Novel derivatives of aminobenzophenone

FIELD: chemistry.

SUBSTANCE: in the compound of general formula R1 represents halogen, C1-4alkyl, or C1-4alkoxy; R2 represents hydrogen, halogen; R3 represents hydrogen, or one or several halogens; R4 represents hydrogen, halogen, R8 or Y1R8; Y1 represents -NRa-; Ra and Rb are similar or different, and each represents hydrogen or C1-4alkyl; R8 represents hydrogen, C1-10alkyl; R7 represents hydrogen, hydroxy, trifluoromethyl, amino, C1-6hydroxyalkyl, C1-4alkoxy, C1-4alkylthio, C1-6alkylamino, C1-4alkoxycarbonyl, -S(O)2R, -COOH, -CONH2, or -NRaC(O)R', where R and R' are similar or different, and each represents hydrogen or C1-3alkyl; R5 represents -COOH, Y2R9, Y2R9Y3R10, C1-6alkyl-Y2R9, C1-10alkyl, or unsaturated C3-8carbocycle, said R5 is substituted with one or several, similar or different substituents, represented by R7; R6 represents hydrogen; Y2 represents -O-, -NRa-, -NRaC(O)NRb-, -NRaC(O)-, -C(O)NRa-, -C(O)-, -NRaC(O)O-, or -OC(O)-; R9 represents C1-10alkyldioxolanyl, C1-10alkylthiazolyl, C1-10alkylmorpholinyl, etc.

EFFECT: obtaining novel compounds, represented by formula I, which possess properties of TNF-α or MAP-kinase p38a inhibitors for obtaining medication to be applied as anti-inflammatory or anti-cancer agent.

24 cl, 4 tbl, 270 ex

 

The invention relates to a new type of aminobenzophenones and to their use in therapy.

BACKGROUND of the INVENTION

Aminobenzophenone well known from the scientific and patent literature.

So, in WO 98/32730, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/05744 and WO 01/05745 described in connection with the frame of the overall structure,

where the phenyl ring C substituted derivatives of amino groups. Moreover, in WO 01/42189 and WO 02/076447 described compounds with a similar structure, but without nitrogen substituent in the phenyl ring C. Finally, in WO 01/90074 and WO 02/083622 described compounds in which the phenyl rings A and C, respectively, replaced by heterocycles.

Indicates that the compounds described in these patent applications, are inhibitors of secretion of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in vitro, which makes possible the use of the compounds in the treatment of inflammatory diseases, the pathogenesis of which is the production of cytokines. Presumably, aminobenzophenone manifest their effect by inhibiting MAP kinase p38, which, in turn, inhibits the production of IL-1β and TNF-α.

Getting close to the structure of aminobenzophenones used as a dye for fabrics that are described in Man-Made Text. India (1987), 30 (6), 275-6, Man-Made Text. India (1986), 29 (5), 224-30, and Man-Made Text. India(1985), 28 (11), 425, 427-9, 431.

The ESSENCE of IZABERETE THE OIA

It has been unexpectedly discovered that the new derivatives aminobenzophenone are strong inhibitors of secretion of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in vitro and in vivo, suggesting the possibility of their use in the treatment and/or prophylaxis of inflammatory diseases and other conditions, the pathogenesis of which is the secretion and modulation of Pro-inflammatory cytokines.

It was found that the anti-inflammatory effect of derivative aminobenzophenone the present invention relates to the inhibition or negative regulation of MAP kinases, more specifically, MAP kinase p38 and stress-activated protein, which is an important element in the path of signal transduction leading to production of proinflammatory cytokines.

Derivatives aminobenzophenone of the present invention, furthermore, can be used in the treatment of cancer or eye diseases or conditions.

Thus, the present invention relates to a compound of General formula I

where

R1represents halogen, hydroxy, mercapto, trifluoromethyl, amino, C1-4alkyl, C2-4alkenyl, C2-4quinil, C1-4alkoxy, C1-4alkylthio, C1-6alkylamino, C1-4alkoxycarbonyl, cyano, -CONH2or nitro;

R2is the Oh hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, C1-4alkyl, C2-4alkenyl, C2-4quinil, C1-4alkoxy, C1-4alkylthio, C1-6alkylamino, C1-4alkoxycarbonyl, cyano, -CONH2, phenyl or nitro;

R3represents one or more, same or different substituents selected from the group comprising hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy, CONH2, nitro, C1-4alkyl, C2-4alkenyl, C2-4quinil, C1-4alkoxy, C1-4alkylthio, C1-4alkoxycarbonyl;

R4represents hydrogen, halogen, nitro, R8or Y1R8;

Y1represents-O-, -S-, -S(O)-, -S(O)2-, -NRa-, -NRaC(O)NRb-, -NRaC(O)-, -C(O)NRa-, -C(O)NRaO-, -C(O)-, -C(O)O-, -NRaC(O)O-, -S(O)2NRa-, -NRaS(O)2-;

Ra, Rband Rcare the same or different and each represents hydrogen, C1-4alkyl, C2-4alkenyl, C2-4quinil, C3-8carbocyclic, C1-12heterocyclyl or aryl, each of C1-4of alkyl, C2-4alkenyl, C2-4the quinil, C3-8carbocycle, C1-12heterocyclyl or aryl optionally substituted by one or more, same or different substituents represented by R7;

R8represents adored, C1-10alkyl-C1-12heterocyclyl, C1-10alkyl-C3-12carbocyclic, C1-10alkyl, C2-10alkenyl, C2-10quinil, C3-12carbocyclic or C1-12heterocyclyl, each of C1-10alkyl-C1-12heterocyclyl, C1-10alkyl-C3-12carbocycle, C1-10of alkyl, C2-10alkenyl, C2-10the quinil, C3-12carbocycle or C1-12heterocyclyl optionally substituted by one or more, same or different substituents represented by R7;

R7represents halogen, hydroxy, mercapto, trifluoromethyl, amino, C1-4alkyl, C1-6hydroxyalkyl, C1-4alkoxy, C1-4alkylthio, C1-6alkylamino, C1-4alkoxycarbonyl, C1-9trialkylamine in combination with anion, cyano, azido, nitro, -S(O)2NH2, -S(O)2NRaRb, -S(O)2R, -COOH, -CONH2, -NRaC(O)R', -CONHR' or-CONRR', where R and R' are the same or different and each represents hydrogen or C1-3alkyl;

one of R5and R6represents-COOH, -C(O)NHOH, -C(O)NHNH2, Y2R9, Y2R9Y3R10C1-6alkyl-Y2R9C1-6alkyl-Y2R9Y3R10C2-6alkenyl-Y2R9C2-6alkenyl-Y2R9Y3R10, Y2R9-C1-6-alkyl-Y3 R10, Y2R9-C2-6alkenyl-Y3R10C3-12carbocyclic-Y2R9C3-12carbocyclic-Y2R9Y3R10C1-12heterocyclyl-Y2R9C1-12heterocyclyl-Y2R9Y3R10C3-12carbocyclic-C1-6alkyl-Y2R9C3-12carbocyclic-C1-6-alkyl-Y2R9Y3R10C1-12heterocyclyl-C1-6-alkyl-Y2R9C1-12heterocyclyl-C1-6-alkyl-Y2R9Y3R10C3-12carbocyclic-C1-6-alkyl-Y3R10C1-12heterocyclyl-C1-6alkyl-Y3R10C1-12heterocyclyl-C1-10alkyl, C3-12carbocyclic-C1-10alkyl, C1-10alkyl-C1-12heterocyclyl, C1-10alkyl-C3-12carbocyclic, C1-10alkyl, C2-10alkenyl, C2-10quinil, C3-12carbocyclic or C1-12heterocyclyl, each of which is optionally substituted by one or more, same or different substituents represented by R7and the other represents hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, C1-4alkyl, C2-4alkenyl, C2-4quinil, C1-4alkoxy, C1-4alkylthio, C1-6alkylamino, C1-4alkoxycarbonyl, cyano, -CONH2or nitro;

provided that when R5what if R 6represents phenyl, C1-5alkyl or C2-3alkenyl specified R5or R6substituted by one or more, same or different substituents represented by R7(with the exception of three fluorine atoms, when R5or R6represents methyl or Y1R8,

the next condition that when R5or R6represents-COOH, Y1can't be a-NRa-, -NRaC(O)NRb-, -NRaC(O) -, or-NRaC(O)O-, and R3or R4cannot be nitro,

the next condition that when R2represents hydrogen, one of R5or R6cannot be hydrogen or optionally substituted C3-18heterocyclyl, C1-7alkyl, C2-7alkenyl, C2-7quinil or C1-7alkoxy);

Y2represents-O-, -S-, -S(O)-, -S(O)2-, -NRa-, -NRaC(O)NRb-, -NRaC(O)-, -C(O)NRa-, -C(O)NRaO-, -C(O)-, -NRaC(O)O-, -NRaS(O)2-, -OC(O)-, -C(O)O-, -C(O)NRaNRbC(S)NRc, -C(O)NRaNRb- or-S(O)2NRa-;

R9represents a C1-10alkyl-C1-12heterocyclyl, C1-10alkyl-C3-12carbocyclic, C1-10alkyl, C2-10alkenyl, C2-10quinil, C3-12carbocyclic, C1-12heterocyclyl, C3-12carbocyclic-C1-10alkyl or C1-12GE is eroticly-C 1-10alkyl, C3-6carbocyclic-C1-6alkenyl, C3-6carbocyclic-C2-6quinil, each of which is optionally substituted by one or more, same or different substituents represented by R7;

provided that, when Y2represents-O-, -NRa-, -S - or-C(O)O-, and R9represents a C1-6alkyl specified C1-6alkyl substituted by one or more, same or different substituents represented by R7or Y3R10;

Y3represents-O-, -S-, -S(O)-, -S(O)2-, -NRa-, -NRaC(O)NRb-, -NRaC(O)-, -C(O)NRa-, -C(O)NRaO-, -C(O)-, -NRaC(O)O-, -NRaS(O)2-, -OC(O)- or-C(O)O-;

R10represents a C1-10alkyl-C1-12heterocyclyl, C1-10alkyl-C3-12carbocyclic, C1-10alkyl, C2-10alkenyl, C2-10quinil, C3-12carbocyclic or C1-12heterocyclyl, each of which is optionally substituted by one or more, same or different substituents represented by R7;

or, when one of R5or R6represents a group-C(O)NRaR9-, Raand R9together with the nitrogen atom to which they are attached, form a C1-12heterocyclic ring, optionally containing one or more heteroatoms selected from the gr is PPI, comprising O, S and N, optionally substituted by one or more substituents represented by R7;

or its pharmaceutically acceptable salt, MES or ester.

In another aspect the invention relates to pharmaceutical compositions containing a compound of formula I or its pharmaceutically acceptable salt, MES or ester together with a pharmaceutically acceptable excipient or the media.

The following aspect of the invention relates to a method of preventing, treating or attenuating the intensity of inflammatory diseases or conditions or eye diseases or conditions, which includes the introduction of the patient, if necessary, an effective amount of the compounds of formula I.

The following aspect of the invention relates to a method of treating or attenuating the intensity of cancer, which includes the introduction of the patient, if necessary, an effective amount of the compounds of formula I.

In another aspect the invention relates to the use of compounds of formula I when receiving medicines to prevent, cure or ameliorate the intensity of inflammatory diseases or conditions or eye diseases or conditions.

In another aspect the invention relates to the use of compounds of formula I when getting medicines for treatment is whether the weakening of the intensity of cancer.

According to another aspect, the invention relates to a method of obtaining compounds of General structural formula I,

where R1, R2, R3, R4, R5and R6have the meanings specified above, comprising the following stages

a) the conversion of compounds of General structural formula VI,

where Hal represents a halogen and R1, R5and R6have the meanings indicated above, each of which are independently protected or unprotected, in ORGANOMETALLIC intermediate connection;

b) Parametrierung specified ORGANOMETALLIC intermediate compounds in tsinkorganicheskih intermediate connection;

c) interaction of the specified tsinkorganicheskih intermediate connection galogenangidridy acid of the General structural formula V,

where R2matter mentioned above, protected or unprotected, in the presence of a catalyst to obtain compounds of General structural formula IV,

where R1, R2, R5and R6have the meanings indicated above, each of which are independently protected or unprotected;

d) optional conversion, protection or removal of protecting one or more substituents or functional what's groups R 1, R2, R5and R6compounds of General structural formula IV with other compounds of General structural formula IV;

e) recovering compounds of General structural formula IV with stage c) or (d) to the amine of General structural formula III,

where R1, R2, R5and R6have the meanings indicated above, each of which are independently protected or unprotected;

f) optional conversion, protection or removal of protecting one or more substituents or functional groups of R1, R2, R5and R6compounds of General structural formula III with other compounds of General structural formula III;

(g) the interaction of the amine of General structural formula III with stage e) or (f) with the compound of General structural formula II,

where L represents triflate or halogen, R3and R4have the meanings indicated above, each of which are independently protected or unprotected, to obtain the compounds of General structural formula I, where R1, R2, R3, R4, R5and R6have the meanings indicated above, each of which are independently protected or unprotected;

h) optional conversion, protection or removal of protecting one or more substituents or functional groups R 1, R2, R3, R4, R5or R6compounds of General structural formula I from step g) with other compounds of General structural formula I.

According to another aspect of the invention relates to a method of obtaining compounds of General structural formula I,

where R1, R2, R3, R4, R5and R6have the meanings specified above, comprising the following stages

a) the conversion of compounds of General structural formula VIIa,

where Hal represents a halogen, W is a halogen or triflate, and R2has the values listed above, secured or unsecured, in ORGANOMETALLIC intermediate connection;

b) Parametrierung specified ORGANOMETALLIC intermediate compounds in tsinkorganicheskih intermediate connection;

c) interaction of the specified tsinkorganicheskih intermediate connection galogenangidridy acid of the General structural formula VIII

where R1, R5and R6have the meanings indicated above, each of which are independently protected or unprotected, in the presence of a catalyst to obtain compounds of General structural formula IIIa,

where W, R1, R2, R5 and R6have the meanings indicated above, each of which are independently protected or unprotected;

d) optional conversion, protection or removal of protecting one or more substituents or functional groups W, R1, R2, R5and R6compounds of General structural formula IIIa with other compounds of General structural formula IIIa;

e) the interaction of compounds of General structural formula IIIa with stage c) or d) with the amine of General structural formula IIa,

where R3and R4have the meanings indicated above, each of which are independently protected or unprotected, to obtain the compounds of General structural formula I,

where R1, R2, R3, R4, R5and R6have the meanings indicated above, each of which are independently protected or unprotected;

f) optional conversion, protection or removal of protecting one or more substituents or functional groups of R1, R2, R3, R4, R5or R6compounds of General structural formula I from stage e) with other compounds of General structural formula I.

DETAILED description of the INVENTION

Definitions

In the context of the present invention, the term "alkyl" is intended to indicate a monovalent radical formed when UD is tion of a hydrogen atom, available at any carbon atom, straight or branched alkane. Alkyl chain typically contains 1-10 carbon atoms, in particular 1 to 6 carbon atoms. The term includes the subclasses of normal alkyl (n-alkyl), secondary 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 indicate a radical of the formula OR'where R' is an alkyl, as defined above, for example, methoxy, ethoxy, propoxy, butoxy and so on.

The term "hydroxyalkyl" is intended to indicate an alkyl radical, above, where one or more hydrogen atoms is replaced by hydroxy.

The term "alkenyl" is intended to indicate mono-, di-, tri-, Tetra - or pentadentate hydrocarbon radical, usually containing 2-10 carbon atoms, in particular 2 to 6 carbon atoms, for example, ethynyl, propenyl, butenyl, pentenyl or hexenyl.

The term "quinil" is intended to indicate a hydrocarbon radical containing 1-5 triple C-C bond, Allenova chain typically contains 2-10 carbon atoms, in particular 2 to 6 carbon atoms, such as ethinyl, PROPYNYL, butynyl, pentenyl or hexenyl.

The term "alkoxycarbonyl" is intended to indicate a radical of the formula-COOR', where R' is an alkyl, as indicated the above, for example, methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and so on.

The term "aryl" is intended to include carbocyclic aromatic ring radicals, in particular 5 - or 6-membered ring, optionally condensed bicyclic ring, for example phenyl or naphthyl.

The term "heteroaryl" is intended to include heterocyclic aromatic ring radicals, in particular 5 - or 6-membered rings, containing 1-4 heteroatoms selected from O, S and N, or optionally condensed bicyclic rings with 1-4 heteroatoms, for example pyridyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolin, benzimidazolyl and benzofuranyl.

The term "carbocycle" includes saturated and unsaturated, optionally condensed bicyclic carbocyclic ring, usually containing 3-12 carbon atoms, in particular 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl; or C3-12cycloalkenyl group, such as cycloprop-2-enyl, cyclobuta-2-enyl, cyclopent-2-enyl, cyclohex-3-enyl, cycloocta-4-enyl, cyclohex-3,5-dienyl, indanyl, indenyl, 1,4-dihydronaphtho, phenyl and naphthyl. The term "carbocyclic also includes cyclic hydrocarbons in which one or more CH2fragments rings would and replaced with-C(O)-fragment and/or Exo-cyclic carbon-carbon double bond, such as oxocyclohexyl, oxocyclopent, 4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl, 1-oxo-1,2,3,4-tetrahydronaphthalen-1-yl, 2-oxocyclopent-3-EN-1-yl and 2-oxocyclopent-1-EN-1-yl

The term "heterocyclyl" is intended to indicate a saturated or unsaturated, optionally condensed carbocyclic rings comprising 1 to 12 carbon atoms, such as 1-12 carbon atoms, particularly 1 to 8 carbon atoms and including one or more heteroatoms selected from the group comprising O, N and S, such as tetrazolyl, triazolyl, pyrrolyl, furanyl, morpholyl, piperazin, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, tetrahydrothiophene, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, putini, morpholinyl, furanyl, DIOXOLANYL, thiophenyl, chinoline, ethenolysis, 1,2-dihydroquinoline and so on. The term "heterocyclyl"thus includes "heteroaryl"as listed above, and also includes heterocyclic group in which one or more CH2fragments rings were replaced by-C(O)-fragment and/or Exo-cyclic carbon-carbon double bond, such as dioxopiperazinyl, dioxoimidazolidin, dioxotetrahydrofuran, oxopyrrolidin, 1-oxo-3,4-dihydroisoquinoline-2(1H)-yl and

The term "alkylthio" designation is to indicate a radical of the formula-SR, where R is an alkyl, as defined above, for example, C1-10alkylthio, C1-4alkylthio, methylthio, ethylthio, n-propylthio, 2-propylthio and so on.

The term "alkylamino" is intended to indicate a radical of the formula-or other-NR2where R is an alkyl, as defined above, and includes, for example, methylamino, dimethylamino, di-(n-propyl)amino, n-butyl(ethyl)amino, and so on.

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

The term "pharmaceutically acceptable salt" is intended to indicate salts obtained by the interaction of the compounds of formula I with the appropriate inorganic or organic acid, such as hydrochloric, Hydrobromic, itestosterone, sulphuric, nitric, phosphoric, formic, acetic, 2,2-dichloracetic, adipic, ascorbic, L-aspartic, L-glutamic, galacturonic, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D-glucuronic methansulfonate, salicylic, succinic, malonic, tartaric, benzolsulfonat, ethane-1,2-disulfonate, 2-hydroxyethanesulfonic acid, toluensulfonate, sulfamic or fumaric acid. Pharmaceutically acceptable salts of compounds of formula I can also be obtained by the interaction with an appropriate base, such as g is droxia sodium, the potassium hydroxide, magnesium hydroxide, calcium hydroxide, ammonia or suitable non-toxic amines, such as lower alkylamines followed, for example, triethylamine, hydroxy-lower alkylamines followed, for example, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, cyclooctylamine, for example, dicyclohexylamine, or benzylamines, for example, N,N'-dibenziletilendiaminom and dibenzylamine, or L-arginine or L-lysine.

The term "MES" is intended to indicate derivatives formed by the interaction of the compounds, for example, the compounds of formula I and a solvent, such as alcohol, glycerine or water, where these derivatives are presented in the form of a solid substance. When water is the solvent, these derivatives are called hydrates.

The term "pharmaceutically acceptable ester" is intended to indicate the easily hydrolyzable esters, such as alkanoyloxy, arachnological, urologically, for example, acetoxymethyl, pivaloyloxymethyl, benzoyloxymethyl esters and the corresponding 1'-oxyethylene derivatives, or alkoxycarbonylmethyl esters, for example, methoxycarbonylmethylene esters and ethoxycarbonylmethylene esters and the corresponding 1'-oxyethylene derivatives, or lactonase esters, for example, telegrafie esters, or dialkylaminoalkyl with whom you esters, for example, dimethylaminoethyl esters. Easily hydrolyzable esters include in vivo hydrolyzable esters of compounds of formula I. Such esters can be obtained by conventional methods known to experts in this field, for example, by the method described in patent GB No. 1490852 included in the description by reference.

"MAP kinase p38 is a stress-activated protein kinase that exists in several isoforms (p38α, p38β, p38β2, p38γ and p38δ). MAP kinase p38 is activated by various stimuli, including thermal, chemical, osmotic, pH and oxidative effects, excluding growth factor, high or low glucose and ultraviolet radiation. p38 is also stimulated by agents that mediate the initial physiological response to failure, infection and inflammation, such as LPS and Pro-inflammatory cytokines IL-1β, TNF-α, FasL, CD40L, and TGF-β. Like other MAP kinases, p38 fosfauriliruetsa kinases, including MKK3, MEK6 and MKK6, threonine and tyrosine in the activation loop (Thr-Xaa-Tyr), close to the ATP and the binding site of the substrate. In turn, p38 phosphorylates and activates the serine-threonine protein kinase MAPKAP kinase-2, MAPKAP kinase-3, MAPKAP kinase-5, MNK-1 and MSK-1. It was found that activation of p38 regulates the biosynthesis of cytokines in different cell types or directly by phosphorylation and activation of the actors transcription involved in the expression of cytokines, or indirectly, for example, phosphorylation of MSK-1, which, when activated, activates the transcription factor CREB. It was also shown that some pyridinedimethanol, for example, SB203580, which inhibit p38, inhibit the production of IL-1β and TNF-α from LPS-treated human monocytes. Thus, it was concluded that p38 probably represents a very interesting target for the development of anti-inflammatory compounds (cf., JC Lee et al., Immunopharmacology 47, 2000, pp. 185-201 and links discussed there; PR Young, "Specific Inhibitors of p38 MAP kinase in Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases, Gutkind JS (Ed.), Humana Press, Inc., Totowa, NJ, and references discussed there).

There are several reports by the MAP kinase p38 and inflammatory cytokines in relation to cell growth and apoptosis, such as the proliferation of the tumor and metastasis. Although the exact mechanism of regulation mediated by MAP kinase p38 cell growth is not known, assume that the MAP kinase p38 probably represents a very interesting target for development of anti-cancer drugs (S Nakada et al., Anticancer Research 21(1A), 2001, pp. 167-171 and links, there are specified; (C Denkert et al., Cancer Letters 195(1), 2003 p.p. 101-109 and references listed there).

The compounds of formula I may contain asymmetrically substituted (chiral) carbon atoms and carbon-carbon double bond, which may lead the to the formation of isomeric forms, for example, enantiomers, diastereomers and geometric isomers. The present invention relates to all such isomers both in pure form and as mixtures thereof. Clean stereoisomeric form compounds and intermediate compounds according to the invention can be obtained using methods known in this field. The diastereomers can be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, the enantiomers can be separated by chromatographic methods using chiral stationary phases. These pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting compounds, provided that the interaction occurs stereoselective or stereospecific. If you need a specific stereoisomer, preferably, the specified connection synthesize stereoselective or stereospecific methods of getting. In these methods, it is preferable to use pure chiral starting materials. Like the e way pure geometric isomers can be obtained from the corresponding pure geometric isomers of suitable starting compounds. A mixture of geometric isomers usually exhibits different physical properties, and they can, therefore, be separated by standard methods, chromatography, well known in this field.

Preferred variants of the compounds of formula I

In the present invention according to a preferred variant of the compounds of formula I, R1can be a halogen, trifluoromethyl, C1-4alkyl, C1-4alkoxy or nitro. In particular, R1may be a methyl, ethyl, methoxy, ethoxy, bromine, fluorine or chlorine.

According to another preferred variant of the compounds of formula I, R2can represent hydrogen, halogen, amino, C1-4alkyl or C1-4alkoxy. In particular, R2can represent hydrogen, methyl, ethyl, methoxy, ethoxy, bromine, fluorine or chlorine.

According to another preferred variant of the compounds of formula I, R3can represent hydrogen, halogen, C1-4alkyl or C1-4alkoxy. In particular, R3can represent hydrogen, methyl, ethyl, methoxy, ethoxy, bromine, fluorine or chlorine.

According to another preferred variant of the compounds of formula I, R3represents one Deputy. the particular R3may be in the meta-position relative to R4and in the para-position relative to the-NH, or R3may be in the meta-position relative to R4and in ortho-position to the-NH, or R3may be in ortho-position to the R4and in meta-position to the-NH.

According to another preferred variant of the compounds of formula I, one of R3and R4can represent fluorine.

According to another preferred variant of the compounds of formula I, Y1can represent-O-, -NRa-, -NRaC(O)NRb-, -NRaC(O)-, -C(O)NRa-, -NRaC(O)O - or-NRaS(O)2-.

According to another preferred variant of the compounds of formula I, R8can be a C1-4alkyl, C2-4alkenyl, C2-4quinil, C3-6carbocyclic or C1-6heterocyclyl.

According to another preferred variant of the compounds of formula I, R4can be a C1-4alkyl, amino, halogen, nitro, -NHC(O)O-C1-4alkyl, -NHC(O)C1-4alkyl, -NHC(O)-C1-4alkyl-COOH, -NHC(O)NH-C1-4alkyl-OH, -CH=CH-C1-4alkyl-NH2, -NHC(O)NH-C1-4alkyl, -NHC(O)NH-C1-6cycloalkyl, -NHC(O)CF3or-NHC(O)O-C1-6cycloalkyl. In particular, R4may be a methyl, ethyl, amino, bromine, fluorine, chlorine, 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.

According to another preferred variant of the compounds of formula I, R7can be a halogen, hydroxy, amino, -S(O)2CH3, trifluoromethyl, cyano, C1-4hydroxyalkyl, C1-4alkoxy, C1-4alkyl, C1-4alkylthio, C1-4alkylamino, C1-4alkoxycarbonyl, -COOH, -CONH2, -S(O)2NH2azido, -CONR' or-CONRR', where R and R' have the values specified above. In particular, R7may be a methyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl, etoxycarbonyl, dimethylamino, acylamino, amino, -COOH, fluorine, chlorine, bromine, -CONH2, -S(O)2NH2azido, methylthio, -S(O)2CH3, trifluoromethyl, cyano or hydroxymethyl.

According to another preferred variant of the compounds of formula I, one of R5and R6can represent Y2R9C1-4alkyl-Y2R9, Y2R9Y3R10C1-4alkyl-Y2R9Y3R10C2-4alkenyl-Y2R9C2-4alkenyl-Y2R9Y3R10, Y2R9-C1-4-alkyl-Y3R10, Y2R9-C2-4alkenyl-Y3R10C1-6heterocyclyl-C1-4alkyl-Y2R C1-4alkyl-C1-6heterocyclyl, C1-4alkyl-C3-6carbocyclic, C3-6carbocyclic-C1-4alkyl, C1-4alkyl, substituted R7C2-4alkenyl, C2-4quinil, C3-6carbocyclic, C1-6heterocyclyl, -COOH, -C(O)NHOH or-C(O)NHNH2and another may be a hydrogen, halogen, C1-4alkyl or C1-4alkoxy. In particular, R5can represent Y2R9C1-4alkyl-Y2R9, Y2R9Y3R10C1-4alkyl-Y2R9Y3R10C2-4alkenyl-Y2R9C2-4alkenyl-Y2R9Y3R10, Y2R9-C1-4-alkyl-Y3R10, Y2R9-C2-4alkenyl-Y3R10C1-6heterocyclyl-C1-4alkyl-Y2R9C1-4alkyl-C1-6heterocyclyl, C1-4alkyl-C3-6carbocyclic, C3-6carbocyclic-C1-4alkyl, C1-4alkyl, substituted R7C2-4alkenyl, C2-4quinil, C3-6carbocyclic, C1-6heterocyclyl, -COOH, -C(O)NHOH or-C(O)NHNH2and R6represents hydrogen, halogen, C1-4alkyl or C1-4alkoxy. In particular, R5and R6is a Y2R9, Y2R9Y3R10, phenyl, were, methyl, propenyl, phenyl-Y2R9, methyl-Y2R9, tetr is angry ethinyl, triazole, thiadiazole, dihydrooxazolo, triazole-Y2R9, -COOH, -C(O)NHOH or-C(O)NHNH2and the other represents hydrogen, fluorine, chlorine, methyl or methoxy.

According to another preferred variant of the compounds of formula I, R5represents hydrogen.

According to another preferred variant of the compounds of formula I, R6represents hydrogen.

According to another preferred variant of the compounds of formula I, when R2represents hydrogen and one of R5or R6does not represent hydrogen or optionally substituted C3-18heterocyclyl, C1-7alkyl, C2-7alkenyl, C2-7quinil or C1-7alkoxy)specified in the optional substituent (C3-18heterocyclyl, C1-7alkyl, C2-7alkenyl, C2-7quinil or C1-7alkoxy) represents a C3-18heterocyclyl, C1-7alkyl, C2-7alkenyl, C2-7quinil or C1-7alkoxy, optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C1-7of alkyl, C1-7alkoxy, C3-18heterocyclyl or-NRxRywhere Rxand Ryindependently represent hydrogen or C1-7alkyl,

where last-mentioned substituents C1-7alkyl, C1-7alkoxy, C3-18heterocyclyl or-NRxRy/sub> can be further substituted by one or more substituents, independently selected from halogen, hydroxy, cyano, C1-7of alkyl, C1-7alkoxy, C3-18heterocyclyl or-NRxRywhere Rxand Ryhave the values specified above.

According to another preferred variant of the compounds of formula I, Y2can represent-O-, -NRa-, -NRaC(O)NRb-, -NRaC(O)-, -C(O)NRa-, -C(O)NRaO-, -C(O)-, -NRaC(O)O-, -NRaS(O)2-, -C(O)NRaNRb- or-S(O)2NRa-.

According to another preferred variant of the compounds of formula I, Y3can represent-O-, -NRaC(O)-, -C(O)NRa-, -C(O)-, -C(O)O - or-NRaC(O)O-.

According to another preferred variant of the compounds of formula I, R9can be a C1-4alkyl-C1-6heterocyclyl, C1-4alkyl-C3-6carbocyclic, C1-6alkyl, C2-4alkenyl, C2-4quinil, C3-10carbocyclic, C1-6heterocyclyl, C3-6carbocyclic-C1-6alkyl, C1-6heterocyclyl-C1-6alkyl, C3-6carbocyclic-C2-4alkenyl or C3-6carbocyclic-C2-4quinil. In particular, R9can be a C1-4heterocyclyl, C1-6alkyl, C1-3alkyl-C1-3heterocyclyl, C6-10carbocyclic, C1-3alkyl-C6carbocyclic,3alkenyl, 6carbocyclic-C1alkyl, C6carbocyclic-C3alkenyl or6carbocyclic-C2quinil. In particular, R9can be a C1-4heterocyclyl, C1-6alkyl, C1-3alkyl-C1-5heterocyclyl, C6-10carbocyclic, C1-3alkyl-C6carbocyclic,3alkenyl,6carbocyclic-C1alkyl, C6carbocyclic-C3alkenyl or6carbocyclic-C2quinil. More specifically, R9may be morpholinyl, propylsulfonyl, piperazinil, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, hexyl, isopropyl, dimethylpropyl, methyltetrahydrofuran, methylpyridine, ethylpiperazine, cyclohexyl, propylaminoethyl, benzyl, methylcyclohexyl, propylphenyl, ethylphenyl, ethylmorpholine, allyl, ethylphenyl, phenyl, methyldeoxycytidine, dioxotetrahydrofuran, thiazolyl, were, ethylphenyl, methyldienolone, methylthiazolyl, propylphenyl, methylfuran, thiophenyl, tetrahydropyranyl or ethynylphenyl.

According to another preferred variant of the compounds of formula I, R10can be a C1-4alkyl, C2-4alkenyl, C3-6carbocyclic or C1-6heterocyclyl. In particular, R10may be a methyl, ethyl methacrylate, tert-butyl, tetrahydropyranyl or ethynyl.

On another one of the preferred variant of the compounds of formula I, the heterocycle or heterocyclyl, as described above, may contain one or two oxygen atom or one sulfur atom, and/or up to two nitrogen atoms, or three or four nitrogen atom, where optionally one or two CH2fragment rings replaced/substituted by one or two-C(O)-fragments, respectively.

