HK1090350B - Novel aminobenzophenone compounds - Google Patents

Description

Novel aminobenzophenone compounds

Technical Field

The present invention relates to a novel class of aminobenzophenones and to their use in therapy.

Background

Aminobenzophenones are well known from the scientific and patent literature. Thus, WO98/32730, WO01/05746, WO01/05749, WO01/05751, WO01/05744 and WO01/05745 all disclose compounds having the following common core structure

Wherein the phenyl ring C is substituted with an amine derivative. Further, WO01/42189 and WO02/076447 disclose compounds having a similar structure but having no nitrogen substituent in the phenyl ring C. Finally, WO01/90074 and WO02/083622 disclose compounds in which the phenyl rings A and C are each replaced by a heterocyclic ring. The compounds disclosed in these patent applications appear to be inhibitors of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) secretion in vitro, which makes the compounds potentially useful for the treatment of inflammatory diseases in which cytokine production is implicated in the pathogenesis. Aminobenzophenones claimed to exert their effect by inhibiting p38MAP kinase and thus the production of IL-1. beta. and TNF-. alpha.s.

The preparation of structurally related aminobenzophenones useful as textile dyes is disclosed in Man-madetext. india (1987), 30(6), 275-6; Man-Madetext. India (1986), 29(5), 224-30 and Man-Madetext. India (1985), 28(11), 425, 427-9, 431.

Summary of The Invention

It has been surprisingly found that novel aminobenzophenone derivatives are potent inhibitors of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) secretion in vitro and in vivo, suggesting their utility in the treatment and/or prevention of inflammatory diseases and other conditions in which the secretion and modulation of pro-inflammatory cytokines are implicated in pathogenesis.

It has been found that aminobenzophenone derivatives of the present invention exert their anti-inflammatory effects by inhibiting or down-regulating MAP kinases, more specifically p38MAP kinase, a stress-activated protein which is an important building block of the signal transduction pathway leading to the production of pro-inflammatory cytokines.

The aminobenzophenone derivatives of the present invention are further useful for the treatment of cancer or ophthalmic diseases or disorders.

Accordingly, the present invention relates to compounds of formula I or a pharmaceutically acceptable salt, solvate or ester thereof,

wherein:

R₁is halogen, hydroxy, mercapto, trifluoromethyl, amino, C _1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-6Alkylamino radical, C_1-4Alkoxycarbonyl, cyano, -CONH₂Or a nitro group;

R₂is hydrogen, halogen, hydroxyl, sulfydryl, trifluoromethyl, amino, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-6Alkylamino radical, C_1-4Alkoxycarbonyl, cyano, -CONH₂Phenyl or nitro;

R₃represents one or more identical or different substituents selected from hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy, CONH₂Nitro group, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, alkynyl,C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4An alkoxycarbonyl group;

R₄is hydrogen, halogen, nitro, R₈Or Y₁R₈；

Y₁is-O, -S-, -S (O)₂-、-NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-C(O)NR_aO-、-C(O)-、-C(O)O-、-NR_aC(O)O-、-S(O)₂NR_a-、-NR_aS(O)₂-；

R_a、R_bAnd R_cThe same or different, each represents hydrogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Carbocyclyl, C_1-12Heterocyclyl or aryl radicals, each C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Carbocyclyl, C_1-12The heterocyclic or aryl group being optionally substituted by one or more R₇The same or different substituents represented by;

R₈is hydrogen, C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12Carbocyclyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclic radical or C_1-12Heterocyclyl radical, each C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12Carbocyclyl, C _1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclic radical or C_1-12The heterocyclic group is optionally substituted by one or more R₇The same or different substituents represented by;

R₇is halogen, hydroxy, mercapto, trifluoromethyl, amino, C_1-4Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-6Alkylamino radical, C_1-4Alkoxycarbonyl, C bound to an anion_1-9Trialkyl(s)Alkylammonium, cyano, azido, nitro, -S (O)₂NH₂、-S(O)₂NR_aR_b、-S(O)₂R、-COOH、-CONH₂、-NR_aC (O) R ', -CONHR' or-CONRR ', wherein R and R', which may be the same or different, each represent hydrogen or C_1-3An alkyl group;

R₅and R₆One of which is-COOH, -C (O) NHOH, -C (O) NHNH₂、Y₂R₉、Y₂R₉Y₃R₁₀、C_1-6alkyl-Y₂R₉、C_1-6alkyl-Y₂R₉Y₃R₁₀、C_2-6alkenyl-Y₂R₉、C_2-6alkenyl-Y₂R₉Y₃R₁₀、Y₂R₉-C_1-6-alkyl-Y₃R₁₀、Y₂R₉-C_2-6-alkenyl-Y₃R₁₀、C_3-12carbocyclyl-Y₂R₉、C_3-12carbocyclyl-Y₂R₉Y₃R₁₀、C_1-12heterocyclyl-Y₂R₉、C_1-12heterocyclyl-Y₂R₉Y₃R₁₀、C_3-12carbocyclyl-C_1-6-alkyl-Y₂R₉、C_3-12carbocyclyl-C_1-6-alkyl-Y₂R₉Y₃R₁₀、C_1-12heterocyclyl-C_1-6-alkyl-Y₂R₉、C_1-12heterocyclyl-C_1-6-alkyl-Y₂R₉Y₃R₁₀、C_3-12carbocyclyl-C_1-6-alkyl-Y₃R₁₀、C_1-12heterocyclyl-C_1-6-alkyl-Y₃R₁₀、C_1-12heterocyclyl-C_1-10Alkyl radical, C_3-12carbocyclyl-C_1-10Alkyl radical, C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12Carbocyclyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclic groupOr C_1-12Heterocyclyl, each optionally substituted with one or more R₇The same or different substituents are substituted and the other is hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, C _1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-6Alkylamino radical, C_1-4Alkoxycarbonyl, cyano, -CONH₂Or a nitro group, or a mixture of nitro groups,

provided that when R is₅Or R₆Is phenyl, C_1-5Alkyl or C_2-3When an alkenyl group, the R₅Or R₆By one or more of R₇The same or different substituents of the formula (when R is₅Or R₆With the exception of three fluorine atoms when it is methyl), or by Y₁R₈The substitution is carried out by the following steps,

with the further proviso that when R₅Or R₆When it is-COOH, Y₁Can not be-NR_a-、-NR_aC(O)NR_b-、-NR_aC (O) -or-NR_aC (O) O-, and R₃Or R₄Can not be a nitro group, and can not be a nitro group,

with the further proviso that when R₂When it is hydrogen, R₅Or R₆One of which is not hydrogen or optionally substituted (C)₃-C₁₈Heterocyclic group, C_1-7Alkyl radical, C_2-7Alkenyl radical, C_2-7Alkynyl or C_1-7Alkoxy groups);

Y₂is-O-, -S (O)₂-、-NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-C(O)NR_aO-、-C(O)-、-NR_aC(O)O-、-NR_aS(O)₂-、-OC(O)-、-C(O)O-、-C(O)NR_aNR_bC(S)NR_c-、-C(O)NR_aNR_b-or-S (O)₂NR_a-；

R₉Is C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12A carbocyclic group,C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclyl, C_1-12Heterocyclic group, C_3-12carbocyclyl-C_1-10Alkyl or C_1-12heterocyclyl-C_1-10Alkyl radical, C_3-6carbocyclyl-C_1-6Alkenyl radical, C_3-6carbocyclyl-C_2-6Alkynyl, each optionally substituted by one or more R₇The same or different substituents are represented,

provided that when Y is₂is-O-, -NR_a-, -S-or-C (O) O-, and R₉Is C_1-6When alkyl, said C_1-6Alkyl being substituted by one or more radicals R₇Are identical or different substituents of the formula, or by Y ₃R₁₀Substitution;

Y₃is-O-, -S (O)₂-、-NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-C(O)NR_aO-、-C(O)-、-NR_aC(O)O-、-NR_aS(O)₂-, -OC (O) -or-C (O) O-;

R₁₀is C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12Carbocyclyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclic radical or C_1-12Heterocyclyl, each optionally substituted with one or more R₇The same or different substituents represented by;

or when R is₅Or R₆One of which is a group-C (O) NR_aR₉When R is_aAnd R₉Together with the nitrogen atom to which they are attached form C_1-12Heterocyclic ring, optionally containing one or more further heteroatoms selected from O, S and N, optionally substituted with one or more R₇The substituents indicated.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate or ester thereof, and a pharmaceutically acceptable excipient or vehicle (vehicle).

In a further aspect, the present invention relates to a method of preventing, treating or ameliorating an inflammatory disease or disorder or an ocular disease or disorder, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I.

In a further aspect, the present invention relates to a method of treating or ameliorating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I.

In a further aspect, the invention relates to the use of a compound of formula I in the manufacture of a medicament for the prevention, treatment or amelioration of an inflammatory disease or disorder or an ocular disease or disorder.

In a further aspect, the invention relates to the use of a compound of formula I in the manufacture of a medicament for the treatment or amelioration of cancer.

In yet another aspect, the present invention is directed to a process for preparing a compound of general structure I,

wherein R is₁、R₂、R₃、R₄、R₅And R₆Are as defined above, comprising the steps of:

a) converting a compound of general structure VI to an organometallic intermediate,

wherein Hal is halogen, and R₁、R₅And R₆Each independently protected or unprotected, as defined above;

b) converting the organometallic intermediate to an organozinc intermediate;

c) coupling the organozinc intermediate with an acyl halide of general structure V in the presence of a catalyst,

wherein R is₂As defined above, protected or unprotected,

to give compounds of general structure IV

Wherein R is₁、R₂、R₅And R₆Each independently protected or unprotected, as defined above;

d) optionally converting, protecting or deprotecting R of a compound of general structure IV₁、R₂、R₅And R₆To another compound of general structure IV;

e) reducing the compound of general structure IV from step c) or d) to an amine of general structure III,

wherein R is₁、R₂、R₅And R₆Each independently protected or unprotected, as defined above;

f) optionally converting, protecting or deprotecting R of a compound of general structure III ₁、R₂、R₅And R₆To give another compound of general structure III;

g) coupling the amine of general structure III from step e) or f) with a compound of general structure II,

wherein L is trifluoromethanesulfonate or halogen, R₃And R₄As defined above, each independently protected or unprotected,

to give a compound of the general structure I wherein R₁、R₂、R₃、R₄、R₅And R₆Each independently protected or unprotected, as defined above;

h) optionally converting, protecting or deprotecting R of a compound of general structure I obtained in step g)₁、R₂、R₃、R₄、R₅Or R₆To give another compound of general structure I.

In yet another aspect, the present invention is directed to a process for preparing a compound of general structure I,

wherein R is₁、R₂、R₃、R₄、R₅And R₆As defined above, it comprises the following steps:

a) converting a compound of general structure VIIa to an organometallic intermediate,

wherein Hal is halogen, W is halogen or triflate, and R₂Protected or unprotected, as defined above;

b) converting the organometallic intermediate to an organozinc intermediate;

c) coupling the organozinc intermediate with an acyl halide of general structure VIII in the presence of a catalyst,

wherein R is ₁、R₅And R₆Each independently protected or unprotected, as defined above, to give compounds of general structure IIIa,

w, R therein₁、R₂、R₅And R₆Each independently protected or unprotected, as defined above;

d) w, R for optional transformation, protection or deprotection of a compound of general structure IIIa₁、R₂、R₅And R₆To give another compound of general structure IIIa;

e) coupling the compound of general structure IIIa from step c) or d) with an amine of general structure IIa,

wherein R is₃And R₄As defined above, each independently protected or unprotected,

to give a compound of the general structure I wherein R₁、R₂、R₃、R₄、R₅And R₆Each independently protected or unprotected, as defined above;

f) optionally converting, protecting or deprotecting R of a compound of general structure I obtained in step e)₁、R₂、R₃、R₄、R₅Or R₆To give another compound of general structure I.

Detailed Description

Definition of

In this context, the term "alkyl" is intended to mean a monovalent group derived from a straight or branched chain alkane by removing one hydrogen atom from any carbon atom. The alkyl chain typically contains 1 to 10 carbon atoms, especially 1 to 6 carbon atoms. The term includes the subgroups n-alkyl (n-alkyl), secondary alkyl and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

The term "alkoxy" is intended to denote a group of formula OR ', wherein R' is alkyl as defined above, e.g. methoxy, ethoxy, propoxy, butoxy and the like.

The term "hydroxyalkyl" is intended to denote an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxyl group.

The term "alkenyl" is intended to denote a mono-, di-, tri-, tetra-or pentaunsaturated hydrocarbon group, typically containing 2 to 10 carbon atoms, in particular 2 to 6 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl or hexenyl.

The term "alkynyl" is intended to denote a hydrocarbon radical comprising 1 to 5 triple C-C bonds, the alkynyl chain usually comprising 2 to 10 carbon atoms, in particular 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl.

The term "alkoxycarbonyl" is intended to denote a group of formula-COOR ', wherein R' is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, and the like.

The term "aryl" is intended to include carbocyclic aromatic ring groups, particularly 5-or 6-membered rings, optionally fused bicyclic rings, such as phenyl or naphthyl.

The term "heteroaryl" is intended to include heterocyclic aromatic ring groups, in particular 5-or 6-membered rings having 1 to 4 heteroatoms selected from O, S and N, or optionally fused bicyclic rings having 1 to 4 heteroatoms, such as pyridyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolyl, benzimidazolyl and benzofuranyl.

The term "carbocyclyl" includes saturated and unsaturated, optionally fused, bicyclic hydrocarbon rings, typically containing 3 to 12 carbon atoms, especially 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl; or C_3-12Cycloalkenyl radicals, such as cyclopropyl-2-enyl, cyclobutyl-2-enyl, cyclopentyl-2-enyl, cyclohex-3-enyl, cyclooct-4-enyl, cyclohex-3, 5-dienyl, indanyl, indenyl, 1, 4-dihydronaphthyl, phenyl and naphthyl. The term "carbocyclyl" also includes cyclic hydrocarbons in which one or more rings-CH₂The fragment having been substituted by a-C (O) -fragment and/or an exocyclic carbon-carbon double bond, such as oxocyclohexyl, oxocyclopentyl, 4-oxo-1, 2, 3, 4-tetrahydronaphthalen-1-yl, 1-oxo-1, 2, 3, 4-tetrahydronaphthalen-1-yl, 2-oxocyclohex-3-en-1-yl and 2-oxocyclohex-1-en-1-yl, and

the term "heterocyclyl" is intended to denote a saturated or unsaturated, optionally fused, carbocyclic ring comprising 1 to 12 carbon atoms, such as 1 to 12 carbon atoms, in particular 1 to 8 carbon atoms, and comprising one or more heteroatoms selected from O, N and S, such as tetrazolyl, triazolyl, pyrrolyl, furyl, morpholyl, piperazinyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, tetrahydrothienyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, putinyl, morpholinyl, furyl, dioxolanyl, thienyl, quinolinyl, isoquinolinyl, 1, 2-dihydroquinolinyl and the like. Thus, the term "heterocyclyl" includes "heteroaryl" as defined above, and also includes wherein one or more rings-CH ₂Heterocyclic radicals in which the fragment has been substituted by a-C (O) -fragment and/or an exocyclic carbon-carbon double bond, such as dioxopiperidinyl, dioxoimidazolidine, dioxohexahydropyrimidine, oxopyrrolidine, 1-oxo-3, 4-dihydroisoquinolin-2 (1H) -yl and

the term "alkylthio" is intended to denote a group of formula-SR, wherein R is alkyl as defined above, e.g. C_1-10Alkylthio radical, C_1-4Alkylthio, methylthio, ethylthio, n-propylthio, 2-propylthio and the like.

The term "alkylamino" is intended to denote a group of formula-NHR or-NR₂Groups wherein R is alkyl as defined above and include, for example, methylamino, dimethylamino, di- (n-propyl) amino, n-butyl (ethyl) amino, and the like.

The term "halogen" is intended to denote fluorine, chlorine, bromine or iodine.

The term "pharmaceutically acceptable salts" is intended to denote salts prepared by reacting a compound of formula I with a suitable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 2-dichloroacetic acid, adipic acid, ascorbic acid, L-aspartic acid, L-glutamic acid, galactaric acid, 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, malonic acid, tartaric acid, benzenesulfonic acid, ethane-1, 2-disulfonic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfamic acid or fumaric acid. Pharmaceutically acceptable salts of the compounds of formula I may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, ammonia, or a suitable non-toxic amine such as a lower alkylamine, for example triethylamine, a hydroxy-lower alkylamine, for example 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine, a cycloalkylamine, for example dicyclohexylamine, or a benzylamine, for example N, N' -dibenzylethylenediamine and dibenzylamine, or L-arginine or L-lysine.

The term "solvate" is intended to mean a species formed by the interaction between a compound, for example a compound of formula I, and a solvent, for example an alcohol, glycerol or water, wherein the species is in solid form. When water is the solvent, this species is called a hydrate.

The term "pharmaceutically acceptable esters" is intended to denote readily hydrolysable esters, such as alkanoyloxyalkyl, aralkyloxyalkyl, aroyloxyalkyl, e.g. acetoxymethyl, pivaloyloxymethyl, benzoyloxymethyl esters and the corresponding 1 '-oxyethyl derivatives, or alkoxycarbonyloxyalkyl esters, e.g. methoxycarbonyloxymethyl esters and ethoxycarbonyloxymethyl esters and the corresponding 1' -oxyethyl derivatives, or lactone esters, e.g. 2-benzofuranonyl esters, or dialkylaminoalkyl esters, e.g. dimethylaminoethyl esters. Readily hydrolyzable esters include in vivo hydrolyzable esters of the compounds of formula I. Such esters may be prepared by conventional methods known to those skilled in the art, such as the method disclosed in GB patent 1490852, which is incorporated herein by reference.

"p 38MAP kinase" is a stress-activated protein kinase that exists in several isoforms (p38 α, p38 β, p38 β 2, p38 γ, and p38 δ). p38MAP kinase is activated by different stimuli, including heat, chemical, osmotic, pH and oxidative stress, growth factor cutoff, high or low glucose and UV radiation. p38 is also stimulated by agents that modulate the initial physiological response to injury, infection and inflammation, such as LPS and the pro-inflammatory cytokines IL-1 β, TNF- α, FasL, CD40L and TGF- β. Like other MAP kinases, p38 is phosphorylated in the activation loop (Thr-Xaa-Tyr) near the binding site of ATP to the substrate, at threonine and tyrosine by kinases including MKK3, MEK6 and MKK 6. And p38 phosphorylates and activates the serine-threonine protein kinases MAPKAP kinase-2, MAPKAP kinase-3, MAPKAP kinase-5, MNK-1 and MSK-1. It has been determined that: activation of p38 regulates cytokine biosynthesis in many cell types, either directly by phosphorylating and activating transcription factors involved in cytokine expression, or indirectly, for example, by phosphorylating MSK-1, which when activated, activates the transcription factor CREB. It has also been demonstrated that: certain pyridyl imidazoles that inhibit p38, such as SB203580, inhibit the production of IL-1 β and TNF- α by LPS-treated human single cells. Thus, it has been concluded that p38 constitutes a potentially highly advantageous target for the development of anti-inflammatory compounds (see JC Lee et al, Immunopharmacology 47, 2000, 185, 201 and references therein; PR Young, "specific inhibitors of p38MAP kinase", Signalling networks and Cell cycle controls: Molecular Basis of Cancer and Other Diseases, JS Gutkind (ed.), Humana Press, Totowa, NJ and references therein).

There are several reports directed to p38MAP kinase and inflammatory cytokines associated with cell growth and apoptosis, such as tumor proliferation and metastasis. Although the exact mechanism of p38MAP kinase-mediated cell growth regulation is unknown, it is believed that p38MAP kinase constitutes a potentially highly advantageous target for the development of anti-Cancer drugs (S Nakada et al, Anticancer Research 21(1A), 2001, 167-.

The compounds of formula I may contain asymmetrically substituted (chiral) carbon atoms with carbon-carbon double bonds, which may lead to isomeric forms, such as enantiomers, diastereomers and geometric isomers. The present invention relates to all such isomers, whether in pure form or as mixtures thereof. Pure stereoisomeric forms of the compounds and intermediates of the present invention may be obtained by applying methods known in the art. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g., liquid chromatography using a chiral stationary phase. The enantiomers may be separated from each other by selective crystallization of their diastereoisomeric salts with optically active acids. Alternatively, the enantiomers may be separated by chromatographic techniques using chiral stationary phases. The pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction takes place stereoselectively or stereospecifically. Preferably, if a particular stereoisomer is desired, the compound is synthesized by stereoselective or stereospecific methods of preparation. These processes will advantageously employ chirally pure starting materials. Likewise, pure geometric isomers can be obtained from their corresponding pure geometric isomers of the appropriate starting materials. Mixtures of geometric isomers will generally exhibit different physical properties and therefore can be separated by standard chromatographic techniques well known in the art.

Preferred embodiments of the Compounds of formula I

In a presently preferred embodiment of the compounds of formula I, R₁Can be halogen, trifluoromethyl, C_1-4Alkyl radical, C_1-4Alkoxy or nitro. In particular, R₁Can be methyl, ethyl, methoxy, ethoxy, bromo, fluoro or chloro.

In a further preferred embodiment of the compounds of the formula I, R₂Can be hydrogen, halogen, amino, C_1-4Alkyl or C_1-4An alkoxy group. In particular, R₂Can be hydrogen, methyl, ethyl, methoxy, ethoxy, bromo, fluoro or chloro.

In a further preferred embodiment of the compounds of the formula I, R₃Can be hydrogen, halogen, C_1-4Alkyl or C_1-4An alkoxy group. In particular, R₃Can be methyl, ethyl, methoxy, ethoxy, bromo, fluoro or chloro.

In a further preferred embodiment of the compounds of the formula I, R₃Represents a substituent. In particular, R₃Can be in the relative relation to R₄Meta with respect to-NH, or R₃Can be in the relative relation to R₄Meta with respect to-NH, or R₃Can be in the relative relation to R₄Ortho, meta relative to-NH.

In a further preferred embodiment of the compounds of the formula I, R₃And R₄One may be fluorine.

In a further preferred embodiment of the compounds of the formula I, Y₁May be-O-, -NR _a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-NR_aC (O) O-or NR_aS(O)₂。

In a further preferred embodiment of the compounds of the formula I, R₈Can be C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Carbocyclic radical or C_1-6A heterocyclic group.

In a further preferred embodiment of the compounds of the formula I, R₄Can be C_1-4Alkyl, amino, halogen, nitro, -NHC (O) O-C_1-4Alkyl, -NHC (O) C_1-4Alkyl, -NHC (O) -C_1-4alkyl-COOH, -NHC (O) NH-C_1-4alkyl-OH, -CH ═ CH-C_1-4alkyl-NH₂、-NHC(O)NH-C_1-4Alkyl, -NHC (O) NH-C_1-6Cycloalkyl, NHC (O) CF₃or-NHC (O) O-C_1-6A cycloalkyl group. In particular, R₄Can be methyl, ethyl, amino, bromo, fluoro, chloro, nitro, -NHC (O) OCH₂CH₃、-NHC(O)CH₂CH₃、-NHC(O)CH₃、-NHC(O)CH₂CH₂COOH、-NHC(O)NHCH₂CH₂OH、-CH＝CHCH₂NH₂、-NHC(O)NHCH₂CH₃-NHC (O) NH-cyclohexyl, NHC (O) CF₃or-NHC (O) O-cyclopentyl.

In a further preferred embodiment of the compounds of the formula I, R₇Can be halogen, hydroxy, amino, -S (O)₂CH₃Trifluoromethyl, cyano, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_1-4Alkoxycarbonyl, -COOH, -CONH₂、-S(O)₂NH₂Azido, -CONR ' or-CONRR ', wherein R and R ' are as defined above. Specifically, R7 can be methyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl, ethoxycarbonyl, dimethylamino, ethylamino, amino, -COOH, fluoro, chloro, bromo, -CONH₂、-S(O)₂NH₂Azido, methylthio, -S (O) ₂CH₃Trifluoromethyl, cyano or hydroxymethyl.

In a further preferred embodiment of the compounds of the formula I, R₅And R₆One of them may be Y₂R₉、C_1-4alkyl-Y₂R₉、Y₂R₉Y₃R₁₀、C_1-4alkyl-Y₂R₉Y₃R₁₀、C_2-4alkenyl-Y₂R₉、C_2-4alkenyl-Y₂R₉Y₃R₁₀、Y₂R₉-C_1-4-alkyl-Y₃R₁₀、Y₂R₉-C_2-4-alkenyl-Y₃R₁₀、C_1-6heterocyclyl-C_1-4-alkyl-Y₂R₉、C_1-4alkyl-C_1-6Heterocyclic group, C_1-4alkyl-C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkyl radical, by R₇Substituted C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Carbocyclyl, C_1-6Heterocyclyl, -COOH, -C (O) NHOH or C (O) NHNH₂And the other is hydrogen, halogen, C_1-4Alkyl or C_1-4An alkoxy group. In particular, R₅Can be Y₂R₉、C_1-4alkyl-Y₂R₉、Y₂R₉Y₃R₁₀、C_1-4alkyl-Y₂R₉Y₃R₁₀、C_2-4alkenyl-Y₂R₉、C_2-4alkenyl-Y₂R₉Y₃R₁₀、Y₂R₉-C_1-4-alkyl-Y₃R₁₀、Y₂R₉-C_2-4-alkenyl-Y₃R₁₀、C_1-6heterocyclyl-C_1-4-alkyl-Y₂R₉、C_1-4alkyl-C_1-6Heterocyclic group, C_1-4alkyl-C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkyl radical, by R₇Substituted C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Carbocyclyl, C_1-6Heterocyclyl, -COOH, -C (O) NHOH or C (O) NHNH₂And R is₆Is hydrogen, halogen, C_1-4Alkyl or C_1-4An alkoxy group. In particular, R₅And R₆One is Y₂R₉、Y₂R₉Y₃R₁₀Phenyl, methylphenyl, methyl, propenyl, phenyl-Y₂R₉methyl-Y₂R₉Tetrazole, ethynyl, triazole, thiadiazole, dihydrooxazole, triazole-Y₂R₉-COOH, -C (O) NHOH or C (O) NHNH₂And the other is hydrogen, fluorine, chlorine, methyl or methoxy.

In a further preferred embodiment of the compounds of the formula I, R₅Is hydrogen.

In a further preferred embodiment of the compounds of the formula I, R⁶Is hydrogen.

In another embodiment of the inventionWhen R is₂Is hydrogen and R₅Or R₆One of which is not hydrogen or optionally substituted (C)₃-C₁₈Heterocyclic group, C_1-7Alkyl radical, C_2-7Alkenyl radical, C_2-7Alkynyl or C_1-7Alkoxy), said optionally substituted (C)₃-C₁₈Heterocyclic group, C_1-7Alkyl radical, C_2-7Alkenyl radical, C_2-7Alkynyl or C_1-7Alkoxy) is C₃-C₁₈Heterocyclic group, C_1-7Alkyl radical, C_2-7Alkenyl radical, C_2-7Alkynyl or C_1-7Alkoxy, independently by one or more halogen, hydroxy, cyano, C_1-7Alkyl radical, C_1-7Alkoxy radical, C₃-C₁₈Heterocyclyl or-NR_xR_yIs substituted in which R_xAnd R_yIndependently is hydrogen or C_1-7Alkyl radical, wherein C is described later_1-7Alkyl radical, C_1-7Alkoxy radical, C3-C₁₈Heterocyclyl or-NR_xR_yThe substituents may be further substituted with one or more substituents independently selected from halogen, hydroxy, cyano, C_1-7Alkyl radical, C_1-7Alkoxy radical, C₃-C₁₈Heterocyclyl or-NR_xR_yWherein R is_xAnd R_yAre as defined above.

In a further preferred embodiment of the compounds of the formula I, Y₂May be-O-, -NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-C(O)NR_aO-、-C(O)-、-NR_aC(O)O-、-NR_aS(O)₂-、-C(O)NR_aNR_b-or-S (O)₂NR_a-。

In a further preferred embodiment of the compounds of the formula I, Y₃May be-O-, -NR_aC(O)-、-C(O)NR_a-, -C (O) -, -C (O) O-or-NR_aC(O)O-。

In a further preferred embodiment of the compounds of the formula I, R ₉Can be C_1-4alkyl-C_1-6Heterocyclic group, C_1-4alkyl-C_3-6Carbocyclic ringBase, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Carbocyclyl, C_1-6Heterocyclic group, C_3-6carbocyclyl-C_1-6Alkyl radical, C_1-6heterocyclyl-C_1-6Alkyl radical, C_3-6carbocyclyl-C_2-4Alkenyl or C_3-6carbocyclyl-C_2-4Alkynyl. In particular, R₉Can be C_1-4Heterocyclic group, C_1-6Alkyl radical, C_1-3alkyl-C_1-5Heterocyclic group, C_6-10Carbocyclyl, C_1-3alkyl-C₆Carbocyclyl, C₃Alkenyl radical, C₆carbocyclyl-C₁Alkyl radical, C₆carbocyclyl-C₃Alkenyl or C₆carbocyclyl-C₂Alkynyl. More specifically, R₉Can be morpholinyl, propylmorpholinyl, piperazinyl, methyl, ethyl, n-propyl, n-butyl, t-butyl, isobutyl, hexyl, isopropyl, dimethylpropyl, methyltetrahydrofuryl, methylpyridyl, ethylpiperazinyl, cyclohexyl, propyloxopyrrolidinyl, benzyl, methylcyclohexyl, propylphenyl, ethylphenyl, ethylmorpholinyl, allyl, ethylfuryl, phenyl, methyldioxoimidazolidinyl, dioxohexahydropyrimidyl, thiazolyl, methylphenyl, ethylphenyl, methyldioxypentyl, methylthiazolyl, propenylphenyl, methylfuryl, thienyl, tetrahydropyranyl or ethynylphenyl.

In a further preferred embodiment of the compounds of the formula I, R ₁₀Can be C_1-4Alkyl radical, C_2-4Alkenyl radical, C_3-6Carbocyclic radical or C_1-6A heterocyclic group. In particular, R₁₀Can be methyl, ethyl, methacryloyl, tert-butyl, tetrahydropyranyl or vinyl.

In a further preferred embodiment of the compounds of the formula I, the heterocycles or heterocycles as described above may contain one or two oxygen atoms or one sulfur atom, and/or up to two nitrogen atoms, or three or four nitrogen atoms, where optionally one or two CH' s₂The loop fragments are replaced by one or two-C (O) -fragments, respectively.

In a further preferred embodiment of the compounds of the formula I, R_a、R_bOr R_cIndependently represents hydrogen, methyl, ethyl, 2-hydroxyethyl or 2-methoxyethyl.

Specific examples of compounds of formula I may be selected from:

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl ] - [ 2-methyl-5- (morpholine-4-carbonyl) phenyl ] -methanone (compound 101),

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl ] - [ 2-methyl-5- (4-methyl-piperazine-1-carbonyl) phenyl ] -methanone (compound 102),

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -N-methoxy-4, N-dimethylbenzamide (Compound 103),

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4-methyl-N- (tetrahydrofuran-2-ylmethyl) benzamide (compound 104),

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4, N-dimethyl-N- (tetrahydrofuran-2-ylmethyl) benzamide (compound 105),

3- [ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) benzoyl ] -N- (2-methoxyethyl) -4-methylbenzamide (Compound 106),

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4-methyl-N- (3-morpholin-4-yl-propyl) benzamide (compound 107),

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl ] - {5- [4- (2-methoxyethyl) piperazine-1-carbonyl ] -2-methylphenyl } -methanone (Compound 108),

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4-methyl-N-pyridin-4-ylmethyl benzamide (compound 109),

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4-methyl-N-pyridin-2-ylmethyl benzamide (compound 110),

3- [ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -benzoyl ] -4-methyl-N-pyridin-3-ylmethyl-benzamide (compound 111),

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide (Compound 112),

3- [4- (2-amino-4-bromophenylamino) -2-chlorobenzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide (Compound 113),

3- [4- (4-bromo-2-methylphenylamino) -2-chlorobenzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide (Compound 114),

3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide (compound 115),

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl ] -N- (2-methoxyethyl) -4-methylbenzamide (Compound 116),

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl ] -N-ethyl-4-methylbenzamide (Compound 117),

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl ] -N- (3-hydroxypropyl) -4-methylbenzamide (Compound 118),

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide (compound 119),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 120),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4, N-dimethyl-benzamide (compound 121),

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetylamino) -acetic acid ethyl ester (Compound 122),

{3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetic acid ethyl ester (Compound 123),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (2-methoxy-ethyl) -4-methyl-benzamide (compound 124),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-cyclohexyl-4-methyl-benzamide (compound 125),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-ethyl-4-methyl-benzamide (compound 126),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (6-hydroxy-hexyl) -4-methyl-benzamide (compound 127),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-isopropyl-4-methyl-benzamide (compound 128),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-isobutyl-4-methyl-benzamide (compound 129),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (2, 2-dimethyl-propyl) -4-methyl-benzamide (compound 130),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (3-methoxy-propyl) -4-methyl-benzamide (compound 131),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -benzamide (compound 132),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (2-dimethylamino-ethyl) -4-methyl-benzamide (compound 133),

2-methyl-acrylic acid 2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -ethyl ester (Compound 134),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-cis- (4-hydroxy-cyclohexyl) -4-methyl-benzamide (compound 135),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-trans- (4-hydroxy-cyclohexyl) -4-methyl-benzamide (compound 136),

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -ethyl) -carbamic acid tert-butyl ester (compound 137),

n- (2-amino-ethyl) -3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzamide (compound 138),

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetylamino) -acetic acid (Compound 139),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methoxy-benzamide (compound 140),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 2-difluoro-ethyl) -4-methoxy-benzamide (compound 141),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methoxy-benzamide (compound 142),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide (compound 143),

n-carbamoylmethyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzamide (compound 144),

n-carbamoylmethyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide (compound 145),

n-benzyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide (compound 146),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methyl-benzamide (compound 147),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzamide (compound 148),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-ethyl-4-methyl-benzamide (compound 149),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-cyclohexylmethyl-4-methyl-benzamide (compound 150),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-propyl) -4-methyl-benzamide (compound 151),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methyl-benzamide (compound 152),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (1-hydroxymethyl-propyl) -4-methyl-benzamide (compound 153),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -benzamide (compound 154),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (3-hydroxy-propyl) -4-methyl-benzamide (compound 155),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-1, 1-dimethyl-ethyl) -4-methyl-benzamide (compound 156),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl) -4-methyl-benzamide (compound 157),

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetic acid ethyl ester (compound 158),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (4-hydroxy-butyl) -4-methyl-benzamide (compound 159),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (3-hydroxy-1, 1-dimethyl-butyl) -4-methyl-benzamide (compound 160),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (3-phenyl-propyl) -benzamide (compound 161),

(R) -3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (1-hydroxymethyl-3-methyl-butyl) -4-methyl-benzamide (compound 162),

3- [4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methyl-benzamide (compound 163),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-isopropyl-4-methyl-benzamide (compound 164),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-cyclohexyl-4-methyl-benzamide (compound 165),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 2-difluoro-ethyl) -4-methyl-benzamide (compound 166),

5- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -4-oxo-pentanoic acid methyl ester (compound 167),

n- [ (2-carbamoyl-ethylcarbamoyl) -methyl ] -3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide (compound 168),

(2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetylamino) -acetic acid ethyl ester (compound 169),

n-allyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide (compound 170),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2-sulfamoyl-ethyl) -benzamide (compound 171),

n- (2-acetylamino-ethyl) -3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide (compound 172),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methoxy-benzamide (compound 173),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methoxy-benzamide (compound 174),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide (compound 175),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (3-hydroxy-propyl) -4-methoxy-benzamide (compound 176),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-N-phenethyl-benzamide (compound 177),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-1, 1-dimethyl-ethyl) -4-methoxy-benzamide (compound 178),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-N- (2-morpholin-4-yl-ethyl) -benzamide (compound 179),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl) -4-methoxy-benzamide (compound 180),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methoxy-N-methyl-benzamide (compound 181),

{3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzoylamino } -acetic acid ethyl ester (compound 182),

(2- {3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzoylamino } -acetylamino) -acetic acid ethyl ester (compound 183),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N, N-bis- (2-hydroxy-ethyl) -4-methoxy-benzamide (compound 184),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-N, N-bis- (2-methoxy-ethyl) -benzamide (compound 185),

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 186),

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl ] -4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzamide (compound 187),

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 188),

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl ] -4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzamide (compound 189),

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 190),

3- (2-chloro-4-phenylamino-benzoyl) -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 191),

3- [ 2-chloro-4- (3, 5-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 192),

3- [ 2-chloro-4- (3-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 193),

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methoxy-benzamide (compound 194),

3- (2-chloro-4-phenylamino-benzoyl) -N- (2-hydroxy-ethyl) -4-methoxy-benzamide (compound 195),

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2, 2-difluoro-ethyl) -4-methoxy-benzamide (compound 196),

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methoxy-benzamide (compound 197),

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide (compound 198),

N-carbamoylmethyl-3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -4-methoxy-benzamide (compound 199),

3- (2-chloro-4-phenylamino-benzoyl) -N- (2, 2-difluoro-ethyl) -4-methoxy-benzamide (compound 200),

3- (2-chloro-4-phenylamino-benzoyl) -N- (2-fluoro-ethyl) -4-methoxy-benzamide (compound 201),

3- (2-chloro-4-phenylamino-benzoyl) -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide (compound 202),

n-carbamoylmethyl-3- (2-chloro-4-phenylamino-benzoyl) -4-methoxy-benzamide (compound 203),

4-chloro-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -benzamide (compound 204),

(2- { 3-chloro-4- [5- (2-hydroxy-ethylcarbamoyl) -2-methyl-benzoyl ] -phenylamino } -phenyl) -carbamic acid ethyl ester (compound 205),

3- [ 2-chloro-4- (2-propionylamino-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 206),

3- [4- (2-acetylamino-phenylamino) -2-chloro-benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 207),

n- (2- { 3-chloro-4- [5- (2-hydroxy-ethylcarbamoyl) -2-methyl-benzoyl ] -phenylamino } -phenyl) -succinamic acid (compound 208),

3- (2-chloro-4- {2- [3- (2-hydroxy-ethyl) -ureido ] -phenylamino } -benzoyl) -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 209),

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [ 2-methyl-4- (morpholine-4-carbonyl) -phenyl ] -methanone (compound 210),

[4- (2-amino-phenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone (Compound 211),

[4- (2-amino-phenylamino) -2-chlorophenyl ] - [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ] -methanone (compound 212),

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl (compound 213),

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ] -methanone (compound 214),

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - { 2-methyl-4- [3- (tetrahydro-pyran-2-yloxy) -propoxy ] -phenyl } -methanone (compound 215),

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - [4- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone (compound 216),

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - [4- (2-fluoro-ethoxy) -2-methyl-phenyl ] -methanone (compound 217),

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] - [4- (2-fluoro-ethoxy) -2-methyl-phenyl ] -methanone (compound 218),

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - [4- (2-methoxy-ethoxy) -2-methyl-phenyl ] -methanone (compound 219),

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone (compound 220),

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] - [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ] -methanone (compound 221),

[4- (2-azido-ethoxy) -2-methyl-phenyl ] - [4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] -methanone (compound 222),

[4- (2-amino-ethoxy) -2-methyl-phenyl ] - [4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] -methanone (compound 223),

[4- (2-bromophenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone (compound 224),

{4- [2- (3-amino-propenyl) -phenylamino ] -2-chlorophenyl } - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone (compound 225),

{4- [2- (3-amino-propenyl) -phenylamino ] -2-chlorophenyl } - [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ] -methanone (compound 226),

1- (2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl ] -phenylamino } -phenyl) -3-ethyl-urea (compound 227),

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -benzoyl } -phenylamino) -phenyl ] -3-ethyl-urea (compound 228),

1- (5-bromo-2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl ] -phenylamino } -phenyl) -3-ethyl-urea (compound 229),

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -benzoyl } -phenylamino) -phenyl ] -3-cyclohexyl-urea (compound 230),

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -benzoyl } -phenylamino) -phenyl ] -3- (2-hydroxy-ethyl) -urea (compound 231),

1- (5-bromo-2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl ] -phenylamino } -phenyl) -3- (2-hydroxy-ethyl) -urea (compound 232),

n- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -benzoyl } -phenylamino) -phenyl ] -succinamic acid (compound 233),

(4-allyloxy-2-methyl-phenyl) - [4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] -methanone (Compound 234),

N- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -acetamide (compound 235),

1- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -3-ethyl-urea (compound 236),

{2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -carbamic acid ethyl ester (Compound 237),

n- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -2, 2, 2-trifluoro-acetamide (compound 238),

n- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -succinamic acid (compound 239),

{2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -carbamic acid cyclopentyl ester (compound 240),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-methoxy-propionamide (compound 241),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -propionamide (compound 242),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -2- (2-methoxy-ethoxy) -acetamide (compound 243),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-morpholin-4-yl-propionamide (compound 244),

N- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-hydroxy-propionamide (compound 245),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-furan-2-yl-propionamide (compound 246),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -2-hydroxy-benzamide (compound 247),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -2- (2, 5-dioxo-imidazolidin-4-yl) -acetamide (compound 248),

2, 6-dioxo-hexahydro-pyrimidine-4-carboxylic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -amide (compound 249),

acrylic acid 2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenylcarbamoyl } -ethyl ester (Compound 250),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-methylsulfanyl-propionamide (compound 251),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-methanesulfonyl-propionamide (compound 252),

ethanesulfonic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -amide (compound 253),

N- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -4-methoxy-benzenesulfonamide (compound 254),

n- (5- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenylsulfamoyl } -4-methyl-thiazol-2-yl) -acetamide (compound 255),

5-acetyl-2-chloro-N- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -benzenesulfonamide (compound 256),

naphthalene-2-sulfonic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -amide (compound 257),

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -C-phenyl-methanesulfonamide (compound 258),

2- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -ureido) -ethyl 2-methyl-acrylate (compound 259),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (2-hydroxy-ethyl) -urea (compound 260),

(3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -ureido) -acetic acid ethyl ester (compound 261),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (3-methoxy-phenyl) -urea (compound 262),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (3-trifluoromethyl-phenyl) -urea (compound 263),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-propyl-urea (compound 264),

3- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -ureido) -propionic acid ethyl ester (compound 265),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-cyclohexyl-urea (compound 266),

1-allyl-3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -urea (compound 267),

1-benzyl-3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -urea (compound 268),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-ethyl-urea (compound 269),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-phenyl-urea (compound 270),

1-butyl-3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -urea (compound 271),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-phenethyl-urea (compound 272),

2- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -ureido) -benzoic acid methyl ester (compound 273),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (3-cyano-phenyl) -urea (compound 274),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-isopropyl-urea (compound 275),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (4-methoxy-phenyl) -urea (compound 276),

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -carbamic acid benzyl ester (compound 277),

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -carbamic acid allyl ester (compound 278),

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -carbamic acid ethyl ester (compound 279),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (3-hydroxy-butylamino) -2-methyl-phenyl ] -methanone (compound 281),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (3' -hydroxymethyl-4-methyl-biphenyl-3-yl) -methanone (compound 282),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (3' -hydroxy-4-methyl-biphenyl-3-yl) -methanone (compound 283),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (4' -methoxy-4-methyl-biphenyl-3-yl) -methanone (compound 284),

n- {3 '- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4' -methyl-biphenyl-3-yl } -acetamide (compound 285),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (4-methyl-3' -trifluoromethoxy-biphenyl-3-yl) -methanone (compound 286),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (3 ', 4 ', 5 ' -trifluoro-4-methyl-biphenyl-3-yl) -methanone (compound 288),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (3 ', 4' -dimethoxy-4-methyl-biphenyl-3-yl) -methanone (289),

3 '- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4' -methyl-biphenyl-3-carbonitrile (compound 290),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzenesulfonamide (compound 291),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2-morpholin-4-yl-ethyl) -benzenesulfonamide (compound 292),

n-allyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzenesulfonamide (compound 293),

n- (2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzenesulfonylamino } -ethyl) -acetamide (compound 294),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N-propyl-benzenesulfonamide (compound 295),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methyl-benzenesulfonamide (compound 296),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-methoxy-ethyl) -4-methyl-benzenesulfonamide (compound 297),

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] - [5- (4-methoxy-benzyloxy) -2-methyl-phenyl ] -methanone (compound 298),

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] - [5- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone (compound 299),

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [5- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone (Compound 300),

[5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-methyl-phenyl ] - [4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] -methanone (compound 301),

[5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl ] - [4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] -methanone (compound 302),

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl ] -methanone (303),

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] - [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone (304),

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone (compound 305),

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [5- (4-methoxy-benzyloxy) -2-methyl-phenyl ] -methanone (compound 306),

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [5- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone (compound 307),

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone (compound 308),

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone (compound 309),

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl ] - [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone (compound 310),

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-methyl-phenyl ] -methanone (compound 311),

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl ] -methanone (compound 312),

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl ] -methanone (compound 313),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone (compound 314),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-fluorophenyl ] -methanone (compound 315),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl ] -methanone (compound 316),

2- {3- [ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -benzoyl ] -4-fluoro-phenoxy } -N-methyl-acetamide (compound 317),

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone (compound 318),

2- {3- [ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -benzoyl ] -4-fluoro-phenoxy } -N, N-dimethyl-acetamide (compound 319),

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-fluorophenyl ] -methanone (Compound 320),

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl ] -methanone (compound 321),

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone (compound 322),

[ 2-chloro-4- (4-fluorophenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone (compound 323),

[ 2-chloro-4- (4-fluorophenylamino) -phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-fluorophenyl ] -methanone (Compound 324),

[ 2-chloro-4- (2-chloro-4-fluorophenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone (Compound 325),

[4- (2-amino-phenylamino) -2-chlorophenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl ] -methanone (compound 326),

[4- (2-amino-phenylamino) -2-chlorophenyl ] - [ 2-fluoro-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone (compound 327),

[ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl ] - [ 2-chloro-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone (compound 328),

(±) - [ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl ] - [ 2-chloro-5- (2, 3-dihydroxy-propoxy) -phenyl ] -methanone (compound 329),

[5- (3-bromo-propoxy) -2-chlorophenyl ] - [ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl ] -methanone (compound 330),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (5-hydroxymethyl-2-methyl-phenyl) -methanone (compound 331),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (5-chloromethyl-2-methyl-phenyl) -methanone (compound 332),

(5-azidomethyl-2-methyl-phenyl) - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] -methanone (compound 333),

(5-aminomethyl-2-methyl-phenyl) - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] -methanone (compound 334),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (5-hydroxymethyl-2-methoxy-phenyl) -methanone (compound 335),

acetic acid 3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzyl ester (compound 336),

n-tert-butoxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzamide (compound 337),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-methoxy-4-methyl-benzamide (compound 338),

n-butoxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide (compound 339),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-cyclohexylmethoxy-4-methyl-benzamide (compound 340),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2-methyl-thiazol-4-ylmethoxy) -benzamide (compound 341),

N-benzyloxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide (compound 342),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (4-methoxy-benzyloxy) -4-methyl-benzamide (compound 343),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoic acid N ', N' -dimethyl-hydrazide (compound 344),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N-morpholin-4-yl-benzamide (compound 345),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-hydroxy-4-methyl-benzamide (compound 346),

4- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -3-methyl-benzamide (compound 347),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (3-hydroxy-propenyl) -2-methyl-phenyl ] -methanone (compound 348),

4- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -thiophene-3-carboxylic acid methyl ester (compound 349),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-furan-2-ylmethyl-4-methyl-benzamide (compound 350),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (3-methoxy-phenyl) -4-methyl-benzamide (compound 351),

2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -benzoic acid methyl ester (Compound 352),

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -thiophene-2-carboxylic acid methyl ester (compound 353),

4- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -thiophene-3-carboxylic acid (compound 354),

2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -benzoic acid (compound 355),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- [2- (2-hydroxy-ethylcarbamoyl) -phenyl ] -4-methyl-benzamide (compound 356),

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -thiophene-2-carboxylic acid (2-hydroxy-ethyl) -amide (compound 357),

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [ 2-methyl-5- (1H-tetrazol-5-yl) -phenyl ] -methanone (compound 358),

[4- (2-amino-phenylamino) -2-chlorophenyl ] - (5-ethynyl-2-methyl-phenyl) -methanone (compound 359),

[4- (2-amino-phenylamino) -2-chlorophenyl ] - (2-methyl-5- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -1H- [1, 2, 3] triazol-4-yl } -phenyl) -methanone (Compound 360),

[4- (2-amino-phenylamino) -2-chlorophenyl ] - {5- [1- (2-hydroxy-ethyl) -1H- [1, 2, 3] triazol-4-yl ] -2-methyl-phenyl } -methanone (Compound 361),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (5-ethynyl-2-methyl-phenyl) -methanone (compound 362),

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -4-methyl-benzoic acid hydrazide (compound 363),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoic acid hydrazide (compound 364),

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoyl } -4-ethyl-3-thiosemicarbazide (compound 365),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (5-ethylamino- [1, 3, 4] thiadiazol-2-yl) -2-methyl-phenyl ] -methanone (compound 366),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [ 2-methyl-5- (1H-tetrazol-5-yl) -phenyl ] -methanone (compound 367),

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-oxo-propionic acid ethyl ester (compound 368),

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (4, 5-dihydro-oxazol-2-yl) -2-methyl-phenyl ] -methanone (compound 369),

3- { 2-chloro-4- [2- (3-ethyl-ureido) -phenylamino ] -benzoyl } -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 370),

3- [ 2-chloro-4- (2-nitrophenylamino) benzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide (compound 417),

3- [4- (4-bromo-2-nitrophenylamino) -2-chlorobenzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide (compound 420),

3- [4- (4-bromo-2-methylphenylamino) -2-chlorobenzoyl ] -4-methylbenzoic acid (compound 422),

3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl ] -4-methylbenzoic acid (compound 424),

2- {3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl ] -4-methylbenzamido } ethyl 2-methacrylate (Compound 425),

3- [ 2-chloro-4- (2-nitrophenylamino) benzoyl ] -N- (2-methoxyethyl) -4-methylbenzamide (compound 426),

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoic acid (compound 432),

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzoic acid (compound 437),

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzoic acid (compound 443),

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl ] -4-methyl-benzoic acid (compound 446),

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl ] -4-methyl-benzoic acid (compound 449),

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -4-methoxy-benzoic acid (compound 457),

3- (2-chloro-4-phenylamino-benzoyl) -4-methoxy-benzoic acid (compound 459),

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone (compound 472),

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl (compound 473),

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl ] - { 2-methyl-4- [3- (tetrahydro-pyran-2-yloxy) -propoxy ] -phenyl } -methanone (compound 477),

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl ] - [4- (2-fluoro-ethoxy) -2-methyl-phenyl ] -methanone (compound 481),

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl ] - [4- (2-methoxy-ethoxy) -2-methyl-phenyl ] -methanone (compound 485),

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl ] - [ 2-fluoro-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone (compound 518),

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-fluorophenyl ] -methanone (compound 519), and

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl ] -methanone (compound 520).

