dioxa-phenylamino)-phenyl]-{2-wind-5-[4-(2-light-ethyl)-[1,2,3] Zin-1-yl]•phenyl} •indolone (compound 159), [2-murine-4-(3-. gas-phenylamino)-phenyl]-{5-[4-(2- Light-ethyl-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 160), [2-Ga-4-(3-murine- Phenylamino)-phenyl]-{5-[4-(2·light-ethyl)-[1,2,3]triazol-1-yl ]-2-methyl-phenyl}-methanone (compound 161), (2-gas-4-mercapto-amino-phenyl)-{5-[4-(2-hydroxy-ethyl) -[1,2,3] triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 162), [2-Ga-4-(3-decyloxy-phenylamino) )-Phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 163 ), [2-Ga-4-(2,3-dioxa-phenylamino)-phenyl]-{5-[4-(2-trans-yl-ethyl)-[1,2,3] Triazol-1-yl]-2-mercapto-phenyl}-fluorenone (Compound 164), [2-Chloro-4-(3,5-dimethyl-n-ylamino)-phenyl]- {5-[4-(2-Phenyl-ethyl)-[1,2,3]triazol-1-yl]-2-indolyl-phenyl}-methanone (Compound 165), [2- 4-(2,5-di-phenyl-phenylamino)-phenyl]-{5-[4-(2-trans-ethyl-ethyl)-[1,2,3]triazole-1- 2-methyl-phenyl}-fluorenone (compound 166) and [2- gas-4-(3,5-difluoro-phenylamino)-phenyl]-{5-[4- (2-Phenyl-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-fluorenone (Compound 167). In another embodiment of the invention of formula la or lb compound, when R4 is -NH2, at least one of R5, R6, 117 or 118 is not hydrogen, or when 118 is -NH2, R4, R5, Κ • At least one of 6 or R7 is not hydrogen. Methods of Preparation 106609.doc -26- 1379829 The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be modified using the methods outlined below, as well as synthetic organic chemistry techniques - known methods of the stomach. Preferred methods include estimating (but not limited to) the methods described below.

Compounds can be prepared using the reactions and techniques described in this section. These reactions are carried out in a solvent which is suitable for the reagents and materials and is suitable for efficient conversion. In addition, in the synthesis method of the following (4), it should be understood that all the proposed reaction conditions, including the solvent, the reaction atmosphere, the reaction temperature, the duration of the experiment, and the choice of the treatment procedure, are selected as the standard conditions for the reaction, which should be familiar with This technology recognizes. Those skilled in the art of organic synthesis should be aware that the functional groups present at different positions of the molecule used as the starting compound or intermediate in the synthesis must be in phase with the proposed reagents and reactions. Not all compounds of the formula I belonging to a particular class are compatible with certain of the reaction conditions required in certain of the methods described. Such limitations of substituents or functional groups that are compatible with the reaction conditions should be apparent to those skilled in the art and alternative methods that may be employed. The compound according to the present invention can be prepared by a method as shown in Scheme 1 which comprises coupling a terminal alkyne of the formula Ila with an ila azide compound to obtain a compound of the formula la; or as shown in Scheme 1, Similarly prepared by a method comprising coupling a formula lib azide compound with an alkyne of formula 111b to obtain a compound of formula lb; wherein R丨, R2, R3, R4, R5, R6' R7 are as defined above Definition; any substituent or functional group that is potentially reactive in the coupling reaction can be protected before the coupling reaction proceeds, and with 106609.doc • 27-1379829

Remove the protecting group afterwards.

Lllb

FGI Q ny or lb denotes the ruler, 112, 113, 114, 115, 2, R3, R4, R5, R6, feet 7 and 118 FGI: functional group interchange R i, R'2, R'3, R , r'5, r'6, R.AR, 8 R6, R? and R8 or any convertible to r1s r suitable fg (functional group) Scheme 1 The above coupling reaction is carried out by using - for ripening organic synthesis The method of 1,4 disubstituted triazole is well known to the skilled person (see, for example, w〇3/101972, Angew. Chem Int. Ed. 2002, 41, No. 14, JOC 2002, , 3 05 7 3 064, and the literature cited therein). A preferred method is a copper (1) catalyzed process which comprises coupling an azide compound to a terminal alkyne at room temperature or higher (e.g., up to). Different copper sources can be used in the process, non-limiting examples of which are Cu(I)I, CU(I)Br, Cu(I)C1, Cu(I)〇Ac, and Cu(0). The current preferred source is "Cu(ii)s〇4.5H2〇 in the presence of a suitable reducing agent such as sodium ascorbate. U06609.doc 8 -28- 1379829 The amount of Cu source in this catalytic process is generally in the range of (% by mole to 1%) of the amount of the alkyne. And the reaction is usually carried out at a low temperature (❹25t), such as methanol, ethanol, third butanol, M• two-hearted acetonitrile, dimethyl hard (DMSO), acetone, N, N_ two Methylmethylamine (DMF), N-methylpyrrolidone (oxime) or tetrahydrogen (THF). # The presence of a reducing agent. Where, when used as a catalytic system, usually less Water (2-40% 'v/v) is added to the reaction.

The above coupling can also be carried out thermally (simply by heating) non-catalyticly (preferably, without 丄, *,, UU). However, this method can also lead to the creation of a triple-substituted yoke. The compounds of formula IIa according to the invention may also be prepared by a number of means known to those skilled in the art of organic synthesis. A useful step in demonstrating a useful sequence in Scheme 2 involves coupling a fragment of formula IV with ethylidene trimethyl to provide a compound of the formula 。. The coupling is typically in the presence of a catalytic amount of palladium (?) source (eg, pd2(dba)3), a catalytic amount of copper (1) salt (eg, copper (I) iodide), and a ligand (eg, triphenylphosphine). Perform to stabilize the catalytic system. This reaction is well described in the literature and is also known as the Sonogashira reaction (see for example: 8〇11〇料311丨1^, {^111]^ by 1-

Catalyzed Reactions, Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998). The protected compound (1) can then be deprotected to the terminal acetylene of the corresponding formula Ila by treatment with K2C〇3, for example, in methanol at room temperature. The iodide of the formula IV can also be prepared by the standard diazonium 106609.doc -29- 1379829 of the amine of the formula v, followed by treatment with the diazonium salt formed by potassium iodide (see the available experimental details for Preparation 5) of a non-limiting example. The amine of formula v can be formed by reduction of a nitro compound of formula VI using a standard reducing agent. Examples of such reducing agents include, but are not limited to, tin chloride dihydrate, hydrogen, ammonium formate or hydrazine hydrate and a catalytic amount of palladium on carbon. As described in, for example, Uu, Q; T.; Org. Lett. 2003, 5, 2571-2572, the azide compound of formula nb can be obtained from a catalytic amount of a copper salt by an amine of formula V (eg Preparation of trifluoromethanesulfonyl azide compound in the presence of copper (II) sulfate pentahydrate

Kasahara

R's R's R' R's FGI: Official $base interchange, R !, R 2, R 3, R 4, R 5, R 6, R 7 and R 8 represent R,, r2, r3, r4, Rs, R6, respectively R7 and R8 or any may be converted to Rh R2, r3, r4, r5, r6, r7 and 106609.doc • 30- suitable FG (functional group) Scheme 2 The compound of formula VI according to the invention may also be used It is familiar to several routes known to those skilled in the art of organic synthesis. A useful sequence is shown in Flow 3. The first critical step comprises, for example, the preparation of other ketones by the method described in j. Am. Chem. Soc. 1973, 95: 14, 4763. 4765. (Activated acid;) Coupling to obtain diphenylphosphonium copper of the general formula VII. The coupling reaction can be accomplished by converting iodide IX to a reactive organometallic intermediate such as by treatment with vaporized isopropylmagnesium to provide the corresponding magnesium derivative. Mixing the reactive magnesium derivative with an ester of formula X produces the product of formula VII. Or 'the reactive magnesium derivative can be converted to zinc by treatment with a zinc salt such as zinc chloride or ZnBr2 or Zn10, and then in the presence of a catalytic amount of Pd(0) / ligand system with an acid Halides (such as the formula &ι < acid chloride) coupling. Examples of such catalysts include, but are not limited to, ruthenium (triphenylphosphine) palladium (0), ruthenium (triphenylphosphonium) palladium (0), Dioxane (triphenylphosphine) palladium (11) or phenylhydrinyl chlorobis(triphenylphosphine)palladium (II). Alternatively, copper (I) or copper at or below the stoichiometric or catalytic enthalpy (ie) The organic compound is coupled to an acid compound (such as an acid vapor) in the presence or in the presence of a salt such as copper acetate (yttrium acetate or soluble complex CuCN.2LiCl or CuCN.2LiBr). The coupling reaction can generally be carried out in an inert solvent (for example under an argon or nitrogen atmosphere) in an inert solvent such as 1,4-dioxane, toluene, benzene and tetrahydrofuran at room temperature. The evolution of the formula VII is coupled with an amine of the formula Vi to yield an aminobenzophenone of the formula VI. The coupling reaction is carried out by using 106609.doc •31 - 1379829 A method for the formation of diphenylamines well known to those skilled in organic synthesis.

The amine is coupled to an aryl halide (or aryltrifluorobenzoate) in the presence of a Pb source and a suitable phosphine ligand in an inert solvent.

get on. A preferred method is a palladium-catalyzed amination process, which comprises, as appropriate, different palladium compounds which may be used in the process, non-limiting examples of which are acetic acid (II), chlorinated (II), desertified sputum ( 11), dioxane (triphenyl scale) with (11), ruthenium (triphenylphosphine) palladium (0), tris(diphenylmethyleneacetone) dipalladium (ruthenium). Preferred phosphine ligands include, but are not limited to, racemic or non-racemic 2,2,-bis(diphenylphosphinobiphthalene (hereinafter referred to as BINAP), tri-o-phenylphosphonium, tri- Tert-butylphosphine, 1, fluorene-bis(diphenylphosphino)-ferrocene, bis[(2-diphenylphosphino)phenyl]ether (DPEphos), 2-dicyclohexylphosphino-2 '-Dimethylaminobiphenyl, 2-(di-tert-butylphosphino)biphenyl and 9,9-dimethyl-4,6-bis(diphenylphosphino)diphenylpyrene (Xantphos) The amount of palladium and ligand used in the catalytic process can generally range from 0.1% to 10% relative to the amount of the family of dentate (or triflate) used. It is proved that sodium butoxide (NaOt-Bu) and cesium carbonate (Cs2C〇3) are preferred in this method, but other tests can be used. The reaction is usually inert under an inert atmosphere such as argon or nitrogen. The solvent (such as 1,4-dioxane, toluene, benzene and tetrahydrofuran) is carried out at a high temperature (8 〇 _ 12 Torr). The thioester of the formula X can be, for example, an acid of the formula XI by triphenyl Prepared in the presence of phosphine with 2,2'-disulfide.tb bite (see for example, usually available non- Preparation of the details of the experimental experiment 1), such as described in Tetrahedron Letters Vol. 22, No. 46, pp. 4647-4650, 1981. Other general methods for preparing thioesters of formula X can be found, for example, in Tetrahedron Letters No. 31, Page 2875-2878, I06609.doc -32· 1379829

1979 and 〇rg· Letters 2003, Vol. 5, flute 5, No. 10, pp. 1633-1635 and the documents cited therein.

FGI: functional group interchange ^ 1' R 2' R 3, R 4, R 5, R 6, R 7 and R 8 respectively 砉 thousand RR Ρ 合适 suitable fg (functional group) Scheme 3 In special cases, according to the invention Compounds can be prepared by simple functional interchange (FGI), meaning one of the standard methods known to those skilled in the art of organic synthesis, in which one or more synthetic steps will have the formula 1 or 1, a combination of: Conversion of a functional group to a different functional group results in a new compound having the general formula. Examples of such methods include, but are not limited to, hydrolyzing an ester under basic conditions to produce an acid. By deprotecting the methyl ether by treatment with, for example, boron tribromide (ΒΒΓ3) 106609.doc • 33-1379829 to produce Phenols, and for example, catalytic hydrogenation of olefins to produce saturated hydrocarbons. Non-limiting examples of such transformations are described in R. C. Larock, VCH 1989, Comprehensive Organic Transformations " and the literature cited therein, which are hereby incorporated by reference in its entirety in its entirety herein in its entirety herein. In particular, the use of a general protecting group in one or more synthetic steps may facilitate the synthesis of a compound of formula I. Examples of such general protecting groups include, but are not limited to, methyl, ethyl, tert-butyl or Benzylmethyl ester serves as a protecting group for a hydroxyl group; tetrahydropiperidyl ether or a nonylalkyl ether serves as a protecting group for a hydroxyl group or a terminal alkyne. As shown in Schemes 1, 2 and 3, each intermediate compound can be converted by a FGI process as described above to produce a new compound of the same general formula (e.g., the base can be a second butyl-dimethyl group). - Shi Xi burn key to protect). This merely illustrates the flexibility of the synthesis' and generally the described method sequence is only one of many possible strategies for synthesizing the compounds of the invention. That is, it may be more advantageous to change the order of the above methods in some cases. The method sequence described is not to be construed as limiting the compounds of the formula la or lb of the present invention, and variations in the order of the reaction may be an alternative to those skilled in the art of organic synthesis. The readily available intermediates can be used as starting points for the synthesis of the various series of compounds encompassed by the formulae la and lb. The synthesis of various aminodibenzophenones and the general methods for synthesizing the intermediates and benzophenones of the present invention can be found, for example, in W〇98/32730, WO 01/05744, WO 01/05746, WO 01/ 05749, W0 01/05751, W0 01/05745, WO 01/42189, WO 01/90074, W0 02/ 083622, W0 03/018535, W0 02/076447 and WO 04/056762 and • 34- I06609.doc (S 1379829 It is found in the literature cited therein, all of which are incorporated herein by reference. Pharmaceutical Composition In another aspect, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, a compound of formula la or lb' and a pharmaceutically acceptable excipient or vehicle. Further, the present invention relates to a medicament for preventing, treating or ameliorating an inflammatory disease or condition using a compound of the formula 13 or 11?. The pharmaceutical composition of the present invention may be in a unit dosage form such as a tablet, a pill, a capsule, a powder, a granule, a wine, a syrup, an emulsion, an ampoule, a suppository or a parenteral solution or suspension; for oral, parenteral, By eye, percutaneous, intradermal, topical, transpulmonary, nasal, spleen or rectal administration, or in any manner suitable for the formulation of anti-inflammatory compounds and according to accepted practices, such as in Remington : The Science and practice

Pharmacy. 19th Ed., Mack Publishing Company, 1995 〇 t//f Unable to disclose the drug. In the composition 16 of the present invention, the active ingredient can be. It is present in an amount from about 0.01% by weight to about 99% by weight, such as from about % by weight to about % by weight. For oral administration in the form of a lozenge or capsule #4, a gelatinous shock, the compound of formula I may suitably be combined with an oral, non-toxic, medically acceptable medium (such as ethanol, glycerol water or the like). combination. Gentry k Further, 'appropriately, a suitable binder, a slip agent, a disintegrant, a fragrance beta, and a colorant are added to the mixture. Combination: The binder includes, for example, 5丨#, g β pore sugar® sugar, starch, gelatin, gum arabic gum, sodium alginate, cellulose methacrylate, polyethylene glycol, wax or its n Like things. Lubricants include, for example, (7) s/from sodium I, sodium stearate, magnesium stearate, sodium 106609.doc • 35-1379829 sodium formate, sodium acetate, sodium chloride or the like. The disintegrant includes, for example, a title powder, methyl cellulose, agar, bentonite, triterpene or the like. For capsules, additional excipients include polyethylene glycol or lipids.

For the preparation of a solid composition such as a tablet, the active compound of the formula I is mixed with one or more excipients (such as those mentioned above) and other pharmaceutical diluents such as water to produce a solid premix containing a homogeneous mixture of the compound of formula I. The composition is formulated. It is to be understood that the term "homogeneous" means that the compound of formula I is uniformly dispersed throughout the combination such that the composition can be readily subdivided into equivalent unit dosage forms, such as lozenges or capsules. The pre-formulated composition can then be subdivided into unit dosage forms containing from about 0.05 to about 1000 mg, especially from about 0.1 to about 500 mg of the active compound of the invention. Liquid formulations for oral or parenteral administration of a compound of the invention include, for example, aqueous solutions, syrups, aqueous or oily suspensions, and emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as yellow

Silicone, alginate, gum arabic, dextran, calcium carboxymethylcellulose, gelatin, sulfhydryl or polystyrene. For parenteral administration, for example, intramuscular, intraperitoneal The subcutaneous or intravenous injection or delivery of the S 'pharmaceutical composition preferably comprises a formula compound dissolved or dissolved in a suitable, pharmaceutically acceptable solvent. For parenteral administration, the compositions of the present invention may comprise A sterile aqueous or non-aqueous solvent, especially water, isotonic saline, isotonic glucose solution, buffer solution or other conventionally used parenteral administration of a therapeutically active solvent. The composition may be retained by the mere-hypergesia遽器过得, adding disinfectant to the composition, irradiation combination 106609.doc

-36- Object or heat the composition to eliminate spring. Alternatively, the compound of the present invention can be administered, for example, in the form of a sterile, solid, scented scented scent of lycopene powder which is directly dissolved in a sterile solvent prior to use. The composition to be used for parenteral administration may additionally contain conventional additives such as a diluent, a buffer or a preservative such as an antioxidant such as methyl hydroxybenzoate or the like. The composition for rectal administration may be in the form of a suppository added to the active ingredient and vehicle (such as cocoa butter) or in the form of an enema. Compositions suitable for intra-articular administration may be formed as a non-toxic aqueous preparation of the active ingredient which may be in the form of crystallites, e.g., in the form of an aqueous microcrystalline suspension. Lipid formulations or biodegradable polymer systems can also be used to provide active ingredients for intra-articular and transocular administration. Compositions suitable for topical administration including ocular treatment include: liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions (such as creams, Ointment or paste); or a solution or emulsion, such as a drop. For topical administration, the compound of formula I may generally be present in an amount from about 0.01% to about 20% by weight of the composition, such as from 0.1% to about 10%, but may also be as high as about 50% of the composition. The amount exists. The composition for ophthalmic treatment may preferably additionally contain a ring paste. Compositions suitable for nasal or buccal administration or for inhalation include powders, auto-propelled and spray formulations, such as aerosols and nebulizers. The compositions may comprise a compound of formula I in an amount of from 1 to 20% by weight (e.g., 2% by weight) of the composition. The compositions may additionally comprise one or more other active ingredients conventionally used in the treatment of various inflammatory conditions and disorders. Examples of such additional active ingredients may be selected from the group consisting of glucocorticoids, vitamin D and vitamin d analogs, antihistamines, platelet activating factor (PAF) antagonists, anticholinergic agents, methyl groups Astragalus, β-adrenergic agent, C0X-2 inhibitor, salicylate, indomethacin, fenfenacate, naproxen Naproxen, timegadine, gold salt, lumiamide, serum cholesterol lowering agent, retinoid, salt and salicylazosulfapyridine. In another aspect, the invention relates to a method of treating an inflammatory disease or condition, or an ophthalmic disease or condition, or cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of the formula. Suitable dosages of the compounds of the invention will depend, inter alia, on the age and condition of the patient, the severity of the condition being treated, and other factors well known to those skilled in the art. The compound can be administered orally, non-successfully or topically depending on the time of administration (e.g., daily or every other week). In general, a single dose will range from 〇〇1 to 4〇〇 mg/kg body weight. The compound can be administered in a single dose (i.e., a human fork and a full day dose) or divided into two or more times a day. An inflammatory disease or condition contemplated for treatment with a compound of the invention is an inflammatory disease wherein modulating the expression and secretion of cytokines is mediated by MAP kinases (such as the p38 MAp kinases discussed above). An example of an inflammatory disease or condition mediated by p38 MAp kinase is selected from the group consisting of the following diseases: rheumatoid arthritis and spinal arthritis, gout atherosclerosis, inflammatory Intestinal disease, Crohn's disease (ΜΑ sease) _ inflammatory inflammation, inflammatory eye disease, proliferative and inflammatory skin I06609.doc 8 -38· 1379829 Atopic dermatitis and acne vulgaris (acne inflammation, sepsis , septic shock and osteoporosis

Treatment may additionally include administration - or a variety of other anti-inflammatory active ingredients, pipimarin, vitamin bismuth and vitamin D analogs, antihistamines, platelet activating factor (PAF) antagonists, anti-cholestases, methyl jaundice吟, Bu = adrenergic drugs, C0X-2 inhibitors, salicylate, ten mexins, fentanic acid vinegar, naproxen, tibecaine, * salt, penicillamine, serum cholesterol lowering agent , retinoids, zinc salts and azobenzene amines. The compounds of the invention and other anti-inflammatory ingredients may be administered concomitantly or sequentially. Ophthalmic diseases or conditions contemplated for treatment with the compounds of the invention include the following ophthalmic diseases or conditions: non-infectious (eg, allergic) conjunctivitis, iritis, keratitis, uveitis, scleritis, sclera, sympathetic ophthalmia , phlegm or dry keratoconjunctivitis. Pharmacological method