According to another preferred variant of the compounds of formula I, Ra, Rbor Rcindependently represent hydrogen, methyl, ethyl, 2-hydroxyethyl or 2-methoxyethyl.

Specific examples of compounds of formula I may be selected from the group including

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-5-(morpholine-4-carbonyl)phenyl]metano (compound 101),

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-5-(4-methylpiperazin-1-carbonyl)phenyl]metano (compound 102),

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-N-methoxy-4,N-dimethylbenzamide (compound 103),

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

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

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-N-(2-methoxyethyl)-4-methylbenzamide (compound 106),

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-(3-morpholine-4-ylpropyl)benzamide (compound (107),

[2-Chloro-4-(4-fluoro-2-methylphen the laminitis)phenyl]-{5-[4-(2-methoxyethyl)piperazine-1-carbonyl]-2-were}mechanon (compound 108),

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-pyridin-4-ylmethylene (compound 109),

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-pyridin-2-ylmethylene (compound 110),

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-pyridin-3-ylmethylene (compound 111),

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

3-[4-(2-Amino-4-brompheniramine)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 113),

3-[4-(4-Bromo-2-methylphenylimino)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 114),

3-[2-Chloro-4-(2,4-dipertanyakan)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-methylphenylimino)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 119),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 120),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4,N-dimethylbenzamide (compound 121),

Ethyl ester of (2-{3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}acetylamino)acetic acid (compound 122),

E. the silt ether {3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}acetic acid (compound 123),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2-methoxyethyl)-4-methylbenzamide (compound 124),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-cyclohexyl-4-methylbenzamide (compound 125),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-ethyl-4-methylbenzamide (compound 126),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(6-hydroxyhexyl)-4-methylbenzamide (compound 127),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-isopropyl-4-methylbenzamide (compound 128),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-isobutyl-4-methylbenzamide (compound 129),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2,2-dimethylpropyl)-4-methylbenzamide (compound 130),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(3-methoxypropyl)-4-methylbenzamide (compound 131),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methyl-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide (compound 132),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2-dimethylaminoethyl)-4-methylbenzamide (compound 133),

2-{3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}ethyl ester 2-methylacrylate acid (compound 134),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-CIS-(4-hydroxycyclohexyl)-4-methylbenzamide (compound 135),

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-TRANS-(4-hydroxycyclohexyl)-4-methylbenzamide (compound 136),

Tert-butyl ether (2-{3-[2-chloro-4-(4-chloro-2-fluoro what enylamine)benzoyl]-4-methylbenzylamino}ethyl) - carbamino acid (compound 137),

N-(2-amino-ethyl)-3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzamide (compound 138),

(2-{3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}acetylamino)acetic acid (compound 139),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 140),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2,2-dottorati)-4-methoxybenzamide (compound 141),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-foradil)-4-methoxybenzamide (compound 142),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 143),

N-Carbamoylmethyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzamide (compound 144),

N-Carbamoylmethyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 145),

N-Benzyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 146),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-foradil)-4-methylbenzamide (compound 147),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2,2,2-triptorelin)benzamide (compound 148),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-ethyl-4-methylbenzamide (compound 149),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-cyclohexylmethyl-4-methylbenzamide (compound 150),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxypropyl)-4-methylbenzamide (compound 151),

3-[2-Chloro-4-(2,4-diphthera is Ino)benzoyl]-N-(2,3-dihydroxypropyl)-4-methylbenzamide (compound 152),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(1-hydroxymethylpropane)-4-methylbenzamide (compound 153),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2,2,3,3,3-pentafluoropropyl)benzamide (compound 154),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(3-hydroxypropyl)-4-methylbenzamide (compound 155),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxy-1,1-dimethylethyl)-4-methylbenzamide (compound 156),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxy-1-hydroxymethyl-1-methylethyl)-4-methylbenzamide (compound 157),

Ethyl ester {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}acetic acid (compound 158),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(4-hydroxybutyl)-4-methylbenzamide (compound 159),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(3-hydroxy-1,1-dimethylbutyl)-4-methylbenzamide (compound 160),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(3-phenylpropyl)benzamide (compound 161),

(R)-3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(1-hydroxymethyl-3-methylbutyl)-4-methylbenzamide (compound 162),

3-[4-(2,4-Dipertanyakan)benzoyl]-N-(2-foradil)-4-methylbenzamide (compound 163),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-isopropyl-4-methylbenzamide (compound 164),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-cyclohexyl-4-methylbenzamide (compound 165),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2,2-diferet the l)-4-methylbenzamide (compound 166),

Methyl ester 5-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}-4-oxopentanoic acid (compound 167),

N-[(2-Carbamoylation)methyl]-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 168),

Ethyl ester of (2-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}acetylamino)acetic acid (compound 169),

N-Allyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 170),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2-sulphatoethyl)benzamide (compound 171),

N-(2-Acetylamino)-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 172),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 173),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-foradil)-4-methoxybenzamide (compound 174),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 175),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(3-hydroxypropyl)-4-methoxybenzamide (compound 176),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxy-N-penicillinase (compound 177),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxy-1,1-dimethylethyl)-4-methoxybenzamide (compound 178),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxy-N-(2-morpholine-4-retil)benzamide (compound 179),

3-[2-Chloro-4-(2,6-differeniate is about)benzoyl]-N-(2-hydroxy-1-hydroxymethyl-1-methylethyl)-4-methoxybenzamide (compound 180),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methoxy-N-methylbenzamide (compound 181),

Ethyl ester {3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzylamine}acetic acid (compound 182),

Ethyl ester of (2-{3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzylamine}acetylamino)acetic acid (compound 183),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N,N-bis-(2-hydroxyethyl)-4-methoxybenzamide (compound 184),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxy-N,N-bis-(2-methoxyethyl)benzamide (compound 185),

3-[2-Chloro-4-(3-fluoro-2-methylphenylimino)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 186),

3-[2-Chloro-4-(3-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-(2,2,2-triptorelin)benzamide (compound 187),

3-[2-Chloro-4-(2-chloro-4-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 188),

3-[2-Chloro-4-(2-chloro-4-forgenerating)benzoyl]-4-methyl-N-(2,2,2-triptorelin)benzamide (compound 189),

3-[2-Chloro-4-(4-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 190),

3-(2-Chloro-4-phenyliminomethyl)-N-(2-hydroxyethyl)-4-methylbenzamide (compound 191),

3-[2-Chloro-4-(3,5-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 192),

3-[2-Chloro-4-(3-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 193),

3-[2-Chloro-4-(4-forgenerating)benzoyl]-N-(2-hydroxide is)-4-methoxybenzamide (compound 194),

3-(2-Chloro-4-phenyliminomethyl)-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 195),

3-[2-Chloro-4-(4-forgenerating)benzoyl]-N-(2,2-dottorati)-4-methoxybenzamide (compound 196),

3-[2-Chloro-4-(4-forgenerating)benzoyl]-N-(2-foradil)-4-methoxybenzamide (compound 197),

3-[2-Chloro-4-(4-forgenerating)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 198),

N-Carbamoylmethyl-3-[2-chloro-4-(4-forgenerating)benzoyl]-4-methoxybenzamide (compound 199),

3-(2-Chloro-4-phenyliminomethyl)-N-(2,2-dottorati)-4-methoxybenzamide (compound 200),

3-(2-Chloro-4-phenyliminomethyl)-N-(2-foradil)-4-methoxybenzamide (compound 201),

3-(2-Chloro-4-phenyliminomethyl)-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 202),

N-Carbamoylmethyl-3-(2-chloro-4-phenyliminomethyl)-4-methoxybenzamide (compound 203),

4-Chloro-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)benzamide (compound 204),

Ethyl ester of (2-{3-chloro-4-[5-(2-hydrooximethylcarbamil)-2-methylbenzoyl]phenylamino}phenyl)carbamino acid (compound 205),

3-[2-Chloro-4-(2-propionylcarnitine)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 206),

3-[4-(2-Acetylaminofluorene)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 207),

N-(2-{3-Chloro-4-[5-(2-hydrooximethylcarbamil)-2-methylbenzoyl]phenylamino}phenyl)monoamide succinic acid (compound 208),

3-(2-Chloro-4-{2-[-(2-hydroxyethyl)ureido]phenylamino}benzoyl)-N-(2-hydroxyethyl)-4-methylbenzamide (compound 209),

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-4-(morpholine-4-carbonyl)phenyl]metano (compound 210),

[4-(2-Aminophenylamino)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 211),

[4-(2-Aminophenylamino)-2-chlorophenyl]-[4-(2-hydroxyethoxy)-2-were]metano (compound 212),

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 213),

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-[4-(2-hydroxyethoxy)-2-were]metano (compound 214),

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-{2-methyl-4-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}mechanon (compound 215),

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-[4-(3-hydroxypropoxy)-2-were]metano (compound 216),

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-[4-(2-floratone)-2-were]metano (compound 217),

[4-(4-Bromo-2-methylphenylimino)-2-chlorophenyl]-[4-(2-floratone)-2-were]metano (compound 218),

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-[4-(2-methoxyethoxy)-2-were]metano (compound 219),

[4-(4-Bromo-2-methylphenylimino)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 220),

[4-(4-Bromo-2-methylphenylimino)-2-chlorophenyl]-[4-(2-hydroxyethoxy)-2-were]metano (compound 221),

[4-(2-Azidoethoxy)-2-were]-[4-(4-bromo-2-methylphenylimino)-2-chlorophenyl]m is the Thanon beach (compound 222),

[4-(2-Aminoethoxy)-2-were]-[4-(4-bromo-2-methylphenylimino)-2-chlorophenyl]metano (compound 223),

[4-(2-Brompheniramine)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 224),

{4-[2-(3-Aminopropyl)phenylamino]-2-chlorophenyl}-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 225),

{4-[2-(3-Aminopropyl)phenylamino]-2-chlorophenyl}-[4-(2-hydroxyethoxy)-2-were]metano (compound 226),

1-(2-{3-Chloro-4-[4-(2-hydroxyethoxy)-2-methylbenzoyl]phenylamino}phenyl)-3-atilmotin (compound 227),

1-[5-Bromo-2-(3-chloro-4-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]-3-atilmotin (compound 228),

1-(5-Bromo-2-{3-chloro-4-[4-(2-hydroxyethoxy)-2-methylbenzoyl]phenylamino}phenyl)-3-atilmotin (compound 229),

1-[5-Bromo-2-(3-chloro-4-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]-3-cyclohexylamine (compound 230),

1-[5-Bromo-2-(3-chloro-4-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]-3-(2-hydroxyethyl)urea (compound 231),

1-(5-Bromo-2-{3-chloro-4-[4-(2-hydroxyethoxy)-2-methylbenzoyl]phenylamino}phenyl)-3-(2-hydroxyethyl)urea (compound 232),

N-[5-Bromo-2-(3-chloro-4-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]monoamide succinic acid (compound 233),

(4 Allyloxy-2-were)-[4-(2-amino-4-brompheniramine)-2 is arvanil]metano (compound 234),

N-{2-[4-(4-Allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}ndimethylacetamide (compound 235),

1-{2-[4-(4-Allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}-3-atilmotin (compound 236),

Ethyl ether {2-[4-(4-allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}carbamino acid (compound 237),

N-{2-[4-(4-Allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}-2,2,2-triptorelin (compound 238),

N-{2-[4-(4-Allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}monoamide succinic acid (compound 239),

Cyclopentyloxy ether {2-[4-(4-allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}carbamino acid (compound 240),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-methoxypropionate (compound 241),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}propionamide (compound 242),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-2-(2-methoxyethoxy)ndimethylacetamide (compound 243),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-morpholine-4-ylpropionic (compound 244),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-hydroxypropionate (compound 245),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-furan-2-ylpropionic (compound 246),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-2-hydroxybenzamide (compound 247),

N-{3-[2-Chloro-4-(2,4-gift is freilino)benzoyl]-4-were}-2-(2,5-dioxoimidazolidin-4-yl)ndimethylacetamide (compound 248),

{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}amide and 2,6-dioxotetrahydrofuran-4-carboxylic acid (compound 249),

2-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylphenylcarbinol}ethyl ester of acrylic acid (compound 250),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-methylsulfinylpropyl (compound 251),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-methanesulfonamide (compound 252),

{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}amide econsultancy acid (compound 253),

N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-4-methoxybenzenesulfonamide (compound 254),

N-(5-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylphenylsulfonyl}-4-methylthiazole-2-yl)ndimethylacetamide (compound 255),

5-Acetyl-2-chloro-N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}benzosulfimide (compound 256),

{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl)-4-were}amide naphthalene-2-sulfonic acid (compound 257),

N-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-C phenylmethanesulfonyl (compound 258),

2-(3-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)ethyl ester 2-methylacrylate acid (compound 259),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(2-hydroxyethyl)urea (compound 260),

Ethyl ester of (3-{3-[2-PI is R-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)acetic acid (compound 261),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(3-methoxyphenyl)urea (compound 262),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(3-triptoreline)urea (compound 263),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-proprotein (compound 264),

Ethyl ester of 3-(3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)propionic acid (compound 265),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-cyclohexylamine (compound 266),

1-Allyl-3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}urea (compound 267),

1-Benzyl-3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}urea (compound 268),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-atilmotin (compound 269),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-phenylacetone (compound 270),

1-Butyl-3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}urea (compound 271),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-phenethylamine (compound 272),

Methyl ester of 2-(3-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)benzoic acid (compound 273),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(3-cyanophenyl)urea(compound 274),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-isoprop lochaven (compound 275),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(4-methoxyphenyl)urea (compound 276),

Benzyl ether of {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 277),

Allyl ether {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 278),

Ethyl ester {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 279),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[5-(3-hydroxyethylamino)-2-were]metano (compound 281),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(3'-hydroxymethyl-4-methylbiphenyl-3-yl)methanon (compound 282),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(3'-hydroxy-4-methylbiphenyl-3-yl)methanon (compound 283),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(4'-methoxy-4-methylbiphenyl-3-yl)methanon (compound 284),

N-{3'-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4'-methylbiphenyl-3-yl}ndimethylacetamide (compound 285),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(4-methyl-3'-cryptomaterial-3-yl)methanon (compound 286),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(3',4',5'-Cryptor-4-methylbiphenyl-3-yl)methanon (compound 288),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(3',4'-dimethoxy-4-methylbiphenyl-3-yl)methanon (289),

3'-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4'-methylbiphenyl-3-carbonitrile (compound 290),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydrox is ethyl)-4-methylbenzenesulfonamide (compound 291),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2-morpholine-4-retil)benzosulfimide (compound 292),

N-Allyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzenesulfonamide (compound 293),

N-(2-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzenesulfonamide}ethyl)ndimethylacetamide (compound 294),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-propylbenzenesulfonyl (compound 295),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methylbenzenesulfonamide (compound 296),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-methoxyethyl)-4-methylbenzenesulfonamide (compound 297),

[4-(4-Fluoro-2-methylphenylimino)-2-nitrophenyl]-[5-(4-methoxybenzyloxy)-2-were]metano (compound 298),

[4-(4-Fluoro-2-methylphenylimino)-2-nitrophenyl]-[5-(3-hydroxypropoxy)-2-were]metano (compound 299),

[2-Amino-4-(4-fluoro-2-methylphenylimino)phenyl]-[5-(3-hydroxypropoxy)-2-were]metano (compound 300),

[5-(2,2-Dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-were]-[4-(4-fluoro-2-methylphenylimino)-2-nitrophenyl]metano (compound 301),

[5-(2,3-Dihydroxypropane)-2-were]-[4-(4-fluoro-2-methylphenylimino)-2-nitrophenyl]metano (compound 302),

[2-Amino-4-(4-fluoro-2-methylphenylimino)phenyl]-[5-(2,3-dihydroxypropane)-2-were]metano (compound 303),

[4-(4-Fluoro-2-methylphenylimino)-2-nitrophenyl]-[2-methyl-5-(2-morpholine-4-ylethoxy)FeNi is]metano (compound 304),

[2-Amino-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 305),

[4-(2,4-Dipertanyakan)-2-nitrophenyl]-[5-(4-methoxybenzyloxy)-2-were]metano (compound 306),

[4-(2,4-Dipertanyakan)-2-nitrophenyl]-[5-(3-hydroxypropoxy)-2-were]metano (compound 307),

[2-Amino-4-(2,4-dipertanyakan)phenyl]-[5-(3-hydroxypropoxy)-2-were]metano (compound 308),

[4-(2,4-Dipertanyakan)-2-nitrophenyl]-[2-methyl-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 309),

[2-Amino-4-(2,4-dipertanyakan)phenyl]-[2-methyl-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 310),

[4-(2,4-Dipertanyakan)-2-nitrophenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-were]metano (compound 311),

[4-(2,4-Dipertanyakan)-2-nitrophenyl]-[5-(2,3-dihydroxypropane)-2-were]metano (compound 312),

[2-Amino-4-(2,4-dipertanyakan)phenyl]-[5-(2,3-dihydroxypropane)-2-were]metano (compound 313),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 314),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-forfinal]metano (compound 315),

[2-Chloro-4-(2,4-differentiability]-[5-(2,3-dihydroxypropane)-2-forfinal]metano (compound 316),

2-{3-[2-Chloro-4-(4-chloro-2-methylphenylimino)benzoyl]-4-fervency}-N-methylacetamide (connected to the e 317),

[2-Chloro-4-(4-chloro-2-methylphenylimino)phenyl]-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 318),

2-{3-[2-Chloro-4-(4-chloro-2-methylphenylimino)benzoyl]-4-fervency}-N,N-dimethylacetamide (compound 319),

[2-Chloro-4-(4-chloro-2-methylphenylimino)phenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-forfinal]metano (compound 320),

[2-Chloro-4-(4-chloro-2-methylphenylimino)phenyl]-[5-(2,3-dihydroxypropane)-2-forfinal]metano (compound 321),

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 322),

[2-Chloro-4-(4-forgenerating)phenyl]-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 323),

[2-Chloro-4-(4-forgenerating)phenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-forfinal]metano (compound 324),

[2-Chloro-4-(2-chloro-4-forgenerating)phenyl-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 325),

[4-(2-Aminophenylamino)-2-chlorophenyl]-[5-(2,3-dihydroxypropane)-2-forfinal]metano (compound 326),

[4-(2-Aminophenylamino)-2-chlorophenyl]-[2-fluoro-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 327),

[2-Chloro-4-(2,6-dipertanyakan)phenyl]-[2-chloro-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 328),

(+)-[2-Chloro-4-(2,6-dipertanyakan)phenyl]-[2-chloro-5-(2,3-dihydroxypropane)phenyl]metano (compound 329),

[5-(3-Bromopropane)-2-chlorophenyl]-[2-chloro-4-(2,6-dipertanyakan)phenyl]metano (compound 330),

[2 the PRS-4-(2,4-dipertanyakan)phenyl]-(5-hydroxymethyl-2-were)methanon (compound 331),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(5-chloromethyl-2-were)methanon (compound 332),

(5-Azidomethyl-2-were)-[2-chloro-4-(2,4-dipertanyakan)phenyl]metano (compound 333),

(5-Aminomethyl-2-were)-[2-chloro-4-(2,4-dipertanyakan)phenyl]metano (compound 334),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-5-hydroxymethyl-2-methoxyphenyl)methanon (compound 335),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzyloxy ether acetic acid (compound 336),

N-tert-Butoxy-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzamide (compound 337),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-methoxy-4-methylbenzamide (compound 338),

N-Butoxy-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 339),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-cyclohexylmethoxy-4-methylbenzamide (compound 340),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2-methylthiazole-4-ylethoxy)benzamide (compound 341),

N-benzyloxy-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 342),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(4-methoxybenzyloxy)-4-methylbenzamide (compound 343),

N',N'-Dimethylhydrazide 3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoic acid (compound 344),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-morpholine-4-ylbenzene (compound 345),

3-[2-Chloro-4-(2,4-differenl the Mino)benzoyl]-N-hydroxy-4-methylbenzamide (compound 346),

4-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-3-methylbenzamide (compound 347),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[5-(3-hydroxypropyl)-2-were]metano (compound 348),

Methyl ester of 4-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}thiophene-3-carboxylic acid (compound 349),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-furan-2-ylmethyl-4-methylbenzamide (compound 350),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(3-methoxyphenyl)-4-methylbenzamide (compound 351),

Methyl ester 2-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}benzoic acid (compound 352),

Methyl ester of 3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}thiophene-2-carboxylic acid (compound 353),

4-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}thiophene-3-carboxylic acid (compound 354),

2-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}benzoic acid (compound 355),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-[2-(2-hydrooximethylcarbamil)phenyl]-4-methylbenzamide (compound 356),

(2-Hydroxyethyl)amide 3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}thiophene-2-carboxylic acid (compound 357),

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]metano (compound 358),

[4-(2-Aminophenylamino)-2-chlorophenyl]-(5-ethinyl--were)methanon (compound 359),

[4-(2-Aminophenylamino)-2-chlorophenyl]-(2-methyl-5-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-[1,2,3]-triazole-4-yl}phenyl)methanon (compound 360),

[4-(2-Aminophenylamino)-2-chlorophenyl]-5-[1-(2-hydroxyethyl)-1H-[1,2,3]-triazole-4-yl]-2-were}mechanon (compound 361),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(5-ethinyl-2-were)methanon (compound 362),

The hydrazide 3-[2-chloro-4-(4-forgenerating)benzoyl]-4-methylbenzoic acid (compound 363),

The hydrazide 3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoic acid (compound 364),

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoyl}-4-ethyl-3-thiosemicarbazide (compound 365),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[5-(5-ethylamino-[1,3,4]thiadiazole-2-yl)-2-were]metano (compound 366),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]metano (compound 367),

Ethyl ester of 3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-oxopropanoic acid (compound 368),

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[5-(4,5-dihydrooxazolo-2-yl)-2-were]metano (compound 369),

3-{2-Chloro-4-[2-(3-ethylurea)phenylamino]benzoyl}-N-(2-hydroxyethyl)-4-methylbenzamide (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-IU is ilfenomeno)-2-chlorobenzoyl]-4-methylbenzoic acid (compound 422),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoic acid (compound 424),

2-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}ethyl ester 2-methylacrylate acid (compound 425),

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

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzoic acid (compound 432),

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzoic acid (compound 437),

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzoic acid (compound 443),

3-[2-Chloro-4-(3-fluoro-2-methylphenylimino)benzoyl]-4-methylbenzoic acid (compound 446),

3-[2-Chloro-4-(2-chloro-4-forgenerating)benzoyl]-4-methylbenzoic acid (compound 449),

3-(2-Chloro-4-(4-forgenerating)benzoyl]-4-methoxybenzoic acid (compound 457),

3-(2-Chloro-4-phenyliminomethyl)-4-methoxybenzoic acid (compound 459),

[2-Chloro-4-(2-nitrophenylamino)phenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 472),

[4-(4-Bromo-2-nitrophenylamino)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 473),

[4-(4-Bromo-2-nitrophenylamino)-2-chlorophenyl]-2-{methyl-4-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}mechanon (compound 477),

[4-(4-Bromo-2-nitrophenylamino)-2-chlorophenyl]-[4-(2-floratone)-2-were]metano (compound 481)

[4-(4-Bromo-2-nitrophenylamino)-2-chlorophenyl]-[4-(2-methoxyethoxy)-2-were]metano (compound 485),

[2-Chloro-4-(2-nitrophenylamino)phenyl]-[2-fluoro-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 518),

[2-Chloro-4-(2-nitrophenylamino)phenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-forfinal]metano (compound 519) and

[2-Chloro-4-(2-nitrophenylamino)phenyl]-[5-(2,3-dihydroxypropane)-2-forfinal]metano (compound 520).

In addition to the definition of R4given above, provided that R4can mean the substituents contained in the definition of R6in WO 03/018535, the contents of which are fully incorporated by reference.

Additionally it is envisaged that the compounds of formula I can be N-substituted on the amino group between rings B and C of the structure of the nucleus, using the deputies, essentially as described in provisional application U.S. No. 60/434798, the contents of which are fully incorporated by reference.

Ways to get

Compounds of the present invention can be obtained in various ways, well known to experts in the field of organic synthesis. Compounds of the present invention can be synthesized using the methods described below, as well as methods known in the field of synthetic organic chemistry, or variations which are understandable to experts in this about the region. Preferred methods include the following, but not limited to.

The compounds of formula I can be obtained by using the reactions and techniques described in this section. The reaction is carried out in solvents which are appropriate for the used reagents and materials which are suitable for transformation. Also note that in the methods of synthesis described below, all the reaction conditions, including choice of solvent, atmosphere interaction, temperature interaction, the duration of the experiment and processing methods, selected as a standard reaction conditions, which can be easily determined by any person skilled in the art. Any specialist in the field of organic synthesis it is clear that the functional group present at different positions of the molecules used as the starting material or intermediates in the synthesis must be compatible with the alleged reagents and reactions. Not all compounds of formula I covered in this class may be compatible with some of the reaction conditions required for some of the described methods. Such restrictions substituents or functional groups that are compatible with the reaction conditions will be readily understood by any specialistov this area, and can be used in alternative methods.

Compounds of the present invention can be obtained by a process comprising a combination of an amine of formula III with a triflate or halide, such as bromide, iodide, fluoride, chloride, formula II, as shown in figure 1; or an alternative method, comprising the combination of an amine of the formula IIa with a triflate or halide, such as bromide or iodide of the formula IIIa, as shown in figure 1; where R1, R2, R3, R4, R5and R6are as defined above; however, any Deputy or functional group, which is potentially reactive in the reaction combinations that can be protected prior to the reaction mixture, and then the protective groups are removed.

L: Br, I, OSO2CF3or F and Cl (in specific cases, for example, when R'4represents the EWG, as NO2)

W: Br, I, or OSO2CF3

FGI: interconversion of functional groups

R'1, R'2, R'3, R'4, R'5and R'6match the R1, R2, R3, R4, R5and R6, respectively, or any suitable FG (functional group)that can be converted to R1, R2, R3, R4, R5and R6

Scheme 1

The reaction mix is syshestvyut using the method of obtaining diphenylamino, well known to any expert in the field of organic synthesis. The preferred method is the method of amination catalyzed by palladium, which includes a combination of an amine with arylhalides (or aritifical) in the presence of a base, a suitable source of Pd and a suitable phosphine ligand in an inert solvent.

This method can be used for various palladium compounds, non-limiting examples are palladium(II)acetate, palladium(II)chloride, bromide, palladium(II), dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)dipalladium(0). Preferred phosphine ligands include, but are not limited to, racemic or narozeniny 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as BINAP), tri-o-tolylphosphino, three-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, bis[(2-diphenylphosphino)phenyl]ether (DPEphos), 2-dicyclohexylphosphino-2'-dimethylaminophenyl, 2-(di-tert-butylphosphino)biphenyl and 9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene (Xantphos). The amount of palladium and ligand used in this catalytic method may typically be in the range from 0.1 to 10 mol.% relative to the number of aromatic halide (or triflate). In particular, it was shown that tert-piperonyl sodium (NaOt-Bu) and the carbonate is Asia (Cs 2CO3) are the preferred bases in this method, however, can also be used and other grounds. The reaction is usually carried out at elevated temperatures (80-120°C) in inert solvents such as 1,4-dioxane, toluene, benzene, and tetrahydrofuran, in an inert atmosphere, e.g. argon or nitrogen.

When R'4represents an electron-withdrawing group (EWG)such as nitro or cyano, the above combination can be done not catalytically in the presence of strong bases such as tert-piperonyl potassium or sodium. The reaction is usually carried out at room temperature or above (20-200°C) in an aprotic solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) or N-methylpyrrolidinone (NMP) in an inert atmosphere, e.g. argon or nitrogen.

Compounds of General formula III according to the present invention can be obtained by several methods known to experts in the field of organic synthesis. One of the used sequence of reactions shown in scheme 2. Key stage includes a combination of a halide, preferably iodide or bromide of the formula VI with an acid chloride of the acid of General formula V and obtaining benzophenone of the General formula IV. Benzophenone IV can then be restored to the corresponding amine of General formula III by treatment standard in osstanavlivayuschie agents. Examples of such reducing agents include, but are not limited to, chloride dihydrate tin, hydrogen, formate, ammonium or hydrazinehydrate and a catalytic amount of palladium on coal. The reaction mix can be done by converting the halide (VI) reactive ORGANOMETALLIC intermediate connection, for example, by treatment with isopropylacrylamide, to obtain the corresponding derivative of magnesium, or the processing of n-butyllithium to obtain the corresponding derivative of lithium.

Hal: I or Br

FGI: interconversion of functional groups

R'1, R'2, R'5and R6match the R1, R2, R5and R6, respectively, or any suitable FG (functional group)that can be converted to R1, R2, R5and R6.

Scheme 2

Reactivity of this ORGANOMETALLIC intermediate is further modified by Parametrierung, for example, zinc, processing ZnCl2, ZnBr2or ZnI2. Then it tsinkorganicheskih connection associated with galogenangidridy, such as the acid chloride of General formula V, in the presence or catalytic amount of a complex of palladium(0). Examples of such palladium catalysts include, but are not ogranichivayutsya, tetrakis(triphenylphosphine)palladium(0), tetrakis(triphenylarsine)palladium(0), dichlorobis(triphenylphosphine)palladium(II) or benzylchloride(triphenylphosphine)palladium(II). Alternatively, tsinkorganicheskih connection associated with galogenangidridy, such as the acid chloride, of General formula V, in the presence or indirectly, equimolar or nearly stoichiometric or catalytic amounts (relative to V), such as 0.1 to 99 mol.%, for example, 0.5 to 10 mol.%, for example, 1-5 mol.%, for example, 2-3 mol.% salts of copper (I) or (II), such as copper acetate (II) or soluble complex CuCN·2LiCl or CuCN·2LiBr. The reaction mix is usually carried out at room temperature in inert solvents such as 1,4-dioxane, toluene, benzene, and tetrahydrofuran, in an inert atmosphere, for example, in an atmosphere of argon or nitrogen.

Compounds of General formula IIIa according to the present invention can be obtained by methods similar to the methods of cross combinations involving zinc, as shown in figure 3.

Hal: I or Br

FGI: vzaimoprevrascheny functional groups

R'1, R'2, R'5and R'6replaces R1, R2, R5and R6respectively, or any suitable FG (functional group)that can be converted to R1, R2, R5and R6.

Scheme 3

Connection of infusion is he to the invention may in particular cases be obtained by a simple interconversion of functional groups (FGI), that is the standard, well-known specialists in the field of organic synthesis, where the functional group in compounds of General formula I or I' is converted into another functional group in one or several stages of the synthesis, to obtain the new compounds of General formula I. Examples of such methods include, but are not limited to, hydrolysis of esters with getting acid in basic conditions, the removal of the protective methyl ester groups with the formation of phenol by treatment with, for example, tribromide boron (BBr3), and catalytic hydrogenation of the olefin with getting saturated hydrocarbon. Non-limiting examples of such transformations are described in "Comprehensive Organic Transformations", R.C. Larock, VCH 1989, which is incorporated into the description by reference, and in General ways. In particular, the use of conventional protective groups in one or more stages of the synthesis can be useful for synthesis of compounds of General formula I. Examples of such conventional protective groups include, but are not limited to, methyl, ethyl, tert-butylene or benzyl esters as a protective group of the hydroxy-group; a simple tetrahydropyranyloxy or Silovye ethers as protective groups of hydroxy group.

As shown in schemes 2 and 3, each of the intermediate compound can be converted by way FGI, as described is use, to obtain a new connection with the same General formula (for example, the hydroxy-group can be protected as tert-butyldimethylsilyl ether). This example is provided only to illustrate possible modifications of the synthesis, and, in General, described the sequence of methods is only one of many possible ways of synthesis of compounds of the present invention. That is, it may be preferable in some cases to change the sequence of processes described above. The described sequence of processes is not considered as limiting the formation of compounds of the present invention of General formula I, and changing the reaction sequence may be an obvious alternative for the specialist in the field of organic synthesis. This aspect of the invention may be particularly useful in the synthesis of compounds with different substituents in the R4, R5and R6groups. Easily accessible intermediate compounds can serve as a starting point for the synthesis of various groups of compounds covered by the General formula I.

The pharmaceutical composition

In another aspect the invention relates to pharmaceutical compositions containing as an active ingredient a compound of the formula I together with pharmaceutically acceptable excipients, media or what ispolnitelem. Further, the invention relates to the use of compounds of formula I when receiving medicines to prevent, cure or ameliorate the intensity of inflammatory diseases or conditions.

The pharmaceutical compositions according to the invention can be in the form of standard dosage forms, such as tablets, pills, capsules, powders, granules, elixirs, syrups, emulsions, capsules, suppositories or parenteral solutions or suspensions; for oral, parenteral, ocular, dermal, intra-articular, local, pulmonary, nasal, buccal or rectal injection or any other method suitable for the preparation of anti-inflammatory compounds, and in accordance with accepted practice, such as described in Remington: The Science and Practice of Pharmacy, 19thEd., Mack Publishing Company, 1995. In the composition according to the invention, the active ingredient may be present in an amount of from about 0.01 to about 99%, for example, from 0.1% to about 10% by weight of the composition.