Except that R is as shown above₄In addition to the definition of R, R is envisaged₄May comprise R as contained in WO03/018535₆Substituents within the definitions, the contents of which are hereby incorporated by reference in their entirety.

It is further contemplated that the compounds of formula I may be N-substituted at the amino group between rings B and C of the core structure, using substituents substantially as disclosed in U.S. provisional application 60/434,798, the contents of which are hereby incorporated by reference in their entirety.

Preparation method

The compounds of the present invention may be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of the invention can be synthesized using the methods outlined below, as well as methods well known in the art of synthetic organic chemistry, or variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.

The compounds of formula I may be prepared using the reactions and techniques described in this paragraph. The reaction is carried out in a solvent which is suitable for the reagents and materials employed and for the conversion carried out. In the following synthetic methods, it should also be understood that all suggested reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, experimental duration and treatment procedures, are selected as standard conditions for the reaction, which should be readily apparent to those skilled in the art. It will be apparent to those skilled in the art of organic synthesis that functional groups present at various positions in the molecules used as starting compounds or intermediates in the synthesis must be compatible with the reagents and reactions suggested. Not all compounds of formula I falling within the given class are compatible with some of the reaction conditions required in some of the processes described. Such limitations of substituents or functional groups compatible with reaction conditions will be apparent to those skilled in the art, and alternative methods may be used.

The compounds according to the invention can be prepared by a process comprising coupling an amine of formula III with a triflate or halide of formula II, such as bromide, iodide, fluoride, chloride, as shown in scheme 1; or alternatively, by: comprising coupling an amine of formula Iia with a triflate or halide of formula IIIA, such as bromide or iodide, as shown in scheme 1; wherein R is₁、R₂、R₃、R₄、R₅And R₆Are all as defined above; with the following exceptions: any substituents or functional groups potentially reactive in the coupling reaction may be protected prior to carrying out the coupling reaction, followed by removal of the protecting group.

L：Br、I、OSO₂CF₃Or F and Cl (in special cases, for example, when R'₄Is EWG such as NO₂Time)

W: br, I or OSO₂CF₃

FGI: mutual conversion of functional groups

R′₁、R′₂、R′₃、R′₄、R′₅And R'₆Each represents R₁、R₂、R₃、R₄、R₅And R₆Or convertible into R₁、R₂、R₃、R₄、R₅And R₆Any suitable FG (functional group)

Scheme 1

The coupling reaction is carried out by using methods well known to those skilled in the art of organic synthesis to form diphenylamines. A preferred process is a palladium catalyzed amination process which involves coupling an amine with an aryl halide (or aryl triflate) in the presence of a base, a suitable Pd source and a suitable phosphine ligand in an inert solvent.

Different palladium compounds can be used in this process, non-limiting examples of which are palladium (II) acetate, palladium (II) chloride, palladium (II) bromide, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0). Preferred phosphine ligands include, but are not limited to, racemic or non-racemic 2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl (hereinafter BINAP), tri-o-tolylphosphine, tri-tert-butylphosphine, 1 ' -bis (diphenylphosphino) -ferrocene, bis [ (2-diphenylphosphino) phenylphenyl]Ethers (DPEphos), 2-dicyclohexylphosphoalkyl (phosphanyl) -2' -dimethylaminobiphenyl, 2- (di-tert-butylphosphino) biphenyl and 9, 9-dimethyl-4, 6-bis (diphenylphosphino) xanthene (xanthphos). The amount of palladium and ligand used in the catalytic process may generally be in the range of 0.1 to 10% on a molar basis relative to the amount of aromatic halide (or triflate) used. In particular, sodium tert-butoxide (NaOt-Bu) with cesium carbonate (Cs)₂CO₃) Bases have proven to be preferred in this process, but other bases may also be used. The reaction is typically carried out at elevated temperature (80-120 ℃) in an inert solvent such as 1, 4-dioxane, toluene, benzene and tetrahydrofuran under an inert atmosphere such as argon or nitrogen.

R'₄In the case of electron-withdrawing groups (EWG) such as nitro or cyano, the coupling can also be carried out in a non-catalytic manner in the presence of strong bases such as potassium tert-butoxide or sodium tert-butoxide. The reaction is usually carried out at room temperature or at elevated temperature (20-200 ℃) in an aprotic solvent such as dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF) or N-methylpyrrolidone (NMP) under an inert atmosphere such as argon or nitrogen.

The compounds of formula III according to the present invention can be prepared by several methods well known to those skilled in the art of organic synthesis. One useful procedure is shown in scheme 2. The key step involves the coupling of a halide, preferably an iodide or bromide, of formula VI with an acid chloride of formula V to give a benzophenone of formula IV. The benzophenone IV can then be reduced to the corresponding amine of formula III by treatment with standard reducing agents. Examples of such reducing agents include, but are not limited to, stannous chloride dihydrate, hydrogen, ammonium formate or hydrazine hydrate, and catalytic amounts of palladium on carbon. This coupling reaction can be achieved by converting the halide (VI) into a reactive organometallic intermediate, such as by treatment with isopropyl magnesium chloride to give the corresponding magnesium derivative, or by treatment with n-butyl lithium to give the corresponding lithium derivative.

Hal: i or Br

FGI: mutual conversion of functional groups

R′₁、R′₂、R′₅And R'₆Each represents R₁、R₂、R₅And R₆Or can be converted to R₁、R₂、R₅And R₆Any suitable FG (functional group)

Scheme 2

The organometallic intermediate is then made reactive by reacting with ZnCl₂、ZnBr₂Or ZnI₂Treatment, via metal exchange, is regulated to, for example, zinc. The organozinc compound is then coupled with an acid halide, such as an acid chloride of formula V, in the presence of or mediated by a catalytic amount of a palladium (0) complex. Examples of such palladium catalysts include, but are not limited to, tetrakis (triphenylphosphine) palladium (0), tetrakis (triphenylarsine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), or benzylchlorobis (triphenylphosphine) palladium (II). Alternatively, the organozinc compound is coupled with an acid halide, such as an acid chloride of formula V, in the presence of or mediated by an equimolar or sub-stoichiometric or catalytic amount (for V) such as 0.1 to 99 mol%, for example 0.5 to 10 mol%, for example 1 to 5 mol%, for example 2 to 3 mol% of a copper (I) or (II) salt, such as copper (II) acetate or a soluble complex cucn.2licl or cucn.2libr. The coupling reaction is generally carried out at room temperature in an inert solvent such as 1, 4-dioxaneToluene, benzene and tetrahydrofuran under an inert atmosphere such as argon or nitrogen.

The compounds of formula IIIa according to the invention can be prepared by a similar zinc-mediated cross-coupling procedure as shown in scheme 3.

Hal: i or Br

FGI: mutual conversion of functional groups

R′₁、R′₂、R′₅And R'₆Each represents R₁、R₂、R₅And R₆Or can be converted to R₁、R₂、R₅And R₆Any suitable FG (functional group)

Scheme 3

The compounds according to the invention can be prepared in special cases by simple Functional Group Interconversion (FGI), meaning standard procedures known to those skilled in the art of organic synthesis, in which the functional groups in the compounds of the formula I or I' are converted into different functional groups in one or more synthetic steps, to give the novel compounds of the formula I. Examples of such processes include, but are not limited to, hydrolysis of esters to acids under basic conditions, by using, for example, boron tribromide (BBR)₃) Work-up to deprotect the methyl ether to give phenol and catalytic hydrogenation of olefins to give saturated hydrocarbons. Non-limiting examples of such transformations are described in the general methods and in "Comprehensive Organic Transformation", r.c. larock, VCH 1989, which is hereby incorporated by reference in the general procedure. In particular, the use of protecting groups in one or more synthetic steps may be appropriate in the synthesis of compounds of formula I. Examples of such general protecting groups include, but are not limited to, methyl, ethyl, t-butyl or benzyl esters as hydroxy protecting groups; tetrahydropyranyl as a hydroxy protecting group -or silyl-ether.

As shown in schemes 2 and 3, each intermediate compound can be converted by the FGI method described above to give a new compound of the same general formula (e.g. the hydroxy group can be protected as tert-butyl-dimethyl-silyl ether). This is merely to illustrate the flexibility of the synthesis and, in general, the process sequence is only one of many possible strategies for synthesizing the compounds of the invention. That is, in some cases, it may be more advantageous to change the order of the above-described methods. The order of the processes described is not to be construed as limiting the preparation of the compounds of general formula I of the present invention and alterations of the reaction sequence are obvious alternatives to those skilled in the art of organic synthesis. This aspect of the invention provides for the synthesis of compounds having different substituents R₄、R₅And R₆Particularly advantageous in terms of the compounds of the radicals. Readily available intermediates can serve as starting points for the synthesis of the respective series of compounds covered by general formula I.

Pharmaceutical composition

In another aspect, the invention relates to a pharmaceutical composition comprising as active ingredient a compound of formula I together with a pharmaceutically acceptable excipient, carrier or vehicle. Furthermore, the present invention relates to the use of a compound of formula I for the preparation of a medicament for the prevention, treatment or amelioration of an inflammatory disease or disorder.

The pharmaceutical compositions of the present invention may be in unit dosage forms such as tablets, pills, capsules, powders, granules, elixirs, syrups, emulsions, ampoules, suppositories, or parenteral solutions or suspensions; for oral, parenteral, ocular, transdermal, intra-articular, topical, pulmonary, nasal, buccal or rectal administration, or in any other manner suitable for the formulation of anti-inflammatory compounds, and in accordance with accepted practice, such as Remington: pharmaceutical science and practice, 19 th edition, Mack publishing company, 1995. In the compositions of the present invention, the active ingredient may be present in an amount of from about 0.01 to about 99%, such as from 0.1% to about 10%, by weight of the composition.

For oral administration in the form of tablets or capsules, the compounds of formula I may suitably be combined with an oral, non-toxic, pharmaceutically acceptable carrier, such as ethanol, glycerol, water and the like. Further, suitable binders, lubricants, disintegrating agents, flavoring agents, and coloring agents may be added to the mixture as appropriate. Suitable binders include, for example, lactose, glucose, starch, gelatin, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Other excipients for capsules include polyethylene glycol or lipids.

For the preparation of solid compositions such as tablets, the active compound of formula I is mixed with one or more excipients as described above and other pharmaceutically acceptable diluents such as water to produce a solid preformulation composition containing a homogeneous mixture of the compound of formula I. The term "homogeneous" is to be understood as meaning that the compound of formula I is dispersed uniformly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets or capsules. The preformulation composition may then be subdivided into unit dosage forms containing from about 0.05 to about 1000mg, especially from about 0.1 to about 500mg, of the active compound of the present 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, for example cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, or polyvinylpyrrolidone.

For parenteral administration, for example intramuscular, intraperitoneal, subcutaneous or intravenous injection or infusion, the pharmaceutical composition preferably comprises a compound of formula I dissolved or solubilized in a suitable pharmaceutically acceptable solvent. For parenteral administration, the compositions of the invention may comprise sterile aqueous or non-aqueous solvents, in particular water, isotonic saline, isotonic glucose solution, buffer solutions or other solvents conventionally used for the parenteral administration of therapeutically active substances. The composition can be sterilized, by, for example, filtering through a bacteria-retaining filter, adding a sterilizing agent to the composition, irradiating the composition, or heating the composition. Alternatively, the compounds of the present invention may be provided as a sterile solid formulation, for example a lyophilized powder, which is dissolved in a sterile solvent immediately prior to use.

Compositions for parenteral administration may additionally comprise conventional additives, such as stabilizers, buffers or preservatives, for example antioxidants, such as methyl hydroxybenzoate and the like.

Compositions for rectal administration may be in the form of suppositories incorporating the active ingredient with a carrier such as cocoa butter, or in the form of enemas.

Compositions suitable for intra-articular administration may be in the form of sterile aqueous preparations of the active ingredient which may be in the form of microcrystals, for example, in the form of aqueous microcrystals suspensions. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredients for intra-articular and ocular administration.

Compositions suitable for topical administration, including ocular treatments, include liquid or semi-liquid formulations such as liniments, lotions, gels, coatings, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes; or solutions or suspensions, such as drops. For topical application, the compound of formula I may be present in an amount generally ranging from 0.01 to 20%, such as from 0.1% to about 10%, by weight of the composition, but may also be present in an amount up to about 50% by weight of the composition.

The composition for ocular treatment may preferably additionally contain cyclodextrin.

Compositions suitable for administration to the nasal or buccal cavity or for inhalation include powder, self-propelled and spray formulations such as aerosols and nebulisers. Such compositions may comprise a compound of formula I in an amount of from 0.01 to 20%, for example 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 diseases and disorders. Examples of such other active ingredients may be selected from glucocorticoids, vitamin D and vitamin D analogues, antihistamines, Platelet Activating Factor (PAF) antagonists, anticholinergics, methylxanthines, β -adrenergic agents, COX-2 inhibitors, salicylates, indomethacin, flufenamate (flufenamate), naproxen, timegadine, gold salts, penicillamine, serum cholesterol lowering agents, retinoids, zinc salts and sulfasalazine.

In a further aspect, the present invention relates to a method of treating an inflammatory disease or disorder or an ocular disease or disorder or cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I.

Suitable dosages for the compounds of the present invention will vary depending upon, among other factors, the age and condition of the patient, the severity of the condition being treated, and other factors well known to practitioners. The compounds may be administered orally, parenterally or topically according to different dosing schedules, e.g., daily or at weekly intervals. Generally, a single dose will be in the range of 0.01 to 400 mg/kg body weight. The compounds may be administered in a bolus (i.e., the entire daily dose is administered simultaneously), or in divided doses of two or more times a day.

Inflammatory diseases or conditions intended to be treated with the compounds of the present invention are those in which modulation of cytokine expression and secretion is modulated by MAP kinases such as the aforementioned p38 MAP kinases. Examples of inflammatory diseases or conditions believed to be modulated by p38 MAP kinase are selected from asthma, arthritis, including rheumatoid arthritis and spondyloarthritis, gout, atherosclerosis, inflammatory bowel disease, crohn's disease, neuroinflammation, inflammatory eye diseases, proliferative and inflammatory skin conditions such as psoriasis, atopic dermatitis and acne vulgaris, uveitis, sepsis, septic shock and osteoporosis.

Treatment may additionally involve the administration of one or more other anti-inflammatory active ingredients such as glucocorticoids, vitamin D and vitamin D analogues, antihistamines, Platelet Activating Factor (PAF) antagonists, anticholinergics, methylxanthines, β -adrenergic agents, COX-2 inhibitors, salicylates, indomethacin, flufenamate (flufenamate), naproxen, timegadine, gold salts, penicillamine, serum cholesterol lowering agents, retinoids, zinc salts, and sulfasalazine. Administration of the compound of the invention and another anti-inflammatory ingredient may be simultaneous or sequential.

Ocular diseases or conditions intended to be treated with the compounds of the present invention include ocular diseases or conditions that are non-infectious (e.g., allergic) conjunctivitis, iritis, keratitis, uveitis, scleritis, episcleritis (episcleritis), sympathetic ophthalmia, blepharitis, or keratoconjunctivitis sicca.

Pharmacological methods

To investigate the in vitro effect of the compounds of the invention, the inhibition of IL-1. beta. and TNF-. alpha.secretion was determined using the following procedure:

cytokine production from Lipopolysaccharide (LPS) -stimulated peripheral blood mononuclear cells was measured in culture medium. By Lymphoprep(Nycomed, Norway) fractionation mononuclear cells were isolated from human peripheral blood and fractionated at 5X 10⁵The individual cells/ml were suspended in RPMI 1640 (growth medium) containing fetal calf serum (FCS, 2%). Cells were incubated in 1ml aliquots in 24-well tissue culture plates. Test compounds were dissolved in dimethyl sulfoxide (DMSO, 10mM) and diluted with medium. The compound was added to the cells over 30 minutes, followed by addition of LPS (final concentration 1 mg/ml). The plates were incubated for 18 hours and the concentrations of IL-1. beta. and TNF-. alpha.in the medium were determined by ELISA. The median inhibitory concentration of the compound (IC50) was calculated. The results are shown in Table 1.

Table 1.Inhibition of cytokine production in vitro by the compounds of the invention

Median Inhibitory Concentration (IC)₅₀，nM)

Compound number IL-1 beta TNF-alpha

Compound 1042.01.3

Compound 1062.01.0

Compound 1073.23.2

Compound 1094.03.2

Compound 1124.00.6

Compound 1134.01.8

Compound 1142.50.4

Compound 1151.30.3

Compound 1161.01.0

Compound 1174.01.0

Table 1.Inhibition of cytokine production in vitro by the compounds of the invention

Median Inhibitory Concentration (IC)₅₀，nM)

Compound number IL-1 beta TNF-alpha

Compound 1182.22.0

Compound 1191.30.4

Compound 1202.72.0

Compound 1212.80.6

Compound 1220.50.2

Compound 1230.50.3

Compound 1262.80.6

Compound 1292.51.3

Compound 1313.21.3

Compound 1354.02.0

Compound 1364.02.0

Compound 1401.41.0

Compound 1410.90.6

Compound 1432.51.6

Compound 1441.00.6

Compound 1451.30.3

Compound 1472.50.8

Compound 1480.60.2

Compound 1491.60.5

Compound 1511.80.4

Compound 1522.80.6

Compound 1538.91.6

Compound 1543.22.5

Compound 1550.60.2

Compound 1564.50.9

Table 1.Inhibition of cytokine production in vitro by the compounds of the invention

Median Inhibitory Concentration (IC)₅₀，nM)

Compound number IL-1 beta TNF-alpha

Compound 1572.20.9

Compound 1580.60.2

Compound 1597.91.3

Compound 1632.52.5

Compound 1641.32.0

Compound 1660.50.4

Compound 1671.72.0

Compound 1682.52.5

Compound 1690.40.4

Compound 1703.22.5

Compound 1732.52.0

Compound 1743.22.0

Compound 1763.22.0

Compound 1786.31.6

Compound 1802.53.2

Compound 1828.92.2

Compound 1832.00.7

Compound 1860.80.5

Compound 1880.90.5

Compound 1900.60.3

Compound 1911.10.5

Compound 1934.02.5

Compound 1940.60.3

Compound 1952.21.0

Compound 1963.21.0

Table 1.Inhibition of cytokine production in vitro by the compounds of the invention

Median Inhibitory Concentration (IC)₅₀，nM)

Compound number IL-1 beta TNF-alpha

Compound 1973.21.8

Compound 1981.10.4

Compound 2017.93.2

Compound 2025.02.0

Compound 2036.33.2

Compound 2411.10.3

Compound 2421.40.5

Compound 2432.81.3

Compound 2441.30.5

Compound 2453.50.9

Compound 2463.2

Compound 2475.61.4

Compound 2481.00.7

Compound 2491.61.1

Compound 2511.10.4

Compound 2520.60.6

Compound 2601.80.5

Compound 2612.21.0

Compound 2622.00.6

Compound 2631.6

Compound 2641.00.3

Compound 2651.00.3

Compound 2660.90.4

Compound 2670.40.2

Compound 2690.80.6

Table 1.Inhibition of cytokine production in vitro by the compounds of the invention

Median Inhibitory Concentration (IC)₅₀，nM)

Compound number IL-1 beta TNF-alpha

Compound 2711.00.4

Compound 2723.21.4

Compound 2755.00.3

Compound 2772.50.8

Compound 2781.30.6

Compound 2790.60.5

Compound 2825.60.6

Compound 2851.40.6

Compound 3142.8

Compound 3352.72.5

Compound 3365.02.0

Reference Compound a 137.1

Reference Compound b 6.36.3

Reference compound c 326.3

Reference Compound d 7.93.2

Reference Compound e 6.33.2

Reference compound f 134.0

Reference compound a: (4- (2-Aminophenylamino) -2-chloro-2' -methylbenzophenone, compound 156 disclosed in WO 98/32730.

Reference compound b: 2' - [ 3-chloro-4- (2-methylbenzoyl) phenylamino ] octanoanilide, compound 102 disclosed in WO 01/05746.

Reference compound c: 1-acetoxymethyl N- [2- [ 3-chloro-4- (2-methylbenzoyl) phenylamino ] phenyl ] carbamate, compound 109 disclosed in WO 01/05749.

Reference compound d: 1-ethyl-3- [2- [ 3-chloro-4- (2-methylbenzoyl) phenylamino ] -5-fluorophenyl ] urea, compound 114 disclosed in WO 01/05751.

Reference compound e: 2, 2, 2-trifluoro-N- [2- [ 3-chloro-4- (2-methylbenzoyl) phenylamino ] -5-fluorophenyl ] acetamide, compound 102 disclosed in WO 01/05745.

Reference compound f: 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -2' -methylbenzophenone, compound 131 disclosed in WO 01/42189.

These results show that: the compounds of the invention are highly potent inhibitors of IL-1 β, TNF- α production and exhibit surprisingly higher cytokine inhibitory activity than the reference compounds, thus making them potentially useful in the treatment of inflammatory diseases.

Furthermore, the novel aminobenzophenone derivatives have surprisingly advantageous pharmacokinetic properties such as absorption and metabolic stability.

p38 alpha MAP kinase assay

Cell culture

COS-1 cells (derived from African green monkey kidney fibroblast containing wild type T antigen under the control of SV40 promoter) were obtained from ATCC (ATCC accession number CRL-1650) and were cultured at 37 ℃ and 5% CO₂Growth was performed in growth medium (DMEM, 10% FCS, 2mM L-glutamine, 100U penicillin and 100. mu.g streptomycin/ml, phenol red free). Cells were passaged twice a week by trypsinization (0.25% trypsin in 1mM EDTA in PBS) and split 1: 10. The medium was changed every second or third day. The cell line was regularly tested by Mycoplasma PCR PrimeSet (Stratagene) and found to be free of Mycoplasma. Tissue culture medium, FCS, L-glutamine, penicillin and streptomycin were obtained from BribcoBRL, Gaithersburg, Md., USA.

Transient expression of COS-1 cells

COS-1 cells were plated at 2X 10 on the first day⁴Individual cell/cm²Is inoculated at a density of 143cm²In growth medium in petri dishes. On day 2, cells were co-transfected with 5 μ g (total) of experimental plasmid DNA expressing FLAG-p38 α and FLAG-MKK6 (EE). Using DOTAP^TM(Boehringer-Mannheim, Mannheim, Germany), the plasmid was introduced into COS-1 cells in serum-free medium. Plasmid DNA was prepared and purified using the QIAGEN endotoxin free Maxiprep-500 kit (Hilden, Germany). Briefly, CO was performed at 37 deg.C₂In an incubator, DNA is mixed with DOTAP^TMMix accurately for 15 minutes. Then theThe transfection mixture was transferred to a 15ml falcon tube and transfection medium (DMEM, containing L-glutamine and penicillin/streptomycin but no serum) was added to the transfection mixture, followed by addition to the cell monolayer. And DOTAP^TMAnd plasmid were incubated for 4 hours, medium containing twice the amount of serum was added to the cells to achieve a final serum concentration of 10%. Then, the cells were incubated for 24 hours before the kinase reaction.

Immunoprecipitation

After 24 hours of incubation, the reaction was stopped by placing the petri dish on an ice bath. The medium was aspirated and the cell monolayer was incubated in ice-cold PBS (137mM NaCl, 1.5mM KH) ₂PO₄、2.7mM KCl、8.1mM Na₂HPO₄.2H₂O) and then dissolved in 1.5ml lysis buffer (50mM HEPES pH7.5, 150mM NaCl, 10mM EDTA, 10mM Na) over a period of 10 minutes₄P₂O₇、100mM NaF、2mM Na₃VO₄1% Triton-X-100, Pefabloc 500. mu.M, leupeptin 10. mu.g/. mu.l, aprotinin 10. mu.g/. mu.l). The cell monolayer was scraped by a rubber broom and transferred to an Eppendorf tube. The lysed cells were clarified by centrifugation at 10.000Xg for 10 minutes at 4 ℃. The supernatant was transferred to 50. mu.l of pre-washed protein G agarose beads in HNT buffer (30mM HEPES pH7.5, 30mM NaCl, 0.1% Triton X-100) and incubated with 2. mu.g/sample of monoclonal anti-FLAG at room temperature^TMM2 antibody (against FLAG-epitope, NH)₂-Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys-COOH) for 1 hour. The anti-FLAG M2 monoclonal antibody was obtained from Sigma (catalog number F-3165). About 60 μ G of clarified cell lysate protein was added to the pre-adsorbed anti-FLAG on protein G Sepharose beads^TMAntibodies and incubated in a blood sample mixer at 4 ℃ for 90 minutes. After the immunoprecipitation period, the agarose beads were washed twice in lysis buffer and twice in kinase reaction buffer (25mM HEPES pH7.5, 10mM magnesium acetate, 50. mu.M ATP).

Compounds and purified p38 alpha kinaseIncubation of (2)

The pre-washed immunoprecipitated anti-FLAG-p 38 adsorbed on protein G agarose beads was washed twice in 1 Xkinase buffer (25mM HEPES pH7.5, 10mM magnesium acetate, 50. mu.M ATP) and the supernatant aspirated. Compounds were diluted in 1x kinase buffer at appropriate concentrations. The compound was added in a volume of 100. mu.l to the washed immunoprecipitated and activated FLAG-p38 adsorbed on protein G sepharose beads for 30 min at 30 ℃. The Eppendorf tube was tapped every 10 minutes to ensure that the beads were in solution with the compound. After 30 minutes of incubation, the beads were centrifuged and the supernatant aspirated.

p38 alpha MAP kinase reaction

The kinase reaction was started by adding 1. mu.g of GST-ATF-2 substrate (Santa Cruz, LaJolla, Calif., USA, Cat. No. sc-4114) and 2. mu. Ci of γ -32P-ATP in 1 Xkinase buffer per sample. The reaction was allowed to proceed at 30 ℃ for 30 minutes and stopped by adding 40. mu.l of 2 xSDS-sample buffer to the kinase reaction. Samples were boiled, centrifuged, and resolved on 15% SDS-PAGE. The dried SDS-PAGE gels were exposed to a phosphor-Imager screen and the radioactive PHAS-1 bands were quantified by STORM860 phosphor-Imager (Molecular Dynamics, Sunnyvale, Calif., USA) using ImageQuaNT software.

In this assay, compound 112 was found to be a potent p38 MAP kinase inhibitor, IC₅₀Was 2 nM.

Mouse in vivo screening model of TNF-alpha response caused by LPS

To investigate the in vivo effect of the compounds of the invention, an in vivo screening model for the LPS-induced TNF-. alpha.response in mice was established as follows: groups of 6 mice (C3H/HeN, female, about 8 weeks (20g), Bomholtgaard) were given test compounds in suspension vehicle 1 hour prior to LPS administration (LPS from E.coli 055: B5, L-4005, Sigma). Mice were given 1.0mg LPS/kg intraperitoneally at time 0. After anaesthesia with Hypnorm/Dormicum, LPS administrationMice were allowed to bleed from the periorbital venous plexus 80-90 minutes after use. Blood samples were collected in tubes stabilized with EDTA and centrifuged at 4000rpm and 4 ℃ for 10 minutes. TNF-. alpha.plasma levels were analyzed by ELISA. Compound 156 of WO 98/32730 was used as reference compound. TNF-. alpha.plasma levels were determined using a sandwich ELISA. Microtiter plates were coated with monoclonal antibodies against murine TNF-. alpha., washed, and blocked with casein buffer. Murine TNF- α recombinant standard samples were added to each well of a microtiter plate and incubated. All standards were tested in triplicate and all plasma samples were tested in a single run. After incubation of the samples with the standards, the plates were washed, incubated with a biotinylated polyclonal secondary antibody against murine TNF- α and washed. The enzyme conjugate was added to all wells and incubated. Substrate was added and after 15 minutes at room temperature 1M H ₂SO₄The enzyme/substrate reaction was stopped. The color development (OD) was measured at 450nm on an ELISA reader and the background OD at 620nm was subtracted. The experiment was approved if the reference compound treated group showed a significant inhibition (p < 0.05) of the TNF-alpha response compared to the LPS treated control group. Results for the test compounds are expressed as percent inhibition compared to the LPS-treated control group. The compounds were tested at 10 mg/kg. The Mann-Whitney test was used to compare drug-treated groups to LPS-treated control groups (p < 0.05). The results are shown in Table 3.

Table 3.In vivo inhibition of TNF-alpha production by LPS (in%)

Compound numbering

Compound 10495

Compound 11296

Compound 11383

Compound 11472

Compound 11596

Compound 11695

Compound 11771

Compound 12086

Compound 12347

Compound 12679

Compound 12973

Compound 13170

Compound 14076

Compound 14146

Compound 14594

Compound 14789

Compound 14871

Compound 14989

Compound 15199

Compound 15299

Compound 15386

Compound 15591

Table 3.In vivo inhibition of TNF-alpha production by LPS (in%)

Compound numbering

Compound 15673

Compound 15783

Compound 16366

Compound 16476

Compound 16683

Compound 17087

Compound 17390

Compound 17464

Compound 17652

Compound 17867

Compound 18692

Compound 18895

Compound 19666

Compound 19876

Compound 20267

Compound 25149

Compound 26095

Compound 26487

Compound 26654

Compound 27865

Compound 42444

Reference Compound a 23

Reference compound a: (4- (2-Aminophenylamino) -2-chloro-2' -methylbenzophenone, compound 156 disclosed in WO 98/32730.

These results show that the compounds of the invention surprisingly show improved in vivo biological activity in terms of inhibiting the production of TNF- α by LPS in mice compared to the reference compound, thus making them potentially useful for the treatment of inflammatory diseases.

The invention is described in more detail in the following examples, which are not intended to limit the scope of the invention as claimed in any way.

Examples

General procedure

All melting points are uncorrected. For the¹H Nuclear Magnetic Resonance (NMR) Spectroscopy (300MHz) and¹³CNMR (75.6MHz), unless otherwise indicated, reference is made to tetramethylsilane (δ ═ 0) relative to the internal standard00) or chloroform (δ ═ 7.26) or deuterated chloroform (δ ═ 76.81, for¹³C NMR) of the deuterated chloroform solution (δ) (in ppm). Unless a range is quoted, multiple peaks at the approximate midpoint are given, whether by definition (doublet (d), triplet (t), quartet (q)) or not (m). All organic solvents used are anhydrous. Chromatography on silica gel using flash technology. An appropriate mixture of ethyl acetate, dichloromethane, methanol and petroleum ether (40-60) was used as eluent unless otherwise indicated.

The following abbreviations are used:

aq solution of aq

dba Diphenylmethylene acetone

DCM dichloromethane

DMAP 4-dimethylaminopyridine

DMF N, N-dimethylformamide

DIEA ethyl diisopropylamine

EDCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EtOAc ethyl acetate

FDPP Diphenyl-phosphinic acid pentafluorophenyl ester

h hours

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

min for

NMP N-methylmorpholine

NMR nuclear magnetic resonance

rac-BINAP rac 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl

RT Room temperature

TBAF tetra-n-butylammonium fluoride

TFA trifluoroacetic acid

THF tetrahydrofuran

THP tetrahydropyrans

TIPSCI Triisopropylsilane chloride

v volume

Compounds of the general formula I as embodied in Table 4

Preparation 1:

3- (2-chloro-4-nitrobenzoyl) -4-methylbenzoic acid methyl ester (Compound 401)

In a dry flask, methyl 3-iodo-4-methylbenzoate (21.6g, 78.2mmol) was added and the flask was evaporated, then filled with argon and the flask was allowed to dryThis process was repeated twice. Anhydrous THF (140ml) was added and the solution was cooled to-50 ℃; isopropyl magnesium chloride (41ml, 2.0M in ether, 82mmol) was then added slowly over 15 minutes, maintaining the temperature below-40 ℃. After the addition was complete, the reaction mixture was stirred at-40 ℃ for 45 minutes. ZnCl was added dropwise over 20 minutes₂A THF solution (10.78g, 79.1mmol, 0.8M). The reaction mixture was stirred at 0 ℃ for 65 minutes; then 2-chloro-4-nitro-benzoyl chloride (17.2g, 78.2mmol) and tetrakis (triphenylphosphine) palladium (0) (4.03g, 3.49mmol) were added and the reaction mixture was allowed to warm to room temperature. After 4 hours, the reaction mixture was poured into a toluene/EtOAc/water mixture, followed by shaking, and separation. The aqueous phase was extracted with two more portions of EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo to give the crude product. Crystallization from an EtOAc/petroleum ether (40-60) mixture afforded the title compound as a yellow solid. The mother liquor was concentrated in vacuo and purified by chromatography using DCM as eluent to obtain a second product of the title compound.

Preparation 2:

3- (4-amino-2-chlorobenzoyl) -4-methylbenzoic acid methyl ester (Compound 402)

To a solution of compound 401(7.83g, 23.5mmol) in methanol (100ml) was added zinc powder (15.3g, 235mmol) and ammonium chloride (6.27g, 117mmol) in one portion with stirring. Adding CaCl₂The tube was mounted on the flask, and the flask was placed in an oil bath at a temperature of 90 ℃. After 2 hours, the reaction mixture was cooled to room temperature, filtered, and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. Crystallization from a EtOAc/petroleum ether (40-60) (2: 3) mixture afforded the title compound as a pale yellow solid.

Preparation 3:

3- (4-amino-2-chlorobenzoyl) -4-methylbenzoic acid (Compound 403)

To a solution of compound 402(1.61g, 5.3mmol) in ethanol (50ml) was added sodium hydroxide solution (2M, 30ml), followed by stirring at reflux for 90 minutes. The reaction mixture was made weakly acidic (pH 5) by slow addition of hydrochloric acid (4N) and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo to give the title compound as an orange solid. Used without any further purification.

Preparation 4:

(4-amino-2-chlorophenyl) - [ 2-methyl-5- (morpholine-4-carbonyl) phenyl]-methanone (Compound 404)

To a solution of compound 403(150mg, 0.47mmol) in DMF (2.00ml) in a reaction vial (8ml) was added morpholine (41. mu.l, 0.47mmol), FDPP (253mg, 0.66mmol) and DIEA (402. mu.l, 2.35 mmol). The vial was flushed with argon, sealed, and then shaken at room temperature for 24 hours. The reaction mixture was concentrated in vacuo at 40 ℃ and then purified by chromatography using EtOAc/petroleum ether (40-60) 4: 1 followed by EtOAc as the eluent to give the title compound as an orange slurry.

Example 1:

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl]- [ 2-methyl-5- (morpholine-4-carbonyl) phenyl group]-methanones (chemotropes) Compound 101)

2-bromo-5-fluorotoluene (47. mu.l, 0.37mmol) was dissolved in 3ml of anhydrous 1, 4-dioxane in a vial under argon atmosphere. Compound 404(110mg, 0.31mmol) was added and dissolved in a solvent. racemic-BINAP (7.3mg, 0.012mmol), Pd were added₂(dba)₃(7.0mg, 0.008mmol) and Cs₂CO₃(141mg, 0.43mmol) and the reaction mixture was stirred under argon at 100 ℃ for 72 h. The reaction mixture was filtered and then purified by continuous gradient flash chromatography using EtOAc/petroleum ether (4) 0-60) (v: v ═ 0: 100 to 50: 50) as eluent to give the title compound as a brown oil.

¹³C NMR(CDCl₃)δ195.4，169.7，160.6，150.3，139.8，139.7，136.6，135.4，134.0，133.7，132.4，131.5，129.2，127.9，127.4，127.0，117.8，115.0，113.8，111.7，66.8，48.3，42.8，20.2，18.1。

Preparation 5:

(4-amino-2-chlorophenyl) - [ 2-methyl-5- (4-methylpiperazine-1-carbonyl) phenyl]-methanone (Compound 405)

The reaction was carried out as described in the preparation of compound 404 using N-methylpiperazine (52 μ l, 0.47mmol) as amine. Purification was done by flash chromatography to afford the title compound as a brown slurry.

Example 2:

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl]- [ 2-methyl-5- (4-methyl-piperazine-1-carbonyl) phenyl]- Ketone (Compound 102)

The reaction was carried out as described in the preparation of compound 101 using compound 405(143mg, 0.45mmol) as the amine. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³CNMR(CDCl₃)δ 195.5，169.6，160.6，150.1，139.6，139.5，136.5，135.5，134.0，133.7，133.0，131.4，129.2，128.0，127.4，127.4，117.9，115.0，113.9，111.7，54.8，47.8，46.0，42.1，20.2，18.1。

Preparation 6:

3- (4-amino-2-chlorobenzoyl) -N-methoxy-4, N-dimethylbenzamide (Compound 406)

The reaction was carried out as described in the preparation of compound 404 using the salt N, O-dimethylhydroxylamine hydrochloride (46mg, 0.47mmol) as the amine. Purification was accomplished by flash chromatography to afford the title compound as an orange solid.

Example 3:

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl]-N-methoxy-4, N-dimethylbenzamide (Compound 103)

The reaction was carried out as described in the preparation of compound 101 using compound 406(125mg, 0.38mmol) as the amine. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³CNMR(CDCl₃)δ195.6，168.9，160.6，150.0，140.7，139.2，136.5，135.5，133.9，133.8，131.1，131.0，130.5，129.5，127.7，127.3，117.9，115.1，113.9，111.7，65.9，61.1，20.4，15.3。

Preparation 7:

3- (4-amino-2-chlorobenzoyl) -4-methyl-N- (tetrahydrofuran-2-ylmethyl) benzamide (compound 407)

The reaction was carried out as described in the preparation of compound 404 using (tetrahydrofuran-2-yl) methylamine (31mg, 0.31mmol) as the amine. Purification was done by flash chromatography to afford the title compound as yellow oil.

Example 4:

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl]-4-methyl-N- (tetrahydrofuran-2-ylmethyl) Benzamide (Compound 104)

The reaction was carried out as described in the preparation of compound 101, using compound 407(85mg, 0.23mmol) as the amine. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³CNMR(CDCl₃)δ195.5，166.8，160.6，150.3，141.1，140.1，136.6，135.7，134.2，133.8，131.8，131.4，128.6，127.6，127.4，127.0，117.8，115.2，113.8，111.6，77.6，68.2，43.7，28.7，25.9，20.2，18.1。

Preparation 8:

(ation) of 3- (4-amino-2-chlorobenzoyl) -4, N-dimethyl-N- (tetrahydrofuran-2-ylmethyl) benzamide Compound 408)

The reaction was carried out as described in the preparation of compound 404 using methyl (tetrahydrofuran-2-ylmethyl) amine (36mg, 0.31mmol) as the amine. Purification was done by flash chromatography to afford the title compound as yellow oil.

Example 5:

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl]-4, N-dimethyl-N- (tetrahydrofuran-2-yl) Methyl) benzamide (compound 105)

The reaction was carried out as described in the preparation of compound 101, using compound 408(85mg, 0.23mmol) as the amine. Purification was done by flash chromatography to afford the title compound as a brown slurry.¹HNMR(CDCl₃)δ7.41-7.24(m，4H)，7.15(dd，1H)，6.97(dd，1H)，6.90(dt，1H)，6.61(d，1H)，6.48(dd，1H)，6.23(bs，1H)，4.17-3.0(m，8H)，2.41(s，3H)，2.21(s，3H)，2.0-1.45(m，4H)。

Preparation 9:

3- (4-amino-2-chlorobenzoyl) -N- (2-methoxyethyl) -4-methylbenzamide (Compound 409)

The reaction was carried out as described in the preparation of compound 404 using 2-methoxyethylamine (23mg, 0.31mmol) as the amine. Purification was done by flash chromatography to afford the title compound as yellow oil.

Example 6:

3- [ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) benzoyl]-N- (2-methoxyethyl) -4-methylbenzyl Amide (Compound 106)

The reaction was carried out as described in the preparation of compound 101 using compound 409(60mg, 0.17mmol) as the amine. Purification was accomplished by flash chromatography to afford the title compound as a syrup.¹³CNMR(CDCl₃)δ 195.6，166.9，160.7，150.2，141.2，140.1，136.5，135.7，134.2，133.6，131.7，131.4，128.7，127.6，127.3，127.3，117.8，115.2，113.9，111.7，71.1，58.9，39.8，20.3，18.1。

Preparation 10:

3- (4-amino-2-chlorobenzoyl) -4-methyl-N- (3-morpholin-4-ylpropyl) benzamide (Compound 410)

The reaction was carried out as described in the preparation of compound 404, using 3-morpholin-4-yl-propylamine (45mg, 0.31mmol) as the amine. Purification was done by flash chromatography to afford the title compound as a foam.

Example 7:

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl]-4-methyl-N- (3-morpholin-4-yl-propyl) benzene Carboxamide (Compound 107)

The reaction was carried out as described in the preparation of compound 101, using compound 410(37mg, 0.09mmol) as the amine. Purification was done by flash chromatography to afford the title compound as a brown oil.¹³CNMR(CDCl₃)δ195.6，166.6，160.6，150.3，140.8，140.3，136.5，135.7，133.7，133.7，131.3，128.6，127.3，127.3，117.8，115.2，113.9，111.7，66.9，58.7，53.9，40.6，24.2，20.2，18.1。

Preparation 11:

(4-amino-2-chlorophenyl) - {5- [4- (2-methoxyethyl) piperazine-1-carbonyl]-2-methylphenyl } -methanone Compound 411)

The reaction was carried out as described in the preparation of compound 404 using 1- (2-methoxyethyl) piperazine (45mg, 0.31mmol) as the amine. Purification was done by flash chromatography to afford the title compound as a foam.

Example 8:

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl]- {5- [4- (2-methoxyethyl) piperazine-1-carbonyl]-2- Methylphenyl } -methanone (Compound 108)

The reaction was carried out as described in the preparation of compound 101 using compound 411(90mg, 0.22mmol) as the amine. Purification was done by flash chromatography to afford the title compound as yellow oil.¹³CNMR(CDCl₃)δ195.5，169.5，160.6，150.3，139.6，139.4，136.5，135.4，134.0，133.8，132.9，131.4，129.1，127.9，127.3，127.0，117.8，115.0，113.8，111.6，70.0，58.9，57.8，53.8，53.2，47.7，42.1，20.2，18.1。

Preparation 12:

3- (4-amino-2-chlorobenzoyl) -4-methyl-N-pyridin-4-ylmethyl benzamide (Compound 412)

The reaction was carried out as described in the preparation of compound 404 using C-pyridin-4-yl-methylamine (31 μ l, 0.31mmol) as the amine. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.

Example 9:

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl]-4-methyl-N-pyridin-4-ylmethyl benzoyl Amine (Compound 109)

Reaction as in compound 101Using compound 412(100mg, 0.26mmol) as the amine. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.¹³CNMR(DMSO-d₆)δ194.3，165.5，159.5，151.0，149.4，148.4，139.7，136.2，134.3，134.1，131.2，131.1，131.0，128.9，127.1，127.0，124.9，122.1，117.4，114.1，113.5，111.0，41.7，19.5，17.6。

Preparation 13:

3- (4-amino-2-chlorobenzoyl) -4-methyl-N-pyridin-2-ylmethyl-benzamide (Compound 413)

The reaction was carried out as described in the preparation of compound 404 using C-pyridin-2-yl-methylamine (31 μ l, 0.31mmol) as the amine. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.

Example 10:

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl]-4-methyl-N-pyridin-2-ylmethyl benzoyl Amine (Compound 110)

The reaction was carried out as described in the preparation of compound 101 using compound 413(79mg, 0.21mmol) as the amine. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.¹³CNMR(DMSO-d₆)δ194.3，165.3，159.5，151.0，148.8，148.0，139.7，139.6，136.2，135.1，134.9，134.3，134.1，131.2，131.0，128.9，127.1，127.0，124.9，123.4，117.4，114.1，113.4，111.0，40.3，19.5，17.6。

Preparation 14:

3- (4-amino-2-chlorobenzoyl) -4-methyl-N-pyridin-3-ylmethyl-benzamide (Compound 414)

The reaction was carried out as described in the preparation of compound 404 using C-pyridin-3-yl-methylamine (31 μ l, 0.31mmol) as the amine. Purification was done by flash chromatography to afford the title compound as a yellow foam.

Example 11:

3- [ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -benzoyl]-4-methyl-N-pyridin-3-ylmethyl-benzyl Amide (Compound 111)

The reaction was carried out as described in the preparation of compound 101 using compound 414(90mg, 0.24mmol) as the amine. Purification was accomplished by flash chromatography to afford the title compound as a solid.¹³CNMR(DMSO-d₆)δ194.4，165.3，159.4，157.8，150.9，148.7，139.7，136.6，136.2，134.3，134.2，134.1，131.3，131.0，128.9，127.1，127.0，125.0，122.0，120.9，117.4，114.1，113.4，111.0，44.6，19.5，17.6。

Preparation 15:

3- [ 2-chloro-4- (2-nitrophenylamino) benzoyl]-4-Methylbenzoic acid methyl ester (Compound 415)

To a Schlenk tube, compound 402(4.00g, 13.1mmol) in 1, 4-dioxane (40ml), 1-iodo-2-nitro-benzene (3.91g, 15.7mmol), Cs were added₂CO₃(5.98g，18.3mmol)、Pd₂(dba)₃(302mg, 0.33mmol) and rac-BINAP (308mg, 0.49 mmol). The tube was capped with a rubber septum, flushed with argon for 5 minutes, and then stirred at 100 ℃ for 2 hours. The reaction mixture was allowed to cool to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted twice with more EtOAc. The combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with petroleum ether (40-60)/EtOAc 4: 1 to give the title compound as a yellow solid.

Preparation 16:

3- [ 2-chloro-4- (2-nitrophenylamino) benzoyl ]-4-Methylbenzoic acid (Compound 416)

To a suspension of compound 415(3.00g, 7.06mmol) in methanol (20ml) was added water (4.0ml), followed by lithium hydroxide (845mg, 35 mmol). The mixture was then stirred at reflux for 30 minutes by slow addition of H₂SO₄(1N) the reaction mixture was made acidic (pH 5) and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was triturated in EtOAc/pentane 1: 1(20mL) to give the title compound as a yellow solid.