Conditions (such as psoriasis, vulgaris), ocular pigmentation. To study the in vitro effects of the compounds of the present invention, the following procedures were used to measure the inhibition of IL-Ιβ and TNF-α secretion: In the culture medium, lipopolysaccharide (LPS) was used to stimulate peripheral blood mononuclear cells to measure cytokines. produce. The monocytes were separated from human peripheral blood by (Nycomed, Norway) fractionation and suspended in RPMI 1640 (growth medium) with fetal bovine serum (FCS, 2%) at a concentration of 5χ1〇5 cells/ml. . The cells were cultured in 1 well aliquots in 24-well tissue culture plates. Test compounds were dissolved in dimethyl hydrazine (DMSO, 10 mM) and diluted in medium. These compounds were added to the cells 106609.doc 8 •39· 1379829 for 30 minutes followed by the addition of LPS (1 mg/ml final concentration). The plates were cultured for 18 hours, and the concentrations of IL-Ιβ and TNF-α in the medium were determined by enzyme-linked immunosorbent assay. The median inhibitory concentration (IC50) of these compounds was calculated. The results are shown in Table 1. Table 1. Inhibition of in vitro production of cytokines by the compounds of the invention

Median Inhibitory Concentration (IC50, nM) Compound No. IL-Ιβ TNF-α Compound 102 1.3 0.5 Compound 104 0.6 0.5 Compound 105 1.4 Compound 106 0.7 0.5 Compound 107 0.8 0.5 Compound 108 1.3 0.7 Compound 109 1.9 1.2 Compound 110 6.3 3.6 Compound 112 5.0 0.3 Compound 113 6.3 0.6 Compound 114 0.4 0.3 Compound 115 0.5 0.5 Compound 117 1.6 1.1 Compound 118 1.3 0.9 Compound 120 5.0 0.8 Compound 122 1.4 0.9 Compound 124 0.8 0.5 Compound 125 1.0 0.5 Compound 127 0.9 0.7 Compound 128 1.0 Compound 129 1.4 Compound 130 1.3 0.6 Compound 131 2.5 1.8 Compound 136 1.6 1.3 106609.doc -40 - 8 1379829 Median inhibitory concentration (IC50, nM) Compound number IL-Ιβ TNF-α Compound 137 1.0 0.3 Compound 138 3.2 2.0 Compound 139 1.6 0.5 Compound 140 2.0 0.8 Compound 14 ί 0.6 0.6 Compound 142 1.0 0.8 Compound 143 4.0 1.0 Compound 145 5.0 2.0 Reference compound a 13 7.1 Reference compound b 6.3 6.3 Reference compound c 32 6.3 Reference compound d 7.9 3.2 Reference Compound e 6.3 3.2 Reference compound f 13 4.0 Reference compound a : (4-(2-Aminophenylamino)-2- gas-2·-methylbenzophenone, compound disclosed in WO 98/32730 156. Reference compound 2: 2'-[3-Ga-4-(2-methylbenzhydryl)phenylamino]octyl anilide disclosed in Jia Yu 01/05746, Compound 102. Reference compound c: N-[2-[3-Ga-4-(2-methylphenylhydrazino)phenylamino]phenyl]amino decanoic acid 1-ethoxy oxime ester disclosed in WO 01/05749, Compound 10 9. Reference compound d: 1-ethyl-3-[2-[3-chloro-4-(2-methylabendyryl)phenylamino]-5- disclosed in WO 01/05751 Fluorine-phenyl]urea, compound 114. Reference compound e: 2,2,2-trifluoro-N-[2-[3-chloro-4-(2-mercaptophenyl)phenylamino]-5 as disclosed in WO 01/05 745 -Fluoro-phenyl]acetamide, compound 102. -41 - I06609.doc 8 Reference compound f: 2-gas-4-(3-fluoro-2-methyl-phenylamino)-2'-methylbenzophenone disclosed in WO 01/42189, Compound 131. These results show that the compounds of the present invention are potent inhibitors of IL-ΐβ, TNF-α production and exhibit a surprisingly higher cytokine inhibitory activity than the reference compound' thus making it possible to treat inflammatory diseases. In addition, such novel amino benzophenone derivatives can have surprisingly good pharmacokinetic properties such as absorption and metabolic stability. P38a MAP kinase assay Cell culture COS-1 cells (obtained from African green monkey kidney fibroblasts containing wild-type tau antigen under the control of the SV40 promoter) were obtained from ATCC (ATCC no. CRL-1650) and The growth medium (DMEM without phenol red, 10% FCS, 2 mM L-glutamic acid, 100 U penicillin and 100 pg streptomycin/ml) was grown at 37 ° C with 5% CO 2 . The cells were subcultured twice weekly by trypsinization (〇.250/0 trypsin, 1 mM EDTA in PBS) and split at 1:1 。. The medium was changed every other day or two. The cell line was periodically tested with Mycoplasma PCR Primer Set (Stratagene) and found to be free of Mycoplasma » tissue culture medium, FCS, L-glutamic acid and penicillin and streptomycin obtained from Bribco BRL, Gaithersburg, MD, USA. . Transient performance of COS-1 cells On the first day, COS-1 cells were seeded at a density of 2 x 104 cells/cm2 in growth medium in a 143 cm petridish dish. The next day, the cells were co-transfected with 5 pg (total) of FLAG-p38a and 106609.doc • 42 1379829

Experimental plastid DNA of FLAG-MKK6 (EE). These plastids were introduced into COS-1 cells in a serum-free medium using DOTAPTM (Boehringer-Mannheim, Mannheim, Germany). The plastid DNA was prepared and purified using the QIAGEN Endo Toxin-free Maxiprep-500 kit (Hilden, Germany). Briefly, DNA was mixed with DOTAPTM for exactly 15 minutes at 37 ° C in a C02 incubator. Thereafter, the transfection mixture was transferred to a 15 ml falcon tube and the transfection medium (DMEM with L-face acid and penicillin/lentin but no serum) was added to the transfection mixture, followed by addition to In the cell monolayer. After 4 hours of incubation with DOTAPTM and plastids, medium containing double serum was added to the cells to produce a final serum concentration of up to 10%. The cells are then cultured for 24 hours prior to the kinase reaction. Immunoprecipitation

After 24 hours of culture, the reaction was terminated by placing the Pateley culture on an ice bath. The medium was withdrawn and the cell monolayer was washed once in ice-cold PBS (137 mM NaC, 1.5 mM KH2P〇4, 2.7 mM KC1, 8.1 mM Na2HP04-2H20), and then dissolved in 1.5 ml of lysis buffer (50 mM HEPES pH 7.5, 150 mM NaC Bu 10 mM EDTA, 10 mM Na4P2〇7, 100 mM NaF, 2 mM Na3V〇4, 1% Triton-X-100, Pefabloc 500 μΜ, Leupeptin 10 pg/μΐ, Aprotinin 10 pg /μΐ) lasts 10 minutes. The cell monolayer was scraped off using a rubber-policeman and transferred to an Eppendorf tube. The solubilized cell lines were clarified by centrifugation at 10 °C for 10 minutes at 4 °C. Transfer the supernatant to soluble in HNT buffer (30 mM HEPES pH 7.5, 30 mM NaCM, 0.1% 106609.doc • 43 ·

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50 μΐ pre-washed G-protein agarose beads from Triton X-100) and 2 μ§/sample of monoclonal anti-FLAGTM M2 antibody (for FLAG epitope, NH2-Asp-Tyr-Lys-Asp- Asp-Asp-Asp-Lys-COOH was cultured) and incubated at room temperature for 1 hour. The anti-FLAG M2 monoclonal antibody system was obtained from Sigma (cat. no. F-3165). About 60 pg of clarified cell lysate protein was added to the pre-adsorbed anti-FLagtm antibody on G protein agarose beads, and cultured in a blood sample mixer at 4C for 90 minutes. After the immunoprecipitation phase, the agarose beads were washed twice in lysis buffer and washed twice in kinase reaction buffer (25 mM HEPES pH 7.5, 10 mM magnesium acetate, 50 μM ATP). Culture of compounds with purified ρ3 8α kinase will be adsorbed on G protein agarose beads by pre-wash immunoprecipitation of anti-FLAG-p38 in 1 激酶 kinase-buffer (25 mM HEPES pH 7.5, 10 mM magnesium acetate, 50 μM) Wash twice in both' and aspirate the supernatant. These compounds are diluted in a suitable concentration of 1 χ kinase buffer. At 3〇<>(:

In a volume of 100 μΐ, the compound was added to the washed immunoprecipitation and activated FLAG_p38 adsorbed on G protein agarose beads for 3 minutes. Tap the Eppendorf tube every 10 knives to ensure that the beads and the compounds are in solution. After 30 minutes of incubation, the beads were spun down and the supernatant was aspirated. P38a MAP Kinase Reaction This kinase reaction was performed by adding 1 ton of GST_ATF_2 substrate per sample (Santa Cruz, LaJolla, CA, USA, cat. no. sc-4114) and 2 μ in lx kinase buffer (: ι γ-32ρ_Ατρ starts with the reaction at 3 (in rc for 30 minutes) and it is added to the 106609.doc by adding 4〇μ1 2xian 5 sample buffer.

-44- 1379829 Kinase reaction to terminate. The samples were boiled, spun down, and resolved on 15% SDS-PAGE. The dry SDS-PAGE gel was exposed to a Phospho-Image and the number of radioactive PHAS-1 bands was determined by using ImageQuaNT software STORM860 Phospho-Imager (Molecular Dynamics, Sunnyvale, CA, USA). In this assay, Compound 102 was found to be a potent p38 MAP kinase inhibitor. In vivo screening model for LPS-induced TNF-α response in mice To study the in vivo effects of the compounds of the present invention, an in vivo screening model for LPS-induced TNF-a response in mice was established as follows: 1 hour before administration of LPS, Several groups of 6 mice (C3H/HeN, female, about 8 weeks (20 g), Bomholtgaard) were administered a test compound (LPS from E. coli 055: B5, L-4005, Sigma) dissolved in a suspension vehicle. At time zero, mice were given 1.0 mg LPS/kg intraperitoneally. After anesthesia with Hypnorm/Dormicum, the mice were bled from the periorbital venous plexus 80-90 minutes after LPS administration of LPS. Blood samples were taken in EDTA-stabilized tubes and centrifuged at 4000 rpm for 10 minutes at 4 °C. The plasma content of TNF-α was analyzed by ELISA. Compound 156 of WO 98/32730 was used as a reference compound. The plasma level of TNF-a was determined using a sandwich ELISA. The microtiter plate was coated with a monoclonal antibody against mouse TNF-a, washed and blocked with casein buffer. A sample of the mouse TNF-a recombinant standard was added to the wells of the microtiter dishes and cultured. All standards were tested in triplicate and all plasmas were made in a single serving to test the samples and standards after incubation, the plates were washed and labeled with biotin against mouse TNF-a. The secondary antibody is cultured and washed. The enzyme conjugate was added to all 106609.doc -45·1379829 wells and cultured. The substrate was added and the enzyme/substrate reaction was terminated with 1 M H2S04 at room temperature after 15 minutes. The color development (OD) was measured at 450 nm on an ELISA reader and the background OD at 620 nm was subtracted. These experiments were approved if the reference compound-treated group exhibited significant inhibition of TNF-α response (p<0.05) compared to the LPS-treated control group. The results of the test compounds are expressed as percentage inhibition of the control group treated with LPS. The compound was tested at 1 mg/kg (p.o.). The drug-treated group and the LPS-treated control group were compared using the Mann-Whitney test (p<0.05). The results are shown in Table 3. Table 3. In vivo inhibition of LPS-induced TNF-ct production (in %) Compound No. Compound 102 94 Compound 104 90 Compound 106 98 Compound 107 91 Compound 108 78 Compound 109 79 Compound 112 49 Compound 114 86 Compound 115 70 Compound 122 96 Compound 124 77 Compound 125 96 Compound 127 94 Compound 128 95 Compound 129 83 Compound 131 80 Reference compound a 23 106609.doc -46- 1379829 Reference compound a: WO 98/32730 (4-(2-amino) Phenylamino)-2-aero-2'-methylbenzophenone, compound 156 (tested at 1 mg/kg 丨p). The results show that the compound of the present invention is more potent than the reference activator. Surprisingly shown to inhibit LPS-induced improved biological in vivo activity in mice' thus making it possible to treat inflammatory diseases. The invention will be described in further detail in the following non-limiting examples, which are not in any way It is intended to limit the scope of the invention as claimed. Summary of Examples All melting points have not been modified. For ιΗ NMR (NMR) spectroscopy) and NMR (75.6 MH) z), unless otherwise stated, reference to the atmosphere-like imitation solution relative to internal tetramethyst (δ = 00) or gas (δ = 7 26) or yttrium-containing (for 13C NMR δ = 76 81 Standard chemical shift value

(δ) (with PPm as a single unless otherwise referenced n is given a multi-state value defined at the approximate midpoint (dual state (4), triplet (1), quadruple state (4)) or undefined (iv). All solvents used are free of water. Chromatography on Shishi gum using flash technique. Unless otherwise noted, an appropriate mixture of ethyl acetate, methylene chloride, methanol and petroleum (iv) is used as the dissolving agent. The following abbreviations are used: aq. Benzamethyleneacetone DCM Dimethylmethane DMAP 4-dimethylaminopyridine I06609.doc

Cs) -47· 1379829 DMF N,N-Dimercaptocarbamide DIEA Ethyldiisopropylamine EDC1 1-(3-Didecylaminopropyl)-3-ethylcarbodiimide

EtOAc ethyl acetate FDPP diphenyl-pentafluorophenyl phosphate h hour HATU 0-(7-azaphthalazintriazol-1-yl)-Ν, Ν, Ν·,Ν'-四曱锞-

Hexafluorophosphate min min NMP N-mercaptomorpholine NMR NMR rac-BINAP racemic 2,2'-bis(diphenylphosphino)-1,1 binaphthyl RT room temperature TBAF fluorinated tetra-n-butyl Glycolate TEA triethylamine

TFA trifluoroacetic acid THF tetrahydro π-pentan ΤΗΡ tetrahydro β-decane TIPSC1 gasified triisopropyl decane ν volume 106609.doc -48- 1379829 Table 4. Exemplary compounds of formula I

Compound Example No. Structure 101 1 Q 0_\ O Cl 102 2 HO^^_-NsN 0 Cl 103 3 Q n; nX〇00l々f H ΐ 104 4 H ί 105 5 ° N: NX〇5dNJprF . h ί . 106609 .doc -49- 1379829

Compound Example No. Structure 106 6 HO HO—^^\ η ϊ 107 7 η ϊ 108 8 ρ N"X〇00LNJprF H l 109 9 <?H |'N^ h '1 110 10 . ‘νΛ 吖 H F 111 11 HO H Ϊ 106609.doc -50- (§) 1379829

Compound Example No. Structure 112 12 h l 113 13 Η ί 114 14 Η ϊ 115 15 0 H l 116 16 /N^N 0 CI F H. H 117 17 __/NirN 0 Cl H. 106609.doc - 51 - 1379829

Compound Example No. Structure 118 18 CI 119 19 a〇s 1 Η Τ 120 20 HO i H ΐ 121 21 O'. , Η 122 22 HO Η 123 23 . ^ϋόάχτ Η 106609.doc 52- 8 1379829

Compound Example No. Structure 124 24 HO Η 125 25 N:N^0SNJ〇rF Η 126 26 Cl KnXC^0l Shore FH l 127 27 H0_V/N^NO Cl H 128 28 nOver吖H ί 29 29 HF 130 30 \ / ^N 0 Cl 131 31 h ί 106609.doc -53-

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Compound Example No. Structure 132 32 —°Ν_0 Cl 133 33 HC\ ,ΝϊϊΝ Ο Cl . 134 34 ΗΟχ__/N;sN 0 Cl 135 35 HO H l 136 36 H2N~\广广 N 0 Cl t^KJprF 137 37 h2n h ^~*N\_yN^N 0 Cl h 1 138 38 H i 139 39 〇9 ' O0aN^TF H i 140 40 ~Λ _/N~\ Wide N 0 Cl 106609.doc .54· 8 1379829

Compound example No. Structure 141 41 H0 142 42 Η^\ /Ν^Ν 0 Cl 143 43 Η°^/Νί=Ν 0 Cl 144 44 ΗΟ Flying N;:N 〇Cl Η ί, 145 45 Η0~\ Ν 0 CI 146 46 H0_V/N^N 0 Cl χΛΧχτ Η 147 47 ~Λ Η^\ /Ν^Ν 0 CI η ι 148 48 H0_V^N^N 0 ι ^xr0LNrrF Η ϊ 149 49 H〇^yN^N 0 ι χ^άΝχχΐ Η 106609.doc •55- 1379829

Compound Example No. Structure 150 50 H0^\/N^N 0 | Η 151 51 Η0^/^Ν 0 I Η ι 152 52 Η0^/Ν^Ν 0 ι Η 153 53 Η0^/^Ν 0 ι Η 卜 154 54 Η0^^Ν>Ν 0 ι ^χχά,χχ; Η 155 55 Η0^/Ν^Ν 0 ι Χ^άΝΧΧ Η 156 56 Η0^/Ν^Ν 0 ι 157 57 Η0^/Ν^Ν 0 ι ό ^Λνχχ: Η 158 58 Η0_^/Ν^Ν 0 I 1^NXU Η Η 106609.doc -56- 1379829

Compound Example No. Structure 159 59 H〇^_yN^N p Cl XWN^rF H l 160 60 H0 Feiguang N 0 Cl ΌόάΝχχΡ H 161 61 H〇飞广N 0 Cl H 162 62 H0飞广々N 0 Cl H 163 63 H0^/NN 0 Cl H 164 64 H0-\ N^n 〇ci Wei Take H Cl 165 65 H0 Fly/*々N 0 Cl I 〜满Λ 166 166 66 H0^/N^N 0 Cl Η 167 67 H0 fly production NO Cl F Η •57- 106609.doc 1379829 Preparation 1: 2-methyl-5-nitro-thiobenzoic acid s-pyridin-2-yl ester (compound 401) 2-methyl-5 - mercaptobenzoic acid (22.5 g, 124 mmol), 2,2'-dithiopyridinium (27.5 g, 124 mmol) and triphenylphosphine (32.6 g, 124 mmol) dissolved in CH3CN (650 mL) . The solution was stirred at room temperature for 18 hours. The reaction mixture was filtered and the solid was washed with a little CHsCN. This provides the title compound as a colorless solid. Preparation 2: (4-Bromo-2-p-phenyl)-(2-methyl-5-nitrophenyl)-methanone (Compound 402) This reaction was carried out using a dry glass apparatus JR under an argon atmosphere. 4-Bromo-2-mosaline (25.5 g, 80.9 mmol) was dissolved in dry THF (400 mL) and cooled to -60. Gasified isopropyl magnesium (2 in THF, 40.4 mL, 80.9 mmol) was added with stirring over 30 min. The reaction mixture was allowed to warm to -40 ° C and the mixture was stirred at EtOAc over 4 hr. Compound 401 (22.2 g' 80.9 mm 〇l) was added and the mixture was stirred at _4 〇 <t>t for 3 hr, then warmed to room temperature and stirred for 17 hours. A saturated aqueous NH4Cl solution (200 mL) was added and the mixture was stirred for one hour. The phases were separated and the aqueous phase was extracted with 玢2 〇 (4×100 mL). The combined organic phases were washed with brine, dried (MgSO 4 EtOAc EtOAc EtOAcjjjjjj The title compound of the compound. Preparation 3: [2_Gas-4-(2,4-di-phenylamino)-phenyl (2-methyl-5-phenyl) ketone (compound) 403) 106609.doc 8 • 58· Compound 402 (5.4 g, 15.2 mmol) was dissolved in anhydrous 1,4-dioxane (150 mL) in a 200 mL screw cap container. Add 2,4-di Gas stearamine (1.7 mL, 16.7 mmol) and argon blowing on the mixture.