For oral administration in the form of tablets or capsules, the compound of the formula I can be appropriately combined with oral non-toxic pharmaceutically acceptable carrier, such as ethanol, glycerol, water or the like. Moreover, if appropriate, to the mixture may be added suitable binders, lubricants,loosening substances, fragrances and dyes. Suitable binders include, for example, lactose, glucose, starch, gelatin, Arabic gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, or the like. Lubricants include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like. Loosening substances include, for example, starch, methylcellulose, agar, bentonite, xanthan resin or the like. Additional excipients for capsules include macrogol or lipids.

For solid compositions such as tablets, the active compound of formula I is mixed with one or more excipients, such as described above, and other pharmaceutical diluents, such as water, to obtain a solid composition of the preliminary preparation containing a homogeneous mixture of the compounds of formula I. the Term "homogeneous" means that the compound of formula I is uniformly dispersed throughout the composition so that the composition could be easily divided into equally effective unit dosage forms such as tablets or capsules. Then the composition of the preliminary preparation may be divided into unit dosage forms containing from about 0.05 to about 1000 mg, frequent in the spine, from about 0.1 to about 500 mg of the active compounds according to the invention.

Liquid preparations for oral or parenteral administration of the compounds according to the invention include, for example, aqueous solutions, syrups, aqueous or oil suspensions and emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic or natural resins, such as tragakant, alginate, gum Arabic, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polivinilpirolidon.

For parenteral administration, for example, intramuscular, intraperitoneal, subcutaneous or intravenous injection or infusion, the pharmaceutical composition preferably contains a compound of formula I dissolved or solubilization in a suitable pharmaceutically acceptable solvent. For parenteral administration, the composition according to the invention may include sterile aqueous or non-aqueous solvent, in particular water, saline, isotonic glucose solution, buffer solution or other solvent commonly used for parenteral administration of therapeutically active substances. The composition may be sterilized, for example, by filtration through inhibiting bacteria is iltr, adding sterilizing agents to the compositions, by irradiating the compositions, or by heating the compositions. Alternatively, the connection according to the invention can be presented in the form of sterile solid preparation, for example, a lyophilized powder, which is dissolved in sterile solvent immediately prior to use.

Composition intended for parenteral administration may additionally contain conventional additives, such as stabilizers, buffers or preservatives, for example, antioxidants, such as methylhydroxybenzoate or the like.

Compositions for rectal injection can be in the form of suppositories comprising the active ingredient and a carrier such as cocoa butter, or in the form of an enema.

Compositions suitable for intraarticular injection, can be in the form of a sterile aqueous preparation of the active component, which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal compositions or biodegradable polymer systems may also be used for delivery of the active component, as in intra-articular and eye introduction.

Compositions suitable for outdoor applications, including treatment of eye diseases include liquid or semi-liquid preparations such as liniments, lotions, gels, apt is the ikats, emulsion oil-in-water" or "water in oil", such as creams, ointments or pastes; or solutions or suspensions such as drops. For external use the connection formula I may generally be present in an amount of from 0.01 to 20% by weight of the composition, for example, from 0.1% to about 10%, but can also be present in an amount of up to 50% of the composition.

Preferably, the composition for the treatment of eye diseases can further comprise a cyclodextrin.

Compositions suitable for introduction into the nasal or buccal cavity or inhalation include powders, free flowing and sprayable compositions, such as aerosols and sprays. Such compositions may contain the compound of formula I in an amount of 0.01-20%, for example, 2% by weight of the composition.

The composition may further contain one or more other active ingredients commonly used in the treatment of various inflammatory diseases and conditions. Examples of such additional active ingredients can be selected from the group including glucocorticoids, vitamin D and vitamin D analogues, antihistamines, antagonists of platelet activating factor (PAF), anticholinergic agents, methylxanthines, β-adrenergic agents, COX-2 inhibitors, salicylates, indomethacin, flufenamic, naproxen, timelady, gold salts, penicillamine, and the coefficients, cholesterol-lowering in serum, retinoids, zinc salts and salicylazosulfapyridine.

The following aspect of the invention relates to a method of treating inflammatory diseases or conditions, or eye diseases or conditions, or cancer, the method comprising administration to the patient, if necessary, an effective amount of the compounds of formula I.

A suitable dose of a compound according to the invention will depend, among others, from the age and condition of the patient, the severity being treated with disease and other factors well known to practitioners. The connection may be administered either orally, parenterally or topically, depending on the different dosage regimen of doses, for example daily or weekly intervals. Usually a single dose is in the range from 0.01 to 400 mg/kg of body weight. The connection can be introduced in the form of a bolus (i.e. the total daily dose taken at one time) or single doses two or more times a day.

Inflammatory disease or condition, considered as the object of treatment using these compounds represent an inflammatory disease, where the modulation of the expression of cytokines and secretion may be mediated by MAP kinases, such as the above MAP kinase p38. Examples of inflammatory diseases or conditions, which, it is to suggest, mediated by MAP kinase selected from the group comprising asthma, arthritis, including rheumatoid arthritis and spondylarthritis, gout, atherosclerosis, inflammatory disease of the alimentary tract, Crohn's disease, neurological inflammation, inflammatory eye disease, proliferative and inflammatory skin diseases such as psoriasis, atopic dermatitis and acne, uveitis, sepsis, septic shock, and osteoporosis.

Treatment may also include the addition of one or more other anti-inflammatory active ingredients, such as glucocorticoids, vitamin D and vitamin D analogues, antihistamines, antagonists of platelet activating factor (PAF), anticholinergics, methylxanthines, β-adrenergic agents, COX-2 inhibitors, salicylates, indomethacin, flufenamic, naproxen, timelady, gold salts, penicillamine, agents, cholesterol-lowering in serum, retinoids, zinc salts and salicylazosulfapyridine. Introduction compounds of the present invention and other anti-inflammatory components may be either simultaneous or sequential.

Eye disease or condition, considered as the object of the treatment of these compounds include ocular disease or condition, which is non-infectious (e.g., allergic) conjunctivitis,Ericom, keratitis, uveitis, scleritis, episcleritis, sympathetic oftalmica, blepharitis or dry keratoconjunctivitis.

Pharmacological methods

To study the effectiveness of the compounds of the present invention in vitro, inhibition of the secretion of IL-1β and TNF-α were determined using the following method:

The cytokine production was measured in culture medium of lipopolysaccharide (LPS) - stimulated mononuclear cells of peripheral blood. Mononuclear cells were separated from human peripheral blood by fractionation Lymphoprep® (Nycomed, Norway) and suspended in RPMI 1640 (medium) fetal calf serum (FCS, 2%), at a concentration equal to 5×105cell/ml Cells were incubated in 24-cell tablet for tissue culture in 1 ml aliquot. The compounds were dissolved in dimethyl sulfoxide (DMSO, 10 mm) and diluted environment. Within 30 minutes the cells were added compounds were then added LPS (final concentration 1 mg/ml). Tablet incubated for 18 hours, and determined the concentration of IL-1β and TNF-α in the environment using solid-phase immunosorbent assay. Expected concentration of 50%inhibition (IC50for connections. The results are shown in table 1.

Table 1
Inhibition of the production of cytokines in vitro by the compounds according to the present invention
A concentration of 50%inhibition (IC50nm)
Connection # IL-1βTNF-α
The connection 1042,01,3
The connection 1062,01,0
Connection 1073,23,2
Connection 1094,03,2
The connection 1124,00,6
Connection 1134,01,8
The connection 1142,50,4
Connection 1151,30,3
The connection 1161,01,0
Connection 117 4,01,0
The connection 1182,22,0
Connection 1191,30,4
Connection 1202,72,0
Connection 1212,80,6
The connection 1220,50,2
Connection 1230,50,3
Connection 1262,80,6
Connection 1292,51,3
Connection 1313,21,3
Connection 1354,02,0
Connection 1364,02,0
The connection 1401,41,0
Connection 1410,90,6
Connection 1432,51,6
Connection 1441,00,6
Connection 1451,30,3
Connection 1472,50,8
Connection 1480,60,2
Connection 1491,60,5
Connection 1511,80,4
Connection 1522,80,6
Connection 1538,91,6
Connection 1543,22,5
Connection 1550,60,2
Connection 1564,50,9
Connection 1572,20,9
Connection 1580,60,2
Connection 1597,91,3
Connection 1632,52,5
Connection 1641,32,0
The connection 1660,50,4
Connection 1671,72,0
Connection 1682,52,5
Connection 1690,40,4
Connection 1703,22,5
Connection 1732,52,0
Connection 1743,22,0
Connection 1763,2 2,0
Connection 1786,31,6
Connection 1802,53,2
Connection 1828,92,2
Connection 1832,00,7
Connection 1860,80,5
Connection 1880,90,5
Connection 1900,60,3
Connection 1911,10,5
Connection 1934,02,5
Connection 1940,60,3
Connection 1952,21,0
Connection 1963,21,0
Connection 197 3,21,8
Connection 1981,10,4
Connection 2017,93,2
The connection 2025,02,0
Connection 2036,33,2
Connection 2411,10,3
Connection 2421,40,5
Connection 2432,81,3
Connection 2441,30,5
Connection 2453,50,9
Connection 2463,2
Connection 2475,61,4
Connection 2481,00,7
Compound 2491,61,1
Connection 2511,10,4
Connection 2520,60,6
Connection 2601,80,5
Connection 2612,21,0
Connection 2622,00,6
Connection 2631,6
Connection 2641,00,3
Connection 2651,00,3
Connection 2660,90,4
Compound 2670,40,2
Connection 2690,80,6
Connection 2711,00,4
Connection 2723,21,4
Connection 2755,00,3
Compound 2772,50,8
Connection 2781,30,6
Compound 2790,60,5
Connection 2825,60,6
Connection 2851,40,6
Connection 3142,8
Connection 3352,72,5
Connection 3365,02,0
Comparative compound a137,1
Comparative compound b6,36,3
Comparative connect the group c 326,3
Comparative compound d7,93,2
Comparative compound e6,33,2
Comparative compound f134,0

Comparative compound a: (4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone, the connection 156 is described in WO 98/32730.

Comparative compound b: 2'-[3-chloro-4-(2-methylbenzoyl)phenylamino]octanamide, connection 102 is described in WO 01/05746.

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

Comparative compound d: 1-ethyl-3-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-5-forfinal]urea, compound 114 is described in WO 01/05751.

Comparative compound e: 2,2,2-Cryptor-N-[2-[3-chloro-4-(2-methylbenzoyl)phenylamino]-5-forfinal]ndimethylacetamide, connection 102 is described in WO 01/05745.

Comparative compound f: 2-chloro-4-(3-fluoro-2-methylphenylimino)-2'-methylbenzophenone, the connection 131 is described in WO 01/42189.

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

Moreover, new derivatives of aminobenzophenone have unexpectedly favorable pharmacokinetic properties such as absorption and metabolic stability.

Analysis of MAP kinase p38α

Cell culture

Cells COS-1 (derived from a fibroblast-like cells of the kidney of the African green monkey, containing the T antigen of a wild type under control of the SV40 promoter) was obtained from ATCC (ATCC No. CRL-1650) and were grown in medium for growth (DMEM without phenol red, 10% FCS, 2 mm L-glutamine, 100 U penicillin and 100 μg streptomycin/ml) at 37°C in 5% CO2. Twice a week was carried out by the passage of cells through trypsinization (0.25% trypsin, 1 mm EDTA in PBS) and were split 1:10. The medium was changed every second or third day. Cell line regularly researched set of Mycoplasma PCR Primer (Stratagene) and it was found that there is no Mycoplasma. Environment for the cultivation of tissues, FCS, L-glutamine and penicillin and streptomycin were obtained from Bribco BRL, Gaithersburg, MD, USA.

Transient expression cells COS-1

On the first day of the cells COS-1 were cultivated in a Petri dish size 143 cm2with a density of 2×104cells/cm2environment for growth. On the second day, the cells were cotranslational 5 μg (total) experimental plasmid DNA expressing FAG-p38α and FLAG-MKK6(EE). Plasmids were introduced into cells COS-1 in medium without serum, using DOTAPTM(Boehringer-Mannheim, Mannheim, Germany). Plasmid DNA was obtained and was purified using the kit QIAGEN EndoToxin-free Maxiprep-500 (Hilden, Germany). Briefly, DNA and DOTAPTMmixed strictly 15 minutes at 37°C in CO2the incubator. Trasferire mixture then was transferred into a 15 ml Falcon tube and transferiram mixture was added to the medium for transfection (DMEM with L-glutamine and penicillin/streptomycin, but without serum), and then to the cell monolayer. After 4 hours incubation with DOTAPTMand plasmids, the cells were added to the medium containing double the quantity of serum, bringing the final concentration of serum to 10%. Then cells were incubated for 24 hours prior to the kinase reaction.

Immunoprecipitate

After 24 hours incubation the reaction was stopped by placing the Petri dish in an ice bath. The medium was aspirated and the cell monolayer once washed in ice-cold PBS (137 mm NaCl, 1.5 mm KH2PO4, 2.7 mm KCl, 8,1 mm Na2HPO4·2H2O), and then solubilizers within 10 minutes and was added 1.5 ml of buffer for lysis (50 mm HEPES, pH 7.5, 150 mm NaCl, 10 mm EDTA, 10 mm Na4P2O7, 100 mm NaF, 2 mm Na3VO4, 1% Triton-X-100, 500 μm Pefabloc, Leupeptin 10 μg/ml, Aprotinin 10 μg/μl). The cell monolayer was otkarmlivali rubber scraper and transferred into an Eppendorf tube. Solubilization cell is separated from impurities by centrifugation at 10000×g for 10 minutes at 4°C. The supernatant was transferred into 50 μl of pre-washed beads Protein G Sepharose in HNT-buffer (30 mm HEPES, pH 7.5, 30 mm NaCl, 0.1% Triton X-100) and incubated with 2 µg/sample monoclonal anti-FLAGTMM2 antibodies (anti-FLAG-epitope, NH2-Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys-COOH) for 1 hour at room temperature. Anti-FLAG M2 monoclonal antibody was obtained from Sigma (No. F-3165). Approximately 60 μg of protein, purified from the cell lysate was added to the pre-adsorbed anti-FLAG antibody on the beads Protein G Sepharose, and incubated for 90 minutes at 4°C in a mixer for blood samples. After a period thus Sepharose beads washed twice in buffer and twice in lysis buffer for kinase reaction (25 mm HEPES pH 7.5, 10 mm magnesium acetate, 50 μm ATP).

Incubation of compounds with purified kinase p38α

Pre-washed immunoprecipitating complex anti-FLAG-p38 adsorbed on the beads Protein G Sepharose, washed twice in 1× kinase buffer (25 mm HEPES, pH 7.5, 10 mm magnesium acetate, 50 μm ATP), and the supernatant was aspirated. Compounds were diluted in 1× kinase buffer at the appropriate concentration. The compounds were added to the washed immunoprecipitates and activated complex FLAG-p38 adsorbed on the beads Protein G Sepharose for 30 minutes at 30°C in a volume of 100 μl. After 10 minutes, the Eppendorf tubes were shaken in order to ensure the beads and the unity in the solution. After 30 minutes incubation the beads were besieged, and the supernatant was aspirated.

The reaction MAR kinase p38a

Kinase reaction was initiated by adding 1 μg of substrate GST-ATF-2 (Santa Cruz, LaJolla, CA, USA, no sc-4114) together with 2 MX γ32P-ATP in 1× kinase buffer in the sample. The reaction mixture was left to perform the reaction for 30 minutes at 30°C, and the reaction was stopped by adding 40 μl of buffer 2×SDS buffer for images to the mixture. The samples were boiled, besieged and separated on 15% SDS-PAGE. Anhydrous gel SDS-PAGE was skanirovali Phospho-Imager, and radioactive bands PHAS-1 quantitatively analyzed STORM860 Phospho-Imager (Molecular Dynamics, Sunnyvale, CA, USA)using the software ImageQuaNT.

In this analysis, it was found that the connection 112 is a strong inhibitor of the MAP kinase p38 with IC50equal to 2 nm.

In vivo mouse model for screening TNF-αresponse induced by LPS

To analyze the effect of the compounds of the present invention in vivo have used the following scheme in vivo mouse model for screening TNF-α response induced by LPS: a group of 6 mice (C3H/HeN, female, age about 8 weeks (20 g), Bomholtgaard) was administered the compounds in suspension media for 1 hour before injection of LPS (LPS from E. coli 055:B5, L-4005, Sigma). In 0 time mice were administered an intravenous dose of 1.0 mg LPS/kg Over 80-90 minutes after administration of LPS, after anaesthesia Hypnorm/Dormicum, mice took the blood of OK is logosnitrog venous plexus. Blood samples were divided into samples in test tubes with EDTA to stabilize and centrifuged at 4000 rpm for 10 minutes at 4°C. the Level of TNF-α in plasma was analyzed using ELISA. Connection 156 WO98/32730 used as reference compounds. The level of TNF-α in plasma was determined using sandwich ELISA. Microtiter plates were coated with monoclonal antibodies against murine TNF-α, washed and blocked casein buffer. To the wells of microtiter plates were added to the sample standard mouse recombinant TNF-α and incubated. All standards were investigated three times, all plasma samples were not copied. After incubation of the samples and standards plates were washed and incubated with biotinylated polyclonal secondary antibody against mouse TNF-α and washed. All wells were added with the enzyme conjugate, and incubated. Added the substrate and the reaction of the enzyme/substrate was stopped after 15 minutes at room temperature with 1M H2SO4. Developed staining (OD) was measured at 450 nm on an ELISA reader and read the background OD at 620 nm. The experiments were taken into account, if the group, which has introduced a comparative compound, observed a significant inhibition (p<0.05) of the response of TNF-α compared with the control group, which was administered LPS. The results from the test compounds were expressed as% of the HT inhibition compared with the control group, which was injected LPS. Compounds were investigated at 10 mg/kg of the Test Mann-Whitney was used to compare the groups, which were injected drug, with the control group, which was administered LPS (p<0,05).

The results are shown in table 3.

tr>
Table 3
Inhibition of in vivo production of TNF-α induced by LPS (%)
Connection#.
The connection 10495
The connection 11296
Connection 11383
The connection 11472
Connection 11596
The connection 11695
Connection 11771
Connection 12086
Connection 12347
Connection 12679
Connection 12973
Connection 13170
The connection 14076
Connection 14146
Connection 14594
Connection 14789
Connection 14871
Connection 14989
Connection 15199
Connection 15299
Connection 15386
Connection 15591
Connection 15673
Connection 15783
Connection 16366
Connection 16476
The connection 16683
Connection 17087
Connection 17390
Connection 17464
Connection 17652
Connection 17867
Connection 18692
Connection 18895
Connection 19666
Connection 19876
The connection 20267
Connection 25149
Connection 26095
Connection 26487
Connection 26654
Connection 27865
Connection 42444
Comparative compound a23

Comparative compound a: (4-(2-aminophenylamino)-2-chloro-2'-methylbenzophenone, the connection 156 is described in WO 98/32730.

The results show that the compounds of the present invention unexpectedly exhibit lucchino biological activity in vivo in relation to production of TNF-α in mice induced by LPS in comparison with the reference compound, thus making them potentially useful in the treatment of inflammatory diseases.

The invention is described in more detail in the following examples, which in no way intended to limit the scope of the invention presented in the claims.

EXAMPLES

General procedures

All melting points are uncorrected. For the spectrum of1H nuclear magnetic resonance (NMR) (300 MHz) and13C NMR (75,6 MHz) the values of chemical shift (δ) (in ppm), unless otherwise specified; for deuterochloroform solutions relative to internal standard tetramethylsilane (δ=0,00) or chloroform (δ=7,26) or deuterochloroform (δ=76,81 for13C NMR). The value of a multiplet, either definite (doublet (d), triplet (t), Quartet (q))or not (m), is given in approximately the middle point, if the limits are set. All the organic solvents were anhydrous. Chromatography was conducted on silica gel using flash method. As eluents used, if not stated otherwise, the appropriate mixture of ethyl acetate, dichloromethane, methanol and petroleum ether (40-60).

We used the following abbreviations:

Aqwater is th
Dbadibenzylideneacetone
DCMdichloromethane
DMAP4-dimethylaminopyridine
DMFN,N-dimethylformamide
DIEAethyldiethanolamine
EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOActhe ethyl acetate
FDPPpentafluorophenyl ester diphenylphosphino acid
hhour(s)
HATUO-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine
minminutes
NMPN-methylmorpholin
NMRnuclear magnetic resonance
rac-BINAPracemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
CTroom temperature
TBAFfluoride, Tetra-n-butylamine
TFAtriperoxonane acid
THFtetrahydrofuran
THPtetrahydropyran
TIPSCItriisopropylsilane
Vvolume

5
Table 4
Compounds of General formula I, represented in the examples
ConnectionExample No.Structure
1011
1022
1033
1044
105
1066
1077
1088
1099
11010
11111
11212
11313
11414
11515
11616
11717
11818
11919
12020
12121
12222
12323
12424
12525
12626
12727
12828
12929
13030
13131
13232
13333
13434
13535
13636
13737
13838
13939
14040
14141
14242
14343
14444
14545
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Getting 1

Methyl ester 3-(2-chloro-4-nitrobenzoyl)-4-methylbenzoic acid (compound 401)

In a dry flask was loaded methyl ester of 3-iodine-4-methylbenzoic acid (21,6 g, 78.2 mmol), and the contents of the flask was evaporated and then filled with argon, and this process was repeated twice. Added anhydrous THF (140 ml)and the solution was cooled to -50°C; then slowly added isopropylaniline (41 ml, 2,0M in diethyl ether, 82 mmol) over 15 minutes, maintaining the temperature below -40°C. After complete addition, the reaction mixture was stirred at -40°C for 45 minutes. Was added dropwise a solution of ZnCl2in THF (10,78 g, 79,1 mmol, 0,8M) for 20 minutes. The reaction mixture was stirred at 0°C for 65 minutes and then was added 2-chloro-4-nitrobenzoate (17,2 g, 78.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (4,03 g, 3,49 mmol)and the reaction is ionic and the mixture was left to warm to room temperature. After 4 hours the reaction mixture was poured into a mixture of toluene/EtOAc/water, then shaken and separated. The aqueous phase is once again was extracted with two portions of EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. Crystallization from mixtures of EtOAc/petroleum ether (40-60) gave specified in the title compound as a yellow solid. The mother liquid was concentrated in vacuo and was purified by chromatography using DCM as eluent, to obtain the second portion specified in the connection header.

Getting 2

Methyl ester of 3-(4-amino-2-chlorobenzoyl)-4-methylbenzoic acid (compound 402)

To a solution of compound 401 (7,83 g, 23.5 mmol) in methanol (100 ml) in one portion was added zinc dust (15.3 g, 235 mmol) and ammonium chloride (6,27 g, 117 mmol) under stirring. The flask was set tube with CaCl2and the flask was placed on an oil bath with a temperature of 90°C. After 2 hours the reaction mixture was cooled to room temperature, filtered and then poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. Crystallization from a mixture of EtOAc/petroleum ether (40-60) (2:3) gave specified in the header is VCE compound as a pale yellow solid.

Getting 3

3-(4-Amino-2-chlorobenzoyl)-4-methylbenzoic acid (compound 403)

To a solution of compound 402 (1,61 g, 5.3 mmol) in ethanol (50 ml) was added sodium hydroxide solution (2M, 30 ml) and then stirred at the boil under reflux for 90 minutes. The reaction mixture was made slightly acidic (pH 5) by slow addition of hydrochloric acid (4n.), and then was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum to obtain specified in the title compound as an orange solid. This product was used without any further purification.

Getting 4

(4-Amino-2-chlorophenyl)-[2-methyl-5-(morpholine-4-carbonyl)phenyl]metano (compound 404)

To a solution of compound 403 (150 mg, 0.47 mmol) in DMF (2.00 ml) in a reaction flask (8 ml) was added morpholine (41 μl, 0.47 mmol), FDPP (253 mg, 0.66 mmol) and DIEA (402 μl, of 2.35 mmol). The flask was purged with argon, closed and then shaken at room temperature for 24 hours.

The reaction mixture was concentrated in vacuum at 40°C and then was purified by chromatography, using as eluent EtOAc/petroleum ether (40-60) 4:1, then EtOAc, to obtain specified in the title compound as an orange syrup.

Example 1

[2-Chloro-4-(4-the Thor-2-methylphenylimino)phenyl]-[2-methyl-5-(morpholine-4-carbonyl)phenyl]metano (compound 101)

2-Bromo-5-vtortola (47 μl, of 0.37 mmol) was dissolved in 3 ml of anhydrous 1,4-dioxane in the vessel in an argon atmosphere. Added connection 404 (110 mg, 0.31 mmol) and was dissolved in the solvent. Added Rac-BINAP (7,3 mg, 0.012 mmol), Pd2(dba)3(7,0 mg, 0,008 mmol) and Cs2CO3(141 mg, 0.43 mmol)and the reaction mixture was stirred in argon atmosphere at 100°C for 72 hours. The reaction mixture was filtered and then purified using flash chromatography with a continuous gradient, using as eluent EtOAc/petroleum ether (40-60) (vol.:about.=0:100-50:50) to obtain the specified title compound as a brown oil.

13C NMR (CDCl3) δ 195,4, 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.

Getting 5

(4-Amino-2-chlorophenyl)-[2-methyl-5-(4-methylpiperazin-1-carbonyl)phenyl]metano (compound 405)

The reaction was carried out similarly as described for obtaining compound 404, using N-methylpiperazine (52 μl, 0.47 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the title compound as a brown syrup.

Example 2

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-5-(4-methylpiperazin-1-carbonyl)phenyl]metano (compound 102)

The reaction was carried out as described for connection 101 using the connection 40 (143 mg, 0.45 mmol) as the amine. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (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.

Getting 6

3-(4-Amino-2-chlorobenzoyl)-N-methoxy-4,N-dimethylbenzamide (compound 406)

The reaction was carried out similarly as described for obtaining compound 404, using the hydrochloride salt of the N,O-dimethylhydroxylamine (46 mg, 0.47 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the title compound as an orange solid.

Example 3

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-N-methoxy-4,N-dimethylbenzamide (compound 103)

The reaction was carried out similarly as described for connection 101 using the connection 406 (125 mg, 0.38 mmol) as the amine. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 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.

Getting 7

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

The reaction was carried out similarly as described for recip is of compound 404, using (tetrahydrofuran-2-yl)methylamine (31 mg, 0.31 mmol) as the amine. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow oil.

Example 4

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-(tetrahydrofuran-2-ylmethyl)benzamide (compound 104)

The reaction was carried out similarly as described for connection 101 using the connection 407 (85 mg, 0.23 mmol) as the amine. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,5, 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.

Getting 8

3-(4-Amino-2-chlorobenzoyl)-4,N-dimethyl-N-(tetrahydrofuran-2-ylmethyl)benzamide (compound 408)

The reaction was carried out similarly as described for obtaining compound 404, using methyl(tetrahydrofuran-2-ylmethyl)amine (36 mg, 0.31 mmol) as the amine. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow oil.

Example 5

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

The reaction was carried out similarly as described for connection 101, connect using the tion 408 (85 mg, 0.23 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the title compound as a brown syrup.

1H NMR (CDCl3) δ 7,41-7,24 (m, 4H), to 7.15 (DD, 1H), 6,97 (DD, 1H), 6.90 to (dt, 1H), is 6.61 (d, 1H), 6.48 in (DD, 1H), 6,23 (Sirs, 1H), 4,17-3,0 (m, 8H), 2,41 (c, 3H), 2,21 (c, 3H), 2.0 to a 1.45 (m, 4H).

9

3-(4-Amino-2-chlorobenzoyl)-N-(2-methoxyethyl)-4-methylbenzamide (compound 409)

The reaction was carried out similarly as described for obtaining compound 404, using 2-methoxyethylamine (23 mg, 0.31 mmol) as the amine. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow oil.

Example 6

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-N-(2-methoxyethyl)-4-methylbenzamide (compound 106)

The reaction was carried out similarly as described for connection 101 using the connection 409 (60 mg, 0,17 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the connection header in the form of syrup.

13C NMR (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.

Receive 10

3-(4-Amino-2-chlorobenzoyl)-4-methyl-N-(3-morpholine-4-ylpropyl)benzamide (compound 410)

The reaction was carried out similarly as described for connection 404, IP is by using 3-morpholine-4-ylpropionic (45 mg, 0.31 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the connection header in the form of foam.

Example 7

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-(3-morpholine-4-ylpropyl)benzamide (compound 107)

The reaction was carried out similarly as described for connection 101 using the connection 410 (37 mg, 0.09 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the title compound as a brown oil.

13C NMR (CDCl3) δ 195,6, 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.

Receipt 11

(4-Amino-2-chlorophenyl)-{5-[4-(2-methoxyethyl)piperazine-1-carbonyl]-2-were}mechanon (compound 411)

The reaction was carried out similarly as described for obtaining compound 404, using 1-(2-methoxyethyl)piperazine (45 mg, 0.31 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the connection header in the form of foam.

Example 8

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-{5-[4-(2-methoxyethyl)piperazine-1-carbonyl]-2-were}mechanon (compound 108)

The reaction was carried out similarly as described for connection 101 using the connection 411 (90 mg, 0.22 mmol) as the amine. Purification was performed with the aid of the using flash chromatography to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,5, 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.

Obtaining 12:

3-(4-Amino-2-chlorobenzoyl)-4-methyl-N-pyridin-4-ylmethylene (compound 412)

The reaction was carried out similarly as described for obtaining compound 404, using C-pyridin-4-ylmethylamino (31 μl, 0.31 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

Example 9

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-pyridin-4-ylmethylene (compound 109)

The reaction was carried out similarly as described for connection 101 using the connection 412 (100 mg, 0.26 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

13C NMR (DMSO-d6) δ 194,3, 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.

13

3-(4-Amino-2-chlorobenzoyl)-4-methyl-N-pyridin-2-ylmethylene (compound 413)

The reaction was carried out similarly as described for obtaining compound 404, using C-pyridine-2-ylmethylamino (31 μl, 0.31 mmol) as the amine. Purification was performed using flash chromatogr is the philosophy of obtaining specified in the title compound as a yellow solid.

Example 10

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-pyridin-2-ylmethylene (compound 110)

The reaction was carried out similarly as described for connection 101 using the connection 413 (79 mg, 0.21 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

13C NMR (DMSO-d6) δ 194,3, 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.

Getting 14

3-(4-Amino-2-chlorobenzoyl)-4-methyl-N-pyridin-3-ylmethylene (compound 414)

The reaction was carried out similarly as described for obtaining compound 404, using C-pyridine-3-ylmethylamino (31 μl, 0.31 mmol) as the amine. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

Example 11

3-[2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-pyridin-3-ylmethylene (compound 111)

The reaction was carried out similarly as described for connection 101 using the connection 414 (90 mg, 0.24 mmol) as the amine. Purification was performed using flash chromatography to obtain specified in the connection header in the form of solids.

13C NMR (DMSO-d6) δ 194,4, 165,3, 159,4, 157,8, 150,9, 148,7, 139,7, 36,6, 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.

Receive 15

Methyl ester of 3-[2-chloro-4-(2-nitrophenylamino)benzoyl]-4-methylbenzoic acid (compound 415)

In the tube Slinka loaded connection 402 (of 4.00 g of 13.1 mmol) in 1,4-dioxane (40 ml), 1-iodine-2-nitrobenzene (3,91 g, 15.7 mmol), Cs2CO3(5,98 g, and 18.3 mmol), Pd2(dba)3(302 mg, 0.33 mmol), and rac-BINAP (308 mg, 0.49 mmol). The tube was closed with a rubber cap was purged with argon for 5 minutes and then stirred at 100°C for 2 hours. The reaction mixture was left to cool to room temperature, and then poured into a mixture of water and EtOAc. The aqueous phase was extracted two more times with EtOAc. The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using chromatography, elwira petroleum ether (40-60)/EtOAc 4:1 to obtain specified in the title compound as a yellow solid.

Getting 16

3-[2-Chloro-4-(2-nitrophenylamino)benzoyl]-4-methylbenzoic acid (compound 416)

To a suspension of compound 415 (3.00 g, 7,06 mmol) in methanol (20 ml) was added water (4.0 ml) and then lithium hydroxide (845 mg, 35 mmol). The mixture was then stirred at the boil under reflux for 30 minutes. The reaction mixture was acidified (pH 5) slow the addition of H 2SO4(1H.), and then was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product is triturated in a mixture of EtOAc/pentane 1:1 (20 ml) to obtain the specified title compound as a yellow solid.