Preparation 17/example 271:

3- [ 2-chloro-4- (2-nitrophenylamino) benzoyl]-N- (2-hydroxyethyl) -4-methylbenzamide (compound) Thing 417)

To a solution of compound 416(2.42g, 5.90mmol) in DMF (20ml) were added 2-amino-ethanol (541mg, 8.85mmol), FDPP (2.72g, 7.08mmol) and DIEA (5ml, 30mmol) at 0 ℃. The flask was flushed with argon and the temperature was returned to room temperature. The reaction mixture was stirred at room temperature for 5 hours, then poured into water (100ml), H₂SO₄(1N, 40ml) and EtOAc (100ml) in a mixture. The phases were separated and the aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with DCM/methanol 100: 2 to give the title compound as an orange solid.

Example 12:

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl]-N- (2-hydroxyethyl) -4-methylbenzamide (compound) Thing 112)

To a solution of compound 417(2.21g, 4.87mmol) in methanol (40ml) was added zinc powder (3.18g,48.7mmol) and ammonium chloride (1.30g, 24.3 mmol). Adding CaCl₂The tube was mounted on the flask, and the flask was placed in an oil bath at a temperature of 90 ℃. After 1 hour, the reaction mixture was cooled to room temperature, filtered, and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography eluting with DCM/methanol 100: 5 (v: v) followed by 100: 7 (v: v) to give the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.7，167.8，150.3，142.8，141.2，140.1，135.6，134.2，131.4，128.9，127.8，127.4，127.0，126.8，125.0，119.2，116.5，115.4，111.9，62.1，42.9，20.2。

Preparation 18:

3- [4- (4-bromo-2-nitrophenylamino) -2-chlorobenzoyl]-4-Methylbenzoic acid methyl ester (Compound 418)

To a solution of compound 402(1.00g, 3.29mmol) and 4-bromo-1-fluoro-2-nitrobenzene (0.4ml, 3.29mmol) in DMSO (7.0ml) was slowly added potassium tert-butoxide (816mg, 7.27mmol) with stirring. After 4 hours at room temperature the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography, eluting with petroleum ether (40-60)/EtOAc 9: 1, to give the title compound as an orange solid.

Preparation 19:

3- [4- (4-bromo-2-nitrophenylamino) -2-chlorobenzoyl]-4-Methylbenzoic acid (Compound 419)

To a suspension of compound 418(540mg, 1.07mmol) in methanol (5ml) was added water (0.5ml) and lithium hydroxide (128mg, 5.35 mmol). Then, the mixture was stirred under reflux for 3 hours. The reaction mixture was made acidic (pH 2) by slow addition of HCl (aqueous solution) (1N),then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the title product as an orange solid. Used without any further purification.

Preparation 20/example 273:

3- [4- (4-bromo-2-nitrophenylamino) -2-chlorobenzoyl]-N- (2-hydroxyethyl) -4-methylbenzamide (Compound 420)

The reaction was carried out as described in the preparation of compound 404 using 2-aminoethanol (56 μ l, 0.94mmol) as amine and compound 419(461mg, 0.94mmol) as carboxylic acid. Purification was accomplished by flash chromatography to afford the title compound as an orange solid.

Example 13:

3- [4- (2-amino-4-bromophenylamino) -2-chlorobenzoyl]-N- (2-hydroxyethyl) -4-methylbenzamide (Compound 113)

The reaction was carried out as described in the preparation of compound 112 using compound 420(280mg, 0.53mmol) as the nitro compound. Purification was accomplished by flash chromatography to afford the title compound as a solid.¹³C NMR(CD3OD)δ197.7，169.5，152.8，147.0，142.0，141.8，136.7，135.4，133.1，132.4，130.2，129.4，128.6，127.2，125.4，121.3，121.3，119.4，116.2，112.7，61.6，43.6，20.2。

Preparation 21:

3- [4- (4-bromo-2-methylphenylamino) -2-chlorobenzoyl]-4-Methylbenzoic acid methyl ester (Compound 421)

To a reaction vial were added compound 402(100mg, 0.33mmol) in 1, 4-dioxane (1.0ml), 4-bromo-1-iodo-2-toluene (56 μ l, 0.38mmol), Cs₂CO₃(15mg，0.46mmol)、Pd₂(dba)₃(7.5mg, 0.008mmol) and rac-BINAP (7.7mg, 0.012 mmol). The tube was flushed with argon for 5 minutes, sealed and then stirred in a microwave oven at 150 ℃ for 1 hour. The reaction mixture was allowed to cool to room temperature and then poured into EtOAc. Filtration and concentration in vacuo afforded the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 10: 90 to 30: 70) as eluent to afford the title compound as an orange solid.

Preparation 22/example 274:

3- [4- (4-bromo-2-methylphenylamino) -2-chlorobenzoyl]-4-Methylbenzoic acid (Compound 422)

The reaction was carried out as described in the preparation of compound 419 using compound 421(525mg, 1.11mmol) as the ester. Purification was accomplished by flash chromatography to afford the title compound as an orange solid.¹³CNMR(DMSO-d₆)δ194.2，166.5，149.8，141.7，139.5，137.8，135.1，133.8，133.8，133.5，131.5，131.1，129.5，129.2，128.2，125.7，125.6，116.7，114.8，111.8，19.8，17.4。

Example 14:

3- [4- (4-bromo-2-methylphenylamino) -2-chlorobenzoyl]-N- (2-hydroxyethyl) -4-methylbenzamide (Compound 114)

The reaction was carried out as described in the preparation of compound 404 using 2-aminoethanol (58. mu.l, 0.97mmol) as amine and compound 422(431mg, 0.97mmol) as carboxylic acid. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.¹³C NMR(DMSO-d₆)δ194.6，165.2，149.8，139.4，139.4，137.8，135.1，134.1，133.9，133.5，131.7，130.9，129.5，128.9，127.0，125.7，125.5，116.6，115.0，111.8，59.6，42.1，19.5，17.4。

Preparation 23:

3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl]-4-Methylbenzoic acid methyl ester (Compound 423)

To a reaction vial was added compound 402(750mg, 2.47mmol), 1-bromo-2, 4-difluorobenzene (0.33ml, 2.96mmol), Cs in toluene (7.5ml)₂CO₃(1.13g，3.46mmol)、Pd₂(dba)₃(114mg, 0.12mmol) and rac-BINAP (116g, 0.18 mmol). The tube was flushed with argon for 5 minutes, sealed and then slowly warmed to 200 ℃. The reaction vial was shaken at 200 ℃ for 4 hours. The reaction mixture was allowed to cool to room temperature and then poured into EtOAc. Filtration and concentration in vacuo afforded the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 2: 98 to 20: 80) as eluent to afford the title compound as a brown slurry.

Preparation 24/example 275:

3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl]-4-Methylbenzoic acid (Compound 424)

The reaction was carried out as described in the preparation of compound 419 using compound 423(360mg, 0.87mmol) as an ester. Purification was accomplished by flash chromatography to afford the title compound as an orange solid.¹³CNMR(DMSO-d₆)δ194.4，166.5，158.8(dd)，155.8(dd)，149.5，141.8，139.3，133.6，131.9，131.5，131.2，129.4，128.3，126.5(m)，126.3，124.1(dd)，114.7，112.0(dd)，111.8，105.0(dd)，19.8。

Preparation 25/example 276:

2-methacrylic acid 2- {3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl]-4-methylbenzoylamino Ethyl ester (Compound 425)

The reaction was as described in the preparation of compound 404, using 2-aminoethyl 2-methacrylate(54mg, 0.33mmol) as amine and compound 424(120mg, 0.30mmol) as carboxylic acid. Purification was done by flash chromatography to afford the title compound as an orange foam.¹³CNMR(CDCl₃)δ 195.5，167.8，166.8，159.2(dd)，155.6(dd)，148.1，141.6，139.7，135.9，135.3，133.7，131.7，131.6，128.9，128.8，127.8，126.3，124.5(dd)，124.2(dd)，116.2，112.8，111.6(dd)，105.0(dd)，63.4，39.7，20.4，18.3。

Example 15:

3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl](meth) acrylic acid (meth) -2-hydroxyethyl-4-methylbenzamide Compound 115)

To a suspension of compound 425(95mg, 0.19mmol) in methanol (1.0ml) was added water (0.1ml) and lithium hydroxide (23mg, 0.95 mmol). The mixture was then stirred at reflux for 45 minutes. The reaction mixture was made acidic (pH 2) by slow addition of HCl (aq) (1N) and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) (v: v. 4: 1 and 6: 1) as eluent to give the title compound as a yellow oil.¹³CNMR(CDCl₃)δ195.6，167.7，159.4，155.7，148.3，141.5，139.8，135.4，133.8，131.6，131.5，129.0，128.6，127.7，124.6，124.2，116.2，112.8，111.7，105.0，62.3，42.9，20.3。

Preparation 26/example 277:

3- [ 2-chloro-4- (2-nitrophenylamino) benzoyl]-N- (2-methoxyethyl) -4-methylbenzamide (Compound 426)

To a solution of compound 409(85mg, 0.25mmol) and 1-fluoro-2-nitrobenzene (26. mu.l, 0.25mmol) in DMSO (2.0ml) was added potassium tert-butoxide (62mg, 0.55mmol) with stirring. In thatAfter 2.5 hours at room temperature the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography eluting with DCM/EtOAc 4: 1 to give the title compound as an orange oil.

Example 16:

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl]-N- (2-methoxyethyl) -4-methylbenzamide (Compound 116)

The reaction was carried out as described in the preparation of compound 112 using compound 426(72mg, 0.15mmol) as the nitro compound. Purification was done by flash chromatography to afford the title compound as a yellow foam. ¹³C NMR(DMSO-d₆)δ194.4，165.2，151.2，144.0，139.9，139.2，134.1，134.0，131.5，130.8，128.7，126.8，126.6，126.2，124.4，123.9，116.3，115.4，114.2，111.2，70.3，59.6，57.8，19.4。

Preparation 27:

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl]-4-Methylbenzoic acid methyl ester (Compound 427)

The reaction was carried out as described in the preparation of compound 112 using compound 415(1.8g, 4.38mmol) as the nitro compound. Purification was accomplished by flash chromatography to afford the title compound as a yellow slurry.

Preparation 28:

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl]-4-methylbenzoic acid (compound 428)

To a solution of compound 427(735mg, 1.86mmol) in ethanol (10ml) was added sodium hydroxide solution (2M, 10 ml). Then, the mixture was stirred under reflux for 2 hours. By slow addition of glacial acetic acid (5.0 ml)) The reaction mixture was made weakly acidic (pH 5) and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using DCM/methanol (v: v ═ 90: 10 to 85: 15) as eluent to afford the title compound as a yellow slurry.¹³C NMR(CD₃OD)δ197.5，169.1，153.3，145.1，143.6，141.7，136.6，135.3，132.6，132.5，131.1，129.6，128.5，128.1，126.8，126.6，119.4，117.6，116.0，112.6，20.4。

Example 17:

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl]-N-ethyl-4-methylbenzamide (Compound 117)

The reaction was carried out as described in the preparation of compound 404 using ethylamine hydrochloride (11mg, 0.14mmol) as the amine and compound 428(54mg, 0.14mmol) as the carboxylic acid. Purification was done by flash chromatography to afford the title compound as yellow oil. ¹³C NMR(CDCl₃)δ 195.7，166.8，162.6，150.4，142.9，140.8，140.1，135.6，134.2，132.0，131.3，128.7，127.6，127.3，127.0，126.7，125.1，118.9，116.4，115.4，111.8，35.0，20.2，14.8。

Example 18:

3- [4- (2-Aminophenylamino) -2-chlorobenzoyl]-N- (3-hydroxypropyl) -4-methylbenzamide (Compound) Thing 118)

The reaction was carried out as described for the preparation of compound 404, using 3-aminopropan-1-ol (11 μ l, 0.14mmol) as amine and compound 428(54mg, 0.14mmol) as carboxylic acid. Purification was done by flash chromatography to afford the title compound as yellow oil.¹³C NMR(CDCl₃)δ195.8，167.7，150.4，142.9，141.1，140.1，135.6，134.2，131.5，131.4，128.8，127.7，127.4，127.0，126.6，125.1，119.1，116.5，115.4，111.8，60.0，37.4，31.8，20.2。

Preparation 29:

3- (4-amino-2-chlorobenzoyl) -N- (2-hydroxyethyl) -4-methylbenzamide (Compound 429)

The reaction was carried out as described in the preparation of compound 404 using 2-aminoethanol (190. mu.l, 3.13mmol) as amine and compound 403(1.00g, 3.13mmol) as carboxylic acid. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.

Preparation 30:

3- (4-amino-2-chlorobenzoyl) -N- [2- (tert-butyldimethylsilyloxy) ethyl]-4-methyl group Benzamide (Compound 430)

A solution of compound 429(490mg, 1.47mmol), 1, 5-diazabicyclo (5.4.0) undec-5-ene (0.9ml, 5.88mmol) and tert-butylchlorodimethylsilane (777mg, 5.15mmol) in acetonitrile (2.0ml) was stirred under argon for 2 hours. The reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo to give a syrup. The slurry was stirred in a mixture of ethanol (5.0ml) and glacial acetic acid (0.5ml) for 18 h and then poured into an EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography eluting with DCM/EtOAc (v: v ═ 4: 1) to give the title compound as a yellow foam.

Example 19:

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl]-N- (2-hydroxyethyl) -4-methylbenzamide (Compound 119)

Under the argon atmosphere, the reaction solution is added,in a vial, 2-bromo-5-fluorotoluene (8 μ l, 0.11mmol) was dissolved in 1ml anhydrous 1, 4-dioxane. Compound 430(42mg, 0.09mmol) was added and dissolved in a solvent. Add rac-BINAP (2.1mg, 0.003mmol), Pd₂(dba)₃(2.0mg, 0.002mmol) and Cs₂CO₃(41mg, 0.13mmol) and the reaction mixture was stirred under argon at 100 ℃ for 72 h. The reaction mixture was filtered and then dissolved in THF (1.00 ml). Tetrabutylammonium fluoride trihydrate (37mg, 0.12mmol) was added to the solution and the mixture was stirred at 60 ℃ for 45 minutes. The reaction mixture was poured into EtOAc/water mixture. Mixing the organic phase with Na ₂CO₃(aqueous solution), Water washing, and drying (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography, eluting with EtOAc, to give the title compound as a yellow/brown oil.¹³C NMR(CDCl₃)δ195.6，167.8，160.6，150.4，141.2，140.2，136.5，135.7，134.3，133.6，131.5，131.4，128.8，127.4，127.4，126.9，117.8，115.2，113.9，111.7，77.2，62.2，42.9，20.2，18.1。

Preparation of 31:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoic acid methyl ester (Compound 431)

1-bromo-4-chloro-2-fluorobenzene (820 μ l, 6.58mmol) was dissolved in 20ml of anhydrous 1, 4-dioxane under an argon atmosphere. Compound 402(2.00g, 6.58mmol) was added and dissolved in the solvent. Dicyclohexyl- (2 ', 4 ', 6 ' -triisopropyl-biphenyl-2-yl) -phosphane (125mg, 0.26mmol), Pd (OAc) were added₂(30mg, 0.13mmol) and Cs₂CO₃(2.68g, 8.22mmol) and the reaction mixture was stirred under argon at 120 ℃ for 48 h. The reaction mixture was filtered and then purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 9 as the eluent to give the title compound as a solid.

Preparation 32/example 278:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoic acid (Compound 432)

The reaction was carried out as described in the preparation of compound 416, using compound 431(1.71g, 3.96mmol) as the ester. The title compound was used without any further purification. ¹³CNMR(DMSO-d₆)δ194.6，166.7，154.8(d)，148.3，141.7，139.0，133.3，131.5，131.4，129.5，128.8，127.7(d)，127.2(d)，127.2，125.2(d)，124.8(d)，116.9(d)，115.6，112.7，19.9。

Preparation 33:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoyl chloride (Compound 433)

To a suspension of compound 432(100mg, 0.24mmol) in toluene (2ml) was added thionyl chloride (35. mu.l, 0.48mmol), followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 20:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methyl-benzoyl Amine (Compound 120)

A solution of compound 433(80mg, 0.18mmol), DIEA (31. mu.l, 0.18mmol) and 2-amino-ethanol (22. mu.l, 0.37mmol) in dry DCM (2ml) was stirred until the reaction was complete by TLC (1 h). The reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 40: 60 to 100: 0) as the eluent gave the title compound as a brown oil.¹³C NMR(CDCl₃)δ195.8，167.7，154.4(d，J＝248Hz)，147.2，141.5，139.6，135.2，133.7，131.6，131.5，129.1，129.1，128.7(d，J＝9.5Hz)，127.8，127.2(d，J＝11.7Hz)，124.9(d，J＝3.6Hz)，122.4(d)，117.1，117.0(d，J＝22.8Hz)，113.6，62.1，42.9，20.4。

Example 21:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4, N-dimethyl-benzamide (compound) 121)

The reaction was carried out in a similar manner using methylamine (0.13mmol) as the amine as described in the preparation of compound 120.¹³C NMR(CDCl₃)δ195.7，167.4，154.4(d)，147.1，141.4，139.4，135.1，133.5，132.0，131.6，129.3，129.0，128.6(d)，127.8，127.3(d)，124.9(d)，122.4(d)，117.1，117.0(d)，113.6，26.8，20.4。

Example 22:

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoylamino } -acetamido Yl) -Ethyl acetate (Compound 122)

The reaction was carried out in an analogous manner as described in the preparation of compound 120, using (2-amino-acetylamino) -acetic acid ethyl ester (0.13mmol) as amine.¹³C NMR(DMSO-d₆)δ194.8，169.6，169.4，165.4，154.8(d)，148.3，139.9，139.1，133.6，133.5，131.3，131.0，129.4，127.7(d)，127.5，127.2(d)，127.1，125.2(d)，124.8(d)，117.0(d)，115.7，112.6，60.3，42.3，40.6，19.6，14.0。

Example 23:

{3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoylamino } -acetic acid ethyl ester (Compound 123)

The reaction was as described in the preparation of compound 120, using amino-acetic acidEthyl ester (0.13mmol) as amine was carried out in a similar manner.¹³C NMR(CDCl₃)δ195.6，170.0，166.7，154.4(d)，147.0，141.9，139.5，135.2，133.6，131.7，131.1，129.3，129.1，128.5(d)，128.1，127.3(d)，124.9(d)，122.3(d)，117.1，117.0(d)，113.7，61.7，41.9，20.4，14.1。

Example 24:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N- (2-methoxy-ethyl) -4-methyl-benzyl

Amide (Compound 124)

The reaction was carried out in a similar manner as described in the preparation of compound 120, using 2-methoxy-ethylamine (0.13mmol) as the amine.¹³C NMR(CDCl₃)δ195.7，166.7，154.4(d)，147.0，141.5，139.5，135.2，133.6，131.9，131.5，129.4，128.9，128.5(d)，128.0，127.3(d)，124.9(d)，122.3(d)，117.1，117.0(d)，113.7，71.1，58.8，39.8，20.4。

Example 25:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N-cyclohexyl-4-methyl-benzamide (compound) Thing 125)

The reaction was carried out in a similar manner as described in the preparation of compound 120, using cyclohexylamine (0.13mmol) as amine. ¹³C NMR(CDCl₃)δ195.7，165.8，154.4(d)，147.1，141.1，139.6，135.2，133.6，132.5，131.4，129.3，128.8，128.6(d)，127.8，127.3(d)，124.9(d)，122.4(d)，1 17.1，1 17.0(d)，113.6，48.9，33.2，25.5，24.9，20.4。

Example 26:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N-ethyl-4-methyl-benzamide (compound) 126)

The reaction was carried out in a similar manner as described in the preparation of compound 120, using ethylamine (0.13mmol) as amine.¹³C NMR(CDCl₃)δ195.7，166.6，154.4(d)，147.1，141.3，139.5，135.2，133.6，132.1，131.5，129.3，128.9，128.6(d)，127.8，127.3(d)，124.8(d)，122.4(d)，117.1，117.0(d)，113.6，35.0，20.4，14.8。

Example 27:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N- (6-hydroxy-hexyl) -4-methyl-benzoyl Amine (Compound 127)

The reaction was carried out in an analogous manner as described in the preparation of compound 120, using 6-aminohexanol (0.13mmol) as amine.¹³C NMR(CDCl₃)δ195.8，166.9，154.5(d)，147.3，141.2，139.5，135.1，133.6，132.1，131.5，129.0，129.0，128.6(d)，127.8，127.3(d)，124.8(d)，122.6(d)，117.1，117.0(d)，113.5，62.6，40.0，32.5，29.5，26.6，25.3，20.3。

Example 28:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N-isopropyl-4-methyl-benzamide (compound) Thing 128)

The reaction was carried out in a similar manner as described in the preparation of compound 120, using isopropylamine (0.13mmol) as the amine.¹³C NMR(CDCl₃)δ195.7，165.9，154.5(d)，147.2，141.1，139.6，135.2，133.6，132.3，131.4，129.2，128.8，128.6(d)，127.7，127.3(d)，124.8(d)，122.5(d)，117.1，117.0(d)，113.6，42.1，22.8，20.3。

Example 29:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzylAcyl radical]-N-isobutyl-4-methyl-benzamide (chemical combination) Thing 129)

The reaction was carried out in a similar manner as described in the preparation of compound 120, using isobutylamine (0.13mmol) as amine.¹³C NMR(CDCl₃)δ195.7，166.8，154.4(d)，147.1，141.3，139.5，135.1，133.6，132.3，131.5，129.3，128.8，128.6(d)，127.9，127.3(d)，124.8(d)，122.4(d)，117.1，1 17.0(d)，1 13.6，47.4，28.6，20.4，20.2。

Example 30:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N- (2, 2-dimethyl-propyl) -4-methyl-benzyl Amide (Compound 130)

The reaction was carried out in a similar manner as described in the preparation of compound 120, using 2, 2-dimethyl-propylamine (0.13mmol) as the amine. ¹³C NMR(CDCl₃)δ195.7，166.9，154.5(d)，147.2，141.3，139.6，135.1，133.6，132.4，131.5，129.2，128.7，128.6(d)，128.0，127.3(d)，124.8(d)，122.5(d)，117.1，117.0(d)，113.6，51.0，32.2，27.3，20.4。

Example 31:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N- (3-methoxy-propyl) -4-methyl-benzyl Amide (Compound 131)

The reaction was carried out in an analogous manner as described in the preparation of compound 120, using 3-methoxy-propylamine (0.13mmol) as amine.¹³C NMR(CDCl₃)δ195.7，166.4，154.4(d)，147.0，141.4，139.4，135.1，133.5，132.1，131.6，129.4，129.0，128.5(d)，127.9，127.3(d)，124.8(d)，122.4(d)，117.1，117.0(d)，113.6，72.4，58.8，39.2，28.7，20.4。

Example 32:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-N- [3- (2-oxo-pyrrolidine-1- Phenyl) -propyl]-benzamide (compound 132)

The reaction was carried out in a similar manner using 1- (3-amino-propyl) -pyrrolidin-2-one (0.13mmol) as the amine as described in the preparation of compound 120.¹³C NMR(CDCl₃)δ195.9，176.3，166.3，154.3(d)，146.8，141.5，139.2，135.0，133.4，131.8，131.6，129.7，128.9，128.7，128.1(d)，127.6(d)，124.8(d)，122.0(d)，117.3，116.9(d)，113.8，47.5，39.6，35.7，30.9，26.2，20.5，18.0。

Example 33:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N- (2-dimethylamino-ethyl) -4-methyl-benzene Carboxamide (Compound 133)

The reaction was carried out in a similar manner as described in the preparation of compound 120, using 2-dimethylamino-ethylamine (0.13mmol) as the amine.¹³C NMR(CDCl₃)δ195.8，166.7，154.5(d)，147.2，141.4，139.4，135.1，133.6，131.8，131.5，129.3，129.0，128.5(d)，128.3，127.4(d)，124.8(d)，122.6(d)，117.1，117.0(d)，113.6，57.8，44.9，37.0，20.4。

Example 34:

2-methyl-acrylic acid 2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoyl Amino } -ethyl ester (Compound 134)

The reaction was carried out in a similar manner as described in the preparation of compound 404, using 2-aminoethyl 2-methacrylate (61mg, 0.37mmol) as the amine and compound 432 as the acid (140mg, 0.33 mmol). Purification was done by flash chromatography to afford the title compound. ¹³C NMR(CDCl₃)δ195.6，167.8，166.7，154.5(d)，146.9，141.8，139.5，135.9，135.2，133.5，131.7，131.6，129.6，129.0，128.6(d)，128.0，127.3(d)，126.3，124.9(d)，122.1(d)，117.2，117.0(d)，113.8，63.4，39.7，20.4，18.3。

Example 35:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N-cis- (4-hydroxy-cyclohexyl) -4-methyl- Benzamide (Compound 135)

The reaction was carried out in an analogous manner as described in the preparation of compound 120, using 4-amino-cyclohexanol (0.13mmol) as amine.¹³C NMR(CDCl₃)δ195.6，165.9，154.3(d)，146.9，141.4，139.5， 135.2，133.6，132.3，131.6，129.6， 128.9， 128.5(d)，127.8，127.3(d)，124.9(d)，122.1(d)，117.3，117.0(d)，113.8，66.1，47.4，31.4，27.2，20.4。

Example 36:

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-N-trans- (4-hydroxy-cyclohexyl) -4-methyl- Benzamide (compound 136)

The reaction was carried out in an analogous manner as described in the preparation of compound 120, using 4-amino-cyclohexanol (0.13mmol) as amine.¹³C NMR(CDCl₃)δ195.6，166.0，154.4(d)，146.9，141.2，139.6，135.2，133.6，132.2，131.5，129.5，128.9，128.7(d)，127.7，127.2(d)，124.9(d)，122.2(d)，117.2，117.1(d)，113.7，69.8，48.3，34.0，30.9，20.4。

Example 37:

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoylamino } -ethyl) -ammonia Tert-butyl carbamate (Compound 137)

The reaction was carried out in a similar manner using (2-amino-ethyl) -carbamic acid tert-butyl ester (2.4mmol) as amine as described in the preparation of compound 120.¹³C NMR(DMSO-d₆)δ194.8，165.3，155.6，154.8(d)，148.4，139.6，139.2，133.6，133.6，131.8，131.0，129.2，127.8(d)，127.2，127.2(d)，127.1，125.2(d)，124.8(d)，117.0(d)，115.8，112.6，77.6，39.7，39.5，28.1，19.6。

Example 38:

n- (2-amino-ethyl) -3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoyl Amine (Compound 138)

A solution of compound 137(100mg, 0.8mmol) in a mixture of EtOAc (5ml), methanol (5ml) and 4M HCl (aq, 1.5ml) was stirred at 70 ℃ for 2 h. The crude mixture was concentrated in vacuo and purified by flash chromatography using MeOH/DCM/triethylamine 20: 80: 1 as eluent to afford the title compound. ¹³C NMR(DMSO-d₆)δ194.8，165.4，154.8(d)，148.4，139.6，139.2，133.6，133.5，131.7，131.0，129.2，127.7(d)，127.3，127.1(d)，127.0，125.2(d)，124.8(d)，117.0(d)，115.7，112.6，40.3，40.0，19.6。

Example 39:

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl]-4-methyl-benzoylamino } -acetamido Yl) -acetic acid (Compound 139)

To a suspension of compound 122(100mg, 0.18mmol) in methanol (2ml) was added water (0.2ml), followed by lithium hydroxide (21mg, 0.89 mmol). The mixture was then stirred at reflux for 90 minutes. By slow addition of H₂SO₄(1N) the reaction mixture was made acidic (pH 5) and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo. CoarseThe product was purified by flash chromatography using EtOAc containing 0 to 2% acetic acid as eluent to give the title compound as a yellow solid.¹³CNMR(DMSO-d₆)δ194.8，171.0，169.1，165.4，154.8(d)，148.3，139.9，139.2，133.5，131.3，131.0，129.4，127.7(d)，127.5，127.2(d)，127.1，125.2(d)，124.8，116.9(d)，115.8，112.6，42.3，40.7，19.6。

Preparation 34:

3- (2-chloro-4-nitro-benzoyl) -4-methoxy-benzoic acid methyl ester (Compound 434)

In a dry flask, 3-iodo-4-methoxy-benzoic acid methyl ester (8.9g, 30.5mmol) was added and the flask was evaporated, then filled with argon and this step was repeated twice. Anhydrous THF (50ml) was added and the solution was cooled to-50 ℃; then over 20 minutes isopropyl magnesium chloride (15.2ml, 2.0M in ether, 30.5mmol) was slowly added, keeping the temperature below-40 ℃. After the addition was complete, the reaction mixture was stirred at-40 ℃ for 45 minutes. ZnCl was added dropwise over 20 minutes ₂A THF solution (5.19g, 38.1mmol, 1.0M). The reaction mixture was stirred at 0 ℃ for 20 minutes; then 2-chloro-4-nitro-benzoyl chloride (7.04g, 32.0mmol) and Cu (OAc) were added₂(122mg, 0.61mmol) and the reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was poured into EtOAc/water mixture, followed by shaking and separation. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 6 followed by 1: 3 as eluent to afford the title compound as a yellow solid.

Preparation 35:

3- (4-amino-2-chloro-benzoyl) -4-methoxy-benzoic acid methyl ester (Compound 435)

The reaction was carried out in a similar manner as described in the preparation of compound 402, using compound 434(22.9mmol) as the nitro compound. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.

Preparation 36:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methoxy-benzoic acid methyl ester (compound) 436)

The reaction was carried out in an analogous manner to compound 435(3.28mmol) using 1-bromo-2, 4-difluorobenzene (3.94mmol) as described in the preparation of compound 431. Purification was done by flash chromatography to afford the title compound as a yellow foam.

Preparation 37/example 279:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methoxy-benzoic acid (Compound 437)

The reaction was carried out as described in the preparation of compound 416, using compound 436(0.92g, 2.13mmol) as the ester. The title compound was used without any further purification.¹³CNMR(DMSO-d₆)δ191.4，166.4，160.6，158.7(dd)，155.7(dd)，149.2，133.8，133.7，133.5，130.6，129.2，126.5，126.4(dd)，124.2(dd)，122.8，114.7，112.0，111.7，105.0(dd)，56.1。

Preparation 38:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methoxy-benzoyl chloride (compound 438)

To a suspension of compound 437(292mg, 0.7mmol) in toluene (3ml) was added thionyl chloride (100. mu.l, 1mmol), followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 40:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methoxy-benzyl Amide (Compound 140)

The reaction was carried out in a similar manner as described for the preparation of compound 120 using 2-amino-ethanol (0.28mmol) and compound 438(0.14 mmol). Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.¹³C NMR(DMSO-d₆)δ191.7，165.0，159.2，158.8(dd)，155.6(dd)，149.2，133.8，133.6，131.6，129.0，128.3，126.6，126.5，126.4(dd)，124.2(dd)，114.8，111.9(dd)，111.7，111.6，105.0(dd)，59.7，56.0，42.1。

Example 41:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2, 2-difluoro-ethyl) -4-methoxy-benzyl Amide (Compound 141)

The reaction was carried out in a similar manner as described in the preparation of compound 120 using 2, 2-difluoro-ethylamine (0.28mmol) and compound 438(0.14 mmol). Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.¹³C NMR(DMSO-d₆)δ191.6，165.5，159.5，158.8(dd)，155.6(dd)，149.2，133.8，133.6，131.8，129.2，128.4，126.5，126.4(dd)，125.5，124.2(dd)，114.8，114.5(t)，112.0(dd)，111.8，111.7，105.0(dd)，56.1，41.5。

Example 42:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-fluoro-ethyl) -4-methoxy-benzoyl Amine (Compound 142)

The reaction was carried out in a similar manner using 2-fluoro-ethylamine (0.28mmol) and compound 438(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ192.7，166.5，160.6，159.1(dd)，155.5(dd)，147.7，134.9，133.4，132.4，129.7，129.5，128.7，126.4，124.5(dd)，124.1(dd)，116.0，112.9，111.6(dd)，111.5，104.9(dd)，82.8(d)，56.1，40.5(d)。

Example 43:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2, 3-dihydroxy-propyl) -4-methoxy-benzene Carboxamide (Compound 143)

The reaction was carried out in a similar manner to compound 438(0.14mmol) using 3-amino-propane-1, 2-diol (0.28mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(DMSO-d₆)δ191.7，165.3，159.2，158.8(dd)，155.6(dd)，149.2，133.8，133.6，131.6，129.0，128.3，126.6，126.4，126.4(dd)，124.2(dd)，114.8，111.9(dd)，111.7，111.6，105.0(dd)，70.4，63.9，56.0，42.9。

Example 44:

n-carbamoylmethyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methoxy-benzyl Amide (Compound 144)

The reaction was carried out in a similar manner using 2-amino-acetamide (0.28mmol) and compound 438(0.14mmol) as described in the preparation of compound 120. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid. ¹³C NMR(DMSO-d₆)δ191.8，171.1，165.2，159.4，158.8(dd)，155.8(dd)，149.3，133.9，133.7，131.9，129.1，128.6，126.7，126.4(dd)，126.2，124.3(dd)，114.9，112.0(dd)，111.8，111.7，105.1(dd)，56.1，42.4。

Preparation 39:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoyl chloride (Compound 439)

To a suspension of compound 424(1.8g, 4.5mmol) in toluene (10ml) was added thionyl chloride (650. mu.l, 9.0mmol), followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 45:

n-carbamoylmethyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoyl Amine (Compound 145)

The reaction was carried out in a similar manner using 2-amino-acetamide (4.48mmol) and compound 439(2.24mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(DMSO-d₆)δ194.7，170.8，165.3，158.9(dd)，155.6(dd)，149.5，139.7，139.3，133.8，133.7，131.4，131.0，129.2，127.3，126.5(dd)，126.3，124.1(dd)，114.8，111.9(dd)，111.8，105.0(dd)，42.3，19.6。

Example 46:

n-benzyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzamide (Compound (I) 146)

The reaction was carried out in a similar manner using benzylamine (0.13mmol) and compound 439(0.11mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.6，166.6，159.2(dd)，155.7(dd)，148.4，141.4，139.8，138.1，135.3，133.8，131.7，131.5，128.9，128.7，128.3，127.9，127.8，127.6，124.8(dd)，124.2(dd)，116.1，112.6，111.6(dd)，104.9(dd)，44.1，20.3。

Example 47:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-fluoro-ethyl) -4-methyl-benzamide (Compound 147)

The reaction was carried out in a similar manner using 2-fluoro-ethylamine (0.13mmol) and compound 439(0.11mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.6，166.9，159.3(dd)，155.7(dd)，148.4，141.6，139.9，135.3，133.8，131.6，131.4，128.9，128.4，127.7，124.7(dd)，124.2(dd)，116.2，112.7，111.6(dd)，104.9(dd)，82.7(d)，40.5(d)，20.3。

Example 48:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzyl Amide (Compound 148)

The reaction was carried out in an analogous manner as described in the preparation of compound 120 using 2, 2, 2-trifluoro-ethylamine (0.13mmol) and compound 439(0.11 mmol). Purification was accomplished by flash chromatography to afford the title compound as a yellow slurry.¹³C NMR(CDCl₃)δ195.5，166.9，159.4(dd)，155.8(dd)，148.5，142.1，140.0，135.4，133.9，131.6，130.6，129.0，128.2，127.8，124.8(dd)，124.2(q)，124.1(dd)，116.2，112.7，111.7(dd)，105.0(dd)，41.1(q)，20.3。

Example 49:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N-ethyl-4-methyl-benzamide (compound) 149)

The reaction was carried out in a similar manner using ethylamine (0.13mmol) and compound 439(0.11mmol) as described in the preparation of compound 120. Purification by flash chromatographyComplete to give the title compound as yellow foam.¹³C NMR(CDCl₃)δ195.7，166.7，159.3(dd)，155.7(dd)，148.4，141.1，139.7，135.3，133.8，132.1，131.5，128.9，128.4，127.6，124.8(dd)，124.2(dd)，116.2，112.6，111.6(dd)，104.9(dd)，35.0，20.3，14.8。

Example 50:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N-cyclohexylmethyl-4-methyl-benzamide (Compound 150)

LEO15592-000

The reaction was carried out in a similar manner using cyclohexyl-methylamine (0.13mmol) and compound 439(0.11mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam. ¹³C NMR(CDCl₃)δ195.6，166.8，159.3(dd)，155.7(dd)，148.2，141.2，139.7，135.3，133.8，132.3，131.5，128.8，128.7，127.7，124.5(dd)，124.2(dd)，116.2，112.7，111.6(dd)，105.0(dd)，46.3，38.0，30.9，26.4，25.8，20.4。

Example 51:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-propyl) -4-methyl-benzoyl Amine (Compound 151)

The reaction was carried out in a similar manner using 1-amino-2-propanol (0.13mmol) and compound 439(0.11mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.7，167.6，159.3(dd)，155.7(dd)，148.4，141.4，139.8，135.4，133.9，131.6，131.5，129.1，128.4，127.7，124.7(dd)，124.2(dd)，116.2，112.7，111.6(dd)，105.0(dd)，67.4，47.6，21.0，20.3。

Example 52:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2, 3-dihydroxy-propyl) -4-methyl-benzyl Amide (Compound 152)

The reaction was carried out in a similar manner using 3-amino-propane-1, 2-diol (4.48mmol) and compound 439(2.24mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.8，168.3，159.3(dd)，155.8(dd)，148.6，141.5，139.9，135.4，134.0，131.5，130.9，129.2，128.0，127.6，124.8(d)，124.1(dd)，116.1，112.6，111.6(dd)，105.0(dd)，71.1，63.8，42.8，20.3。

Example 53:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (1-hydroxymethyl-propyl) -4-methyl-benzyl Amide (Compound 153)

The reaction was carried out in a similar manner using 2-amino-butan-1-ol (0.13mmol) and compound 439(0.11mmol) as described in the preparation of compound 120. Purification was accomplished by flash chromatography to afford the title compound as a yellow slurry.¹³C NMR(CDCl₃)δ195.7，167.4，159.3(dd)，155.7(dd)，148.5，141.2，139.8，135.4，133.9，131.8，131.4，128.9，128.2，127.7，124.8(dd)，124.2(dd)，116.2，112.6，111.6(dd)，105.0(dd)，64.9，53.8，24.2，20.3，10.7。

Example 54:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ]-4-methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -ketone Benzamide (compound 154)

The reaction was as described in the preparation of compound 120, using 2, 2, 3, 3, 3-pentafluoro-propylamine (0.13mmol)This was done in a similar manner to compound 439(0.11 mmol). Purification was accomplished by flash chromatography to afford the title compound as a yellow slurry.¹³C NMR(CDCl₃)δ195.4，166.9，159.4(dd)，155.7(dd)，148.4，142.2，140.0，135.4，133.8，131.7，130.6，129.0，128.4，127.9，124.8(dd)，124.1(dd)，116.2，112.7，111.7(dd)，105.0(dd)，39.2(t)，20.4。

Example 55:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (3-hydroxy-propyl) -4-methyl-benzoyl Amine (Compound 155)

The reaction was carried out in a similar manner using 3-amino-propanol (0.13mmol) and compound 439(0.11mmol) as described in the preparation of compound 120. Purification was accomplished by flash chromatography to afford the title compound as a yellow slurry.¹³C NMR(CDCl₃)δ195.7，167.6，159.3(dd)，155.7(dd)，148.4，141.4，139.8，135.3，133.8，131.5，128.9，128.4，127.7，124.8(dd)，124.2(dd)，116.2，112.7，111.6(dd)，105.0(dd)，60.0，37.4，31.9，20.3。

Example 56:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-1, 1-dimethyl-ethyl) -4-methyl Yl-benzamide (Compound 156)

The reaction was carried out in an analogous manner using 2-amino-2-methyl-propan-1-ol (0.28mmol) and compound 439(0.14mmol), as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.5，167.6，159.3(dd)，155.7(dd)，148.4，141.3，140.0，135.4，133.9，132.2，131.5，128.7，128.4，127.6，124.7(dd)，124.1(dd)，116.2，112.7，111.6(dd)，105.0(dd)，70.6，56.6，24.7，20.3。

Example 57:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl ester Yl) -4-methyl-benzamide (compound 157)

The reaction was carried out in an analogous manner using 2-amino-2-methyl-propane-1, 3-diol (0.28mmol) and compound 439(0.14mmol), as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.6，167.7，159.3(dd)，155.7(dd)，148.4，141.5，140.0，135.4，133.9，132.0，131.5，128.7，128.4，127.7，124.7(dd)，124.1(dd)，116.2，112.8，111.7(dd)，105.0(dd)，67.7，59.2，20.3，20.0。

Example 58:

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoylamino } -acetic acid ethyl ester (Compound 158)

The reaction was carried out in a similar manner using amino-ethyl acetate (0.28mmol) and compound 439(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.5，170.0，166.6，159.2(dd)，155.6(dd)，148.2，141.9，139.7，135.3，133.7，131.6，131.1，129.0，128.7，128.0，124.5(dd)，124.3(dd)，116.2，112.8，111.6(dd)，105.0(dd)，61.7，41.9，20.4，14.1。

Example 59:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (4-hydroxy-butyl) -4-methyl-benzoyl Amine (Compound 159)

The reaction was performed as described in the preparation of Compound 120, using 4-amino-butanol (0.28mmol) and reactingCompound 439(0.14mmol) was carried out in a similar manner. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.7，166.8，159.3(dd)，155.7(dd)，148.2，141.2，139.6，135.3，133.7，132.1，131.5，129.0，128.7，127.7，124.6(dd)，124.2(dd)，116.2，112.7，111.6(dd)，105.0(dd)，62.4，39.9，29.8，26.3，20.4。

Example 60:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (3-hydroxy-1, 1-dimethyl-butyl) -4-methyl Yl-benzamide (Compound 160)

The reaction was carried out in an analogous manner using 4-amino-4-methyl-pentan-2-ol (0.28mmol) and compound 439(0.14mmol), as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ 196.0，165.8，159.2(dd)，155.6(dd)，147.9，141.0，139.2，135.1，133.5，133.3，131.4，129.1，128.9，128.2，124.6(dd)，124.3(dd)，116.1，112.7，111.6(dd)，105.0(dd)，65.7，53.8，50.5，28.4，25.7，24.6，20.4。

Example 61:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-N- (3-phenyl-propyl) -benzoyl Amine (Compound 161)

The reaction was carried out in an analogous manner as described for the preparation of compound 120, using 3-phenyl-propylamine (0.28mmol) and compound 439(0.14 mmol). Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.6，166.6，159.3(dd)，155.6(dd)，148.2，141.4，141.2，139.6，135.3，133.8，132.0，131.5，128.8，128.7，128.6，128.4，127.6，126.1，124.6(dd)，124.2(dd)，116.2，112.7，111.6(dd)，105.0(dd)，39.9，33.5，31.0，20.3。

Example 62:

(R) -3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (1-hydroxymethyl-3-methyl-butyl) -4- Methyl-benzamide (compound 162)

The reaction was carried out in a similar manner using (R) -leucinol (0.28mmol) and compound 439(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.6，167.4，159.3(dd)，155.7(dd)，148.3，141.4，139.8，135.4，133.8，131.8，131.5，128.8，128.6，127.8，124.6(dd)，124.2(dd)，116.2，112.8，111.6(dd)，105.0(dd)，66.2，50.6，40.3，25.1，23.0，22.3，20.4。

Example 63:

3- [4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-fluoro-ethyl) -4-methyl-benzamide (compound) Thing 163)

The reaction was carried out in a similar manner using 2-fluoro-ethylamine (0.28mmol) and compound 439(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam. ¹³C NMR(CDCl₃)δ196.0，167.1，159.1(dd)，155.6(dd)，149.2，140.0，139.9，132.6，131.3，131.1，128.6，128.2，126.1，124.6(dd)，124.5(dd)，114.1，111.5(dd)，104.8(dd)，82.6(d)，40.5(d)，19.7。

Example 64:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N-isopropyl-4-methyl-benzamide (compound) Thing 164)

The reaction was as described in the preparation of compound 120, using isopropylamine (0)28mmol) was carried out in a similar manner to compound 439(0.14 mmol). Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.7，165.9，159.2(dd)，155.6(dd)，148.2，141.0，139.8，135.4，133.8，132.3，131.4，128.7，128.7，127.6，124.6(dd)，124.2(dd)，116.2，112.7，111.6(dd)，105.0(dd)，42.0，22.8，20.3。

Example 65:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N-cyclohexyl-4-methyl-benzamide (compound) Thing 165)

The reaction was carried out in a similar manner using cyclohexylamine (0.28mmol) and compound 439(0.14mmol), as described for the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.7，165.8，159.3(dd)，155.7(dd)，148.3，141.0，139.8，135.4，133.8，132.5，131.4，128.8，128.6，127.6，124.7(dd)，124.3(dd)，116.2，112.7，111.6(dd)，105.0(dd)，48.9，33.2，25.6，24.9，20.3。

Example 66:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2, 2-difluoro-ethyl) -4-methyl-benzoyl Amine (Compound 166)

The reaction was carried out in a similar manner using 2, 2-difluoro-ethylamine (0.28mmol) and compound 439(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.4，167.1，159.3(dd)，155.7(dd)，148.3，142.0，140.0，135.4，133.8，131.7，130.8，129.0，128.6，127.7，124.6(dd)，124.1(dd)，116.2，113.6(t)，112.8，111.7(dd)，105.0(dd)，42.3(t)，20.4。

Example 67:

5- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoylamino } -4-oxo-pentan Acid methyl ester (Compound 167)

The reaction was carried out in a similar manner using methyl 5-amino-4-oxo-pentanoate (0.28mmol) and compound 439(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ203.9，195.5，172.9，166.5，159.2(dd)，155.5(dd)，148.2，141.9，139.7，135.3，133.8，131.6，131.0，129.0，128.6，127.9，124.4(dd)，124.3(dd)，116.2，112.8，111.6(dd)，105.0(dd)，52.0，49.6，34.6，27.6，20.4。

Example 68:

n- [ (2-carbamoyl-ethylcarbamoyl) -methyl]-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzyl Acyl radical]-4-methyl-benzamide (compound 168)

The reaction was carried out in an analogous manner using 3- (2-amino-acetylamino) -propionamide (0.28mmol) and compound 439(0.14mmol) as described in the preparation of compound 120. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.¹³C NMR(CD₃OD)δ197.6，176.6，171.8，169.4，161.2(dd)，158.0(dd)，151.6，142.5，141.5，136.4，135.2，132.5，130.5，129.0，128.3，127.7(dd)，125.8(dd)，116.6，113.0，112.7(dd)，105.8(dd)，44.2，37.0，35.9，20.3。

Example 69:

(2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoylamino } -acetamido Yl) -Ethyl acetate (Compound 169)

Reactions such as preparation of Compound 120The reaction was carried out in an analogous manner to that described for compound 439(0.14mmol) using (2-amino-acetylamino) -acetic acid ethyl ester (0.28 mmol). Purification was done by flash chromatography to afford the title compound as a yellow foam.¹³C NMR(DMSO-d₆)δ194.7，169.7，169.4，165.4，158.9(dd)，155.7(dd)，149.4，139.9，139.4，133.8，133.8，131.2，131.0，129.3，127.4，126.5(dd)，126.4，124.1(dd)，114.9，112.0(dd)，111.8，105.0(dd)，60.3，42.2，40.5，19.6，14.0。

Example 70:

n-allyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ]-4-methyl-benzamide (compound) Thing 170)

The reaction was carried out in a similar manner using allylamine (0.50mmol) and compound 439(0.25mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ195.6，166.5，159.3(dd)，155.6(dd)，148.1，141.5，139.7，135.3，134.0，133.7，131.8，131.6，128.9，128.8，127.7，124.5(dd)，124.2(dd)，116.9，116.2，112.8，111.6(dd)，105.0(dd)，42.5，20.4。

Example 71:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-N- (2-sulfamoyl-ethyl) -benzene Carboxamide (Compound 171)

The reaction was carried out in an analogous manner using 2-amino-ethanesulfonamide (0.50mmol) and compound 439(0.25mmol), as described for the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(DMSO-d₆)δ194.6，165.3，158.8(dd)，155.8(dd)，149.5，139.8，139.5，133.8，131.4，131.1，129.0，127.1，126.5(dd)，126.2，124.1(dd)，114.9，112.0(dd)，111.8，105.0(dd)，53.5，34.7，19.6。

Example 72:

n- (2-acetylamino-ethyl) -3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzene Carboxamide (Compound 172)

The reaction was carried out in an analogous manner using N- (2-amino-ethyl) -acetamide (0.50mmol) and compound 439(0.25mmol), as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ195.9，172.1，167.6，159.3(dd)，155.8(dd)，148.6，141.3，139.8，135.3，133.8，131.5，131.3，129.0，128.1，127.9，124.9(dd)，124.2(dd)，116.2，112.5，111.6(dd)，104.9(dd)，40.9，39.8，23.0，20.3。

Preparation 40:

4-bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (Compound 440)

A mixture of 4-bromo-3-chlorobenzoic acid (5.00g, 21.24mmol), 2' -dithiodipyridine (4.68g, 21.24mmol) and triphenylphosphine (5.57g, 21.24mmol) in acetonitrile (150ml) was stirred at room temperature for 0.5 h. The crystals were filtered and washed with petroleum ether to give the title compound.