Cs2C03 (14.9 g, 45.7 mmol), BINAP (0.38 g, 0.6 mmol) and

Pd(OAc)2 (0.14 g, 0.6 mmol) and argon gas was blown through the mixture and the screw cap container was closed. The mixture was stirred at 10 ° C for 7 hours. The reaction mixture was poured into EtOAc (EtOAc) (EtOAc) The aqueous phase was extracted with EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography using CH2C12 / petroleum ether (40-60) 2:3 -> 1:1 -> 1:0 followed by EtOAc as eluent to provide a yellow crystalline compound The title compound. Preparation 4: (5-Amino-2-mercaptophenyl)-[2- gas-4-(2,4-difluoro-phenylamino)-phenyl]-methanone (Compound 404) 403 (6.0 g, 14.9 mmol) was dissolved in MeOH (350 mL). Zinc powder (12.69 g, 194 mmol) and NH4C1 (5.59 g, 104 mmol) were added. The reaction mixture was heated to reflux temperature for 1 hour. The mixture was filtered and washed with MeOH. The filtrate was concentrated and EtOAc (EtOAc mEtOAc m. The crude product was purified by flash chromatography using EtOAc/ pet ether (40-60): Preparation 5: [2-Ga-4-(2,4-difluoro-phenylaminophenyl)_(5-iodo-2-methylphenyl)-methyl 106609.doc • 59· 1379829 Ketone ( Compound 405) A mixture of 404 (0.62 g, 1.66 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) 1.99 mmol) was dissolved in H20 (1 mL) and added to the above solution over 15 min. The internal temperature was maintained at 〇 ° C - 2 ° C during the addition. The suspension was stirred on an ice bath for 5 hours. Then, a solution of KI (0.41 g, 2.45 mmol) and 12 (0.31 g, 1.22 mmol) in H.sub.2 (4 mL) was added dropwise over 5 min. The mixture was stirred at 〇 ° C for 2 hours. H2 〇 (20 mL) and EtOAc (20 mL) were stirred and evaporated and evaporated. The crude product was purified by flash chromatography using EtOAc/EtOAc (EtOAc: EtOAc (EtOAc) 2,4-difluoro-phenylamino)-benzene _(2_Methyl_s_trimethyldecylethylidene-phenyl)·曱嗣 (Compound 406) Compound 405 (400 mg, 0.83 mmol) and ethynyl tridecyl sulphate (115 pL) , 0.83 mmol) dissolved in degassed triethylamine (u mL) $. Next, triphenylphosphine (21.7 mg, 0.083 mmol), pd2 (dba) 3 (15 mg, 0.017 mmol) and copper (1) ( 3 mg, 0.017 mmol) was added to the solution. The flask was closed, filled with argon and then stirred at 9 (TC) for 18 hours. The reaction mixture was filtered with EtOAc and concentrated in vacuo. Ether (40-60) 0: 100 to 25:75 as a lysing solvent for continuous gradient flash chromatography to purify 'to provide the title compound as a syrup. 106609.doc 8 -60 - 1379829 Preparation 7 : [2-gas 4-(2,4-Difluoro-phenylamino)-phenyl]-(s-ethynyl-2-methylphenyl)-methyl (Compound 407) Compound 406 (426 mg, 0.94 mmol) A solution of K.sub.2CO.sub.3 (195 mg, 1.41 mmol) in MeOH (4.0 mL). The organic phase was washed with water, brine and dried (MgSO4). This product was used without any further purification. 2-(2-N-nitro-ethoxy)tetrahydro-Ben (Compound 4〇8) 2-(2-Bromo-ethoxy)-tetrahydro-pyran (1 〇〇mL, 6.62 mmol A mixture of NaN3 (4.34 g, 66 mmol) and EtOAc (EtOAc: EtOAc (EtOAc) The reaction mixture was poured into a mixture of EtOAc / water. The organic phase was washed with water, brine and dried (MgSO4) filtered and concentrated in vacuo to afford crude. The crude product was purified by EtOAc (EtOAc/EtOAc/EtOAc/EtOAc (EtOAc) 2-ox-4-(2,4-difluoro-phenylamino)-phenyl]_(2_methyl_5_{ΐ·[2-(tetrahydro-Brigade-2-yloxy) _Ethyl]-1Η-[1,2,3]trimethyl-4-yl}-phenyl)-methanone (Compound 101) Compound 407 (300 mg, 0-79 mmol) and Compound 408 (135 mg, 0.79) Methyl) was dissolved in ethanol (6.0 mL). Add a freshly prepared solution of copper sulfate (h) (7 8 -61 - 106609.doc 8 1379829 mg, 0.031 mmol) and sodium ascorbate (31 mg, 0.16 mmol) in water (〇·9 mL) to In the reaction mixture. The flask was closed and stirred at room temperature for 48 hours. The reaction mixture was poured into a mixture of Et. The organic phase was washed with water, brine, and then dried (Mzjjjjjj The crude product was purified by EtOAc (EtOAc/EtOAc) 13C NMR (CDC13) δ 196.1, 159.1 (dd), 155.5 (dd), 147.8, 146.9, 139.8, 137.7, 135.3, 133.7, 131.9, 129.4, 128.3, 127.9, 126.5, 124.4 (dd), 124.3 (dd), 120.8, 116.3, 112.8, 111.6 (dd), 104.9 (dd), 99. Bu 65.8, 62.4, 50.5, 30.4, 25.2, 20.2 ' 19.4 Example 2: [2-Ga-4-(2,4-difluoro- Phenylamino)phenyl]hydroxy-ethyl)-1Η-[1,2,3]triazole·4·yl]-2-indenyl-phenyl- ketone (Compound 102) Toluene-4 The sulfonic acid (60 mg, 0.32 mmol) was added to a solution of the compound 1 〇1 (35 mg, 0.63 mmol) in methanol (4.0 mL), and the mixture was stirred at room temperature for 7 hr. The reaction mixture was poured into a mixture of Et〇Ac/water. The organic phase was washed with NaOH (aq., 2 M), water, brine, and then dried (MgSCU) and filtered to afford crude product. The crude product was purified by flash chromatography eluting with EtOAc/EtOAc (EtOAc) i3Cnmr (CDC13) δ 196.2, 159.2 (dd), 155.6 (dd), 148.1, 146.7 '139.9, 137.6, 135.2, 133.8, 131.8, 128.9, 127.8, 126.2, 106609.doc -62- 1379829 124.6 (dd), 124.3 (dd), 121.1, 116.2, 112.7, 111.6 (dd), 104.9 (dd) '61.1 ' 52.8 ' 20.1 Preparation 9 : 2-(3-azido-propoxy)-tetrahydro-pyran (compound 409 2-(3-Chloro-propoxy)-tetrahydro-propanol (6.28 g, 35.2 mmol), NaN3 (11.4 g, 176 mmol) and potassium iodide (584 mg, 3.52 mmol) in DMF (50) The mixture in mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into a mixture of Et20/water. The organic phase was washed with water, brine and dried (MgSO4), filtered and evaporated The crude product was purified by EtOAc (EtOAc/EtOAc) Example 3: [2-Ga-4-(2,4·Difluoro-phenylamino)-phenyl]-(2-methyl-5-{1-[3-(tetrahydro-pyran-2-) · oxy)-propyl]-1 Η-[1,2,3]triazol-4-yl}-phenyl)-methanone (Compound 103) Compound 407 (0.44) was used as described in the preparation of compound 101. The reaction was carried out analogously with mmol) and compound 409 (0.44 mmol). The crude product was purified by EtOAc/EtOAc (EtOAc:EtOAc:EtOAc 13C NMR (CDC13) δ 196.1, 147.8, 146.9, 139.8, 137.6, 135.3, 133·7, 131.9, 129.4, 128·2, 127.9, 126.4, 124.4 (dd), 124.3 (dd), 120.2, 116.3, 112.8, 111.6 (dd), 104.9 (dd), 99.4, 63.8, 62.9, 47.5, 30.7, 30.5, 25.4, 20_2, 106609.doc -63- 1379829 19.9 Example 4: [2-Ga-4-(2,4-II) · phenylamino)·phenyl]·丨5·[ι(3·hydroxypropyl)-1Η-[1'2'3]triterpene-4·yl]·2 methylphenyl bromide (Compound 1〇4) The reaction was carried out analogously as described in the preparation of the compound 1 〇2 using Compound 103 (0.2 mmol). The crude product was obtained by using EtOAc/ petroleum ether (40-60) 5G: 5G. 1GG: G was purified by continuous gradient flash chromatography as a dissolving agent to provide the title compound as a colorless foam. Nc NMR (CDC13) δ 196.1, 159.2 (dd), 155.6 (dd), 148.0, 146.9, 139.9, 137.7, 135.3, 133.8, 131.9, 129.1, 128.0, 127.9, 126.4, 124.5 (dd), 124.3 (dd), 120.3, 116.3, 112.8, 111.6 (dd), 104.9 (dd), 58.8, 47.0, 32.6, 20.2 Preparation of 10 azidomethyl-2,2-dimethyl-[1,3]dioxolane (compound) 410) The reaction was similarly carried out using indole-4-sulfonic acid 2,2-dimercapto-[1,3]dioxolan-4-ylmethyl ester (37.8 mmol) as described in the preparation of compound 408. . The granules were purified by EtOAc (EtOAc/EtOAc/EtOAc) Example 5: [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl-2-dimethyl-[1,3]dioxolan-4-ylmethyl)-111 -[1,2,3]tris-ol-4-yl]-2-methyl-phenylphenone (Compound 105) Compound 407 (1.37 mmol) and 106609.doc were used as described in the preparation of compound 101. 64 - 1379829 Compound 410 (1.62 mmol) was similarly carried out. The crude product was purified by EtOAc (EtOAc/EtOAc) (EtOAc) 13C NMR (DMSO-d6) δ 194.9 ' 158.7 (dd) ' 155.7 (dd) ' 149.4, 145.2, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.5, 126.5 (dd), 125.0, 124.2 (dd ), 122.3, 114.8, 111.9 (dd), 111.8, 109.0, 105.0 (dd), 73.7, 65.8, 52.0, 26.4, 25.1, 19.4 Example 6: [2-Ga-4-(2,4-difluoro-benzene) Amino)-phenyl]-{5-[1_(2,3-dihydroxy-propyl)-1Η-[1,2,3]triazol-4-yl]-2-methyl-phenyl a solution of the compound 105 (535 mg, 1.16 mmol) in THF (6.0 mL). . The reaction mixture was poured into a mixture of EtOAc / sat. NaHC. The aqueous phase was washed with more EtOAc. The collected organic phase was washed with water, brine and dried (MgSO4), filtered and concentrated in vacuo to give crude. The crude product was purified by sequential gradient flash chromatography using 1⁄2 〇 11 / 1 1 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 13C NMR (DMSO-d6) δ 194.9, 158.7 (dd), 155.7 (dd), 149.3 '145.0, 139.8, 135.7, 133.7, 133.7, 131.6, 128.4, 127", 126.6, 126.5 (dd), 124.9, 124.2 ( Dd), 122.3, 114.8, 112.0 (dd), 111.8, 105.0 (dd), 70.3, 63.2, 53.0, 19.4 Preparation 11: • 65·106609.doc

1379829 2 -Arsyl-acetamide (Compound 411) 2-N-Ethylamine (2.00 g, 21.4 mmol), NaN3 (6.95 g, 1 〇7 mmol) and tetrabutylammonium chloride (79 破) The mixture of mg, 2 14 mm 〇 1) in ϋ]νηρ (30.〇mL) was stirred at 50 ° C for 48 hours. The reaction mixture was poured into a mixture of EtOAc / water. The organic phase was washed with water, brine and dried (MgSO4) filtered elute elute Example 7: 2-(4-{3-[2-Ga-4-(2,4-difluoro-phenylamino)-benzimidyl-4-methyl-phenyl}-[1, 2,3]triazol-1-yl)-acetamide (Compound 107)

The reaction was carried out analogously as described in the preparation of compound 101 using compound 407 (0.44 mmol) and compound 411. The crude product was purified by EtOAc EtOAc (EtOAc) 13C NMR (DMSO-d6) δ 194.9, 167", 158.7 (dd), 155.7 (dd), 149.3, 145.2, 139.8, 135_9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.6, 126.4 (dd), 125.0, 124.2 (dd), 123.0, 114.9, 112.0 (dd), 111.8 > 105.0 (dd) > 51.5 > 19.4 Preparation 12: 3-azido-propan-1-sulfonamide (compound 412) such as compound 411 The reaction was carried out in the same manner as in the preparation of the compound 3-carbo-propanthroline (19.0 mmol). The crude β product was obtained by using EtOAc/ petroleum ether (40-60) 35:65 to 65:35. Continuous gradient flash layer of dissolving agent 106609.doc -66-

Purification by 1379829 to give the title compound as a colourless oil. Example 8: {3·[2-Ga-4-(2,4-difluoro-phenylamino)-benzimidyl-4-methylphenyl}-[1,2,3]triazole·1 • propyl-1-sulfonamide (Compound 1 〇 8) This reaction was carried out analogously using Compound 407 (1 37 mm 〇i) and Compound 412 (2.79 mmol) as described in the preparation of compound 101. The crude product was purified by EtOAc (EtOAc/EtOAc) elute l3C NMR (DMSO-d6) δ 194.9, 158.8 (dd), 155.7 (dd), 149.4, 145.5, 139.9, 135.9, 133.7, 133.7, 131.7, 128.2, 127", 126.5, 126.4 (dd), 124.9, 124.1 ( Dd), 121.6, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 51.4, 47, 9, 24.6, 19.4 Preparation 13: N-(2-azido-ethyl)-methylantamine (compound) 413) 2-Oxide hydrochloride (5.0 g, 43.1 mmol) and dioxane (5 mL) were placed in a 100 mL flask. When the temperature is maintained at _3 to 5. (Between: N-Mercaptomorpholine (10 mL, 91 mmol) was added to the suspension. Toluene sulfonium chloride (4.0 mL, 51.7 mmol) was slowly added to the reaction mixture. The reaction mixture was washed with water, 4N EtOAc and water. &lt;&quot;&quot;&&&&&&&&&&&&&&&&&&&&&&& Mg, 1.97 mmol) and NaN3 (1.92 g, 29.5 mmo 1) were added to the solution. The reaction mixture was stirred at 5 Torr for 48 hours and then poured into a mixture of EtOAc/water. And then dried (MgS04), filtered and concentrated in vacuo to give a crude material. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The crude product was used without any further purification. Example 9: Ν-[2-(4- {3-[2·Ga-4-(2,4-difluoro-phenylamino)·benzimidyl]_4_methyl_phenyl}-[1,2,3]triazole-1- -ethyl]-methanesulfonamide (Compound 1 〇 9) The reaction was carried out analogously as described in the preparation of compound 101 using compound 407 (0 87 mmol) and compound 413 (1.3 mmol). Used by EtOAc/petroleum ether (40-60): EtOAc: EtOAc: EtOAc (EtOAc) (dd), 155:7 (dd), 149.4, 145.3, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.5, 126.4 (dd), 124.9, 124.1 (dd), 121.9, 114.8, 111.9 (dd ), 111.8, 105.0 (dd), 49.8, 42.2, 39.5, 19.4 Example 10: (4_ {3-丨2_chloro-4-(2,4-difluoro-phenylamino)-benzoinyl] 4-methyl-phenyl}-[1,2,3]triazol-1-yl)-acetic acid (compound no) Compound 407 (243 mg, 0.64 mmol) and the compound azido-acetic acid B A solution of the ester (0,0.7 mmol) in hydrazine (60 mL) was dissolved in ethyl ketone (3.5 mL). Copper sulphate (π) (7. 〇mg, 0.026 mmol) and sodium ascorbate ( A freshly prepared solution of 25 mg, 0.13 mmol) in water (0.5 mL) was added to the reaction mixture. The flask was closed under argon and stirred at room temperature for 24 hours. The reaction mixture was poured into EtOAc/water mixture. The organic phase was washed with water, brine <RTI ID=0.0>, </RTI> then dried (MgSO4), filtered and concentrated in vacuo to yield crude product of -68 - 106609.doc 8 1379829. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) nCNMRWDey δ 196.0, 166.3, 159.1 (dd), 155.5 (dd), 147 8, 147 5, 139 9, 137.9, 135.3, 133.7, 131.9, 129.3, 128.0, 127.9, 126 6, 124.4 (dd), 124.3 (dd ), 121.0, 116.4, 112.9, 111.6 (dd), 104.9 (dd), 62.5, 51.0, 20.2, 14.1 Example 11: (4-{3-[2-Ga-4-(2,4-difluoro-benzene) Aminomethyl)_benzyl]_4_methyl_phenyl}-[1,2,3]triazol-1-yl)-acetic acid (compound m) LiOH (55 mg, 2.31 mmol) and water (0.3 mL) was added to a solution of Compound 1 <RTI ID=0.0>(</RTI> </RTI> <RTIgt; The reaction mixture was stirred for 2 hours under reflux. The reaction mixture was poured into a dressing Ac/saturated NaCl. Add Aq. HC1 (1 N, 0.5 mL). The aqueous phase was washed with more EtOAc. The collected organic phase was washed with water, brine and dried (MgSO4), filtered and evaporated The crude product was purified by flash chromatography eluting with EtOAc/EtOAc:EtOAc: 13C NMR (DMSO-d6) δ 194.9, 168.4, 158.7 (dd), 155.7 (dd), 149.3, 145_3, 139.8, 136.0, 133.7, 133.7, 131.7, 128.1, 127.1, 126.5, 126.4 (dd), 125.0, 124.2 (dd), 122.8, 114.8, 112.0 (dd), 111.8, 105.0 (dd), 50.9, 19.4 Example 12: 2-(4-{3-[2·Ga-4·(2,4-difluoro-benzene) Aminomethyl)-benzylidene]-4-methyl-benzene 106609.doc • 69·

1379829 }}-[1,2,3]triazol-1-yl)-indoleethylamine (Compound 112) Ethyl ammonium hydrochloride (20 mg, 0.08 mmol), FDPP (43 mg, 0.11 mmol) And DIEA (68 μM, 0.4 mmol) was added to a solution of compound 111 (39 mg, 0.08 mmol) in DMF (30.0 mL). The flask was flushed with argon and the reaction mixture was stirred at room temperature for a period of 72 s and then poured into a mixture of water (4 mL), EtOAc (4N, 2 mL) and EtOAc. The phases are separated. The organic phase was concentrated in vacuo on a vermiculite. The crude product was purified by chromatography eluting with EtOAc / pet ether (40-60) 50:50 to 100:0 as eluting solvent to afford the title compound as white foam.丨3C NMR (DMSO-d6) δ 194.9, 164.8, 149.3, 145.2, 139.8, 135.9, 133.7 ' 133.7, 131, 7, 128.2, 127.1, 126.6, 126.4 (dd), 125.0, 124.2 (dd), 123.0 ^ 114.8 &gt; 111.9 (dd) '111.8 &gt; 105.0 (dd) ' 51.7 &gt; 33.6 ^ 19.4, 14.4 Example 13: 2-(4-{3-[2-gas_4-(2,4-difluoro-benzene) Aminomethyl)-benzylidene]_4_methyl_phenyl b. U,2,3]triazol-1·yl)_Ν-(2·hydroxy-1,1·didecyl-ethyl)· Acetamide (Compound 113) This reaction was carried out analogously using compound 111 (〇〇8 mm〇1) and -τyl-1-propanol (0 08 mm〇l) as described in the preparation of compound 112. The crude product was purified by EtOAc (EtOAc) (EtOAc) i3CNMR(DMS〇d6)§ 8 74 (s , 8 1H), 7 90 (1) τ, ' .υ (dd, 1Η), 7.85 (bs, 1Η), 7.75 (d, 1Η), 7.50-7.33 (m , 4H&quot;) ^7ii/ ' • 1 (m,1H), 6.83 (m,1H), 6.78 (m,1H), 5.07 (s, 106609.doc -70- 1379829 2H), 4.80 (t,1H) , 3.40 (d, 2H), 2.33 (s' 3H), 1.21 (s, 6H) Example 14: 2-(4-{3-[2-Ga-4-(2,4-di-phenylamine) Base)-benzonitrile]-4·methyl_phenyl}-[1,2,3]triazin-1-yl)-1-lalopot-1-yl-ethylamine (Compound 114) This reaction was carried out analogously using compound 111 (〇.12 mmol) and pyrrolidine (0-12 mmol) as described in the preparation of compound 112. The crude product was obtained by using 1^011/£1〇8 (0:100 to 5) :95 as a leaching agent for continuous gradient flash chromatography