Getting 17/Example 271

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

To a solution of compound 416 (2,42 g 5,90 mmol) in DMF (20 ml) was added 2-aminoethanol (541 mg, cent to 8.85 mmol), FDPP (2,72 g, was 7.08 mmol) and DIEA (5 ml, 30 mmol) at 0°C. the Flask was purged with argon and left to warm to room temperature. The reaction mixture was stirred at room temperature for 5 hours and then poured into a mixture of water (100 ml), H2SO4(1H., 40 ml) and EtOAc (100 ml). The phases were separated, and the aqueous phase again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using chromatography, elwira DCM/methanol 100:2 with obtaining specified in the title compound as an orange solid.

Example 12:

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

To a solution of compound 417 (2,21 g, to 4.87 mmol) in methanol (40 ml) was added zinc dust(3,18 g, of 48.7 mmol) and ammonium chloride (1.30 grams, a 24.3 mmol) in one portion under stirring. The flask was set tube with CaCl2and the flask was placed on an oil bath with a temperature of 90°C. After 1 hour the reaction mixture was cooled to room temperature, filtered and then poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using chromatography, elwira DCM/methanol 100:5 (vol.:about.) then 100:7 (vol.:about.) obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,7, 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.

Getting 18

Methyl ester of 3-[4-(4-bromo-2-nitrophenylamino)-2-chlorobenzoyl]-4-methylbenzoic acid (compound 418)

To a solution of compound 402 (1,00 g, 3,29 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (0.4 ml, 3,29 mmol) in DMSO (7.0 ml) under stirring was slowly added tert-piperonyl potassium (816 mg, 7,27 mmol). After 4 hours at room temperature the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product is about what imali using chromatography elwira petroleum ether (40-60)/EtOAc 9:1 to obtain specified in the title compound as an orange solid.

Getting 19

3-[4-(4-Bromo-2-nitrophenylamino)-2-chlorobenzoyl]-4-methylbenzoic acid (compound 419)

To a suspension of compound 418 (540 mg, 1.07 mmol) in methanol (5 ml) was added water (0.5 ml) and lithium hydroxide (128 mg, to 5.35 mmol). Then the mixture was stirred at the boil under reflux for 3 hours. The reaction mixture was acidified (pH 2) by slow addition of HCl (aq.) (1H.) and then was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the product specified in the header, in the form of an orange solid. The product was used further without any additional purification.

20/Example 273

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

The reaction was carried out similarly as described for obtaining compound 404, using 2-aminoethanol (56 μl, of 0.94 mmol) as the amine and the compound 419 (461 mg, of 0.94 mmol) as the carboxylic acid. Purification was performed using flash chromatography to obtain specified in the title compound as an orange solid.

Example 13

3-[4-(2-Amino-4-is brompheniramine)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 113)

The reaction was carried out similarly as described for connection 112 using the connection 420 (280 mg, of 0.53 mmol) as the nitro compounds. Purification was performed using flash chromatography to obtain specified in the connection header in the form of solids.

13C NMR (CD3OD) δ 197,7, 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.

Getting 21

Methyl ester of 3-[4-(4-bromo-2-methylphenylimino)-2-chlorobenzoyl]-4-methylbenzoic acid (compound 421)

Into a reaction vessel were loaded connection 402 (100 mg, 0.33 mmol) in 1,4-dioxane (1.0 ml), 4-bromo-1-iodine-2-methylbenzo (56 μl, 0.38 mmol), Cs2CO3(15 mg, 0.46 mmol), Pd2(dba)3(7.5 mg, 0,008 mmol) and rac-BINAP (7.7 mg, 0.012 mmol). The tube was purged with argon for 5 minutes, closed it, and then was stirred at 150°C for 1 hour in a microwave oven. The reaction mixture was left to cool to room temperature and then was poured into EtOAc. Filtration and concentration in vacuo gave the crude product. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=10:90-30:70) as eluent to obtain specified in the title compound as an orange solid.

Getting 22/Example 274

3-[4-(4-Bromo-2-methylphenylamine is)-2-chlorobenzoyl]-4-methylbenzoic acid (compound 422)

The reaction was carried out similarly as described for connection 419 using the connection 421 (525 mg, 1.11 mmol) as a complex ester. Purification was performed using flash chromatography to obtain specified in the title compound as an orange solid.

13C NMR (DMSO-d6) δ 194,2, 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-methylphenylimino)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 114)

The reaction was carried out similarly as described for obtaining compound 404, using 2-aminoethanol (58 μl, 0.97 mmol) as the amine and the compound 422 (431 mg, 0.97 mmol) as the carboxylic acid. Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

13C NMR (DMSO-d5) δ 194,6, 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.

23

Methyl ester of 3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoic acid (compound 423)

Into a reaction vessel were loaded connection 402 (750 mg, 2,47 mmol) in toluene (7.5 ml), 1-bromo-2,4-differental (0.33 ml, 2,96 mmol), Cs2CO3(1.13 g, 3.46 mmol), Pd2(dba)3(114 mg, 0.12 mmol) and rac-BINAP (116 g, 0.18 mmol). The tube was purged what ergonom for 5 minutes, closed and then slowly heated to 200°C. the Reaction vessel was shaken at 200°C for 4 hours. The reaction mixture was left to cool to room temperature and then was poured into EtOAc. Filtration and concentration in vacuo gave the crude product. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=2:98-20:80) as eluent to obtain specified in the title compound as a brown syrup.

Obtaining 24/Example 275

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoic acid (compound 424)

The reaction was carried out similarly as described for connection 419 using the connection 423 (360 mg, 0.87 mmol) as a complex ester. Purification was performed using flash chromatography to obtain specified in the title compound as an orange solid.

13C NMR (DMSO-d6) δ 194,4, KZT 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, of 124.1 (DD), to 114.7, 112,0 (DD), 111,8, 105,0 (DD), 19,8.

Getting 25/Example 276:

2-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}ethyl ester 2-methylacrylate acid (compound 425)

The reaction was carried out similarly as described for obtaining compound 404, using 2-aminoethylamide ether 2-methylacrylate acid (54 m is, 0.33 mmol) as the amine and the compound 424 (120 mg, 0.30 mmol) as the carboxylic acid. Purification was performed using flash chromatography to obtain specified in the title compound as an orange foam.

13C NMR (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), to 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-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 115)

To a suspension of compound 425 (95 mg, 0,19 mmol) in methanol (1.0 ml) was added water (0.1 ml) and lithium hydroxide (23 mg, 0.95 mmol). Then the mixture was stirred at the boil under reflux for 45 minutes. The reaction mixture was acidified (pH 2) by slow addition of HCl (aq.) (1H.), and then was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) (vol.:about.=4:1 and 6:1) as eluent, obtaining specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,6, 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.

Getting 26/Example 277:

3-[2-Chloro-4-(2-nitrophenylamino)benzoyl]-N-(2-methoxyethyl)-4-m is etilbenzene (compound 426)

To a solution of compound 409 (85 mg, 0.25 mmol) and 1-fluoro-2-nitrobenzene (26 μl, 0.25 mmol) in DMSO (2.0 ml) under stirring was added tert-piperonyl potassium (62 mg, 0.55 mmol). After 2.5 hours the reaction mixture at room temperature was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using chromatography, elwira DCM/EtOAc 4:1 to obtain specified in 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 similarly as described for connection 112 using the connection 426 (72 mg, 0.15 mmol) as the nitro compounds. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 194,4, 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.

Getting 27

Methyl ester of 3-[4-(2-aminophenylamino)-2-chlorobenzoyl]-4-methylbenzoic acid (compound 427)

The reaction was carried out similarly as described for connection 112 using the connection 415 (1.8 g, of 4.38 mmol) as the nitro compounds. About what will isdu was performed using flash chromatography to obtain specified in the title compound as a yellow syrup.

Getting 28

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

To a solution of compound 427 (735 mg, of 1.86 mmol) in ethanol (10 ml) was added a solution of sodium hydroxide (2 M, 10 ml). Then the mixture was stirred at the boil under reflux for 2 hours. The reaction mixture was made slightly acidic (pH 5) by slow addition of glacial acetic acid (5.0 ml) and then poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography with a continuous gradient using DCM/methanol (vol.:about.=90:10-85:15) as eluent to obtain specified in the title compound as a yellow syrup.

13C NMR (CD3OD) δ 197,5, 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 similarly as described for obtaining compound 404, using etilamingidrokhlorida (11 mg, 0.14 mmol) as the amine and the compound 428 (54 mg, 0.14 mmol) as the carboxylic acid. Purification was performed using flash chromatography to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl 3) 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 118)

The reaction was carried out similarly as described for obtaining compound 404, using 3-aminopropan-1-ol (11 μl, 0.14 mmol) as the amine and the compound 428 (54 mg, 0.14 mmol) as the carboxylic acid. Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,8, 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.

Getting 29

3-(4-Amino-2-chlorobenzoyl)-N-(2-hydroxyethyl)-4-methylbenzamide (compound 429)

The reaction was carried out similarly as described for obtaining compound 404, using 2-aminoethanol (190 μl, of 3.13 mmol) as the amine and the compound 403 (1,00 g of 3.13 mmol) as the carboxylic acid. Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

30

3-(4-Amino-2-chlorobenzoyl)-N-[2-(tert-butyldimethylsilyloxy)ethyl]-4-methylbenzamide (compound 430)

A solution of compound 429 (490 mg, about 1.47 mmol), 1,5-diazabicyclo(5.4.0)undecene-5-ene (0.9 ml, 5,88 mmol) and tert-BUTYLCARBAMATE the LAN (777 mg, further 5.15 mmol) in acetonitrile (2.0 ml) was stirred for 2 hours in argon atmosphere. The reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain a syrup. The syrup was stirred in a mixture of ethanol (5.0 ml) and glacial acetic acid (0.5 ml) for 18 hours and then poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using chromatography, elwira DCM/EtOAc (vol.:about.=4:1) obtaining specified in the title compound as a yellow foam.

Example 19

3-2-Chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 119)

2-Bromo-5-vtortola (8 μl, 0.11 mmol) was dissolved in 1 ml of anhydrous 1,4-dioxane in the flask in an argon atmosphere. Added connection 430 (42 mg, 0.09 mmol) and was dissolved in the solvent. Added Rac-BINAP (2.1 mg, of 0.003 mmol), Pd2(dba)3(2.0 mg, 0.002 mmol) and Cs2CO3(41 mg, 0.13 mmol)and the reaction mixture was stirred in argon atmosphere at 100°C for 72 hours. The reaction mixture was filtered and then dissolved in THF (1,00 ml). To the solution was added trihydrate tetrabutylammonium fluoride (37 mg, 012 mmol) and the mixture was stirred at 60°C for 45 minutes. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed Na2CO3(aq.), water, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using chromatography, elwira EtOAc to obtain specified in the title compound as a yellow/brown oil.

13C NMR (CDCl3) δ 195,6, 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.

Getting 31

Methyl ester of 3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl-4-methylbenzoic acid (compound 431)

1-Bromo-4-chloro-2-torbenson (820 μl, to 6.58 mmol) was dissolved in 20 ml of anhydrous 1,4-dioxane in an argon atmosphere. Added connection 402 (2.00 g, to 6.58 mmol) and was dissolved in the solvent. Added DICYCLOHEXYL-(2',4',6'-triisopropylsilyl-2-yl)Foshan (125 mg, 0.26 mmol), Pd(OAc)2(30 mg, 0.13 mmol) and Cs2CO3(2,68 g, by 8.22 mmol)and the reaction mixture was stirred in argon atmosphere at 120°C for 48 hours. The reaction mixture was filtered and then purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:9 as eluent to obtain specified in the connection header in the form of solids.

Getting 32/Example 278

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzoic acid (connected to the e 432)

The reaction was carried out similarly as described for connection 416, using the connection 431 (1,71 g of 3.96 mmol) as a complex ester. Specified in the title compound was used without any further purification.

13C NMR (DMSO-d6) δ to 194.6, 166,7, 154,8 (d), 148,3, 141,7, 139,0, 133,3, 131,5, 131,4, 129,5, 128,8, 127,7 (d), to 127.2 (d), 127,2, 125,2 (d), of 124.8 (d), 116,9 (d), 115,6, 112,7, 19,9.

Receive 33

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzoate (compound 433)

To a suspension of compound 432 (100 mg, 0.24 mmol) in toluene (2 ml) was added thionyl chloride (35 μl, 0.48 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 20

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 120)

A solution of compound 433 (80 mg, 0.18 mmol), DIEA (31 μl, 0.18 mmol) and 2-aminoethanol (22 μl, of 0.37 mmol) in anhydrous DCM (2 ml) was stirred to complete the reaction, defined according to TLC (1 hour). The reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. Purification using flash chromatography with continuous the main gradient using EtOAc/petroleum ether (40-60) (vol.:about.=40:60-100:0) as eluent, gave specified in the title compound as a brown oil.

13C NMR (CDCl3) δ 195,8, 167,7, 154,4 (d, J=248 Hz), 147,2, 141,5, 139,6, 135,2, 133,7, 131,6, 131,5, 129,1, 129,1, 128,7 (d, J=9.5 Hz), 127,8, to 127.2 (d, J=11.7 Hz), was 124.9 (d, J=3.6 Hz), 122,4 (d), 117,1, 117,0 (d, J=22,8 Hz), 113,6, 62,1, 42,9, 20,4.

Example 21

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4,N-dimethylbenzamide (compound 121)

The reaction was carried out similarly as described for connection 120, using methylamine (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,7, 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, RUB 127.3 (d), was 124.9 (d), 122,4 (d), 117,1, 117,0 (d), 113,6, 26,8, 20,4.

Example 22

Ethyl ester of (2-{3-2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}acetylamino)acetic acid (compound 122)

The reaction was carried out similarly as described for connection 120, using ethyl ether (2 aminoethylamino)acetic acid (0.13 mmol) as the amine.

13C NMR (DMSO-d6) δ 194,8, 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, to 127.2 (d), 127,1, 125,2 (d), of 124.8 (d), 117,0 (d), 115,7, 112,6, 60,3, 42,3, 40,6, 19,6, 14,0.

Example 23

Ethyl ester {3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}acetic acid (compound 123)

The reaction was carried out similarly as described in the La receiving the connection 120, using ethyl ether aminouksusnoy acid (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,6, 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, RUB 127.3 (d), was 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-forgenerating)benzoyl]-N-(2-methoxyethyl)-4-methylbenzamide (compound 124)

The reaction was carried out similarly as described for obtaining compound 120, using 2-methoxyethylamine (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,7, 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), USD 128.0, RUB 127.3 (d), was 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-forgenerating)benzoyl]-N-cyclohexyl-4-methylbenzamide (compound 125)

The reaction was carried out similarly as described for connection 120, using cyclohexylamine (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,7, is 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, RUB 127.3 (d), was 124.9 (d), 122,4 (d), 117,1, 117,0 (d), 113,6, 48,9, 33,2, 25,5, 24,9, 20,4.

Example 26

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-ethyl-4-methylbenzamide (compound 126)

The reaction was carried out similarly as described for connection 120, using ethylamine (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,7, 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, RUB 127.3 (d), of 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-forgenerating)benzoyl]-N-(6-hydroxyhexyl)-4-methylbenzamide (compound 127)

The reaction was carried out similarly as described for connection 120, using 6-aminohexanoic (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,8, 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, RUB 127.3 (d), of 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-forgenerating)benzoyl]-N-isopropyl-4-methylbenzamide (compound 128)

The reaction was carried out similarly as described for connection 120, using Isopropylamine (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,7, 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, RUB 127.3 (d), of 124.8 (d), of 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-forgenerating)benzoyl]-N-isobutyl-4-methylbenzamide (compound 129)

The reaction was carried out similarly as described for connection 120, using isobutylamine (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,7, 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, RUB 127.3 (d), of 124.8 (d), 122,4 (d), 117,1, 117,0 (d), 113,6, 47,4, 28,6, 20,4, 20,2.

Example 30

3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2,2-dimethylpropyl)-4-methylbenzamide (compound 130)

The reaction is carried out and just as described to obtain compound 120, using 2,2-dimethylpropylene (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,7, 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), USD 128.0, RUB 127.3 (d), of 124.8 (d), of 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-forgenerating)benzoyl]-N-(3-methoxypropyl)-4-methylbenzamide (compound 131)

The reaction was carried out similarly as described for connection 120, using 3-methoxypropylamine (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,7, 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, RUB 127.3 (d), of 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-forgenerating)benzoyl]-4-methyl-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide (compound 132)

The reaction was carried out similarly as described for connection 120, using 1-(3-aminopropyl)pyrrolidin-2-he (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,9, 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), uniforms, 127.6 (d), of 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-forgenerating)benzoyl]-N-(2-dimethylaminoethyl)-4-methylbenzamide (compound 133)

The reaction was carried out similarly as described for obtaining compound 120, using 2-diethylaminoethylamine (0.13 mmol) as the amine

13C NMR (CDCl3) δ 195,8, 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), of 124.8 (d), 122,6 (d), 117,1, 117,0 (d), 113,6, 57,8, 44,9, 37,0, 20,4.

Example 34

2-{3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}ethyl ester 2-methylacrylate acid (compound 134)

The reaction was carried out similarly as described for obtaining compound 404, using 2-aminoethylamide ether 2-methylacrylate acid (61 mg, and 0.37 mmol) as the amine and the connection 432 as acid (140 mg, 0.33 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 195,6, 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), USD 128.0, RUB 127.3 (d), 126,3, was 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-forgenerating)benzoyl]-N-CIS-(4-hydroxycyclohexyl)-4-methylbenzamide (compound 135)

The reaction was carried out similarly as described for connection 120, using 4-aminocyclohexanol (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,6, 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, RUB 127.3 (d), was 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-forgenerating)benzoyl]-N-TRANS-4-hydroxycyclohexyl)-4-methylbenzamide (compound 136)

The reaction was carried out similarly, campisano for connection 120, using 4-aminocyclohexanol (0.13 mmol) as the amine.

13C NMR (CDCl3) δ 195,6, 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, to 127.2 (d), was 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

Tert-butyl ether (2-{3-[2-Chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}ethyl) - carbamino acid (compound 137)

The reaction was carried out similarly as described for connection 120, using tert-butyl ether (2-amino-ethyl)carbamino acid (2.4 mmol) as the amine.

13C NMR (DMSO-d6) δ 194,8, 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, to 127.2 (d), 127,1, 125,2 (d), of 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-forgenerating)benzoyl]-4-methylbenzamide (compound 138)

A solution of compound 137 (100 mg, 0.8 mmol) in a mixture of EtOAc (5 ml), methanol (5 ml) and 4M HCl (aq., 1.5 ml) was stirred at 70°C for 2 hours. The crude mixture was concentrated in vacuo and purified using flash chromatography using MeOH/DCM/triethylamine 20:80:1 as the eluent, to obtain specified in the connection header.

13C NMR (DMSO-d6) δ 194,8, 165,4, 154,8 (d), 148,4, 139,6, 139,2, 133,6, 133,5, 131,7, 131,0, 129,2, 127,7 (d), RUB 127.3, 127,1 (d), 127,0, 125,2 (d), of 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-forgenerating)benzoyl]-4-methylbenzylamino}and is ethylamino)acetic acid (compound 139)

To a suspension of compound 122 (100 mg, 0.18 mmol) in methanol (2 ml) was added water (0.2 ml), then lithium hydroxide (21 mg, 0.89 mmol). Then the mixture was stirred at the boil under reflux for 90 minutes. The reaction mixture was acidified (pH 5) by slow addition of H2SO4(1H.) and then was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography, using EtOAc with 0-2% acetic acid as eluent to obtain specified in the title compound as a yellow solid.

13C NMR (DMSO-d6) δ 194,8, 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, to 127.2 (d), 127,1, 125,2 (d), of 124.8, 116,9 (d), 115,8, 112,6, 42,3, 40,7, 19,6.

Getting 34

Methyl ester 3-(2-chloro-4-nitrobenzoyl)-4-methoxybenzoic acid (compound 434)

In a dry flask was loaded methyl ester of 3-iodine-4-methoxybenzoic acid (8,9 g of 30.5 mmol)and the contents of the flask was evaporated and then filled with argon, and this process was repeated twice. Added anhydrous THF (50 ml)and the solution was cooled to -50°C; then slowly added chloride Isopropylamine (15.2 ml, 2,0M in diethyl ether to 30.5 mmol) over 20 minutes, keeping the temperature below -40°C. After complete addition, the reaction see what camping was stirred at -40°C for 45 minutes. Was added dropwise THF solution ZnCl2(5,19 g, 38,1 mmol, 1,0M) for 20 minutes. The reaction mixture was stirred at 0°C for 20 minutes; then added 2-chloro-4-nitrobenzoate (? 7.04 baby mortality g of 32.0 mmol) and Cu(OAc)2(122 mg, 0.61 mmol)and the reaction mixture was left to warm to room temperature. After 16 hours the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:6, then 1:3 as eluent to obtain specified in the title compound as a yellow solid.

Receive 35

Methyl ester of 3-(4-amino-2-chlorobenzoyl)-4-methoxybenzoic acid (compound 435)

The reaction was carried out similarly as described for connection 402 using the connection 434 (22,9 mmol) as the nitro compounds. Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

Getting 36

Methyl ester of 3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzoic acid (compound 436)

The reaction was carried out similarly as described in the La receive connections 431, using 1-bromo-2,4-differental (3,94 mmol) and compound 435 (or 3.28 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

Getting 37/Example 279

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzoic acid (compound 437)

The reaction was carried out similarly as described for connection 416, using the connection 436 (0,92 g, 2,13 mmol) as a complex ester. Specified in the title compound was used without any further purification.

13C NMR (DMSO-d6) δ 191,4, 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.

Getting 38

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzoate (compound 438)

To a suspension of compound 437 (292 mg, 0.7 mmol) in toluene (3 ml) was added thionyl chloride (100 μl, 1 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 40

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 140)

The reaction was carried out similarly as described for obtaining compound 120, using 2-aminoethanol (0.28 mmol) and compound 438 (0.14 mmol). the cleaning was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

13C NMR (DMSO-d6) δ 191,7, 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-dipertanyakan)benzoyl]-N-(2,2-dottorati)-4-methoxybenzamide (compound 141)

The reaction was carried out similarly as described for connection 120, 2,2-deperately (0.28 mmol) and compound 438 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

13C NMR (DMSO-d6) δ to 191.6, 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), output reached 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-dipertanyakan)benzoyl]-N-(2-foradil)-4-methoxybenzamide (compound 142)

The reaction was carried out similarly as described for obtaining compound 120, using 2-foreteller (0.28 mmol) and compound 438 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 192,7, KZT 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), of 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-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 143)

The reaction is s spent just as described to obtain compound 120, using 3-aminopropane-1,2-diol (0.28 mmol) and compound 438 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 191,7, 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-dipertanyakan)benzoyl]-4-methoxybenzamide (compound 144)

The reaction was carried out similarly as described for obtaining compound 120, using 2-aminoacetate (0.28 mmol) and compound 438 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

13C NMR (DMSO-d6) δ 191,8, 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), USD 114.9, 112,0 (DD), 111,8, 111,7, 105,1 (DD), 56,1, 42,4.

Getting 39

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoate (compound 439)

To a suspension of compound 424 (1.8 g, 4.5 mmol) in toluene (10 ml) was added thionyl chloride (650 μl, 9.0 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 45

N-Carbamoylmethyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 145)

The reaction was carried out similarly as described for obtaining compound 120, using 2-aminoacetate (4,48 mmol) and compound 439 (2,24 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 194,7, 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, of 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-dipertanyakan)benzoyl]-4-methylbenzamide (compound 146)

The reaction was carried out similarly as described for connection 120, using benzylamine (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 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), 44.1kHz, 20,3.

Example 47

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-foradil)-4-methylbenzamide (compound 147)

The reaction was carried out similarly as described for obtaining compound 120, using 2-foreteller (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography, obtaining pointed to by the th in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 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), to 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-dipertanyakan)benzoyl]-4-methyl-N-(2,2,2-triptorelin)benzamide (compound 148)

The reaction was carried out similarly as described for connection 120, using 2,2,2-triptorelin (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow syrup.

13C NMR (CDCl3) δ 195,5, 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 (kV)of 124.1 (DD), to 116.2, 112,7, 111,7 (DD), 105,0 (DD), 41,1 (kV), 20,3.

Example 49

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-ethyl-4-methylbenzamide (compound 149)

The reaction was carried out similarly as described for connection 120, using ethylamine (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,7, 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), to 116.2, 112,6, 111,6 (DD), 104,9 (DD), 35,0, 20,3, 14,8.

Example 50

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-cyclohexylmethyl-4-methylbenzamide (compound 150)

LEO15592-000

The reaction was carried out under the but to as described to obtain compound 120, using cyclohexylethylamine (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 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), to 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-dipertanyakan)benzoyl]-N-(2-hydroxypropyl)-4-methylbenzamide (compound 151)

The reaction was carried out similarly as described for connection 120, using 1-amino-2-propanol (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,7, 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), to 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-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methylbenzamide (compound 152)

The reaction was carried out similarly as described for connection 120, using 3-aminopropane-1,2-diol (4,48 mmol) and compound 439 (2,24 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,8, 168,3, 159,3 (DD)15,8 (DD), 148,6, 141,5, 139,9, 135,4, 134,0, 131,5, 130,9, 129,2, 128,0, 127,6, 124,8 (d), of 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-dipertanyakan)benzoyl]-N-(1-hydroxymethylpropane)-4-methylbenzamide (compound 153)

The reaction was carried out similarly as described for obtaining compound 120, using 2-aminobutane-1-ol (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow syrup.

13C NMR (CDCl3) δ 195,7, 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), to 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-dipertanyakan)benzoyl]-4-methyl-N-(2,2,3,3,3-pentafluoropropyl)benzamide (compound 154)

The reaction was carried out similarly as described for connection 120, using 2,2,3,3,3-pentafluoropropyl (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow syrup.

13C NMR (CDCl3) δ 195,4, 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), of 124.1 (DD), to 116.2, 112,7, 111,7 (DD), 105,0 (DD), 39,2 (t), 20,4.

Example 55

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(3-hydroxypropyl)-4-methylbenzamide (compound 155)

The reaction was carried out similarly as described for p is obtaining connection 120, using 3-aminopropanol (0.13 mmol) and compound 439 (0.11 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow syrup.

13C NMR (CDCl3) δ 195,7, 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), to 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-dipertanyakan)benzoyl]-N-(2-hydroxy-1,1-dimethylethyl)-4-methylbenzamide (compound 156)

The reaction was carried out similarly as described for obtaining compound 120, using 2-amino-2-methylpropan-1-ol (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,5, 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), of 124.1 (DD), to 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-dipertanyakan)benzoyl]-N-(2-hydroxy-1-hydroxymethyl-1-methylethyl)-4-methylbenzamide (compound 157)

The reaction was carried out similarly as described for obtaining compound 120, using 2-amino-2-methylpropan-1,3-diol (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 167,7, 159,3 (DD)155,7 (DD), of 148.4, 141,5, 40,0, 135,4, 133,9, 132,0, 131,5, 128,7, 128,4, 127,7, 124,7 (DD), of 124.1 (DD), to 116.2, 112,8, 111,7 (DD), 105,0 (DD), 67,7, 59,2, 20,3, 20,0.

Example 58

Ethyl ester {3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}acetic acid (compound 158)

The reaction was carried out similarly as described for connection 120, using ethyl ether aminouksusnoy acid (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,5, 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), to 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-dipertanyakan)benzoyl]-N-(4-hydroxybutyl)-4-methylbenzamide (compound 159)

The reaction was carried out similarly as described for connection 120, using 4-aminobutanol (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,7, 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), to 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-dipertanyakan)benzoyl]-N-(3-hydroxy-1,1-dimethylbutyl)-4-methylbenzamide (compound 160)

The reaction was carried out similarly, campisano for connection 120, using 4-amino-4-methylpentan-2-ol (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 196,0, is 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-dipertanyakan)benzoyl]-4-methyl-N-(3-phenylpropyl)benzamide (compound 161)

The reaction was carried out similarly as described for connection 120, using 3-phenylpropylamine (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 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), to 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-dipertanyakan)benzoyl]-N-(1-hydroxymethyl-3-methylbutyl)-4-methylbenzamide (compound 162)

The reaction was carried out similarly as described for obtaining compound 120, using (R)-leucinol (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 167,4, 159,3 (DD)155,7 (DD), 148,3, 141,4, 139,8, 135,4, 33,8, 131,8, 131,5, 128,8, 128,6, 127,8, 124,6 (DD), 124,2 (DD), to 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-Dipertanyakan)benzoyl]-N-(2-foradil)-4-methylbenzamide (compound 163)

The reaction was carried out similarly as described for obtaining compound 120, using 2-foreteller (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 196,0, 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-dipertanyakan)benzoyl]-N-isopropyl-4-methylbenzamide (compound 164)

The reaction was carried out similarly as described for connection 120, using Isopropylamine (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,7, 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), to 116.2, 112,7, 111,6 (DD), 105,0 (DD), 42,0, 22,8, 20,3.

Example 65

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-cyclohexyl-4-methylbenzamide (compound 165)

The reaction was carried out similarly as described for connection 120, using cyclohexylamine (0.28 mmol) and compound 43 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,7, is 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), to 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-dipertanyakan)benzoyl]-N-(2,2-dottorati)-4-methylbenzamide (compound 166)

The reaction was carried out similarly as described for connection 120, 2,2-deperately (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,4, 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), of 124.1 (DD), to 116.2, 113,6 (t), 112,8, 111,7 (DD), 105,0 (DD), 42,3 (t), 20,4.

Example 67

Methyl ester 5-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}-4-oxopentanoic acid (compound 167)

The reaction was carried out similarly as described for connection 120, using methyl ester of 5-amino-4-oxopentanoic acid (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 203,9, 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), 12,3 (DD), to 116.2, 112,8, 111,6 (DD), 105,0 (DD), 52,0, 49,6, 34,6, 27,6, 20,4.

Example 68

N-[(2-Carbamoylation)methyl]-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 168)

The reaction was carried out similarly as described for connection 120, using 3-(2-aminoethylamino)propionamide (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

13C NMR (CD3OD) δ 197,6, 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), for 125.8 (DD), 116,6, level 113.0, 112,7 (DD), or 105.8 (DD), 44,2, 37,0, 35,9, 20,3.

Example 69

Ethyl ester of (2-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}acetylamino)acetic acid (compound 169)

The reaction was carried out similarly as described for connection 120, using ethyl ether (2 aminoethylamino)acetic acid (0.28 mmol) and compound 439 (0.14 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 194,7, 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, of 124.1 (DD), USD 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-dipertanyakan)benzoyl]-4-methylbenzamide (compound 170)

The reactions is carried out just as described to obtain compound 120, using allylamine (0.50 mmol) and compound 439 (0.25 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 195,6, KZT 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 to 20.4.

Example 71

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2-sulphatoethyl)benzamide (compound 171)

The reaction was carried out similarly as described for connection 120, using amide 2-aminoethanesulfonic acid (0.50 mmol) and compound 439 (0.25 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (DMSO-d6) δ to 194.6, 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, of 124.1 (DD), USD 114.9, 112,0 (DD), 111,8, 105,0 (DD), 53,5, 34,7, 19,6.

Example 72

N-(2-Acetylamino)-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 172)

The reaction was carried out similarly as described for connection 120, using N-(2-amino-ethyl)ndimethylacetamide (0.50 mmol) and compound 439 (0.25 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 195,9, 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), and 12.2 (DD), to 116.2, 112,5, 111,6 (DD), 104,9 (DD), 40,9, 39,8, 23,0, 20,3.

Receive 40

S-Pyridine-2-silt ether 4-bromo-2-chlorobenzoic acid (compound 440)

A mixture of 4-bromo-3-chlorbenzoyl acid (5,00 g, 21,24 mmol), 2,2'-dithiodipyridine (4.68 g, 21,24 mmol) and triphenylphosphine (5,57 g, 21,24 mmol) in acetonitrile (150 ml) was stirred at room temperature for 0.5 hours. The crystals were filtered and washed with petroleum ether to obtain specified in the connection header.

Getting 41

Methyl ester of 3-(4-bromo-2-chlorobenzoyl)-4-methoxybenzoic acid (compound 441)

To a solution of methyl ester of 3-iodine-4-methoxybenzoic acid (of 6.31 g, 21.6 mmol) in THF (20 ml) was added 2M solution of chloride Isopropylamine in THF (11,0 ml, 22,00 mmol) at -50°C. the Reaction mixture was stirred at the same temperature for 30 minutes. Then add the connection 440 (5,91 g, 18 mmol). The solution was heated to room temperature and was stirred for 2 hours at the same temperature. Then, the solution extinguished saturated aqueous NH4Cl. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over MgSO4and concentrated in vacuum. The crude product was dissolved in ethyl acetate and was added silica gel. The mixture was concentrated in vacuum. The residue was purified by chromatography (petroleum ether/ethyl acetate :1) to obtain specified in the connection header in the form of oil, which hardened to a white solid.