Preparation 41:

3- (4-bromo-2-chloro-benzoyl) -4-methoxy-benzoic acid methyl ester (compound 441)

To a solution of 3-iodo-4-methoxy-benzoic acid methyl ester (6.31g, 21.6mmol) in THF (20ml) at-50 deg.C was added a 2M solution of isopropyl magnesium chloride in THF (11.0ml, 22.00 mmol). The reaction mixture was stirred at the same temperature for 30 minutes. Then compound 440(5.91g, 18mmol) was added. The solution was allowed to warm to room temperature and stirred at the same temperature for 2 hours. Then with NH₄The solution was quenched with saturated aqueous Cl. The aqueous phase was extracted twice with diethyl ether.The combined organic phases were washed with MgSO₄Dried and concentrated in vacuo. The crude material was dissolved in ethyl acetate and silica gel was added. The mixture was concentrated in vacuo. The residue was chromatographed (petroleum ether/ethyl acetate 5: 1) to provide the title compound as an oil which solidified to a white solid.

Preparation 42:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-4-methoxy-benzoic acid methyl ester (compound) 442)

Compound 441(4.65g, 12.1mmol), 2, 6-difluoroaniline (1.87g, 14.5mmol), dicyclohexyl- (2 ', 4 ', 6 ' -triisopropyl-biphenyl-2-yl) -phosphane (231mg, 0.48mmol), Pd (OAc) ₂(54mg，0.24mmol)、Cs₂CO₃A mixture of (8.3g, 16.9mmol) and celite (4.0g) in 1, 4-dioxane (30ml) was stirred at 130 ℃ for 18 h. The mixture was concentrated with silica gel. The residue was purified by chromatography (petroleum ether/ethyl acetate 3: 1) to give the title compound as a yellow solid.

Preparation 43/example 280:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-4-methoxy-benzoic acid (compound 443)

The reaction was carried out as described in the preparation of compound 416, using compound 442(1.00g, 2.40mmol) as the ester. The title compound was used without any further purification.¹³CNMR(DMSO-d₆)δ191.5，166.4，160.6，157.5(dd)，149.0，133.9，133.5，133.3，130.6，129.1，126.7，126.5(t)，122.9，116.4(t)，114.6，112.5(m)，112.0，111.7，56.1。

Preparation 44:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-4-methoxy-benzoyl chloride (compound 444)

To a suspension of compound 443(590mg, 1.4mmol) in toluene (7ml) was added thionyl chloride (206. mu.l, 2.8mmol), followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 73:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methoxy-benzyl Amide (Compound 173)

The reaction was carried out in a similar manner using 2-amino-ethanol (0.28mmol) and compound 444(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound. ¹³C NMR(CD₃CN)δ193.6，167.5，161.1，159.0(dd)，149.9，135.0，134.4，132.8，130.5，129.7，129.4，127.9，127.6(t)，117.8(t)，116.3，113.3(m)，113.2，112.8，62.0，56.9，43.5。

Example 74:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-N- (2-fluoro-ethyl) -4-methoxy-benzoyl Amine (Compound 174)

The reaction was carried out in a similar manner using 2-fluoro-ethylamine (0.28mmol) and compound 444(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.9，166.6，160.6，157.5(dd)，147.7，134.6，133.0，132.4，129.5，129.4，128.7，126.4，125.7(t)，117.1(t)，116.0，112.8，112.2(m)，111.5，82.7(d)，56.0，40.5(d)。

Example 75:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-N- (2, 3-dihydroxy-propyl) -4-methoxy-benzene Carboxamide (Compound 175)

The reaction was carried out in a similar manner using 3-amino-propane-1, 2-diol (0.28mmol) and compound 444(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR (acetone-D)₆)δ192.8，167.7，161.1，159.0(dd)，149.8，134.8，134.1，132.8，130.6，129.6，129.5，127.6，127.4(t)，118.1(t)，116.1，113.1(m)，113.0，112.4，72.2，64.6，56.5，43.9。

Example 76:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-N- (3-hydroxy-propyl) -4-methoxy Phenyl-methyl Amide (Compound 176)

The reaction was carried out in a similar manner using 3-amino-propan-1-ol (0.28mmol) and compound 444(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ193.1，167.4，160.5，157.5(dd)，147.9，134.6，133.2，132.4，129.3，129.1，128.7，126.4，125.7(t)，117.1(t)，116.0，112.7，112.2(m)，111.5，59.7，56.0，37.1，32.1。

Example 77:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-4-methoxy-N-phenethyl-benzamide (chemosynthesis) Compound 177)

The reaction was carried out in a similar manner using phenylethylamine (0.28mmol) and compound 444(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.8，166.3，160.5，157.4(dd)，147.5，138.9，134.5，132.9，132.5，129.8，129.2，128.8，128.7，128.4，126.9，126.6，125.6(t)，117.1(t)，116.0，112.8，112.2(m)，111.6，56.0，41.3，35.8。

Example 78:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-1, 1-dimethyl-ethyl) -4-methyl Oxy-benzamides (Compound 178)

The reaction was carried out in an analogous manner using 2-amino-2-methyl-propan-1-ol (0.28mmol) and compound 444(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.9，167.3，160.5，157.5(dd)，147.8，134.6，133.1，132.5，129.3，129.3，128.5，127.0，125.7(t)，117.1(t)，116.0，112.7，112.2(m)，111.5，70.7，56.6，56.0，24.7。

Example 79:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-4-methoxy-N- (2-morpholin-4-yl-ethyl) - Benzamide (Compound 179)

The reaction was carried out in an analogous manner as described for the preparation of compound 120 using 2-morpholin-4-yl-ethylamine (0.28mmol) and compound 444(0.14 mmol). Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.9，166.3，160.5，157.5(dd)，147.7，134.5，133.0，132.5，129.5，129.3，128.6，126.9，125.7(t)，117.1(t)，116.0，112.7，112.2(m)，111.6，66.9，57.0，56.0，53.3，36.2。

Example 80:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl ester Yl) -4-methoxy-benzamide (compound 180)

The reaction was as described in the preparation of Compound 120, using 2-Ammonia The radical-2-methyl-propane-1, 3-diol (0.28mmol) is carried out in a similar manner to compound 444(0.14 mmol). Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ193.0，167.6，160.6，157.4(dd)，147.7，134.7，133.2，132.4，129.3，129.3，128.8，126.8，125.7(t)，117.1(t)，116.0，112.8，112.2(m)，111.4，67.6，59.3，56.0，20.0。

Example 81:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methoxy-N-methyl Yl-benzamide (Compound 181)

The reaction was carried out in a similar manner as described for the preparation of compound 120 using 2-methylamino-ethanol (0.28mmol) and compound 444(0.14 mmol). Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.8，159.4，157.4(dd)，147.5，134.5，133.0，132.7，129.7，129.7，129.1，125.6(t)，117.1(t)，116.0，112.8，112.2(m)，111.6，61.2，56.0。

Example 82:

{3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-4-methoxy-benzoylamino } -acetic acid ethyl ester (Compound 182)

The reaction was carried out in a similar manner using amino-ethyl acetate (0.84mmol) and compound 444(0.42mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.8，170.1，166.4，160.7，157.5(dd)，147.6，134.6，133.1，132.4，129.5，129.4，128.9，126.0，125.6(t)，117.1(t)，116.0，112.8，112.2(m)，111.5，61.6，56.0，41.9，14.2。

Example 83:

(2- {3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-4-methoxy-benzoylamino } -acetyl Amino) -acetic acid ethyl ester (Compound 183)

The reaction was carried out in an analogous manner using (2-amino-acetylamino) -acetic acid ethyl ester (0.84mmol) and compound 444(0.42mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound. ¹³C NMR(CDCl₃)δ192.9，169.9，169.7，166.9，160.7，157.5(dd)，147.8，134.6，133.2，132.4，129.4，129.3，129.2，125.7，125.6(t)，117.1(t)，116.0，112.8，112.2(m)，111.4，61.5，56.0，43.7，41.4，14.1。

Example 84:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-N, N-bis- (2-hydroxy-ethyl) -4-methoxy- Benzamide (Compound 184)

The reaction was carried out in a similar manner using 2- (2-hydroxy-ethylamino) -ethanol (0.28mmol) and compound 444(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ193.0，172.8，159.1，157.4(dd)，147.6，134.5，133.1，132.5，129.8，129.5，129.2，128.3，125.6(t)，117.1(t)，116.0，112.8，112.2(m)，111.6，60.7(bs)，53.5(bs)，49.9(bs)。

Example 85:

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl]-4-methoxy-N, N-bis- (2-methoxy-ethyl) Yl) -benzamide (compound 185)

The reaction was carried out in an analogous manner using bis- (2-methoxy-ethyl) -amine (0.28mmol) and compound 444(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.9，171.4，158.8，157.5(dd)，147.7，134.5，133.1，132.2，129.5，129.5，129.1，128.8，125.6(t)，117.2(t)，115.9，112.6，112.1(m)，111.5，70.6，58.8，56.0，49.9(bs)，45.5(bs)。

Preparation 45:

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl]-4-methyl-benzoic acid methyl ester (compound) 445)

1-bromo-3-fluoro-2-methyl-benzene (189mg, 1.0mmol) was dissolved in 4ml of anhydrous 1, 4-dioxane under an argon atmosphere. Compound 402(304mg, 1.00mmol) was added and dissolved in a solvent. Dicyclohexyl- (2 ', 4 ', 6 ' -triisopropyl-biphenyl-2-yl) -phosphane (19mg, 0.04mmol), Pd (OAc) were added₂(5mg, 0.02mmol) and Cs ₂CO₃(407mg, 1.25mmol) and the reaction mixture was stirred under argon at 120 ℃ for 60 h. The reaction mixture was filtered and then purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 4 as the eluent to give the title compound as a solid.¹³C NMR(CDCl₃)δ

Preparation 46/example 281:

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl]-4-methyl-benzoic acid (compound 446)

The reaction was carried out as described in the preparation of compound 416, using compound 445(185mg, 0.45mmol) as the ester. The title compound was used without any further purification.¹³CNMR(DMSO-d₆)δ194.3，166.5，161.3(d)，149.9，141.7，140.3(d)，139.4，133.8，133.7，131.5，131.2，129.2，128.2，127.3(d)，125.9，119.4(d)，119.2(d)，115.0，112.0，111.2(d)，19.8，9.5(d)。

Preparation 47:

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzylAcyl radical]-4-methyl-benzoyl chloride (Compound 447)

To a suspension of compound 446(158mg, 0.4mmol) in toluene (3ml) was added thionyl chloride (58. mu.l, 0.8mmol), followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 86:

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methyl-benzyl Amide (Compound 186)

The reaction was carried out in a similar manner as described for the preparation of compound 120 using 2-amino-ethanol (0.26mmol) and compound 447(0.13 mmol). Purification was done by flash chromatography to afford the title compound. ¹³C NMR(CDCl₃)δ195.6，167.8，162.0(d)，149.1，141.4，140.0，139.8(d)，135.5，134.0，131.5，128.9，127.9，127.6，127.2(d)，119.7(d)，119.0(d)，116.3，112.8，112.0(d)，62.3，42.9，20.3，9.6(d)。

Example 87:

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl]-4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzene Carboxamide (Compound 187)

The reaction was carried out in a similar manner as described in the preparation of compound 120 using 2, 2, 2-trifluoro-ethylamine (0.26mmol) and compound 447(0.13 mmol). Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ195.4，166.8，162.0(d)，149.2，142.0，140.2，139.7(d)，135.5，134.0，131.6，130.5，128.9，127.7，127.2(d)，124.1(q)，119.9(d)，119.2(d)，116.3，112.7，112.1(d)，41.1(q)，20.3，9.6(d)。

Preparation 48:

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl]-4-methyl-benzoic acid methyl ester (Compound 448)

The reaction was carried out in an analogous manner as described in the preparation of compound 445, using 1-bromo-2-chloro-4-fluoro-benzene (209mg, 1.0mmol) as bromide. Purification was done by flash chromatography to afford the title compound.

Preparation 49/example 282:

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl]-4-methyl-benzoic acid (compound 449)

The reaction was carried out as described in the preparation of compound 416, using compound 448(142mg, 0.33mmol) as the ester. The title compound was used without any further purification.¹³CNMR(DMSO-d₆)δ194.4，166.5，158.9(d)，149.7，141.8，139.3，133.6，131.5，131.2，129.6(d)，129.3，128.2，127.6(d)，126.3，117.4(d)，115.3(d)，114.9，111.9，19.8。

Preparation 50:

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl]-4-methyl-benzoyl chloride (Compound 450)

To a suspension of compound 449(102mg, 0.24mmol) in toluene (3ml) was added thionyl chloride (35 μ l, 0.5mmol), followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 88:

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methyl-benzoyl Amine (Compound 188)

The reaction was as described in the preparation of compound 120 using 2-amino-ethanol (0.26mmol) and compound 450(0.13mmol)This is done in a similar manner. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ195.6，167.7，158.6(d)，147.7，141.5，139.6，135.3，133.7，133.4(d)，131.6，131.5，129.1，127.8，127.3(d)，123.2(d)，117.5(d)，117.0，114.9(d)，113.5，62.2，42.9，20.4。

Example 89:

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl]-4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzyl Amide (Compound 189)

The reaction was carried out in a similar manner as described in the preparation of compound 120 using 2, 2, 2-trifluoro-ethylamine (0.26mmol) and compound 450(0.13 mmol). Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ195.4，166.7，158.7(d)，147.7，142.3，139.9，135.4，133.7，133.3(d)，131.7，130.6，129.0，127.9，127.3(d)，124.1(q)，123.2(d)，117.6(d)，116.9，114.9(d)，113.5，41.1(q)，20.4。

Preparation 51:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-4-methyl-benzoic acid methyl ester (Compound 451)

The reaction was carried out in a similar manner using 1-bromo-4-fluoro-benzene (110 μ l, 1.0mmol) as bromide, as described in the preparation of compound 445. Purification was done by flash chromatography to afford the title compound.

Example 90:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl](meth) -N- (2-hydroxy-ethyl) -4-methyl-benzamide Compound 190)

To a solution of compound 451(96mg, 0.24mmol) in acetonitrile (0.7ml) and 2-amino-ethanol (0.50ml) was added K ₂CO₃(50mg, 0.36mmol) and stirred at room temperature for 18 h. The reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and concentrated in vacuo onto silica gel. Purification was done by flash chromatography eluting with a MeOH/DCM mixture to give the title compound as a yellow slurry.¹³C NMR(CDCl₃)δ195.9，167.9，159.5(d)，149.5，141.0，140.0，135.8(d)，135.5，134.2，131.4，128.9，127.4，126.8，123.9(d)，116.3(d)，115.7，112.1，61.7，42.9，20.2。

Preparation 52:

3- (2-chloro-4-phenylamino-benzoyl) -4-methyl-benzoic acid methyl ester (compound 452)

The reaction was carried out in an analogous manner as described in the preparation of compound 445, using bromo-benzene (110 μ l, 1.0mmol) as bromide. Purification was done by flash chromatography to afford the title compound.

Example 91:

3- (2-chloro-4-phenylamino-benzoyl) -N- (2-hydroxy-ethyl) -4-methyl-benzamide (compound 191)

The reaction was carried out in a similar manner to compound 452(0.26mmol) using 2-amino-ethanol (0.50ml) as described in the preparation of compound 190. Purification was done by flash chromatography to afford the title compound.¹³C NMR(DMSO-d₆)δ194.6，165.2，148.7，140.3，139.4，134.1，133.9，131.7，130.9，129.4，129.0，127.1，126.1，122.8，120.2，115.3，112.2，59.6，42.1，19.5。

Preparation 53:

3- [ 2-chloro-4- (3, 5-difluoro-phenylamino) -benzoyl]-4-methyl-benzoic acid methyl ester (Compound 453)

The reaction was carried out in an analogous manner as described in the preparation of compound 445, using 1-bromo-3, 5-difluoro-benzene (115 μ l, 1.0mmol) as the bromide. Purification was done by flash chromatography to afford the title compound.

Example 92:

3- [ 2-chloro-4- (3, 5-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methyl-benzoyl Amine (Compound 192)

The reaction was carried out in a similar manner using 2-amino-ethanol (0.50ml) and compound 453(0.26mmol) as described in the preparation of compound 190. Purification was done by flash chromatography to afford the title compound.¹³C NMR(DMSO-d₆)δ194.9，165.2，163.1(dd)，146.5，143.9(t)，139.8，138.8，133.5，133.3，131.8，131.1，129.3，128.5，127.5，117.4，114.1，101.2(m)，96.7(t)，59.6，42.1，19.7。

Preparation 54:

3- [ 2-chloro-4- (3-fluorophenylamino) -benzoyl]-4-methyl-benzoic acid methyl ester (Compound 454)

The reaction was carried out in a similar manner using 1-bromo-3-fluoro-benzene (110 μ l, 1.0mmol) as bromide, as described in the preparation of compound 445. Purification was done by flash chromatography to afford the title compound.

Example 93:

3- [ 2-chloro-4- (3-fluorophenylamino) -benzoyl](meth) -N- (2-hydroxy-ethyl) -4-methyl-benzamide Compound 193)

The reaction was carried out in a similar manner using 2-amino-ethanol (0.50ml) and compound 454(0.26mmol) as described in the preparation of compound 190. Purification was done by flash chromatography to afford the title compound.¹³C NMR(DMSO-d₆)δ194.8，165.2，162.8(d)，147.6，142.6(d)，139.6，139.1，133.8，133.6，131.8，131.0(d)，131.0，129.2，127.3，116.3，115.2，113.1，108.7(d)，105.9(d)，59.6，42.1，19.6。

Preparation 55:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-4-methoxy-benzoic acid methyl ester (compound 455)

The reaction was carried out in an analogous manner using 1-bromo-4-fluoro-benzene (1.88mmol) and compound 435(1.56mmol), as described in the preparation of compound 431. Purification was done by flash chromatography to afford the title compound as a yellow foam.

Example 94:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methoxy-benzamide (Compound 194)

The reaction was carried out in a similar manner to compound 455(0.15mmol) using 2-amino-ethanol (0.50ml) as described in the preparation of compound 190. Purification was done by flash chromatography to afford the title compound.¹³C NMR(DMSO-d₆)δ 191.6，165.0，159.1，158.0(d)，148.9，136.6(d)，134.1，133.8，131.5，129.1，128.2，126.4，126.2，122.6(d)，116.0(d)，114.8，111.7，111.5，59.7，56.0，42.1。

Preparation 56:

3- (2-chloro-4-phenylamino-benzoyl) -4-methoxy-benzoic acid methyl ester (Compound 456)

The reaction was carried out in a similar manner using bromobenzene (1.88mmol) and compound 435(1.56mmol) as described in the preparation of compound 431. Purification was done by flash chromatography to afford the title compound as a yellow foam.

Example 95:

3- (2-chloro-4-phenylamino-benzoic acid methyl esterAcyl) -N- (2-hydroxy-ethyl) -4-methoxy-benzamide (compound) 195)

The reaction was carried out in a similar manner using 2-amino-ethanol (0.50ml) and compound 456(0.15mmol) as described in the preparation of compound 190. Purification was done by flash chromatography to afford the title compound.¹³C NMR(DMSO-d₆)δ191.6，165.0，159.1，148.4，140.4，134.0，133.7，131.5，129.4，129.1，128.2，126.4，126.4，122.7，120.0，115.2，112.1，111.5，59.7，56.0，42.1。

Preparation 57/example 283:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-4-methoxy-benzoic acid (Compound 457)

The reaction was carried out as described in the preparation of compound 416, using compound 455(230mg, 0.56mmol) as the ester. The title compound was used without any further purification.

Preparation 58:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-4-methoxy-benzoyl chloride (Compound 458)

A suspension of compound 457(0.56mmol) in toluene (2ml) was added with thionyl chloride (81. mu.l, 1.1mmol), followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 96:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-N- (2, 2-difluoro-ethyl) -4-methoxy-benzamide (Compound 196)

The reaction was carried out in a similar manner as described for the preparation of compound 120 using 2, 2-difluoro-ethylamine (0.28mmol) and compound 458(0.14 mmol). The purification is carried out by means of flash chromatography,the title compound was obtained.¹³C NMR(CDCl₃)δ192.6，166.8，160.7，159.6(d)，148.8，135.9(d)，135.2，133.7，132.3，129.8，128.7，128.5，125.7，124.1(d)，116.4(d)，115.5，113.7(t)，112.3，111.5，56.1，42.3(t)。

Example 97:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl](meth) -N- (2-fluoro-ethyl) -4-methoxy-benzamide Compound 197)

The reaction was carried out in a similar manner using 2-fluoro-ethylamine (0.28mmol) and compound 458(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.6，166.6，160.5，159.6(d)，148.7，136.0(d)，135.2，133.7，132.1，129.7，128.6，128.6，126.4，124.0(d)，116.4(d)，115.5，112.3，111.5，82.8(d)，56.1，40.5(d)。

Example 98:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-N- (2, 3-dihydroxy-propyl) -4-methoxy-benzoyl Amine (Compound 198)

The reaction was carried out in a similar manner using 3-amino-propane-1, 2-diol (0.28mmol) and compound 458(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR (mixed) δ 193.2, 168.1, 160.5, 159.5(d), 149.0, 136.1(d), 135.3, 134.0, 132.4, 129.6, 128.9, 128.0, 126.0, 123.8(d), 116.4(d), 115.5, 112.2, 111.5, 71.1, 63.7, 56.1, 42.7.

Example 99:

n-carbamoylmethyl-3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-4-methoxy-benzamide (Compound 199)

The reaction was carried out in a similar manner using 2-amino-acetamide (0.28mmol) and compound 458(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(DMSO-d₆)δ191.7，171.1，165.3，159.4，158.1(d)，149.0，136.8(d)，134.1，133.9，131.8，129.2，128.5，126.4，126.2，122.7(d)，116.1(d)，114.9，111.8，111.7，56.1，42.4。

Preparation 59/example 284:

3- (2-chloro-4-phenylamino-benzoyl) -4-methoxy-benzoic acid (compound 459)

The reaction was carried out as described in the preparation of compound 416, using compound 456(264mg, 0.67mmol) as the ester. The title compound was used without any further purification.

Preparation 60:

3- (2-chloro-4-phenylamino-benzoyl) -4-methoxy-benzoyl chloride (Compound 460)

To a suspension of compound 459(0.67mmol) in toluene (2ml) was added thionyl chloride (98. mu.l, 1.3mmol) followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 100:

3- (2-chloro-4-phenylamino-benzoyl) -N- (2, 2-difluoro-ethyl) -4-methoxy-benzamide (chemical combination) Thing 200)

The reaction was carried out in a similar manner as described in the preparation of compound 120 using 2, 2-difluoro-ethylamine (0.28mmol) and compound 460(0.14 mmol). Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.6，166.8，160.7，148.1，140.1，135.1，133.6，132.4，129.8，129.6，128.7，125.7，123.9，121.1，116.1，113.7(t)，112.9，111.5，56.1，42.3(t)。

Example 101:

3- (2-chloro-4-phenylamino-benzoyl) -N- (2-fluoro-ethyl) -4-methoxy-benzamide (compound 201)

The reaction was carried out in a similar manner using 2-fluoro-ethylamine (0.28mmol) and compound 460(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound.¹³C NMR(CDCl₃)δ192.6，166.6，160.5，148.0，140.2，135.1，133.6，132.2，129.7，129.6，128.9，128.6，126.4，123.8，121.1，116.1，113.0，111.5，82.8，56.1，40.5。

Example 102:

3- (2-chloro-4-phenylamino-benzoyl) -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide (chemotropylization) Compound 202)

The reaction was carried out in a similar manner using 3-amino-propane-1, 2-diol (0.28mmol) and compound 460(0.14mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound. ¹³C NMR (mixed) δ 193.2, 168.1, 160.5, 148.3, 140.1, 135.2, 133.9, 132.4, 129.6, 128.9, 128.2, 126.0, 123.7, 121.0, 116.0, 112.8, 111.5, 71.1, 63.7, 56.1, 42.7.

Example 103:

n-carbamoylmethyl-3- (2-chloro-4-phenylamino-benzoyl) -4-methoxy-benzamide (compound 203)

The reaction was as described in the preparation of compound 120 using 2-amino-acetamide (0.28mmol) and compound 460(0.14 mmol)l) was performed in a similar manner. Purification was done by flash chromatography to afford the title compound.¹³C NMR (mixed) δ 193.2, 172.2, 167.3, 160.7, 148.6, 140.3, 135.3, 133.9, 132.3, 129.8, 129.6, 129.2, 128.1, 125.7, 123.7, 121.0, 116.0, 112.8, 111.5, 56.1, 43.1.

Preparation 61:

4-chloro-3- (2-chloro-4-nitro-benzoyl) -benzoic acid methyl ester (Compound 461)

In a dry flask, 4-chloro-3-iodo-benzoic acid methyl ester (5.0g, 16.9mmol) was added and the flask was evaporated, then filled with argon and this step was repeated twice. Anhydrous THF (35ml) was added and the solution was cooled to-40 ℃; then over 20 minutes isopropyl magnesium chloride (8.85ml, 2.0M in ether, 17.7mmol) was slowly added, keeping the temperature below-40 ℃. After the addition was complete, the reaction mixture was stirred at-40 ℃ for 45 minutes. ZnCl was added dropwise over 20 minutes ₂Solution of THF (2.32g, 17.0mmol, 0.9M). The reaction mixture was stirred at 0 ℃ for 20 minutes; 2-chloro-4-nitro-benzoyl chloride (3.7g, 17mmol) and Cu (OAc) were then added₂(68mg, 0.34mmol) and the reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was poured into EtOAc/water mixture, followed by shaking and separation. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1: 6 as eluent to afford the title compound as a yellow solid.

Preparation 62:

3- (4-amino-2-chloro-benzoyl) -4-chloro-benzoic acid methyl ester (Compound 462)

To a solution of compound 461(3.31g, 9.35mmol) in methanol (125ml) were added zinc powder (6.1g, 94mmol) and ammonium chloride (2.5g, 47mmol) in one portion with stirring. Adding CaCl₂The tube is mounted on the flask, anThe flask was placed in an oil bath at a temperature of 90 ℃. After 18 h, the reaction mixture was cooled to room temperature, filtered, and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/pentane 1: 1 as eluent. The product was triturated in DCM, then filtered and dried to give the title compound as a light yellow solid.

Preparation 63:

4-chloro-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-benzoic acid methyl ester (compound 463)

1-bromo-2, 4-difluorobenzene (87. mu.l, 0.77mmol) was dissolved in 2.5ml of anhydrous toluene under argon. Compound 462(250mg, 0.77mmol) was added and dissolved in a solvent. Adding 4, 5-bis-diphenylphosphinyl-9, 9-dimethyl-9H-xanthene (13mg, 0.023mmol), Pd (OAc)₂(3.5mg, 0.015mmol) and Cs₂CO₃(352mg, 1.08mmol) and the reaction mixture was stirred under argon at 120 ℃ for 24 h. The reaction mixture was filtered and then purified by flash chromatography using EtOAc/petroleum ether 1: 2 as the eluent to give the title compound as a solid.

Example 104:

4-chloro-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -benzamide (Compound 204)

The reaction was carried out in a similar manner as described in the preparation of compound 190 using 2-amino-ethanol (0.50ml) and compound 463(0.12 mmol). Purification was done by flash chromatography using MeOH/DCM 7: 93 to afford the title compound.¹³C NMR(DMSO-d₆)δ190.9，164.6，159.1(dd)，156.0(dd)，150.4，139.4，134.9，134.8，133.4，132.9，130.4，130.0，127.8，127.0(dd)，124.4，123.9(dd)，115.2，112.1(dd)，111.9，105.2(dd)，59.6，42.4。

Example 105:

(2- { 3-chloro-4- [5- (2-hydroxy-ethylcarbamoyl) -2-methyl-benzoyl]-phenylamino } -phenyl) - Ethyl carbamate (Compound 205)

To a solution of compound 112(100mg, 0.24mmol) in DMF (1ml) was added K with stirring₂CO₃(66mg, 0.48mmol) and ethyl chloroformate (23. mu.l, 0.24 mmol). After 1 hour, pour the reaction mixture into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography eluting with DCM/methanol (v: v ═ 100: 0 to 98: 2) to afford the title compound as a yellow foam.¹³C NMR(DMSO-d₆)δ194.6，165.3，154.0，149.9，139.6，139.3，133.8，133.8，132.4，131.8，131.6，130.8，128.9，127.0，125.6，125.0，124.6，124.5，124.0，114.9，111.8，60.3，59.6，42.1，19.5，14.4。

Example 106:

3- [ 2-chloro-4- (2-propionylamino-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methyl-benzene Carboxamide (Compound 206)

To a solution of compound 112(100mg, 0.24mmol) in glacial acetic acid (1ml) was added propionic anhydride (33. mu.l, 0.26mmol) with stirring. After 1 hour, the reaction mixture was concentrated in vacuo. Cyclohexane was added and the mixture was concentrated in vacuo. The crude product was purified by sequential gradient flash chromatography eluting with DCM/(EtOAc: MeOH: acetic acid 95: 5: 0.5) (v: v. 95: 5 to 90: 10) to give the title compound as a yellow foam.¹³C NMR(DMSO-d₆)δ194.6，172.3，165.3，149.7，139.6，139.3，133.7，132.3，132.1，131.8，130.8，128.9，127.1，125.7，125.1，124.7，124.2，115.0，111.9，59.6，42.1，29.0，19.5，9.5。

Example 107:

3- [4- (2-acetylamino-phenylamino) -2-chloro-benzoyl ]-N- (2-hydroxy-ethyl) -4-methyl-benzyl Amide (Compound 207)

To a solution of compound 112(100mg, 0.24mmol) in glacial acetic acid (1ml) was added acetic anhydride (25. mu.l, 0.26mmol) with stirring. After 1 hour, the reaction mixture was concentrated in vacuo. Cyclohexane was added and the mixture was concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc: MeOH: acetic acid 95: 5: 0.5 to give the title compound as a yellow foam.¹³CNMR(DMSO-d₆)δ194.6，168.6，165.3，149.6，139.5，139.4，133.7，133.7，132.1，131.8，130.9，128.9，127.2，125.8，125.1，124.6，123.9，115.2，111.9，59.6，42.1，23.4，19.5。

Example 108:

n- (2- { 3-chloro-4- [5- (2-hydroxy-ethylcarbamoyl) -2-methyl-benzoyl]-phenylamino Phenyl radical Yl) -succinamic acid (Compound 208)

To a solution of compound 112(100mg, 0.24mmol) in glacial acetic acid (1ml) was added succinic anhydride (26mg, 0.26mmol) with stirring. After 1 hour, the reaction mixture was concentrated in vacuo. Cyclohexane was added and the mixture was concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc: MeOH: acetic acid 90: 10: 1 to give the title compound as a yellow foam.¹³CNMR(DMSO-d₆)δ194.6，173.8，171.9，165.3，149.6，139.5，139.3，133.8，133.7，132.1，131.9，131.7，130.9，128.9，127.1，125.8，125.1，124.9，124.5，123.7，115.2，112.0，59.6，42.1，30.7，28.9，19.5。

Preparation of 64:

2-methyl-acrylic acid 2- [3- (2- { 3-chloro-4- [5- (2-hydroxy-ethylcarbamoyl) -2-methyl-benzoyl]- Phenylamino } -phenyl) -ureido]-ethyl ester (Compound 464)

To a solution of compound 112(149mg, 0.35mmol) in anhydrous pyridine (1ml) was added 2-isocyano-ethyl 2-meth-acrylate (55. mu.l, 0.39mmol) with stirring. After 1 hour, pour the reaction mixture into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography eluting with EtOAc/methanol (v: v ═ 100: 0 to 95: 5) to give the title compound as a yellow foam.

Example 109:

3- (2-chloro-4- {2- [3- (2-hydroxy-ethyl) -ureido]-phenylamino } -benzoyl) -N- (2-hydroxy-ethyl Yl) -4-methyl-benzamide (compound 209)

To a solution of compound 464(115mg, 0.20mmol) in ethanol (1ml) was added NaOH (2M, 150. mu.l, 0.30mmol), followed by refluxing for 2 hours. The reaction mixture was allowed to cool to room temperature and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography eluting with MeOH/DCM 5: 95 and 10: 90 to afford the title compound as a solid.¹³C NMR(DMSO-d₆)δ194.7，165.4，155.4，151.4，139.8，139.4，136.6，134.1，134.0，131.8，130.9，128.9，128.1，127.2，126.4，126.3，125.3，121.8，120.2，114.8，111.4，60.4，59.7，42.2，41.9，19.6。

Preparation 65:

4- (2-chloro-4-nitro-benzoyl) -3-methyl-benzoic acid methyl ester (compound 465)

The reaction was carried out in a similar manner using methyl 4-iodo-3-methylbenzoate (3.5g, 12.5mmol) as iodide as described in the preparation of compound 401. Purification was done by flash chromatography using EtOAc/pentane 1: 9 to afford the title compound as a light brown solid.

Preparation 66:

4- (4-amino-2-chloro-benzoyl) -3-methyl-benzoic acid methyl ester (Compound 466)

The reaction was carried out in a similar manner using compound 465(3.0g, 9.1mmol) as the nitro compound as described in the preparation of compound 402. Purification was done by flash chromatography using EtOAc/DCM 1: 15 to give the title compound as a yellow foam.

Preparation 67:

4- (4-carboxy-2-methyl-benzoyl) -3-chlorophenyl-ammonium acetate (Compound 467)

To a solution of compound 466(250mg, 0.82mmol) in ethanol (10ml) was added a sodium hydroxide solution (2M, 10ml), followed by stirring at reflux for 90 minutes. The reaction mixture was made weakly acidic (pH 4) by slow addition of acetic acid (100) and then poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the title compound as a yellow slurry. Used without any further purification.

Preparation 68:

(4-amino-2-chlorophenyl) - [ 2-methyl-4- (morpholine-4-carbonyl) -phenyl]-methanone (Compound 468)

The reaction was carried out in a similar manner using compound 467(106mg, 0.37mmol) as the acid as described in the preparation of compound 404. Purification was accomplished by flash chromatography using MeOH/DCM 0: 100, 1: 100, and 2: 100 to afford the title compound as a foam.

Example 110:

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl]- [ 2-methyl-4- (morpholine-4-carbonyl) -phenyl]-methanones (Compound 210)

In a vial under argon, 2-bromo-5-fluorotoluene (56 μ l, 0.44mmol) was dissolved in 3ml of anhydrous 1, 4-dioxane, compound 468(132mg, 0.37mmol) was added, and dissolved in the solvent. racemic-BINAP (8.6mg, 0.014mmol) and Pd were added₂(dba)₃(8.5mg, 0.009mmol) and Cs₂CO₃(169mg, 0.52mmol) and the reaction mixture was stirred under argon at 100 ℃ for 48 h. The reaction mixture was filtered and then purified by flash chromatography using EtOAc/DCM 1: 3 as the eluent to give the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.5，169.8，160.7，150.2，141.1，138.1，137.2，136.5，135.7，134.2，133.6，129.7，129.2，127.3，127.3，123.9，117.9，115.2，113.9，111.5，66.9，48.2，42.5，20.2，18.1。

Preparation 69:

2- [2- (4-bromo-3-methyl-phenoxy) -ethoxy]-tetrahydro-pyran (compound 469)

A solution of 4-bromo-3-methyl-phenol (10.6g, 56.9mmol) and 2- (2-bromo-ethoxy) -tetrahydro-pyran (11.9g, 56.9mmol) was dissolved in anhydrous DMF (25 ml). Addition of K ₂CO₃(19.7g, 142mmol) and the resulting reaction mixture was stirred at 80 ℃ for 48 hours. The reaction mixture was cooled to room temperature and poured into a mixture of EtOAc and aqueous NaOH (2N). The organic phase was separated and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/pentane 1: 20 as eluent to give the title compound as a colorless oil.

Preparation 70:

(2-chloro-4-nitro-phenyl) - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy]-phenyl } -methanone (Compound 470)

N-butyllithium (30.3ml, 1.46M in hexane, 44.3mmol) was added dropwise (30 min) to a solution of compound 469(13.95g, 44.3mmol) in THF (40ml) at-78 ℃ and the resulting mixture was stirred for 30 min. Adding anhydrous ZnCl by a syringe₂Was added to the reaction solution (55mmol, 1.0M, 55ml) and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was cooled to 0 ℃ and tetrakis (triphenylphosphine) palladium (0) (2.55g, 2.21mmol) was added followed by 2-chloro-4-nitrobenzoyl chloride (10.9g, 46.0mmol) in THF (10 ml). The stirred reaction mixture was allowed to warm to room temperature overnight. The mixture was partitioned between EtOAc (200ml) and 1N HCl (200ml) and the aqueous phase was extracted with more EtOAc (200 ml). The combined organic extracts were washed with brine, over MgSO ₄Dried and concentrated in vacuo. The residue was purified by flash chromatography using petroleum ether/EtOAc 9: 1 to afford the title compound as a yellow slurry.

Preparation 71:

(4-amino-2-chlorophenyl) - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy]-phenyl } -methanone (Compound 471)

The reaction was carried out in a similar manner as described in the preparation of compound 402, using compound 470(3.0g, 9.1mmol) as nitro compound. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 4 followed by 1: 2 to give the title compound as a yellow foam.

Preparation 72/example 285:

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl]- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -ethyl Base of]-phenyl } -methanone (Compound 472)

1-iodo-2-nitro-benzene (1.38g, 5.54mmol) was dissolved in 40ml of anhydrous 1, 4-dioxane under argon atmosphere. Compound 471(1.77g, 4.54mmol) was added and dissolved in the solvent. Add rac-BINAP (106mg, 0.17mmol), Pd₂(dba)₃(104mg, 0.11mmol) and Cs₂CO₃(2.07g, 6.30mmol) and the reaction mixture was stirred under argon at 100 ℃ for 24 h. The reaction mixture was poured into a mixture of EtOAc and water. The aqueous phase was washed with more EtOAc. The organic phases were combined and washed with brine and dried (MgSO) ₄) Filtration and subsequent purification by flash chromatography using EtOAc/petroleum ether 1: 5 as the eluent afforded the title compound.

Example 111:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -ethyl Base of]-phenyl } -methanone (Compound 211)

The reaction was carried out in a similar manner as described in the preparation of compound 402, using compound 472(2.14g, 4.19mmol) as the nitro compound. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 4 followed by 1: 2 to give the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.6，161.1，148.9，142.8，141.7，134.4，133.4，132.6，131.3，129.6，127.5，126.8，125.7，119.2，117.7，116.4，115.1，112.0，111.0，99.1，67.4，65.7，62.2，30.5，25.4，21.4，19.4。

Example 112:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- [4- (2-hydroxy-ethoxy) -2-methyl-phenyl]-methanones (chemotropes) Compound 212)

Compound 211(1.10g, 2.29mmol) was stirred with a solution of toluene-4-sulfonic acid (653mg, 3.43mmol) in MeOH (20ml) at room temperature for 3 h. The reaction mixture was poured into aqueous NaOH (2N) andEtOAc in a mixture. The aqueous phase was washed with more EtOAc. The organic phases were combined and washed with brine and dried (MgSO)₄) Filtration and subsequent purification by flash chromatography using EtOAc/petroleum ether 1: 1 followed by 2: 1 as the eluent afforded the title compound as a yellow foam. ¹³CNMR(CDCl₃)δ195.6，160.8，149.0，142.8，141.7，134.5，133.3，132.7，131.7，129.4，127.5，126.8，125.6，119.2，117.5，116.4，115.2，112.0，110.9，69.2，61.3，21.3。

Preparation 73/example 286:

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl]- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethyl Oxy radical]-phenyl (compound 473)

To a solution of compound 471(2.74g, 7.02mmol) and 4-bromo-1-fluoro-2-nitro-benzene (1.49g, 6.76mmol) in DMSO (8.0ml) was slowly added potassium tert-butoxide (1.68g, 14.9mmol) with stirring. After 4 hours at room temperature the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography eluting with EtOAc/petroleum ether 1: 9 to give the title compound as an orange slurry.

Example 113:

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl group]- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethyl Oxy radical]-phenyl (Compound 213)

The reaction was carried out in a similar manner as described in the preparation of compound 402, using compound 473(1.10g, 1.86mmol) as the nitro compound. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 3 to afford the title compound as a foam.¹³C NMR(CDCl₃)δ195.5，161.2，148.3，144.2，141.8，134.3，133.5，132.5，131.1，130.1，128.2，124.7，121.9，120.5，118.9，117.7，115.3，112.1，111.0，99.1，67.4，65.7，62.3，30.5，25.4，21.4，19.4。

Example 114:

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl group]- [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ]-methanones (Compound 214)

The reaction was carried out in a similar manner using compound 213(1.10g, 1.86mmol) as the THP ether protected compound as described in the preparation of compound 212. Purification was done by flash chromatography using EtOAc/petroleum ether 3: 7 to give the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.6，160.9，148.4，144.2，141.9，134.4，133.4，132.6，131.5，129.9，128.2，124.6，121.9，120.5，118.9，117.6，115.2，112.1，110.9，69.2，61.3，21.4。

Preparation 74:

2- [3- (4-bromo-3-methyl-phenoxy) -propoxy]-tetrahydro-pyran (compound 474)

The reaction was carried out in a similar manner using 2- (3-bromo-propoxy) -tetrahydro-pyran (5.58g, 25mmol) as the aliphatic bromide, as described in the preparation of compound 469. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 4 to give the title compound as a colorless oil.

Preparation 75:

(2-chloro-4-nitro-phenyl) - { 2-methyl-4- [3- (tetrahydro-pyran-2-yloxy) -propoxy]-phenyl } -methanone (Compound 475)

The reaction was carried out in a similar manner using compound 474(8.56g, 26mmol) as bromide, as described in the preparation of compound 470. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 9 to afford the title compound as a yellow oil.

Preparation of 76:

(4-amino-2-chlorophenyl) - { 2-methyl-4- [3- (tetrahydro-pyran-2-yloxy) -propoxy]-phenyl } -methanone (Compound 476)

The reaction was carried out in a similar manner as described in the preparation of compound 402, using compound 475(5.95g, 13.71mmol) as the nitro compound. The title compound was obtained as yellow oil without any further purification.

Preparation 77/example 287:

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl]- { 2-methyl-4- [3- (tetrahydro-pyran-2-yloxy) -propane Oxy radical]-phenyl } -methanone (Compound 477)

The reaction was carried out in a similar manner using compound 476(1.45g, 3.59mmol) as the amine as described in the preparation of compound 473. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 6 to give the title compound as an orange oil.

Example 115:

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl group]- { 2-methyl-4- [3- (tetrahydro-pyran-2-yloxy) -propane Oxy radical]-phenyl } -methanone (Compound 215)

The reaction was carried out in a similar manner as described in the preparation of compound 402, using compound 477(5.95g, 13.71mmol) as the nitro compound. The title compound was obtained as a yellow foam without any further purification.¹³C NMR(CDCl₃)195.6，161.4，148.2，142.9，142.0，134.2，133.7，132.4，130.7，130.2，128.0，125.4，122.7，120.2，119.5，117.6，115.4，112.3，110.9，99.0，65.0，63.9，62.4，30.7，29.6，25.4，21.5，19.6。

Example 116:

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl group]- [4- (3-hydroxy-propoxy) -2-methyl-phenyl]-methanones (Compound 216)

The reaction was carried out in a similar manner using compound 215(1.30g, 2.27mmol) as the THP ether protected compound as described in the preparation of compound 212. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 1 to afford the title compound as a yellow foam. Trituration in a mixture of diethyl ether and pentane afforded the title compound as a white solid.¹³C NMR(CDCl₃)δ195.5，161.1，148.4，144.3，141.9，134.3，133.5，132.5，131.1，130.0，128.2，124.7，121.9，120.5，118.8，117.6，115.2，112.1，110.8，65.5，60.1，31.9，21.4。

Preparation 78:

1-bromo-4- (2-fluoro-ethoxy) -2-methyl-benzene (compound 478)

A solution of 4-bromo-3-methyl-phenol (3.74g, 20mmol), 2-fluoro-ethanol (2.29ml, 22mmol) and triphenylphosphine (5.77g, 22mmol) in dry THF (15ml) was cooled to 0 ℃ with stirring. Diethyl azodicarboxylate (40% in toluene, 10ml, 22mmol) was added and the reaction mixture was allowed to come to room temperature overnight. After 18 hours at room temperature the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography eluting with DCM/petroleum ether 1: 6 to give the title compound as a colorless oil.

Preparation of 79:

(2-chloro-4-nitro-phenyl) - [4- (2-fluoro-ethoxy) -2-methyl-phenyl]-methanone (Compound 479)

The reaction was carried out in a similar manner as described in the preparation of compound 470, using compound 478(4.25g, 18.2mmol) as bromide. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 9 followed by 1: 6 to give the title compound as a yellow solid.

Preparation 80:

(4-amino-2-chlorophenyl) - [4- (2-fluoro-ethoxy) -2-methyl-phenyl]-methanone (Compound 480)

A mixture of compound 479(2.31g, 6.84mmol) and stannous chloride dihydrate (7.72g, 34.2mmol) in anhydrous ethanol was heated to reflux. After 1 hour, the solution was allowed to cool to room temperature and then poured into an ice/aqueous NaOH (7N)/EtOAc mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined, washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was triturated in a 1: 1 mixture of diethyl ether and petroleum ether to give the title compound as a solid.

Preparation 81/example 288:

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl]- [4- (2-fluoro-ethoxy) -2-methyl-phenyl]-methanones (Compound 481)

The reaction was carried out in a similar manner using compound 480(595mg, 1.93mmol) as the amine as described in the preparation of compound 473. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 9 followed by 1: 6 to give the title compound as a foam. Trituration in ethanol afforded a solid.

Example 117:

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl group]- [4- (2-fluoro-ethoxy) -2-methyl-phenyl]-methanones (Compound 217)

The reaction was carried out in a similar manner using compound 481(585mg, 1.15mmol) as the nitro compound as described in the preparation of compound 480. Purifying by flash chromatographyTo this end, EtOAc/petroleum ether 1: 7 followed by 1: 4 was used to afford the title compound as a foam. Trituration in a 2: 3 mixture of diethyl ether and petroleum ether afforded the title compound as a solid.¹³C NMR(CDCl₃)δ195.5，160.6，148.4，144.3，141.8，134.4，133.3，132.6，131.7，129.9，128.2，124.6，121.9，120.5，118.8，117.6，115.3，112.1，110.9，81.7(d)，67.0(d)，21.3。

Example 118:

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl]- [4- (2-fluoro-ethoxy) -2-methyl-phenyl]-methanones (Compound 218)

To a Schlenk tube, compound 480(402mg, 1.31mmol), 5-bromo-1-iodo-toluene (358mg, 1.19mmol), sodium tert-butoxide (160mg, 1.67mmol), Pd in 1, 4-dioxane (3.0ml) were added₂(dba)₃(27mg, 0.03mmol) and rac-BINAP (28mg, 0.045 mmol). The tube was capped with a rubber septum, flushed with argon for 5 minutes, and then stirred at 100 ℃ for 72 hours. The reaction mixture was allowed to cool to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted twice with more EtOAc. The combined organic phases were washed with brine and dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with petroleum ether/EtOAc 4: 1 to give the title compound as a yellow oil.¹³C NMR(CDCl₃)δ195.4，160.6，147.7，141.9，137.7，134.3，134.0，133.9，133.4，132.6，131.6，130.3，130.0，124.5，117.6，117.6，116.1，112.9，111.0，81.7，67.0，21.3，17.8。

Preparation 82:

1-bromo-4- (2-methoxy-ethoxy) -2-methyl-benzene (compound 482)

The reaction was carried out in a similar manner as described in the preparation of compound 478, using 2-methoxy-ethanol (4.66ml, 58.8mmol) as the aliphatic alcohol. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 0: 100 to 20: 80) as eluent to give the title compound as a colorless oil.