Purified to provide the title compound as a yellow syrup. I3c NMR (CDC13) δ 196.0, 163.1, 159.0 (dd), 155.4 (dd), 147.8, 147.1, 139.7, 137.9, 135.2, 133.7, 131.9, 129.3, 128.0, 127.8, 126.6, 124.5 (dd), 124.2 (dd ), 121.5, 116.4, 112.9, 111.5 (dd), 104.9 (dd), 51.9, 46.4, 26.1, 24.1, 20.2 Example 15: 2-(4-{3-[2-Ga-4-(2,4- Difluoro-phenylamino)-benzhydryl-4-bu-4_fluorenyl-phenyl}-[1,2,3]sanjun-1_yl)-1-morphin_4_yl-ethanone Compound 115) The reaction was carried out analogously using compound lu (〇 12 mmol) and morpholine hydrochloride (0·12 mmol) as described in the preparation of compound 112. The crude product was purified by EtOAc (EtOAc/EtOAc) elute: Nmr (CDC13) δ 196.0, 163.5, 147.9, 147.3, 139.8, 138.0, 135.3, 133.7, 131.9, 129.2, 128.0, 127.7, 126.5, 124.4 (dd), 124.2 (dd), 121.4, 116.3, ιΐ2·8, 111.6 (dd), 104.9 (dd), 66.6, 66.4, 50.9, 45.9, 42.6, 20.2 Preparation 14 106609.doc •71· [2-Ga-4-(4-trifluoromethyl-phenylamino)-benzene Keb (2-methyl-5-nitro-phenyl)-methanone (Compound 414) 'Compound 4〇2 (i〇〇mg, 0.28 mmol) in anhydrous water in an 8 mL screw cap bottle , 4-dioxane (2 mL). Add 4-trifluoromethyl-aniline (35 μί, 0.28 mmol) 'Cs2C03 (276 mg, 0.85 mmol) » BINAP (7 mg, 0.011 mmol) and Pd(OAc) 2 (3 mg, 0.011 mm〇i) Argon was blown through the mixture and the screw cap container was closed. The mixture was stirred at 1 〇〇〇C for 18 hours. The reaction mixture was filtered through Decalite and concentrated on EtOAc. The crude product was purified by sequential gradient flash chromatography using EtOAc/ petroleum ether (40-60) EtOAc (EtOAc): Preparation 15 (5. Amino-2-mercapto-phenyl)-[2- gas-4-(4-trifluoromethyl-phenylamino)-phenyl]-methanone (Compound 415) 414 (134 mg, 0.31 mmol) was dissolved in MeOH (4 mL). Zinc powder (203 mg, 3.1 mmol) and NH4C1 (84 mg, 1.57 mmol) were added. The reaction mixture was heated at reflux temperature for 3 hours. The mixture was filtered through EtOAc (EtOAc) elute Preparation 16 (S-azido-2-indenyl-phenyl)-[2- gas-4-(4-trifluoromethyl-phenylamino)-phenyl]-fluorenone (Compound 416) Compound 41 5 (110 mg, 0.27 mmol) was dissolved in acetone (2 mL). Concentrated HC1 (37%, 0.113 mL, 1.36 mmol) was added and the 106609.doc-72- 1379829 solution was cooled on an ice bath. NaN02 (22 mg, 0.32 mmol) was dissolved in η2 〇 (〇ΐ8ι 且 and added to the above solution within 5 minutes. The internal temperature was maintained at 〇 ° C - 2 ° C in addition _. The suspension was in ice The mixture was stirred for a few hours, then a solution of NaN3 (27 mg, 0.41 mmol) in H.sub. H2〇 (5 mL) and

Et0Ae (1 () mL) was dispensed and the phases were separated. The organic phase was concentrated in vacuo to give the title compound. This crude product can be used without any further purification. Example 16: [2-Chloro-4-(4-trifluoromethyl)phenylamino)-phenyl b{5_[4(2-hydroxyethyl)-[1,2,3]triazole-1 -yl]-2-methyl-phenylphenone (Compound 116) In a vial, but-3-yn-1-ol (23 pL, 0.30 mmol) &amp; compound 416 (116 mg ' 0.27 mmol ) Dissolved in acetone (2.6 mL). A freshly prepared solution of copper sulfate pentahydrate (11) (7.0 mg, 0.028 mmol) and sodium ascorbate (27 mg, 〇 14 mmol) in water (0.135 mL) was added to the reaction mixture. The vial was blocked under argon and stirred at room temperature for 24 hours. The reaction mixture was poured into a mixture of EtOAc / water. The organic phase was washed with water, brine, filtered and concentrated in vacuo to give crude. The crude product was purified by continuous gradient flash chromatography eluting with EtOAc / pet ether (4 </ </ </RTI> </ </ </ </ RTI> <RTIgt; Compound. 13C NMR (DMSO-d6) δ 194.1, 147.1, 145.8, 144.6, 140.4, 136.5, 134.6, 134.0, 133.8, 132_6, 127, 8, 126.7 (4), 121.7, 120.8, 119.4, 118.2, 117.3, 114.2, 60.2, 29.2 , 19.3 I06609.doc • 73- 1379829 Preparation 17 (2-Ga-4-o-tolylamino-phenyl)-(2-methyl-5-nitro-phenyl)-methanone (Compound 417) This reaction was carried out analogously using compound 402 (0.28 mmol) and compound 2-toluamine (0.28 mmol). The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) Preparation 18 (5-Amino-2-methyl-phenyl)-(2- gas-4-o-tolylamino-phenyl)-methanone (Compound 418) as described in the preparation of compound 41 5 Compound 417 (0.39 mmol) was similarly carried out. The crude product can be used without any further purification. Preparation 19 (5-azido-2-methyl)phenyl)-(2-ox-4-o-tolylamino-phenyl)-anthone (Compound 419) as described in the preparation of compound 41 6 The reaction was carried out analogously using compound 4 18 (0.39 mmol). The crude product can be used without any further purification. Example 17: (2. gas-4-o-phenylphenylamino-phenyl)_{5-[4-(2-hydroxyethyl)-[1,2,3]triter-1-yl]- 2-f-Phenyl-phenyl}-formamidine (Compound 117) The reaction was carried out analogously as described in the preparation of compound 116 using compound 419 (0.40 mmol) and but-3-yn-1-ol (0-40 mmol). The crude product was purified by continuous gradient flash chromatography eluting with EtOAc/ petroleum ether (40-60) 20:80 to 0:100 as eluting solvent to afford the title of pale yellow foam by 106609.doc -74 - 1379829 Compound. 13C NMR (CDC13) 5 194.7, 149.9, 146.2, 141.2, 138.0, 137.7, 135.7, 134.7, 134.2, 132.8, 132.5, 131.4, 127.1, 126.9, 125.8, 124.4, 122.1, 120.6, 120.0, 115.7, 112 3, 61.5, 28.7, 19.9, 17.9 Preparation 20 [2-Acety-4-(2- gas-4-fluoro-phenylamino)-phenyl]-(2-methyl-based phenyl)-methanone (Compound 420 The reaction was carried out analogously as described for the preparation of compound 414 using compound 4 〇 2 ( 〇········· The crude product was purified by EtOAc (EtOAc: EtOAc: EtOAc) -2-methyl-phenyl)-[2-nitro-4-(2-azin-4-fluoro-phenylamino)-phenyl]-methanone (compound 421) as described in the preparation of compound 415 The reaction was carried out analogously using compound 42 (〇· 21 mm 〇 1). The crude product was used without any further purification. Preparation 22 (5-azido-2-methylphenyl)-[ 2-Chloro- 4-(2-aze-4-fluoro-phenylamino)-phenyl]-fluorenone (Compound 422) was used as described in the preparation of compound 41 6 using compound 421 (〇 21 mmol). The reaction is carried out. The crude product can be used without any further purification - 75-106609.doc 8 1379829. Example 18: [2- gas-4-(2-indole-4-fluoro-phenylamino)- Phenyl]-{5-[4-(2-hydroxyethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 118) This reaction was similarly carried out using compound 422 (0.21 mmol) and but-3-yn-1-ol (0-21 mmol) as described in the preparation of compound 116. The crude product was purified by EtOAc (EtOAc/EtOAc (EtOAc) (EtOAc) (CDC13) δ 194·8, 158.7 (4), 147.9, 146.3, 140.7, 138.4, 135.4, 134.8, 133.8, 133.3 (d), 132.6, 128.8, 127.5 (d), 123.4 (d), 122.4, 120.9, 120.0, 117.6 (d), 116.9, 114.9 (d), 113.5, 61.5, 28.7, 20.0 Preparation 23 (5-actin-2-methoxy-benyl)_(2- gas-4-mercapto-phenyl)- Methyl net (compound 423) 1-di-4-methoxy-benzene (7.48 g, 40 mmol) under argon atmosphere, 2- gas- 4-nitro-benzoic chloride (8.79 g, 40 mmol) And trifluorobenzoic acid (1.31 g, 2.0 mmol) was stirred at room temperature for 20 minutes. The temperature was raised to 80 ° C and the mixture was continuously stirred for 90 minutes. DCM was added to the reaction mixture and aq. l N, 0.5 mL) and NaHCCMaq.) Wash the organic phase. The organic phase is dried (MgSO4), filtered and evaporated in vacuo to give crystals crystals crystals Preparation 24 (4-Amino-2- gas-phenyl)-(5-bromo-2-methoxy-phenyl)-methanone (Compound I06609.doc -76·424) 1379829 4 The reaction was carried out analogously using the compound "mm〇1) as described in the preparation. The crude product was subjected to continuous gradient flash chromatography using EtOAc/petroleum ether (40 60) 2G.8G to 45:55 as the eluent. To purify 'to provide the title compound as a yellow solid. Preparation 25 (5, odor-2-methoxy phenyl)_[2 gas_4 (2,4·di-phenylphenyl phenyl) ketone (compound 425) in 2 〇〇 mL helix In a lid container, compound 424 (4 39 g, 12 9 _〇1) was suspended in anhydrous scorpion (1 〇〇 。. Add Bu Mo ^ Xin Di Benzene (1·75 mL, 15.5 mmol) and in the mixture Argon gas was blown in. Add Cs2C〇3 (5·88 g' 18·1 mmol), 4,5•bis-diphenylphosphinoalkyl-99 dimethyl·9Η_ a clumsy pecan (0.22 g, 0.39 Methyl) and Pd(〇Ac) 2 (58 mg, 0.26 mmol) and argon was blown through the mixture and the screw cap container was closed. The mixture was stirred at 120 C for 72 hours. The reaction mixture was filtered through decalite and then The mixture was concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using Et.Ac/5 oil ether (40-60) 5:95 to 30:70 as solvent. The title compound was obtained as a solid. Preparation 26 [2-[rho]-4-(2,4-difluoro-phenylamino)-phenyl (2-methoxy-5-trimethylmethyl-ethynyl-benzene Methyl ketone (compound 426) as described in the preparation of compound 406, using compound 425 (〇99) Mm 〇 1) and ethynyl trimethyl decane (0.99 mmol) were similarly carried out. The crude product was obtained by using EtOAc/petroleum (4〇-60) 0:1 〇〇 to ι〇:9 〇 as dissolution. Agent-77·106609.doc

Purification by continuous gradient flash chromatography of 1379829 to provide the title compound as a pale orange syrup. Preparation 27 [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl]-(5-ethynyl-2-methoxy-phenyl)-methanone (Compound 427) This reaction was carried out analogously using compound 426 (0.44 mmol) as described in the preparation of compound 407. The crude product can be used directly in the next reaction without any further purification. Example 19: [2-Ga-4-(2,4·difluoro-phenylamino)-phenyl]-(2- Methoxy-5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1Η-[1,2,3]triazol-4-yl}-phenyl)- Methyl ketone (Compound 119) The reaction was carried out analogously using compound 427 (0.42 mmol) and compound 408 (0.42 mmol) as used in the preparation of compound 101. The crude product was obtained by using EtOAc/ petroleum ether (40-60) 20 Purification by continuous gradient flash chromatography of 80 to 60:40 as a solvent to afford the title compound as a pale orange foam. 13C NMR (CDC13) δ 193.2, 159.0 (dd), 158", 155.4 (dd), 147.3, 146.9, 134.8, 133.3, 130.2, 127.7, 124.8 (dd), 123.9 (dd), 123.8, 120.3, 116.2, 113.0 , 112.3, 111.5 (dd), 104.9 (dd), 99.2, 65·8, 62.5, 56.1, 50.6, 30.5, 25.3, 19.4 Example 20: [2-Ga-4_(2,4-difluoro-benzene) Amino)-phenyl]-{5-[l-(2-hydroxy-6yl)-1Η-[1,2,3]tris--4-yl]-2-methoxy-phenyl} -methanone (compound 106609.doc -78 *

120) 120) 1379829 The compound was similarly formulated using compound U9 (0 11 mm 〇i) as described in the preparation of compound 101 by using EtOAc/petroleum ether (40-60) 2G: 8G. Purification by continuous gradient flash chromatography to 1 GG:G to afford the title compound as a yellow foam. C NMR (CDC13) δ 193.3, 158.1, 147.4, 146.7, 134.8, 13 3.4, 13 (Μ, 127.6, 124.6 (dd), 123.9 (m), 123.7, 123.3, 120.5, 116. 112_b 111·5 (dd), 104.9 (dd), 61.3, 56.0, 52.8 Preparation 28 [2-Chloro-4-(4-fluoro-phenylamino)-phenyl (2-methyl·s•nitro-phenyl) Ketone (Compound 428) The reaction was similarly carried out using compound 402 (22.6 mmol) and 4-fluoroaniline (24.8 mmol), except for a reaction time of 16 hr. Purification by flash chromatography using EtOAc/ petroleum ether (40-60) 1 : 5 as eluting solvent to give the title compound as a yellow solid. Preparation 29 (S-Amino-2-methyl-phenyl) [2_Gas_4_(4_Fluoro-phenylamino)-phenyl]-methanone (Compound 429) The reaction was similarly carried out using Compound 428〇9 2 mm〇i) as described in the preparation of Compound 404. . The crude product was purified by flash chromatography using EtOAc (EtOAc:EtOAc:EtOAc: 106609.doc •79· 1379829 Preparation 30 [2-Ga-4-(4-Gas-phenylamino)-phenyl]-(5-iodo-2-methyl-phenyl)-methanone (Compound 430 The reaction was carried out analogously using compound 429 (8.46 mmol) as described in the preparation of compound 405. The crude product was purified by flash chromatography using EtOAc/EtOAc (EtOAc) Preparation 31

[2-Aza-4(4-fluoro-phenylamino)-phenyl]-(2-methyl-5-trimethyldecylethylidene-phenyl)-methanone (Compound 431) This reaction was carried out analogously using compound 430 (7.17 mmol) and ethynyl dimethyl decane (7.17 mm 〇1) as described in the preparation of compound 406. The crude product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) Preparation 32

[2_Gas_4-(4.Fluoro-phenylamino)-phenylpyr (s_6-blockyl-2-methyl-phenyl)methanone (Compound 432) As described in the preparation of Compound 407, The reaction was similarly carried out by the compound 431 (5.95 mmol). The crude product can be used in the presence of any further purification. Example 21: gas-phenylamino)-styl]-(2•methyl_5-[2(tetrahydro-2-yloxy)ethyl]·1H_U, 2,3]tri-kappaphenyl ) 曱 exposure 121) 106609.doc

80. 1379829 The reaction was carried out analogously as described in the preparation of compound 101 using compound 432 (2.06 mmol) and compound 408 (2.06 mmol). The crude product was purified by EtOAc EtOAc/EtOAc (EtOAc) C NMR (CDC13) δ 196.1, 159.6 (4), 148.8, 147.0, 140.0, 137.5, 135.9 (4), 135.4, 134_0, 131.8, 128.4, 128.2, 127.8, 126.4, 124.2 (4), 120.8, 116.4 (4), 115.8, 112.3, 99.1. 65.8, 62.4, 50.6, 30.4, 25.2, 20.2, 19.4 Example 22: [2-Chloro-4-(4.fluoro-phenylaminophenyl)-hydroxyl-ethyl)-1Η-[1,2,3 Disi-4-yl-2-methyl-phenyl}-methyl (Compound 122) This reaction was similarly carried out using Compound 121 (1 63 mm 〇 1) as described in the preparation of Compound 102. The crude product was purified by sequential gradient flash chromatography eluting with Et0Ac / petroleum ether (40-60) 50: 50 13C NMR (DMSO-d6) δ 194.8, 158.1 (4), 149.1, 145.2, 139.9, 136.6 (d), 135.7, 134.0, 133.9, 131.6, 128.4, 127.0, 126.3, 124.8, 122.7 (d), 121·9, 116.1 (d), 114.9, 111.8, 59.7, 52.3, 19.4 Example 23: [2-Ga-4-(4-fluoro-phenylaminopolyphenyl){5_[1(2,2 dimethyldioxolan) Ring_4_ylmethyl)-1Η-[ΐ,2,3]triazol-4-yl]-2-methyl-stupylmethanone (Compound 123) Compounds as described in the preparation of compound ιοί 432 (2 75 and I06609.doc -81 * 1379829 Compound 410 (2.75 mmol) was carried out in a similar manner. The crude product was obtained by using EtOAc/ petroleum ether (40-60) 20:80 to 65:35 as a solvent. Purification by continuous gradient flash chromatography to provide the title compound as a foam. C NMR (CDCI3) δ 196.1, 159.7 (d), 148.9, 147.1, 140.1, 137.6, 135.9 (4), 135.5, 134.0' 131.8, 128.4, 128.0 , 127.8, 126.4, 124.2 (d), 121.0, 116.4 (d), 115.8, 112.3, 110.3 ' 74.1 &gt; 66.5 ' 52.4 ' 26.7 &gt; 25.2 &gt; 20.2 Example 24 : [2-Qi-4-(4- Fluorine-phenylamino)-phenyl]-(541(2,3- Hydroxy-propyl)-1Η-[1,2,3]triazol-4(yl)-2-fyl-phenyl}-methanone (Compounds Compound 123 (1.05 g, 2.02 mmol) in THF (10 mL) was added to aq. HCl (1 mL, aq., EtOAc, 1 N) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a mixture of EtOAc/water/NaHC03 The organic phase was washed with water, brine, and then dried (MgSO.sub.4), filtered and concentrated in vacuo to give a crude product. </ RTI> </ RTI> MeOH/DCM from 0:100 to 10:90 as a dissolving agent. Purification by continuous gradient flash chromatography to give the title compound as a white solid. C NMR (DMSO-d6) δ 194.3, 158.1 (4), 149.1, 145.1, 139.9, 136.6 (d), 135.7, 134.0, 133.9, 131.6, 128.4, 127.0, 126.3, 124.8, 122.7 (d), 122.3, 116.0 (d), 114.9, 111.8, 7〇·3, 63.2, 53.9, 19.4 Example 2S: 2-(4-(3-丨2-气· 4·(4-Fluoro-phenylamino)·benzimidyl]_4_methyl-phenyl}-[1,2,3]dicol-1-yl)-acetamide (Compound^25) -82 - 106609.doc

1379829 This reaction was carried out analogously using compound 432 (1 〇4 mrn〇l) and compound 411 (1.5 mmol) as described in the preparation of compound 101. Crude product by use

EtOAc/DCM/petroleum ether (40-60) 0:80:20, 0:1 〇〇: 〇 and 〇: 90:10 as a solvent. Title compound·. 13C NMR (DMSO-d6) δ 194.8, 167.1, 158.0 (d), 149.1, 145.2, 139.9, 136.6 (d), 135.8, 134.0, 133.9, 131.6, 128.2, 127.0, 126.3, 124.9, 123.0, 122.7 (d) , 116.0 (d), 114.8, 111.8, 51.5, 19.4 Example 26: [2-Ga-4-(2,4-difluoro-phenylaminophenyl-ethyl)-1Η-[1,2, 3] Triazol-4-yl]-2-methyl-phenyl- ketone (Compound 126) Addition of azide tetra-N-butyl s to a triphenylphosphine (3 9 mg) at room temperature , 0.15 mmol) and 4,5-dioxa-3,6-dioxo-cyclohexyl, 4-diene-1,2-dicarbonitrile (44.5 mg, 0.20 mmol) in anhydrous DCM (3.0 mL) The mixture was stirred in a flask. Compound 102 (46 mg, 0.10 mmol) was then added and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and purified by EtOAc EtOAc (EtOAc) 13C NMR (CDC13) δ 196. Bu 159.2 (dd), 155.6 (dd), 148.0, 147.0, 139.9, 137.8, 135.3, 133.8, 131 · 9, 129.0, 127.9, 127.8, 126.4, 124.5 (dd), 124.3 ( Dd), 120.8, 116.3, 112.7, 111.6 (dd), 104.9 (dd), 51.8, 42.4, 20.2. Preparation 33 106609.doc • 83 - 1379829 (5-azido-2-methyl-phenyl)-[2-gas-4·(4-fluoro-phenylamino)·stupyl copper (compound) 433) A mixture of NaN3 (3.3 g), H20 (8 mL) and DCM (2.8 mL) was cooled to 0 °C. Trifluoromethanesulfonic anhydride (1.34 mL, 8.46 mmol) was slowly added and the temperature was maintained at -2 to 1 °C. After 2 hours, the reaction mixture was separated in a sep. funnel. W EtOAc was washed with water. The organic phase was washed with saturated NaHCO.sub.3 and concentrated in vacuo to give crude succinic acid. A solution of copper ruthenate (11) (35.2 1118, 0_14 111111〇1) in 1120 (4. 1111^) and TEA (1.18 mL, 8_45 mmol) was added to compound 429 (1.00 g, 2.82 mmol) In a suspension in DCM (5.0 mL), crude azide trifluoromethanesulfonic acid was slowly added to the reaction mixture, followed by MeOH (5 mL). After 18 hours at room temperature, the reaction was carried out. The mixture was poured into EtOAc / EtOAc (EtOAc) (EtOAc) (EtOAc) Purification by continuous gradient flash chromatography to 25:75 as a solvent to give the title compound as a yellow solid. Example 27: [2-[sup.4-(4-fluoro-phenylamino)-phenyl] _{5-[4-(2-Pyryl-ethyl)-[1,2,3]triazol-1-yl]2-methyl-phenyl}-methanone (compound) This reaction was carried out analogously using compound 433 (1.1 〇mm〇l) and 3-butyn-1-ol (1.10 mmol) as described in the preparation of 101. The crude product was obtained by using EtOAc/ petroleum ether (40-60) 50:50 to 100:0 as a continuous gradient flash layer of dissolving agent Purification to provide the title compound as a foam. 13C NMR (CDC13) δ 194.8, 159.8 (d), 149.5, 146.3, • 84 · 106609.doc 8 1379829 141 · Bu 138. Bu 135.7 (d), 135.6 , 134.8, 134.0, 132.5, 127.6, 124.5 (d), 122.2, 120.8, 119.9, 116.5 (d), 115.8, 112.4, 61.6, 28.8, 19.9 Preparation 34: (S-azido-2-methyl-benzene Base)_[2_Gas_4_(2,4-difluoro-phenylamino)-phenyl]-methylnet (Compound 434) A mixture of 404 (5.40 g, 14.5 mmol) was dissolved in acetone (1 〇〇) Concentrated HC1 (37%, 6.04 mL, 72 mmol) was added and the solution was cooled on an ice bath. NaNO2 (1.20 g, 17.4 mmol) was dissolved in H20 (9 mL) and added over 20 min. In the above solution, the internal temperature was maintained at 〇 ° C - 2 ° C during the addition. The suspension was stirred on an ice bath for 1 hour, after which NaN 3 (1.20 g, 17.4 mmol) was added dropwise to H20 over 5 minutes ( Solution in 12 mL). The mixture was stirred at 0 ° C for 2 hours. H2O (50 mL) and EtOAc (100 mL) were added and stirred and the phases were separated. The organic phase was concentrated in vacuo to give the title compound. This crude product can be used without any further purification. The crude product was purified by continuous gradient flash chromatography eluting with EtOAc/ petroleum ether (40-60) 0:100 to 50:50 as a solvent to afford the title compound. Example 28: [2-Ga-4-(2,4·difluoro-phenylamino)-phenyl]_{5_[4·(2-hydroxy-ethyl)-[1,2,3] Zin-1-yl]-2-methyl-phenyl}-methanone (Compound 128) Compound 434 (6.87 mmol) and 3-butyn-1-ol (8-24 mmol) were used as described for the preparation of compound 110. The reaction was carried out analogously. The crude product was obtained by using EtOAc/petroleum ether (4〇_60) 50:5 〇 to 100:0 as the eliminating agent. 106609.doc -85-