Getting 42

Methyl ester of 3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzoic acid (compound 442)

A mixture of compound 441 (4,65 g, 12.1 mmol), 2,6-diferencia (1,87 g, 14.5 mmol), DICYCLOHEXYL-(2',4',6'-triisopropylsilyl-2-yl)Fofana (231 mg, 0.48 mmol), Pd(OAc)2(54 mg, 0.24 mmol), Cs2CO3(8,3 g of 16.9 mmol) and celite (4.0 g) in 1,4-dioxane (30 ml) was stirred at 130°C for 18 hours. The mixture was concentrated with silica gel. The residue was purified by chromatography (petroleum ether/ethyl acetate 3:1) to obtain the specified title compound as a yellow solid.

Getting 43/Example 280

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzoic acid (compound 443)

The reaction was carried out similarly as described for connection 416, using the connection 442 (1,00 g is 2.40 mmol) as a complex ester. Specified in the title compound was used without any further purification.

13C NMR (DMSO-d6) δ 191,5, 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.

Getting 44

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzoate (compound 444)

To a suspension of compound 443 (590 mg, 1.4 mmol) in toluene (7 ml) was added thionyl chloride (206 m is l, 2.8 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 73

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 173)

The reaction was carried out similarly as described for obtaining compound 120, using 2-aminoethanol (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CD3CN) δ 193,6, 167,5, owed 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-dipertanyakan)benzoyl-N-(2-foradil)-4-methoxybenzamide (compound 174)

The reaction was carried out similarly as described for obtaining compound 120, using 2-foreteller (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,9, 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, to 112.2 (m), 111,5, 82,7 (d), 56,0, 40,5 (d).

Example 75

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 175)

The reaction was carried out similarly as described is for connection 120, using 3-aminopropane-1,2-diol (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (acetone-D6) δ 192,8, 167,7, owed 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-dipertanyakan)benzoyl]-N-(3-hydroxypropyl)-4-methoxybenzamide (compound 176)

The reaction was carried out similarly as described for connection 120, using 3-aminopropan-1-ol (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 193,1, 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, to 112.2 (m), 111,5, 59,7, 56,0, 37,1, 32,1.

Example 77

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxy-N-penicillinase (compound 177)

The reaction was carried out similarly as described for connection 120, using phenethylamine (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,8, 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, to 112.2 (m), 111,6, 56,0, 41,3, 35,8.

Example 78

3-[2-Chloro-4-(2,6-dipertanyakan)benzo is l]-N-(2-hydroxy-1,1-dimethylethyl)-4-methoxybenzamide (compound 178)

The reaction was carried out similarly as described for obtaining compound 120, using 2-amino-2-methylpropan-1-ol (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,9, 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, to 112.2 (m), 111,5, 70,7, 56,6, 56,0, 24,7.

Example 79

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxy-N-(2-morpholine-4-retil)benzamide (compound 179)

The reaction was carried out similarly as described for obtaining compound 120, using 2-morpholine-4-ylethylamine (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,9, 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, to 112.2 (m), 111,6, 66,9, 57,0, 56,0, 53,3, 36,2.

Example 80

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxy-1-hydroxymethyl-1-methylethyl)-4-methoxybenzamide (compound 180)

The reaction was carried out similarly as described for obtaining compound 120, using 2-amino-2-methylpropan-1,3-diol (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 193,0, 167,6, 160,6, 157,4 (DD), 147,7, 134,7, 133,2, 132,4, 1293, to 129.3, 128,8, to 126.8, 125,7 (t), 117,1 (t), 116,0, 112,8, to 112.2 (m), 111,4, 67,6, 59,3, 56,0, 20,0.

Example 81

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methoxy-N-methylbenzamide (compound 181)

The reaction was carried out similarly as described for obtaining compound 120, using 2-methylaminoethanol (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,8, 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, to 112.2 (m), 111,6, 61,2, 56,0.

Example 82

Ethyl ester {3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzylamine}acetic acid (compound 182)

The reaction was carried out similarly as described for connection 120, using ethyl ether aminouksusnoy acid (0.84 mmol) and compound 444 (0.42 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,8, 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, to 112.2 (m), 111,5, 61,6, 56,0, 41,9, 14,2.

Example 83

Ethyl ester of (2-{3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzylamine}acetylamino)acetic acid (compound 183)

The reaction was carried out similarly as described for connection 120, using ethyl ether (2-aminoacetyl is amino)acetic acid (0.84 mmol) and compound 444 (0.42 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,9, 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, to 112.2 (m), 111,4, 61,5, 56,0, 43,7, 41,4, 14,1.

Example 84

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-N,N-bis-(2-hydroxyethyl)-4-methoxybenzamide (compound 184)

The reaction was carried out similarly as described for obtaining compound 120, using 2-(2-hydroxyethylamino)ethanol (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 193,0, 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, to 112.2 (m), 111,6, 60,7 (Sirs), 53,5 (Sirs), a 49.9 (Sirs).

Example 85

3-[2-Chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxy-N,N-bis-(2-methoxyethyl)benzamide (compound 185)

The reaction was carried out similarly as described for connection 120, using bis-(2-methoxyethyl)amine (0.28 mmol) and compound 444 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,9, 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 (Sirs), 45,5 (Sirs).

45

Methyl ester of 3-[2-chloro-4-(3-fluoro-2-methylp is ylamino)benzoyl]-4-methylbenzoic acid (compound 445)

1-Bromo-3-fluoro-2-methylbenzo (189 mg, 1.0 mmol) was dissolved in 4 ml of anhydrous 1,4-dioxane in an argon atmosphere. Added connection 402 (304 mg, 1.00 mmol) and was dissolved in the solvent. Added DICYCLOHEXYL-(2',4',6'-triisopropylsilyl-2-yl)Foshan (19 mg, 0.04 mmol), Pd(OAc)2(5 mg, 0.02 mmol) and Cs2CO3(407 mg, 1.25 mmol)and the reaction mixture was stirred in argon atmosphere at 120°C for 60 hours. The reaction mixture was filtered and then purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:4 as eluent to obtain specified in the connection header in the form of solids.

13C NMR (CDCl3) δ

Getting 46/Example 281

3-[2-Chloro-4-(3-fluoro-2-methylphenylimino)benzoyl]-4-methylbenzoic acid (compound 446)

The reaction was carried out similarly as described for connection 416, using the connection 445 (185 mg, 0.45 mmol) as a complex ester. Specified in the title compound was used without any further purification.

13C NMR (DMSO-d6) δ for 194.3, KZT 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, of 111.2 (d), 19,8, and 9.5 (d).

Getting 47

3-[2-Chloro-4-(3-fluoro-2-methylphenylimino)benzoyl]-4-methylbenzoate (compound 447)

To a suspension of compound 446 (158 mg, 0.4 mmol) in toluene (3 ml) was added thionyl chloride (CL, 0.8 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 86

3-[2-Chloro-4-(3-fluoro-2-methylphenylimino)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 186)

The reaction was carried out similarly as described for obtaining compound 120, using 2-aminoethanol (0.26 mmol) and compound 447 (0.13 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 195,6, 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-methylphenylimino)benzoyl]-4-methyl-N-(2,2,2-triptorelin)benzamide (compound 187)

The reaction was carried out similarly as described for connection 120, using 2,2,2-triptorelin (0.26 mmol) and compound 447 (0.13 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 195,4, 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), of 124.1 (kV), 119,9 (d), 119,2 (d), 116,3, 112,7, 112,1 (d), 41,1 (kV), 20,3, and 9.6 (d).

Getting 48

Methyl ester of 3-[2-chloro-4-(2-chloro-4-forgenerating)benzoyl]-4-methylbenzoic acid (compound 448)/u>

The reaction was carried out similarly as described for connection 445, using 1-bromo-2-chloro-4-torbenson (209 mg, 1.0 mmol) as the bromide. Purification was performed using flash chromatography to obtain specified in the connection header.

Getting 49/Example 282

3-[2-Chloro-4-(2-chloro-4-forgenerating)benzoyl]-4-methylbenzoic acid (compound 449)

The reaction was carried out similarly as described for connection 416, using the connection 448 (142 mg, 0.33 mmol) as a complex ester. Specified in the title compound was used without any further purification.

13C NMR (DMSO-d6) δ 194,4, KZT 166.5, 158,9 (d), 149,7, 141,8, 139,3, 133,6, 131,5, 131,2, 129,6 (d), to 129.3, 128,2, uniforms, 127.6 (d), 126,3, 117,4 (d), 115,3 (d), 114,9, 111,9, 19,8.

Receive 50

3-[2-Chloro-4-(2-chloro-4-forgenerating)benzoyl]-4-methylbenzoate (compound 450)

To a suspension of compounds 449 (102 mg, 0.24 mmol) in toluene (3 ml) was added thionyl chloride (35 μl, 0.5 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 88

3-[2-Chloro-4-(2-chloro-4-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 188)

The reaction was carried out similarly as described for connection 120, ISOE is isua 2-aminoethanol (0.26 mmol) and compound 450 (0.13 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 195,6, 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), of 123.2 (d), 117,5 (d), 117,0, USD 114.9 (d), 113,5, 62,2, 42,9, 20,4.

Example 89

3-[2-chloro-4-(2-chloro-4-forgenerating)benzoyl]-4-methyl-N-(2,2,2-triptorelin)benzamide (compound 189)

The reaction was carried out similarly as described for connection 120, using 2,2,2-triptorelin (0.26 mmol) and compound 450 (0.13 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 195,4, 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), of 124.1 (kV)of 123.2 (d), of 117.6 (d), 116,9, USD 114.9 (d), 113,5, 41,1 (kV), 20,4.

Getting 51

Methyl ester of 3-[2-Chloro-4-(4-forgenerating)benzoyl]-4-methylbenzoic acid (compound 451)

The reaction was carried out similarly as described for connection 445, using 1-bromo-4-torbenson (110 μl, 1.0 mmol) as the bromide. Purification was performed using flash chromatography to obtain specified in the connection header.

Example 90

3-[2-Chloro-4-(4-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 190)

To a solution of compound 451 (96 mg, 0.24 mmol) in acetonitrile (0.7 ml) and 2-aminoethanol (0,50 ml) was added K2CO3(50 mg, 036 mmol) and was stirred for 18 hours at room temperature. The reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined and concentrated onto silica gel in vacuo. Purification was performed using flash chromatography, elwira mixtures of MeOH/DCM to obtain specified in the title compound as a yellow syrup.

13C NMR (CDCl3) δ 195,9, 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.

Getting 52

Methyl ester 3-(2-chloro-4-phenyliminomethyl)-4-methylbenzoic acid (compound 452)

The reaction was carried out similarly as described for connection 445 using brobinson (110 ml, 1.0 mmol) as the bromide. Purification was performed using flash chromatography to obtain specified in the connection header.

Example 91

3-(2-Chloro-4-phenyliminomethyl)-N-(2-hydroxyethyl)-4-methylbenzamide (compound 191)

The reaction was carried out similarly as described for connection 190, using 2-aminoethanol (0,50 ml) and compound 452 (0.26 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (DMSO-d6) δ 194,6, 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.

Getting 53

Methyl ester of 3-[2-chloro-4-(3,5-dipertanyakan)benzoyl]-4-methylbenzoic acid (Conn the imposition of 453)

The reaction was carried out similarly as described for connection 445, using 1-bromo-3,5-differental (115 μl, 1.0 mmol) as the bromide. Purification was performed using flash chromatography to obtain specified in the connection header.

Example 92

3-[2-Chloro-4-(3,5-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 192)

The reaction was carried out similarly as described for connection 190, using 2-aminoethanol (0,50 ml) and compound 453 (0.26 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (DMSO-d6) δ 194,9, 165,2, to 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.

Getting 54

Methyl ester of 3-[2-chloro-4-(3-forgenerating)benzoyl]-4-methylbenzoic acid (compound 454)

The reaction was carried out similarly as described for connection 445, using 1-bromo-3-torbenson (110 μl, 1.0 mmol) as the bromide. Purification was performed using flash chromatography to obtain specified in the connection header.

Example 93

3-[2-Chloro-4-(3-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 193)

The reaction was carried out similarly as described for connection 190, using 2-aminoethanol (0,50 ml) and compound 454 (0.26 mmol). the cleaning was performed using flash chromatography to obtain specified in the connection header.

13C NMR (DMSO-d6) δ 194,8, 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.

Receive 55

Methyl ester of 3-[2-chloro-4-(4-forgenerating)benzoyl]-4-methoxybenzoic acid (compound 455)

The reaction was carried out similarly as described for connection 431, using 1-bromo-4-torbenson (1.88 mmol) and compound 435 (1.56 mmol). Purification was performed using flash chromatography and obtaining specified in the title compound as a yellow foam.

Example 94

3-[2-Chloro-4-(4-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 194)

The reaction was carried out similarly as described for connection 190, using 2-aminoethanol (0,50 ml) and compound 455 (0.15 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (DMSO-d6) δ to 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.

Getting 56

Methyl ester 3-(2-chloro-4-phenyliminomethyl)-4-methoxybenzoic acid (compound 456)

The reaction was carried out similarly as described for connection 431 using brobinson (1.88 mmol) and compound 435 (1.56 mmol). Purification was performed using flash chromatography and obtaining specified in the header soy is inane in the form of a yellow foam.

Example 95

3-(2-Chloro-4-phenyliminomethyl)-N-(2-hydroxyethyl)-4-methoxybenzamide (compound No. 195)

The reaction was carried out similarly as described for connection 190, using 2-aminoethanol (0,50 ml) and compound 456 (0.15 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (DMSO-d6) δ 191,6, 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.

Getting 57/Example 283

3-(2-Chloro-4-(4-forgenerating)benzoyl]-4-methoxybenzoic acid (compound 457)

The reaction was carried out similarly as described for connection 416, using the connection 455 (230 mg, 0,56 mmol) as a complex ester. Specified in the title compound was used without any further purification.

Getting 58

3-[2-Chloro-4-(4-forgenerating)benzoyl]-4-methoxybenzoate (compound 458)

To a suspension of compound 457 (0,56 mmol) in toluene (2 ml) was added thionyl chloride (81 μl, 1.1 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 96

3-[2-Chloro-4-(4-forgenerating)benzoyl]-N-(2,2-dottorati)-4-methoxybenzamide (compound 196)

Reaction about the-Odile just as described to obtain compound 120, using 2,2-deperately (0.28 mmol) and compound 458 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,6, 166,8, 160,7, 159,6 (d), 148, 8 persons, to 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-forgenerating)benzoyl-N-(2-foradil)-4-methoxybenzamide (compound 197)

The reaction was carried out similarly as described for obtaining compound 120, using 2-foreteller (0.28 mmol) and compound 458 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,6, 166,6, 160,5, 159,6 (d), 148, 7mm, 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-forgenerating)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 198)

The reaction was carried out similarly as described for connection 120, using 3-aminopropane-1,2-diol (0.28 mmol) and compound 458 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (mixture. rest.) δ 193,2, 168,1, 160,5, 159,5 (d), of 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-Carbama metil-3-[2-chloro-4-(4-forgenerating)benzoyl]-4-methoxybenzamide (compound 199)

The reaction was carried out similarly as described for obtaining compound 120, using 2-aminoacetate (0.28 mmol) and compound 458 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (DMSO-d6) δ 191,7, 171,1, 165,3, 159,4, 158,1 (d), of 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.

Getting 59/Example 284

3-(2-Chloro-4-phenyliminomethyl)-4-methoxybenzoic acid (compound 459)

The reaction was carried out similarly as described for connection 416, using the connection 456 (264 mg, 0.67 mmol) as a complex ester. Specified in the title compound was used without any further purification.

Getting 60

3-(2-Chloro-4-phenyliminomethyl)-4-methoxybenzoate (compound 460)

To a suspension of compounds 459 (0.67 mmol) in toluene (2 ml) was added thionyl chloride (98 μl, 1.3 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 100

3-(2-Chloro-4-phenyliminomethyl)-N-(2,2-dottorati)-4-methoxybenzamide (compound 200)

The reaction was carried out similarly as described for connection 120, 2,2-deperately (0.28 mmol) and connect the imposition 460 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,6, 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-phenyliminomethyl)-N-(2-foradil)-4-methoxybenzamide (compound 201)

The reaction was carried out similarly as described for obtaining compound 120, using 2-foreteller (0.28 mmol) and compound 460 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (CDCl3) δ 192,6, 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-phenyliminomethyl)-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 202)

The reaction was carried out similarly as described for connection 120, using 3-aminopropane-1,2-diol (0.28 mmol) and compound 460 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (mixture. rest.) 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-phenyliminomethyl)-4-methoxybenzamide (compound 203)

The reaction was carried out similarly as described for obtaining compound 120, using 2-and inoceramid (0.28 mmol) and compound 460 (0.14 mmol). Purification was performed using flash chromatography to obtain specified in the connection header.

13C NMR (mixture. rest.) 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.

Getting 61

Methyl ether 4-chloro-3-(2-chloro-4-nitrobenzoyl)benzoic acid (compound 461)

In a dry flask was loaded methyl ether 4-chloro-3-iodobenzoyl acid (5.0 g, 16.9% mmol) and the contents of the flask was evaporated and then filled with argon, and this process was repeated twice. Added anhydrous THF (35 ml)and the solution was cooled to -40°C; then slowly added chloride Isopropylamine (cent to 8.85 ml, 2,0M in diethyl ether, to 17.7 mmol) over 20 minutes, keeping the temperature below -40°C. After complete addition, the reaction mixture was stirred at -40°C for 45 minutes. Was added dropwise THF solution ZnCl2(2,32 g of 17.0 mmol, 0,9M) for 20 minutes. The reaction mixture was stirred at 0°C for 20 minutes; then added 2-chloro-4-nitrobenzoate (3.7 g, 17 mmol) and Cu(OAc)2(68 mg, 0.34 mmol)and the reaction mixture was left to warm to room temperature. After 16 hours the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum to obtain neojidanno what about the product. The crude product was purified using flash chromatography using EtOAc/petroleum ether 1:6 as eluent to obtain specified in the title compound as a yellow solid.

Getting 62

Methyl ester of 3-(4-amino-2-chlorobenzoyl)-4-chlorbenzoyl acid (compound 462)

To a solution of compound 461 (of 3.31 g, 9,35 mmol) in methanol (125 ml) was added zinc dust (6,1 g, 94 mmol) and ammonium chloride (2.5 g, 47 mmol) in one portion under stirring. The flask was set tube with CaCl2and the flask was placed on an oil bath with a temperature of 90°C. After 18 hours the reaction mixture was cooled to room temperature, filtered and then poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography using EtOAc/pentane 1:1 as eluent. The product is triturated in DCM and then filtered and dried to obtain specified in the title compound as a pale yellow solid.

Getting 63

Methyl ether 4-chloro-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]benzoic acid (compound 463)

1-Bromo-2,4-differental (87 μl, 0.77 mmol) was dissolved in 2.5 ml of anhydrous toluene in an argon atmosphere. Time to relax is if the connection 462 (250 mg, 0.77 mmol) and was dissolved in the solvent. Added 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (13 mg, is 0.023 mmol), Pd(OAc)2(3.5 mg, 0.015 mmol) and Cs2CO3(352 mg, of 1.08 mmol)and the reaction mixture was stirred in argon atmosphere at 120°C for 24 hours. The reaction mixture was filtered and then purified using flash chromatography using EtOAc/petroleum ether 1:2 as eluent to obtain specified in the connection header in the form of solids.

Example 104

4-Chloro-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)benzamide (compound 204)

The reaction was carried out similarly as described for connection 190, using 2-aminoethanol (0,50 ml) and compound 463 (0.12 mmol). Purification was performed using flash chromatography, using MeOH/DCM 7:93 obtaining specified in the connection header.

13C NMR (DMSO-d6) δ 190,9, 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), to 124.4, 123,9 (DD), 115,2, 112,1 (DD), 111,9, 105,2 (DD), 59,6, 42,4.

Example 105

Ethyl ester of (2-{3-chloro-4-[5-(2-hydrooximethylcarbamil)-2-methylbenzoyl]phenylamino}phenyl)carbamino acid (compound 205)

To a solution of compound 112 (100 mg, 0.24 mmol) in DMF (1 ml) was added K2CO3(66 mg, 0.48 mmol) and ethylchloride (23 μl, 0.24 mmol) with stirring. After 1 hour the reaction mixture was poured into a mixture of EtOAc/water. Water is th phase again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography with a gradient, elwira DCM/methanol (vol.:about.=100:0-98:2) obtaining specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 194,6, 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-propionylcarnitine)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 206)

To a solution of compound 112 (100 mg, 0.24 mmol) in glacial acetic acid (1 ml) was added propionic anhydride (33 μl, 0.26 mmol) with stirring. After 1 hour the reaction mixture was concentrated in vacuum. Added cyclohexane and the mixture was concentrated in vacuum. The crude product was purified using flash chromatography with a continuous gradient, elwira DCM/(EtOAc:MeOH:acetic acid 95:5:0.5) with (.:about.=95:5-90:10) to obtain the specified title compound as a yellow foam.

13C NMR (DMSO-d6) δ 194,6, 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-Acetylaminofluorene)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 207)

To a solution of compound 112 (100 mg, 0.24 mmol) in ice UKS the red acid (1 ml) was added acetic anhydride (25 μl, 0.26 mmol) with stirring. After 1 hour the reaction mixture was concentrated in vacuum. Added cyclohexane, and the mixture was concentrated in vacuum. The crude product was purified using flash chromatography elwira EtOAc:MeOH:acetic acid 95:5:0.5 to obtaining specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 194,6, 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-hydrooximethylcarbamil)-2-methylbenzoyl]phenylamino}phenyl)succinic acid (compound 208)

To a solution of compound 112 (100 mg, 0.24 mmol) in glacial acetic acid (1 ml) was added succinic anhydride (26 mg, 0.26 mmol) with stirring. After 1 hour the reaction mixture was concentrated in vacuum. Added cyclohexane and the mixture was concentrated in vacuum. The crude product was purified using flash chromatography elwira EtOAc:MeOH: acetic acid 90:10:1 and obtaining specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 194,6, 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.

Getting 64

2-[3-(2-{3-chloro-4-[5-(2-hydrooximethylcarbamil)-2-methylbenzoyl]phenylamino}phenyl)ureido]ethyl ester 2-methylacrylate acid (compound 464)

To a solution of compound 112 (149 mg, 0.35 IMO the ü) in anhydrous pyridine (1 ml) was added 2-isocyanatoacetate ether 2-methylacrylate acid (55 μl, 0,39 mmol) under stirring. After 1 hour the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography with a continuous gradient, elwira EtOAc/methanol (vol.:about.=100:0-95:5) obtaining specified in the title compound as a yellow foam.

Example 109

3-(2-Chloro-4-{2-[3-(2-hydroxyethyl)ureido]phenylamino}benzoyl)-N-(2-hydroxyethyl)-4-methylbenzamide (compound 209)

To a solution of compounds 464 (115 mg, 0.20 mmol) in ethanol (1 ml) was added NaOH (2M, 150 μl, 0.30 mmol) and then boiled under reflux for 2 hours. The reaction mixture was cooled to room temperature and then poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography elwira MeOH/DCM 5:95 and 10:90 to obtaining specified in the connection header in the form of solids.

13C NMR (DMSO-d6) δ 194,7, 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.

Getting 65

Methyl ester of 4-(2-chloro-4-nitro is enzoyl)-3-methylbenzoic acid (compound 465)

The reaction was carried out similarly as described for connection 401, using methyl ether 4-iodine-3-methylbenzoic acid (3.5 g, 12.5 mmol) as iodide. Purification was performed using flash chromatography, using EtOAc/pentane 1:9 obtaining specified in the title compound as a light brown solid.

Getting 66

Methyl ester of 4-(4-Amino-2-chlorobenzoyl)-3-methylbenzoic acid (compound 466)

The reaction was carried out similarly as described for connection 402 using the connection 465 (3.0 g, 9.1 mmol) as the nitro compounds. Purification was performed using flash chromatography, using EtOAc/DCM 1:15 obtaining specified in the title compound as a yellow foam.

Getting 67

4-(4-Carboxy-2-methylbenzoyl)-3-chlorophenylalanine (compound 467)

To a solution of compound 466 (250 mg, 0.82 mmol) in ethanol (10 ml) was added sodium hydroxide solution (2M, 10 ml) and then stirred at the boil under reflux for 90 minutes. The reaction mixture was made slightly acidic (pH 4) by slow addition of acetic acid (100), and then poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum to obtain specified in the title compound as a yellow si is the ASO. It was used without any further purification.

Getting 68

(4-Amino-2-chlorophenyl)-[2-methyl-4-(morpholine-4-carbonyl)phenyl]metano (compound 468)

The reaction was carried out similarly as described for obtaining compound 404, using the connection 467 (106 mg, and 0.37 mmol) as the acid. Purification was performed using flash chromatography, using MeOH/DCM, 0:100, 1:100 and 2:100 with obtaining specified in the connection header in the form of foam.

Example 110

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-4-(morpholine-4-carbonyl)phenyl]metano (compound 210)

In an argon atmosphere in the flask was dissolved 2-bromo-5-vtortola (56 μl, 0.44 mmol) in 3 ml of anhydrous 1,4-dioxane. Added connection 468 (132 mg, and 0.37 mmol) and was dissolved in the solvent. Added Rac-BINAP (8.6 mg, 0.014 mmol), Pd2(dba)3(8.5 mg, 0,009 mmol) and Cs2CO3(169 mg, 0.52 mmol)and the reaction mixture was stirred in argon atmosphere at 100°C for 48 hours. The reaction mixture was filtered and then purified using flash chromatography, using EtOAc/DCM 1:3 as eluent obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,5, 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.

Getting 69

2-[2-(4-Bromo-3-methylphenoxy)ethoxy]tetrahydropyran (compound 46)

A solution of 4-bromo-3-METHYLPHENOL (10.6 g, 56,9 mmol) and 2-(2-bromoethoxy)tetrahydropyran (11,9, 56,9 mmol) was dissolved in anhydrous DMF (25 ml). Added K2CO3(19.7 g, 142 mmol) and the resulting reaction mixture was stirred at 80°C for 48 hours. The reaction mixture was cooled to room temperature and was poured into a mixture of EtOAc and aqueous NaOH (2n.). The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography using EtOAc/pentane 1:20 as eluent to obtain specified in the title compounds as colorless oils.

Getting 70

(2-Chloro-4-nitrophenyl)-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 470)

To a solution of compound 469 (13,95 g, 44,3 mmol) in THF (40 ml) at -78°C was added dropwise (30 min) n-utility (30,3 ml, 1,46M in hexane, 44,3 mmol)and the resulting mixture was stirred for 30 minutes. From a syringe was added a THF solution of anhydrous ZnCl2(55 mmol, 1,0M, 55 ml)and the reaction mixture was left to warm to room temperature. After 2 hours the reaction mixture was cooled to 0°C and was added tetrakis(triphenylphosphine)palladium (0) (2.55 g, 2.21 mmol)was then added 2-chloro-4-nitrobenzoate (10,9 g, 46,0 mmol) in THF (10 ml). With stirring, the reaction mixture is left is to warm to room temperature over night. The mixture was distributed between EtOAc (200 ml) and 1N. HCl (200 ml)and the aqueous phase again was extracted with EtOAc (200 ml). The combined organic extracts were washed with saline, dried over MgSO4and concentrated in vacuum. The residue was purified using flash chromatography using petroleum ether/EtOAc 9:1 to obtain specified in the title compound as a yellow syrup.

Getting 71

(4-Amino-2-chlorophenyl)-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 471)

The reaction was carried out similarly as described for connection 402 using the connection 470 (3.0 g, 9.1 mmol) as the nitro compounds. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:4, then 1:2, and obtaining specified in the title compound as a yellow foam.

Getting 72/Example 285

[2-Chloro-4-(2-nitrophenylamino)phenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 472)

1-Iodine-2-nitrobenzene (1,38 g, 5,54 mmol) was dissolved in 40 ml of anhydrous 1,4-dioxane in an argon atmosphere. Added connection 471 (1.77 g, of 4.54 mmol) and was dissolved in the solvent. Added Rac-BINAP (106 mg, 0,17 mmol), Pd2(dba)3(104 mg, 0.11 mmol) and Cs2CO3(2,07 g, 6,30 mmol)and the reaction mixture was stirred in argon atmosphere at 100°C for 24 hours. The reaction mixture was poured into the mixture the EtOAc and water. The aqueous phase was washed again EtOAc. The organic phases were combined and washed with saline, dried (MgSO4), was filtered and then purified using flash chromatography using EtOAc/petroleum ether 1:5 as eluent to obtain specified in the connection header.

Example 111

[4-(2-Aminophenylamino)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 211)

The reaction was carried out similarly as described for connection 402 using the connection 472 (2.14 g, 4,19 mmol) as the nitro compounds. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:4 then 1:2 and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 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-Aminophenylamino)-2-chlorophenyl]-[4-(2-hydroxyethoxy)-2-were]metano (compound 212)

A solution of compound 211 (1.10 g, to 2.29 mmol) and toluene-4-sulfonic acid (653 mg, of 3.43 mmol) in MeOH (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of aqueous NaOH (2n.) and EtOAc. The aqueous phase was washed again EtOAc. The organic phases were combined and washed with saline, dried (MgSO4), was filtered and then purified with POM is using flash chromatography using EtOAc/petroleum ether 1:1, then 2:1 as eluent obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 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.

Getting 73/Example 286

[4-(4-Bromo-2-nitrophenylamino)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 473)

To a solution of compound 471 (2,74 g, 7,02 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (1,49 g, 6,76 mmol) in DMSO (8.0 ml) was slowly added tert-piperonyl potassium (1.68 g, 14.9 mmol) under stirring. After 4 hours at room temperature the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using chromatography, elwira EtOAc/petroleum ether 1:9 obtaining specified in the title compound as an orange syrup.

Example 113

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 213)

The reaction was carried out similarly as described for connection 402 using the connection 473 (1.10 g, of 1.86 mmol) as the nitro compounds. Purification was performed using flash chromatography, use the Zuya EtOAc/petroleum ether 1:3 with obtaining specified in the connection header in the form of foam.

13C NMR (CDCl3) δ 195,5, 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-brompheniramine)-2-chlorophenyl]-[4-(2-hydroxyethoxy)-2-were]metano (compound 214)

The reaction was carried out similarly as described for connection 212 using the connection 213 (1.10 g, of 1.86 mmol) as the protected connections THP ether. Purification was performed using flash chromatography, using EtOAc/petroleum ether 3:7 obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,6, 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.

Getting 74

2-[3-(4-Bromo-3-methylphenoxy)propoxy]tetrahydropyran (compound 474)

The reaction was carried out similarly as described for connection 469, using 2-(3-bromopropane)tetrahydropyran (5,58 g, 25 mmol) as the aliphatic bromide. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:4 with receipt specified in the title compounds as colorless oils.

Getting 75

(2-Chloro-4-nitrophenyl)-{2-methyl-4-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl]metano (compound 475)

The reaction was carried out similarly as described for connection 470 using the giving 474 (8,56 g, 26 mmol) as the bromide. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:9, and obtaining specified in the title compound as a yellow oil.

Getting 76

(4-Amino-2-chlorophenyl)-{2-methyl-4-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}mechanon (compound 476)

The reaction was carried out similarly as described for connection 402 using the connection 475 (5,95 g, 13,71 mmol) as the nitro compounds. Specified in the title compound was obtained without further purification as a yellow oil.

Getting 77/Example 287

[4-(4-Bromo-2-nitrophenylamino)-2-chlorophenyl]-2-{methyl-4-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}mechanon (compound 477)

The reaction was carried out similarly as described for connection 473 using the connection 476 (1.45 g, 3,59 mmol) as the amine. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:6 with obtaining specified in the title compound as an orange oil.

Example 115

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-{2-methyl-4-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}mechanon (compound 215)

The reaction was carried out similarly as described for connection 402 using the connection 477 (5,95 g, 13,71 mmol) as the nitro compounds. Specified in the header of the link is received without any further purification as a yellow foam.

13C NMR (CDCl3) δ 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-brompheniramine)-2-chlorophenyl]-[4-(3-hydroxypropoxy)-2-were]metano (compound 216)

The reaction was carried out similarly as described for connection 212 using the connection 215 (1.30 grams, of 2.27 mmol) as the protected connections THP ether. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:1 and obtaining specified in the title compound as a yellow foam. Rubbing in a mixture of diethyl ether and pentane gave specified in the title compound as a white solid.

13C NMR (CDCl3) δ 195,5, 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.