Preparation 83:

(2-chloro-4-nitro-phenyl) - [4- (2-methoxy-ethoxy) -2-methyl-phenyl]-methanone (Compound 483)

The reaction was carried out in a similar manner as described in the preparation of compound 470, using compound 482(4.66ml, 58.8mmol) as bromide. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 15: 85 to 50: 50) as eluent to afford the title compound as a yellow slurry.

Preparation 84:

(4-amino-2-chlorophenyl) - [4- (2-methoxy-ethoxy) -2-methyl-phenyl]-methanone (Compound 484)

The reaction was carried out in a similar manner as described in the preparation of compound 480, using compound 483(6.21g, 17.8mmol) as the nitro compound. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 2 to 2: 1) as eluent to afford the title compound as a yellow solid.

Preparation 85/example 289:

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl]- [4- (2-methoxy-ethoxy) -2-methyl-phenyl]- Methanone (Compound 485)

The reaction was carried out in a similar manner using compound 484(2.00g, 6.25mmol) as the amine as described in the preparation of compound 473. The crude product was purified by continuous gradient flash chromatography using DCM/petroleum ether (40-60) (v: v ═ 20: 80 to 50: 50) as eluent to afford the title compound as an orange foam.

Example 119:

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl group]- [4- (2-methoxy-ethoxy) -2-methyl-phenyl]-first of all Ketones (Compound 219)

The reaction was carried out in a similar manner using compound 485(1.75g, 3.37mmol) as the nitro compound as described in the preparation of compound 402. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 20: 80 to 50: 50) as eluent. The title compound was obtained as a solid by crystallization from DCM.¹³C NMR(DMSO-d₆)δ194.3，160.4，149.5，145.6，140.3，132.6，132.5，132.3，131.0，127.4，127.1，123.9，118.5，118.3，117.1，114.0，111.4，111.1，70.1，66.9，58.1，20.6。

Example 120:

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl]- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethyl Oxy radical]-phenyl } -methanone (Compound 220)

To a Schlenk tube, compound 471(4.25g, 10.9mmol) in 1, 4-dioxane (40ml), 5-bromo-1-iodo-toluene (3.88g, 13.1mmol), Cs were added ₂CO₃(4.97g，15.26mmol)、Pd₂(dba)₃(250mg, 0.27mmol) and rac-BINAP (255mg, 0.41 mmol). The tube was capped with a rubber septum, flushed with argon for 5 minutes, and then stirred at 100 ℃ for 72 hours. The reaction mixture was allowed to cool to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted twice with more EtOAc. The combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with petroleum ether/EtOAc 4: 1 to give the title compound as a yellow foam.¹H NMR(CDCl₃)δ7.39(d，1H)，7.35-7.25(m，3H)，7.14(d，1H)，6.81(m，2H)，6.69(m，2H)，5.63(bs，1H)，4.70(bt，1H)，4.23-4.00(m，3H)，3.95-3.77(m，2H)，3.53(m，1H)，2.51(s，3H)，2.23(s，3H)，1.92-1.45(m，6H)。

Example 121:

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl]- [4- (2-hydroxy-ethoxy) -2-methyl-phenyl]-first of all Ketone (Compound 221)

The reaction was carried out in a similar manner using compound 220(3.82g, 6.83mmol) as the THP ether protected compound as described in the preparation of compound 212. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 2 followed by 2: 3 to give the title compound as a yellow foam.¹³CNMR(CDCl₃)δ195.4，160.9，147.7，141.9，137.8，134.3，134.0，133.9，133.4，132.5，131.5，130.3，130.0，124.5，117.6，117.5，116.1，112.9，110.9，69.2，61.4，21.4，17.8。

Example 122:

[4- (2-azido-ethoxy) -2-methyl-phenyl]- [4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl]- Methanone (Compound 222)

To a solution of compound 221(101mg, 0.21mmol) in anhydrous pyridine (2ml) was added 4-methyl-benzenesulfonyl chloride (81mg, 0.43mmol) at 0 ℃ with stirring. After 5 hours at room temperature, the reaction mixture was poured into a mixture of water and EtOAc. The aqueous phase was extracted twice with more EtOAc. The combined organic phases were washed with brine and dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude tosylate was dissolved in anhydrous DMF and sodium azide (17mg, 0.26mmol) was added to the solution. After 18 hours at room temperature the reaction mixture was poured into a mixture of water and EtOAc. The aqueous phase was extracted twice with more EtOAc. The combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with petroleum ether/EtOAc 2: 1 to afford the title compound.¹³C NMR(CDCl₃)δ195.5，160.4，147.8，141.8，137.7，134.4，134.0，134.0，133.3，132.6，131.8，130.1，130.0，124.6，117.6，116.1，112.8，110.9，66.9，50.1，21.3，17.8。

Example 123:

[4- (2-amino-ethoxy) -2-methyl-phenyl]- [4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl]-first of all Ketone (Compound 223)

A solution of compound 222(22mg, 0.051mmol), triphenylphosphine (15mg, 0.056mmol) and water (1. mu.l, 0.056mmol) in THF (1ml) was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography using DCM/MeOH/NH₄OH 90: 10: 1 as eluent gave the title compound.¹³C NMR(DMSO-d₆)δ 194.3，160.8，148.5，140.5，138.3，134.5，133.4，132.9，132.6，132.3，130.5，129.5，128.2，124.8，117.3，116.0，114.8，112.1，111.1，70.2，40.7，20.7，17.4。

Example 124:

[4- (2-bromophenylamino) -2-chlorophenyl group]- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy]- Phenyl } -methanone (Compound 224)

The reaction was carried out in a similar manner as described in the preparation of compound 220 using 1-bromo-2-iodo-benzene (1.19ml, 9.23mmol) as iodide. Purification was accomplished by flash chromatography using EtOAc/petroleum ether 1: 4 followed by 1: 2. The title compound was obtained as a beige solid by crystallization from a mixture of diethyl ether and petroleum ether. ¹³C NMR(CDCl₃)δ195.4，161.4，145.3，142.2，139.0，133.9，133.4，132.3，132.0，130.6，128.3，123.6，119.2，118.1，117.9，115.1，114.8，111.0，99.0，67.4，65.7，62.2，30.5，25.4，21.6，19.3。

Example 125:

{4- [2- (3-amino-propenyl) -phenylamino group]-2-chlorophenyl } - { 2-methyl-4- [2- (tetrahydro-pyran-2-yl) Oxy) -ethoxy]-phenyl } -methanone (Compound 225)

Mixing compound 224(1.09g, 2.00mmol) with Pd₂(dba)₃A solution of (55mg, 0.06mmol), 3-tributylstannyl-allylamine (727mg, 2.1mmol), CsF (668mg, 4.4mmol) and tri-tert-butyl-phosphane (0.2mmol, 0.4ml, 0.5M in hexanes) in dry 1, 4-dioxane (5.0ml) was stirred under argon at 35 ℃ for 120 hours. The reaction mixture was filtered. Acetonitrile (50ml) was added and the resulting mixture was washed with petroleum ether (x 3). The acetonitrile phase was concentrated in vacuo. The crude product was purified by chromatography in petroleum ether/EtOAc 2: 1 followed by DCM/MeOH/Et₃Elution N94: 3 gave the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.7，161.2，148.1，141.7，138.0，134.0，133.5，132.4，131.2，130.7，129.8，129.0，128.7，128.6，127.5，124.4，122.4，117.7，116.3，113.1，111.0，99.1，67.4，65.7，62.2，43.0，30.5，25.4，21.4，19.4。

Example 126:

{4- [2- (3-amino-propenyl) -phenylamino group]-2-chlorophenyl } - [4- (2-hydroxy-ethoxy) -2-methyl-benzene Base of]-methanone (Compound 226)

The reaction was carried out in a similar manner using compound 225(50mg, 0.096mmol) as the THP ether protected compound as described in the preparation of compound 212. Purification was done by flash chromatography using DCM/MeOH/Et₃N92: 5: 3 to give the title compound as a yellow oil. ¹³C NMR(DMSO-d₆)δ194.3，160.8，149.4，140.3，137.3，132.7，132.6，132.6，132.3，131.9，130.7，128.0，127.6，126.4，124.9，124.5，124.4，117.2，114.6，111.8，111.1，69.6，59.3，43.5，20.7。

Example 127:

1- (2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl]-phenylamino } -phenyl) -3-ethyl Urea (compound 227)

To a solution of compound 212(150mg, 0.38mmol) in anhydrous pyridine (1ml) was added ethyl isocyanate (75. mu.l, 0.95mmol) with stirring. After 5 hours, the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography eluting with EtOAc/petroleum ether (v: v ═ 10: 90 to 67: 33) to give the title compound as a yellow slurry.¹³C NMR(DMSO-d₆)：δ194.4，160.8，155.0，149.9，140.4，136.1，132.6，132.5，132.3，130.7，128.7，127.5，125.8，125.7，121.8，120.3，117.2，114.3，111.5，111.1，69.6，59.4，33.8，20.7，15.2。

Example 128:

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -ethyl]-benzoyl } -benzene Phenylamino) -phenyl]-3-Ethyl-Urea (Compound 228)

To a solution of compound 213(158mg, 0.28mmol) in anhydrous pyridine (2ml) was added ethyl isocyanate (33. mu.l, 0.42mmol) with stirring. After 16 h, the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography eluting with EtOAc/petroleum ether 2: 3 to afford the title compound. ¹³C NMR(CDCl₃)196.3，161.5，155.7，148.3，141.9，135.1，134.0，133.8，132.3，130.8，130.2，129.9，126.9，126.0，125.0，118.5，117.9，116.0，112.7，111.1，99.2，67.5，65.8，62.4，35.3，30.5，25.4，21.5，19.5，15.2。

Example 129:

1- (5-bromo-2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl]-phenylamino } -phenyl) -3- Ethyl-urea (Compound 229)

The reaction was carried out in a similar manner using compound 228(138mg, 0.22mmol) as the THP ether protected compound as described in the preparation of compound 212. Purification was done by flash chromatography using EtOAc/petroleum ether 3: 1 as eluent to afford the title compound as a yellow solid.¹³CNMR(DMSO-d₆)δ194.4，160.8，154.7，149.5，140.5，137.9，132.8，132.4，132.2，130.6，128.0，127.7，127.5，124.1，121.8，118.1，117.3，114.6，111.7，111.1，69.6，59.4，33.8，20.7，15.1。

Example 130:

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -ethyl]-benzoyl } -benzene Phenylamino) -phenyl]-3-cyclohexyl-urea (Compound 230)

To a solution of compound 213(151mg, 0.34mmol) in anhydrous pyridine (2ml) was added cyclohexyl isocyanate (65. mu.l, 0.51mmol) with stirring. After 18 h, the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography eluting with EtOAc/petroleum ether 1: 2 to give the title compound as a yellow solid.¹³CNMR(DMSO-d₆)δ194.4，160.6，154.0，149.5，140.5，138.0，132.7，132.5，132.2，130.7，128.0，127.6，127.5，124.0，121.7，118.1，117.3，114.6，111.7，111.2，98.0，67.2，65.0，61.2，47.7，33.2，32.7，30.0，24.9，24.2，20.7，18.9。

Preparation 86:

2-methyl-acrylic acid 2- {3- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yl) Oxy) -ethoxy Base of]-benzoyl } -phenylamino) -phenyl]-ureido } -ethyl ester (compound 486)

To a solution of compound 213(158mg, 0.28mmol) in anhydrous pyridine (2ml) was added 2-isocyano-ethyl 2-meth-acrylate (60 μ l, 0.42mmol) with stirring. After 16 h, the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography eluting with EtOAc/methanol 1: 2 to afford the title compound as a gray foam.

Example 131:

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -ethyl]-benzoyl } -benzene Phenylamino) -phenyl]-3- (2-hydroxy-ethyl) -urea (compound 231)

A solution of compound 486(110mg, 0.15mmol) in ethanol (5ml) was added sodium hydroxide solution (2M, 0.5ml), followed by stirring at reflux for 90 minutes. The reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc/petroleum ether 6: 1 to afford the title compound as a solid. ¹³C NMR(CDCl₃)δ196.5，161.6，156.8，148.5，142.1，135.1，134.0，130.6，129.8，126.9，126.3，124.8，118.6，117.9，115.8，112.6，111.1，99.2，67.5，65.7，62.4，42.7，30.5，25.4，21.6，19.4。

Example 132:

1- (5-bromo-2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl]-phenylamino } -benzene Yl) -3- (2-hydroxy-ethyl)-urea (Compound 232)

The reaction was carried out in a similar manner as described in the preparation of compound 212 using compound 231(70mg, 0.11mmol) as the THP ether protected compound. Purification was done by flash chromatography using EtOAc as eluent to afford the title compound as yellow slurry.¹³C NMR(CD₃CN)δ196.1，162.2，156.7，149.9，142.2，137.8，134.1，134.0，133.0，131.9，130.3，130.1，128.0，126.5，124.5，119.1，118.4，116.1，113.3，111.8，70.5，62.1，61.1，43.2，21.2。

Example 133:

n- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -ethyl]-benzoyl } - Phenylamino) -phenyl]-succinamic acid (Compound 233)

To a solution of compound 213(200mg, 0.36mmol) in pyridine (3ml) was added succinic anhydride (62mg, 0.62mmol) with stirring. After 24 h at 100 ℃ the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc to give the title compound as a foam.¹³C NMR(CDCl₃)δ198.0，171.0，162.0，146.8，142.5，134.7，134.2，133.3，131.2，130.3，130.2，129.9，129.4，128.2，122.1，118.1，116.6，115.2，113.7，111.2，99.1，67.5，65.7，62.3，30.5，29.2，25.4，21.8，19.3。

Preparation 87:

4-allyloxy-1-bromo-2-methyl-benzene (Compound 487)

The reaction was carried out in a similar manner using allyl bromide (5.44g, 45mmol) as bromide, as described in the preparation of compound 469. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 25 to give the title compound as a colorless oil.

Preparation 88:

(4-allyloxy-2-methyl-phenyl) - (2-chloro-4-nitro-phenyl) -methanone (Compound 488)

The reaction was carried out in a similar manner as described in the preparation of compound 470 using compound 487(6.85g, 30.2mmol) as bromide. Purification was done by flash chromatography using EtOAc/petroleum ether 1: 15 followed by 1: 10 to afford the title compound.

Preparation 89:

(4-allyloxy-2-methyl-phenyl) - (4-amino-2-chlorophenyl) -methanone (Compound 489)

The reaction was carried out in a similar manner as described in the preparation of compound 480, using compound 488(6.26g, 18.9mmol) as the nitro compound. The crude product was filtered through a pad of silica gel to afford the pure title compound.

Preparation 90:

(4-allyloxy-2-methyl-phenyl) - [4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl]-methanones (chemical combination) Thing 490)

The reaction was carried out in a similar manner as described in the preparation of compound 473, using compound 489(1.86g, 6.16mmol) as the amine. Purification was done by flash chromatography using DCM/petroleum ether 3: 2 followed by 7: 3 to give the title compound.

Example 134:

(4-allyloxy-2-methyl-phenyl) - [4- (2-amino-4-bromophenylamino) -2-chlorophenyl]-methanones (chemical combination) Thing 234)

The reaction was as described in the preparation of compound 480, using compound 490(2.01g, 4.01mmol) as the nitro groupThe compounds were performed in a similar manner. The crude product was filtered through a pad of silica gel to afford the pure title compound.¹³C NMR(CDCl₃)δ195.5，160.9，148.3，144.2，141.9，134.3，133.5，132.7，132.5，131.1，130.1，128.2，124.7，121.9，120.5，118.9，118.0，117.8，115.3，112.1，111.1，68.8，21.4。

Example 135:

n- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino]-5-bromophenyl } -acetamide (Compound 235)

Compound 134(50mg, 0.1mmol) was placed in a vial (4 ml). Acetic acid (0.5ml) and acetic anhydride (1.0ml) were added to a vial. After 2 hours at 30 ℃ the reaction mixture was poured into EtOAc/water mixture. The organic phase was concentrated in vacuo and the residue was purified by continuous gradient flash chromatography using a mixture of 1, 2-dichloro-ethane and petroleum ether to afford the title compound.¹³CNMR(CDCl₃)δ195.8，169.4，160.9，147.5，141.7，133.8，133.5，132.9，132.4，132.0，131.5，130.5，130.1，128.6，126.1，125.4，117.8，117.6，117.5，116.0，112.7，110.9，68.5，23.9，21.3。

Example 136:

1- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino]-5-bromophenyl } -3-ethyl-urea (Compound 236)

Compound 134(50mg, 0.1mmol) was placed in a vial (4 ml). Pyridine (2.0ml) and ethyl isocyanate (60mg, 0.8mmol) were added to a vial. After 2 hours at 30 ℃ the reaction mixture was poured into EtOAc/water mixture. The organic phase was concentrated in vacuo and the residue was purified by crystallization from a mixture of diethyl ether and hexanes to give the title compound as a solid. ¹³CNMR(DMSO-d₆)δ194.5，160.4，154.8，149.6，140.6，138.0，133.3，132.8，132.6，132.3，130.9，128.0，127.8，127.6，124.2，121.9，118.2，117.8，117.6，114.7，111.8，111.4，68.3，33.9，20.8，15.2。

Example 137:

{2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino]-5-bromophenyl } -carbamic acid ethyl ester Ester (Compound 237)

To a solution of compound 134(50mg, 0.1mmol) in DCM (2ml) was added K with stirring₂CO₃(45mg) with ethyl chloroformate (40. mu.l, 0.4 mmol). After 22 hours at room temperature the reaction mixture was poured into EtOAc/water mixture. The organic phase was concentrated in vacuo and the residue was purified by crystallization from ethanol to afford the title compound as a solid.¹³C NMR(DMSO-d₆)δ194.3，160.3，153.8，148.0，140.5，133.4，133.2，132.8，132.3，132.0，131.3，130.7，128.4，127.0，126.7，125.3，117.7，117.5，115.7，115.0，112.3，111.3，68.2，60.6，20.7，14.3。

Example 138:

n- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino]-5-bromophenyl } -2, 2, 2-tris Fluoro-acetamide (Compound 238)

To a solution of compound 134(50mg, 0.1mmol) in DCM (2ml) was added trifluoroacetic anhydride (95mg) and pyridine (50. mu.l) with stirring. After 1 hour at room temperature the reaction mixture was poured into EtOAc/water mixture. The organic phase was concentrated in vacuo to afford the title compound as a syrup.¹³C NMR(CDCl₃)δ195.7，161.3，155.1(q)，147.3，142.4，134.0，134.0，132.6，132.1，132.0，131.9，131.1，130.5，130.3，127.3，125.6，119.7，118.1，118.0，116.5，115.5(q)，113.3，11 1.2，68.8，21.6。

Example 139:

n- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino]-5-bromophenyl } -succinamide Acid (Compound 239)

To a solution of compound 134(50mg, 0.1mmol) in acetic acid (2ml) was added succinic anhydride (63mg) with stirring. After 1 hour at room temperature the reaction mixture was poured into a DCM/water mixture. The organic phase was concentrated in vacuo to afford the title compound as a syrup. ¹³C NMR(CDCl₃)δ198.3，179.0，170.9，161.8，146.7，142.7，134.9，134.5，133.2，132.5，131.0，130.1，129.9，129.5，128.4，121.7，118.2，116.6，114.9，113.7，111.3，68.8，30.4，29.1，21.9。

Example 140:

{2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino]-5-bromophenyl } -carbamic acid ring Pentyl ester (Compound 240)

To a solution of compound 134(50mg, 0.1mmol) in DCM (2ml) was added K with stirring₂CO₃(45mg) with cyclopentyl chloroformate (0.4 mmol). After 22 hours at room temperature the reaction mixture was poured into EtOAc/water mixture. The organic phase was concentrated in vacuo and the residue was purified by crystallization from ethanol to afford the title compound as a solid.¹³C NMR(CDCl₃)δ195.6，161.0，153.6，148.3，142.0，135.2，134.1，133.6，132.7，132.3，130.9，130.6，129.2，127.2，127.2，123.8，119.6，118.0，117.8，116.0，112.7，111.1，78.8，68.8，32.7，23.7，21.5。

Preparation 91:

2-methyl-5-nitro-thiobenzoic acid S-pyridin-2-yl ester (Compound 491)

2-methyl-5-nitrobenzoic acid (22.5g, 124mmol), 2' -dithiopyridine (2)7.5g, 124mmol) and triphenylphosphine (32.6g, 124mmol) were dissolved in CH₃CN (650 ml). The solution was stirred at room temperature for 18 hours. The reaction mixture was filtered and the solid was taken up in a small amount of CH₃And (5) CN washing. The title compound was obtained as a colorless solid.

Preparation 92:

(4-bromo-2-chlorophenyl) - (2-methyl-5-nitro-phenyl) -methanone (Compound 492)

The reaction was carried out under an argon atmosphere using a dry glass ware. 4-bromo-2-chloroiodobenzene (25.5g, 80.9mmol) was dissolved in anhydrous THF (400ml) and cooled to-60 ℃. Isopropyl magnesium chloride (2M in THF, 40.4ml, 80.9mmol) was added during 30 minutes with stirring. The reaction mixture was allowed to warm to-40 ℃ and the mixture was stirred at-40 ℃ for 4 hours. Compound 491(22.2g, 80.9mmol) was added and the mixture was stirred at-40 ℃ for 3 h, then allowed to warm to room temperature and stirred for 17 h. Addition of NH ₄Aqueous solution (200ml) was saturated with Cl, and the mixture was stirred for 1 hour. The phases are separated and washed with Et₂The aqueous phase was extracted with O (4X 100 ml). The combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using CH₂Cl₂Petroleum ether (40-60) 2: 3 as eluent to give the title compound as yellow crystalline compound.

Preparation 93:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (2-methyl-5-nitro-phenyl) -methanone (Compound 493)

Compound 492(5.4g, 15.2mmol) was dissolved in anhydrous 1, 4-dioxane (150ml) in a 200ml screw cap container. 2, 4-difluoroaniline (1.7ml, 16.7mmol) was added and argon was blown through the mixture. Addition of Cs₂CO₃(14.9g, 45.7mmol), BINAP (0.38g, 0.6mmol) and Pd (OAc)₂(0.14g, 0.6mmol) and argon was blown through the mixture and the screw cap container was closed. Mixing the raw materialsThe mixture was stirred at 100 ℃ for 7 hours. The reaction mixture is poured into H₂O (100ml) in EtOAc (200 ml). The aqueous phase was extracted with EtOAc (× 3) and the combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using CH₂Cl₂Petroleum ether (40-60) 2: 3- > 1: 1- > 1: 0, followed by EtOAc as eluent, afforded the title compound as a yellow crystalline compound.

Preparation 94:

(5-amino-2-methyl-phenyl) - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]-methanone (Compound 494)

Compound 493(6.0g, 14.9mmol) was dissolved in MeOH (350 ml). Zinc powder (12.69g, 194mmol) and NH were added₄Cl (5.59g, 104 mmol). The reaction mixture was heated at reflux temperature for 1 hour. The mixture was filtered and washed with MeOH. The filtrate was concentrated, and the solid was dissolved in EtOAc (150mL) and Na₂CO₃Saturated aqueous solution (100 ml). The aqueous phase was extracted with EtOAc and the combined organic phases were dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 2 as eluent to afford the title compound as a slightly colored crystalline compound.

Preparation 95:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (5-iodo-2-methyl-phenyl) -methanone (Compound 495)

Compound 494(0.62g, 1.66mmol) was dissolved in acetone (14 ml). Concentrated HCl (37%, 0.69ml, 8.3mmol) was added and the solution was cooled on an ice bath. Reacting NaNO₂(0.14g, 1.99mmol) in H₂O (1ml) and added to the above solution over a period of 15 minutes. During the addition, the internal temperature was maintained at 0 ℃ to 2 ℃. The suspension was stirred on an ice bath for 0.5 h, then KI (0.41g, 2.45mmol) and I were added dropwise over a period of 5 min ₂(0.31g, 1.22mmol) in H₂Solution in O (4 ml). The mixture was stirred at 0 ℃ for 2 hours. Addition of H₂O (20ml) was mixed with EtOAc (20ml) and stirred, the phases were separated. The organic phase is treated with NaHSO₃Aqueous solution, followed by Na₂CO₃Washed with aqueous solution and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 5 to afford the title compound as a slightly colored crystalline compound.

Example 141:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-methoxy-propionyl Amine (Compound 241)

3-Methoxypropionic acid (0.022ml, 0.23mmol) was dissolved in anhydrous DMF (5 ml). O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (0.09g, 0.23mmol) was added followed by 2, 4, 6-collidine (0.048ml, 0.36 mmol). The mixture was stirred for 0.5 h, then compound 494(0.067g, 0.18mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 4- > 4: 1 as the eluent. The title compound was obtained as a slightly colored crystalline compound. ¹³C NMR(CDCl₃)δ195.8，169.8，159.1(dd)，155.5(dd)，147.7，139.6，135.6，135.2，133.7，133.4，131.8，129.2，124.4(dd)，124.2(dd)，122.5，120.8，116.3，112.8，111.6(dd)，104.9(dd)，68.5，58.9，37.9，19.8。

Example 142:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -propionamide (compound) 242)

Propionic acid (0.01ml, 0.13mmol) was dissolved in anhydrous DMF (5 ml). Additive for foodHATU (0.05g, 0.13mmol) was added followed by 2, 4, 6-trimethylpyridine (0.027ml, 0.2 mmol). The mixture was stirred for 0.5 h, then compound 494(0.038g, 0.10mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 4- > 4: 1 as the eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ196.1，172.4，159.2(dd)，155.6(dd)，148.0，139.5，135.7，135.1，133.7，133.2，131.8，128.8，124.6(dd)，124.3(dd)，122.5，120.7，116.2，112.6，111.6(dd)，104.9(dd)，30.5，19.7，9.6。

Example 143:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -2- (2-methoxy-ethane Oxy) -acetamide (Compound 243)

2- (2-methoxyethoxy) acetic acid (0.017ml, 0.15mmol) was dissolved in anhydrous DMF (5 ml). HATU (0.055g, 0.15mmol) was added followed by 2, 4, 6-trimethylpyridine (0.03ml, 0.22 mmol). The mixture was stirred for 0.5 h, then compound 494(0.042g, 0.11mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 4- > 4: 1 as the eluent. The title compound was obtained as a yellow oil. ¹³C NMR(CDCl₃)δ195.9，168.4，159.1(dd)，155.6(dd)，147.9，139.4，135.1，135.1，133.7，133.5，131.9，129.2，124.5(dd)，124.4(dd)，122.3，120.7，116.1，112.7，111.6(dd)，104.9(dd)，71.4，71.3，70.4，58.9，19.8。

Example 144:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-morpholin-4-yl-propane Amide (Compound 244)

3- (4-Morpholino) propionic acid hydrochloride (0.027g, 0.14mmol) was dissolved in anhydrous DMF (5 ml). HATU (0.052g, 0.14mmol) was added followed by 2, 4, 6-trimethylpyridine (0.035ml, 0.26 mmol). The mixture was stirred for 0.5 h, then compound 494(0.039g, 0.10mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of MeOH/dichloromethane 1: 50- > 1: 12 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ195.9，170.2，159.1(dd)，155.5(dd)，147.6，138.9，136.2，134.8，133.5，133.2，132.1，129.6，124.5(dd)，124.2(dd)，122.1，121.0，116.1，112.8，111.6(dd)，104.9(dd)，66.9，54.0，52.7，32.1，20.0。

Example 145:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-hydroxy-propionamide (Compound 245)

Reacting 3-hydroxypropionic acid (30% in H)₂In O, 0.33mmol) was dissolved in anhydrous DMF (5 ml). HATU (0.125g, 0.33mmol) was added followed by 2, 4, 6-trimethylpyridine (0.061ml, 0.5 mmol). The mixture was stirred for 0.5 h, then compound 494(0.094g, 0.25mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 1 as the eluent. The title compound was obtained as a yellow oil. ¹³C NMR(DMSO-d₆)δ195.1，169.8，158.8(dd)，155.6(dd)，149.1，139.0，136.9，133.4，133.3，131.3，130.9，127.0，126.4(dd)，124.3(dd)，121.1，119.4，114.7，111.9(dd)，111.8，105.0(dd)，57.3，40.0，19.1。

Example 146:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-furan-2-yl-propane Amide (Compound 246)

3- (2-Furanylmethyl) propionic acid (0.02g, 0.14mmol) was dissolved in anhydrous DMF (4 ml). HATU (0.053g, 0.14mmol) was added followed by 2, 4, 6-trimethylpyridine (0.029ml, 0.22 mmol). The mixture was stirred for 0.5 h, then compound 494(0.040g, 0.11mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 9- > 2: 3 as the eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ196.0，170.1，159.2(dd)，155.6(dd)，154.1，147.9，141.3，139.5，135.4，135.1，133.7，133.5，131.8，128.9，124.4(dd)，124.3(dd)，122.6，120.8，116.2，112.7，111.6(dd)，110.3，105.7，104.9(dd)，35.8，23.8，19.8。

Example 147:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -2-hydroxy-benzoyl Amine (Compound 247)

2-hydroxybenzoic acid (0.019g, 0.14mmol) was dissolved in anhydrous DMF (4 ml). HATU (0.053g, 0.14mmol) was added followed by 2, 4, 6-trimethylpyridine (0.029ml, 0.22 mmol). The mixture was stirred for 0.5 h, then compound 494(0.040g, 0.11mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 9- > 3: 2 as the eluent. The title compound was obtained as a yellow oil. ¹³C NMR(CDCl₃)δ196.0，168.5，161.7，159.2(dd)，155.6(dd)，148.1，139.7，135.3，134.7，134.5，134.4，133.8，132.0，128.7，125.9，124.5(dd)，124.2(dd)，124.0，122.1，119.0，118.8，116.2，114.6，112.7，111.6(dd)，105.0(dd)，19.8。

Example 148：

N- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -2- (2, 5-di Oxo- Imidazolidin-4-yl) -acetamide (Compound 248)

Hydantoin-5-acetic acid (0.022g, 0.14mmol) was dissolved in anhydrous DMF (4 ml). HATU (0.053g, 0.14mmol) was added followed by 2, 4, 6-trimethylpyridine (0.029ml, 0.22 mmol). The mixture was stirred for 0.5 h, then compound 494(0.040g, 0.11mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using MeOH/CH₂Cl₂3: 100 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CD₃OD)δ198.1，177.6，169.6，161.1(dd)，160.0，157.9(dd)，151.3，141.1，137.5，136.1，134.9，134.1，132.7，128.8，127.5(dd)，126.0(dd)，123.4，121.8，116.5，113.0，112.7(dd)，105.8(dd)，56.7，39.2，19.8。

Example 149:

2, 6-dioxo-hexahydro-pyrimidine-4-carboxylic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4- Methyl-phenyl } -amide (Compound 249)

D, L-dihydroorotic acid (0.022g, 0.14mmol) was dissolved in anhydrous DMF (4 ml). HATU (0.053g, 0.14mmol) was added followed by 2, 4, 6-trimethylpyridine (0.029ml, 0.22 mmol). The mixture was stirred for 0.5 h, then compound 494(0.040g, 0.11mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using EtOAc/acetone 10: 1 as the eluent. The title compound was obtained as a colorless solid. ¹³C NMR(DMSO-d₆)δ194.9，169.2，169.0，158.7(dd)，155.7(dd)，153.6，149.2，139.2，136.1，133.4，133.3，131.7，131.5，126.8，126.4(dd)，124.2(dd)，121.4，119.6，114.7，112.0(dd)，111.8，105.0(dd)，50.3，38.9，19.1。

Example 150:

acrylic acid 2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenylcarbamoyl } - Ethyl ester (Compound 250)

2-Carboxyethyl acrylate (0.041ml, 0.35mmol) was dissolved in anhydrous DMF (7 ml). HATU (0.13g, 0.35mmol) was added followed by 2, 4, 6-trimethylpyridine (0.07ml, 0.54 mmol). The mixture was stirred for 0.5 h, then compound 494(0.10g, 0.27mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15: 85- > 70: 30 as eluent. The title compound was obtained as oil.¹³C NMR(DMSO-d₆)δ196.1，168.3，166.1，159.2(dd)，155.6(dd)，148.2，139.6，135.4，135.1，133.8，133.5，131.8，131.4，128.6，128.0，124.6(dd)，124.3(dd)，122.6，120.7，116.2，112.6，111.6(dd)，104.9(dd)，60.4，36.6，19.7。

Example 151:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-methylsulfanyl-propionyl Amine (Compound 251)

3-Methylthiopropionic acid (0.067g, 0.55mmol) was dissolved in anhydrous DMF (16 ml). HATU (0.21g, 0.55mmol) was added followed by 2, 4, 6-trimethylpyridine (0.11ml, 0.86 mmol). The mixture was stirred for 0.5 h, then compound 494(0.16g, 0.43mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 9- > 1: 1 as eluent. The title compound was obtained as a yellow oil. ¹³C NMR(CDCl₃)δ196.1，169.8，159.2(dd)，155.6(dd)，148.0，139.6，135.5，135.2，133.8，133.5，131.8，128.7，124.5(dd)，124.3(dd)，122.6，120.7，116.2，112.6，111.6(dd)，104.9(dd)，37.2，29.7，19.8，15.7。

Example 152:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-methanesulfonyl-propane Amide (Compound 252)

Compound 251(0.22g, 0.45mmol) was dissolved in CH₂Cl₂(5 ml). 3-Chloroperoxybenzoic acid (0.3g, ca. 1.4mmol) was added slowly and the mixture was stirred at room temperature for 1 hour. Adding Na₂S₂O₅(0.34g), and stirring was continued for 0.5 hour. Filtering the mixture and mixing the filtrate with K₂CO₃Stirred together for 0.5 hours. Adding MgSO₄And the mixture was filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 30: 70- > 100: 0 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ196.0，167.4，159.2(dd)，155.6(dd)，148.0，139.7，135.3，135.2，133.8，133.6，131.9，128.8，124.5(dd)，124.2(dd)，122.6，120.6，116.2，112.7，111.6(dd)，105.0(dd)，50.1，41.6，29.4，19.8。

Example 153:

ethanesulfonic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -amide (chemization) Compound 253)

Compound 494(0.045g, 0.12mmol) was dissolved in pyridine (0.3 ml). Ethanesulfonyl chloride (0.017ml, 0.18mmol) was added and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the oil was dissolved in EtOAc as H₂And O washing. The aqueous phase was extracted with EtOAc and the combined organic phases were dried (MgSO)₄) Filtered and concentrated in vacuo. Coarse The product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15: 85- > 40: 60 as eluent. The title compound was obtained as a yellow solid.¹³C NMR(CDCl₃)δ195.5，159.3(dd)，155.7(dd)，148.3，140.4，135.3，134.5，134.5，133.8，132.5，128.5，124.6(dd)，124.2(dd)，123.2，121.6，116.1，112.8，111.6(dd)，105.0(dd)，45.9，19.7，8.1。

Example 154:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -4-methoxy-benzenesulfonic acid Amide (Compound 254)

This compound was prepared as described for the preparation of compound 253, using compound 494(0.04g, 0.11mmol) in pyridine (0.3ml) and 4-methoxybenzenesulfonyl chloride (0.033g, 0.16 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10: 90- > 50: 50 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ195.6，163.1，159.2(dd)，155.6(dd)，148.0，139.8，135.1，134.9，134.1，133.5，132.2，130.3，129.4，128.7，124.6，124.5(dd)，124.3(dd)，122.9，116.1，114.2，112.7，111.6(dd)，104.9(dd)，55.6，19.7。

Example 155:

n- (5- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenylsulfamoyl } -4-methyl Yl-thiazol-2-yl) -acetamide (Compound 255)

This compound was prepared as described in the preparation of compound 253, using compound 494(0.042g, 0.11mmol) in pyridine (0.3ml) and 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (0.043g, 0.17 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 25: 75- > 0: 100 as eluent. The title compound was obtained as a yellow oil. ¹³C NMR(CDCl₃)δ 195.9，169.1，159.7，159.2(dd)，155.6(dd)，153.3，148.4，140.2，135.5，135.1，133.7，133.6，132.3，128.0，125.5，124.6(dd)，124.2(dd)，123.6，122.0，116.2，112.7，111.6(dd)，104.9(dd)，22.9，19.8，16.3。

Example 156:

5-acetyl-2-chloro-N- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl- Benzenesulfonamide (compound 256)

This compound was prepared as described for the preparation of compound 253, using compound 494(0.043g, 0.12mmol) in pyridine (0.3ml) and 2-chloro-5-acetylbenzenesulfonyl chloride (0.044g, 0.17 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10: 90- > 50: 50 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ195.6，195.3，159.3(dd)，155.7(dd)，148.3，140.2，136.5，136.2，135.8，135.6，135.1，133.5，133.3，132.8，132.4，132.1，131.9，128.4，124.7(dd)，124.6，124.1(dd)，122.7，116.0，112.7，111.7(dd)，105.0(dd)，26.6，19.7。

Example 157:

naphthalene-2-sulfonic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -amide (chemization) Compound 257)

This compound was prepared as described in the preparation of compound 253, using compound 494(0.041g, 0.11mmol) in pyridine (0.3ml) and naphthalene-2-sulfonyl chloride (0.037g, 0.16 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10: 90- > 50: 50 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ195.4，159.1(dd)，155.5(dd)，147.7，139.8，135.8，135.4，135.0，135.0，133.8，133.3，132.3，132.0，129.4，129.4，128.9，128.8，127.9，127.5，125.0，124.4(dd)，124.2(dd)，123.4，122.3，116.1，112.7，111.6(dd)，105.0(dd)，19.7。

Example 158:

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -C-phenyl-methanesulphonyl radical Amine (Compound 258)

This compound was prepared as described for the preparation of compound 253, using compound 494(0.041g, 0.11mmol) in pyridine (0.3ml) and α -toluenesulfonyl chloride (0.031g, 0.16 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10: 90- > 50: 50 as eluent. The title compound was obtained as a yellow oil. ¹³C NMR(CDCl₃)δ195.5，159.3(dd)，155.7(dd)，148.2，140.2，135.1，134.4，134.4，133.7，132.5，130.8，128.9，128.9，128.7，128.4，124.7(dd)，124.2(dd)，122.8，121.2，116.0，112.8，111.6(dd)，105.0(dd)，57.4，19.7。

Example 159:

2-methyl-acrylic acid 2- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzene Yl } -ureido) -ethyl ester (Compound 259)

Compound 494(0.055g, 0.15mmol) was dissolved in anhydrous pyridine (0.3ml), and isocyanoethyl methacrylate (0.031ml, 0.22mmol) was added. The solution was stirred at room temperature for 1 hour. Addition of H₂O, and the aqueous phase was extracted with EtOAc (× 2). The combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2: 1 as eluent. The title compound was obtained as oil.¹³C NMR(CDCl₃)δ196.5，167.5，159.2(dd)，155.8，155.6(dd)，148.2，139.7，136.3，135.9，135.1，133.9，132.4，132.0，128.6，126.1，124.5(dd)，124.2(dd)，123.3，121.2，116.3，112.7，111.6(dd)，104.9(dd)，63.9，39.3，19.6，18.2。

Example 160:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3- (2-hydroxy-phenyl) Ethyl) alkyl-substituted benzene Urea (Compound 260)

Compound 259(0.05g, 0.095mmol) was dissolved in EtOH (2.5 ml). 2N NaOH (0.25ml) was added and the solution was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and NaHCO was added₃Saturated aqueous solution (2 ml). Addition of H₂O with EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as eluent. The title compound was obtained as a slightly colored solid. ¹³C NMR(CD₃OD)δ198.5，161.1(dd)，158.4，157.9(dd)，151.2，141.0，138.8，136.1，135.0，132.7，132.2，128.9，127.4(dd)，126.0(dd)，122.6，120.9，116.6，112.9，112.7(dd)，105.8(dd)，62.3，43.3，19.7。

Example 161:

(3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -ureido) -acetic acid ethyl ester (Compound 261)

Compound 494(0.047g, 0.13mmol) was dissolved in pyridine (0.3ml), and ethyl isocyanoacetate (0.022ml, 0.19mmol) was added. The solution was stirred at room temperature for 2 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 1 as eluent. The title compound was obtained as a slightly colored solid.¹³CNMR(DMSO-d₆)δ 195.2，170.7，158.7(dd)，155.7(dd)，155.0，149.0，139.0，137.8，133.3，131.4，129.1，127.0，126.3(dd)，124.3(dd)，120.0，118.1，114.8，111.9(dd)，111.8，105.0(dd)，60.2，41.3，19.0，14.0。

Example 162:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3- (3-methoxy-benzene) Yl) -Urea (Compound 262)

Compound 494(0.03g, 0.08mmol) was dissolved in pyridine (0.2ml), and 3-methoxyphenyl isocyanate (0.016ml, 0.12mmol) was added. The solution was stirred at room temperature for 1.5 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2: 3 as eluent. The title compound was obtained as a slightly colored solid.¹³CNMR(CD₃OD)δ198.3，161.7，161.0(dd)，157.9(dd)，155.3，151.2，141.6，141.2，138.3，136.2，135.0，132.7，132.6，130.6，128.7，127.4(dd)，126.0(dd)，122.8，121.1，116.7，113.0，112.7，112.6(dd)，109.5，106.3，105.8(dd)，55.7，19.7。

Example 163:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3- (3-trifluoromethyl-) Phenyl) -urea (compound 263)

Compound 494(0.03g, 0.08mmol) was dissolved in pyridine (0.2ml), and 3- (trifluoromethyl) phenyl isocyanate (0.017ml, 0.12mmol) was added. The solution was stirred at room temperature for 1.5 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2: 3 as eluent. The title compound was obtained as a slightly colored solid.¹³CNMR(CD₃OD)δ198.3，161.1(dd)，157.9(dd)，155.0，151.3，141.5，141.2，138.1，136.2，135.0，132.9，132.8，132.2(q)，130.7，128.8，127.5(dd)，126.0(dd)，125.6(q)，123.4，123.0，121.2，120.0(q)，116.6，116.5(q)，113.0，112.6(dd)，105.8(dd)，19.7。

Example 164:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-propyl-urea (chemical combination) Thing 264)

Compound 494(0.03g, 0.08mmol) was dissolved in pyridine (0.2ml), and n-propyl isocyanate (0.011ml, 0.12mmol) was added. The solution was stirred at room temperature for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 1 as eluent. The title compound was obtained as a slightly colored solid.¹³C NMR(CD₃OD)δ198.5，161.0(dd)，158.3，157.9(dd)，151.1，141.0，138.9，136.1，135.0，132.7，132.1，128.9，127.4(dd)，126.0(dd)，122.5，120.9，116.6，112.9，112.6(dd)，105.8(dd)，42.6，24.4，19.7，11.6。

Example 165:

3- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -ureido) -propionic acid ethyl ester Ester (Compound 265)

Compound 494(0.03g, 0.08mmol) was dissolved in pyridine (0.2ml), and ethyl 3-isocyanopropionate (0.016ml, 0.12mmol) was added. The solution was stirred at room temperature for 1.5 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 1 as eluent. The title compound was obtained as a slightly colored solid. ¹³CNMR(CD₃OD)δ198.4，173.8，161.0(dd)，158.0，157.8(dd)，151.1，141.0，138.7，136.1，135.0，132.7，132.2，128.8，127.4(dd)，126.0(dd)，122.6，120.9，116.6，112.9，112.6(dd)，105.8(dd)，61.7，36.7，35.8，19.7，14.5。

Example 166:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-cyclohexyl-urea Compound 266)

Compound 494(0.07g, 0.18mmol) was dissolved in pyridine (0.5ml) and cyclohexyl isocyanate (0.036ml, 0.28mmol) was added. The solution was stirred at room temperature for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15: 85- > 60: 40 as eluent. The title compound was obtained as a slightly colored solid.¹³C NMR(CD₃OD)δ198.5，161.0(dd)，157.9(dd)，157.4，151.1，141.0，138.9，136.1，135.0，132.7，132.0，128.9，127.4(dd)，126.0(dd)，122.5，120.8，116.6，112.9，112.6(dd)，105.8(dd)，49.8，34.5，26.7，26.0，19.7。

Example 167:

1-allyl-3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -urea (urethanization) Compound 267)

Compound 494(0.07g, 0.18mmol) was dissolved in pyridine (0.5ml), and allyl isocyanate (0.025ml, 0.28mmol) was added. The solution was stirred at room temperature for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15: 85- > 60: 40 as eluent. The title compound was obtained as a slightly colored solid.¹³C NMR(CD₃OD)δ 198.5，161.1(dd)，158.0，157.9(dd)，151.2，141.0，138.8，136.6，136.1，135.0，132.7，132.2，128.9，127.5(dd)，126.0(dd)，122.6，121.0，116.6，115.7，112.9，112.7(dd)，105.8(dd)，43.2，19.7。

Example 168:

1-benzyl-3- {3- [ 2-chloro-4- (2, 4)-difluoro-phenylamino) -benzoyl ]-4-methyl-phenyl } -urea (Compound No.) Thing 268)

Compound 494(0.07g, 0.18mmol) was dissolved in pyridine (0.5ml) and benzyl isocyanate (0.035ml, 0.28mmol) was added. The solution was stirred at room temperature for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using MeOH/CH₂Cl₂1: 100 as eluent. The title compound was obtained as a slightly colored solid.¹³C NMR(DMSO-d₆)δ195.3，158.8(dd)，155.8(dd)，155.2，149.1，140.3，139.1，138.2，133.4，131.4，129.0，128.3，127.1，126.7，126.4(dd)，124.4(dd)，120.1，118.2，114.9，112.0(dd)，111.9，105.1(dd)，42.7，19.1。

Example 169:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-ethyl-urea (Compound No.) Thing 269)

Compound 494(0.04g, 0.11mmol) was dissolved in 1, 4-dioxane (0.5ml) and ethyl isocyanate (0.013ml, 0.16mmol) was added. The solution was stirred at room temperature for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 30: 70- > 100: 0 as eluent. The title compound was obtained as an amorphous compound.¹³C NMR(DMSO-d₆)δ195.6，159.0(dd)，156.0(dd)，155.3，149.2，139.3，138.3，133.7，133.5，131.5，129.2，127.5，126.4(dd)，124.5(dd)，120.2，118.4，115.1，112.1(dd)，112.0，105.1(dd)，34.0，19.1，15.4。

Example 170:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-phenyl-urea (Compound No.) Thing 270)

Compound 494(0.03g, 0.08mmol) was dissolved in 1, 4-dioxane (0.5ml) and phenyl isocyanate (0.013ml, 0.12mmol) was added. The solution was stirred at 50 ℃ for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15: 85- > 60: 40 as eluent. The title compound was obtained as an amorphous compound. ¹³C NMR(DMSO-d₆)δ195.1，158.7(dd)，155.7(dd)，152.3，148.9，139.3，139.1，137.2，133.4，131.5，129.6，128.7，127.0，126.2(dd)，124.2(dd)，121.8，120.3，118.4，118.2，118.1，114.8，111.9(dd)，111.8，105.0(dd)，19.0。

Example 171:

1-butyl-3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -urea (Compound No.) Object 271)

Compound 494(0.03g, 0.08mmol) was dissolved in 1, 4-dioxane (0.5ml) and n-butyl isocyanate (0.014ml, 0.12mmol) was added. The solution was stirred at 50 ℃ for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15: 85- > 60: 40 as eluent. The title compound was obtained as a slightly colored solid.¹³C NMR(CD3OD)δ198.5，161.0(dd)，158.3，157.9(dd)，151.1，141.0，138.9，136.1，135.0，132.7，132.1，128.9，127.4(dd)，126.0(dd)，122.5，120.9，116.6，112.9，112.6(dd)，105.8(dd)，40.6，33.3，21.0，19.7，14.1。

Example 172:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-phenethyl-urea (urethanization) Compound 272)

Compound 494(0.03g, 0.08mmol) was dissolved in 1, 4-dioxane (0.5ml), and 2-phenylethyl isocyanate (II) was added0.016ml, 0.12 mmol). The solution was stirred at 50 ℃ for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15: 85- > 60: 40 as eluent. The title compound was obtained as a slightly colored solid.¹³C NMR(CDCl₃)δ196.5，159.2(dd)，156.0，155.6(dd)，148.1，139.6，138.9，136.5，135.1，133.9，132.2，131.9，128.7，128.5，126.4，124.6(dd)，124.2(dd)，123.1，121.1，116.2，112.7，111.6(dd)，104.9(dd)，41.5，36.3，19.6。