Purification by gradient flash chromatography to provide the title compound as a yellow foam. l3C NMR (CDC13) δ 194.8, 159.4 (dd), 155.7 (dd), 148.4, 146.3, 140.8, 13 8.3, 135.5, 134.8, 133.8, 132.6, 128.4, 124.8 (dd), 124.1 (dd), 122.3, 120.9 , 119.9, 116.2, 112.8, 111.7 (dd) ' 105.0 (dd) &gt; 61.6 ' 28.7 ' 20.0 Example 29 : [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl] _{5_[4-(1-Hydroxy-1-methyl-hexyldiol-1-yl)-2-methyl-phenyl}-indole (Compound 129) as described in the preparation of compound 116, using a compound The reaction was carried out analogously with 434 (0.125 mmol) and 2-methyl-but-3-yn-2-ol (0.125 mmol). The crude product was obtained from EtOAc/ petroleum ether (40-60) 30: 70 to 70 Purification by continuous gradient flash chromatography as a dissolving solvent to afford the title compound. 13 C NMR (CDC13) δ 194.9, 159.4 (dd), 156.4, 155.8 (dd), 148.6, 140.8, 138.2, 135.5, 134.8, 133.8, 132.6, 128.2, 125.0 (dd), 124.1 (dd), 122.4, 120.9, 117.6, 116.1, 112.7, 111.7 (dd), 105.0 (dd), 68.7, 30.5, 19.9 Example 30: l-(l-{ 3-[2-Chloro-4-(2,4·difluoro-phenylamino)-benzhydryl]_4-methyl-phenyl}-111-[ 1,2,3]dissense-4·yl)·B (Compound 13〇) Compound 434 (〇125 mm〇1) and but-3-yne-2-one (using compound 434 (〇125 mm〇1) as described in the preparation of compound 116 0.125 mmol) The reaction was carried out in a similar manner. The crude product was purified by EtOAc EtOAc/EtOAc (EtOAc (EtOAc) -CNMR (DMSO-d6) δ 193.6. 191.2. 159.0 (dd). 155.8 l06609.doc -86 - 1379829 (dd), 149.9, 147.6, 140.9, 137.3, 134.3, 134.2, 133.8, 132.5, 126.7 (dd ), 125.6, 125.5, 124.0 (dd), 122.0, 119.8, 115.0, 112.0 (dd), 111.8, 105.1 (dd), 27.3, 19.1 Example 31: {5-[4-(l-Amino-1-L) -ethyltriazol-1-yl]-2-methyl-phenyl}-[2-nitro-4-(2,4-difluoro-phenylamino)-phenyl]-methanone (compound) 131) The reaction was carried out analogously using compound 434 (0.125 mmol) and 1,1-monomethyl-prop-2-ytamine (0.125 mmol) as described in the preparation of compound 116. The crude product was purified by sequential gradient flash chromatography eluting with EtOAc / EtOAc (EtOAc): 13C NMR (CDC13) δ 194.9, 159.4 (dd), 155.8 (dd), 148.5, 140.8, 138.1, 135.4, 134.9, 133.8, 132.6, 128.3, 124.9 (dd), 124.1 (dd), 122.4, 120.8, 117" , 116", 112.8, 111.7 (dd), 105.0 (dd), 31.2 (bs), 20.0 Example 32: [2-Ga-4-(2,4-difluoro-phenylamino)-benzimidyl 4-methyl-phenylpyr 111-[1,2,3]triazole-4-carboxylic acid methyl ester (Compound 132) Compound 434 (0.50 mmol) and propyne were used as described in the preparation of compound 116. The reaction was carried out analogously with methyl ester (〇. 5 mmol). The crude product was purified by EtOAc (EtOAc/EtOAc) 13C NMR (CDC13) δ 194.4, 161.0, 159.5 (dd), 155.8 (dd), 148.0, 141", 140.6, 139.3, 135.5, 134.0, 133.9, 132.8, 128.1, 125.6, 124.9 (dd), 124.0 (dd) , 122.6, 121.0, 116.1, 106609.doc • 87- 112.9, 111.7 (dd), 105.0 (dd), 52.4, 20.0 Example 33: l-{3-[2-chloro-4-(2,4·difluoro) -Phenylamino)-benzylidenyl]-4-methyl-phenyl}-111-[1,2,3]triazole-4-carboxylic acid (Compound 133) H2〇(〇.6 mL) And a solution of the compound 132 (100 mg, 0.21 mmol) in MeOH (5.0 mL). EtOAc was added to the reaction and the pH was adjusted to 1-2 with concentrated HCl (37%, 6 drops). The organic phase was separated and the aqueous phase was extracted with more EtOAc. The organic phase was collected and washed with EtOAc EtOAc m. 13C NMR (DMSO-d6) δ 193.6, 161.3, 159.0 (dd), 155.7 (dd), 149.8, 140.8, 140.7, 137.1, 134.3, 134.1, 133.8, 132.4, 127.0, 126.7 (dd), 125.5, 124.0 (dd ), 121.9, 119.7, 114.9, 112.0 (dd), 111.8, 105.0 (dd), 19.1 Example 34: [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl]-[ 5-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-2-methyl-phenyl]-methanone (Compound 134) Compound 434 was used as described for the preparation of compound 116 (0.125 mmol) and prop-2-yn-1-ol (0.125 mmol) were similarly carried out. The crude product was purified by sequential gradient flash chromatography eluting with EtOAc/ petroleum ether (40-60): 13C NMR (CDC13) δ 194.8, 159.4 (dd)' 155.8 (dd), 148.5, 148.4, 140.8, 13 8.5, 135.5, 134.7, 133.8, 132.7, 128.2, 106609.doc -88 - 1379829 124.8 (dd), 124.0 (dd), 121.0, 12 (M, 116. Bu 112.8, 111.8, 111.7 (dd), 105_0 (dd), 56.6, 20.0 Example 35: [2-Ga-4-(2,4-difluoro-phenyl) Amino)-phenyl]-{5-[4-(3-carbyl-propyl)-[1,2,3]triazol-1-yl-2-methylphenyl}-methanone (Compound 135) The reaction was similarly carried out using compound 434 (0.15 mmol) and pent-2-ylidene 4-indole-1 (0·30 mmol) as described in the preparation of compound 116. Purification by EtOAc/petroleum ether (40-60) EtOAc (EtOAc) , 155.8, 149.8, 145.9, 140.8, 136.3, 134.3, 134.0, 133.2, 132.4, 126.6 (dd), 125.6, 124.0 (dd), 121.3, 119.3, 119.0, 116.8, 114.9, 112.0 (dd), 111.8, 105.0 ( Dd), 60.9, 19.1 Preparation 35: toluene-4-sulfonic acid 2-(l-{3-[2-nitro-4-(2,4-di) Fluoro-phenylamino)benzhydryl]-4-mercapto-pupidyl ih-[1,2,3J triazol-4-yl)-ethyl ester (Compound 435) Compound 12 8 (2 50 The solution of mg, 0.5 3 mmol) in anhydrous pyrimidine (2 〇 mL) was flushed with argon and cooled to 〇 ° C. Add 4-methyl-benzenesulfonium chloride (1 〇 2 mg, 0.53 mmol) and The reaction was allowed to reach room temperature and stirred overnight. The mixture was poured from EtOAc EtOAc EtOAc. / petroleum hydrazine (.6G) 25:75 to 5 (d) as a dissolving agent by continuous gradient flash chromatography to provide the title compound. 106609.doc •89· Preparation 36 : {5-[4-(2-Stack 1 Base-ethyl)-[1,2,3]triazol-1-yl]-2.methyl-phenyl H2_gas-4·(2,4-difluoro-phenylamino)-phenyl ( Compound 436) Compound 435 (167 mg, 〇.27mmQ), NaN3 (26 mg, 0.40 mmol) and a filling clock (4.4 mg, 0.027 mmol) in DMF (5.0 mL) at 50 ° C under argon The mixture was stirred for 18 hours. The reaction mixture was poured into a mixture of EtOAc / EtOAc (EtOAc)EtOAc. The crude product was purified by a continuous gradient flash s s s s s s s s s s s s s s s s s s s s s s s s s s . Example 36: {5-[4-(2-Amino-ethyl)-[1,2,3]triazol-1-yl]-2-methyl·phenylpyrazine 2_qi_ 4-( 2,4-Difluoro-phenylamino)phenyl]-methanone (Compound 136) 3 drops of water and triphenylphosphine (1 〇 2 mg, 0.39 mmol) were added to compound 436 (96 mg, 0.20 mmol) It was stirred in a solution of THF (2.5 mL) and then at room temperature for 18 hours. The reaction mixture was poured into a mixture of EtOAc / water. The organic phase was washed with water, brine, filtered and concentrated in vacuo. This crude product was purified by flash chromatography using MeOH to elute to afford the title compound. 13C NMR (CDC13) δ 194.8, 159.4 (dd), 155.8 (dd), 148.4, 146.8, 140.8, 138.1, 135.5, 134.9, 133.8, 132.6, 128.4, 124.8 (dd), 124.1 (dd), 122.3, 120.8, 119.6, 116.2, 112.8, 111.7 (dd), 105.0 (dd), 41.6, 29.7, 20.0 Example 37: 106609.doc -90- 1379829 (l-{3-[2-氱-4-(2,4-two) Fluoro-phenylamino)-benzylidene]-4-methyl-phenyl}-111-[1,2,3]triazol-4-ylmethyl)-urea (compound 137) such as compound 116 The reaction was carried out analogously using compound 434 (0.15 mmol) and prop-2-ynyl-urea (0.30 mmol). The crude product was purified by flash chromatography eluting elut elut elut elut 13C NMR (DMSO-d6) δ 193.7, 158.9 (dd), 158.3, 155.8 (dd), 149.7, 147.2, 140.7, 136.3, 134.3, 134.2, 134.0, 132.4, 126.6 (dd), 125.6, 124.0 (dd), 121.4, 120.7, 119.2, 114.9, 112.0 (dd), 111.8, 105.0 (dd), 34.7, 19.1 Example 38: [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl] -{2-Methyl-5-[4.(2-morpholin-4-yl-ethyl)-[1,2,3]triazol-1-yl]-phenyl}-methanone (Compound 138 Compound 435 (150 mg, 0.24 mmol), K2C 〇3 (50 mg, 0.36 mmol) and morpholine (0.5 mL) were placed in a small vial (8 mL). DMF (0.5 mL) was added and the resulting mixture was taken 5 EtOAc. (: stirring for 18 hours. HCl (4 mL, 0.5 N) was added to the reaction mixture and then extracted twice with Et EtOAc (2 mL). The organic phase was concentrated on silica gel and MeOH DCM 0: 100 to 10.9 0 was purified by continuous gradient flash chromatography as a bath to give the title compound as a white foam. 3C NMR (CDC13) δ 194.8 ' 159.4 (dd) ' 155.8 (dd) ' 148.4 ' 146.7, 140.7, 138.1, 135.4, 134.9, 133.8, 132.6, 128.4, 124.8 (dd), 124.1 (dd), 122.3, 120.9, 119.6, 116.2' 112.8, 111.7 (dd), 105.0 (dd), 66.8, 57.9 , 53.5, 23.0, 20.0 • 91 - 106609.doc ^S) 1379829 Example 39: [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl]-(2-methyl_ 5-{4-[2-(4-Methyl-Bound-1-yl)-ethyl]-oxime 1,2,3]triazole-i-yl}•phenyl)-methanone (compound 139 The reaction was carried out analogously using compound 435 (0.24 mmol) and 1-mercapto-piperazine (0.5 mL) as described in the preparation of compound 138. The crude product was purified by EtOAc EtOAc (EtOAc): 13C NMR (CDC13) δ 194.8, 148.4, 146.9, 140.8, 138.1, 135.5, 134.9, 133.8, 132.6, 128.4, 124.8 (dd), 124,1 (dd), 122.3, 120.9, 119.5, 116.2, 112.8, 111.7 ( Dd), 105.0 (dd), 57.5, 55.0, 52.7, 45.8, 23.4, 20.0 Example 40: [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl]-{5- [4-(2-Diethylamino-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 140) Prepared as Compound 138 In the above, it was similarly carried out using Compound 435 (0.24 mmol of hydrazine and diethylamine (0.5 mL). The crude product was obtained by using MeOH/DCM 0:100 to 15:85 as a continuous gradient of the eluent. Purified to provide the title compound as a yellow foam. 13C NMR (CDC13) δ 194.9, 159.4 (dd), 155.8 (dd), 148.5, 147.0, 140.8, 138.0, 135.4, 134.9, 133.8, 132.5, 128.3, 124.9 (dd), 124.1 (dd), 122.3, 120.8, 119.6, 116.2, 112.8, 111.7 (dd), 105.0 (dd), 52.2, 46.9, 23.4, 20.0, U 5 Example 41: -92· 106609.doc

1379829 [2-Aza-4-(2,4-diindole-phenylamino)-phenyl]_(5_〖4-丨2-(2-alkyl-ethylamino)-ethyl]- [1,2,3]triazol-1-yl}-2-methyl-phenyl)-methanone (Compound 141) As described in Preparation of Compound 138 'Use Compound 435 (〇.24 mmol) and 2- The reaction was carried out analogously with amino-ethanol (0.5 mL). The crude product was purified by sequential gradient flash chromatography using MeOH / DCM 0: 100 to 15:85 as eluting solvent to afford the title compound as yellow foam. 13C NMR (CDC13) δ 194.8, 148.6, 146.1, 140.8, 138.2, 134.4, 134.7, 133.9, 132.6, 128.2, 124.9 (dd), 124.1 (dd), 122.2, 120.8, 119.9, 116.1, 112.8, 111.8 (dd) , 105.0 (dd), 60.0, 50.7, 48.1, 25.3, 19.9 Example 42: [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl]_2_methyl-5 -[4-(2-propylamino-ethyl)-[1,2,3]triin-1-yl]•phenylpyridinium (Compound 142) as described in Preparation of Compound 138 The reaction was carried out analogously with 435 (0.24 mmol) and propylamine (0.5 mL). The crude product was purified by EtOAc EtOAc (EtOAc): 13C NMR (CDC13) δ 194.8' 159.4 (dd)' 155.8 (dd)' 148.5 ' 146.3, 140.8, 138.2, 135.4, 134_8, 133.8, 132.6, 128.3, 124.8 (dd), 124.1 (dd), 122.3, 120.8, 119.8, 116.2, 112.8, 111.7 (dd), 105.0 (dd), 51.1, 48.3, 25.2, 22.2, 20.0, 11.6 Preparation 37: [2-Ga-4-(4-It-2-decyl-phenylamine) ))_phenyl]_(2-methyl_5_nitro-benzene 106609.doc •93·1379829 base)-formamidine (Compound 437) Compound 4〇2 (〇) as described in the preparation of compound 414 56 mmol) and 4-fluoro-2-indolyl-aniline (0.56 mm〇i) were similarly carried out by using EtOAc/petroleum ether (4〇_6〇) 〇: 1〇〇 to 25 Purification by continuous gradient flash chromatography as a solvent to afford the title compound as a yellow foam. Preparation 38 : (5-Amino-2-indenyl-phenyl)_[2_gas_4_(4-fluoro-2-methyl-phenylamino)-phenyl]-methanone (Compound 438) The reaction was carried out analogously using compound 437 (〇41 mm〇i) as described in the preparation of compound 415. The crude product was used without any further purification. Preparation 39 : (5-azido-2-methyl-phenyl)-[2-chloro-4-(4-fluoro-2-methyl-phenylamino)-phenyl]-methanone (compound) 439) The reaction was carried out analogously as described in the preparation of compound 416 using compound 438 (0.29 mmol). The crude product can be used without any further purification. Example 43: [2-Ga-4-(4-fluoro-2-methyl-phenylamino)-phenyl]_{5-[4-(2-hydroxy-ethyl)-[1,2, 3] Triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 143) Compound 439 (0.29 mmol) and but-3-yn-1-ol were used as described in the preparation of compound 116. (〇. 4〇mmol) The reaction was carried out analogously. The crude product was purified by chromatography using EtOAc EtOAc: EtOAc: EtOAc: nC NMR (DMSO-d6) δ 193.5, 159.5 (4), 151.2, 145.7, 141.1, 136.3 (d), 135.9, 134.6, 134.4, 134.2 (d), 132.3, 127.1 (d), 124.3, 121.0, 120.6, 118.8, 117.4 (d), 114.2, 113.5 (d), 111.1, 60.1, 29.1, 19.0, 17.6 Preparation 40 ·· [2·Ga-4-(2·methoxy-phenylamino)-phenyl]_( 2·Methyl·5_Acidyl-phenyl)_methanone (Compound 440) As described in the preparation of compound 414, compound 4〇2 (〇56〇1111〇1) and 2-methoxy-aniline ( The reaction was carried out analogously with 0.56 mmol. The crude product was purified by EtOAc EtOAc/EtOAc (EtOAc) Preparation 41 : (5-Amino-2-methyl-phenyl)-[2-Ga-4-(2-methoxy-phenylamino)-phenyl]-anthone (Compound 441) as a compound The reaction was carried out analogously using compound 44 (〇28111111〇1) as described in the preparation of 415. The crude product can be used without any further purification. Preparation 42: (5-azido-2-indenyl-phenyl)-[2·gas_4_(2-methoxy-phenylamino)-phenyl]-methanone condensate 442) This reaction was carried out analogously using compound 441 (〇27111111〇1) as described in the preparation of compound 416. The crude product can be used without any further purification 106609.doc, 95-1379829. Example 44: [2·Gas-4_(2-roxo-n-ylamino)·phenyl]_{5_[4_(2_transyl.ethyl)-丨1,2,3]triazole- 1-yl]-2.methyl-phenylpyridamole (Compound 144) Compound 442 (〇27 mm〇1) &amp; But-3-yn-1-ol (0.3) was used as described in the preparation of compound 116. The reaction was carried out in a similar manner. The crude product was purified by EtOAc EtOAc (EtOAc) i3C NMr (DMSO-d6) δ 193.6, 152.4, 150.2, 145.6, 141.1, 135.9, 134.4, 134.2, 134.0, 132.3, 128.2, 125.3, 124.6, 123.4, U 1.0, 120·6, 118.8, 115.1, 112.2, 111_7 , 60.1, 55.4, 29.1, 19.0 Preparation 43: [2·Ga-4-(4-Ga-2-methyl-phenylamino)-phenyl]_(2_methyl·5·nitro-benzene Methyl ketone (Compound 443) This reaction was carried out analogously using compound 402 (0.56 mmol) and 4-br. The crude product was purified by EtOAc (EtOAc/EtOAc) Preparation 44: (S-Amino-2.methyl-phenyl)_[2 gas_4 (4-Chloro-2-methylphenylaminophenyl methanone (Compound 444) as in Preparation 415 Said reaction was carried out analogously using compound 443 (〇24111111〇1) class 106609.doc 8 •96-1379829. The crude product can be used without any further purification. * Preparation 45 : (5-azido-2 -methyl·phenyl)-[2·gas_4-(4-Gas-2-methyl-phenylamino)-phenyl]-methanone (Compound 445) as described in the preparation of compound 416, used Compound 444 (〇〇9 mm〇1) was carried out in a similar manner. The crude product was used without any further purification. Example 45: [2- gas-4-(4- s. Alkyl)·phenyl]^544-(2-hydroxy-ethyl)-[1,2,3]tris--1-yl]-2-methyl-phenyl-dipyridin (Compound 145)