Getting 78

1-Bromo-4-(2-floratone)-2-methylbenzo (compound 478)

A solution of 4-bromo-3-METHYLPHENOL (3,74 g, 20 mmol), 2-fluoro-ethanol (to 2.29 ml, 22 mmol) and triphenylphosphine (5,77 g, 22 mmol) in anhydrous THF (15 ml) was cooled to 0°C under stirring. Added diethylazodicarboxylate (40% in toluene, 10 ml, 22 mmol)and the reaction mixture was left to warm to room temperature over night. After 18 hours at room temperature the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again were extracted what EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using chromatography, elwira DCM/petroleum ether 1:6, obtaining specified in the title compounds as colorless oils.

Getting 79

(2-Chloro-4-nitrophenyl)-[4-(2-floratone)-2-were]metano (compound 479)

The reaction was carried out similarly as described for connection 470 using the connection 478 (4,25 g, 18.2 mmol) as the bromide. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:9, then 1:6, obtaining specified in the title compound as a yellow solid.

80

(4-Amino-2-chlorophenyl)-[4-(2-floratone)-2-were]metano (compound 480)

The mixture of compounds 479 (2,31 g, at 6.84 mmol) and chloride dihydrate tin (7,72 g, 34,2 mmol) in absolute ethanol was boiled under reflux. After 1 hour the solution was cooled to room temperature and then poured into a mixture of ice/water NaOH (7h.)/EtOAc. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuum. The crude product is triturated in a mixture of diethyl ether and petroleum ether 1:1, to obtain specified in the header is soedineniya in the form of solids.

Getting 81/Example 288

[4-(4-Bromo-2-nitrophenylamino)-2-chlorophenyl]-[4-(2-floratone)-2-were]metano (compound 481)

The reaction was carried out similarly as described for connection 473 using the connection 480 (595 mg, of 1.93 mmol) as the amine. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:9, then 1:6, obtaining specified in the connection header in the form of foam. Rubbing in ethanol gave a solid.

Example 117

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-[4-(2-floratone)-2-were]metano (compound 217)

The reaction was carried out similarly as described for connection 480 using the connection 481 (585 mg, 1.15 mmol) as the nitro compounds. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:7, then 1:4, obtaining specified in the connection header in the form of foam. Rubbing in a mixture of diethyl ether and petroleum ether 2:3 gave specified in the title compound in the form of solids.

13C NMR (CDCl3) δ 195,5, 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-methylphenylimino)-2-chlorophenyl]-[4-(2-floratone)-2-were]metano (compound 218)

In the tube Slinka loaded connection 480 (402 mg, 1,31 mmol) in 1,4-dioxane (3 ml), 5-bromo-1-idcolor (358 mg, 1,19 mmol), tert-piperonyl sodium (160 mg, 1,67 mmol), Pd2(dba)3(27 mg, 0.03 mmol) and rac-BINAP (28 mg, 0.045 mmol). The tube was closed with a rubber cap was purged with argon for 5 minutes, and then stirred at 100°C for 72 hours. The reaction mixture was left to cool to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted two more times with EtOAc. The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using chromatography, elwira petroleum ether/EtOAc 4:1 and obtaining specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,4, 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.

Getting 82

1-Bromo-4-[2-methoxyethoxy)-2-methylbenzo (compound 482)

The reaction was carried out similarly as described for connection 478, using 2-methoxyethanol (of 4.66 ml, 58.8 mmol) as an aliphatic alcohol. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=0:100-20:80) as eluent, to obtain specified in the title compounds as colorless oils.

Getting 83

(2-Chloro-4-nitrophenyl)-[4-(2-marks is etoxy)-2-were]metano (compound 483)

The reaction was carried out similarly as described for connection 470 using the connection 482 (of 4.66 ml, 58.8 mmol) as the bromide. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=15:85 BC-50:50) as eluent, to obtain specified in the title compound as a yellow syrup.

Getting 84

(4-Amino-2-chlorophenyl)-[4-(2-methoxyethoxy)-2-were]metano (compound 484)

The reaction was carried out similarly as described for connection 480 using the connection 483 (6,21 g, 17.8 mmol) as the nitro compounds. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:2-2:1) as eluent, to obtain specified in the title compound as a yellow solid.

Getting 85/Example 289

[4-(4-Bromo-2-nitrophenylamino)-2-chlorophenyl]-[4-(2-methoxyethoxy)-2-were]metano (compound 485)

The reaction was carried out similarly as described for connection 473 using the connection 484 (2.00 g, and 6.25 mmol) as the amine. The crude product was purified using flash chromatography with a continuous gradient using DCM/petroleum ether (40-60) (vol.:about.=20:80-50:50) as eluent, to obtain specified in the connection header in the IDA orange foam.

Example 119

[4-(2-Amino-4-brompheniramine)-2-chlorophenyl]-[4-(2-methoxyethoxy)-2-were]metano (compound 219)

The reaction was carried out similarly as described for connection 402 using the connection 485 (1.75 g, 3,37 mmol) as the nitro compounds. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=20:80-50:50) as eluent. Crystallization from DCM gave specified in the title compound in the form of solids.

13C NMR (DMSO-d6) δ 194,3, 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-methylphenylimino)-2-chlorophenyl]-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 220)

In the tube Slinka downloaded compound 471 (4,25 g, 10.9 mmol) in 1,4-dioxane (40 ml), 5-bromo-1-idcolor (3.88 g, 13,1 mmol), Cs2CO3(equal to 4.97 g, 15,26 mmol), Pd2(dba)3(250 mg, 0.27 mmol) and rac-BINAP (255 mg, 0.41 mmol). The tube was closed with a rubber cap was purged with argon for 5 minutes and then stirred at 100°C for 72 hours. The reaction mixture was left to cool to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted two more times with EtOAc. The combined organic phases are washed with saline, dried (MgSO4), f is literaly and concentrated in vacuum. The crude product was purified using chromatography, elwira petroleum ether/EtOAc 4:1 to obtain specified in the title compound as a yellow foam.

1H NMR (CDCl3) δ 7,39 (d, 1H), 7,35-7,25 (m, 3H), 7,14 (d, 1H), for 6.81 (m, 2H), 6,69 (m, 2H), 5,63 (Sirs, 1H), 4,70 (shirt, 1H), 4,23-4,00 (m, 3H), 3.95 to of 3.77 (m, 2H), 3,53 (m, 1H), of 2.51 (c, 3H), 2.23 to (c, 3H), 1,92-of 1.45 (m, 6H).

Example 121

[4-(4-Bromo-2-methylphenylimino)-2-chlorophenyl]-[4-(2-hydroxyethoxy)-2-were]metano (compound 221)

The reaction was carried out similarly as described for connection 212 using the connection 220 (3,82 g, 6,83 mmol) as the protected connections THP ether. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:2, then 2:3, obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,4, 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-Azidoethoxy)-2-were]-[4-(4-bromo-2-methylphenylimino)-2-chlorophenyl]metano (compound 222)

To a solution of compound 221 (101 mg, 0.21 mmol) in anhydrous pyridine (2 ml) was added 4-methylbenzenesulfonate (81 mg, 0.43 mmol) in C under stirring. After 5 hours at room temperature the reaction mixture was poured into a mixture of water and EtOAc. The aqueous phase was extracted two more times with EtOAc. The combined organic phases are washed with the salt solution, dried (MgSO4), filtered and concentrated in vacuum. Untreated tosylate was dissolved in anhydrous DMF and to the solution was added sodium azide (17 mg, 0.26 mmol). After 18 hours at room temperature the reaction mixture was poured into a mixture of water and EtOAc. The aqueous phase was extracted two more times with EtOAc. The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using chromatography, elwira petroleum ether/EtOAc 2:1, obtaining specified in the connection header.

13C NMR (CDCl3) δ 195,5, 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-Aminoethoxy)-2-were]-[4-(4-bromo-2-methylphenylimino)-2-chlorophenyl]metano (compound 223)

A solution of compound 222 (22 mg, 0,051 mmol), triphenylphosphine (15 mg, 0,056 mmol) and water (1 ál, 0,056 mmol) in THF (1 ml) was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and purified using flash chromatography using DCM/MeOH/NH4OH 90:10:1 as eluent, to obtain specified in the connection header.

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-Brompheniramine)-2-chlorophenyl]-{2-METI the-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 224)

The reaction was carried out similarly as described for connection 220, using 1-bromo-2-iodobenzoyl (1,19 ml, 9,23 mmol) as iodide. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:4 then 1:2. Crystallization from mixtures of diethyl ether and petroleum ether gave specified in the title compound as a beige solid.

13C NMR (CDCl3) δ 195,4, 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-Aminopropyl)phenylamino)-2-chlorophenyl}-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}mechanon (compound 225)

A solution of compound 224 (1,09 g, 2.00 mmol), Pd2(dba)3(55 mg, 0.06 mmol), 3-tributylstannyl-allylamine (727 mg, 2.1 mmol), CsF (668 mg, 4.4 mmol) and tri-tert-butylphosphine (0.2 mmol, 0.4 ml, 0,5M in hexane) in anhydrous 1,4-dioxane (5.0 ml) was stirred at 35°C for 120 hours in an argon atmosphere. The reaction mixture was filtered. Added acetonitrile (50 ml) and the resulting mixture was washed with petroleum ether (×3). Phase of acetonitrile was concentrated in vacuum. The crude product was purified using chromatography, elwira petroleum ether/EtOAc 2:1, then DCM/MeOH/Et3# 94:3:3, obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,7, 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-Aminopropyl)phenylamino]-2-chlorophenyl}-[4-(2-hydroxyethoxy)-2-were]metano (compound 226)

The reaction was carried out similarly as described for connection 212 using the connection 225 (50 mg, 0,096 mmol) as the protected connections THP ether. Purification was performed using flash chromatography, using DCM/MeOH/Et3N 92:5:3, and obtaining specified in the title compound as a yellow oil.

13C NMR (DMSO-d6) δ 194,3, 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-hydroxyethoxy)-2-methylbenzoyl]phenylamino}phenyl)-3-atilmotin (compound 227)

To a solution of compound 212 (150 mg, 0.38 mmol) in anhydrous pyridine (1 ml) was added under stirring utilizationa (75 μl, 0.95 mmol). After 5 hours the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography with a continuous gradient, elwira EtOAc/petroleum ether (vol.:about.=10:90-67:33), obtaining specified in the title compounds as yellow is Eropa.

13C NMR (DMSO-d6): δ 194,4, 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-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]-3-atilmotin (compound 228)

To a solution of compound 213 (158 mg, 0.28 mmol) in anhydrous pyridine (2 ml) was added under stirring utilizationa (33 μl, 0.42 mmol). After 16 hours the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography elwira EtOAc/petroleum ether 2:3, obtaining specified in the connection header.

13C NMR (CDCl3) δ 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-hydroxyethoxy)-2-methylbenzoyl]phenylamino}phenyl)-3-atilmotin (compound 229)

The reaction was carried out similarly as described for connection 212 using the connection 228 (138 mg, 0.22 mmol) as the protected connections THP ether. Purification was performed using flash chromatography, using EtOAc/petroleum ether 3:1 as eluent, to obtain the decree of the tion in the title compound as a yellow solid.

13C NMR (DMSO-d6) δ 194,4, 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-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]-3-cyclohexylamine (compound 230)

To a solution of compound 213 (151 mg, 0.34 mmol) in anhydrous pyridine (2 ml) was added under stirring cyclohexylsulfamate (65 μl, 0.51 mmol). After 18 hours the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography elwira EtOAc/petroleum ether 1:2, to obtain the specified title compound as a yellow solid.

13C NMR (DMSO-d6) δ 194,4, 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.

Getting 86

2-{3-[5-Bromo-2-(3-chloro-4-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]ureido}ethyl ester 2-methylacrylate acid (compound 486)

To a solution of compound 213 (158 mg, 0.28 mmol) in anhydrous pyridine (2 ml) was added with stirring 2-isocyanatoacetate ether 2-methylacrylate acid (60 μl, 0.42 mmol). Across the 16 hours the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography elwira EtOAc/methanol 1:2, to obtain the specified title compound as a grey foam.

Example 131

l-[5-Bromo-2-(3-chloro-4-{2-methyl-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]-3-(2-hydroxyethyl)urea (compound 231)

To a solution of compound 486 (110 mg, 0.15 mmol) in ethanol (5 ml) was added a solution of sodium hydroxide (2 M, 0.5 ml) and then stirred at the boil under reflux for 90 minutes. The reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography elwira EtOAc/petroleum ether 6:1, obtaining specified in the connection header in the form of solids.

13C NMR (CDCl3) δ 196,5, 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-hydroxyethoxy)-2-methylbenzoyl]phenylamino}phenyl)-3-(2-hydroxyethyl)urea (compound 232)

The reaction was carried out similarly as described for the floor of the possible connections 212, using the connection 231 (70 mg, 0.11 mmol) as the protected connections THP ether. Purification was performed using flash chromatography, using EtOAc as eluent, to obtain specified in the title compound as a yellow syrup.

13C NMR (CD3CN) δ 196,1, 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-(tetrahydropyran-2-yloxy)ethoxy]benzoyl}phenylamino)phenyl]monoamide succinic acid (compound 233)

To a solution of compound 213 (200 mg, 0.36 mmol) in pyridine (3 ml) under stirring was added succinic anhydride (62 mg, of 0.62 mmol). After 24 hours at 100°C the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography elwira EtOAc, obtaining specified in the connection header in the form of foam.

13C NMR (CDCl3) δ 198,0, 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.

Getting 87

4 Allyloxy-1-bromo-2-methylbenzo (compound 487)

The reaction was carried out similarly as described for connection 469 using allylbromide (5,44 g, 45 mmol) as the bromide. About what will isdu was performed using flash chromatography, using EtOAc/petroleum ether 1:25, with the receipt specified in the title compounds as colorless oils.

Getting 88

(4 Allyloxy-2-were)-(2-chloro-4-nitrophenyl)methanon (compound 488)

The reaction was carried out similarly as described for connection 470 using the connection 487 (6.85 g, 30.2 mmol) as the bromide. Purification was performed using flash chromatography, using EtOAc/petroleum ether 1:15, then 1:10, to obtain specified in the connection header.

Getting 89

(4 Allyloxy-2-were)-(4-amino-2-chlorophenyl)methanon (compound 489)

The reaction was carried out similarly as described for connection 480 using the connection 488 (of 6.26 g of 18.9 mmol) as the nitro compounds. The crude product was filtered through a layer of silica gel to obtain pure specified in the connection header.

Getting 90

(4 Allyloxy-2-were)-4-(4-bromo-2-nitrophenylamino)-2-chlorophenyl]metano (compound 490)

The reaction was carried out similarly as described for connection 473 using the connection 489 (1.86 g, 6,16 mmol) as the amine. Purification was performed using flash chromatography, using DCM/petroleum ether 3:2 then 7:3, to obtain specified in the connection header.

Example 134

(4 Allyloxy-2-were)4-(2-amino-4-brompheniramine)-2-chlorp the Nile]metano (compound 234)

The reaction was carried out similarly as described for connection 480 using the connection 490 (2,01 g, 4,01 mmol) as the nitro compounds. The crude product was filtered through a layer of silica gel to obtain specified in the header of the net connection.

13C NMR (CDCl3) δ 195,5, 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-methylbenzoyl)-3-chlorpheniramine]-5-bromophenylacetate} (compound 235)

Compound 134 (50 mg, 0.1 mmol) were loaded into the flask (4 ml). To the flask was added acetic acid (0.5 ml) and acetic anhydride (1.0 ml). After 2 hours at 30°C the reaction mixture was poured into a mixture of EtOAc/water. The organic phase was concentrated in vacuo, and the residue was purified using flash chromatography with a continuous gradient, using a mixture of 1,2-dichloroethane and petroleum ether, to obtain specified in the connection header.

13C NMR (CDCl3) δ 195,8, 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-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}-3-atilmotin (compound 236)

Compound 134 (50 mg, 0.1 mmol) were loaded into the flask (4 ml). To the flask was added pyridine (2.0 ml) and utilizationa (60 mg, 0.8 mmol). After 2 hours at 30°C the reaction mixture was crying with the Ali in a mixture of EtOAc/water. The organic phase was concentrated in vacuo, and the residue was purified by crystallization from a mixture of diethyl ether and hexane to obtain specified in the connection header in the form of solids.

13C NMR (DMSO-d6) δ 194,5, 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

Ethyl ether {2-[4-(4-allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}carbamino acid (compound 237)

To a solution of compound 134 (50 mg, 0.1 mmol) in DCM (2 ml) under stirring was added K2CO3(45 mg) and ethylchloride (40 ml, 0.4 mmol). After 22 hours at room temperature the reaction mixture was poured into a mixture of EtOAc/water. The organic phase was concentrated in vacuo, and the residue was purified by crystallization from ethanol to obtain specified in the connection header in the form of solids.

13C NMR (DMSO-d6) δ 194,3, 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-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}-2,2,2-triptorelin (compound 238)

To a solution of compound 134 (50 mg, 0.1 mmol) in DCM (2 ml) was added under stirring anhydride triperoxonane acid (95 mg) and pyridine (50 μl). After 1 hour at room temperature the reaction mixture was poured into CME is ü EtOAc/water. The organic phase was concentrated in vacuum to obtain specified in the connection header in the form of syrup.

13C NMR (CDCl3) δ 195,7, 161,3, 155, 1mm (kV), 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 (kV), 113,3, 111,2, 68,8, 21,6.

Example 139

N-{2-[4-(4-Allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}monoamide succinic acid (compound 239)

To a solution of compound 134 (50 mg, 0.1 mmol) in acetic acid (2 ml) was added succinic anhydride (63 mg) under stirring. After 1 hour at room temperature the reaction mixture was poured into a mixture of DCM/water. The organic phase was concentrated in vacuum to obtain specified in the connection header in the form of syrup.

13C NMR (CDCl3) δ 198,3, 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

Cyclopentyloxy ether {2-[4-(4-allyloxy-2-methylbenzoyl)-3-chlorpheniramine]-5-bromophenyl}carbamino acid (compound 240)

To a solution of compound 134 (50 mg, 0.1 mmol) in DCM (2 ml) under stirring was added K2CO3(45 mg) and cyclopentylamine (0.4 mmol). After 22 hours at room temperature the reaction mixture was poured into a mixture of EtOAc/water. The organic phase was concentrated in vacuo, and the residue was purified by crystallization from ethanol to obtain specified in the header joint is in the form of solids.

13C NMR (CDCl3) δ 195,6, 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.

Getting 91

S-Pyridine-2-silt ester 2-methyl-5-nitrothiazole acid (compound 491)

2-Methyl-5-nitrobenzoic acid (22,5 g, 124 mol), 2,2'-zitieren (27.5 g, 124 mmol) and triphenylphosphine (32,6 g, 124 mmol) was dissolved in CH3CN (650 ml). The solution was stirred at room temperature for 18 hours. The reaction mixture was filtered and the solid washed with a small amount of CH3CN. This gave specified in the title compound as a colourless solid.

Getting 92

(4-Bromo-2-chlorophenyl)-(2-methyl-5-nitrophenyl)methanon (compound 492)

The reaction was carried out in argon atmosphere using dry glassware. In anhydrous THF (400 ml) was dissolved 4-bromo-2-chlorobenzo (25,5 g of 80.9 mmol) and cooled to -60°C. was Added isopropylaniline (2M in THF, 40,4 ml of 80.9 mmol) under stirring for 30 minutes. The reaction mixture was left to warm to -40°C, and the mixture was stirred at -40°C for 4 hours. Added connection 491 (22,2 g of 80.9 mmol)and the mixture was stirred at -40°C for 3 hours, then left to warm to room temperature and was stirred for 17 hours. Was added a saturated aqueous solution of NH4Cl (200 ml)and the mixture is displaced is ivali for 1 hour. The phases were separated, and the aqueous phase was extracted with Et2O (4×100 ml). The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using CH2Cl2/petroleum ether (40-60) 2:3 as the eluent, to obtain specified in the title compound as a yellow crystalline substance.

Getting 93

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(2-methyl-5-nitrophenyl)methanon (compound 493)

Connection 492 (5,4 g of 15.2 mmol) was dissolved in anhydrous 1,4-dioxane (150 ml) in a 200 ml vessel with screw cap. Added 2,4-diptiranjan (1.7 ml, and 16.7 mmol), and blowing the mixture with argon. Added Cs2CO3(14.9 g, of 45.7 mmol), BINAP (0,38 g, 0.6 mmol) and Pd(OAc)2(0.14 g, 0.6 mmol), blew a mixture of argon and closed vessel screw cap. The mixture was stirred at 100°C for 7 hours. The reaction mixture was poured into H2O (100 ml) and EtOAc (200 ml). The aqueous phase was extracted with EtOAc (×3), and the combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using CH2Cl2/petroleum ether (40-60) 2:3→1:1→1:0, then EtOAc as eluent, to obtain specified in the header connect the Oia in the form of a yellow crystalline substance.

Getting 94

(5-Amino-2-were)-[2-chloro-4-(2,4-dipertanyakan)phenyl]metano (compound 494)

Compound 493 (6.0 g, 14.9 mmol) was dissolved in MeOH (350 ml). Was added zinc dust (12,69 g, 194 mmol) and NH4Cl (5,59 g, 104 mmol). The reaction mixture was heated at the boiling point under reflux for 1 hour. The mixture was filtered and washed with MeOH. The filtrate was concentrated, and the solid was dissolved in EtOAc (150 ml) and saturated aqueous Na2CO3(100 ml). The aqueous phase was extracted with EtOAc, and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as eluent, to obtain specified in the connection header in the form of slightly colored crystalline substance.

Getting 95

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(5-iodine-2-were)methanon (compound 495)

Compound 494 (0,62 g of 1.66 mmol) was dissolved in acetone (14 ml). Added concentrated HCl (37%, to 0.69 ml, 8.3 mmol)and the solution was cooled in an ice bath. NaNO2(0.14 g, 1,99 mmol) was dissolved in H2O (1 ml) and was added to the above solution over 15 minutes. During the addition the temperature of the reaction mass was maintained equal to 0-2°C. the Suspension was stirred in an ice bath for 0.5 hour, the, then was added dropwise a solution of KI (0,41 g, 2.45 mmol) and (I2(0.31 g, 1,22 mmol) in H2O (4 ml) for 5 minutes. The mixture was stirred at 0°C for 2 hours. H2O (20 ml) and EtOAc (20 ml) was added and stirred, and the phases were separated. The organic phase is washed with aqueous NaHSO3then water Na2CO3, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:5, to obtain specified in the connection header in the form of slightly colored crystalline substance.

Example 141

N-3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-methoxypropionate (compound 241)

3-Methoxypropionate acid (of 0.022 ml, 0.23 mmol) was dissolved in anhydrous DMF (5 ml). Added O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine (HATU) (0.09 g, 0.23 mmol)was then added 2,4,6-trimethylpyridine (0,048 ml, 0.36 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0,067 g, 0.18 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:4→4:1 as eluent. This gave specified in the title compound in the form of faintly colored Krista is symbolic of the connection.

13C NMR (CDCl3) δ 195,8, 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-dipertanyakan)benzoyl]-4-were}propionamide (compound 242)

Propionic acid (0.01 ml, 0.13 mmol) was dissolved in anhydrous DMF (5 ml). Added HATU (0.05 g, 0.13 mmol)was then added 2,4,6-trimethylpyridine (0,027 ml, 0.2 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0,038 g, 0.10 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:4→4:1 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 196,1, 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-dipertanyakan)benzoyl]-4-were}-2-(2-methoxyethoxy)ndimethylacetamide (compound 243)

2-(2-Methoxyethoxy)acetic acid (of 0.017 ml, 0.15 mmol) was dissolved in anhydrous DMF (5 ml). Added HATU (by 0.055 g, 0.15 mmol)was then added 2,4,6-trimethylpyridine one (0.03 ml, 0.22 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0,042 g, 0.11 mmol)SMEs was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:4→4:1 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,9, 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), to 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-dipertanyakan)benzoyl]-4-were}-3-morpholine-4-ylpropionic (compound 244)

Hydrochloride 3-(4-morpholino)propionic acid (or 0.027 g, 0.14 mmol) was dissolved in anhydrous DMF (5 ml). Added HATU (0,052 g, 0.14 mmol)was then added 2,4,6-trimethylpyridine (or 0.035 ml, 0.26 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0,039 g, 0.10 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using a gradient of MeOH/dichloromethane 1:50→1:12 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,9, 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-dipertanyakan)benzoyl]-4-were}-3-hydroxyp piramid (compound 245)

3-Hydroxypropionic acid (30% in H2O, 0.33 mmol) was dissolved in anhydrous DMF (5 ml). Added HATU (0.125 g, 0.33 mmol)was then added 2,4,6-trimethylpyridine (0,061 ml, 0.5 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0,094 g, 0.25 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (DMSO-d6) δ 195,1, 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-dipertanyakan)benzoyl]-4-were}-3-furan-2-ylpropionic (compound 246)

3-(2-Furfuryl)propionic acid (0.02 g, 0.14 mmol) was dissolved in anhydrous DMF (4 ml). Added HATU (0,053 g, 0.14 mmol)was then added 2,4,6-trimethylpyridine (0,029 ml, 0.22 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0,040 g, 0.11 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:9→2:3 as eluent. This, on the Valo specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 196,0, USD 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-dipertanyakan)benzoyl]-4-were}-2-hydroxybenzamide (compound 247)

2-Hydroxybenzoic acid is 0.019 g, 0.14 mmol) was dissolved in anhydrous DMF (4 ml). Added HATU (0,053 g, 0.14 mmol)was then added 2,4,6-trimethylpyridine (0,029 ml, 0.22 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0,040 g, 0.11 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:9→3:2 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 196,0, 168,5, of 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-dipertanyakan)benzoyl]-4-were-2-2,5-dioxoimidazolidin-4-yl)ndimethylacetamide (compound 248)

The as-5-acetic acid (0,022 g, 0.14 mmol) was dissolved in anhydrous DMF (4 ml). Added HATU (0,053 g, 0.14 mmol)was then added 2,4,6-trimethylpyridine (0,029 ml, 0.22 mmol). The mixture was stirred for 0.5 hours is, then was added the compound 494 (0,040 g, 0.11 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using MeOH/CH2Cl23:100 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CD3OD) δ 198,1, 177,6, 169,6, owed 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

{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}amide and 2,6-dioxotetrahydrofuran-4-carboxylic acid (compound 249)

D,L-Dihydroorotate acid (0,022 g, 0.14 mmol) was dissolved in anhydrous DMF (4 ml). Added HATU (0,053 g, 0.14 mmol)was then added 2,4,6-trimethylpyridine (0,029 ml, 0.22 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0,040 g, 0.11 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography, using EtOAc/acetone 10:1 as eluent. This gave specified in the title compound as a colourless solid.

13C NMR (DMSO-d6) δ 194,9, 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, 05,0 (DD), 50,3, 38,9, 19,1.

Example 150

2-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylphenylcarbinol}ethyl ester of acrylic acid (compound 250)

2-Carboxyethylidene level (0.041 ml, 0.35 mmol) was dissolved in anhydrous DMF (7 ml). Added HATU (of 0.13 g, 0.35 mmol)was then added 2,4,6-trimethylpyridine (of 0.07 ml, 0.54 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0.10 g, 0.27 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→70:30 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (DMSO-d6) δ 196,1, 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-dipertanyakan)benzoyl]-4-were}-3-methylsulfinylpropyl (compound 251)

3-Methylthiopropionate acid (0,067 g, 0.55 mmol) was dissolved in anhydrous DMF (16 ml). Added HATU (0.21 g, 0.55 mmol)was then added 2,4,6-trimethylpyridine (of 0.11 ml, 0.86 mmol). The mixture was stirred for 0.5 hours, then was added the compound 494 (0.16 g, 0.43 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture conc the Wali in vacuum, and the crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:9→1:1 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 196,1, 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-dipertanyakan)benzoyl]-4-were-3-methanesulfonamide (compound 252)

Compound 251 (0,22 g, 0.45 mmol) was dissolved in CH2Cl2(5 ml). Was slowly added 3-chloroperoxybenzoic acid (0.3 g, about 1.4 mmol)and the mixture was stirred at room temperature for 1 hour. Added Na2S2O5(0.34 g) and stirring continued for 0.5 hours. The mixture was filtered, and the filtrate was stirred with K2CO3for 0.5 hours. Added MgSO4and the mixture was filtered. The filtrate was concentrated in vacuo, and the crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 30:70→100:0 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 196,0, 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

{3-[2-Chloro-4-(2,4-gift is freilino)benzoyl]-4-were}amide econsultancy acid (compound 253)

Compound 494 (of 0.045 g, 0.12 mmol) was dissolved in pyridine (0.3 ml). Added acanaloniidae (0,017 ml, 0.18 mmol)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 and washed with H2O. the Aqueous phase was extracted with EtOAc, and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85->40:60 as the eluent. This gave specified in the title compound as a yellow solid.

13C NMR (CDCl3) δ 195,5, 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-dipertanyakan)benzoyl]-4-were}-4-methoxybenzenesulfonamide (compound 254)

The compound was obtained in the same way as described for connection 253 using the connection 494 (0.04 g, 0.11 mmol) and 4-methoxybenzenesulfonamide (0,033 g, 0.16 mmol) in pyridine (0.3 ml). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10:90->50:50 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,6, to 163.1, 159,2 (DD), 155,6 (DD), 148,0, 1398, 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-dipertanyakan)benzoyl]-4-methylphenylsulfonyl}-4-methylthiazole-2-yl)ndimethylacetamide (compound 255)

The compound was obtained in the same way as described for connection 253 using the connection 494 (0,042 g, 0.11 mmol) and 2-acetamido-4-methyl-5-thiazolecarboxamide (0,043 g, 0,17 mmol) in pyridine (0.3 ml). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 25:75→0:100 as eluent. This gave specified in the title compound 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-dipertanyakan)benzoyl]-4-were}benzosulfimide (compound 256)

The compound was obtained in the same way as described for connection 253 using the connection 494 (0,043 g, 0.12 mmol) and 2-chloro-5-acetylbenzenesulfonyl (0,044 g, 0,17 mmol) in pyridine (0.3 ml). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10:90→50:50 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3 ) δ 195,6, 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, of 124.1 (DD), 122,7, 116,0, 112,7, 111,7 (DD), 105,0 (DD), 26,6, 19,7.

Example 157

{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}amide naphthalene-2-sulfonic acid (compound 257)

The compound was obtained in the same way as described for connection 253 using the connection 494 level (0.041 g, 0.11 mmol) and naphthalene-2-sulphonylchloride (0.037 g, 0.16 mmol) in pyridine (0.3 ml). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10:90→50:50 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,4, 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-dipertanyakan)benzoyl]-4-were}-C phenylmethanesulfonyl (compound 258)

The compound was obtained in the same way as described for connection 253 using the connection 494 level (0.041 g, 0.11 mmol) and α-toluensulfonate (0,031 g, 0.16 mmol) in pyridine (0.3 ml). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10:90→50:50 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,5, 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-(3-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)ethyl ester 2-methylacrylate acid (compound 259)

Compound 494 (by 0.055 g, 0.15 mmol) was dissolved in anhydrous pyridine (0.3 ml), was added isocyanatoacetate (0,031 ml, 0.22 mmol). The solution was stirred at room temperature for 1 hour. Added H2O, and the aqueous phase was extracted with EtOAc (×2). The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 2:1 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (CDCl3) δ 196,5, 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-dipertanyakan)benzoyl]-4-were}-3-(2-hydroxyethyl)urea (compound 260)

Compound 259 (0.05 g, 0,095 mmol) was dissolved in EtOH (2.5 ml). Added 2n. NaOH (0.25 ml)and the solution boiled under reflux for 3 hours. The reaction mixture was cooled to room temperature, and doba is Lyali saturated aqueous NaHCO 3(2 ml). Added H2O and EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography, using EtOAc as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CD3OD) δ 198,5, owed 161.1 (DD), to 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

Ethyl ester of (3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)acetic acid (compound 261)

Compound 494 (0,047 g, 0.13 mmol) was dissolved in pyridine (0.3 ml) was added utilizationfocused (0,022 ml to 0.19 mmol). The solution was stirred at room temperature for 2 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13With NMR (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-differeni is amino)benzoyl]-4-were}-3-(3-methoxyphenyl)urea (compound 262)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 ml) was added 3-methoxyphenylalanine (to 0.016 ml, 0.12 mmol). The solution was stirred at room temperature for 1.5 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 2:3 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CD3OD) δ 198,3, of 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-dipertanyakan)benzoyl]-4-were}-3-(3-triptoreline)urea (compound 263)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 ml) was added 3-(trifluoromethyl)phenylisocyanate (of 0.017 ml, 0.12 mmol). The solution was stirred at room temperature for 1.5 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 2:3 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CD3OD) δ 198,3, owed 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 (kV), 130,7, 128,8, 127,5 (DD)16,0 (DD), 125,6 (kV), 123,4, 123,0, 121,2, 120,0 (kV), 116,6, 116,5 (kV)level 113.0, 112,6 (DD), or 105.8 (DD), 19,7.