Example 173:

2- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ]-4-methyl-phenyl } -ureido) -benzoic acid Methyl ester (Compound 273)

Compound 494(0.03g, 0.08mmol) was dissolved in 1, 4-dioxane (0.5ml) and methyl 2-isocyanatobenzoate (0.021ml, 0.12mmol) was added. The solution was stirred at 50 ℃ for 24 hours. Methyl 2-isocyanatobenzoate (0.01ml, 0.06mmol) was added. The solution was stirred at 50 ℃ for 24 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10: 90- > 40: 60 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ195.8，169.0，159.0(dd)，155.4(dd)，152.4，147.6，142.5，139.5，135.6，135.1，134.6，133.6，133.4，132.1，130.8，129.4，124.5(dd)，124.1(dd)，123.3，121.7，121.3，119.8，116.3，114.3，112.8，111.5(dd)，104.9(dd)，52.2，19.8。

Example 174:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3- (3-cyano-phenyl) -substituted benzene Urea (Compound 274)

Compound 494(0.03g, 0.08mmol) was dissolved in 1,4-dioxane (0.5ml), and 3-cyanobenzene isocyanate (0.017g, 0.12mmol) was added. The solution was stirred at 50 ℃ for 24 hours. 3-cyanophenyl isocyanate (0.09g, 0.06mmol) was added. The solution was stirred at 50 ℃ for 24 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using MeOH/CH₂Cl₂1: 100 as eluent. The title compound was obtained as a yellow oil. ¹³CNMR(DMSO-d₆)δ195.1，158.8(dd)，155.8(dd)，152.4，149.2，140.5，139.3，137.0，133.5，131.6，130.2，130.1，126.9，126.5(dd)，125.4，124.3(dd)，123.0，121.1，120.8，118.9，118.8，114.9，112.0(dd)，111.9，111.6，105.1(dd)，19.1。

Example 175:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3-isopropyl-urea Compound 275)

Compound 494(0.03g, 0.08mmol) was dissolved in 1, 4-dioxane (0.5ml) and isopropyl isocyanate (0.012ml, 0.12mmol) was added. The solution was stirred at 50 ℃ for 24 hours. Isopropyl isocyanate (0.006ml, 0.06mmol) was added. The solution was stirred at 50 ℃ for 24 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15: 85- > 60: 40 as eluent. The title compound was obtained as a slightly colored solid.¹³C NMR(CD₃OD)δ198.4，160.9(dd)，157.8(dd)，157.4，151.1，140.9，138.7，136.1，134.9，132.6，131.9，128.7，127.3(dd)，125.9(dd)，122.4，120.7，116.6，112.9，112.6(dd)，105.7(dd)，42.8，23.4，19.6。

Example 176:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -3- (4-methoxy-benzene) Yl) -Urea (Compound 276)

Compound 494(0.03g, 0.08mmol) was dissolved in 1, 4-dioxane (0.5ml), and 4-methoxyphenyl isocyanate (0.016ml, 0.12mmol) was added. The solution was stirred at 50 ℃ for 18 hours. The treatment was as described in the preparation of compound 259. The crude product was purified by flash chromatography using MeOH/CH₂Cl₂1: 100 as eluent. The title compound was obtained as oil.¹³CNMR(DMSO-d₆)δ195.2，158.8(dd)，155.8(dd)，154.6，152.7，149.1，139.2，137.6，133.5，132.5，131.5，129.5，127.0，126.4(dd)，124.4(dd)，120.4，120.2，119.9，118.5，114.9，114.0，112.0(dd)，111.9，105.1(dd)，55.2，19.1。

Example 177:

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -carbamic acid benzyl ester (Compound 277)

Compound 494(0.06g, 0.16mmol) is suspended in anhydrous CH in a screw cap container under argon atmosphere₂Cl₂(1.5 ml). Addition of K₂CO₃(0.044g, 0.32mmol) followed by the addition of benzyl chloroformate (0.046ml, 0.032 mmol). The suspension was stirred at room temperature for 18 hours. Addition of H₂O and CH₂Cl₂And the phases were separated. With CH₂Cl₂The aqueous phase was washed (x2) and the combined organic phases were washed with brine, dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 4 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CD₃OD)δ 198.3，161.0(dd)，157.8(dd)，155.8，151.1，141.1，138.0，136.2，135.0，132.8，132.7，129.5，129.1，129.0，128.7，127.3(dd)，126.0(dd)，122.3，120.6，1 16.7，1 12.9，1 12.6(dd)，105.7(dd)，67.6，19.7。

Example 178:

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -carbamic acid allyl ester (Compound 278)

Compound 494(0.06g, 0.16mmol) is suspended in anhydrous CH in a screw cap container under argon atmosphere₂Cl₂(1.5 ml). Addition of K₂CO₃(0.044g, 0.32mmol) followed by allyl chloroformate (0.034ml, 0.032 mmol). The suspension was stirred at room temperature for 48 hours. Treatment was as described for the preparation of compound 277. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 5: 95- > 30: 70 as eluent. The title compound was obtained as a yellow oil. ¹³CNMR(CDCl₃)δ195.8，159.1(dd)，155.5(dd)，153.2，147.7，139.6，135.4，135.2，133.6，132.9，132.3，132.0，129.3，124.4(dd)，124.2(dd)，121.3，119.7，118.3，116.3，112.8，111.6(dd)，105.0(dd)，65.9，19.7。

Example 179:

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-phenyl } -carbamic acid ethyl ester (esterification) Compound 279)

Compound 494(0.039g, 0.1mmol) was suspended in anhydrous CH under argon atmosphere₂Cl₂(1 ml). Addition of K₂CO₃(0.029g, 0.21mmol) followed by the addition of ethyl chloroformate (0.02ml, 0.021 mmol). The suspension was stirred at room temperature for 48 hours. Treatment was as described for the preparation of compound 277. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 2 as eluent. The title compound was obtained as oil.¹³C NMR(CDCl₃)δ 196.0，159.1(dd)，155.6(dd)，153.7，147.9，139.5，135.6，135.1，133.6，132.6，131.9，129.1，124.4(dd)，124.3(dd)，121.3，119.8，116.2，112.7，111.6(dd)，104.9(dd)，61.3，19.7，14.5。

Example 181:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- [5- (3-hydroxy-butylamino) -2-methyl-phenyl]-methanones (Compound 281)

Compound 494(0.033g, 0.09mmol) was suspended in MeOH (1 ml). 3-hydroxy-butyraldehyde (0.023g, 0.27mmol) and NaCN (BH) were added₃) (0.055g, 0.88 mmol). The suspension was stirred at room temperature for 18 hours. 3-hydroxy-butyraldehyde (0.023g, 0.27mmol) and NaCN (BH) were added again₃) (0.055g, 0.88mmol) and the suspension stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with brine. The aqueous phase was extracted with EtOAc and the combined organic phases were dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using MeOH/CH₂Cl₂1: 50 as eluent. The title compound was obtained as oil.¹³C NMR(CDCl₃)δ196.7，159.0(dd)，155.4(dd)，147.3，146.0，139.6，135.0，133.5，132.0，129.9，126.7，124.6(dd)，124.0(dd)，116.3，115.9，114.6，112.8，111.6(dd)，104.9(dd)，67.5，42.1，38.0，24.0，19.4。

Example 182:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (3' -hydroxymethyl-4-methyl-biphenyl-3-yl) -methanone Thing 282)

In a screw cap container, compound 495(0.039g, 0.081mmol) was dissolved in 1, 2-dimethoxyethane (0.8 ml). 3- (hydroxymethyl) phenyldihydroxyborane (boronic acid) (0.015g, 0.097mmol) and NaHCO were added₃Saturated aqueous solution (0.4 ml). Argon was blown through the mixture and Pd (PPh) was added₃)₄(0.005g, 0.004 mmol). The reaction mixture was stirred at reflux temperature under argon atmosphere for 2 hours. Addition of H₂O with EtOAc and extract the aqueous phase with EtOAc (× 2). The combined organic phases were dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 1 as eluent. The title compound was obtained as oil.¹³CNMR(CDCl₃)δ 196.3，159.1(dd)，155.5(dd)，147.8，141.5，140.6，139.6，138.3，137.0，135.3，133.7，131.8，129.4，129.1，128.0，126.3，126.0，125.6，124.4(dd)，124.3(dd)，116.3，112.8，111.6(dd)，104.9(dd)，65.3，20.1。

Example 183:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (3' -hydroxy-4-methyl-biphenyl-3-yl) -methanone (compound) 283)

This compound was prepared as described for the preparation of compound 282. Starting material was compound 495(0.039g, 0.081mmol), 3-hydroxyphenyl dihydroxy borane (0.013g, 0.097mmol) in 1, 2-dimethoxyethane (0.8ml), NaHCO ₃Saturated aqueous solution (0.4ml) and Pd (PPh)₃)₄(0.005g, 0.004 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 2 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ196.7，159.2(dd)，156.1，155.5(dd)，147.9，141.8，139.4，138.1，137.1，135.3，133.7，131.8，130.0，129.5，129.3，128.1，124.3(m)，119.4，116.3，114.5，114.0，112.8，111.6(dd)，104.9(dd)，20.1。

Example 184:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (4' -methoxy-4-methyl-biphenyl-3-yl) -methanone (compound Thing 284)

This compound was prepared as described for the preparation of compound 282. Starting material was compound 495(0.042g, 0.087mmol), 4-methoxyphenyl dihydroxy borane (0.016g, 0.11mmol) in 1, 2-dimethoxyethane (1ml), NaHCO₃Saturated aqueous solution (0.5ml) and Pd (PPh)₃)₄(0.005g0.004 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 5 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ196.4，159.3，159.1(dd)，155.5(dd)，147.7，139.4，138.1，136.3，135.2，133.6，132.7，131.8，129.6，129.0，128.0，127.8，124.4(dd)，124.2(dd)，116.3，114.3，112.8，111.6(dd)，104.9(dd)，55.4，20.1。

Example 185:

n- { 3' - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4' -methyl-biphenyl-3-yl } -acetamide (Compound 285)

This compound was prepared as described for the preparation of compound 282. Starting material was compound 495(0.048g, 0.1mmol), 3-acetamidophenyldihydroxyborane (0.021g, 0.12mmol) in 1, 2-dimethoxyethane (1ml), NaHCO₃Saturated aqueous solution (0.5ml) and Pd (PPh) ₃)₄(0.006g, 0.005 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 1 as eluent. The title compound was obtained as a slightly colored solid.¹³C NMR(DMSO-d₆)δ195.0，168.4，158.8(dd)，155.8(dd)，149.4，140.0，139.9，139.6，137.5，135.8，133.9，133.8，131.9，129.4，128.7，126.6，126.5，126.4(dd)，124.3(dd)，121.2，118.2，116.9，115.0，112.0(dd)，111.9，105.1(dd)，24.0，19.4。

Example 186:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (4-methyl-3' -trifluoromethoxy-biphenyl-3-yl) -methanone (Compound 286)

This compound was prepared as described for the preparation of compound 282. Starting material was compound 495(0.048g, 0.1mmol), 3- (trifluoromethoxy) benzenedihydroxyborane (0.025g, 0.12 mmol) in 1, 2-dimethoxyethane (1.2ml))、NaHCO₃Saturated aqueous solution (0.6ml) and Pd (PPh)₃)₄(0.006g, 0.005 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 2: 98- > 10: 90 as eluent. The title compound was obtained as a yellow oil.

Example 188:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (3 ', 4 ', 5 ' -trifluoro-4-methyl-biphenyl-3-yl) -methanone Compound 288)

This compound was prepared as described for the preparation of compound 282. The starting material was compound 495(0.055g, 0.11mmol), 3, 4, 5-trifluorobenzene dihydroxyborane (0.024g, 0.14mmol) in 1, 2-dimethoxyethane (1.2ml), NaHCO ₃Saturated aqueous solution (0.6ml) and Pd (PPh)₃)₄(0.007g, 0.006 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 2: 98- > 10: 90 as eluent. The title compound was obtained as a yellow oil.¹³CNMR(CDCl₃)δ195.8，159.3(dd)，155.6(dd)，151.4(m)，148.1，140.1，139.3(dt)，138.0，136.3(m)，135.5，135.3，133.8，132.1，128.9，127.5，124.6(dd)，124.2(dd)，116.2，112.7，111.6(dd)，110.9(m)，105.0(dd)，20.1。

Example 189:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (3 ', 4' -dimethoxy-4-methyl-biphenyl-3-yl) -methanone (289)

This compound was prepared as described for the preparation of compound 282. The starting material was compound 495(0.055g, 0.11mmol), 3, 4-dimethoxybenzenedihydroxyborane (0.025g, 0.15mmol), NaHCO in 1, 2-dimethoxyethane (1.2ml), NaHCO₃Saturated aqueous solution (0.6ml) and Pd (PPh)₃)₄(0.007g, 0.006 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 12: 88- > 50: 1Gradient 50 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ196.4，159.1(dd)，155.5(dd)，149.2，148.7，147.8，139.5，138.4，136.3，135.2，133.7，133.2，131.7，129.3，129.1，127.8，124.3(m)，119.3，116.3，112.7，111.6(dd)，111.5，110.4，105.0(dd)，56.0，20.0。

Example 190:

3' - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4' -methyl-biphenyl-3-carbonitrile (Compound 290)

This compound was prepared as described for the preparation of compound 282. The starting material was compound 495(0.057g, 0.12mmol), 3-cyanobenzene dihydroxyborane (0.021g, 0.14mmol), NaHCO in 1, 2-dimethoxyethane (1.2ml) ₃Saturated aqueous solution (0.6ml) and Pd (PPh)₃)₄(0.007g, 0.006 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 2: 3- > 4: 1 as eluent. The title compound was obtained as a yellow oil.¹³C NMR(CDCl₃)δ195.9，159.2(dd)，155.6(dd)，148.1，141.4，140.1，138.1，136.2，135.3，133.7，132.2，131.4，130.8，130.5，129.7，129.2，128.9，127.7，124.5(dd)，124.2(dd)，118.8，116.2，113.0，112.8，111.6(dd)，105.0(dd)，20.1。

Preparation 96:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzenesulfonyl chloride (Compound 496)

Compound 494(1.03g, 2.76mmol) was dissolved in CH by heating₃CN (65 ml). The solution was allowed to cool to room temperature and concentrated HCl (37%, 1.2ml, ca. 14mmol) and AcOH (99%, 2.3ml) were added. The solution was cooled on an ice bath and the internal temperature was monitored. Adding dissolved H under stirring within 15 min₂NaNO in O (0.6ml)₂(0.23g, 3.31 mmol). Internal temperature not exceedingAnd passing through 2 ℃. The mixture was stirred for 20 minutes on an ice bath, and then SO was allowed to stir on an ice bath₂Gas was bubbled through the mixture for 45 minutes. CuCl (0.37g, 3.8mmol) was added followed by dissolution in H₂CuCl in O (0.6ml)₂.2H₂O (0.59g, 3.46 mmol). The mixture was stirred at 0 ℃ for 10 minutes, followed by stirring at room temperature for 1 hour. The mixture was concentrated in vacuo, dissolved in EtOAc and H₂And (4) in O. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine and dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 4 as eluent to afford the title compound as a pale brown crystalline compound.

Example 191:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -4-methyl-benzenesulfonyl Amine (Compound 291)

Compound 496(0.07g, 0.15mmol) was dissolved in pyridine (0.4ml) and ethanolamine (0.011ml, 0.18mmol) was added. The solution was kept at room temperature for 1 hour and then concentrated in vacuo. The residue was dissolved in EtOAc and H₂O, and separating the phases. The aqueous phase was extracted with EtOAc (× 2) and the combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 3: 7- > 1: 0 as eluent. The title compound was obtained as a solid.¹³C NMR(CD₃OD)δ196.5，161.2(dd)，158.0(dd)，151.9，143.3，142.0，139.5，136.5，135.2，133.2，129.9，128.2，127.8，127.8(dd)，125.7(dd)，116.5，113.1，112.7(dd)，105.8(dd)，61.8，46.3，20.3。

Example 192:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-N- (2-morpholin-4-yl-ethyl) -benzene Sulfonamides (Compound 292)

The compound was prepared and worked up as described in the preparation of compound 291. The starting material was compound 496(0.081g, 0.18mmol) in pyridine (0.5ml) with 4- (2-aminoethyl) morpholine (0.028ml, 0.21 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 1- > 1: 0 as eluent. The title compound was obtained as an amorphous compound. ¹³C NMR(CDCl₃)δ194.5，159.5(dd)，155.9(dd)，148.8，142.8，140.5，137.0，135.4，134.0，132.1，128.7，127.9，127.3，125.0(dd)，123.9(dd)，116.0，112.9，111.7(dd)，105.1(dd)，66.8，56.2，53.0，38.9，20.4。

Example 193:

n-allyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzenesulfonamide (compound) Thing 293)

The compound was prepared and worked up as described in the preparation of compound 291. The starting materials were compound 496(0.071g, 0.16mmol) and allylamine (0.014ml, 0.19mmol) in pyridine (0.4 ml). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 4- > 2: 3 as eluent. The title compound was obtained as oil.¹³C NMR(CDCl₃)δ194.6，159.4(dd)，155.8(dd)，148.7，143.0，140.4，137.4，135.5，133.9，132.8，132.1，128.8，128.0，127.5，124.9(dd)，124.0(dd)，118.0，116.1，112.9，111.7(dd)，105.0(dd)，45.8，20.4。

Example 194:

n- (2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzenesulfonylamino } -ethyl) - Acetamide (Compound 294)

The compound was prepared and worked up as described in the preparation of compound 291. The starting material is pyridine (0)4ml) with N-acetylethylenediamine (0.019ml, 0.2 mmol). The crude product was purified by flash chromatography using a gradient of DCM/MeOH 95: 5- > 80: 20 as eluent. The title compound was obtained as oil.¹³C NMR(CDCl₃)δ194.6，171.5，159.5(dd)，155.9(dd)，149.0，142.7，140.5，137.1，135.6，134.2，132.2，128.6，127.4，127.2，125.2(dd)，123.9(dd)，116.1，112.7，111.7(dd)，105.0(dd)，43.2，39.3，23.1，20.3。

Example 195:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-N-propyl-benzenesulfonamide (compound) 295)

The compound was prepared and worked up as described in the preparation of compound 291. The starting materials were compound 496(0.074g, 0.16mmol) in pyridine (0.4ml) and n-propylamine (0.016ml, 0.2 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 4- > 3: 2 as eluent. The title compound was obtained as oil. ¹³C NMR(CDCl₃)δ194.7，159.4(dd)，155.8(dd)，148.6，142.8，140.3，137.4，135.5，133.9，132.1，128.8，128.1，127.5，124.9(dd)，124.0(dd)，116.1，112.9，111.7(dd)，105.0(dd)，45.0，22.9，20.4，11.1。

Example 196:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2, 3-dihydroxy-propyl) -4-methyl-benzenesulfonic acid Amide (Compound 296)

The compound was prepared and worked up as described in the preparation of compound 291. The starting material was compound 496(0.073g, 0.16mmol) in pyridine (0.4ml) with 3-amino-1, 2-propanediol (0.017g, 0.19 mmol). The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 1- > 1: 0 as eluent. The title compound was obtained as oil.¹³C NMR(CDCl₃)δ194.8，159.5(dd)，155.8(dd)，149.0，142.7，140.5，136.9，135.6，134.2，132.2，128.7，127.4，127.2，125.1(bd)，123.9(dd)，116.1，112.7，111.7(dd)，105.0(dd)，70.4，64.0，45.4，20.3。

Example 197:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-methoxy-ethyl) -4-methyl-benzenesulfonic acid Amide (Compound 297)

The compound was prepared and worked up as described in the preparation of compound 291. The starting material was compound 496(0.03g, 0.066mmol) in pyridine (0.15ml) with 2-methoxy-ethylamine (0.007ml, 0.08 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 3: 2 as eluent. The title compound was obtained as oil.¹³C NMR(CDCl₃)δ194.5，159.4(dd)，155.8(dd)，148.6，142.9，140.3，137.3，135.5，134.0，132.1，128.7，128.1，127.5，124.9(dd)，124.0(dd)，116.1，112.9，111.7(dd)，105.0(dd)，70.4，58.8，42.9，20.4。

Preparation 97:

2-methyl-5-nitro-benzoic acid methyl ester (compound 497)

Acetyl chloride (15ml) was added to MeOH (500ml) at room temperature. After 10 min, 2-methyl-5-nitro-benzoic acid (25.00g, 138.00mmol) was added. The reaction solution was heated to reflux for 18 hours. The solution was then concentrated in vacuo. The residue is dissolved in diethyl ether and separately treated with H ₂O and NaHCO₃Washing with saturated aqueous solution. The organic phase is washed with MgSO₄Dried and concentrated in vacuo to afford the title compound as a white solid.

Preparation 98:

5-amino-2-methyl-benzoic acid methyl ester (Compound 498)

Compound 497(26.5g, 135.78mmol) in ethanol (200ml) was hydrogenated in the presence of Pd/C5% (2.00g) at 1 atm and room temperature for 3 h. The catalyst was filtered off after the reaction. The filtrate was concentrated in vacuo to provide the title compound as a brown oil.

Preparation 99:

5-hydroxy-2-methyl-benzoic acid methyl ester (Compound 499)

At 2N H₂SO₄(200ml), H was added dropwise at 0 deg.C₂NaNO in O (100ml)₂(11.50g, 167.00 mmol). After stirring at the same temperature for 20 minutes, the reaction mixture was heated under reflux for 2 hours. The solution was then allowed to cool to room temperature and stirred at the same temperature overnight. With CHCl₃The mixture was extracted three times. The combined organic phases were washed with MgSO₄Dried and concentrated in vacuo. The residue is purified by Chromatography (CH)₂Cl₂Ethyl acetate 50: 1) to afford the title compound as a red solid.

Preparation of 100:

5- (4-methoxy-benzyloxy) -2-methyl-benzoic acid methyl ester (Compound 500)

Compounds 499(4.4g, 26.48mmol), 4-methoxybenzyl chloride (4.4g, 28.09mmol), K ₂CO₃A mixture of (4.4g, 31.83mmol) and NaI (20mg) was heated under reflux for 3 hours. The solid was filtered off after the reaction. The filtrate was concentrated in vacuo. The residue was purified by chromatography (petroleum ether/CH)₂Cl₂2: 1, then CH₂Cl₂) The title compound was obtained as a yellow solid.

Preparation 101:

[5- (4-methoxy-benzyloxy) -2-methyl-phenyl]-methanol (Compound 501)

In the presence of compound 500(6.0g, 21.00mmol) in CH₂Cl₂To a solution at-78 deg.C in (100ml) was added DIBAL-H (1M in n-hexane, 55ml, 55 mmol). The solution was allowed to warm to room temperature and stirred for 1 hour. Then with NH₄The reaction solution was quenched with a saturated aqueous solution of Cl. The mixture was filtered and washed with acetone. The combined liquids were concentrated in vacuo to remove acetone and CH₂Cl₂. Mixing the aqueous mixture with CH₂Cl₂Extraction was carried out three times. The combined organic phases were washed with MgSO₄Dried and concentrated in vacuo to afford the title compound as a grayish solid.

Preparation 102:

5- (4-methoxy-oxy) -2-methyl-benzaldehyde (Compound 502)

In the presence of compound 501(5.06g, 19.59mmol) in CH₂Cl₂To a solution in (100ml) was added Dess-Martin periodinane (8.36g, 19.71mmol) at room temperature over 20 minutes, and the mixture was stirred for 1 hour. After complete conversion, the reaction mixture was concentrated in vacuo together with silica gel. The residue is purified by Chromatography (CH) ₂Cl₂) The title compound is provided as a yellow solid.

Preparation 103:

(4-bromo-2-nitro-phenyl) - [5- (4-methoxy-benzyloxy) -2-methyl-phenyl]-methanol (Compound 503)

To a solution of 1, 4-dibromo-2-nitro-benzene (5.89g, 21.00mmol) in THF (300ml) was added a PhLi solution (1.8M in cyclohexane/diethyl ether 7: 3, 12.8ml, 23.1mmol) at-110 ℃. The mixture was stirred at the same temperature for 1 hour. Compound 502(4.45g, 17.4mmol) in THF (100ml) was added dropwise to the mixture. The reaction mixture was then warmed to-78 ℃ and stirred at the same temperature for 4 hours. Then with NH₄The reaction mixture was quenched with saturated aqueous Cl solution. With diethyl etherThe aqueous phase was extracted once. The combined organic phases were washed with MgSO₄Dried and concentrated in vacuo. The residue was chromatographed (petroleum ether/ethyl acetate 5: 1) to give a reddish foam.

Preparation 104:

(4-bromo-2-nitro-phenyl) - [5- (4-methoxy-benzyloxy) -2-methyl-phenyl]-methanone (Compound 504)

To a solution of compound 503(6.47g, 14.12mmol) was added Dess-Martin periodinane (8.00g, 18.86mmol) at room temperature in one portion. After stirring at room temperature for 3 hours, the reaction mixture was chromatographed (petroleum ether/ethyl acetate 10: 1) to provide the title compound as a brown oil.

Example 198:

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl]- [5- (4-methoxy-benzyloxy) -2-methyl-benzene Base of]-methanone (Compound 298)

Compound 504(0.6g, 1.35mmol) was dissolved in 1, 4-dioxane (15 ml). 4-fluoro-2-methylaniline (0.22ml, 2.0mmol) and Cs were added₂CO₃(0.61g, 1.88mmol), BINAP (0.06g, 0.1mmol) and Pd₂(dba)₃(0.031g, 0.03mmol) and the reaction mixture is stirred under argon at 100 ℃ for 18 h. Addition of H₂O, and the aqueous phase was extracted with EtOAc (× 2). The combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 0: 100- > 30: 70. The title compound was obtained.¹H NMR(CDCl₃)δ7.32(d，1H)，7.30-7.14(m，4H)，7.11(d，1H)，7.06-6.91(m，3H)，6.88(m，2H)，6.84-6.77(m，2H)，5.87(bs，1H)，4.88(s，2H)，3.80(s，3H)，2.49(s，3H)，2.25(s，3H)。

Preparation 105:

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl]- (5-hydroxy-2-methyl-phenyl) -methanone (compound) 505)

Compound 298(0.57g, 1.14mmol) is dissolved in CH₂Cl₂(10ml), and CF was added₃COOH (10 ml). The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated. Making the solid from CH₂Cl₂And (4) recrystallizing. The title compound was obtained as a solid.

Example 199:

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl]- [5- (3-hydroxy-propoxy) -2-methyl-phenyl ]- Methanone (Compound 299)

Compound 505(0.05g, 0.13mmol) and 3-chloro-propanol (0.022ml, 0.26mmol) were dissolved in CH₃CN (3 ml). Addition of K₂CO₃(0.1g, 0.72mmol) and NaI (0.005g, 0.03mmol), and the suspension was heated in a microwave oven at 100 ℃ for 20 minutes. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/CH₂Cl₂1: 9 as eluent. The title compound was obtained.¹H NMR(CDCl₃)δ7.36(d，1H)，7.22(dd，1H)，7.1 7(d，1H)，7.10(d，1H)，7.06-6.89(m，3H)，6.83(dd，1H)，6.79(d，1H)，5.88(bs，1H)，4.04(t，2H)，3.82(t，2H)，2.47(s，3H)，2.25(s，3H)，1.99(m，2H)。

Example 200:

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl]- [5- (3-hydroxy-propoxy) -2-methyl-phenyl]- Methanone (Compound 300)

Compound 299(0.026g, 0.059mmol) was dissolved in MeOH (2 ml). A catalytic amount of palladium on carbon was added and the mixture was stirred under hydrogen atmosphere for 1 hour. The suspension was filtered and the filtrate was concentrated in vacuo.The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 1- > 3: 1 as eluent. The title compound was obtained.¹H NMR(CDCl₃)δ7.18(dd，1H)，7.11(d，1H)，7.03(d，1H)，7.00-6.80(m，3H)，6.76(d，1H)，6.45(bs，2H)，5.89(dd，1H)，5.75(d，1H)，5.59(s，1H)，4.08(t，2H)，3.83(t，2H)，2.22(s，3H)，2.1 8(s，3H)，2.01(m，2H)。

Preparation 106:

toluene-4-sulfonic acid 2, 2-dimethyl- [1, 3%]Dioxolan-4-ylmethyl ester (Compound 506)

2, 2-dimethyl-4-hydroxymethyl-1, 3-dioxolane (3.96g, 30mmol) and triethylamine (5ml) were dissolved in CH₂Cl₂(50 ml). P-toluenesulfonyl chloride (3.8g, 20mmol) was added. The solution was stirred for 3 hours, then 4-dimethylaminopyridine (0.05g, 0.04mmol) was added. The solution was stirred for 0.5 h, then the solution was concentrated in vacuo. The residue was dissolved in CH ₂Cl₂And the organic phase is washed with H₂O washing and drying (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford the title compound.

Example 201:

[5- (2, 2-dimethyl- [1, 3 ]]Dioxolan-4-ylmethoxy) -2-methyl-phenyl]- [4- (4-fluoro-2-methyl-benzene) Aminoyl) -2-nitro-phenyl]-methanone (Compound 301)

Compound 505(0.05g, 0.13mmol) and compound 506(0.056g, 0.2mmol) were dissolved in CH₃CN (3 ml). Addition of K₂CO₃(0.1g, 0.72mmol) and NaI (0.005g, 0.03mmol), and the suspension was heated in a microwave oven at 100 ℃ for 20 minutes and stirred at room temperature for 16 hours. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 0: 1- > 1: 4 as eluent. The title compound was obtained.¹HNMR(CDCl₃)δ7.34(d，1H)，7.22(dd，1H)，7.17(d，1H)，7.10(d，1H)，7.05-6.87(m，3H)，6.85-6.77(m，2H)，5.99(bs，1H)，4.42(m，1H)，4.17-4.06(m，1H)，3.96(dd，1H)，3.90-3.78(m，2H)，2.46(s，3H)，2.25(s，3H)，1.43(s，3H)，1.38(s，3H)。

Example 202:

[5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl]- [4- (4-fluoro-2-methyl-phenylamino) -2-nitro-benzene Base of]-methanone (Compound 302)

Compound 301(0.025g, 0.05mmol) was dissolved in THF (2ml) and 1MHCl (0.2ml) was added. The solution was kept at room temperature for 3 hours, then the solution was concentrated in vacuo. The title compound was obtained.¹H NMR(CDCl₃)δ7.36(d，1H)，7.22(dd，1H)，7.18(d，1H)，7.10(d，1H)，7.06-6.88(m，3H)，6.87-6.77(m，2H)，5.89(bs，1H)，4.05(m，1H)，3.95(m，2H)，3.85-3.65(m，2H)，2.46(s，3H)，2.25(s，3H)。

Example 203:

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl]- [5- (2, 3-dihydroxy-propoxy) -2-methyl-benzene Base of]-methanone (303)

Compound 302(0.025g, 0.055mmol) was dissolved in MeOH (2 ml). A catalytic amount of palladium on carbon was added and the mixture was stirred under hydrogen atmosphere for 1 hour. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC. The title compound was obtained.¹H NMR(CDCl₃)δ7.19(dd，1H)，7.13(d，1H)，7.05-6.82(m，4H)，6.76(d，1H)，6.46(bs，2H)，5.89(dd，1H)，5.75(d，1H)，5.56(bs，1H)，4.15-3.93(m，3H)，3.80(dd，1H)，3.71(dd，1H)，2.65(bs，1H)，2.23(s，3H)，2.19(s，3H)，2.10(bs，1H)。

Example 204:

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl]- [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -benzene Base of]-a ketone (304)

Compound 505(0.083g, 0.22mmol) and N- (2-chloroethyl) morpholine hydrochloride (0.082g, 0.44mmol) are suspended in CH₃CN (5 ml). Addition of K₂CO₃(0.17g, 1.2mmol) and NaI (0.008g, 0.05mmol) and the suspension was heated in a microwave oven at 130 ℃ for 40 minutes. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 2: 3- > 1: 0 as eluent. The title compound was obtained.¹HNMR(CDCl₃)δ7.34(d，1H)，7.21(dd，1H)，7.17(d，1H)，7.10(d，1H)，7.05-6.88(m，3H)，6.85-6.78(m，2H)，6.16(s，1H)，4.02(t，2H)，3.72(m，4H)，2.75(t，2H)，2.54(m，4H)，2.45(s，3H)，2.25(s，3H)。

Example 205:

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl]- [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -benzene Base of]-methanone (Compound 305)

Compound 304(0.041g, 0.083mmol) was dissolved in MeOH (2 ml). A catalytic amount of palladium on carbon was added and the mixture was stirred under hydrogen atmosphere for 1 hour. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 3: 1- > 6: 1 as eluent. The title compound was obtained. ¹H NMR(CDCl₃)δ7.19(dd，1H)，7.11(d，1H)，7.03(d，1H)，7.00-6.80(m，3H)，6.76(d，1H)，6.46(bs，2H)，5.89(dd，1H)，5.75(d，1H)，5.60(s，1H)，4.07(t，2H)，3.71(m，4H)，2.77(t，2H)，2.55(m，4H)，2.23(s，3H)，2.18(s，3H)。

Example 206:

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl]- [5- (4-methoxy-benzyloxy) -2-methyl-phenyl]-first of all Ketone (Compound 306)

2, 4-difluoro-aniline (26 μ l, 0.25mmol) was dissolved in anhydrous 1, 4-dioxane (3ml) in a vial under argon atmosphere. Compound 504 (114mg, 0.25mmol) was added and dissolved in a solvent. racemic-BINAP (7.0mg, 0.012mmol), Pd were added₂(dba)₃(7.0mg, 0.008mmol) and Cs₂CO₃(114mg, 0.35mmol) and the reaction mixture was stirred under argon at 100 ℃ for 16 h. The reaction mixture was filtered through celite and then purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 1: 3) as the eluent to give the title compound as curry (curry) yellow solid.¹³C NMR(CDCl₃)δ194.5，159.6(dd)，159.5，156.1，155.9(dd)，149.6，147.1，137.2，132.8，131.8，131.7，129.2，128.5，126.8，124.8(dd)，123.8(dd)，117.9，117.1，114.1，111.8(dd)，109.5，105.2(dd)，70.1，55.3，19.9。

Preparation 107:

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl]- (5-hydroxy-2-methyl-phenyl) -methanone (compound) 507)

Compound 306(90mg, 0.178mmol) was dissolved in dry DCM (5 ml). TFA (5ml) was added and the reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo to afford the crude product as a beige/off-white solid.

Example 207:

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ]- [5- (3-hydroxy-propoxy) -2-methyl-phenyl]-methanones (Compound 307)

Compound 507(66mg, 0.17mmol) was dissolved in acetonitrile (3ml) in a reaction vial. Addition of 3-chloro-Propan-1-ol (22. mu.l, 0.26mmol), K₂CO₃(36mg, 0.26mmol) and NaI (catalytic amount). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 170 ℃ for 15 minutes. The reaction mixture was allowed to cool to room temperature and then poured into EtOAc/water mixture. The layers were separated and the organic phase was dried (MgSO₄) Filtered and concentrated in vacuo to afford the crude product. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 1: 1) as eluent gave the title compound as a yellow oil.¹³C NMR(CDCl₃)δ194.4，159.7(dd)，156.2，155.9(dd)，149.9，147.4，137.4，132.8，131.9，131.6，126.5，125.0(dd)，123.8(dd)，117.8，117.5，116.4，111.9(dd)，109.4，105.2(dd)，65.8，60.2，31.9，19.8。

Example 208:

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl]- [5- (3-hydroxy-propoxy) -2-methyl-phenyl]-methanones (Compound 308)

Compound 307(46mg, 0.1mmol) was dissolved in EtOH (5ml), flushed with argon, and Pd/C (catalytic amount) added. The flask was washed with H₂Purge for 2 minutes and at H₂Stirring under atmosphere at room temperature for 1 hour. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by successive gradient flash chromatography using DCM/MeOH (v: v ═ 100: 0 to 95: 5) as eluent gave the title compound as a yellow oil. ¹³C NMR(DMSO-d₆)δ196.3，158.9(dd)，156.2，155.6(dd)，154.2，150.8，142.2，135.6，131.1，127.0(dd)，125.2，124.8(dd)，114.5，112.2，111.6(dd)，109.7，104.8(dd)，104.0，96.9，64.6，57.2，32.1，17.9。

Example 209:

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl]- [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -benzene Base of]-methanone (Compound 309))

Compound 507(50mg, 0.13mmol) was dissolved in acetonitrile (3ml) in a reaction vial. 4- (2-chloro-ethyl) -morpholine hydrochloride (48mg, 0.26mmol), K were added₂CO₃(72mg, 0.52mmol) and NaI (catalytic amount). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 170 ℃ for 10 minutes, followed by reflux in an oil bath for 40 hours. The reaction mixture was added EtOAc (30mL) and as H₂O (2X 20ml), brine (2X 20 ml). The organic phase was dried (Na)₂SO₄) Filtered, concentrated in vacuo, and purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 2: 1 to 100: 0) as the eluent, to give the title compound as a yellow oil.¹³C NMR(CDCl₃)δ194.3，159.7(dd)，156.1，155.9(dd)，149.9，147.3，137.4，132.8，131.9，131.8，126.7，124.9(dd)，123.8(dd)，117.9，117.6，116.6，111.9(dd)，109.4，105.2(dd)，66.8，65.7，57.5，54.0，19.8。

Example 210:

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl]- [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -benzene Base of]-methanone (Compound 310)

The reaction was carried out as described in the preparation of compound 308 using compound 309(18mg, 0.036mmol) as the nitro-compound. In H₂Stirring under atmosphere for 16 hours. Purification by flash chromatography using EtOAc as eluent gave the title compound as an oil. ¹³C NMR(CDCl₃)δ198.4，156.4，153.5，149.7，141.9，137.1，131.4，126.9，124.8(dd)，115.5，112.8，112.2，111.3(dd)，105.1，104.8，104.7(dd)，98.9，66.9，66.1，57.7，54.1，18.4。

Example 211:

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl]- [5- (2, 2-dimethyl- [1, 3 ]]DioxygenRunne-4-ylmethyl Oxy) -2-methyl-phenyl]-methanone (Compound 311)

Compound 507(50mg, 0.13mmol) was dissolved in acetonitrile (3ml) in a reaction vial. Compound 506(75mg, 0.26mmol) and K were added₂CO₃(36mg, 0.26mmol) and NaI (catalytic amount). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 170 ℃ for 10 minutes, followed by reflux in an oil bath for 40 hours. To the reaction mixture was added EtOAc (30mL) and H₂O (2X 20ml), brine (2X 20 ml). The organic phase was dried (Na)₂SO₄) Filtered, concentrated in vacuo, and purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 1: 3) as the eluent, to give the title compound as a yellow oil.¹³C NMR(CDCl₃)δ194.3，159.7(dd)，156.0，155.9(dd)，149.9，147.3，137.5，132.8，132.0，131.8，126.6，124.9(dd)，123.8(dd)，117.9，117.3，116.6，111.9(dd)，109.9，109.5，105.2(dd)，73.9，69.2，66.7，26.8，25.3，19.8。

Example 212:

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl]- [5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl]- Ketone (Compound 312)

Compound 311(48mg, 0.01mmol) was dissolved in TFA: H₂O (3: 1, 8ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 1) as eluent to give the title compound as a yellow oil. ¹³C NMR(DMSO-d₆)δ193.5，156.3，150.1，148.8，137.5，132.5，132.3，129.3，126.6(dd)，123.9(dd)，122.9，117.3，116.1，115.6，112.1(dd)，108.6，105.1(dd)，69.8，62.5，19.0。

Example 213

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl]- [5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl]- Methanone (Compound 313)

The reaction was carried out as described in the preparation of compound 308 using compound 312(48mg, 0.096mmol) as the nitro-compound. In H₂Stirring under atmosphere for 16 hours. Purification by flash chromatography using EtOAc/petroleum ether (40-60) (1: 1) as the eluent gave the title compound as a colorless oil.¹HNMR(DMSO-d₆)δ8.32(s，1H)，7.42-7.29(m，2H)，7.15(d，1H)，7.09(m，1H)，6.89(dd，1H)，6.82(d，1H)，6.66(d，1H)，6.02-5.92(m，2H)，3.97(dd，1H)，3.87-3.30(m，4H)，2.05(s，3H)。

Preparation 108:

2-fluoro-5-hydroxy-benzaldehyde (Compound 508)

2-fluoro-5-methoxy-benzaldehyde (4g, 26mmol) was dissolved in anhydrous DCM (25ml), cooled to 0 ℃ under argon and boron tribromide (26ml, 1.0M, 26mmol in DCM) was added slowly. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred under argon for 16 hours. The reaction was carefully quenched with water (10ml) and saturated NaHCO was added₃(30ml), followed by shaking, and the layers were separated. The aqueous phase was extracted with two more portions of DCM. The organic phases were combined and extracted with 2N NaOH (2X 100 ml). The combined NaOH phases were acidified with HCl (concentrated) and extracted with DCM (4 × 150 ml). The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. Purification by chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 5) as the eluent gave the title compound as a white solid.

Preparation 109:

5- (tert-butyl-dimethyl-silyloxy) -2-fluoro-benzaldehyde (Compound 509)

Reacting the compound under argon atmosphere508(1.5g, 10.7mmol) was dissolved in anhydrous DMF (40 ml). Tert-butyl-chloro-dimethyl-silane (2.43g, 16.1mmol) and imidazole (1.1g, 16.1mmol) were added. Stirred at room temperature for 2 h, EtOAc (250ml) was added followed by water (2X 100ml), 4% MgSO₄(2X 75ml) washed and dried (MgSO₄) Filtered and concentrated in vacuo to give the crude product as a yellow oil. Purification by chromatography using EtOAc/petroleum ether (40-60) (1: 20) as the eluent gave the title compound as a colorless, transparent oil.

Preparation 110:

(4-bromo-2-chlorophenyl) - [5- (tert-butyl-dimethyl-silyloxy) -2-fluorophenyl]-methanol (compound) 510)

In a dry flask, 4-bromo-2-chloro-1-iodo-benzene (10.9g, 34.5mmol) was added and the flask was evaporated, then filled with argon, and this step was repeated twice. Anhydrous THF (100ml) was added and the solution was cooled to-50 ℃; isopropyl magnesium chloride (17.3ml, 2.0M in ether, 34.5mmol) was then added slowly over 15 minutes, maintaining the temperature below-40 ℃. After the addition was complete, the reaction mixture was stirred at-40 ℃ for 45 minutes. The temperature was raised to-25 ℃ for 5 minutes and then lowered to-40 ℃ followed by the slow addition of a solution of compound 509 in anhydrous THF (15 ml). After the addition was complete, the reaction mixture was stirred at-40 ℃ for 10 minutes and then allowed to warm to 5 ℃ over 2.5 hours. The reaction mixture was slowly poured into ice-cold 2N H ₂SO₄(200ml) and extracted with EtOAc. The aqueous phase was extracted with four more portions of EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product as a brown oil. It was used without further purification.

Preparation 111:

(4-bromo-2-chlorophenyl) - (2-fluoro-5-hydroxy-phenyl) -methanone (Compound 511)

Compound 510(15.9g, 35.6mmol) was dissolved under argon atmosphereIn dry DCM (80ml) and dry acetonitrile (10 ml). The mixture was cooled to 0 ℃ and 4-methyl-morpholine 4-oxide (6.27g, 53.5mmol), milled molecular sieve (4) were added17.8 g). Ammonium tetra-N-propylperruthenate (VII) (250mg, 0.71mmol) was added in 5 portions (5X 50mg) and the reaction mixture was stirred at 0 ℃ for 10 min, evaporated to 1/3 vol and filtered through silica gel. The silica gel was washed with EtOAc (300 mL). The organic phase was concentrated in vacuo to afford the crude product. Purification by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 80 to 1: 10) as eluent gave the title compound as a yellow solid.

Preparation of 112:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (2-fluoro-5-hydroxy-phenyl) -methanone (Compound 512)

Compound 511(200mg, 0,6mmol) was dissolved in anhydrous 1, 4-dioxane (5ml) in a reaction vial under argon atmosphere. 2, 4-difluoro-aniline (78mg, 62. mu.l, 0.6mmol) was added and dissolved in a solvent. Add rac-BINAP (17mg, 0.028mmol), Pd ₂(dba)₃(17mg, 0.018mmol) and Cs₂CO₃(277mg, 0.85 mmol). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 130 ℃ for 40 minutes. The reaction mixture was cooled to room temperature, filtered through celite, and purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 7 to 1: 3) as the eluent to give the title compound as a yellow solid.