The reaction was carried out analogously using compound 445 (0.03 mmol) and but-3-yn-1-ol (0.06 mmol) as described in the preparation of compound 116. The crude product was obtained by using EtOAc/ petroleum (40-60) 30:70 to 1 Torr: Purified by continuous gradient flash chromatography as a dissolving agent to provide the title compound. 13C NMR (CDC13) δ 194.7, 149.5, 146.2, 141", 138.2, 136.4, 13 5.7, 134.7, 134", 132.6, 131.2, 130.8, 127.4, 127.2, 125.6, 122.1, 120.7, 120.1, 115.8, 112.4, 61.5 , 28.6, 19.9, 17.9 Preparation 46: [2-Ga-4-(4-methoxy-phenylamino)-phenyl]-U-methyl-5-nitro-phenyl)-methanone ( Compound 446) The reaction was similarly carried out using compound 402 (0.56 mmol) and 4-methoxy-aniline (0.56 mmol) as described in the preparation of compound 414. The crude product was purified by EtOAc EtOAc/EtOAc (EtOAc:EtOAc:EtOAc: Preparation 47: (5-Amino-2-methyl-stupyl _4_(4-methoxyphenyl)amino) ketone (Compound 447) as described in the preparation of compound 415, using compound This reaction was carried out analogously to 446 (〇3i mm〇i). The crude product was used without any further purification. Preparation 48: (5-azido-2-methyl-phenyl)_[2_chloro _4_(4_Methoxy-phenylamino)phenyl]-methanone (Compound 448) The reaction was similarly carried out using compound 447 (〇〇8 mm〇1) as described in the preparation of compound 416. The product can be used without any further purification. Example 46: [2-chloro-4-(4-methoxy.phenylamino)-phenyl]-{5 [heart (2-hydroxyethyl) -[1,2,3]diazol-1-yl]methyl-phenylmethanone (Compound 146) Compound 448 (〇〇3 mm〇1) and D-3 were used as described in the preparation of compound 116. The reaction was carried out analogously with acetylene-oxime-ol (0·06 mm〇1). The crude product was obtained by using EtOAc/petroleum ether (40-60) 30:70 to 1 〇〇:0 as a continuous gradient of the dissolving agent. Purification by flash chromatography to provide the title compound nc NMR (CDC13) δ 194.7^ 157.3M50.5&Gt; 146.2^141.4^ 138.1^ 135.8^ 134.6, 134.22, 132.5, 132.2, 126.5, 125.3, 122.1, 120.6, I06609.doc 8 · 98· 1379829 120.1, 115.2, 115.0, 111.8, 61.5, 55.6, 28.6, 19.9 Examples 47 : [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl]_{5·[4·(2-hexylamino-ethyl)-[1,2,3 Dijun-1-yl]-2-methyl-phenylpyridinium (Compound 147) Compound 435 (〇 24 mmol) and hydrogenated ethylamine (0.55 mg) were similarly used as described for the preparation of compound 138. The reaction was carried out. The crude product was purified by EtOAc EtOAc: EtOAc: EtOAc (CD) ), 155.8 (dd), 148.6, 144.7, 140.8, 138.3, 135.4, 134.6, 133.9, 132.6, 128.2, 124.9 (dd), 124.1 (dd), 122.2, 120.8, 120.4, 116", 112.7, 111.7 (dd) , 105.0 (dd), 46.5, 42.8, 23_2, 19_9, 12.1 Preparation 49: (4-Bromo-2-methyl-phenyl)·(2-methyl-5-nitrophenyl)methanone (Compound 449 Using a dry glass m under an argon atmosphere to carry out the reaction . 4_Bromo-2-indenyl iodobenzene (2.40 mL, 16.8 mmol) was dissolved in dry THF (15 mL) and cooled to -60 C. Add isopropyl magnesium chloride (2 μ) to the mixture under stirring for 30 minutes.

'8.4 mL, 16.8 mmol in THF. The reaction mixture was allowed to warm to _4 (TC) and the mixture was stirred at -40 °C for 4 hrs. Compound 401 (4.62 g, 16.8 mmol) was added and the mixture was stirred for 3 hours. After that, it was allowed to warm up and stirred for 17 hours. A saturated aqueous solution of nh 4 C1 (100 mL) was added and the mixture was stirred for 1 hour. The phases were separated and the aqueous phase was extracted with Et EtOAc (2×l 〇〇mL). The organic phase was washed with brine, dried (MgSO.sub.4), filtered, and then evaporated, EtOAc EtOAc EtOAc EtOAc EtOAc Purification by flash chromatography as a dissolving agent to give the title compound as a yellow material. Preparation 50: (5-Amino-2-methyl-phenyl)-(4-bromo-2-methyl- Methyl ketone (Compound 450) Compound 449 (1.85 g, 5.54 mmol) was dissolved in MeOH (75 mL) EtOAc. &lt The reaction mixture was heated at reflux temperature for 2 hours. The mixture was filtered over EtOAc (EtOAc) eluting with EtOAc. Purification by (40-60) 0: 100 to 30: 70 as a solvent gradient eluting to give the title compound as a yellow paste. Preparation 51: (5-azido-2-methyl- Phenyl)-(4-bromo-2-methyl-phenyl)-methanone (Compound 451) A mixture of 450 (1.91 g, 6.28 mmol) was dissolved in acetone (45 mL). 2.61 mL, 31 mmol) and the solution was cooled on an ice bath. NaNO 2 (520 mg, 7.54 mmol) was dissolved in η 2 〇 (4·5 mL) and added to the above solution over 20 min. The internal temperature was maintained at 0 C - 2 C. The suspension was dropped on an ice bath for 3 〇 minutes, then NaN3 (618 mg, 9.42 mmol) was added dropwise to H2 〇 (i3 mL) within 3 〇 minutes. The solution was stirred at 0 ° C for 2 hours. Add h 2 hydrazine (50 mL) and EtOAc (2×75 mL) and stir and separate the phases. Wash with brine 106609.doc •100-1379829 Concentrate in vacuo to give the title compound. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m ·Ethyl)-[1,2,3 Triazolyl]-2-methyl·p-yl}·methanone (Compound 452) But-3-yn-1-ol (39 μ, 0.51 mmol) was added to compound 541 (17 mg, 0.51 mmol) In a solution of ethanol (2 mL). A freshly prepared solution of copper sulfate pentoxide (5. 0 mg, 0.020 mmol) and sodium ascorbate (20 mg, 〇.1 〇 mm〇i) in water (0.5 mL) was added to the reaction mixture. . The flask was sealed under argon and stirred at room temperature for 24 hours. The reaction mixture was poured into a mixture of EtOAc / water. The organic phase was washed with water, brine, and then dried (MgSO4) filtered and concentrated in vacuo to afford crude. The crude product was purified by EtOAc (EtOAc:EtOAc:EtOAc: Example 48: [4-(2,4-Difluoro-phenylamino)-2-methyl-phenyl]-{5-[4·(2-hydroxy-hexyl)_[1,2,3 Disin-1-yl]-2-methyl-phenyl}-methylamine (Compound 148) ' Compound 452 (78 mg, 0.19 mmol) was dissolved in anhydrous I,4- in an 8 mL screw cap container Dioxane (1 mL). 2,4-Difluoroaniline (20 pL, 0.19 mmol) was added and argon was bubbled through the mixture. Cs2C03 (186 mg, 0·57 mmol), BINAP (5 mg, 0.008 mmol) and Pd(OAc) 2 (2 mg, 0.008 mmol) were added and argon was blown through the mixture and the screw cap container e was closed. Stir at 90 ° C for 18 hours. The reaction was filtered through Decalite to mix 106609.doc -101 - 1379829 and vacuumed on Shishijiao. The crude product was purified by sequential gradient flash chromatography using EtOAc (EtOAc): EtOAc (EtOAc) (CDC13) δ 197.1, 158.9 (dd), 155.4 (dd), 147.6, 146.3 ' 143.3 '142.3 ' 137.1 . 135.3 ' 134.7 ' 132.2 ' 128.2 ' 124.7 (dd), 124.0 (dd), 121.5, 120.0, 119.9, 118.0, 111.4 (dd), 111.2, 104.8 (dd), 61.6, 28.7, 22.2, 19.6 Example 49: [4_(3_Chloro_4_fluoro-phenylamino)-2-methylphenyl]- {5-[4-(2-Hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-indenyl-phenyl- phenone (Compound 149) as in the preparation of compound 148 The reaction was carried out analogously using compound 452 (〇13 mm〇i) and 3-fluoro-4-methyl-aniline (〇.13 mmol). The crude product was obtained from MeOH/DCM/ petroleum ether (40-60 0:50:50, 0:100:0, and 5:95:0 were purified by EtOAc EtOAc (EtOAc: EtOAc: 152.6 (d), 147.6, 145.8, 142.3, 142.3, 138.6 (d), 135.3 (d), 134.4, 132.2, 126.9, 121.1, 120.7, 120.5, 120.0 (d), 119.9 (d), 118.4, 117.7, 117.5 (d), 111.3, 60.2, 29.2, 22.0, 18.9 Example 50: {5-[4-(2-hydroxy- Ethyl)_[i,2,3]triazole-! •Kibu 2-methyl-phenyl}-(2-methyl-4-phenylaminophenyl)-methanone (compound 15〇) The reaction was carried out analogously using compound 452 (0.13 mmol) and aniline (0.13 mmol) as described in the preparation of compound 148. The crude product was obtained from MeOH/DCM/ petroleum ether (40-60) 0:50:50. 0:100:0 and 5:95:0 as the title compound of a continuous gradient of the solvent 106609.doc-102-offer. Purified by 13C Nmr to provide a yellow solid (CDC13) δ 197.0, 147.9, 146.3, 143.4, 142.5 140.4, 137.0, 135.5, 134.6, 132.2, 129.5, 127.6' 1235' ιοί • 121.4, 121.0, 119.9, 118.1, 111.4, 61.6, 28.7 ' 22.3 '19 5 Example 51 : 1_[3_(4· {5-[4-(2-Ph-ethyl)-[12,3] triterpenoid] 2-methylbenzyldibu 3_methyl-phenylamino)phenyl]- Ethylene Steel (Compound 151) As described in the preparation of Compound 148, Compound 452 (0.13 mmol) and 1 (3-Amino-Benzene) were used. The reaction was carried out analogously with ethyl ketone (〇 13 mm 〇 1). The crude product was purified by continuous gradient flash chromatography using Me〇H/DCM/ petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the dissolving agent to provide The title compound is a yellow solid. I3c nmR (CDC13) δ 197.8, 197.1, 147.1, 146.3, 143.3, 142.3, 141.2, 138.5, 137.1, 135.3, 134.7, 132.3, 129.8, 128.5, 124.8, 123.2, 121.5, 120, 0, 119.9, 119.6' 118.7, 111.8, 61.6, 28, 7, 26.7, 22.2, 19.6 Example 52: 3-(4-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl] -2-Methyl-benzimidyl}-3-fluorenyl-phenylamino)·Bistonitrile (Compound 152) Compound 452 (0.13 mmol) and 3-amino group were used as described in the preparation of compound 148. -benzonitrile (0.13 mmol) was similarly carried out. The crude product was purified by continuous gradient flash chromatography to purify MeOH/DCM/ petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as a dissolving agent to provide the title compound as a yellow solid. 13C NMR (DMSO-d6) δ 196.5, 106609.doc -103· 146.5 '145.7, 142.4, 142.1, 142", 135.4, 135.0, 134.5, 130.7, 127.7, 124.9, 123.3, 121.1, 120.7, 120.6, 118.8, 118.6, 118.5, 112.2, 60.2, 29.2, 21.9, 18.9 Example 53: {5-[4·(2-carbyl-hexyl)-[1,2,3]triazol-1-yl]-2-methyl -phenylH2-indolyl-4(3-trifluoromethyl)phenyl)-phenyl]-fluorenone (Compound 1S3), as described in the preparation of compound 148, using compound 452 (0.13 mmol) The reaction was carried out analogously with difluorodecyl-aniline (〇, 13mniol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/ petroleum ether (4 〇 -6 〇) 〇: 50:50, 0:1 〇〇: 〇, and 5:95:0 as a dissolving agent. To provide the title compound as a yellow solid. 13C NMR (DMSO-d6) δ 196.5, 146.8, 145.7, 142.3, 142.2, 142.1, 135.3, 135.1, 134.4, 132.2, 130.6, 130.2 (q), 127.6, 124.1 (q), 122.0, 120.7, 120.5, 118.5, 117.7(q), 114.9 (q), 112.0, 60.2, 29.2, 21.9, 18.9 Example 54: [4-(3·4-Difluoro•phenylamino)_2_indolyl-phenyl]-{5- [4-(2-Hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-fluorenone (Compound 154) as described in the preparation of compound 148, The reaction was carried out analogously using compound 452 (0.13 mmol) and 3,4-difluoro-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography eluting with MeOH/DCM/ petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as solvent. The title compound of the solid. 13C NMR (DMSO-d6) δ 196.4, 149.6 (dd), 147.5, 145.7, 144.7 (dd), 142.3, 142.2, 138.4 (dd), 135.3, 135.2, 134.4, 132.1, 127.0, 120.7, 120.5, 118.4, 117.9 106609.doc • 104- (d), 117.7, 116.0 (dd), 111.4, 108.5 (d), 60.2, 29.2, 22.0, 18.9 Example 55: [4-(3,4-Dimercapto-phenylamino) )-2-methyl-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}- Methyl Ketone (Compound 155) This reaction was carried out analogously as described for the preparation of compound 148 using compound 452 (0.13 mmol) and &lt;RTI ID=0.0&gt;&gt; The crude product was purified by continuous gradient flash chromatography of MgOH/DCM/ petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the dissolving agent to provide yellow The title compound of the solid.丨3C NMR (DMSO-d6) δ 196.0, 148.9, 145.7, 142_7, 142.3, 138.4, 137", 135.5, 135], 134.4, 132.0, 130.5, 130.2, 125.4, 121.9, 120.7, 120.2, 118.2 '118.0, 117.0 , 110.4, 60.2, 29.2, 22.2, 19.5, 18.8, 18.7 Example 56: [4-(3-Chloro-2-methyl-phenylamino)-2-methyl-phenyl]-{5-[4 -(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 156) as described in the preparation of compound 148, using a compound The reaction was carried out analogously with 452 (0.13 mmol) and 3-yield-2-methyl-methanolamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography eluting with MeOH/DCM / petroleum EtOAc (40-60) 0:50:50, 0:100:0 and 5:95:0 as solvent. The title compound of the solid. 13C NMR (CDC13) δ 197.0, 148.6, 146.3, 143.5, 142.5, 139.9' 137.0, 135.7, 135·5, 134.6, 132.2, 130.9, 127.5, 127.1, 126.0, 122.4, 121.3, 119.9, 119.9, 117.8, 111.1, 61.6 , 28·7, 22.3, 19.5, 15.0 106609.doc -105- 1379829 Example 57: [4-(3,4-Dichloro-phenylamino)-2.methyl-phenyl]-{5-[ 4·(2·hydroxyethyl)-[1,2,3]triazol-1yl]_2•methyl-phenyl}-methanone (Compound 157) Compound 452 was used as described in Preparation of Compound 148. (0.13 mmol) and 3,4-dichloro-aniline (〇13 mm〇i) were similarly carried out. The crude product was purified by continuous gradient flash chromatography eluting with MeOH/DCM/ petroleum ether (40-60) 0:50:50, 0:1 〇〇: 〇 and 5:95:0 as the eluent to provide The title compound is a yellow solid. nC NMR (DMSO-d6) δ 196.4, 146, 4, 145.6, 142.0, 141.9, 141.6, 135.3, 134.9, 134.3, 132", 131.5, 131.0, 127.6, 122.5, 120.6, 120.5, 119.7, 118.6, 118.4, 112.2 , 60.1, 29.1, 21.8, 18.8 Example 58: Ν-[3-(4-{5-[4_(2-hydroxyethyl)-[1,2,3]triazol-1-yl]-2-A Benzo-phenylhydrazinyl}-3-methyl-phenylamino)-phenylethylideneamine (Compound 158) Compound 452 (0.13 mmol) and N-(3- The reaction was carried out analogously with amino-phenyl)-acetamide (〇.13 mm〇l). The crude product was purified by EtOAc EtOAc (EtOAc) l3C NMR (DMSO-d6) δ 196. Bu 168.2, 147.9, 145.6, 142.4, 142.0, 141.2, 140. 135.1, 135.0, 134.3, 131.9, 129.3, 126.0, 120.6, 120.2, 118.2, 117.6, 114.2, 112.7, 111.1, 110.0, 60.1, 29.1, 24.0, 22.1, 18.7 Preparation of S3: (4-bromo-2-a-phenyl)-(2-a-5-nitro-phenyl)-methanone (Compound 453) 106609 .doc -106- 8 1379829 The reaction was carried out using a dry glassware under an argon atmosphere. 4_Bromo-2_gas·methyliodobenzene (5.00 g, 15.8 mmol) was dissolved in dry THF (25 mL) and cooled to -35. Gasified isopropyl magnesium (2 μ in THF 8_27 mL, 16.5 mmol) was added with stirring over 90 min. A solution of ZnCl2 (2.17 g, 15.9 mmol) in anhydrous THF (35 mL) was slowly added to the reaction mixture at -35 ° C. After 1 hour, the reaction mixture was allowed to reach room temperature and was added. A solution of chloro-5-nitro-benzhydryl chloride (3.64 g, 16.5 mmol) in THF (45 mL). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into a mixture of Et 〇 Ac / water / HCl (IN). The organic phase was washed with water, brine and dried (MgSO4) filtered and evaporated The crude product was purified by flash chromatography using EtOAc (EtOAc:EtOAc:EtOAc: Preparation 54: (5-Amino-2-chloro-phenyl)-(4-bromo-2-a-phenyl)-methanone (Compound 454) Compound 453 (2.17 g, 5.. 50 mL) 811 (: 12.21120 (5.49 §, 28.9 〇 1111 〇 1) was added in ° °. The reaction mixture was heated at reflux temperature for 1 hour. The reaction mixture was poured into a mixture of Et 〇 Ac / water. Wash with water, brine, and then dry (MgS 〇 4) 'transition and vacuum concentrate' to give a crude product by using DCM / petroleum ether (40-60) 50:50 to 1 〇〇: 〇 Purification by continuous gradient flash chromatography as a dissolving agent to give the title compound as a yellow solid. Preparation SS: (5-fluorenyl-2-chlorophenyl)-(4_m-phenyl-phenyl) Formamidine (Compound 455) 106609.doc 8 -107· 1379829 Mixture 454 (1.21 g, 3.51 mmol) was dissolved in acetone (25 mL)*β Concentrated HC1 (37%, 1.46 mL, 17.5 mmol) The solution was cooled. NaN02 (291 mg, 4.21 mmol) was dissolved in H.sub.2 (2.5 mL) and added to the above solution over 20 min. The internal temperature was maintained between 0 °C and 2 °C during the addition. Will hang The solution was stirred on an ice-bath for 30 min, then a solution of NaN3 (348 mg, 5.31 «1111 〇1) in 1120 (7.5 mL) was added dropwise over 3 min. H2O (50 mL) and EtOAc. (2 x 75 mL) and the phases are separated. The organic phase is washed with EtOAcqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Base)-{2-chloro-5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-phenyl}-fluorenone (compound 456) 3-yn-1-ol (0.3 mL, 3.91 mmol) was added to a solution of compound 455 (1.3; 2 g, 3.56 mmol) in ethanol (2 mL). The freshly prepared solution of sodium ascorbate (141 mg, 〇71 mmol) in water (3.2 mL) was added to the reaction mixture. The flask was closed under argon and stirred at room temperature for 24 hours. The reaction mixture was poured into a mixture of EtOAc / EtOAc. EtOAc EtOAc EtOAc. / Petroleum mystery (40-60) 40: 60 to 95:5 was purified by continuous gradient flash chromatography as a dissolving agent to afford the title compound as a white paste. Example 59: [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl b{2-gas-5-[4-(2-hydroxy-B 106609.doc • 108- 1379829 Base)-[1,2,3]triazol-yl]-phenylphenone (Compound 159) Compound 456 (0.91 mmol) and 2,4-difluoro-, as described in the preparation of compound 148. Aniline (0.91 mmol) was similarly carried out. The crude product was purified by EtOAc EtOAc (EtOAc) Nc NMR (CDC13) δ 191. Bu 159.6 (dd), 155.9 (dd), 149.1' 146.7, 141.1, 136.1, 135.7, 134.5, 131.7, 131.6, 126.9, 125.1 (dd), 123.8 (dd), 122.8, 121.0 , 119.9, 116.1, 112.8, 111.7 (dd), 105.1 (dd), 61.5, 28.7 Preparation 57 [2-Ga-4-(3-fluoro-phenylamino)-phenyl (2_methyl_5) _Nitro-phenyl)-methanone (Compound 457) This reaction was similarly carried out using compound 4 〇 2 (2 82 111111 〇 1) and 3- fluoro-phenylamine (2.82 mmol) as described in the preparation of compound 414. The crude product was purified by EtOAc (EtOAc/EtOAcEtOAcEtOAcEtOAc Preparation 58 (5-Amino-2.methylphenyl)-[2·Ga-4-(3-fluoro-phenylamino)-phenyl]-methanone (Compound 458) as in compound 415 The reaction was carried out analogously using compound 457 (2 25 1 〇 111 〇 1). The crude product was purified by flash chromatography eluting with EtOAc (EtOAc: EtOAc (EtOAc): 5-azido-2-methyl-phenyl)-[2-nitro-4-(3-fluoro-phenylamino)phenyl]methanone (compound 459) as described in the preparation of compound 416, The reaction was carried out analogously using compound 458 (1 83 mm 〇 1). The crude product was purified by flash chromatography using EtOAc (EtOAc/EtOAc) (EtOAc) Example 60: [2-Ga-4-(3-Fluoro-phenylamino)-phenyl]-{S-[4-(2-hydroxy-ethylb.) Triazol-1-yl] -2-methyl-phenyl}-methanone (compound 16〇)