Example 164

1-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-proprotein (compound 264)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 ml) was added n-propositional (to 0.011 ml, 0.12 mmol). The solution was stirred at room temperature for 18 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CD3OD) δ 198,5, 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

Ethyl ester of 3-(3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)propionic acid (compound 265)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 ml) was added ethyl 3-isocyanatopropyl (to 0.016 ml, 0.12 mmol). The solution was stirred at room temperature for 1.5 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as eluent. This gave specified in the header of the giving slightly colored solid.

13C NMR (CD3OD) δ 198,4, 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-dipertanyakan)benzoyl]-4-were}-3-cyclohexylamine (compound 266)

Compound 494 (0.07 g, 0.18 mmol) was dissolved in pyridine (0.5 ml) was added cyclohexylsulfamate (0.036 ml, 0.28 mmol). The solution was stirred at room temperature for 18 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CD3OD) δ 198,5, 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-dipertanyakan)benzoyl]-4-were}urea (compound 267)

Compound 494 (0.07 g, 0.18 mmol) was dissolved in pyridine (0.5 ml) was added arylisocyanate (of 0.025 ml, 0.28 mmol). The solution was stirred at room temperature for 18 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using a gradient tOAc/petroleum ether (40-60) 15:85→60:40 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CD3OD) δ 198,5, owed 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-dipertanyakan)benzoyl]-4-were}urea (compound 268)

Compound 494 (0.07 g, 0.18 mmol) was dissolved in pyridine (0.5 ml) was added benzylsuccinic (or 0.035 ml, 0.28 mmol). The solution was stirred at room temperature for 18 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using MeOH/CH2Cl21:100 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (DMSO-d6) δ 195,3, 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), to 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-dipertanyakan)benzoyl]-4-were}-3-atilmotin (compound 269)

Compound 494 (0.04 g, 0.11 mmol) was dissolved in 1,4-dioxane (0.5 ml) was added utilizationa (of 0.013 ml, 0.16 mmol). The solution was stirred at room temperature for 18 hours. Worked just as described for connection 259. The crude product is about what imali using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 30:70→100:0 as eluent. This gave specified in the title compound as an amorphous compound.

13C NMR (DMSO-d6) δ 195,6, 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-dipertanyakan)benzoyl]-4-were}-3-phenylacetone (compound 270)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxane (0.5 ml) was added phenylisocyanate (of 0.013 ml, 0.12 mmol). The solution was stirred at 50°C for 18 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as eluent. This gave specified in the title compound as an amorphous compound.

13C NMR (DMSO-d6) δ 195,1, 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-dipertanyakan)benzoyl]-4-were}urea (compound 271)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxane (0.5 ml), was added n-utilizationa (of 0.014 ml, 0.12 mmol). The solution was stirred at 50°C for 18 hours. Worked just as described to get connected what I 259. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CD3OD) δ 198,5, 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-dipertanyakan)benzoyl]-4-were}-3-phenethylamine (compound 272)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxane (0.5 ml) was added 2-generatesessionid (to 0.016 ml, 0.12 mmol). The solution was stirred at 50°C for 18 hours. Were processed as described for connection 259. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CDCl3) δ 196,5, 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

Methyl ester of 2-(3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)benzoic acid (compound 273)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxane (0.5 ml) was added methyl 2-isocyanatobenzene the (0,021 ml, 0.12 mmol). The solution was stirred at 50°C for 24 hours. Was added methyl 2-isocyanatobenzene (0.01 ml, 0.06 mmol). The solution was stirred at 50°C for 24 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10:90→40:60 as the eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,8, 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), of 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-dipertanyakan)benzoyl]-4-were}-3-(3-cyanophenyl)urea (compound 274)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxane (0.5 ml) was added 3-cyanobenzylidene (of 0.017 g, 0.12 mmol). The solution was stirred at 50°C for 24 hours. Added 3-cyanobenzylidene (0.09 g, 0.06 mmol). The solution was stirred at 50°C for 24 hours. Were processed as described for connection 259. The crude product was purified using flash chromatography using MeOH/CH2Cl21:100 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (DMSO-d6) δ 195,1, 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), 13,0, 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-dipertanyakan)benzoyl]-4-were}-3-Isopropylamine (compound 275)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxane (0.5 ml), and added isopropyltoluene (a 0.012 ml, 0.12 mmol). The solution was stirred at 50°C for 24 hours. Added isopropyltoluene (0,006 ml, 0.06 mmol). The solution was stirred at 50°C for 24 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (CD3OD) δ 198,4, 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-dipertanyakan)benzoyl]-4-were}-3-(4-methoxyphenyl)urea (compound 276)

Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxane (0.5 ml) was added 4-methoxyphenylalanine (to 0.016 ml, 0.12 mmol). The solution was stirred at 50°C for 18 hours. Worked just as described for connection 259. The crude product was purified using flash chromatography using MeOH/CH2Cl21:100 as eluent. Uh what about gave specified in the title compound in the form of oil.

13C NMR (DMSO-d6) δ 195,2, 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), to 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

Benzyl ether of {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 277)

Compound 494 (0.06 g, 0.16 mmol) suspended in anhydrous CH2Cl2(1.5 ml) in an argon atmosphere in a vessel with a screw cap. Added K2CO3storage capacity (0.044 g, 0.32 mmol), then benzylchloride (0,046 ml, to 0.032 mmol). The suspension was stirred for 18 hours at room temperature. Was added N2O and CH2Cl2and the phases were separated. The aqueous phase was washed CH2Cl2(×2) and the combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:4 as eluent. This gave specified in the title compound 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, 116,7, 112,9, 112,6 (DD)105,7 (DD), 67,6, 19,7.

Example 178

Allyl ether {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 278)

Compound 494 (0.06 g, 0.16 mmol) suspended the Wali in anhydrous CH 2Cl2(1.5 ml) in an argon atmosphere in a vessel with a screw cap. Added K2CO3storage capacity (0.044 g, 0.32 mmol), then allylchloroformate (0,034 ml, to 0.032 mmol). The suspension was stirred for 48 hours at room temperature. Were processed as described for connection 277. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 5:95→30:70 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,8, 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

Ethyl ester {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 279)

Compound 494 (0,039 g, 0.1 mmol) suspended in anhydrous CH2Cl2(1 ml) in an argon atmosphere. Added K2CO3(0,029 g, 0.21 mmol), then ethylchloride (0,02 ml, 0,021 mmol). The suspension was stirred for 48 hours at room temperature. Were processed as described for connection 277. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (CDCl3) δ 196,0, 159,1 (DD), 155,6 (DD), 153,7, 147,9, 1395, 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-dipertanyakan)phenyl]-[5-(3-hydroxyethylamino)-2-were]metano (compound 281)

Compound 494 (0,033 g, 0.09 mmol) suspended in MeOH (1 ml). Added 3-hydroxybutiric aldehyde (0,023 g, 0.27 mmol) and NaCN(BH3) (by 0.055 g, 0.88 mmol). The suspension was stirred at room temperature for 18 hours, again, was added 3-hydroxybutiric aldehyde (0,023 g, 0.27 mmol) and NaCN(BH3) (by 0.055 g, 0.88 mmol), and the suspension was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuum. The residue was dissolved in EtOAc and the organic phase is washed with salt solution. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using MeOH/CH2Cl21:50 as the eluent. This gave specified in the title compound in the form of oil.

13C NMR (CDCl3) δ 196,7, 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-dipertanyakan)phenyl]-(3'-hydroxymethyl-4-methylbiphenyl-3-yl)methanon (compound 282)

Compound 495 (0,039 g of 0.081 mmol) was dissolved in 1,2-Dimitar is ethane (0.8 ml) in a vessel with a screw cap. Was added 3-(hydroxymethyl)phenylboronic acid (0.015 g, 0,097 mmol) and saturated aqueous NaHCO3(0.4 ml). Argon was blown through the mixture, was added Pd(PPh3)4(0.005 g, 0.004 percent mmol). The reaction mixture was stirred at the boiling point under reflux in an argon atmosphere for 2 hours. Added H2O and EtOAc, and the aqueous phase was extracted with EtOAc (×2). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (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-dipertanyakan)phenyl]-(3'-hydroxy-4-methylbiphenyl-3-yl)methanon (compound 283)

The compound was obtained as described for connection 282. The original substance was compound 495 (0,039 g of 0.081 mmol), 3-hydroxyflavanone acid (0,013 g, 0,097 mmol) in 1,2-dimethoxyethane (0.8 ml), saturated aqueous NaHCO3(0.4 ml) and Pd(PPh3)4(0.005 g, 0.004 percent mmol). The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as eluent. This gave specified the title compound as a yellow oil.

13C NMR (CDCl3) δ 196,7, 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-dipertanyakan)phenyl]-(4'-methoxy-4-methylbiphenyl-3-yl)methanon (compound 284)

The compound was obtained as described for connection 282. The original substance was compound 495 (0,042 g, 0,087 mmol), 4-methoxyphenylalanine acid (0,016 g, 0.11 mmol) in 1,2-dimethoxyethane (1 ml), saturated aqueous NaHCO3(0.5 ml) and Pd(PPh3)4(0.005 g, 0.004 percent mmol). The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:5 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 196,4, 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-dipertanyakan)benzoyl]-4'-methylbiphenyl-3-yl}ndimethylacetamide (compound 285)

The compound was obtained as described for connection 282. The original substance was compound 495 (0,048 g, 0.1 mmol), 3-acetaminophenydrocodone acid (0,021 g, 0.12 mmol) in 1,2-dimethoxyethane (1 ml), saturated aqueous NaHCO3(0.5 ml) and Pd(PPh3)4(0,006 g, of 0.005 mmol). The crude product was purified using flash chromatography, ISOE is isua EtOAc/petroleum ether (40-60) 1:1 as eluent. This gave specified in the title compound in the form of faintly colored solid.

13C NMR (DMSO-d6) δ 195,0, 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-dipertanyakan)phenyl]-(4-methyl-3'-cryptomaterial-3-yl)methanon (compound 286)

The compound was obtained as described for connection 282. The original substance was compound 495 (0,048 g, 0.1 mmol), 3-(triptoreline)bentlebanonrola acid (0.025 g, 0.12 mmol) in 1,2-dimethoxyethane (1.2 ml), saturated aqueous NaHCO3(0.6 ml) and Pd(PPh3)4(0,006 g, of 0.005 mmol). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether(40-60) 2:98→10:90 as eluent. This gave specified in the title compound as a yellow oil.

Example 188

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(3',4',5'-Cryptor-4-methylbiphenyl-3-yl)methanon (compound 288)

The compound was obtained as described for connection 282. The original substance was compound 495 (by 0.055 g, 0.11 mmol), 3,4,5-triftorbyenzola acid (0,024 g, 0.14 mmol) in 1,2-dimethoxyethane (1.2 ml), saturated aqueous NaHCO3(0.6 ml) and Pd(PPh3)4(0,007 g 0,006 mmol). The crude product was purified using flash chromatography, IP is by using a gradient of EtOAc/petroleum ether (40-60) 2:98→10:90 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,8, 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), to 116.2, 112,7, 111,6 (DD), 110,9 (m), 105,0 (DD), 20,1.

Example 189

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(3',4'-dimethoxy-4-methylbiphenyl-3-yl)methanon (289)

The compound was obtained as described for connection 282. The original substance was compound 495 (by 0.055 g, 0.11 mmol), 3,4-dimethoxybenzophenone acid (0.025 g, 0.15 mmol) in 1,2-dimethoxyethane (1.2 ml), saturated aqueous NaHCO3(0.6 ml) and Pd(PPh3)4(0,007 g 0,006 mmol). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 12:88→50:50 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 196,4, 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-dipertanyakan)benzoyl]-4'-methylbiphenyl-3-carbonitrile (compound 290)

The compound was obtained as described for connection 282. The original substance was compound 495 (0,057 g, 0.12 mmol), 3-cyanobenzeneboronic acid (0,021 g, 0.14 mmol) in 1,2-dimethoxyethane (1.2 ml), saturated aqueous NaHCO3(0.6 ml) and Pd(PPh3) (0,007 g 0,006 mmol). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 2:3→4:1 as eluent. This gave specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 195,9, 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.

Getting 96

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzenesulfonamide (compound 496)

Compound 494 (1,03 g, was 2.76 mmol) was dissolved in CH3CN (65 ml) under heating. The solution was cooled to room temperature and was added concentrated HCl (37%, 1.2 ml, approximately 14 mmol) and AcOH (99%, and 2.3 ml). The solution was cooled in an ice bath, and controlling the temperature of the reaction mass. NaNO2(0,23 g of 3.31 mmol), dissolved in H2O (0.6 ml)was added over 15 minutes with stirring. The temperature of the reaction mixture did not exceed 2 ° C objective. The mixture was stirred in an ice bath for 20 minutes, then barbotirovany gaseous SO2through the mixture for 45 minutes with stirring in an ice bath. Added CuCl (0,37 g, 3.8 mmol), then CuCl2·H2O (0,59 g, 3.46 mmol) was dissolved in H2O (0.6 ml). The mixture was stirred at C for 10 minutes, then stirred at room temperature for 1 hour. The mixture was concentrated in in the cosmology vacuum and dissolved in EtOAc and H 2O. the Phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:4 as eluent to obtain specified in the title compounds as a pale brown crystalline substance.

Example 191

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide (compound 291)

Connection 496 (0.07 g, 0.15 mmol) was dissolved in pyridine (0.4 ml), was added ethanolamine (to 0.011 ml, 0.18 mmol). The solution was left at room temperature for 1 hour, then concentrated in vacuo. The residue was dissolved in EtOAc and H2O, and the phases were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 3:7→1:0 as eluent. This gave specified in the title compound in the form of solids.

13C NMR (CD3OD) δ 196,5, 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), or 105.8 (DD), 61,8, 46,3, 20,3.

Example 192

3-[2-Chloro-4-(2,4-dipertanyakan is)benzoyl]-4-methyl-N-(2-morpholine-4-retil)benzosulfimide (compound 292)

The connection was received and processed similarly as described for connection 291. The original substance was compound 496 (of 0.081 g, 0.18 mmol) and 4-(2-amino-ethyl)morpholine (0,028 ml, 0.21 mmol) in pyridine (0.5 ml). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:1→1:0 as eluent. This gave specified in the title compound as an amorphous compound.

13C NMR (CDCl3) δ 194,5, 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-dipertanyakan)benzoyl]-4-methylbenzenesulfonamide (compound 293)

The connection was received and processed similarly as described for connection 291. The original substance was compound 496 (0,071 g, 0.16 mmol) and allylamine (of 0.014 ml, 0,l9 mmol) in pyridine (0.4 ml) the Crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:4→2:3 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (CDCl3) δ to 194.6, 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-dipertanyakan)benzoyl]-4-methylbenzenesulfonamide}ethyl)ndimethylacetamide (with the unity 294)

The connection was received and processed similarly as described for connection 291. The original substance was compound 496 (0.075 g, 0,17 mmol) and N-acetylethylenediamine is 0.019 ml, 0.2 mmol) in pyridine (0.4 ml). The crude product was purified using flash chromatography using a gradient of DCM/MeOH 95:5→80:20 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (CDCl3) to 194.6 δ, which is 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-dipertanyakan)benzoyl]-4-methyl-N-propylbenzenesulfonyl (compound 295)

The connection was received and processed similarly as described for connection 291. The original substance was compound 496 (0,074 g, 0.16 mmol) and N-Propylamine (0,016 ml, 0.2 mmol) in pyridine (0.4 ml). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:4→3:2 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (CDCl3) δ 194,7, 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-dipertanyakan)benzoyl-N-(2,3-dihydroxypropyl)-4-methylbenzenesulfonamide (compound 296)

Connection p which were given and treated like as described for connection 291. The original substance was compound 496 (0,073 g, 0.16 mmol) and 3-amino-1,2-propandiol (0,017 g 0,19 mmol) in pyridine (0.4 ml). The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:1→1:0 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (CDCl3) δ 194,8, 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 (sird), 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-dipertanyakan)benzoyl]-N-(2-methoxyethyl)-4-methylbenzenesulfonamide (compound 297)

The connection was received and processed similarly as described for connection 291. The original substance was compound 496 (0.03 g, of 0.066 mmol) and 2-methoxyethylamine (0,007 ml, 0.08 mmol) in pyridine (0.15 ml). The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 3:2 as eluent. This gave specified in the title compound in the form of oil.

13C NMR (CDCl3) δ 194,5, 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.

Getting 97

Methyl ester of 2-methyl-5-nitrobenzoic acid (compound 497)

Acetylchloride (15 ml) was added to MeOH (500 ml) at room temperature. After 10 minutes add ulali 2-methyl-5-nitrobenzoic acid (25,00 g, 138,00 mmol). The reaction solution was boiled under reflux for 18 hours. Then the solution was concentrated in vacuum. The residue was dissolved in diethyl ether and washed with H2O and saturated aqueous NaHCO3, respectively. The organic phase was dried over MgSO4and concentrated in vacuum to obtain specified in the title compound as a white solid.

Getting 98

Methyl ester of 5-amino-2-methylbenzoic acid (compound 498)

Connection 497 (26.5 g, 135,78 mmol) in ethanol (200 ml) was first made under the pressure of 1 ATM at room temperature in the presence of Pd/C 5% (2.00 g) for 3 hours. After completion of the reaction the catalyst was filtered. The filtrate was concentrated in vacuum to obtain specified in the title compound as a brownish oil.

Getting 99

Methyl ester of 5-hydroxy-2-methylbenzoic acid (compound 499)

To 2n. H2SO4(200 ml) was added dropwise NaNO2(11,50 g, 167,00 mmol) in H2O (100 ml) at 0°C. After stirring at the same temperature for 20 minutes, the reaction mixture is boiled under reflux for 2 hours. Then the solution was cooled to room temperature and stirred at the same temperature throughout the night. The mixture was extracted three times with CHCl3. The combined organic f the PS was dried over MgSO 4and concentrated in vacuum. The residue was purified by chromatography (CH2Cl2/ethyl acetate 50:1), obtaining specified in the title compound as a red solid.

Getting 100

Methyl ester 5-(4-methoxybenzyloxy)-2-methylbenzoic acid (compound 500)

The mixture of compounds 499 (4.4 g, 26,48 mmol), 4-methoxybenzylamine (4.4 g, 28,09 mmol), K2CO3(4.4 g, 31,83 mmol) and NaI (20 mg) was boiled under reflux for 3 hours. After completion of the reaction, the solid was filtered. The filtrate was concentrated in vacuum. The residue was purified by chromatography (petroleum ether/CH2Cl22:1, then CH2Cl2), with specified title compound as a yellow solid.

Getting 101

[5-(4-Methoxybenzyloxy)-2-were]methanol (compound 501)

To a solution of compound 500 (6.0 g, 21.00 mmol) in CH2Cl2(100 ml) at -78°C was added DIBAL-H (1M in n-hexane, 55 ml, 55 mmol). The solution was heated to room temperature and was stirred for 1 hour. Then the reaction solution was suppressed saturated aqueous NH4Cl. The mixture was filtered and washed with acetone. The combined liquids were concentrated in vacuo to remove acetone and CH2Cl2. The aqueous mixture was extracted three times with CH2Cl2. Together the major organic phase was dried over MgSO 4and concentrated in vacuum to obtain specified in the title compound as grayish solid.

Getting 102

5-(4-Methoxybenzyloxy)-2-methylbenzaldehyde (compound 502)

To a solution of compound 501 (of 5.06 g, 19,59 mmol) in CH2Cl2(100 ml) was added periodinane dessa-Martin (at 8.36 g, 19,71 mmol) at room temperature for 20 minutes. Then the mixture was stirred for 1 hour. After complete conversion the reaction mixture was concentrated in vacuo with silica gel. The residue was purified by chromatography (CH2Cl2) obtaining specified in the title compound as a yellow solid.

Getting 103

(4-Bromo-2-nitrophenyl)-[5-(4-methoxybenzyloxy)-2-were]methanol (compound 503)

To a solution of 1,4-dibromo-2-nitrobenzene (of 5.89 g, 21.00 mmol) in THF (300 ml) solution was added PhLi (1.8m in cyclohexane/diethyl ether 7:3, of 12.8 ml of 23.1 mmol) at -110°C. the Mixture was stirred at the same temperature for 1 hour. To the mixture was added dropwise the compound 502 (4,45 g of 17.4 mmol) in THF (100 ml). Then the reaction mixture was left to warm to -78°C and stirred at the same temperature for 4 hours. Then the reaction mixture was extinguished saturated aqueous NH4Cl. The aqueous phase was extracted once with diethyl ether. The combined organic phases sushi is whether over MgSO 4and concentrated in vacuum. The residue was purified by chromatography (petroleum ether/ethyl acetate 5:1), with a reddish foam.

Getting 104

(4-Bromo-2-nitrophenyl)-[5-(4-methoxybenzyloxy)-2-were]metano (compound 504)

To a solution of compound 503 (6,47 g of 14.12 mmol) was added in one portion at room temperature periodinane dessa-Martin (8.00 g, 18,86 mmol). After stirring at room temperature for 3 hours, the reaction mixture was purified by chromatography (petroleum ether/ethyl acetate 10:1) obtaining specified in the title compound as a brownish oil.

Example 198

[4-(4-Fluoro-2-methylphenylimino)-2-nitrophenyl]-[5-4-methoxybenzyloxy)-2-were]metano (compound 298)

Connection 504 (0.6 g, 1.35 mmol) was dissolved in 1,4-dioxane (15 ml). Was added 4-fluoro-2-methylaniline (to 0.22 ml, 2.0 mmol), Cs2CO3(0,61 g, 1.88 mmol), BINAP (0.06 g, 0.1 mmol) and Pd2(dba)3(0,031 g, 0.03 mmol)and the reaction mixture was stirred in argon atmosphere at 100°C for 18 hours. Added H2O and the aqueous phase was extracted with EtOAc (×2). The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 0:100→30:70. This Ravalomanana in the header of the connection.

1H NMR (CDCl3) δ to 7.32 (d, 1H), 7,30-7,14 (m, 4H), 7,11 (d, 1H), 7,06-6,91 (m, 3H), to 6.88 (m, 2H), 6,84-6,77 (m, 2H), by 5.87 (Sirs, 1H), 4,88 (c, 2H), 3,80 (c, 3H), 2.49 USD (c, 3H), 2,25 (c, 3H).

Getting 105

[4-(4-Fluoro-2-methylphenylimino)-2-nitrophenyl]-(5-hydroxy-2-were)methanon (compound 505)

Compound 298 (0,57 g to 1.14 mmol) was dissolved in CH2Cl2(10 ml) and added CF3COOH (10 ml). The reaction mixture was stirred at room temperature for 2 hours, then the solvent was concentrated. The solid is recrystallized from CH2Cl2. This gave specified in the title compound in the form of solids.

Example 199

[4-(4-Fluoro-2-methylphenylimino)-2-nitrophenyl]-[5-(3-hydroxypropoxy)-2-were]metano (compound 299)

Compound 505 (0.05 g, 0.13 mmol) and 3-chloropropanol (of 0.022 ml, 0.26 mmol) was dissolved in CH3CN (3 ml). Added K2CO3(0.1 g, to 0.72 mmol) and NaI (0.005 g, 0.03 mmol) and the suspension was heated in a microwave oven at 100°C for 20 minutes. The suspension was filtered, and the filtrate was concentrated in vacuum. The crude product was purified using flash chromatography, using EtOAc/CH2Cl21:9 as eluent. This gave specified in the header of the connection.

1H NMR (CDCl3) δ of 7.36 (d, 1H), 7,22 (DD, 1H), 7,17 (d, 1H), 7,10 (d, 1H), 7,06-6,89 (m, 3H), 6,83 (DD, 1H), 6,79 (d, 1H), 5,88 (Sirs, 1H), Android 4.04 (t, 2H), 3,82 (t, 2H), 2,47 (c, 3H), 2,25 (c, 3H), of 1.99 (m, 2H).

Example 200

[2-Amino-4-(4-fluoro-2-methylphenylimino)phenyl]-[5-(3-hydroxypropoxy)-2-were]metano (compound 300)

Compound 299 (was 0.026 g, 0,059 mmol) was dissolved in MeOH (2 ml). Added a catalytic amount of palladium on charcoal, and the mixture was stirred in hydrogen atmosphere for 1 hour. The suspension was filtered, and the filtrate was concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:1→3:1 as eluent. This gave specified in the header of the connection.

1H NMR (CDCl3) δ 7.18 in (DD, 1H), 7,11 (d, 1H), 7,03 (d, 1H), 7,00-to 6.80 (m, 3H), 6,76 (d, 1H), 6,45 (Sirs, 2H), of 5.89 (DD, 1H), of 5.75 (d, 1H), 5,59 (c, 1H), 4,08 (t, 2H), 3,83 (t, 2H), 2,22 (c, 3H), 2,18 (c, 3H), a 2.01 (m, 2H,).

Getting 106

2,2-Dimethyl-[1,3]-dioxolane-4-ymetray ester toluene-4-sulfonic acid (compound 506)

2,2-Dimethyl-4-hydroxymethyl-1,3-dioxolane (3,96 g, 30 mmol) and triethylamine (5 ml) was dissolved in CH2Cl2(50 ml). Added p-toluensulfonate (3.8 g, 20 mmol). The solution was stirred for 3 hours, then was added 4-dimethylaminopyridine (0.05 g, 0.04 mmol). The solution was stirred for 0.5 hours, then the solution was concentrated in vacuum. The residue was treated with CH2Cl2and the organic phase is washed with H2O, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using F. the ash-chromatography with obtaining specified in the connection header.

Example 201

[5-(2,2-Dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-were]-[4-(4-fluoro-2-methylphenylimino)-2-nitrophenyl]metano (compound 301)

Compound 505 (0.05 g, 0.13 mmol) and compound 506 (0,056 g, 0.2 mmol) was dissolved in CH3CN (3 ml). Added K2CO3(0.1 g, to 0.72 mmol) and NaI (0.005 g, 0.03 mmol), and the suspension was heated in a microwave oven at 100°C for 20 minutes and stirred at room temperature for 16 hours. The suspension was filtered, and the filtrate was concentrated in vacuum. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 0:1→1:4 as eluent. This gave specified in the header of the connection.

1H NMR (CDCl3) δ 7,34 (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 (Sirs, 1H), 4,42 (m, 1H), 4,17-4,06 (m, 1H), 3.96 points (DD, 1H), 3,90-of 3.78 (m, 2H), 2,46 (c, 3H), 2,25 (c, 3H), 1,43 (c, 3H), 1,38 (c, 3H).

Example 202

[5-(2,3-Dihydroxypropane)-2-were]-[4-(4-fluoro-2-methylphenylimino)-2-nitrophenyl]metano (compound 302)

Compound 301 (0.025 g, 0.05 mmol) was dissolved in THF (2 ml) was added 1M HCl (0.2 ml). The solution was left at room temperature for 3 hours, then the solution was concentrated in vacuum. This gave specified in the header of the connection.

1H NMR (CDCl3) δ of 7.36 (d, 1H), 7,22 (DD, 1H), 7,18 (d, 1H), 7,10 (d, 1H), 7,06-to 6.88 (m, 3H), 6.87 in-6,77 (m, 2H), of 5.89 (Sirs, 1H), of 4.05 (m, 1H), 3,95 (m, 2H), 3,85-the 3.65 (m, 2H), 2,46 (c, H), 2,25 (c, 3H).

Example 203

[2-amino-4-(4-fluoro-2-methylphenylimino)phenyl]-[5-(2,3-dihydroxypropane)-2-were]metano (compound 303)

Compound 302 (0.025 g, by 0.055 mmol) was dissolved in MeOH (2 ml). Added a catalytic amount of palladium on charcoal, and the mixture was stirred in hydrogen atmosphere for 1 hour. The suspension was filtered, and the filtrate was concentrated in vacuum. The crude product was purified using preparative HPLC. This gave specified in the header of the connection.

1H NMR (CDCl3) δ 7,19 (DD, 1H), 7,13 (d, 1H), 7,05-PC 6.82 (m, 4H), 6,76 (d, 1H), 6,46 (Sirs, 2H), of 5.89 (DD, 1H), of 5.75 (d, 1H), 5.56mm (Sirs, 1H), 4,15-3,93 (m, 3H), 3,80 (DD, 1H), 3,71 (DD, 1H), 2,65 (Sirs, 1H), 2,23 (c, 3H), 2,19 (c, 3H), 2,10 (Sirs, 1H).

Example 204

[4-(4-fluoro-2-methylphenylimino)-2-nitrophenyl]-[2-methyl-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 304)

Compound 505 (0.083 g, 0.22 mmol) and the hydrochloride of N-(2-chloroethyl)of the research (0,082 g, 0.44 mmol) suspended in CH3CN (5 ml). Added K2CO3(0.17 g, 1.2 mmol) and NaI (0.008 g, 0.05 mmol), and the suspension was heated in a microwave oven at 130°C for 40 minutes. The suspension was filtered, and the filtrate was concentrated in vacuum. The crude product was purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 2:3→1:0 as eluent. This gave specified in the header of the connection.

1H NMR (CDCl3) δ 7,34 (d, 1H), 7,21 (DD 1H), 7,17 (d, 1H), 7,10 (d, 1H), 7,05-to 6.88 (m, 3H), 6,85-of 6.78 (m, 2H), 6,16 (c, 1H), was 4.02 (t, 2H), and 3.72 (m, 4H), to 2.75 (t, 2H), 2,54 (m, 4H), 2,45 (c, 3H), 2,25 (c, 3H).

Example 205

[2-Amino-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 305)

Connection 304 level (0.041 g, 0,083 mmol) was dissolved in MeOH (2 ml). Added a catalytic amount of palladium on charcoal, and the mixture was stirred in hydrogen atmosphere for 1 hour. The suspension was filtered, and the filtrate was concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 3:1→6:1 as eluent. This gave specified in the header of the connection.

1H NMR (CDCl3) δ 7,19 (DD, 1H), 7,11 (d, 1H), 7,03 (d, 1H), 7,00-to 6.80 (m, 3H), 6,76 (d, 1H), 6,46 (Sirs, 2H), of 5.89 (DD, 1H), of 5.75 (d, 1H), ceiling of 5.60 (c, 1H), 4,07 (t, 2H), 3,71 (m, 4H), 2,77 (t, 2H), by 2.55 (m, 4H), 2,23 (c, 3H), 2,18 (c, 3H).

Example 206

[4-(2,4-Dipertanyakan)-2-nitrophenyl]-[5-(4-methoxybenzyloxy)-2-were]metano (compound 306)

2,4-Dipertanyakan (26 μl, 0.25 mmol) was dissolved in anhydrous 1,4-dioxane (3 ml) in a flask in an argon atmosphere. Added connection 504 (114 mg, 0.25 mmol) and was dissolved in the solvent. Added rac-BINAP (7,0 mg, 0.012 mmol), Pd2(dba)3(7,0 mg, 0,008 mmol) and Cs2CO3(114 mg, 0.35 mmol)and the reaction mixture was stirred in argon atmosphere at 100°C for 16 hours. The reaction mixture was filtered through celite and the ZAT is purified using flash chromatography with a continuous gradient, using EtOAc/petroleum ether (40-60) (vol.:about. = 1:9-1:3) as eluent to obtain specified in the connection header in the form of solid colors of yellow curry.

13C NMR (CDCl3) δ 194,5, 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.

Getting 107

[4-(2,4-Dipertanyakan)-2-nitrophenyl]-(5-hydroxy-2-were)methanon (compound 507)

Connection 306 (90 mg, 0,178 mmol) was dissolved in anhydrous DCM (5 ml). Added TFA (5 ml)and the reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuum to obtain the crude product as a beige/not quite white solid.