Example 214:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl]-methanones (chemotropes) Compound 314)

In a reaction vial, the compound is allowed to react512(38mg, 0.1mmol) was dissolved in acetonitrile (2 ml). 3-chloro-propan-1-ol (11. mu.l, 0.12mmol), K were added₂CO₃(17mg, 0.12mmol) and NaI (catalytic amount). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 130 ℃ for 20 minutes. The reaction mixture was allowed to cool to room temperature and then poured into EtOAc/water mixture. The aqueous phase was acidified with HCl (4N) and the layers were separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to afford the crude product. Purification by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 3 to 1: 1) as eluent gave the title compound as a yellow solid. ¹³C NMR(CDCl₃)δ190.8，159.1(dd)，155.6(dd)，155.3(d)，155.0(d)，148.0，134.7，133.0，129.4，127.9(d)，124.4(m)，120.4(d)，117.1(d)，116.0，115.1(d)，112.8，111.6(dd)，104.9(dd)，66.3，60.0，32.0。

Example 215:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- [5- (2, 2-dimethyl- [1, 3 ]]Dioxolan-4-ylmethoxy radical 2-fluorophenyl) -radical]-methanone (Compound 315)

In a reaction vial, compound 512(54mg, 0.14mmol) was dissolved in acetonitrile (4 ml). Compound 506(61mg, 0.21mmol) and K were added₂CO₃(30mg, 0.21 mmol). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 110 ℃ for 50 minutes, followed by reflux in an oil bath for 24 hours. The reaction mixture was concentrated in vacuo and purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 7 to 1: 3) as eluent to give the title compound as a yellow oil.¹³C NMR(CDCl₃)δ190.6，159.1(dd)，154.7，154.5(d)，154.4(dd)，147.8，134.7，132.9，129.6，127.9(d)，124.4(dd)，124.2(dd)，120.6(d)，117.1(d)，116.0，115.1(d)，112.9，111.6(dd)，109.9，104.9(dd)，73.9，69.6，66.6，26.8，25.4。

Example 216:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl]-methanones (Compound 316)

Compound 315 was dissolved in TFA: water (3: 1, 8ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 2 to 100: 0) as eluent to give the title compound as a yellow foam.¹³CNMR(DMSO-d₆)δ189.3，158.8(dd)，155.7(dd)，154.9(d)，153.8(d)，149.5，133.5，133.4，127.8(d)，126.5(dd)，126.3，124.1(dd)，119.7(d)，117.1(d)，114.9(d)，114.7，112.0(dd)，111.7，105.0(dd)，70.4，69.8，62.5。

Preparation 113:

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl ]- (2-fluoro-5-hydroxy-phenyl) -methanones (Compound 513)

4-chloro-2-methyl-aniline (73 μ l, 0.60mmol) was dissolved in 5ml of anhydrous 1, 4-dioxane in a reaction vial under argon atmosphere. Compound 511(200mg, 0.60mmol) was added and dissolved in a solvent. Add rac-BINAP (18mg, 0.028mmol), Pd₂(dba)₃(17mg, 0.018mmol) and Cs₂CO₃(277mg, 0.84 mmol). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 130 ℃ for 10 minutes. The reaction mixture was filtered through celite and then purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 1: 4) as the eluent to give the title compound as a yellow solid.¹³C NMR(CDCl₃)δ

Example 217:

2- {3- [ 2-chloro-4- (4-chloro-2-methyl-phenylamino)-benzoyl radical]-4-fluoro-phenoxy } -N-methyl-acetyl Amine (Compound 317)

In a reaction vial, compound 513(36mg, 0.09mmol) was dissolved in acetonitrile (2 ml). 2-chloro-N-methyl-acetamide (30mg, 0.28mmol), K were added₂CO₃(38mg, 0.28 mmol). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 130 ℃ for 45 minutes. The reaction mixture was poured into EtOAc: H₂O (1: 1, 10ml) mixture. The layers were separated and the aqueous phase was extracted with EtOAc (3X 5 mL). The combined organic layers were dried (MgSO) ₄) Filtered, concentrated in vacuo, and purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 3 to 100: 0) as the eluent, to give the title compound as a yellow oil.¹³C NMR(CDCl₃)δ190.1，168.2，155.7(d)，153.2(d)，149.2，136.6，135.0，134.5，133.4，131.2，130.5，128.7(d)，128.1，127.1，125.3，119.6(d)，117.4(d)，116.1(d)，115.6，112.4，68.0，25.8，17.9。

Example 218:

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl]- [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl]-methanones (Compound 318)

The reaction was carried out as described in the preparation of compound 317 using compound 513(31mg, 0.079mmol) as phenol and 3-chloro-propan-1-ol (20 μ l, 0.24mmol) as alkyl-chloro. Stirred in a microwave oven at 130 ℃ for 15 minutes. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 15: 85 to 60: 40) as the eluent gave the title compound as a yellow oil.¹³CNMR(CDCl₃)δ190.7，155.2(d)，154.9(d)，148.8，136.7，134.9，134.3，133.2，131.1，130.4，128.7，128.1(d)，127.1，125.1，120.2(d)，117.0(d)，115.7，115.0(d)，112.5，66.3，60.2，32.0，17.9。

Example 219:

2- {3- [ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -benzoyl]-4-fluoro-phenoxy } -N, N-dimethyl- Acetamide (Compound 319)

The reaction was carried out as described in the preparation of compound 317 using compound 513(36mg, 0.092mmol) as phenol and 2-chloro-N, N-dimethyl-acetamide as alkyl-chloro (29 μ l, 0.28 mmol). Stirred in a microwave oven at 130 ℃ for 15 minutes. Purification by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 1 to 100: 0) as the eluent gave the title compound as an oil. ¹³C NMR(CDCl₃)δ190.3，167.2，155.6(d)，154.2(d)，148.9，136.7，134.9，134.3，133.3，131.1，130.4，128.4，128.1(d)，127.1，125.1，120.4(d)，117.2(d)，115.7，112.4，67.7，36.5，35.7，17.9。

Example 220:

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl]- [5- (2, 2-dimethyl- [1, 3 ]]Dioxolan-4-yl methyl Oxy) -2-fluorophenyl]-methanone (Compound 320)

The reaction was carried out as described in the preparation of compound 311, using compound 513(34mg, 0.087mmol) as phenol. Stirred in a microwave oven at 130 ℃ for 45 minutes. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 1: 1) as eluent gave the title compound as a yellow oil.¹³C NMR(CDCl₃)δ190.5，155.4(d)，154.7(d)，148.8，136.7，134.9，134.3，133.2，131.2，130.4，128.6，128.1(d)，127.1，125.1，120.4(d)，117.1(d)，115.7，115.1(d)，112.5，109.9，73.9，69.6，66.6，26.8，25.3，17.9。

Example 221:

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl]- [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl]-first of all Ketone (Compound 321)

Compound 320(31mg, 0.07mmol) is dissolved in TFA: H₂O (3: 1, 10ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by flash chromatography using DCM/MeOH (v: v ═ 99.5: 0.5 to 98.5: 1.5) as eluent to give the title compound as an oil.¹³C NMR(CDCl₃)δ190.5，155.4(d)，154.6(d)，148.9，136.7，134.9，134.3，133.3，131.2，130.4，128.5，128.2(d)，127.1，125.1，120.2(d)，117.1(d)，115.7，115.2(d)，112.5，70.3，69.9，63.5，17.9。

Preparation of 114:

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl]- (2-fluoro-5-hydroxy-phenyl) -methanone (Compound 514)

The reaction was carried out as described in the preparation of compound 513, using compound 511(49mg, 0.15mmol) as the bromine compound and 4-fluoro-2-methyl-aniline (17 μ l, 0.15mmol) as the amine. Stirred in a microwave oven at 110 ℃ for 40 minutes. Purification by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 5 to 1: 2) as eluent gave the title compound as a yellow solid.

Example 222:

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl]- [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl]-methanones (Compound 322)

The reaction was carried out as described for the preparation of compound 317 using compound 514(31mg, 0.083mmol) as phenol and 3-chloro-propan-1-ol (21 μ l, 0.25mmol) as alkyl chloride. Stirred in a microwave oven at 130 ℃ for 75 minutes. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 4 to 4: 1) as the eluent afforded the title compound.¹³C NMR(CDCl₃)δ190.6，160.6(d)，155.1(d)，154.9(d)，149.9，136.4(d)，135.1，133.8(d)，133.4，128.2(d)，127.9，127.2(d)，120.1(d)，117.8(d)，117.0(d)，115.1(d)，114.9，113.8(d)，11 1.7，66.3，60.2，32.0，18.1。

Preparation 115:

[ 2-chloro-4- (4-fluorophenylamino) -phenyl]- (2-fluoro-5-hydroxy-phenyl) -methanone (Compound 515)

The reaction was carried out as described in the preparation of compound 513 using compound 511(99mg, 0.3mmol) as the bromine compound and 4-fluorophenylamine (29 μ l, 0.3mmol) as the amine. Stirred in a microwave oven for 30 minutes at 130 ℃. Purification by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 5 to 1: 2) as eluent gave the title compound as a yellow solid.

Example 223:

[ 2-chloro-4- (4-fluorophenylamino) -phenyl]- [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl]-methanones (compounds) 323)

The reaction was carried out as described in the preparation of compound 317 using compound 515 as phenol and 3-chloro-propan-1-ol (24 μ l, 0.29mmol) as alkyl-chloro. Stirred in a microwave oven at 130 ℃ for 60 minutes. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 4 to 4: 1) as the eluent afforded the title compound. ¹³C NMR(CDCl₃)δ190.7，159.6(d)，155.2(d)，155.0(d)，148.9，136.0(d)，134.9，133.3，128.5，128.1(d)，124.1(d)，120.2(d)，117.0(d)，116.4(d)，115.5，115.1(d)，112.3，66.3，60.0，32.0。

Example 224:

[ 2-chloro-4- (4-fluorophenylamino) -phenyl]- [5- (2, 2-dimethyl- [1, 3 ]]Dioxolan-4-ylmethoxy) -2- Fluorophenyl group]-methanone (Compound 324)

The reaction was carried out as described in the preparation of compound 311, using compound 515(35mg, 0.097mmol) as phenol. Stirred in a microwave oven at 130 ℃ for 75 minutes. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 2: 3) as the eluent afforded the title compound.¹³C NMR(CDCl₃)δ190.5，159.7(d)，155.4(d)，154.7(d)，148.8，135.9(d)，134.9，133.2，128.8，128.1(d)，124.2(d)，120.4(d)，117.1(d)，116.5(d)，115.5，115.1(d)，112.4，109.9，74.0，69.6，66.7，26.8，25.4。

Preparation 116:

[ 2-chloro-4- (2-chloro-4-fluorophenylamino) -phenyl]- (2-fluoro-5-hydroxy-phenyl) -methanone (Compound 516)

The reaction was carried out as described in the preparation of compound 513, using compound 511(95mg, 0.29mmol) as the bromine compound and 2-chloro-4-fluoroaniline (35. mu.l, 0.29mmol) as the amine. Stirred in a microwave oven at 130 ℃ for 10 minutes. Purification by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 5 to 1: 2) as eluent gave the title compound as a yellow solid.

Example 225:

[ 2-chloro-4- (2-chloro-4-fluorophenylamino) -phenyl]- [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl]-methanones (chemotropes) Compound 325)

The reaction was carried out as described for the preparation of compound 317 using compound 516(27mg, 0.068mmol) as phenol and 3-chloro-propan-1-ol (17 μ l, 0.2mmol) as alkyl-chloro. Stirred in a microwave oven at 130 ℃ for 60 minutes. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 4 to 4: 1) as eluent gave the title compound as a yellow oil. ¹³CNMR(CDCl₃)δ190.7，158.5(d)，155.2(d)，155.0(d)，147.1，134.6，133.7(d)，132.8，130.3，127.7(d)，126.7(d)，122.5(d)，120.6(d)，117.5(d)，117.1(d)，116.9，115.0，114.9(d)，113.7，66.4，60.2，32.0。

Preparation 117:

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl]- (2-fluoro-5-hydroxy-phenyl) -methanone (Compound 517)

The reaction was carried out as described in the preparation of compound 513, using compound 511(200mg, 0.6mmol) as the bromine compound and 2-nitro-aniline (84mg, 0.6mmol) as the amine. Stirred in a microwave oven at 130 ℃ for 10 minutes. Purification by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 1: 4) as eluent gave the title compound as an orange solid.

Preparation 118/example 290:

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl]- [ 2-fluoro-5- (2-morpholin-4-yl-ethoxy) -phenyl]-methanones (Compound 518)

In a reaction vial, compound 517(30mg, 0.08mmol) was dissolved in acetonitrile (2 ml). 4- (2-chloro-ethyl) -morpholine hydrochloride (44mg, 0.24mmol) and K were added₂CO₃(33mg, 0.24 mmol). The reaction vial was flushed with argon, sealed, and then stirred in a microwave oven at 130 ℃ for a total of 105 minutes. The reaction mixture was poured into EtOAc: H₂O (1: 1, 10ml) mixture. The layers were separated and the aqueous phase was extracted with EtOAc (2X 10 mL). The combined organic layers were dried (MgSO)₄) Filtered, concentrated in vacuo, and purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 3: 2) as the eluent, to give the title compound as a pale yellow oil.

Preparation 119/example 291:

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl]- [5- (2, 2-dimethyl- [1, 3 ]]Dioxolan-4-ylmethoxy radical 2-fluorophenyl) -radical]-methanone (Compound 519)

The reaction was carried out as described in the preparation of compound 311, using compound 517(36mg, 0.093mmol) as the phenol. Stirred in a microwave oven at 130 ℃ for 15 minutes. Purification by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 1: 9 to 2: 3) as the eluent gave the title compound as a pale yellow oil.

Preparation 120/example 292:

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl]- [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl]-methanones (chemotropes) Compound 520)

Compound 519(46mg, 0.092mmol) is dissolved in TFA: H₂O (3: 1, 10ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by flash chromatography using DCM/MeOH (v: v ═ 4: 1 to 1: 4) as eluent to give the title compound.

Example 226:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl]-methanones (chemotropes) Compound 326)

Compound 520(37mg, 0.08mmol) was dissolved in MeOH (2ml), and NH was added₄Cl (29mg, 0.55mmol) and Zn powder (72mg, 1.10 mmol). Reflux for 0.5 h, allow to cool to room temperature, and filter. Purification by flash chromatography using DCM: MeOH (v: v ═ 95: 5) as eluent gave the title compound. ¹³C NMR(CD₃OD)δ 192.4，156.5(d)，156.2(d)，153.1，144.8，136.3，135.1，129.9(d)，128.4，128.1，127.1，126.8，120.8(d)，119.6，118.0(d)，117.7，116.5(d)，115.8，112.5，71.7，71.2，64.0。

Example 227:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- [ 2-fluoro-5- (2-morpholin-4-yl-ethoxy) -phenyl]-methanones (Compound 327)

The reaction was carried out as described in the preparation of compound 326 using compound 518(37mg, 0.074mmol) as the nitro compound. Purification by flash chromatography using DCM: MeOH (v: v ═ 95: 5) as eluent gave the title compound.¹³C NMR(CDCl₃)δ190.6，155.2(d)，154.6，149.8，142.9，135.0，133.4，128.3(d)，128.0，127.7，127.0，125.2，120.2(d)，119.2，117.0(d)，116.4，115.2(d)，115.1，111.9，66.5，66.1，57.4，53.9。

Preparation 121:

(4-bromo-2-chlorophenyl) - (2-chloro-5-methoxy-phenyl) -methanol (Compound 521)

To a solution of 4-bromo-2-chloro-1-iodo-benzene (10.0g, 31.5mmol) in THF (120ml) was added a 2M solution of isopropyl magnesium chloride in THF (17.3ml, 34.60mmol) at-65 ℃. The reaction mixture was stirred at-40 ℃ for 20 minutes. After addition of 2-chloro-5-methoxy-benzaldehyde (5.5g, 32.20mmol), the reaction mixture was allowed to warm to room temperature and stirred overnight. Then with NH₄The solution was quenched with saturated aqueous Cl. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with MgSO₄Dried and concentrated in vacuo. The crude material was purified by chromatography (petroleum ether/CH)₂Cl₂1: 1) to provide the title compound as a yellowish oil.

Preparation 122:

(4-bromo-2-chlorophenyl) - (2-chloro-5-methoxy-phenyl) -methanone (Compound 522)

In the presence of compound 521(5.18g, 14.3mmol) in CH₂Cl₂To a solution (100ml) was added Dess-Martin periodinane (6.11g, 14.40mmol) in portions at room temperature. At room temperatureAfter stirring for 1 hour, the reaction mixture was concentrated together with silica gel in vacuo. The residue was purified by chromatography (petroleum ether/CH)₂Cl₂1: 1) to give the title compound as a colorless oil.

Preparation 123:

(4-bromo-2-chlorophenyl) - (2-chloro-5-hydroxy-phenyl) -methanone (Compound 523)

In the presence of compound 522(4.63g, 12.86mmol) in CH₂Cl₂(50ml) to the solution, BBr was added dropwise at-40 deg.C₃In CH₂Cl₂1M solution of (1). The reaction solution was allowed to warm to room temperature and stirred overnight. After the reaction, the solution was poured into brine. Mixing the water phase with CH₂Cl₂The extraction was performed twice. The combined organic phases were washed with MgSO₄Drying and concentrating in vacuo to give a solid which is treated with petroleum ether/CH₂Cl₂Washing 1: 1 gave the title compound as a grey solid.

Preparation 124:

[ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl]- (2-chloro-5-hydroxy-phenyl) -methanone (Compound 524)

Compound 523(1.00g, 3.00mmol), 2, 6-difluoroaniline (0.47g, 3.60mmol), rac-BINAP (74mg, 0.12mmol), Pd₂(dba)₃And Cs₂CO₃A mixture of (1.95g, 6.00mmol) in 1, 4-dioxane (30ml) was stirred at 120 ℃ for 2 days. The mixture was filtered and washed with 1, 4-dioxane. The filtrate was concentrated in vacuo together with silica gel and purified by chromatography (petroleum ether/ethyl acetate 3: 1) to provide the title compound as a solid.

Example 228:

[ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl]- [ 2-chloro-5- (2-morpholin-4-yl-ethoxy) -phenyl]-first of all Ketone (Compound 3)28)

Compound 524(42mg, 0.11mmol), 4- (2-chloro-ethyl) -morpholine (50mg, 0.27mmol) and K in a sealed glass₂CO₃(100mg, 0.72mmol) in CH₃The mixture in CN (2ml) was stirred at 90 ℃ for 18 h. The mixture was then filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography (ethyl acetate) to afford the title compound as a brown oil.¹³C NMR(CDCl₃)δ192.5，157.5(dd)，157.2，148.2，140.2，135.6，134.0，131.0，127.8，126.1(t)，123.5，118.2，116.7(t)，116.4，115.4，112.7，112.2(m)，66.6，66.1，57.4，54.0。

Example 229:

(±) - [ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl]- [ 2-chloro-5- (2, 3-dihydroxy-propoxy) -phenyl]- Methanone (Compound 329)

Adding 524(42mg, 0.11mmol) and (+ -) -toluene-4-sulfonic acid 2, 2-dimethyl- [1, 3%]Dioxolan-4-ylmethyl ester (50mg, 0.17mmol) and K₂CO₃(100mg, 0.72mmol) of the mixture was treated as described for compound 328. Chromatography (petroleum ether/ethyl acetate 3: 1) afforded the acetonate. Acetonide dissolved in TFA/H at room temperature₂O3: 1(1ml), and the resulting solution was stirred at the same temperature for 0.5 hour. The mixture was then concentrated in vacuo. The residue was purified by chromatography (ethyl acetate) to give the title compound as a colorless foam. ¹³C NMR(CDCl₃)δ192.6，157.5(dd)，157.1，148.4，140.3，135.6，134.1，131.1，127.5，126.1(t)，123.7，118.0，116.7(t)，116.4，115.4，112.7，112.2(m)，70.2，69.6，63.4。

Example 230:

[5- (3-bromo-propoxy) -2-chlorophenyl]- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl]-methanones (compounds) 330)

Compound 524(0.20g, 0.51mmol), 1, 3-dibromopropane (0.62g, 3.06mmol) and K₂CO₃(0.21g, 1.53mmol) of the mixture was treated as described for compound 328. Chromatography (petroleum ether/ethyl acetate 4: 1) afforded the title compound.¹³C NMR(CDCl₃)δ192.6，157.5(dd)，157.3，148.2，140.2，135.6，134.1，131.0，127.8，126.0(t)，123.4，118.0，116.7(t)，116.4，115.3，112.7，112.2(m)，65.8，32.2，29.7。

Preparation of 125:

3- (4-bromo-2-chloro-benzoyl) -4-methyl-benzoic acid methyl ester (Compound 525)

To a solution of 3-iodo-4-methyl-benzoic acid methyl ester (13.50g, 48.92mmol) in THF (260ml) was added a 2M solution of isopropyl magnesium chloride in THF (24.5ml, 49.00mmol) at-50 ℃. After the reaction mixture was stirred at the same temperature for 30 minutes, compound 440(13.39g, 40.70mmol) was added. The solution was allowed to warm to room temperature and stirred at the same temperature for 2 hours. By NH₄The reaction was quenched with saturated aqueous Cl solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with MgSO₄Dried and concentrated in vacuo. The crude material was dissolved in ethanol and heated to reflux. The resulting solution was allowed to cool to room temperature. The crystals were filtered and dried.

Preparation 126:

(4-bromo-2-chlorophenyl) - (5-hydroxymethyl-2-methyl-phenyl) -methanol (Compound 526)

Compound 525(4.01g, 10.90mmol) is reacted with LiAlH₄A mixture (0.83g, 21.82mmol) in THF (100ml) was heated at reflux for 1.5 h. After cooling to room temperature, the reaction mixture is poured into H₂O, and adding H₂SO₄Aqueous solution (2M, 50 ml). The mixture was then extracted twice with diethyl ether. The combined organic phases were washed with Na₂SO₄DryingAnd concentrated in vacuo to afford the title compound.

Preparation 127:

(4-bromo-2-chlorophenyl) - (2-methyl-5-triisopropylsilyloxymethyl-phenyl) -methanol (Compound) 527)

To a solution of compound 526(3.68g, 10.80mmol) and imidazole (1.47g, 21.60mmol) in DMF (40ml) was added TIPSCl (2.30ml, 10.80mmol) at room temperature. The reaction solution was stirred at the same temperature for 3 hours, and then poured into H₂And (4) in O. The aqueous mixture was extracted three times with diethyl ether. The combined organic phases were washed with brine, with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by chromatography (ethyl acetate/petroleum ether 1: 10) to provide the title compound.

Preparation of 128:

(4-bromo-2-chlorophenyl) - (2-methyl-5-triisopropylsilyloxymethyl-phenyl) -methanone (Compound) 528)

Compound 527(4.12g, 8.27mmol) was treated as described for compound 522. Flash chromatography (petroleum ether/ethyl acetate 3: 97) afforded the title compound.

Preparation of 129:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (2-methyl-5-triisopropylsilyloxymethyl-) Phenyl) -methanone (Compound 529)

Compound 528(505mg, 1.02mmol), 2, 4-difluoroaniline (0.14ml, 1.32mmol), Cs₂CO₃(995mg, 3.65mmol), BINAP (26mg, 0.041 mg) and Pd (OAc)₂A mixture of (9mg, 0.041mmol) in 1, 4-dioxane (15ml) was stirred in a sealed flask at 100 ℃ for 18 h. The mixture was filtered. The filtrate was concentrated in vacuo together with silica gel. Make residue remainedPurification by flash chromatography (ethyl acetate/petroleum ether: from 0/100 onwards to 40/60) afforded the title compound.

Example 231:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (5-hydroxymethyl-2-methyl-phenyl) -methanone 331)

To a solution of compound 529(1.85g, 3.40mmol) in THF (40ml) was added a 1M solution of TBAF in THF (4.1ml, 4.10mmol) at room temperature. The reaction solution was stirred at room temperature for 30 minutes and then poured into H₂O, and extracted with diethyl ether. The combined organic phases were washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/petroleum ether: from 20/80 onwards to 50/50) to yield the title compound. ¹³C NMR(DMSO-d₆)δ195.4，158.7(dd)，155.7(dd)，149.0，139.9，138.8，134.8，133.3，130.8，128.7，127.1，126.7，126.3(dd)，124.3(dd)，114.8，111.9(dd)，111.7，105.0(dd)，62.1，19.4。

Example 232:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (5-chloromethyl-2-methyl-phenyl) -methanone (compound) 332)

In the presence of compound 331(0.79g, 2.09mmol), Et₃N (0.58ml, 4.18mmol) and DMAP (10mg) in CH₂Cl₂To a solution in (50ml) was added p-toluenesulfonyl chloride (0.60g, 3.14mmol) at room temperature. The reaction mixture was stirred at the same temperature for 18 hours and then poured into H₂And (4) in O. Mixing the water phase with CH₂Cl₂Extraction was carried out three times. The combined organic phases were washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate: from 90/10 onwards to 75/25) to yield the title compound.¹³C NMR(CDCl₃)δ195.7，159.2(dd)，155.5(dd)，147.8，139.4，138.3，135.2，134.8，133.5，131.8，131.0，129.6，129.4，124.4(dd)，124.3(dd)，116.2，112.8，111.6(dd)，105.0(dd)，45.6，20.2。

Example 233:

(5-azidomethyl-2-methyl-phenyl) - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]-methanones (chemical combination) Thing 333)

Compound 332(56mg, 0.14mmol) was reacted with NaN₃A mixture of (18mg, 0.28mmol) in DMF (4ml) was stirred at 80 ℃ for 3 h. The reaction mixture is poured into H₂In O and with CH₂Cl₂Extraction was carried out three times. The combined organic phases were washed with brine, with Na₂SO₄Dried and concentrated in vacuo to provide the title compound.¹³C NMR(CDCl₃)δ195.9，159.2(dd)，155.6(dd)，147.9，139.6，138.1，135.2，133.6，132.6，131.9，130.6，129.3，124.4(dd)，116.2，112.8，111.6(dd)，105.0(dd)，54.1，20.2。

Example 234:

(5-aminomethyl-2-methyl-phenyl) - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]-methanones (compounds) 334)

To a solution of compound 333(46mg, 0.11mmol) was added triphenylphosphine (67mg, 0.26mmol) at room temperature. The solution was stirred at the same temperature for 18 hours. Addition of H₂O (0.5 ml). The mixture was then heated to reflux for 4 hours and concentrated in vacuo together with silica gel. The residue was purified by chromatography (MeOH/ethyl acetate: from 13/87 gradually to 30/70) to provide the title compound.¹³CNMR(CDCl₃)δ196.4，159.1(dd)，155.5(dd)，147.8，139.6，139.3，136.5，135.1，133.5，131.6，129.8，129.5，128.3，124.5(dd)，124.3(dd)，116.2，112.8，111.6(dd)，104.9(dd)，45.6，20.1。

Preparation 130：

(4-bromo-2-chlorophenyl) - (5-hydroxymethyl-2-methoxy-phenyl) -methanol (Compound 530)

Compound 441(1.05g, 2.70mmol) was treated as described for compound 526. Flash chromatography (ethyl acetate/petroleum ether: from 25/75 onwards to 45/55) afforded the title compound.

Preparation of 131:

(4-bromo-2-chlorophenyl) - (2-methoxy-5-triisopropylsilyloxymethyl-phenyl) -methanol (Compound No. 4 Thing 531)

Compound 530(766mg, 2.14mmol) was treated as described for compound 527. Flash chromatography (ethyl acetate/petroleum ether: from 4/96 onwards to 30/70) afforded the title compound.

Preparation 132:

(4-bromo-2-chlorophenyl) - (2-methoxy-5-triisopropylsilyloxymethyl-phenyl) -methanone (Compound No. 4 Thing 532)

Compound 531(710mg, 1.38mmol) was treated as described for compound 504. Flash chromatography (petroleum ether/ethyl acetate 3: 97) afforded the title compound.

Preparation 133:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (2-methoxy-5-triisopropyl-silyloxysilyl) Yl-phenyl) -methanone (533)

Compound 532(449mg, 0.87mmol) and 2, 4-difluoroaniline (0.12ml, 1.14mmol) were treated as described for compound 529. Flash chromatography (ethyl acetate/petroleum ether: from 10/90 onwards to 25/75) afforded the title compound.

Example 235:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (5-hydroxymethyl-2-methoxy-phenyl) -methanone (compound) 335)

Compound 533(163mg, 0.29mmol) was treated as described for compound 331. Flash chromatography (ethyl acetate/petroleum ether: from 50/50 onwards to 75/25) afforded the title compound.¹³CNMR(CD₃OD)δ196.0，161.0(dd)，158.9，157.8(dd)，150.8，135.8，135.1，134.7，133.0，130.7，130.1，129.7，127.3(dd)，126.2(dd)，116.4，112.9，112.9，1 12.6(dd)，105.7(dd)，64.5，56.4。

Example 236:

acetic acid 3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methoxy-benzyl ester (Compound) 336)

In compound 335(45mg, 0.11mmol), Et₃N (46. mu.l, 0.34mmol) and DMAP (3mg) in CH₂Cl₂Ac was added to the solution (5ml) at room temperature₂O (13. mu.l, 0.13 mmol). The solution was stirred at room temperature for 0.5 h. The reaction solution is then washed with H₂O and NaHCO₃Washing with saturated aqueous solution over MgSO₄Dried and concentrated in vacuo. The residue is purified by chromatography (ethyl acetate/petroleum ether 1: 4) to yield the title compound. ¹³C NMR(CDCl₃)δ193.1，170.9，158.9(dd)，158.2，155.3(dd)，147.2，134.7，133.2，133.2，130.8，130.4，129.5，128.3，124.7(dd)，123.8(dd)，116.1，112.9，111.7，111.5(dd)，104.9(dd)，65.6，56.0，21.0。

Example 237:

n-tert-butoxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methoxy-benzamide (Compound 337)

In transformingCompound 437(51mg, 0.12mmol), O-tert-butylhydroxylamine (31mg, 0.24mmol), N-methylmorpholine (26mg, 0.24mmol) and 1-hydroxybenzotriazole (16mg, 0.12mmol) in CH₂Cl₂To the mixture (5ml) was added EDCl (30mg, 0.16mmol) at room temperature. The reaction mixture was stirred at the same temperature for 6 hours and then with H₂And O quenching. Mixing the water phase with CH₂Cl₂Extraction was performed five times. The combined organic phases were washed with MgSO₄Dried and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/petroleum ether 2: 1) to provide the title compound.¹³CNMR(DMSO-d₆)δ191.6，164.8，159.4，158.7(dd)，155.7(dd)，149.2，133.8，133.6，131.7，129.1，128.4，126.5，126.4(dd)，124.7，124.2(dd)，114.8，111.9(dd)，111.8，111.7，105.0(dd)，80.8，56.0，26.4。

Example 238:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N-methoxy-4-methyl-benzamide (compound) Thing 338)

Compound 424(50mg, 0.12mmol) was treated with N-methylhydroxylamine hydrochloride (21mg, 0.25mmol) as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: from 67/33 onwards to 100/0) afforded the title compound.¹³C NMR(DMSO-d₆)δ 194.5，158.8(dd)，155.8(dd)，149.5，140.1，139.5，133.8，133.7，131.2，129.4，128.8，126.9，126.5(dd)，126.2，124.1(dd)，114.8，111.9(dd)，111.8，105.0(dd)，63.2，19.6。

Example 239:

n-butoxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzamide (compound) Thing 339)

Compound 424(100mg, 0.25mmol) was treated with O-butyl-hydroxylamine (63mg, 0.50mmol) as described for compound 337. Flash chromatography (B)Ethyl acid ester/petroleum ether: from 20/80 to 60/40) to provide the title compound.¹³C NMR(CDCl₃)δ195.4，165.9，159.3(dd)，155.7(dd)，148.3，142.0，139.8，135.4，133.8，131.7，129.5，129.1，128.6，127.7，124.6(dd)，124.1(dd)，116.2，112.8，111.7(dd)，105.0(dd)，76.9，30.1，20.4，19.1，13.8。

Example 240:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N-cyclohexylmethoxy-4-methyl-benzoyl Amine (Compound 340)

Compound 424(50mg, 0.12mmol) was treated with O-cyclohexyl-hydroxylamine (42mg, 0.25mmol) as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: from 67/33 onwards to 100/0) afforded the title compound.¹H NMR(CDCl₃)δ8.68(bs，1H)，7.72(bd，1H)，7.66(bs，1H)，7.43-7.28(m，3H)，7.00-6.82(m，3H)，6.75(dd，1H)，5.94(bs，1H)，3.80(d，2H)，2.44(s，3H)，1.89-1.56(m，6H)，1.35-1.09(m，3H)，1.07-0.84(m，2H)。

Example 241:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-N- (2-methyl-thia-ne Azol-4-ylmethoxy Yl) -benzamide (compound 341)

Compound 424(50mg, 0.12mmol) was treated with O- (2-methyl-thiazol-4-ylmethyl) -hydroxylamine (36mg, 0.25mmol) as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: from 67/33 onwards to 100/0) afforded the title compound.¹H NMR(CDCl₃)δ10.0-9.0(bs，1H)，7.76(dd，1H)，7.67(d，1H)，7.42-7.30(m，3H)，7.15(s，1H)，7.00-6.84(m，3H)，6.75(dd，1H)，5.98(bs，1H)，5.04(s，2H)，2.64(s，3H)，2.45(s，3H)。

Example 242:

n-benzyloxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzamide (compound) Thing 342)

Compound 424(100mg, 0.25mmol) was treated with O-benzyl-hydroxylamine (80mg, 0.50mmol) as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: from 80/20 onwards to 60/40) afforded the title compound. ¹³C NMR(CDCl₃)δ195.3，165.8，159.3(dd)，155.7(dd)，148.2，142.2，139.8，135.4，135.1，133.8，131.7，129.4，129.1，128.9，128.7，127.8，124.6(dd)，124.1(dd)，116.2，112.8，111.7(dd)，105.0(dd)，78.5，20.4。

Example 243:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (4-methoxy-benzyloxy) -4-methyl-benzene Carboxamide (Compound 343)

Compound 424(100mg, 0.25mmol) was treated with O- (4-methoxy-benzyl) -hydroxylamine (65mg, 0.34mmol) as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: from 80/20 onwards to 60/40) afforded the title compound.¹³C NMR(CDCl₃)δ 195.3，165.6，160.1，159.3(dd)，155.7(dd)，148.2，142.1，139.7，135.3，133.8，131.7，131.1，129.4，129.1，128.6，127.8，127.2，124.6(dd)，124.2(dd)，116.2，114.1，112.8，111.6(dd)，105.0(dd)，78.0，55.3，20.4。

Example 244:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoic acid N ', N' -dimethyl-hydrazide (Compound 344)

Compound 424(50mg, 0.12mmol) was treated with N, N-dimethyl-hydrazine (19 μ l, 0.25mmol) as described for compound 337.Flash chromatography (ethyl acetate/petroleum ether: from 67/33 onwards to 80/20) afforded the title compound.¹³C NMR(DMSO-d₆)δ194.7，163.2，158.9(dd)，155.9(dd)，149.6，139.6，139.5，133.9，133.8，131.3，131.0，129.1，127.2，126.7(dd)，126.3，124.2(dd)，114.9，112.0(dd)，111.9，105.1(dd)，46.1，19.6。

Example 245:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-N-morpholin-4-yl-benzamide (chemosynthesis) Compound 345)

Compound 424(50mg, 0.12mmol) and N-amino-morpholine hydrochloride (35mg, 0.25mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: from 67/33 onwards to 100/0) afforded the title compound.¹³C NMR(DMSO-d₆)δ194.5，168.2，158.9(dd)，155.8(dd)，149.5，139.1，138.2，133.7，133.7，132.9，131.3，129.3，127.5，126.5(dd)，126.5，124.3(dd)，114.8，112.0(dd)，111.9，105.1(dd)，66.0，19.7。

Example 246:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ]-N-hydroxy-4-methyl-benzamide (compound) 346)

Compound 424(202mg, 0.50mmol) was reacted with O- [ (dimethyl-t-butyl) silyl]Hydroxylamine (148mg, 1.01mmol) was treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: from 67/33 onwards to 100/0) afforded the title compound.¹³C NMR(DMSO-d₆)δ194.6，162.9，158.8(dd)，155.8(dd)，149.4，139.5，139.1，133.6，131.1，130.3，128.7，127.0，126.5(m)，126.4，124.1(dd)，114.8，111.9(dd)，111.8，105.0(dd)，19.6。

Preparation of 134:

4- (4-bromo-2-chloro-benzoyl) -3-methyl-benzoic acid methyl ester (compound 534)

4-iodo-3-methyl-benzoic acid methyl ester (0.83g, 3.00mmol) and compound 440(0.75g, 3.00mmol) were treated as described for compound 525. Flash chromatography (ethyl acetate/petroleum ether 1: 15) afforded the title compound as a white solid.

Preparation of 135:

4- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-3-methyl-benzoic acid methyl ester (compound 535)

Compound 534(184mg, 0.50mmol) was treated with 2, 4-difluoroaniline (0.066ml, 0.65mmol) as described for compound 529. Flash chromatography (ethyl acetate/petroleum ether: from 0/100 onwards to 20/80) afforded the title compound.

Example 247:

4- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (2-hydroxy-ethyl) -3-methyl-benzoyl Amine (Compound 347)

Compound 535(127mg, 0.30mmol) with K ₂CO₃(63mg, 0.45mmol) in Ethanolamine/CH₃The mixture in CN 1: 1(4ml) was stirred at room temperature for 18 hours. The reaction mixture is then poured into H₂O, and extracted three times with ethyl acetate. The combined organic phases were washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was purified by chromatography (ethyl acetate/petroleum ether 5: 1) to provide the title compound as a yellow solid.¹³C NMR(CD₃OD)δ197.7，169.8，161.2(dd)，158.0(dd)，151.7，144.0，138.5，137.5，136.4，135.1，131.0，130.0，128.2，127.7(dd)，125.8(dd)，125.7，116.5，113.0，112.7(dd)，105.8(dd)，61.6，43.7，20.3。

Example 248:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- [5- (3-hydroxy-propenyl) -2-methyl-phenyl]-methanones (Compound 348)

Compound 495(0.132g, 0.27mmol) was dissolved in anhydrous 1, 4-dioxane (1.5ml) in a screw cap container under argon atmosphere. Tris (2-furyl) phosphine (0.013g, 0.05mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.007g, 0.008mmol) were added and shaken. (E) -3- (tri-n-butyltin) prop-2-en-1-ol (0.104g, 0.3mmol) was added and the reaction mixture was heated on a shaking table for 16 hours under argon atmosphere at 100 ℃. Will CH₃CN was added to the reaction mixture and the solution was washed three times with petroleum ether. The acetonitrile phase was concentrated in vacuo and purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1: 3- > 3: 1 as eluent. The title compound was obtained as a yellow oil.

Example 249:

4- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoylamino } -thiophene-3-carba Acid methyl ester (Compound 349)

The reaction was carried out in a similar manner using methyl 4-amino-thiophene-3-carboxylate (0.5mmol) and compound 439(0.5mmol), as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a foam.¹³C NMR(CDCl₃)δ195.6，164.8，163.9，159.1(dd)，155.5(dd)，147.9，142.4，139.7，136.5，135.2，133.6，132.6，131.9，131.3，129.1，128.9，128.6，124.4(dd)，124.2(dd)，121.6，116.3，113.0，111.6(dd)，110.8，104.9(dd)，52.1，20.5。

Example 250:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N-furan-2-ylmethyl-4-methyl-benzoyl Amine (Compound 350)

The reaction was carried out in an analogous manner using furan-2-yl-methylamine (0.5mmol) and compound 439(0.5mmol), as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a foam.¹³C NMR(CDCl₃)δ 195.6，166.4，159.2(dd)，155.6(dd)，151.0，148.2，142.4，141.6，139.8，135.3，133.7，131.6，128.9，128.8，127.8，124.5(dd)，124.2(dd)，116.2，112.8，111.6(dd)，110.5，107.8，105.0(dd)，37.0，20.4。

Example 251:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- (3-methoxy-phenyl) -4-methyl-benzyl Amide (Compound 351)

The reaction was carried out in an analogous manner using 3-methoxy-aniline (0.5mmol) and compound 439(0.5mmol), as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a foam.¹³C NMR(CDCl₃)δ195.5，165.0，160.2，159.3(dd)，155.7(dd)，148.3，141.8，139.9，139.1，135.4，133.8，132.3，131.8，129.7，129.0，128.5，127.7，124.6(dd)，124.1(dd)，116.2，112.8，112.3，111.6(dd)，110.6，105.9，105.0(dd)，55.3，20.4。

Example 252:

2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ]-4-methyl-benzoylamino } -benzoic acid methyl ester Ester (Compound 352)

The reaction was carried out in a similar manner using methyl 2-amino-benzoate (0.5mmol) and compound 439(0.5mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a foam.¹³C NMR(CDCl₃)δ195.6，169.0，164.9，159.1(dd)，155.5(dd)，147.8，142.4，141.7，139.6，135.2，134.8，133.6，132.3，131.9，130.9，129.3，129.1，129.0，124.4(dd)，124.2(dd)，122.7，120.4，116.3，115.2，113.0，111.6(dd)，104.9(dd)，52.4，20.6。

Example 253:

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoylamino } -thiophene-2-carba Acid methyl ester (Compound 353)

The reaction was carried out in a similar manner using methyl 3-amino-thiophene-2-carboxylate (1.0mmol) and compound 439(0.5mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a foam.¹³C NMR(DMSO-d₆)δ194.2，163.9，162.4，158.8(dd)，155.7(dd)，149.6，143.7，141.4，139.8，133.8，133.7，133.3，131.9，130.6，128.7，127.5，126.5(dd)，126.0，124.1(dd)，121.9，114.8，112.0(dd)，111.9，105.0(dd)，52.1，19.7。

Example 254:

4- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoylamino } -thiophene-3-carba Acid (Compound 354)

To a suspension of compound 349(75mg, 0.14mmol) in methanol (5ml) was added water (0.5ml), followed by lithium hydroxide (17mg, 0.7 mmol). The mixture was then stirred at reflux for 30 minutes. The reaction mixture was made acidic (pH 5) by slowly adding HCl (1N), followed by pouring into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo to give the title compound as a solid.¹³CNMR(DMSO-d₆)δ194.3，165.6，162.6，158.8(dd)，155.8(dd)，149.6，140.7，139.9，135.8，133.9，133.8，131.8，131.0，128.2，127.0，126.5(dd)，126.0，124.0(dd)，122.6，114.8，112.1，112.0(dd)，111.9，110.8，105.0(dd)，19.6。

Example 255:

2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoylamino } -benzoic acid (Compound 355)

The reaction was carried out in a similar manner using compound 352(0.5mmol) as described in the preparation of compound 354. The title compound was obtained as a solid.¹³C NMR(DMSO-d₆)δ194.3，169.9，163.7，158.8(dd)，155.8(dd)，149.6，140.8，140.6，140.0，134.0，133.9，133.8，131.9，131.7，131.1，128.5，127.2，126.6(dd)，125.9，124.0(dd)，122.9，119.9，117.0，114.9，112.0(dd)，111.9，105.0(dd)，19.6。

Preparation of 136:

2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoylamino } -benzoyl chloride (Compound 536)

To a suspension of compound 355(68mg, 0.13mmol) in toluene (2ml) was added thionyl chloride (19. mu.l, 0.26mmol), followed by reflux for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound without any further purification.

Example 256:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-N- [2- (2-hydroxy-ethylcarbamoyl) -benzene Base of]-4-methyl-benzamide (compound 356)

The reaction was carried out in a similar manner using 2-amino-ethanol (0.26mmol) and compound 536(0.13mmol) as described in the preparation of compound 120. Purification was done by flash chromatography to afford the title compound as a foam.¹³C NMR(CDCl₃)δ 195.8，169.9，164.8，159.0(dd)，155.4(dd)，147.9，142.2，139.8，139.5，135.2，133.6，132.8，132.2，131.9，129.1，128.9，126.7，124.5(m)，124.1(m)，123.0，121.5，120.2，116.4，113.0，111.6(dd)，104.9(dd)，61.8，42.5，20.5。

Example 257:

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ]-4-methyl-benzoylamino } -thiophene-2-carba Acid (2-hydroxy-ethyl) -amide (compound 357)

To a solution of compound 353(124mg, 0.23mmol) in acetonitrile (2.0ml) and 2-amino-ethanol (0.50ml) was added K₂CO₃(50mg, 0.36mmol) and stirred at room temperature for 18 h. The reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and concentrated on silica gel in vacuo. Purification was done by flash chromatography eluting with a MeOH/DCM mixture to afford the title compound.¹³C NMR(DMSO-d₆)δ193.8，163.5，161.5，158.2(dd)，155.2(dd)，149.0，141.8，140.5，139.3，133.2，133.2，131.3，130.5，128.5，127.8，127.1，125.9(dd)，125.6，123.6(dd)，121.1，114.3，113.3，111.4(dd)，111.4，104.5(dd)，58.8，41.3，19.2。

Preparation 137:

3- (2-chloro-4-nitro-benzoyl) -4-methyl-benzonitrile (compound 537)

In a dry flask, 3-iodo-4-methyl-benzonitrile (5.15g, 21.2mmol) was added and the flask was evaporated, then filled with argon, and this step was repeated twice. Anhydrous THF (15ml) was added and the solution was cooled to-35 ℃; isopropyl magnesium chloride (10.6ml, 2.0M in ether, 21mmol) was then added slowly over 20 minutes, maintaining the temperature below-35 ℃. After the addition was complete, the reaction mixture was stirred at-35 ℃ for 30 minutes. ZnCl was added dropwise over 20 minutes₂A THF solution (3.61g, 26.5mmol, 1.0M). The reaction mixture was stirred at 0 ℃ for 20 minutes; then 2-chloro is added -4-Nitro-benzoyl chloride (4.9g, 22.3mmol) with Cu (OAc)₂(85mg, 0.42mmol) and the reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was poured into EtOAc/water mixture, followed by shaking and separation. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1: 6 followed by 1: 4 as eluent to afford the title compound as a yellow solid.

Preparing 138:

3- (4-amino-2-chloro-benzoyl) -4-methyl-benzonitrile (Compound 538)

A mixture of compound 537(1.05g, 3.49mmol) and stannous chloride dihydrate (3.31g, 17.46mmol) in anhydrous ethanol (20ml) was heated to reflux. After 90 minutes, the solution was allowed to cool to room temperature and then poured into an ice/aqueous NaOH (7N)/EtOAc mixture. The aqueous phase was extracted with more EtOAc followed by DCM. The organic phases were combined, washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1: 2 as eluent to afford the title compound as a yellow solid.

Preparation 139:

3- [ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -benzoyl ]-4-methyl-benzonitrile (Compound 539)

To a glass vial (8ml) with a screw cap, compound 538(100mg, 0.37mmol) in 1, 4-dioxane (2ml), 2-bromo-5-fluoro-toluene (55 μ l, 0.44mmol), Cs were added₂CO₃(169mg，0.52mmol)、Pd₂(dba)₃(9mg, 0.009mmol) and rac-BINAP (9mg, 0.014 mmol). The tube was capped with a rubber septum, flushed with argon for 5 minutes, and then stirred at 100 ℃ for 18 hours. The reaction mixture was allowed to cool to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted twice with more EtOAc. Will be provided withThe combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with EtOAc/petroleum ether 1: 3 to give the title compound as a pale brown oil.

Example 258:

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl]- [ 2-methyl-5- (1H-tetrazol-5-yl) -phenyl]-methanones (Compound 358)

Compound 539(100mg, 0.26mmol), TBAF.H was added to a glass vial with a screw cap equipped with a magnetic stirrer₂O (41mg, 0.13mmol) and TMSN₃(105. mu.l, 0.80mmol) and THF (0.3ml) and the resulting mixture was heated at 85 ℃ for 18 hours with vigorous stirring. The reaction mixture was allowed to cool to room temperature and then poured into a mixture of HCl (1N) and EtOAc. The aqueous phase was extracted with more EtOAc. The combined organic phases were washed with brine and dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude product was purified by chromatography with DCM/MeOH/CH₃COOH 100: 2.5: 0.25 gave the title compound as a yellow foam.¹³C NMR(DMSO-d₆)δ193.9，159.5(d)，154.8，151.1，140.7，139.4，136.2(d)，134.4，134.3，132.1，128.5，127.1(d)，126.4，124.7，121.8，117.4(d)，114.1，113.5(d)，111.1，19.5，17.6。

Preparation 140:

(5-bromo-2-methyl-phenyl) - (2-chloro-4-nitro-phenyl) -methanone (Compound 540)

In a dry flask, 4-bromo-2-iodo-1-methyl-benzene (6.85g, 23.1mmol) was added and the flask was evaporated, then filled with argon, and this step was repeated twice. Anhydrous THF (20ml) was added and the solution was cooled to-35 ℃; isopropyl magnesium chloride (11.5ml, 2.0M in ether, 23mmol) was then added slowly over 40 minutes, maintaining the temperature below-35 ℃. After the addition was complete, the reaction mixture was stirred at-35 ℃ for 30 minutes. Dropwise in 20 minutesAddition of ZnCl₂A THF solution (3.93g, 28.9mmol, 0.7M). The reaction mixture was stirred at 0 ℃ for 20 minutes; then 2-chloro-4-nitro-benzoyl chloride (5.33g, 24.2mmol) and Cu (OAc) were added₂(92mg, 0.46mmol) and the reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was poured into EtOAc/water mixture, followed by shaking and separation. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1: 14 as eluent to afford the title compound as an almost white solid.

Preparation 141:

(4-amino-2-chlorophenyl) - (5-bromo-2-methyl-phenyl) -methanone (Compound 541)

The reaction was carried out in a similar manner using compound 540(5.64mmol) as the nitro compound as described in the preparation of compound 538. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.

Preparation of 142:

(5-bromo-2-methyl-phenyl) - [ 2-chloro-4- (2-nitro-phenylamino) -phenyl]-methanone (Compound 542)

To a solution of compound 541(1.42g, 4.37mmol) and 1-fluoro-2-nitrobenzene (0.42ml, 4.0mmol) in DMSO (10ml) was slowly added potassium tert-butoxide (992mg, 8.84mmol) with stirring. After 20 hours at room temperature the reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by chromatography eluting with EtOAc/petroleum ether 1: 8 to give the title compound as an orange solid.

Preparation 143:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- (5-bromo-2-methyl-phenyl) -methanone (Compound 543)

The reaction was carried out in a similar manner using compound 542(2.36mmol) as the nitro compound as described in the preparation of compound 538. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.

Preparation 144:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- (2-methyl-5-trimethylsilylethynyl-phenyl) - Methanone (Compound 544)

In a glass vial (8ml) with a screw cap, anhydrous degassed triethylamine (3.0ml) was placed under argon with a magnetic stirrer. Compound 543(200mg, 0.48mmol), Pd₂(dba)₃(9.0mg, 0.01mmol), triphenylphosphine (13mg, 0.048mmol), CuI (2mg) and ethynyl-trimethyl-silane (66. mu.l, 0.48mmol) were added to a glass vial and the reaction mixture was heated at 90 ℃ for 20 h with vigorous stirring. The cooled reaction mixture was filtered through Decalite and concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 5: 95 to 30: 70) as eluent to afford the title compound as a yellow foam.