The reaction was carried out analogously as described in the preparation of compound 116 using compound 459 (〇26 mm〇1) and but-3-yn-1-ol (0.29 mmol) by using EtOAc/oil (40) -60) 6:1 Purification by flash chromatography as a dissolving agent to provide the title compound as a pale yellow foam. i3C NMR (CDC1J δ 194.9, 163.6 (4), 147.6, 146.3, 141.8 (4), 140.7, 138.3, 135.4, 134.8, 133.8, 132.6, 130.9 (d), 128.7, 122.4, 120.9, 120.0, 117", 116, 1 (d ), 113.7, 110.5 (d), 107.6 (d), 61.6, 28.7, 20.0 Preparation 60 [2-Gas-4-(3-chloro-phenylamino)-phenyl]-(2-f--5 _Nitro-phenyl)-methanone (Compound 460) The reaction was similarly carried out using compound 402 (2.82 mmol) and 3- gas-aniline (3.10 mmol) as described in the preparation of compound 414. Purification by EtOAc/petroleum ether (40-60) EtOAc (EtOAc: EtOAc: EtOAc) (5-Amino-2-methyl-phenyl)-[2-amino-4-(3-carbo-phenylamino)-phenylpyridinium (Compound 461) as described in the preparation of compound 41 5 The reaction was carried out in a similar manner using compound 460 (2.13 mmol). The crude product was purified by flash chromatography eluting with EtOAc/ petroleum ether (40-60) 1:2 as solvent. Compound 62 (5-azido) 2-Mercapto-phenyl)-[2- gas-4-(3-carbo-phenylamino)-phenyl methanone (Compound 462) Compound 461 (1.40) was used as described in the preparation of compound 416. This reaction was carried out in a similar manner. The crude product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) [2-Gas-4-(3-chloro-phenylamino)-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl 2-methyl-phenyl}-methanone (Compound 161) This reaction was carried out analogously as described in the preparation of compound 116 using compound 462 (0.23 mmol) and butyl-3-propane-propanol (0.28 mmol). The crude product was purified by flash chromatography eluting with EtOAc/EtOAc (EtOAc (EtOAc:EtOAc) , 141.4, 140.7, 138.3, 135.4, 135.3, 134.8, 133.8 ' 132.6, 130.7, 128.7, 123.8, 122.4, 120.9, 120.7, 120.0, 118.8, 117.1, 113.6, 61.6, 28.7, 20.0 -Ill - 106609.doc

Cs) 1379829 Preparation 63 (2-Ga-4-m-tolylamino-phenyl)-(2-methyl-5-nitro-phenyl)-methanone (Compound 463) as described in the preparation of compound 414 The reaction was carried out analogously using compound 4〇2 (2 82 mm〇1) and 3-mercapto-aniline (3.10 mm〇l). The crude product was purified by EtOAc EtOAc/EtOAc (EtOAc) Preparation 64 (5-Amino-2-indolyl-phenylene-4-m-tolylamino-phenyl)-methane (Compound 464) Compound 463 (1 78 mm) as described in the preparation of compound 415 〇 1) The reaction was carried out analogously. The crude product was purified by flash chromatography using EtOAc (EtOAc:EtOAc:EtOAc: Preparation 65 (5-azido-2-methyl-phenyl)-(2- gas-4-m-tolylamino-phenyl-methyl mesh (Compound 465&gt; as described in the preparation of compound 41 6 ' Compound 464 (1.17 mmol) was similarly subjected to the reaction. The crude product was purified by flash chromatography using Et EtOAc/ petroleum ether (40-60) 1:9 and 1:6 as a solvent. The title compound is a yellow paste. Example 62: (2-Gas 4-m-tolylamino-phenyl)-{5-[4-(2-hydroxyethyl)-[1,2,3] Tris-7-yl]-2-methyl-phenyl}-methanone (compound m2) 106609.doc -112- as described in the preparation of compound 116 'using compound 465 (0.25 mmol) and but-3-yne The reaction was carried out analogously with 1-propanol (0.30 mmol). The crude product was purified by flash chromatography eluting with EtOAc/ petroleum ether (40-60) 6:1 as solvent. Title compound. &quot;C NMR (CDC13) δ 194.8, 148.9, 146.3, 141", 139.7, 139.6, 138. 135.6, 134.8, 134.0, 132.5, 129.5, 127.5, 125.2, 122.3, 122.2, 120.7, 119.9, 118.7 , 116.3, 112.8, 61.6, 28.7, 21.5, 19.9 Preparation 66 [ 2-Chloro-4-(3-methoxy-phenylamino)-phenyl]-(2-methyl-5-nitro-phenyl)-methanone (Compound 466) as prepared in compound 414 The reaction was carried out analogously using compound 402 (2.82 mmol) and 3-methoxy-aniline (3.10 mmol). The crude product was obtained by using EtOAc/ petroleum ether (40-60) from 0:1 to 30: 70. Purification by continuous gradient flash chromatography as a dissolving agent to provide the title compound. Preparation 67 (5-Amino-2-methylphenyl)-[2-chloro-4-(3-methoxy- Stupylamino)·Phenylmethanone (Compound 467) The reaction was similarly carried out as described in the preparation of compound 41 5 using compound 466 (2.32 mmol). The crude product was obtained by using EtOAc/oil scales (40-60 Purification by flash chromatography as a dissolving agent to provide the title compound as a yellow foam. Preparation 68 (5-methanol-mercapto-phenyl-phenyl)-[2- gas-4-( 3-methoxy-phenylamino)- phenyl 106609.doc -113· 1379829 carbomer (compound 468) The compound 467 (1.77 mmol) was used to carry out the reaction similarly as described for the preparation of compound 416. The product was obtained by using EtOAc/petroleum ether (40-60) 1 and 1:6 It is purified from the solution by flash chromatography of the agent to provide the title compound. Example 63: [2-Ga-4-(3-methoxy-phenylaminophenyl)hydroxyethyl)-[1,2,3]triazol-1-yl]-2-indenyl-benzene Kebone (Compound 163) This reaction was carried out analogously as described in the preparation of compound 116 using compound 468 (〇22 mm〇i) and but-3-yn-1-ol (0.28 mmol). The crude product was purified by flash chromatography eluting with EtOAc/EtOAc (EtOAc)丨3C NMR (CDCl3) δ 194.8, 160.8, 148.5, 141.1, 141.0, 138.1, 135.5, 134.8, 133.9, 132.6, 130.4, 127·8, 122.2, 120.7, 119.9, 116.6, 113.6, 113.2, 109.4, 107.3, 61.6 , 55.4, 28.7, 19.9 Preparation 69 (Amino 2-methyl-benyl) _(4_ _ _ _ gas-phenyl) ketone (Compound 469) Compound 402 (5.09 g, 14.4 mmol) was dissolved In MeOH (200 mL). Zinc powder (9.38 g, 144 mmol) and NH4C1 (3.84 g, 71.8 mm 〇l) were added. The reaction mixture was heated at reflux temperature for 2 hours. The mixture was passed through Deealite and washed with Me()H. Concentrate the mash on the 7 gel. The crude product was purified by continuous gradient flash chromatography using 4 〇 / / petroleum ether (4 〇 -6 〇) 〇: 1 〇〇 to 2 〇: 8 〇 as a 4 eliminator to provide a yellow paste. The title compound of the slurry. 106609.doc 1379829 Preparation 70 (5-rises of rabbit-2-methyl-phenyl)-(4-bromo-2-a-phenyl)·methyl steel (compound 470) 469 (1.00 g, 3.08 mmol ) Dissolved in acetone (23 mL). Concentrated HCl (37e /., 1.30 mL, 15 mmol) was added and the solution was cooled on ice. NaN02 (255 mg, 3.70 mmol) was dissolved in H20 (2.3 mL) and added to the above solution over 20 min. The internal temperature is maintained at 0 C -2 C during the addition. The suspension was stirred on an ice bath for 3 min, then a solution of NaN3 (303 mg, 4.60 mmol) in H.sub.2 (7 mL). The mixture was stirred at 0&lt;0&gt;C for 1 h. &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The organic phase was washed with EtOAc (EtOAc EtOAc) The crude product was purified by flash chromatography using EtOAc/EtOAc (EtOAc) Preparation 71 (4-Bromo-2-chloro-phenyl)-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-indolyl- Phenyl group (compound 471) butyl-3 -block-1-ol (225 μΐ^, 2.97 mmol), copper sulfate pentahydrate (11) (30 mg, 0.12 mmol) and sodium ascorbate (119 mg, 0.6 mmol) A solution in water (3.0 mL) was added to a solution of compound 47 (^ 4 g, 2 97 mm 〇 1) M ethanol (18 mL). The flask was sealed under argon and stirred at room temperature for 24 hours. After 18 hours, 1,4-3·yne-丨-alcohol (225 pL, 2.97 mmol), copper sulfate pentahydrate (11) (30 mg, 0.12 mmol) and sodium ascorbate (119 mg, 0.6 mmol) in water (3.0) were added. Solution in mL). After 2 hours, the mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine and dried (MgSO4), filtered and concentrated in vacuo to afford crude. The crude product was purified by flash chromatography eluting with EtOAc (EtOAc:EtOAc) Example 64: [2-Ga-4-(2,3-dichlorophenylamino)phenyl]_{5_[4_(2hydroxy-ethyl)-[1,2,3] triazole Keb 2-methyl-phenyl}-methanone (Compound 164) As described in the preparation of compound 148, compound 471 (〇13 mm〇1) and 2.3-di-p-amine (0.131111)1〇1) were used. The reaction was carried out analogously. The crude product was purified by flash chromatography using EtOAc/EtOAc:EtOAc: 13C NMR (CDC13) δ 194.9, U6 4, 140.4, 139. 13 13 8.5, 135], 134.8, 134.0, 133.5, 132.7, 130.0, 127.6, 124.3, 123.2, 122.5, 121.0, 119.9, 118.6, 117·4, 115.2, 61.5, 28.7, 20.1 Example 65: [2-Ga-4-(3,5-dimercapto-phenylamino)-phenyl]_{5_[4_(2•hydroxy-ethyl)-[ 1,2,3]disin-1-yl]-2-methyl-phenyl}-carboxamidine (Compound 165) Compound 47 1 (0..13 mm〇i) was used as described in the preparation of compound 148. This reaction was carried out analogously with 3,5·dimethyl-stupamine (〇_13 mmol). The crude product was purified by flash chromatography using MeOH / DCM 1:20 as elutant to afford title compound.丨3C NMR (CDC13) δ 194.8, 149.2, 146.3, 141.2, 139.6, 139.4, 137.9, 135.6, 134.7, 134.1, 132·5, 126.9, 126.0, 122. Bu 120.5, 120.0, 119_3, 116.3, 106609.doc 8 -116- 1379829 112.7, 67.1, 61.5, 28.8, 21.3, 19.8 Example 66: [2-Ga-4(2,5-difluoro-phenylamino)-phenyl]-{5-[4-( 2-Phenyl-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenylphenone (Compound 166) Compound 47 1 was used as described in the preparation of compound 148 (0.13 mmol) and 2.5-bis-aniline (0.13 mmol) were similarly carried out. The crude product was purified by flash chromatography using EtOAc/EtOAc:EtOAc: UC NMR (CDC13) δ 194.9, 158.8 (d), 150.2 (d), 146.3 (d), 140.4, 138.4, 135.2, 134.8, 133.5, 132.7, 129.9, 122.5, 121.0, 119.9, 117_9, 116.6 (dd), 114.5, 109.5 (dd), 107.1 (d), 61.6, 28.7, 20.1 Example 67: [2-Ga-4-(3,5-difluoro-phenylamino)-phenylindole 5·[4·(2 _Hydroxyethyl)-[1,2,3]triazol-1·yl]_2-methyl-phenylphenone (Compound 167) As described in Preparation of Compound 148 'Use Compound 471 (0.13 mm 〇) 1) and 3.5-difluoro-aniline (0.13 mm 〇 1) were similarly carried out. The crude product was purified by flash chromatography using EtOAc/EtOAc:EtOAc: &quot;C NMR (CDC13) δ 195.0, 163.8 (dd), 146.6, 146.4, 143.1 (t), 140.5, 138.4, 135.2, 134.8, 133.6, ^2.7, 132·6, 132.3, 129.4, 122.5, 121.0, 120 , ι18.!, !14·5, ΐ〇2·2 (m), 98.2 (t), 61.5, 28.8, 20.0 106609.doc 8 •117-

Claims (1)

1379829 Patent application scope: - Compound of formula la or lb: Patent application No. 094142321 Chinese patent application scope replacement (May 101) liof I R R la R, Wherein Ri is methyl, chloro, bromo or methoxy; Κ·2 is gas or sulfhydryl; Κ·3 represents Cu alkyl, c2.6 dilute, C2.6 alkynyl, C!.6 via alkane Base, CN6 Haloalkyl, Ci.6 alkoxy, C,6 alkoxycarbonyl, cN6 amine, ureido, thiourea, C!-6 alkylcarbonyloxy, c, -6 alkylcarbonyl, Cw alkoxy a carbonyloxy group, a Cl. 6 alkoxysulfonyloxy group, a Cl. 6 alkoxyamine indenyl group or a Ci 6 aminocarbonyl group, each of which is optionally selected from the group consisting of the following groups; Substituted by one or more, the same or different substituents: dentate, hydroxy, fluorenyl, tri-l-decyl, cyano, carboxy, CONH2, nitro, keto, ·δ(0)2ΝΗ2, Ci-4 alkyl , C2-4 alkenyl, c2.4 alkynyl, Cm hydroxyalkyl, Cu haloalkyl, C,-4 alkoxy, C!·4 alkoxycarbonyl, ureido, thiourea, Ci 4 alkyl Carbonyloxy 106609-1010511.doc 1379829, Cw alkoxycarbonyloxy, Cm alkoxysulfonyloxy, CN4 alkoxyamine indenyl, Cw aminocarbonyl, Ci-4 alkylthio, 〇3.6 cycloalkyl, C3-6 cycloalkenyl, amino 'imine, Cw amine sulfonyl, Cw aminocarbonyloxy, CN4 alkylsulfonylamino, C, .4 alkoxy Amino, Cm alkylcarbonylamino, C, .4 alkylsulfonyl, Cw heteroaryl, C!-6 heterocycloalkyl or c2-6 heterocycloalkenyl, wherein the Cw Alkyl, C2.4 alkenyl, c2_4 alkynyl, Cm hydroxyalkyl, CN6 haloalkyl 'Cm alkoxy, C, .4 alkoxycarbonyl, ureido, thiourea, Cw alkylcarbonyloxy, Cu4 alkoxycarbonyloxy, (^-4 alkoxysulfonyloxy, C-7-4 alkoxyamine, mercapto, Cm aminocarbonyl, Cm alkylthio, c3.6 cycloalkyl 'C3-6 cycloalkenyl, amine, imine, Cw aminosulfonyl, Cw aminocarbonyloxy, CN4 alkylsulfonylamino, Cm alkoxyimido, Cm alkylcarbonylamine a Cm alkylsulfonyl 'Cm heteroaryl group, a Cw heterocycloalkyl group or a C2.6 heterocycloalkenyl group, optionally further selected from the group consisting of one or more of the following groups, the same or different Substituent substitution: halogen, hydroxy, -Nh2, sulfhydryl, difluoromethyl, cyano, enantiomer, C〇NH2, schlossyl, keto, -S(0)2NH2, Ci-4 alkyl or C! .4 burned base; or R3 represents hydrogen 'hydroxyl or carboxyl group; R4, R5, R6 'foot 7 and r8 independently of each other represent hydrogen, halogen, _Nh2, thiolmethyl, methoxy, ethoxy , cyano, ethyl, acetamido, methyl or ethyl; the limitation is that the compound is not [4_(2_ Aminophenyl)amino-2 chlorobenzyl]-[2·methyl·5-[1_[2·[(tetrahydro-2H-pyran-2-yl)oxy]ethyl 106609-1010511.doc - 2- 1379829 base]-11^-1,2,3-tris-s--4-phenylphenyl]-anthone or [4_[(2-aminophenyl)amino]oxyphenyl]-[5 -[1-(2·Hydroxyethyl)-1Η-1,2,3-triazol-4·yl]-2-methylphenyl]-carboxamidine; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein the sizing 3 represents c, -6 decyl, c2_6 alkenyl, C26 alkynyl, Cl. 6 hydroxyalkyl, Cl. 6 alkoxycarbonyl, c -6 alkylcarbonyl, Urea or c16 aminocarbonyl, each of which is optionally substituted with one or more, the same or different substituents selected from the group consisting of: a hydroxyl group, a hydroxy group, a fluorenyl group, a trifluoromethyl group, Cyano, carboxyl, conh2, nitro, keto, -S(0)2NH2, Cm alkyl, C2.4 alkenyl, C2.4 alkynyl, C, 4 hydroxyalkyl, Cw alkoxy, Cm alkane Oxycarbonyl, ureido, thiourea, Cl. 4 alkylcarbonyloxy, (^-4 alkoxycarbonyloxy, Cm alkoxysulfonyloxy, cN4 alkoxyamine, mercapto, Cm amine Carbonyl group, C _4 alkylthio group, c3_6 cycloalkyl group, C3_6 cycloalkenyl group, amine group, imino group, Cm aminosulfonyl group, Cw aminocarbonyloxy group, Cw alkylsulfonylamino group, C, _4 alkoxyimino, Cw alkylcarbonylamino, Ci.4 alkylsulfonyl, CN6 heteroaryl, Cw heterocycloalkyl or C2-6 heterocycloalkenyl, wherein the last 27 groups are The condition is further selected by one or more, the same or different ones selected from the group consisting of the following groups Substituent substitution: halogen, hydroxy, -NH2, fluorenyl, trifluoromethyl, cyano, carboxy, CONH2, nitro, keto, -S(0)2NH2, C, _4 alkyl or Cm hydroxyalkyl; R3 represents a hydrogen, a hydroxyl group or a carboxyl group. 3. A compound according to claim 1 or 2, wherein R4, R5, R6, R7 and R8 independently of each other represent hydrogen, a hydroxyl group, a mercapto group, a trimethyl group, a decyloxy group, Ethoxy 106609-1010511.doc 1379829, thiol or ethyl 4. The compound of claim 1 or 2 wherein &amp;, Re and I independently of each other represent hydrogen, halogen, -NH2, hydroxy, trifluoromethyl a methoxy group, an ethoxy group, a cyano group, an ethyl fluorenyl group, an acetamino group, a fluorenyl group or an ethyl group, and which means that the heart and the hydrazine independently represent hydrogen 'halogen, hydroxy, trifluoromethyl, A An oxy group, an ethoxy group, a cyano group, an ethyl fluorenyl group, an acetamino group, a methyl group or an ethyl group. 5. The compound of claim 1 or 2, wherein I, Rs, R6, R7 &amp; r8 are independently of each other Argon, fluorine or gas 6. The compound of claim 1 or 2, wherein at least three of &amp;, Rs ' R6, r74r8 represent hydrogen. 7. The compound of claim 1 or 2, wherein Rs, R? And R8 Hydrogen, or wherein R5, R6, uldent 7 and Rs represent hydrogen, or wherein R4, R5, uldent 7 and uldentum 8 represent hydrogen. 8. The compound of claim 1 or 2, wherein &amp;, ruler 7 and ruler 8 , or r6, ruler 7 and Rs, or R4, R6, ruler 7 and R8, or ruler 4, feet 6 and 118, or R4, 116 and 117 represent hydrogen. 9. A compound according to claim 1 or 2, wherein R , is a methyl group and the ruler 2 is gas. The compound of claim 1 or 2, wherein R3 represents a CN4 alkyl group, a C2_4 alkenyl group or a Cw hydroxyalkyl group, each of which is optionally selected from the group consisting of one or more of the following groups, the same Or a different substituent substitution: halogen, hydroxy, thiol, -NH2, carboxy, CONH2, nitro, keto, -S(0)2NH2, CU2 hydroxyalkyl, Cw alkoxy, Ci.2 alkoxycarbonyl , Cw urea group, Ci.2 thiourea group, CN2 alkylcarbonyloxy group, Cw alkoxycarbonyloxy group, Cu alkoxysulfonyloxy 'Cw alkoxyamine methyl sulfonyl group, C, _2 amine Carbonyl group, C, _2 alkylthio group 'CN2 amine group, Cm imine group, Cu amine sulfonyl group, Cw 106609-1010511.doc -4- 1379829 Amino methoxy group, c, · group (four) wire , Ci 2 -based residue, c, 2 alkyldethione, c, 2 alkylsulfonyl, c 2 5 heteroaryl, c 2 5 heterocycloalkyl or C3-5 heterocycloalkenyl, - the last 22 bases are optionally substituted with a group selected from groups I or more, the same or different substituents consisting of: a base group, a-2, a carboxyl group, a C0Nh2, a ketone group or a C|3 . 11. The compound of claim 2 or 2, wherein R3 represents Ci.3, C23 or 匸, 3 hydroxyalkyl, each of which is optionally selected from the group consisting of the following groups or Substituted by multiple, identical or different substituents: hydroxy, cis, 2, carboxy, chloro, CONH.2, keto, _s(〇)2NH2, c 2 alkyl, C, 2 alkoxy, Cw Alkoxycarbonyl, Cq 2 ureido, Ci 2 aminocarbonyl, C!-2 amine, Cw alkylsulfonylamino, (^^heterocycloalkyl, wherein the last 8 groups are further selected from One or more, the same or different substituents of the group consisting of hydroxy 4C12 alkyl groups are substituted. 12. The compound of claim 1 or 2, wherein the rule 3 represents a methyl, ethyl, propyl, propenyl group wherein all of the groups are selected from one, two, three or selected from the group consisting of the following groups: Substitution of four, identical or different substituents: transradical, CONH2, keto, diethylamino, ethylaminocarbonyl, decyl, hydroxymethyl, pyrrolidinyl, morpholinyl, gas, H2N- C(0)-NH-, methoxycarbonyl, decyloxy, -NH2, ethoxycarbonyl, ethoxy, methylsulfonylamino, -S(0)2NH2, tetrahydropyranyl, [I, 3]-dioxolanyl, ethylamino, piperazinyl, the last four groups being optionally selected from one, two, three or four, the same or a group consisting of methyl or ethyl Substituted by different substituents. The compound of claim 1 or 2, wherein R3 is 2-hydroxyethyl, 3-hydroxypropyl, amine-mercaptomethyl, 2,3-dihydroxypropyl, 2· (Methylsulfonylamino)ethyl, continuary aminopropyl, 2,2,didecyl-[1,3]dioxolan-4-ylmethyl, 2-(tetrahydro-··peri Ethyl-2-yloxy)ethyl, 3-(tetrahydro-pyran-2-yloxy)-propyl, ethoxycarbonylmethyl, carboxymethyl, ethylaminocarbonylcarbonyl (2-hydroxy-1,1·dimethyl-ethyl)aminomethyl, 1·n, piroxime, 1 yl, 1-morpholin-4-yl-ethanone, 2-oxyethyl , 1-hydroxy-1-indolyl-ethyl, ethyl hydrazino, 1-amino-1-methyl-ethyl, oxime carbonyl, thiol, methyl, 3-cysyl-propyl, 2 -Amino-ethyl, decyl gland, 2-norphin-4-yl-ethyl, (4. quinone azine oxazide) ethyl <2-diethylamino}ethyl, 2 ( 2. Hydroxy-ethylamino)-ethyl, propylaminoethyl or diethylamine. 14 'A compound of claim 1 or 2 which is of the formula Ia. 15. A compound according to claim 1 or 2 which is of a general formula. 16. The compound of claim 1 or 2 which is selected from the group consisting of: [2-chloro-4-(2,4-difluoro-phenylamino)-phenyl]-(2_ Methyl_5_^_[2-(tetrahydro-pyran-2-ylindenyl)-ethyl]-11^[1,2,3]triazol-4-ylphenyl)-methanone 101), [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[1-(2-hydroxy-ethyl)-1Η-[1,2, 3] Dipyridyl-4-yl]-2-methyl-phenyl}-methyl-(compound 102), [2-chloro-4-(2,4-difluoro-phenylamino)-phenyl] _(2-Methyl_5_(1_[3-(tetrahydro-pyran-2-yloxy)-propyl]-1Η-[1,2,3]triazole-4-yl}•phenyl )-曱_(Compound 103), [2-Chloro-4·(2,4-difluoro-phenylamino)-phenyl; Hydroxy-Pro-I06609-1010511.doc -6-yl)·1Η-[ 1,2,3]triazol-4-yl]-2-indolyl-phenyl}•anthrone (Compound 104), [2-Ga-4-(2,4-difluoro-phenylamino) -phenyl]-{5-[l-(2,2-dimercapto-[1,3]dioxolan-4-ylmethyl)-lH-[l,2,3]triazole-4 -yl]-2-methyl-phenyl}-fluorenone (compound 105), U-gas-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[1- (2,3-dihydroxy-propyl)-111-[1,2,3]tris(4-yl)-2-indolyl- }--anthone (Compound 106), 2-(4-{3-[2-Ga-4-(2,4-difluoro-phenylamino)-benzylidene]-4-indenyl- Phenyl}-[1,2,3]triazol-1-yl)-ethanoamine (Compound 1〇7), 3- (4-{3-[2-Ga-4-(2,4-II) Fluoro-phenylamino)-benzylidenyl]-4-methyl-phenyl}-[1,2,3]triazol-1-yl)-propan-1-sulfonamide (Compound 108), 1^-[2-(4-{3-[2-chloro-4-(2,4-difluoro-phenylamino)-benzylidene]-4-indolyl-phenyl}-[1 ,2,3]triazol-1-yl)-ethyl]-nonylsulfonamide (Compound 109), (4-{3-[2-Ga-4-(2,4-difluoro-phenylamine) ))-benzylidenyl]-4-methyl-benyl}-[1,2,3]triter-1-yl)-acetic acid ethyl ke (compound 11 〇), (4-{3-[ 2-Chloro-4-(2,4-difluoro-phenylamino)-phenylindenyl]-4-methyl-phenyl}-[1,2,3]triazol-1-yl)- Acetic acid (compound 111), 2-(4-{3-[2-gas-4-(2,4-difluoro-phenylamino)-benzoquinone]-4-indolyl-phenyl}- [1,2,3]triazol-1-yl)-N-ethyl-acetamide (Compound 112), 2-(4-{3-[2-Ga-4-(2,4-difluoro) -phenylamino)-benzolic]-4-methyl-phenyl}-[1,2,3]triazol-1-yl)-N-(2-hydroxy-1,1-diindole Base-ethyl)_ B Indoleamine (Compound 113), 106609-I010511.doc 2-(4-{3-[2-Ga-4-(2,4-difluoro-phenylamino)-phenylindenyl]_4_fluorenyl -phenyl}-[1,2,3]triazol-1-yl)-1-pyrrolidin-bupropion-ethanone (Compound 114), 2-(4-{3-[2-Chloro-4- (2,4-Difluoro-phenylamino)-benzylidenyl]-4-methyl-phenyl}-[1,2,3]triazol-1-yl)-1-morpholine-4 -yl-ethanone (Compound 115), [2-Ga-4-(4-Trifluoromethyl-phenylamino)-phenyl]-{5-[4-(2-hydroxy-ethyl)-[ 1,2,3]triazol-1-yl]-2-methyl-phenyl}-fluorenone (Compound 116), (2-Ga-4-o-indolylphenylamino)phenyl)-{ 5-[4-(2-Hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-anthone (Compound 117) ' [2-Gas- 4-(2-Ga-4-fluoro-phenylamino)-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl] -2-methyl-phenyl}-methanone (compound 118), [2-chloro-4-(2,4-difluoro-phenylamino)-phenyl]-(2-methoxy-5 -{l-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-[1,2,3]triazole-'yl}-phenyl)-methanone (Compound 119 ), [2-Ga-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[1-(2-hydroxy-hexyl) -1Η-[1,2,3]triazol-4-yl]-2-methoxy-phenyl}-fluorenone (Compound 120), [2·Ga-4-(4-fluoro-phenylamine) -phenyl]-(2-methyl-5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-[1,2,3]triazole 4-yl}-phenyl)-methanone (Compound 121), [2-Ga-4-(4-fluoro-phenylamino)-phenyl]-{5-[1-(2-hydroxy- Ethyl)-111-[1,2,3]triazol-4-yl]-2-methyl-phenyl}-methanone (Compound 122), 106609-1010511 .doc [2-Ga-4-( 4-氤·Phenylamino)·phenyl]-{5-[l-(2,2-dimethyl-[1,3]dioxolan-4-ylindenyl)-1Η-[1 , 2,3]triazol-4-yl]-2-methyl-phenyl}-formamidine (Compound 123), [2-Chloro-4-(4-fluoro-phenylamino)-phenyl] -{5-[1-(2,3-dihydroxy-propyl)·1Η-[1,2,3]triazol-4-yl]-2-methyl-phenylphenone (Compound 124) , 2-(4-{3-[2-Ga-4-(4-fluoro-phenylamino)-benzylidenyl]-4-mercapto-phenyl}-[1,2,3]III Zin-1-yl)-acetamide (Compound 125), [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[ 1-(2-gas -ethyl)-1Η-[1,2,3]triazol-4-yl]-2·indolyl-styl}-anthone (Compound 126), [2-Ga-4-(4-Fluorine) Amino))phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-methanone (Compound 127), [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl;)_{5·[4-(2-hydroxy-ethyl)-[1,2 , 3] triazol-1-yl]-2-mercapto-phenyl}-fluorenone (Compound 128), [2-Chloro-4-(2,4-difluoro-phenylaminophenyl)_ {5_[4-(1-Hydroxy-1·methyl-ethyl)-[1,2,3]disindol-1-yl]_2-methylphenyl}-carboxamidine (Compound 129), 1 -(1-{3-[2-Ga-4-(2,4-difluoro-phenylamino)-benzylidenyl]-4-indolyl-phenyl}-111-[1,2, 3] Triazol-4-yl)-ethanone (Compound 130), {5-[4-(1-Amino-1-methyl-ethyl)_[i,2,3]triazole-1_ 2-methyl-phenyl}-[2- gas-4-(2,4-difluoro-phenylamino)-phenyl]-anthone (Compound 131), 1-{3-[ 2-Chloro-4-(2,4-difluoro-phenylamino)·Athranyl]-4·Methyl-I06609-I0105ll.doc •9- 1379829 Phenyl}-1Η-[1,2, 3] Triazole-4-carboxylic acid oxime ester (Compound 132), 1-{3-[2-chloro-4-(2,4-difluoro-phenylamino)-benzoinyl]-4- Mercapto-phenyl}-1Η-[1,2,3]triazole-4-carboxylic acid (compound 133), [2- gas-4-(2,4-difluoro) -phenylamino)-phenyl]-[5-(4-hydroxymethyl-[1,2,3]triazol-1-yl)-2-indolyl-phenyl]-methanone (Compound 134 ) '[2-Ga-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[4-(3-hydroxy-propenyl)-[1,2,3] Zin-1-yl]-2-indolyl-phenyl}-methanone (Compound 135), {5-[4-(2-Amino-ethyl)-[1,2,3]triazole-1 -yl], 2-methyl-phenyl}-[2-chloro-4-(2,4-difluoro-phenylamino)-phenyl]-methanone (Compound 136), (1-{3 -[2-chloro-4-(2,4-difluoro-phenylamino)-benzylidenyl]-4-methyl-phenyl}-1Η-[1,2,3]triazole-4 -carbyl)-urea (compound 137), [2- gas-4-(2,4-difluoro-phenylamino)-phenyl]-{2-methyl-5-[4-(2 -morpholin-4-yl-ethyl)-[1,2,3]triazol-1-yl]-phenyl}-fluorenone (Compound 138), [2-Ga-4-(2,4- Difluoro-phenylamino)-phenyl]-(2-methyl-5-{4_[2-(4-methyl-piperazin-1-yl)-ethyl]-[1,2,3 Triazol-1-yl}-phenyl)-methanone (compound 139), [2- gas-4-(2,4-difluoro-phenylamino)-phenyl]-{5-[4 -(2-diethylamino-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-fluorenone (Compound 140), [2-Chloro- 4-(2,4-difluoro-benzene Amino)-phenyl]-(5-{4-[2-(2-trans)ethylamino)-ethyl]-[1,2,3]triazol-1-yl}-2- Mercapto-phenyl)-methanone (compound 141), 106609-1010511.doc -10- 1379829 [2-chloro-4-(2,4-difluoro-phenylamino)-phenyl]-{2 - mercapto- 5-[4-(2-propylamino)ethyl]-[1,2,3]triazol-1-yl]-phenyl}-methanone (Compound 142), [2 - Chloro-4-(4- gas-2-methyl-phenylamino)-phenyl]-{5-[4-(2-trans-ethyl-ethyl)-[1,2,3]triazole- 1-yl]-2-fluorenyl-phenyl}-methanone (compound 143), [2-chloro-4-(2-decyloxy-phenylamino)-phenyl]-{5-[4 -(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-indolyl-phenyl}-fluorenone (Compound 144), [2-Chloro-4-(4 -Gas-2-methyl-phenylamino)-phenyl]-{5-[4-(2-hydroxy-•ethyl)-[1,2,3]triazole-buyl]-2- Methyl-phenyl}-fluorenone (Compound 145), [2-Chloro-4-(4-methoxy-phenylamino)-phenyl]-{5-[4-(2-hydroxy-B ))-[1,2,3]triazol-1-yl]-2-methyl-phenyl ketone (Compound 146), [2-Ga-4-(2,4-difluoro-phenyl) Amino)-phenyl]-{5-[4-(2-ethylamino-ethyl)-[1,2,3]triazol-1-yl]-2-indolyl-phenyl }-methanone (compound 147), [4-(2,4-di-Is-phenylamino)-2-indolyl-phenyl]-{5-[4-(2-yl-ethyl) -[1,2,3]triazol-1-yl]-2-indolyl-phenyl}-methanone (compound 148), [4-(3-chloro-4-say-phenylamino)- 2-indenyl-phenyl]-{5-[4.(2-carbyl-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}- Methyl ketone (compound 149), {5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-mercapto-phenyl}-(2-A 4-phenylamino-phenyl)-methanone (compound 150), 1-[3-(4-{5-[4-(2-hydroxy-ethyl)-[1,2,3] Triazol-1-yl]-2-mercapto-azinocarbazyl}-3-methyl-phenylamino)-phenyl]-ethanone (Compound 151), 3_(4-{5-[4 -(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenylhydrazino}-3-mercapto-phenylamino)-benzoquinone (Compound 152), {5-[4-(2-Hydroxy-ethyl)-[1,2,3]triazol-1-yl]_2-fluorenyl-benzene 106609-1010511.doc -11 - 1379829 }-[2-Mercapto-4-(3-tridecyl-phenylamino)-phenyl]-fluorenone (Compound 153), [4-(3,4-Difluoro-phenylamino) )-2-mercapto-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2 -methyl-phenyl}-fluorenone (compound 154), [4-(3,4-dimercapto-p-stylamino)-2-indolyl-styl]-{5-[4-(2 -hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-mercapto-phenyl}-fluorenone (Compound 155), [4-(3-Ga-2-methyl) -phenylamino)-2-methyl-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triin-1-yl]-2-methyl -phenyl}-fluorenone (compound 156), [4-(3,4-di-phenylamino)-2-methyl-phenyl]-{5-[4-(2-hydroxy-B Base)-[1,2,3]triazol-1-yl]-2-methyl-phenyl}-methanone (compound 157), Ν-[3·(4·{5-[4-(2 -hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-methyl-benzimidyl}-3-mercapto-phenylamino)-phenyl]-acetamidine Amine (Compound 158), [2-Chloro-4-(2,4-dioxa-phenylamino)-phenyl]-{2-Ga-5-[4-(2-Ph-ethyl) -[1,2,3]triazol-1-yl]-phenyl}-methanone (compound 159), [2-chloro-4-(3-fluoro-phenylamino)-phenyl]-{ 5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-indolyl-styl}-anthone (Compound 160), [2-Chloro- 4-(3-Chloro-phenylamino)-phenyl]-{5-[4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-yl Base-phenyl}-methanone Compound 161), (2-Chloro-n-phenylphenylamino-phenyl)-{5-[4.(2-hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2 -methyl-phenyl}-methanone (compound 162), [2-chloro-4-(3-indolyl-phenylamino)-phenyl]-{5-[4-(2-yl) -ethyl)-[1,2,3]triazol-1-yl]-2-methyl-phenylindolone (Compound 163), [2-Chloro-4-(2,3-dichloro- Phenylamino)-phenyl]-{5-[4-(2-hydroxy-ethyl 106609-1010511.doc • 12. 17. 18. s pharmaceutical composition comprising as claimed in claims 1-16 a compound s, a pharmaceutically acceptable salt, and a pharmaceutically acceptable vehicle 19. 20. 21. 22.) D, 2'3] diazole-1·yl l·2-methyl -phenyl}-methanone (compound 164), [qi-heart (3,5·dimethyl-phenylamino)-phenyl]_{5_[4_(2·hydroxy-yl)[1'2 , 3] trisporinyl]-2-methyl-phenyl}-methanone (compound 165), sense [2 gas-4·(25 5difluorophenylamino)phenyl]_{5_[ 4_(2·基基乙土) D'2'3]diazole·1-yl]-2-methyl-phenyl}-methanone (compound 166) and base j2 gas·4_(3,5·2 Fluorophenylamino)-phenyl]-{5-[4-(2-carbamic-ethyl[1'2'3]diazole_1-yl]-2- Yl - phenyl} - Yue-one (Compound 167). The composition of claim 17 which further comprises another active ingredient selected from the group consisting of glucocorticoids, vitamin D analogs, anti-, and amine amines, platelet activating factor (PAF) antagonists, and anti- Choline, methyl yellow 7, beta-adregenic agent, c〇X_2 inhibitor, salicylate, indomethacin, flufenamate, naphthalene Napr〇xen, timegadine, gold salt, penicillamine, serum cholesterol lowering agent, retinoid, zinc salt and saUcylaz〇sulfapyridin. A compound of claim 1 or 2 which is used as a medicament. A compound according to claim 1 or 2 which is for use as an anti-inflammatory or anti-cancer agent. Use of a compound according to any one of claims 16 to manufacture a medicament for the treatment or amelioration of an inflammatory disease or condition or an ophthalmic disease or condition. A use of a compound according to any one of claims 16 to manufacture a medicament for the treatment or amelioration of cancer. The use of claim 21, wherein the drug is co-administered with another active ingredient selected from the group consisting of glucocorticoids, vitamin D analogs, antihistamines. , platelet activating factor (PAF) antagonist, anti-cholinergic agent, methylxanthine, β-adrenergic, COX-2 inhibitor, salicylate, indomethacin, flufenate, naphthalene Pusheng, tiramidine, gold salt, penicillamine, serum cholesterol lowering agent, retinoid 'salt salt and lysine azodiamine pyridine. 24 'If the use of claim 2 1 or 23, wherein the inflammatory disease or condition is asthma, allergy, arthritis, With inflammatory skin disorders, porcine mesangitis, sepsis, loss. For example, the speed of request 2T, its 'gout, atherosclerosis, chronic inflammatory bowel disease' Crohn's disease, nerve Sexual inflammation, inflammatory eye disease, proliferative psoriasis, atopic dermatitis, hemorrhoids, septic shock or acne 'osteoporosis. * . . · Age-related macular degeneration. The ophthalmic disease is acute macular degeneration or 106609-1010511.doc 14-