Example 259:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- (5-ethynyl-2-methyl-phenyl) -methanone (compound 359)

Compound 544(59mg, 0.14mmol) is reacted with K₂CO₃A mixture of (28mg, 0.20mmol) in methanol (1.0ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo to give the title compound without any further purification.¹³C NMR(CDCl₃)δ195.5，149.9，142.9，139.8，138.5，135.5，133.9，132.6，131.3，127.8，127.4，127.0，125.1，119.3，119.2，116.4，115.4，111.8，83.0，20.3。

Example 260:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- (2-methyl-5- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl Base of]-1H-[1，2，3]Triazol-4-yl } -phenyl) -methanone (Compound 360)

Compound 359(25mg, 0.07mmol), 2- (2-azido-ethoxy) -tetrahydro-pyran (25mg, 0.14mmol) and EtOH (0.5mL) were added to a screw-cap vial with a magnetic stirrer, followed by addition of CuSO₄.H₂O (0.3mg) and aqueous L-ascorbic acid sodium solution (200. mu.l, 0.2mmol, 1M). The reaction mixture was stirred at room temperature for 3 hours and then at 40 ℃ for 30 minutes. The reaction mixture was concentrated on silica gel and purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 50: 50 to 100: 0) as eluent to give the title compound as a yellow foam.¹³C NMR(CDCl₃)δ196.1，149.9，147.0，142.9，140.2，137.4，135.5，134.1，131.7，128.1，127.7，127.6，127.0，126.3，125.2，120.8，119.1，116.4，115.4，111.8，99.1，65.7，62.4，50.5，30.4，25.2，20.1，19.4。

Example 261:

[4- (2-amino-phenylamino) -2-chlorophenyl group]- {5- [1- (2-hydroxy-ethyl) -1H- [1, 2, 3]Triazole-4- Base of]-2-methyl-phenyl } -methanone (Compound 361)

A solution of compound 360(20mg, 0.038mmol) and toluene-4-sulfonic acid (11mg, 0.057mmol) in MeOH (0.3ml) was stirred at room temperature for 2 h. The reaction mixture was poured into a mixture of aqueous NaOH (2N) and EtOAc. The aqueous phase was washed with more EtOAc. The organic phases were combined and washed with brine and dried (MgSO) ₄) Filtered and then purified by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v. 40: 60 to20: 80) as eluent to give the title compound as a solid.¹³C NMR(DMSO-d₆)δ194.7，151.0，145.3，143.3，140.4，135.4，134.0，131.4，128.3，126.7，126.5，126.1，124.7，124.6，124.4，121.8，116.8，115.8，114.3，11 1.3，59.7，52.3，19.3。

Preparation 145:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (2-methyl-5-trimethylsilylethynyl-benzene Yl) -methanone (Compound 545)

In a glass vial (8ml) with a screw cap, anhydrous degassed triethylamine (4.0ml) was placed under argon with a magnetic stirrer. 495(100mg, 0.21mmol) of compound and Pd₂(dba)₃(3.8mg), triphenylphosphine (5.4mg, 0.02mmol), CuI (1mg) and ethynyl-trimethyl-silane (29. mu.l, 0.21mmol) were added to a glass vial and the reaction mixture was heated at 90 ℃ for 20 h with vigorous stirring. The cooled reaction mixture was filtered through Decalite and concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 0: 100 to 10: 90) as eluent to afford the title compound as a foam.

Example 262:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- (5-ethynyl-2-methyl-phenyl) -methanone (compound) 362)

Compound 545(36mg, 0.08mmol) is reacted with K₂CO₃A mixture of (17mg, 0.13mmol) in methanol (3.0ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 0: 100 to 20: 80) as eluent to afford the title compound as a foam.¹³CNMR(CDCl₃)δ195.4，159.2(dd)，155.5(dd)，147.8，139.3，138.8，135.2，134.2，133.5，132.9，131.5，129.2，124.3(dd)，119.4，116.2，112.8，111.6(dd)，105.0(dd)，82.9，20.4。

Example 263:

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl]-4-methyl-benzoic acid hydrazide (compound 363)

A mixture of compound 451(100mg, 0.25mmol) and hydrazine hydrate (0.12ml, 2.5mmol) in methanol (5ml) was stirred at reflux for 24 h. The reaction mixture was concentrated in vacuo onto silica gel. The crude product was purified by flash chromatography using MeOH/DCM 2: 98 as eluent to afford the title compound as a yellow foam.¹³C NMR(CDCl₃)δ195.5，167.8，159.7(d)，149.2，141.9，139.9，135.7(d)，135.4，133.9，131.7，129.9，128.9，127.7，127.5，124.3(d)，116.5(d)，115.6，112.3，20.4。

Example 264:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoic acid hydrazide (compound 364)

A mixture of compound 423(1.00g, 2.4mmol) and hydrazine hydrate (1.17ml, 24mmol) in methanol (40ml) was stirred at reflux for 48 h. The reaction mixture was poured into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and concentrated in vacuo. The crude product was purified by sequential gradient flash chromatography using MeOH/DCM (v: v ═ 5: 95 to 10: 90) as eluent to afford the title compound as a yellow foam. ¹³C NMR(CDCl₃)δ195.5，167.8，159.3(dd)，155.7(dd)，148.3，142.0，139.7，135.3，133.7，131.8，129.9，129.0，128.6，127.7，124.6(dd)，124.2(dd)，116.1，112.8，111.6(dd)，105.0(dd)，20.4。

Example 265:

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzoyl } -4-ethyl-3-amino Thiourea (Compound 365)

In a glass vial with screw cap (8ml), isothiocyanato-ethane (69 μ l, 0.79mmol), compound 364(300mg, 0.72mmol), methanol (6ml) and magnetic stirrer were placed. The reaction mixture was heated at 95 ℃ for 3 hours with stirring. The cooled reaction mixture was filtered through Decalite and concentrated in vacuo. The crude product was purified by flash chromatography using THF/petroleum ether 2: 3 as eluent to afford the title compound as a yellow foam.¹³C NMR(DMSO-d₆)δ194.6，181.3，165.0，158.8(dd)，155.8(dd)，149.5，140.3，139.4，133.8，133.8，130.9，129.9，129.7，127.7，126.6(dd)，126.2，124.1(dd)，114.8，112.0(dd)，111.7，105.0(dd)，38.4，19.6，14.4。

Example 266:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- [5- (5-ethylamino- [1, 3, 4 ]]Thiadiazol-2-yl) -2-methyl -phenyl radical]-methanone (Compound 366)

Compound 365(122mg, 0.24mmol) was reacted with POCl₃A mixture (29 μ l, 0.32mmol) in 1, 4-dioxane (1.0ml) was stirred at 95 ℃ for 20 hours. The reaction mixture was poured into EtOAc/NaHCO₃Saturated aqueous solution mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 20: 80 to 50: 50) as eluent to afford the title compound as a yellow solid. ¹³C NMR(DMSO-d₆)δ194.4，168.3，158.8(dd)，155.8(dd)，154.7，149.5，139.9，137.9，133.8，133.7，131.9，128.4，126.5(dd)，126.2，125.7，124.1(dd)，114.8，112.0(dd)，111.8，105.0(dd)，39.6，19.5，14.1。

Preparation of 146:

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl]-4-methyl-benzonitrile (Compound 546)

Into the flask were added compound 538(500mg, 1.85mmol), 1-bromo-2, 4-difluorobenzene (0.25ml, 2.22mmol), Cs in toluene (10ml)₂CO₃(841mg，2.59mmol)、Pd(OAc)₂(8mg, 0.04mmol) and 4, 5-bis-diphenylphosphinyl-9, 9-dimethyl-9H-xanthene (32mg, 0.056 mmol). The flask was flushed with argon for 5 minutes, sealed, and then slowly warmed to 120 ℃. The reaction vial was stirred at 120 ℃ for 24 hours. The reaction mixture was cooled to room temperature and then filtered through Decalite. Concentration in vacuo afforded the crude product. The crude product was purified by sequential gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 15: 85 to 33: 67) as eluent to afford the title compound as a brown foam.

Example 267:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- [ 2-methyl-5- (1H-tetrazol-5-yl) -phenyl]-methanones (chemotropes) Compound 367)

The reaction was carried out in an analogous manner as described in the preparation of compound 358, using compound 546(0.84mmol) as nitrile. Purification was accomplished by flash chromatography to afford the title compound as a yellow solid.¹³C NMR(DMSO-d₆)δ 194.2，171.9，158.9(dd)，155.8(dd)，149.7，140.3，139.7，134.0，133.9，132.2，128.7，126.6，126.0，124.0(dd)，121.7，1 14.8，112.0(dd)，111.8，105.0(dd)，19.6。

Example 268:

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ]-4-methyl-phenyl } -3-oxo-propionic acid ethyl ester (Compound 368)

A solution of ethoxycarbonyl-potassium acetate (136 mg, 0.80mmol) in EtOAc (1.25ml) was cooled to 0 ℃ in an ice bath. Triethylamine (279. mu.l, 2.0mmol) and anhydrous magnesium chloride (91mg, 0.96mmol) were added to the solution, and the mixture was stirred at 35 ℃ for 7 hours. The reaction mixture was cooled to 0 ℃ and a solution of compound 439(230mg, 0.57mmol) in EtOAc (1ml) was added. The temperature was allowed to rise to room temperature and stirring was continued for 18 hours. The reaction mixture was cooled to 0 ℃ and aqueous HCl (1.5ml, 12%) was slowly added. The aqueous phase was separated and washed with EtOAc (10 mL). The organic phases were combined and washed with aqueous HCl (5ml, 12%), NaHCO₃The aqueous solution (5ml, 50%), water (5ml) and brine (5ml) were washed and then dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM/petroleum ether 2: 3 followed by diethyl ether/petroleum ether 1: 2 as eluent to afford the title compound as a yellow solid.¹³C NMR(CDCl₃)δ195.2，191.6，167.3，159.3(dd)，155.6(dd)，148.2，144.2，139.9，135.4，133.7，133.6，131.9，130.5，129.2，128.7，124.6(d)，124.2(dd)，116.2，112.9，111.7(dd)，105.0(t)，61.5，46.0，20.7，14.1。

Example 269:

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl]- [5- (4, 5-dihydro-oxazol-2-yl) -2-methyl Phenyl radical]- Methanone (Compound 369)

To a suspension of compound 115(400mg, 0.90mmol) in DCM (4.0ml) was added thionyl chloride (229. mu.l, 3.15mmol), and the resulting mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture followed by EtOAc. The organic phase was separated, washed with brine and dried (MgSO) ₄) Filtered and concentrated in vacuo. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v: v ═ 5: 95 to 40: 60) as eluent to afford the title compound as a foam.¹³C NMR(CDCl₃)δ195.6，164.0，159.2(dd)，155.5(dd)，147.9，141.4，139.5，135.3，133.7，131.5，130.2，129.1，128.9，125.2，124.3(m)，116.2，112.8，111.6(dd)，1 05.0(dd)，67.7，54.9，20.5。

Example 270:

3- { 2-chloro-4- [2- (3-ethyl-ureido) -phenylamino]-benzoyl } -N- (2-hydroxy-ethyl) -4-methyl- Benzamide (Compound 370)

To a solution of compound 112(100mg, 0.24mmol) in anhydrous pyridine (1ml) was added ethyl isocyanate (28. mu.l, 0.35mmol) with stirring. After 1 hour, pour the reaction mixture into EtOAc/water mixture. The aqueous phase was extracted with more EtOAc. The organic phases were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography eluting with EtOAc/MeOH (v: v ═ 100: 0 to 98: 2) to give the title compound as a yellow slurry.¹³C NMR(DMSO-d₆)：δ194.6，165.3，155.0，151.1，139.6，139.3，136.3，133.9，133.8，131.7，130.8，128.8，128.1，127.1，126.2，126.1，125.3，121.8，120.2，114.7，111.4，59.6，42.1，33.8，19.5，15.2。

Claims (38)

1. A compound of formula I or a pharmaceutically acceptable salt or ester thereof,

wherein:

R₁is halogen, hydroxy, mercapto, trifluoromethyl, amino, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-6Alkylamino radical, C_1-4Alkoxycarbonyl, cyano, -CONH₂Or a nitro group;

R₂is hydrogen, halogen, hydroxyl, sulfydryl, trifluoromethyl, amino, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-6Alkylamino radical, C_1-4Alkoxycarbonyl, cyano, -CONH₂Phenyl or nitro;

R₃represents one or more identical or different substituents selected from hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy, CONH₂Nitro group, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4An alkoxycarbonyl group;

R₄is hydrogen, halogen, nitro, R₈Or Y₁R₈；

Y₁is-O-, -S (O)₂-、-NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-C(O)NR_aO-、-C(O)-、-C(O)O-、-NR_aC(O)O-、-S(O)₂NR_a-、-NR_aS(O)₂-；

R_a、R_bAnd R_cThe same or different, each represents hydrogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Carbocyclyl, C_1-12Heterocyclyl or aryl radicals, each C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Carbocyclyl, C_1-12The heterocyclic or aryl group being optionally substituted by one or more R₇The same or different substituents represented by;

R₈is hydrogen, C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C _3-12Carbocyclyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclic radical or C_1-12Heterocyclyl radical, each C_1-10Alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12Carbocyclyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclic radical or C_1-12The heterocyclic group is optionally substituted by one or more R₇The same or different substituents represented by;

R₇is halogen, hydroxy, mercapto, trifluoromethyl, amino, C_1-4Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-6Alkylamino radical, C_1-4Alkoxycarbonyl, C bound to an anion_1-9Trialkylammonium, cyano, azido, nitro, -S (O)₂NH₂、-S(O)₂NR_aR_b、-S(O)₂R、-COOH、-CONH₂、-NR_aC (O) R ', -CONHR' or-CONRR ', wherein R and R', which may be the same or different, each represent hydrogen or C_1-3An alkyl group;

R₅and R₆One of which is-COOH, -C (O) NHOH, -C (O) NHNH₂、Y₂R₉、Y₂R₉Y₃R₁₀、C_1-6alkyl-Y₂R₉、C_1-6alkyl-Y₂R₉Y₃R₁₀、C_2-6alkenyl-Y₂R₉、C_2-6alkenyl-Y₂R₉Y₃R₁₀、Y₂R₉-C_1-6-alkyl-Y₃R₁₀、Y₂R₉-C_2-6-alkenyl-Y₃R₁₀、C_3-12carbocyclyl-Y₂R₉、C_3-12carbocyclyl-Y₂R₉Y₃R₁₀、C_1-12heterocyclyl-Y₂R₉、C_1-12heterocyclyl-Y₂R₉Y₃R₁₀、C_3-12carbocyclyl-C_1-6-alkyl-Y₂R₉、C_3-12carbocyclyl-C_1-6-alkyl-Y₂R₉Y₃R₁₀、C_1-12heterocyclyl-C_1-6-alkyl-Y₂R₉、C_1-12heterocyclyl-C_1-6-alkyl-Y₂R₉Y₃R₁₀、C_3-12carbocyclyl-C_1-6-alkyl-Y₃R₁₀、C_1-12heterocyclyl-C_1-6-alkyl-Y₃R₁₀、C_1-12heterocyclyl-C_1-10Alkyl radical, C_3-12carbocyclyl-C_1-10Alkyl radical, C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12Carbocyclyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclic radical or C_1-12Heterocyclyl, each optionally substituted with one or more R ₇The same or different substituents are substituted and the other is hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-6Alkylamino radical, C_1-4Alkoxycarbonyl, cyano, -CONH₂Or a nitro group, or a mixture of nitro groups,

provided that when R is₅Or R₆Is phenyl, C_1-5Alkyl or C_2-3When an alkenyl group, the R₅Or R₆By one or more of R₇The same or different substituents are indicated, but when R is₅Or R₆In the case of a methyl group, the three fluorine groups are excluded,

provided that when R is₅Or R₆When it is-COOH, Y₁Can not be-NR_a-、-NR_aC(O)NR_b-、-NR_aC (O) -or-NR_aC (O) O-, and R₃Or R₄Can not be a nitro group, and can not be a nitro group,

provided that when R is₂When it is hydrogen, R₅Or R₆One of which is not optionally substituted "C₃-C₁₈Heterocyclic group, C_1-7Alkyl radical, C_2-7Alkenyl radical, C_2-7Alkynyl or C_1-7Alkoxy groups ";

Y₂is-O-, -S (O)₂-、-NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-C(O)NR_aO-、-C(O)-、-NR_aC(O)O-、-NR_aS(O)₂-、-OC(O)-、-C(O)O-、-C(O)NR_aNR_bC(S)NR_c-、-C(O)NR_aNR_b-or-S (O)₂NR_a-；

R₉Is C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12Carbocyclyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclyl, C_1-12Heterocyclic group, C_3-12carbocyclyl-C_1-10Alkyl or C_1-12heterocyclyl-C_1-10Alkyl radical, C_3-6carbocyclyl-C_1-6Alkenyl radical, C_3-6carbocyclyl-C_2-6Alkynyl, each optionally substituted by one or more R₇The same or different substituents are represented,

provided that when Y is₂is-O-, -NR_a-, -S-or-C (O) O-, and R ₉Is C_1-6When alkyl, said C_1-6Alkyl being substituted by one or more radicals R₇The same or different substituents represented by;

Y₃is-O-, -S (O)₂-、-NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-C(O)NR_aO-、-C(O)-、-NR_aC(O)O-、-NR_aS(O)₂-, -OC (O) -or-C (O) O-;

R₁₀is C_1-10alkyl-C_1-12Heterocyclic group, C_1-10alkyl-C_3-12Carbocyclyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-12Carbocyclic radical or C_1-12Heterocyclyl, each optionally substituted with one or more R₇The same or different substituents represented by;

or when R is₅Or R₆One of which is a group-C (O) NR_aR₉When R is_aAnd R₉Together with the nitrogen atom to which they are attached form C_1-12Heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, S and N, optionallyBy one or more of R₇The substituent represented by (1);

with the proviso that the following compounds are excluded: 4- (2-amino-4-bromophenylamino) -4 '-n-butyl-2-chloro-2' -methylbenzophenone and 2-chloro-4- (4-bromo-2-methyl-phenylamino) -4 '-ethoxy-2' -methylbenzophenone.

2. A compound according to claim 1, wherein R₁Is halogen, trifluoromethyl, C_1-4Alkyl radical, C_1-4Alkoxy or nitro.

3. A compound according to claim 2, wherein R₁Is methyl, ethyl, methoxy, ethoxy, bromo, fluoro or chloro.

4. A compound according to claim 1, wherein R ₂Is hydrogen, halogen, amino, nitro, C_1-4Alkyl or C_1-4An alkoxy group.

5. A compound according to claim 4, wherein R₂Hydrogen, methyl, ethyl, methoxy, ethoxy, nitro, bromo, fluoro or chloro.

6. A compound according to claim 1, wherein R₃Is hydrogen, halogen, C_1-4Alkyl or C_1-4An alkoxy group.

7. A compound according to claim 6, wherein R₃Hydrogen, methyl, ethyl, methoxy, ethoxy, bromo, fluoro or chloro.

8. A compound according to claim 1, wherein R₃Represents a substituent.

9. A compound according to claim 8, wherein R₃In relation to R₄Meta, phase ofPara to-NH, or wherein R₃In relation to R₄Meta, ortho relative to-NH, or wherein R₃In relation to R₄Ortho-position to-NH, meta-position relative to-NH.

10. A compound according to claim 1, wherein R₃And R₄One of which is fluorine.

11. A compound according to claim 1, wherein Y is₁is-O-, -NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-NR_aC (O) O-or-NR_aS(O)₂。

12. A compound according to claim 1, wherein R₈Is hydrogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Carbocyclic radical or C_1-6A heterocyclic group.

13. A compound according to claim 1, wherein R₄Is C_1-4Alkyl, amino, halogen, nitro, -NHC (O) O-C _1-4Alkyl, -NHC (O) C_1-4Alkyl, -NHC (O) -C_1-4alkyl-COOH, -NHC (O) NH-C_1-4alkyl-OH, -CH ═ CH-C_1-4alkyl-NH₂、-NHC(O)NH-C_1-4Alkyl, -NHC (O) NH-C_1-6Cycloalkyl, NHC (O) CF₃or-NHC (O) O-C_1-6A cycloalkyl group.

14. A compound according to claim 13, wherein R₄Is methyl, ethyl, amino, bromo, fluoro, chloro, nitro, -NHC (O) OCH₂CH₃、-NHC(O)CH₂CH₃、-NHC(O)CH₃、-NHC(O)CH₂CH₂COOH、-NHC(O)NHCH₂CH₂OH、-CH＝CHCH₂NH₂、-NHC(O)NHCH₂CH₃-NHC (O) NH-cyclohexyl, NHC (O) CF₃or-NHC (O) O-cyclopentyl.

15. A compound according to claim 1, wherein R₇Is halogen, hydroxy, amino, -S (O)₂CH₃Trifluoromethyl, cyano, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Alkyl radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_1-4Alkoxycarbonyl, -COOH, -CONH₂、-S(O)₂NH₂-CONR ', or-CONRR ', wherein R and R ' are as set forth in claim 1.

16. A compound according to claim 15, wherein R₇Is methyl, ethyl, methoxy, ethoxy, hydroxyl, methoxycarbonyl, ethoxycarbonyl, dimethylamino, ethylamino, amino, -COOH, fluorine, chlorine, bromine, -CONH₂、-S(O)₂NH₂Azido, methylthio, -S (O)₂CH₃Trifluoromethyl, cyano or hydroxymethyl.

17. A compound according to claim 1, wherein R₅And R₆One is Y₂R₉、C_1-4alkyl-Y₂R₉、Y₂R₉Y₃R₁₀、C_1-4alkyl-Y₂R₉Y₃R₁₀、C_2-4alkenyl-Y₂R₉、C_2-4alkenyl-Y₂R₉Y₃R₁₀、Y₂R₉-C_1-4-alkyl-Y₃R₁₀、Y₂R₉-C_2-4-alkenyl-Y₃R₁₀、C_1-6heterocyclyl-C _1-4-alkyl-Y₂R₉、C_1-4alkyl-C_1-6Heterocyclic group, C_1-4alkyl-C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkyl radical, by R₇Substituted C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Carbocyclyl, C_1-6Heterocyclyl, -COOH, -C (O) NHOH or C (O) NHNH₂And the other is hydrogen, halogen, C_1-4Alkyl or C_1-4An alkoxy group.

18. A compound according to claim 17, wherein R₅Is Y₂R₉、C_1-4alkyl-Y₂R₉、Y₂R₉Y₃R₁₀、C_1-4alkyl-Y₂R₉Y₃R₁₀、C_2-4alkenyl-Y₂R₉、C_2-4alkenyl-Y₂R₉Y₃R₁₀、Y₂R₉-C_1-4-alkyl-Y₃R₁₀、Y₂R₉-C_2-4-alkenyl-Y₃R₁₀、C_1-6heterocyclyl-C_1-4-alkyl-Y₂R₉、C_1-4alkyl-C_1-6Heterocyclic group, C_1-4alkyl-C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkyl radical, by R₇Substituted C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Carbocyclyl, C_1-6Heterocyclyl, -COOH, -C (O) NHOH or C (O) NHNH₂And R is₆Is hydrogen, halogen, C_1-4Alkyl or C_1-4An alkoxy group.

19. A compound according to claim 17, wherein R₅And R₆One is Y₂R₉、Y₂R₉Y₃R₁₀Phenyl, methylphenyl, methyl, propenyl, phenyl-Y₂R₉methyl-Y₂R₉Tetrazole, ethynyl, triazole, thiadiazole, dihydrooxazole, triazole-Y₂R₉-COOH, -C (O) NHOH or C (O) NHNH₂And the other is hydrogen, fluorine, chlorine, methyl or methoxy.

20. According to claimA compound of claim 1, wherein R₆Is hydrogen.

21. A compound according to claim 1, wherein R₅Is hydrogen.

22. A compound according to claim 1, wherein Y is ₂is-O-, -NR_a-、-NR_aC(O)NR_b-、-NR_aC(O)-、-C(O)NR_a-、-C(O)NR_aO-、-C(O)-、-NR_aC(O)O-、-NR_aS(O)₂-、-C(O)NR_aNR_b-or-S (O)₂NR_a-。

23. A compound according to claim 1, wherein Y is₃is-O-, -NR_aC(O)-、-C(O)NR_a-, -C (O) -, -C (O) O-or-NR_aC(O)O-。

24. A compound according to claim 1, wherein R₉Is C_1-4alkyl-C_1-6Heterocyclic group, C_1-4alkyl-C_3-6Carbocyclyl, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Carbocyclyl, C_1-6Heterocyclic group, C_3-6carbocyclyl-C_1-6Alkyl radical, C_1-6heterocyclyl-C_1-6Alkyl radical, C_3-6carbocyclyl-C_2-4Alkenyl or C_3-6carbocyclyl-C_2-4Alkynyl.

25. A compound according to claim 1, wherein R₉Is C_1-4Heterocyclic group, C_1-6Alkyl radical, C_1-3alkyl-C_1-5Heterocyclic group, C_6-10Carbocyclyl, C_1-3alkyl-C₆Carbocyclyl, C₃Alkenyl radical, C₆carbocyclyl-C₁Alkyl radical, C₆carbocyclyl-C₃Alkenyl or C₆carbocyclyl-C₂Alkynyl.

26. A compound according to claim 25, wherein R₉Is morpholinyl, propylmorpholinyl, piperazinyl, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, hexyl, isopropyl, dimethylpropyl, methyltetrahydrofuryl, methylpyridyl, ethylpiperazinyl, cyclohexyl, propyloxopyrrolidinyl, benzyl, methylcyclohexyl, propylphenyl, ethylphenyl, ethylmorpholinyl, allyl, ethylfuryl, phenyl, methyldioxoimidazolidinyl, dioxohexahydropyrimidyl, thiazolyl, methylphenyl, ethylphenyl, methyldioxypentyl, methylthiazolyl, propenylphenyl, methylfuryl, thienyl, tetrahydropyranyl or ethynylphenyl.

27. A compound according to claim 1, wherein R₁₀Is C_1-4Alkyl radical, C_2-4Alkenyl radical, C_3-6Carbocyclic radical or C_1-6A heterocyclic group.

28. A compound according to claim 27, wherein R₁₀Is methyl, ethyl, methacryloyl, tert-butyl, tetrahydropyranyl or vinyl.

29. A compound according to any one of claims 1 to 28, wherein the heterocycle or heterocyclyl contains one or two oxygen atoms or one sulphur atom, and/or up to two nitrogen atoms, or three or four nitrogen atoms, wherein optionally one or two CH₂The loop fragment is replaced by one or two-C (O) -fragments, respectively.

30. A compound according to claim 1, wherein R_a、R_bOr R_cIndependently represents hydrogen, methyl, ethyl, 2-hydroxyethyl or 2-methoxyethyl.

31. A compound according to claim 1 selected from

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl ] - [ 2-methyl-5- (morpholine-4-carbonyl) phenyl ] -methanone,

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl ] - [ 2-methyl-5- (4-methyl-piperazine-1-carbonyl) phenyl ] -methanone,

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -N-methoxy-4, N-dimethylbenzamide,

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4-methyl-N- (tetrahydrofuran-2-ylmethyl) benzamide,

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4, N-dimethyl-N- (tetrahydrofuran-2-ylmethyl) benzamide,

3- [ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) benzoyl ] -N- (2-methoxyethyl) -4-methylbenzamide,

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4-methyl-N- (3-morpholin-4-yl-propyl) benzamide,

[ 2-chloro-4- (4-fluoro-2-methylphenylamino) phenyl ] - {5- [4- (2-methoxyethyl) piperazine-1-carbonyl ] -2-methylphenyl } -methanone,

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4-methyl-N-pyridin-4-ylmethyl benzamide,

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -4-methyl-N-pyridin-2-ylmethyl benzamide,

3- [ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -benzoyl ] -4-methyl-N-pyridin-3-ylmethyl-benzamide,

3- [4- (2-aminophenylamino) -2-chlorobenzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide,

3- [4- (2-amino-4-bromophenylamino) -2-chlorobenzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide,

3- [4- (4-bromo-2-methylphenylamino) -2-chlorobenzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide,

3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide,

3- [4- (2-aminophenylamino) -2-chlorobenzoyl ] -N- (2-methoxyethyl) -4-methylbenzamide,

3- [4- (2-aminophenylamino) -2-chlorobenzoyl ] -N-ethyl-4-methylbenzamide,

3- [4- (2-aminophenylamino) -2-chlorobenzoyl ] -N- (3-hydroxypropyl) -4-methylbenzamide,

3- [ 2-chloro-4- (4-fluoro-2-methylphenylamino) benzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4, N-dimethyl-benzamide,

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetylamino) -acetic acid ethyl ester,

{3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetic acid ethyl ester,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (2-methoxy-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-cyclohexyl-4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-ethyl-4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (6-hydroxy-hexyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-isopropyl-4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-isobutyl-4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (2, 2-dimethyl-propyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (3-methoxy-propyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N- (2-dimethylamino-ethyl) -4-methyl-benzamide,

2-methyl-acrylic acid 2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -ethyl ester,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-cis- (4-hydroxy-cyclohexyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -N-trans- (4-hydroxy-cyclohexyl) -4-methyl-benzamide,

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -ethyl) -carbamic acid tert-butyl ester,

N- (2-amino-ethyl) -3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzamide,

(2- {3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetylamino) -acetic acid,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 2-difluoro-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide,

n-carbamoylmethyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzamide,

n-carbamoylmethyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide,

n-benzyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-ethyl-4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-cyclohexylmethyl-4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-propyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (1-hydroxymethyl-propyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2, 2, 3, 3, 3-pentafluoro-propyl) -benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (3-hydroxy-propyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-1, 1-dimethyl-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl) -4-methyl-benzamide,

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetic acid ethyl ester,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (4-hydroxy-butyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (3-hydroxy-1, 1-dimethyl-butyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (3-phenyl-propyl) -benzamide,

(R) -3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (1-hydroxymethyl-3-methyl-butyl) -4-methyl-benzamide,

3- [4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-isopropyl-4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-cyclohexyl-4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 2-difluoro-ethyl) -4-methyl-benzamide,

5- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -4-oxo-pentanoic acid methyl ester,

n- [ (2-carbamoyl-ethylcarbamoyl) -methyl ] -3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide,

(2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -acetylamino) -acetic acid ethyl ester,

n-allyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2-sulfamoyl-ethyl) -benzamide,

n- (2-acetylamino-ethyl) -3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (3-hydroxy-propyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-N-phenethyl-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-1, 1-dimethyl-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-N- (2-morpholin-4-yl-ethyl) -benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methoxy-N-methyl-benzamide,

{3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzoylamino } -acetic acid ethyl ester,

(2- {3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzoylamino } -acetylamino) -acetic acid ethyl ester,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -N, N-bis- (2-hydroxy-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-N, N-bis- (2-methoxy-ethyl) -benzamide,

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl ] -4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzamide,

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl ] -4-methyl-N- (2, 2, 2-trifluoro-ethyl) -benzamide,

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- (2-chloro-4-phenylamino-benzoyl) -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (3, 5-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (3-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methoxy-benzamide,

3- (2-chloro-4-phenylamino-benzoyl) -N- (2-hydroxy-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2, 2-difluoro-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2-fluoro-ethyl) -4-methoxy-benzamide,

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide,

n-carbamoylmethyl-3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -4-methoxy-benzamide,

3- (2-chloro-4-phenylamino-benzoyl) -N- (2, 2-difluoro-ethyl) -4-methoxy-benzamide,

3- (2-chloro-4-phenylamino-benzoyl) -N- (2-fluoro-ethyl) -4-methoxy-benzamide,

3- (2-chloro-4-phenylamino-benzoyl) -N- (2, 3-dihydroxy-propyl) -4-methoxy-benzamide,

n-carbamoylmethyl-3- (2-chloro-4-phenylamino-benzoyl) -4-methoxy-benzamide,

4-chloro-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -benzamide,

(2- { 3-chloro-4- [5- (2-hydroxy-ethylcarbamoyl) -2-methyl-benzoyl ] -phenylamino } -phenyl) -carbamic acid ethyl ester,

3- [ 2-chloro-4- (2-propionylamino-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- [4- (2-acetylamino-phenylamino) -2-chloro-benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

n- (2- { 3-chloro-4- [5- (2-hydroxy-ethylcarbamoyl) -2-methyl-benzoyl ] -phenylamino } -phenyl) -succinamic acid,

3- (2-chloro-4- {2- [3- (2-hydroxy-ethyl) -ureido ] -phenylamino } -benzoyl) -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [ 2-methyl-4- (morpholine-4-carbonyl) -phenyl ] -methanone,

[4- (2-amino-phenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone,

[4- (2-amino-phenylamino) -2-chlorophenyl ] - [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ] -methanone,

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl,

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ] -methanone,

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - { 2-methyl-4- [3- (tetrahydro-pyran-2-yloxy) -propoxy ] -phenyl } -methanone,

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - [4- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone,

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - [4- (2-fluoro-ethoxy) -2-methyl-phenyl ] -methanone,

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] - [4- (2-fluoro-ethoxy) -2-methyl-phenyl ] -methanone,

[4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] - [4- (2-methoxy-ethoxy) -2-methyl-phenyl ] -methanone,

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone,

[4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] - [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ] -methanone,

[4- (2-azido-ethoxy) -2-methyl-phenyl ] - [4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] -methanone,

[4- (2-amino-ethoxy) -2-methyl-phenyl ] - [4- (4-bromo-2-methyl-phenylamino) -2-chlorophenyl ] -methanone,

[4- (2-bromophenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone,

{4- [2- (3-amino-propenyl) -phenylamino ] -2-chlorophenyl } - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone,

{4- [2- (3-amino-propenyl) -phenylamino ] -2-chlorophenyl } - [4- (2-hydroxy-ethoxy) -2-methyl-phenyl ] -methanone,

1- (2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl ] -phenylamino } -phenyl) -3-ethyl-urea,

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -benzoyl } -phenylamino) -phenyl ] -3-ethyl-urea,

1- (5-bromo-2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl ] -phenylamino } -phenyl) -3-ethyl-urea,

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -benzoyl } -phenylamino) -phenyl ] -3-cyclohexyl-urea,

1- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -benzoyl } -phenylamino) -phenyl ] -3- (2-hydroxy-ethyl) -urea,

1- (5-bromo-2- { 3-chloro-4- [4- (2-hydroxy-ethoxy) -2-methyl-benzoyl ] -phenylamino } -phenyl) -3- (2-hydroxy-ethyl) -urea,

n- [ 5-bromo-2- (3-chloro-4- { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -benzoyl } -phenylamino) -phenyl ] -succinamic acid,

(4-allyloxy-2-methyl-phenyl) - [4- (2-amino-4-bromophenylamino) -2-chlorophenyl ] -methanone,

n- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -acetamide,

1- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -3-ethyl-urea,

{2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -carbamic acid ethyl ester,

n- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -2, 2, 2-trifluoro-acetamide,

n- {2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -succinamic acid,

{2- [4- (4-allyloxy-2-methyl-benzoyl) -3-chlorophenylamino ] -5-bromophenyl } -carbamic acid cyclopentyl ester,

N- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-methoxy-propionamide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -propionamide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -2- (2-methoxy-ethoxy) -acetamide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-morpholin-4-yl-propionamide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-hydroxy-propionamide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-furan-2-yl-propionamide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -2-hydroxy-benzamide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -2- (2, 5-dioxo-imidazolidin-4-yl) -acetamide,

2, 6-dioxo-hexahydro-pyrimidine-4-carboxylic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -amide,

acrylic acid 2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenylcarbamoyl } -ethyl ester,

N- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-methylsulfanyl-propionamide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-methanesulfonyl-propionamide,

ethanesulfonic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -amide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -4-methoxy-benzenesulfonamide,

n- (5- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenylsulfamoyl } -4-methyl-thiazol-2-yl) -acetamide,

5-acetyl-2-chloro-N- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -benzenesulfonamide,

naphthalene-2-sulfonic acid {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -amide,

n- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -C-phenyl-methanesulfonamide,

2-methyl-acrylic acid 2- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -ureido) -ethyl ester,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (2-hydroxy-ethyl) -urea,

(3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -ureido) -acetic acid ethyl ester,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (3-methoxy-phenyl) -urea,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (3-trifluoromethyl-phenyl) -urea,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-propyl-urea,

3- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -ureido) -propionic acid ethyl ester,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-cyclohexyl-urea,

1-allyl-3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -urea,

1-benzyl-3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -urea,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-ethyl-urea,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-phenyl-urea,

1-butyl-3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -urea,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-phenethyl-urea,

2- (3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -ureido) -benzoic acid methyl ester,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (3-cyano-phenyl) -urea,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-isopropyl-urea,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3- (4-methoxy-phenyl) -urea,

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -carbamic acid benzyl ester,

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -carbamic acid allyl ester,

{3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -carbamic acid ethyl ester,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (3-hydroxy-butylamino) -2-methyl-phenyl ] -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (3' -hydroxymethyl-4-methyl-biphenyl-3-yl) -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (3' -hydroxy-4-methyl-biphenyl-3-yl) -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (4' -methoxy-4-methyl-biphenyl-3-yl) -methanone,

n- {3 '- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4' -methyl-biphenyl-3-yl } -acetamide,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (4-methyl-3' -trifluoromethoxy-biphenyl-3-yl) -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (3 ', 4 ', 5 ' -trifluoro-4-methyl-biphenyl-3-yl) -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (3 ', 4' -dimethoxy-4-methyl-biphenyl-3-yl) -methanone,

3 '- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4' -methyl-biphenyl-3-carbonitrile,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -4-methyl-benzenesulfonamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2-morpholin-4-yl-ethyl) -benzenesulfonamide,

n-allyl-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzenesulfonamide,

n- (2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzenesulfonylamino } -ethyl) -acetamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N-propyl-benzenesulfonamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2, 3-dihydroxy-propyl) -4-methyl-benzenesulfonamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-methoxy-ethyl) -4-methyl-benzenesulfonamide,

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] - [5- (4-methoxy-benzyloxy) -2-methyl-phenyl ] -methanone,

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] - [5- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone,

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [5- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone,

[5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-methyl-phenyl ] - [4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] -methanone,

[5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl ] - [4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] -methanone,

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl ] -methanone,

[4- (4-fluoro-2-methyl-phenylamino) -2-nitro-phenyl ] - [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone,

[ 2-amino-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone,

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [5- (4-methoxy-benzyloxy) -2-methyl-phenyl ] -methanone,

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [5- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone,

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (3-hydroxy-propoxy) -2-methyl-phenyl ] -methanone,

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone,

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl ] - [ 2-methyl-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone,

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-methyl-phenyl ] -methanone,

[4- (2, 4-difluoro-phenylamino) -2-nitro-phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl ] -methanone,

[ 2-amino-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-methyl-phenyl ] -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-fluorophenyl ] -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl ] -methanone,

2- {3- [ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -benzoyl ] -4-fluoro-phenoxy } -N-methyl-acetamide,

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone,

2- {3- [ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -benzoyl ] -4-fluoro-phenoxy } -N, N-dimethyl-acetamide,

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-fluorophenyl ] -methanone,

[ 2-chloro-4- (4-chloro-2-methyl-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl ] -methanone,

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone,

[ 2-chloro-4- (4-fluorophenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone,

[ 2-chloro-4- (4-fluorophenylamino) -phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-fluorophenyl ] -methanone,

[ 2-chloro-4- (2-chloro-4-fluorophenylamino) -phenyl ] - [ 2-fluoro-5- (3-hydroxy-propoxy) -phenyl ] -methanone,

[4- (2-amino-phenylamino) -2-chlorophenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl ] -methanone,

[4- (2-amino-phenylamino) -2-chlorophenyl ] - [ 2-fluoro-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone,

[ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl ] - [ 2-chloro-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone,

(±) - [ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl ] - [ 2-chloro-5- (2, 3-dihydroxy-propoxy) -phenyl ] -methanone,

[5- (3-bromo-propoxy) -2-chlorophenyl ] - [ 2-chloro-4- (2, 6-difluoro-phenylamino) -phenyl ] -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (5-hydroxymethyl-2-methyl-phenyl) -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (5-chloromethyl-2-methyl-phenyl) -methanone,

(5-azidomethyl-2-methyl-phenyl) - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] -methanone,

(5-aminomethyl-2-methyl-phenyl) - [ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (5-hydroxymethyl-2-methoxy-phenyl) -methanone,

acetic acid 3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzyl ester,

n-tert-butoxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-methoxy-4-methyl-benzamide,

N-butoxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-cyclohexylmethoxy-4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N- (2-methyl-thiazol-4-ylmethoxy) -benzamide,

n-benzyloxy-3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (4-methoxy-benzyloxy) -4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoic acid N ', N' -dimethyl-hydrazide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-N-morpholin-4-yl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-hydroxy-4-methyl-benzamide,

4- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (2-hydroxy-ethyl) -3-methyl-benzamide,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (3-hydroxy-propenyl) -2-methyl-phenyl ] -methanone,

4- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -thiophene-3-carboxylic acid methyl ester,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N-furan-2-ylmethyl-4-methyl-benzamide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- (3-methoxy-phenyl) -4-methyl-benzamide,

2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -benzoic acid methyl ester,

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -thiophene-2-carboxylic acid methyl ester,

4- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -thiophene-3-carboxylic acid,

2- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -benzoic acid,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -N- [2- (2-hydroxy-ethylcarbamoyl) -phenyl ] -4-methyl-benzamide,

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoylamino } -thiophene-2-carboxylic acid (2-hydroxy-ethyl) -amide,

[ 2-chloro-4- (4-fluoro-2-methyl-phenylamino) -phenyl ] - [ 2-methyl-5- (1H-tetrazol-5-yl) -phenyl ] -methanone,

[4- (2-amino-phenylamino) -2-chlorophenyl ] - (5-ethynyl-2-methyl-phenyl) -methanone,

[4- (2-amino-phenylamino) -2-chlorophenyl ] - (2-methyl-5- {1- [2- (tetrahydro-pyran-2-yloxy) -ethyl ] -1H- [1, 2, 3] triazol-4-yl } -phenyl) -methanone,

[4- (2-amino-phenylamino) -2-chlorophenyl ] - {5- [1- (2-hydroxy-ethyl) -1H- [1, 2, 3] triazol-4-yl ] -2-methyl-phenyl } -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - (5-ethynyl-2-methyl-phenyl) -methanone,

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -4-methyl-benzoic acid hydrazide,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoic acid hydrazide,

1- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-benzoyl } -4-ethyl-3-thiosemicarbazide,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (5-ethylamino- [1, 3, 4] thiadiazol-2-yl) -2-methyl-phenyl ] -methanone,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [ 2-methyl-5- (1H-tetrazol-5-yl) -phenyl ] -methanone,

3- {3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methyl-phenyl } -3-oxo-propionic acid ethyl ester,

[ 2-chloro-4- (2, 4-difluoro-phenylamino) -phenyl ] - [5- (4, 5-dihydro-oxazol-2-yl) -2-methyl-phenyl ] -methanone,

3- { 2-chloro-4- [2- (3-ethyl-ureido) -phenylamino ] -benzoyl } -N- (2-hydroxy-ethyl) -4-methyl-benzamide,

3- [ 2-chloro-4- (2-nitrophenylamino) benzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide,

3- [4- (4-bromo-2-nitrophenylamino) -2-chlorobenzoyl ] -N- (2-hydroxyethyl) -4-methylbenzamide,

3- [4- (4-bromo-2-methylphenylamino) -2-chlorobenzoyl ] -4-methylbenzoic acid,

3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl ] -4-methylbenzoic acid,

2- {3- [ 2-chloro-4- (2, 4-difluorophenylamino) benzoyl ] -4-methylbenzoylamino } ethyl 2-methacrylate,

3- [ 2-chloro-4- (2-nitrophenylamino) benzoyl ] -N- (2-methoxyethyl) -4-methylbenzamide,

3- [ 2-chloro-4- (4-chloro-2-fluorophenylamino) -benzoyl ] -4-methyl-benzoic acid,

3- [ 2-chloro-4- (2, 4-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzoic acid,

3- [ 2-chloro-4- (2, 6-difluoro-phenylamino) -benzoyl ] -4-methoxy-benzoic acid,

3- [ 2-chloro-4- (3-fluoro-2-methyl-phenylamino) -benzoyl ] -4-methyl-benzoic acid,

3- [ 2-chloro-4- (2-chloro-4-fluorophenylamino) -benzoyl ] -4-methyl-benzoic acid,

3- [ 2-chloro-4- (4-fluorophenylamino) -benzoyl ] -4-methoxy-benzoic acid,

3- (2-chloro-4-phenylamino-benzoyl) -4-methoxy-benzoic acid,

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl } -methanone,

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl ] - { 2-methyl-4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy ] -phenyl,

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl ] - { 2-methyl-4- [3- (tetrahydro-pyran-2-yloxy) -propoxy ] -phenyl } -methanone,

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl ] - [4- (2-fluoro-ethoxy) -2-methyl-phenyl ] -methanone,

[4- (4-bromo-2-nitro-phenylamino) -2-chlorophenyl ] - [4- (2-methoxy-ethoxy) -2-methyl-phenyl ] -methanone,

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl ] - [ 2-fluoro-5- (2-morpholin-4-yl-ethoxy) -phenyl ] -methanone,

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl ] - [5- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -2-fluorophenyl ] -methanone, and

[ 2-chloro-4- (2-nitro-phenylamino) -phenyl ] - [5- (2, 3-dihydroxy-propoxy) -2-fluorophenyl ] -methanone.

32. A pharmaceutical composition comprising a compound according to any one of claims 1-31, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable vehicle or excipient.

33. Use of a compound according to any one of claims 1-31 in the manufacture of a medicament for the prevention, treatment or amelioration of an inflammatory disease or disorder.

34. The use of claim 33, wherein the inflammatory disease or disorder is asthma, allergy, arthritis, rheumatoid arthritis, spondyloarthritis, gout, atherosclerosis, chronic inflammatory bowel disease, crohn's disease, neurogenic inflammation, inflammatory eye diseases, proliferative and inflammatory skin disorders, psoriasis, atopic dermatitis, acne, uveitis, sepsis, septic shock or acne, and osteoporosis.

35. Process for preparing compounds of general structure I

Wherein R is₁、R₂、R₃、R₄、R₅And R₆As defined in claim 1, comprising the steps of:

a) converting a compound of general structure VI to an organometallic intermediate,

wherein Hal is halogen, and R₁、R₅And R₆Each independently protected or unprotected, as defined in claim 1;

b) converting the organometallic intermediate to an organozinc intermediate;

c) coupling the organozinc intermediate with an acyl halide of general structure V in the presence of a catalyst,

wherein R is₂As defined in claim 1, protected or unprotected,

to give compounds of general structure IV

Wherein R is₁、R₂、R₅And R₆Each independently protected or unprotected, as defined above;

d) optionally converting, protecting or deprotecting R of a compound of general structure IV ₁、R₂、R₅And R₆To another compound of general structure IV;

e) reducing the compound of general structure IV from step c) or d) to an amine of general structure III,

wherein R is₁、R₂、R₅And R₆Each independently protected or unprotected, as defined above;

f) optionally converting, protecting or deprotecting R of a compound of general structure III₁、R₂、R₅And R₆To give another compound of general structure III;

g) coupling the amine of general structure III from step e) or f) with a compound of general structure II,

wherein L is trifluoromethanesulfonate or halogen, R₃And R₄As defined in claim 1, each independently protected or unprotected,

to give a compound of the general structure I wherein R₁、R₂、R₃、R₄、R₅And R₆Each independently protected or unprotected, as defined above;

h) optionally converting, protecting or deprotecting R of a compound of general structure I obtained in step g)₁、R₂、R₃、R₄、R₅Or R₆To give another compound of general structure I.

36. The process according to claim 35, wherein the coupling in step c) is carried out in the presence of a copper salt.

37. A process for the preparation of a compound of general structure I,

wherein R is ₁、R₂、R₃、R₄、R₅And R₆As defined in claim 1, comprising the steps of:

a) converting a compound of general structure VIIa to an organometallic intermediate,

wherein Hal is halogen, W is halogen or triflate, and R₂As defined in claim 1, the first and second,

protected or unprotected;

b) converting the organometallic intermediate to an organozinc intermediate;

c) coupling the organozinc intermediate with an acyl halide of general structure VIII in the presence of a catalyst,

wherein R is₁、R₅And R₆As defined in claim 1, each independently protected or unprotected, to give a compound of general structure IIIa,

w, R therein₁、R₂、R₅And R₆Each independently protected or unprotected, as defined above;

d) w, R for optional transformation, protection or deprotection of a compound of general structure IIIa₁、R₂、R₅And R₆To give another compound of general structure IIIa;

e) coupling the compound of general structure IIIa from step c) or d) with an amine of general structure IIa,

wherein R is₃And R₄Each independently protected or unprotected, as defined in claim 1, to give a compound of general structure I, wherein R is₁、R₂、R₃、R₄、R₅And R₆As defined above, the above-mentioned,

each independently protected or unprotected;

f) Optionally converting, protecting or deprotecting R of a compound of general structure I obtained in step e)₁、R₂、R₃、R₄、R₅Or R₆To give another compound of general structure I.

38. The process according to claim 37, wherein the coupling in step c) is carried out in the presence of a copper salt.