Example 207

[4-(2,4-Dipertanyakan)-2-nitrophenyl]-[5-(3-hydroxypropoxy)-2-were]metano (compound 307)

Connection 507 (66 mg, 0,17 mmol) was dissolved in acetonitrile (3 ml) in a reaction flask. Added 3-chloropropane-1-ol (22 μl, 0.26 mmol), K2CO3(36 mg, 0.26 mmol) and NaI (catalytic amount). The reaction vessel was purged with argon, closed and then stirred at 170°C for 15 minutes in a microwave oven. The reaction mixture was left to cool to room temperature and then poured into a mixture of EtOAc/water. The layers were separated, and the organic phase was dried (MgSO4), filtered and the end of what was tribali in vacuum to obtain the crude product. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about. = 1:9-1:1) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 194,4, 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-dipertanyakan)phenyl]-[5-(3-hydroxypropoxy)-2-were]metano (compound 308)

Compound 307 (46 mg, 0.1 mmol) was dissolved in EtOH (5 ml)was purged with argon was added Pd/C (catalytic amount). The flask was purged H2within 2 minutes and was stirred in an atmosphere of H2at room temperature for 1 hour. The reaction mixture was filtered through celite and concentrated in vacuum. Was purified using flash chromatography with a continuous gradient, using DCM/MeOH (vol.:about. = 100:0-95:5) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (DMSO-d6) δ 196,3, 158,9 (DD), 156,2, 155,6 (DD), 154,2, 150,8, 142,2, 135,6, 131,1, 127,0 (DD), 125,2, of 124.8 (DD), 114,5, to 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-Dipertanyakan)-2-nitrophenyl]-[2-methyl-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 309)

Connection 507 (50 mg, 0.13 mmol) was dissolved in acetonitrile (3 ml) in a reaction flask, add recipients is whether hydrochloride 4-(2-chloroethyl)of the research (48 mg, 0.26 mmol), K2CO3(72 mg, 0.52 mmol) and NaI (catalytic amount). The reaction vessel was purged with argon, closed and then stirred at 170°C for 10 minutes in a microwave oven, then boiled under reflux on an oil bath for 40 hours. Was added to the reaction mixture EtOAc (30 ml) and washed with H2O (2×20 ml), brine (2×20 ml). The organic phase was dried (Na2SO4), filtered, concentrated in vacuo and purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about. = 2:1-100:0) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ for 194.3, 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-dipertanyakan)phenyl]-[2-methyl-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 310)

The reaction was carried out similarly as described for connection 308, using the connection 309 (18 mg, being 0.036 mmol) as the nitro compounds. Was stirred in an atmosphere of H2for 16 hours. Was purified using flash chromatography, using EtOAc as eluent, to obtain specified in the connection header in the form of oil.

13C NMR (CDCl3) δ 198,4, 156,4, 153,5, 149,7, 141,9, 137,1, 131,4, 126,9, 124,8 DD), 115,5, 112,8, to 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-Dipertanyakan)-2-nitrophenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-were]metano (compound 311)

Connection 507 (50 mg, 0.13 mmol) was dissolved in acetonitrile (3 ml) in a reaction flask. Added connection 506 (75 mg, 0.26 mmol), K2CO3(36 mg, 0.26 mmol) and NaI (catalytic amount). The reaction vessel was purged with argon, closed and then stirred at 170°C for 10 minutes in a microwave oven, then boiled under reflux in an oil bath for 40 hours. Was added to the reaction mixture EtOAc (30 ml) and washed with H2O (2×20 ml), brine (2×20 ml). The organic phase was dried (Na2SO4), filtered, concentrated in vacuo and purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:9-1:3) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ for 194.3, 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-Dipertanyakan)-2-nitrophenyl]-[5-(2,3-dihydroxypropane)-2-were]metano (compound 312)

Compound 311 (48 mg, 0.01 mmol) was dissolved in TFA:H2O (3:1, 8 ml) and stirred at anatoy temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified using flash chromatography using EtOAc/petroleum ether (40-60) (vol.:about.=1:1) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (DMSO-d6) δ 193,5, 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-dipertanyakan)phenyl]-[5-(2,3-dihydroxypropane)-2-were]metano (compound 313)

The reaction was carried out similarly as described for connection 308, using the connection 312 (48 mg, 0,096 mmol) as the nitro compounds. Was stirred in an atmosphere of H2for 16 hours. Was purified using flash chromatography using EtOAc/petroleum ether (40-60) (1:1) as eluent, to obtain specified in the title compounds as colorless oils.

1H NMR (DMSO-d6) δ 8,32 (c, 1H), 7,42-7,29 (m, 2H), 7,15 (d, 1H), to 7.09 (m, 1H), 6.89 in (DD, 1H), PC 6.82 (d, 1H), 6,66 (d, 1H), 6,02-of 5.92 (m, 2H), 3,97 (DD, 1H), a 3.87-3,30 (m, 4H), 2.05 is (c, 3H).

Getting 108

2-Fluoro-5-hydroxybenzaldehyde (compound 508)

2-Fluoro-5-methoxybenzaldehyde (4 g, 26 mmol) was dissolved in anhydrous DCM (25 ml) in an argon atmosphere, was cooled to 0°C and slowly added tribromide boron (26 ml, 1,0M in DCM, 26 mmol). After complete addition, the reaction mixture was left to warm to room temperature the s and was stirred for 16 hours in an argon atmosphere. Reaction carefully extinguished with water (10 ml)was added saturated NaHCO3(30 ml), then was shaken and the layers were separated. The aqueous phase was extracted with two more portions of DCM. The organic phases were combined, extracted with 2n. NaOH (2×100 ml). United NaOH-phase was acidified with HCl (concentrated) and was extracted with DCM (4×150 ml). The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. Was purified by chromatography using EtOAc/petroleum ether (40-60) (vol.:about.=1:5) as eluent to obtain specified in the title compound as a white solid.

Getting 109

5-(tert-Butyldimethylsilyloxy)-2-forbindelse (compound 509)

Connection 508 (1.5 g, of 10.7 mmol) was dissolved in anhydrous DMF (40 ml) in an argon atmosphere. Added tert-BUTYLCARBAMATE (2,43 g, 16,1 mmol) and imidazole (1.1 g, 16,1 mmol). Was stirred at room temperature for 2 hours, was added EtOAc (250 ml) and then washed with water (2×100 ml), 4% MgSO4(2×75 ml), dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product as a yellow oil. Was purified by chromatography using EtOAc/petroleum ether (40-60) (1:20) as eluent, to obtain specified in the title compounds as a colorless, clear oil.

Poluchenie

(4-Bromo-2-chlorophenyl)-[5-(tert-butyldimethylsilyloxy)-2-forfinal]methanol (compound 510)

In a dry flask was loaded with 4-bromo-2-chloro-1-iodobenzoyl (10,9 g, 34.5 mmol) and the flask was evaporated and then filled with argon, this process was repeated twice. Added anhydrous THF (100 ml)and the solution was cooled to -50°C; then slowly added isopropylaniline (17.3 ml, 2,0M in diethyl ether, 34.5 mmol) over 15 minutes, maintaining the temperature below -40°C. After complete addition, the reaction mixture was stirred at -40°C for 45 minutes. The temperature was raised to -25°C for 5 minutes and then lowered to -40°C, then slowly added the solution of compound 509 in anhydrous THF (15 ml). After complete addition, the reaction mixture was stirred at -40°C for 10 minutes and then left to warm to 5°C for 2.5 hours. The reaction mixture was slowly poured into ice-cold 2n. a solution of H2SO4(200 ml) and was extracted with EtOAc. The aqueous phase was extracted with four portions of EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product as a brown oil. Used without any additional purification.

Getting 111

(4-Bromo-2-chlorophenyl)-(2-fluoro-5-hydroxyphenyl)methanon (compound 511)

Connection 510 (15.9 g, a 35.6 mmol) was dissolved in betw the bottom DCM (80 ml) and anhydrous acetonitrile (10 ml) in an argon atmosphere. The mixture was cooled to 0°C was added 4-oxide 4-methylmorpholine (6,27 g, of 53.5 mmol), powdered molecular sieve (4Å, 17.8 g). Added perruthenate Tetra-N-Propylamine (VII) (250 mg, 0.71 mmol) in 5 portions (5×50 mg)and the reaction mixture was stirred for 10 minutes at 0°C, was evaporated to 1/3 volume and filtered through silica gel. The silica gel was washed with EtOAc (300 ml). The organic phase was concentrated in vacuum to obtain the crude product. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:80-1:10) as eluent, to obtain specified in the title compound as a yellow solid.

Getting 112

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(2-fluoro-5-hydroxyphenyl)methanon (compound 512)

Connection 511 (200 mg, 0.6 mmol) was dissolved in anhydrous 1,4-dioxane (5 ml) in a reaction flask in an argon atmosphere. Added 2,4-dipertanyakan (78 mg, 62 μl, 0.6 mmol) and was dissolved in the solvent. Added rac-BINAP (17 mg, 0,028 mmol), Pd2(dba)3(17 mg, 0.018 mmol) and Cs2CO3(277 mg, 0.85 mmol). The reaction vessel was purged with argon, closed and then was stirred at 130°C for 40 minutes in a microwave oven. The reaction mixture was left to cool to room temperature, filtered through celite and then purified using flash chromatography with continuous Gras is antom, using EtOAc/petroleum ether (40-60) (vol.:about.=1:7-1:3) as eluent, to obtain specified in the title compound as a yellow solid.

Example 214

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 314)

Connection 512 (38 mg, 0.1 mmol) was dissolved in acetonitrile (2 ml) in a reaction flask. Added 3-chloropropane-1-ol (11 μl, 0.12 mmol), K2CO3(17 mg, 0.12 mmol) and NaI (catalytic amount). The reaction vessel was purged with argon, closed and then was stirred at 130°C for 20 minutes in a microwave oven. The reaction mixture was left to cool to room temperature and then poured into a mixture of EtOAc/water. The aqueous phase was acidified with HCl (4n.), and the layers were separated. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:3-1:1) as eluent, to obtain specified in the title compound as a yellow solid.

13C NMR (CDCl3) δ 190,8, 159,1 (DD), 155,6 (DD), was 155.3 (d), 155,0 (d), 148,0, 134,7, 133,0, 129,4, 127,9 (d), to 124.4 (m), to 120.4 (d), 117,1 (d), 116,0, or 115.1 (d), 112,8, 111,6 (DD), 104,9 (DD), 66,3, 60,0, 32,0.

Example 215

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[5-(,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-forfinal]metano (compound 315)

Connection 512 (54 mg, 0.14 mmol) was dissolved in acetonitrile (4 ml) in a reaction flask. Added connection 506 (61 mg, 0.21 mmol) and K2CO3(30 mg, 0.21 mmol). The reaction vessel was purged with argon, closed and then was stirred at 110°C for 50 minutes in the microwave, then boiled under reflux in an oil bath for 24 hours. The reaction mixture was concentrated in vacuo and purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:7-1:3) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 190,6, 159,1 (DD), 154,7, 154,5 (d), 154,4 (DD), 147,8, 134,7, 132,9, 129,6, 127,9 (d), to 124.4 (DD), 124,2 (DD)120,6 (d), 117,1 (d), 116,0, or 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-differentiability]-[5-(2,3-dihydroxypropane)-2-forfinal]metano (compound 316)

Compound 315 was dissolved in TFA:water (3:1, 8 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:2-100:0) as eluent, to obtain specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 189,3, 158,8 (DD)155,7 (DD), 154,9 (d), 153,8 (d), of 149.5, 133,5, 133,4, 127,8 d), 126,5 (DD), 126,3, of 124.1 (DD), 119,7 (d), 117,1 (d), USD 114.9 (d), to 114.7, 112,0 (DD), 111,7, 105,0 (DD), 70,4, 69,8, 62,5.

Getting 113

[2-Chloro-4-(4-chloro-2-methylphenylimino)phenyl]-(2-fluoro-5-hydroxyphenyl)methanon (compound 513)

4-Chloro-2-methylphenylamine (73 μl, of 0.60 mmol) was dissolved in 5 ml of anhydrous 1,4-dioxane in the reaction flask in an argon atmosphere. Added connection 511 (200 mg, of 0.60 mmol) and was dissolved in the solvent. Added rac-BINAP (18 mg, 0,028 mmol), Pd2(dba)3(17 mg, 0.018 mmol) and Cs2CO3(277 mg, 0.84 mmol). The reaction vessel was purged with argon, closed and then was stirred at 130°C for 10 minutes in a microwave oven. The reaction mixture was filtered through celite and then purified using flash chromatography with a continuous gradient. using EtOAc/petroleum ether (40-60) (vol.:about.=1:9-1:4) as eluent to obtain specified in the title compound as a yellow solid.

13C NMR (CDCl3) δ

Example 217

2-{3-[2-Chloro-4-(4-chloro-2-methylphenylimino)benzoyl]-4-fervency}-N-methylacetamide (compound 317)

Connection 513 (36 mg, 0.09 mmol) was dissolved in acetonitrile (2 ml) in a reaction flask. Was added 2-chloro-N-methylacetamide (30 mg, 0.28 mmol), K2CO3(38 mg, 0.28 mmol). The reaction vessel was purged with argon, closed and then was stirred at 130°C for 45 minutes in a microwave oven. The reaction mixture was crying with the Ali in a mixture of EtOAc:H 2O (1:1, 10 ml). The layers were separated, and the aqueous phase was extracted with EtOAc (3×5 ml). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:3 to 100:0) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 190,1, 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-methylphenylimino)phenyl-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 318)

The reaction was carried out similarly as described for connection 317 using the connection 513 (31 mg, 0,079 mmol) as a phenol and 3-chloropropane-1-ol (20 μl, 0.24 mmol) as alkylchloride. Was stirred at 130°C for 15 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=15:85-60:40) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 190,7, 155, 2mm (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), by 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-methylphenylimino)benzoyl)-4-fervency}-N,N-dimethylacetamide connection 319)

The reaction was carried out similarly as described for connection 317 using the connection 513 (36 mg, 0,092 mmol) as a phenol and 2-chloro-N,N-dimethylacetamide as alkylchloride (29 μl, 0.28 mmol). Was stirred at 130°C for 15 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:1-100:0) as eluent, to obtain specified in the connection header in the form of oil.

13C NMR (CDCl3) δ 190,3, of 167.2, 155,6 (d), to 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, to 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-methylphenylimino)phenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-forfinal]metano (compound 320)

The reaction was carried out similarly as described for connection 311, using the connection 513 (34 mg, 0,087 mmol) as a phenol. Was stirred at 130°C for 45 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:9-1:1) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) to 190.5 δ, 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, to 120.4 (d), 117,1 (d), 115, 7mm, or 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-methylp is ylamino)phenyl]-[5-(2,3-dihydroxypropane)-2-forfinal]metano (compound 321)

Connection 320 (31 mg, 0.07 mmol) was dissolved in TFA:H2O (3:1, 10 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified using flash chromatography using DCM/MeOH (vol.:about.=99,5:0,5-98,5:1,5) as the eluent, to obtain specified in the connection header in the form of oil.

13C NMR (CDCl3) to 190.5 δ, 155,4 (d), 154, 6mm (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), by 115.7, 115,2 (d), 112,5, 70,3, 69,9, 63,5, 17,9.

Getting 114

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-(2-fluoro-5-hydroxyphenyl)methanon (compound 514)

The reaction was carried out similarly as described for connection 513 using the connection 511 (49 mg, 0.15 mmol) as poslednego connection and 4-fluoro-2-methylphenylamine (17 μl, 0.15 mmol) as the amine. Was stirred at 110°C for 40 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:5-1:2) as eluent, to obtain specified in the title compound as a yellow solid.

Example 222

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 322)

The reaction was carried out similarly as described for connection 317 using the connection 514 (31 mg, 0,083 mmol) as a Hairdryer is La and 3-chloropropane-1-ol (21 μl, 0.25 mmol) as alkylchloride. Was stirred at 130°C for 75 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:4-4:1) as eluent, to obtain specified in the connection header.

13C NMR (CDCl3) δ 190,6, 160,6 (d), 155, 1mm (d), 154,9 (d), 149,9, to 136.4 (d), 135,1, 133,8 (d), 133,4, 128,2 (d), 127,9, to 127.2 (d), 120,1 (d), 117,8 (d), 117,0 (d), or 115.1 (d), USD 114.9, 113,8 (d), 111,7, 66,3, 60,2, 32,0, 18,1.

Getting 115

[2-Chloro-4-(4-forgenerating)phenyl]-(2-fluoro-5-hydroxyphenyl)methanon (compound 515)

The reaction was carried out similarly as described for connection 513 using the connection 511 (99 mg, 0.3 mmol) as poslednego connection and 4-forfinally (29 μl, 0.3 mmol) as the amine. Was stirred at 130°C for 30 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:5-1:2) as eluent, to obtain specified in the title compound as a yellow solid.

Example 223

[2-Chloro-4-(4-forgenerating)phenyl]-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 323)

The reaction was carried out similarly as described for connection 317 using the connection 515 as phenol and 3-chloropropane-1-ol (24 μl, 0.29 mmol) as alkylchloride. Paramesh the Wali at 130°C for 60 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:4-4:1) as eluent, to obtain specified in the connection header.

13C NMR (CDCl3) δ 190,7, 159,6 (d), 155, 2mm (d), 155,0 (d), 148,9, 136,0 (d), 134,9, 133,3, 128,5, 128,1 (d), of 124.1 (d), 120,2 (d), 117,0 (d), 116,4 (d), 115,5, or 115.1 (d), 112,3, 66,3, 60,0, 32,0.

Example 224

[2-Chloro-4-(4-forgenerating)phenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-forfinal]metano (compound 324)

The reaction was carried out similarly as described for connection 311, using the connection 515 (35 mg, 0,097 mmol) as a phenol. Was stirred at 130°C for 75 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:9-2:3) as eluent, to obtain specified in the connection header.

13C NMR (CDCl3) to 190.5 δ, 159,7 (d), 155,4 (d), 154,7 (d), 148, 8 persons, to 135.9 (d), 134,9, 133,2, 128,8, 128,1 (d), to 124.2 (d), to 120.4 (d), 117,1 (d)116,5 (d), 115,5, or 115.1 (d), 112,4, 109,9, 74,0, 69,6, 66,7, 26,8, 25,4.

Getting 116

[2-Chloro-4-(2-chloro-4-forgenerating)phenyl]-(2-fluoro-5-hydroxyphenyl)methanon (compound 516)

The reaction was carried out similarly as described for connection 513 using the connection 511 (95 mg, 0.29 mmol) as poslednego connection and 2-chloro-4-forfinally (35 μl, 0.29 mmol) as the amine. Was stirred at 130°C in ECENA 10 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:5-1:2) as eluent, to obtain specified in the title compound as a yellow solid.

Example 225

[2-Chloro-4-(2-chloro-4-forgenerating)phenyl-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 325)

The reaction was carried out similarly as described for connection 317 using the connection 516 (27 mg, 0,068 mmol) as a phenol and 3-chloropropane-1-ol (17 μl, 0.2 mmol) as alkylchloride. Was stirred at 130°C for 60 minutes in a microwave oven. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:4-4:1) as eluent, to obtain specified in the title compound as a yellow oil.

13C NMR (CDCl3) δ 190,7, 158,5 (d), 155, 2mm (d), 155,0 (d), 147,1, 134,6, 133,7 (d), 132,8, 130,3, of 127.7 (d), a 126.7 (d), of 122.5 (d), 120,6 (d)117,5 (d), 117,1 (d), 116,9, 115,0, USD 114.9 (d), 113,7, 66,4, 60,2, 32,0.

Getting 117

[2-Chloro-4-(2-nitrophenylamino)phenyl]-(2-fluoro-5-hydroxyphenyl)methanon (compound 517)

The reaction was carried out similarly as described for connection 513 using the connection 511 (200 mg, 0.6 mmol) as poslednego connection and 2-nitrophenylamino (84 mg, 0.6 mmol) as the amine. Was stirred at 130°C for 10 minutes in a microwave oven. The cleansing and using flash chromatography with a continuous gradient, using EtOAc/petroleum ether (40-60) (vol.:about.=1:9-1:4) as eluent, to obtain specified in the title compound as an orange solid.

Getting 118/Example 290

[2-Chloro-4-(2-nitrophenylamino)phenyl]-[2-fluoro-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 518)

Connection 517 (30 mg, 0.08 mmol) was dissolved in acetonitrile (2 ml) in a reaction flask. Added the hydrochloride of 4-(2-chloroethyl)of the research (44 mg, 0.24 mmol) and K2CO3(33 mg, 0.24 mmol). The reaction vessel was purged with argon, closed and then was stirred at 130°C during the entire 105 minutes in the microwave. The reaction mixture was poured into a mixture of EtOAc:H2O (1:1, 10 ml). The layers were separated, and the aqueous phase was extracted with EtOAc (2×10 ml). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:9-3:2) as eluent, to obtain specified in the title compound as a pale yellow oil.

Getting 119/Example 291

[2-Chloro-4-(2-nitrophenylamino)phenyl]-[5-(2,2-dimethyl-[1,3]-dioxolane-4-ylethoxy)-2-forfinal]metano (compound 519)

The reaction was carried out similarly as described for connection 311, using the connection 517 (36 mg, 0,093 mmol) as a phenol. Was stirred at 130°C in techenie minutes in the microwave. Was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=1:9-2:3) as eluent, to obtain specified in the title compound as a pale yellow oil.

Getting 120/Example 292

[2-Chloro-4-(2-nitrophenylamino)phenyl]-[5-(2,3-dihydroxypropane)-2-forfinal]metano (compound 520)

Connection 519 (46 mg, 0,092 mmol) was dissolved in TFA:H2O (3:1, 10 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified using flash chromatography using DCM/MeOH (vol.:about.=4:1-1:4) as eluent, to obtain specified in the connection header.

Example 226

[4-(2-Aminophenylamino)-2-chlorophenyl]-[5-(2,3-dihydroxypropane)-2-forfinal]metano (compound 326)

Connection 520 (37 mg, 0.08 mmol) was dissolved in MeOH (2 ml), NH4Cl (29 mg, 0.55 mmol) was added zinc dust (72 mg, 1.10 mmol). Boiled under reflux for 0.5 hours, left to cool to room temperature and filtered. Was purified using flash chromatography using DCM:MeOH (vol.:about.=95:5) as eluent, to obtain specified in the connection header.

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-Aminophenylamino)-2-chloro who enyl]-[2-fluoro-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 327)

The reaction was carried out similarly as described for connection 326 using the connection 518 (37 mg, 0,074 mmol) as the nitro compounds. Was purified using flash chromatography using DCM:MeOH (vol.:about.=95:5) as eluent, to obtain specified in the connection header.

13C NMR (CDCl3) δ 190,6, 155, 2mm (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.

Getting 121

(4-Bromo-2-chlorophenyl)-(2-chloro-5-methoxyphenyl)methanol (compound 521)

To a solution of 4-bromo-2-chloro-1-iodobenzoyl (10.0 g, to 31.5 mmol) in THF (120 ml) was added 2M solution of chloride Isopropylamine in THF (17.3 ml, 34,60 mmol) at -65°C. the Reaction mixture was stirred at -40°C for 20 minutes. Then were added 2-chloro-5-methoxybenzaldehyde (5.5 g, 32,20 mmol), the reaction mixture was heated to room temperature and was stirred overnight. Then the solution is extinguished saturated aqueous NH4Cl. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over MgSO4and concentrated in vacuum. The crude material was purified by chromatography (petroleum ether/CH2Cl21:1) obtaining specified in the title compound as yellowish oil.

Getting 122

(4-Bromo-2-chlorophenyl)-(2-chloro-5-methoxyphenyl)methanon (compound 522)

It is astory connection 521 (5,18 g, of 14.3 mmol) in CH2Cl2(100 ml) portions was added periodinane dessa-Martin (6.11 g, 14,40 mmol) at room temperature. Next was stirred at room temperature for 1 hour, the reaction mixture was concentrated with silica gel in a vacuum. The residue was purified by chromatography (petroleum ether/CH2Cl21:1) to obtain specified in the title compounds as colorless oils.

Getting 123

(4-Bromo-2-chlorophenyl)-(2-chloro-5-hydroxyphenyl)methanon (compound 523)

To a solution of compound 522 (4,63 g, 12,86 mmol) in CH2Cl2(50 ml) was added dropwise 1M solution of BBr3in CH2Cl2at -40°C. the Reaction solution was heated to room temperature and was stirred overnight. After the reaction solution was poured into brine. The aqueous phase was extracted twice, CH2Cl2. The combined organic phases were dried over MgSO4and concentrated in vacuum to obtain solid, which was washed with a mixture of petroleum ether/CH2Cl21:1, to obtain specified in the title compound as grayish solid.

Getting 124

[2-Chloro-4-(2,6-dipertanyakan)phenyl]-(2-chloro-5-hydroxyphenyl)methanon (compound 524)

The mixture of compounds 523 (a 1.00 g, 3.00 mmol), 2,6-diferencia (0,47 g of 3.60 mmol), rac-BINAP (74 mg, 0.12 mmol), Pd 2(dba)3and Cs2CO3(1,95 g, 6,00 mmol) in 1,4-dioxane (30 ml) was stirred at 120°C for 2 days. The mixture was filtered and washed with 1,4-dioxane. The filtrate was concentrated with silica gel in vacuo and purified by chromatography (petroleum ether/ethyl acetate 3:1) obtaining specified in the connection header in the form of solids.

Example 228

[2-Chloro-4-(2,6-dipertanyakan)phenyl]-[2-chloro-5-(2-morpholine-4-ylethoxy)phenyl]metano (compound 328)

A mixture of compound 524 (42 mg, 0.11 mmol), 4-(2-chloroethyl)of the research (50 mg, 0.27 mmol) and K2CO3(100 mg, to 0.72 mmol) in CH3CN (2 ml) in a sealed vessel was stirred at 90°C for 18 hours. Then the mixture was filtered. The filtrate was concentrated in vacuum. The residue was purified by chromatography (ethyl acetate), obtaining specified in the title compound as a brownish oil.

13C NMR (CDCl3) δ 192.5 kg, 157,5 (DD), 157,2, 148,2, 140,2, 135,6, 134,0, 131,0, 127,8, 126,1 (t), 123,5, 118,2, of 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-dipertanyakan)phenyl]-[2-chloro-5-(2,3-dihydroxypropane)phenyl]metano (compound 329)

A mixture of compound 524 (42 mg, 0.11 mmol), 2,2-dimethyl-[1,3]-dioxolane-4-ymetray ether (+)-toluene-4-sulfonic acid (50 mg, 0,17 mmol) and K2CO3(100 mg, to 0.72 mmol) were processed as described for the floor of the possible connection 328. Chromatography (petroleum ether/ethyl acetate 3:1) gave the acetonide. Acetonide processed in TFA/H2O 3:1 (1 ml) at room temperature and the resulting solution was stirred at the same temperature for 0.5 hours. The mixture is then concentrated in vacuum. The residue was purified by chromatography (ethyl acetate), obtaining specified in the title compound as a colourless foam.

13C NMR (CDCl3) δ 192,6, 157,5 (DD), 157,1, 148,4, 140,3, 135,6, 134,1, 131,1, 127,5, 126,1 (t), 123,7, 118,0, of 116.7 (t), 116,4, 115,4, 112,7, 112,2 (m), 70,2, 69,6, 63,4.

Example 230

[5-(3-Bromopropane)-2-chlorophenyl]-[2-chloro-4-(2,6-dipertanyakan)phenyl]metano (compound 330)

A mixture of compound 524 (0.20 g, 0.51 mmol), 1,3-dibromopropane (0,62 g, a 3.06 mmol) and K2CO3(0.21 g, 1.53 mmol) were processed as described for connection 328. Chromatography (petroleum ether/ethyl acetate 4:1) gave specified in the header of the connection.

13C NMR (CDCl3) δ 192,6, 157,5 (DD), 157,3, 148,2, 140,2, 135,6, 134,1, 131,0, 127,8, 126,0 (t), 123,4, 118,0, of 116.7 (t), 116,4, 115,3, 112,7, 112,2 (m), 65,8, 32,2, 29,7.

Getting 125

Methyl ester of 3-(4-Bromo-2-chlorobenzoyl)-4-methylbenzoic acid (compound 525)

To a solution of methyl ester of 3-iodine-4-methylbenzoic acid (13,50 g, 48,92 mmol) in THF (260 ml) was added 2M solution of chloride Isopropylamine in THF (24.5 ml, 49,00 mmol) at -50°C. Then the reaction mixture was stirred at the same temperature the re within 30 minutes, added connection 440 (13,39 g, 40,70 mmol). The solution was heated to room temperature and stirred at the same temperature for 2 hours. Then the interaction extinguished saturated aqueous NH4Cl. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over MgSO4and concentrated in vacuum. The crude material was treated in ethanol and boiled under reflux. The resulting solution was cooled to room temperature. The crystals were filtered off and dried.

Getting 126

(4-Bromo-2-chlorophenyl)-(5-hydroxymethyl-2-were)methanol (compound 526)

A mixture of compound 525 (4,01 g, 10,90 mmol) and LiAlH4(0,83 g, 21,82 mmol) in THF (100 ml) was boiled under reflux for 1.5 hours. Then cooled to room temperature, the reaction mixture was poured into H2O, and added an aqueous solution of H2SO4(2M, 50 ml). Then the mixture was extracted twice with diethyl ether. The combined organic phases were dried over Na2SO4and concentrated in vacuum, obtaining specified in the connection header.

Getting 127

(4-Bromo-2-chlorophenyl)-(2-methyl-5-triisopropylbenzenesulfonyl)methanol (compound 527)

To a solution of compound 526 (3,68 g, 10,80 mmol) and imidazole (1.47 g, 21.60 mmol) in DMF (40 ml) was added TIPSCl (2.30 ml, 10,80 shall mol) at room temperature. The reaction solution was stirred at the same temperature for 3 hours and then poured into H2O. the Aqueous mixture was extracted three times with diethyl ether. The combined organic phases are washed with saline, dried over Na2SO4and concentrated in vacuum. The residue was purified by chromatography (ethyl acetate/petroleum ether 1:10), obtaining specified in the connection header.

Getting 128

(4-Bromo-2-chlorophenyl)-(2-methyl-5-triisopropylbenzenesulfonyl)methanon (compound 528)

Connection 527 (4.12 g, of 8.27 mmol) was treated as described for connection 522. Flash chromatography (petroleum ether/ethyl acetate 3:97) gave specified in the header of the connection.

Getting 129

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(2-methyl-5-triisopropylbenzenesulfonyl)methanon (compound 529)

A mixture of compound 528 (505 mg, of 1.02 mmol), 2,4-diptiranjan (0,14 ml of 1.32 mmol), Cs2CO3(995 mg, 3.65 mmol), BINAP (26 mg, 0,041 mg) and Pd(OAc)2(9 mg, 0,041 mmol) in 1,4-dioxane (15 ml) was stirred in a sealed vessel at 100°C for 18 hours. The mixture was filtered. The filtrate was concentrated in vacuo with silica gel. The residue was purified using flash chromatography (ethyl acetate/petroleum ether: gradient from 0/100 to 40/60), obtaining specified in the connection header.

<> Example 231

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(5-hydroxymethyl-2-were)methanon (compound 331)

To a solution of compound 529 (1.85 g, 3,40 mmol) in THF (40 ml) was added 1M solution of TBAF in THF (4,1 ml, 4,10 mmol) at room temperature. The reaction solution was stirred at room temperature for 30 minutes and then poured into H2O and was extracted with diethyl ether. The combined organic phases were dried over Na2SO4and concentrated in vacuum. The residue was purified using flash chromatography (ethyl acetate/petroleum ether: the gradient of 20/80 to 50/50), obtaining specified in the connection header.

13C NMR (DMSO-d6) δ 195,4, 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-dipertanyakan)phenyl]-(5-chloromethyl-2-were)methanon (compound 332)

To a solution of compound 331 (0,79 g of 2.09 mmol), Et3N (of 0.58 ml, 4,18 mmol) and DMAP (10 mg) in CH2Cl2(50 ml) was added p-toluensulfonate (0,60 g, 3.14 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 18 hours and then poured into H2O. the Aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried over Na2SO4and concentrated in vacuum. The residue was purified POM is by chromatography (petroleum ether/ethyl acetate in a gradient from 90/10 to 75/25), obtaining specified in the connection header.

13C NMR (CDCl3) δ 195,7, 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), to 116.2, 112,8, 111,6 (DD), 105,0 (DD), 45,6, 20,2.

Example 233

(5-Azidomethyl-2-were)-[2-chloro-4-(2,4-dipertanyakan)phenyl]metano (compound 333)

A mixture of compound 332 (56 mg, 0.14 mmol) and NaN3(18 mg, 0.28 mmol) in DMF (4 ml) was stirred at 80°C for 3 hours. The reaction mixture was poured into H2O and was extracted three times with CH2Cl2. The combined organic phases are washed with saline, dried over Na2SO4and concentrated in vacuum, obtaining specified in the connection header.

13C NMR (CDCl3) δ 195,9, 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, 2mm, 112,8, 111,6 (DD), 105,0 (DD), 54,1, 20,2.

Example 234

(5-Aminomethyl-2-were)-[2-chloro-4-(2,4-dipertanyakan)phenyl]metano (compound 334)

To a solution of compound 333 (46 mg, 0.11 mmol) was added triphenylphosphine (67 mg, 0.26 mmol) at room temperature. The solution was stirred at the same temperature for 18 hours. Added H2O (0.5 ml). The mixture is then boiled under reflux for 4 hours and then concentrated with silica gel in a vacuum. The residue was purified by chromatography (MeOH/ethyl acetate in a gradient from 13/87 to 30/70), with ukazannoj is in the connection header.

13C NMR (CDCl3) δ 196,4, 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), to 116.2, 112,8, 111,6 (DD), 104,9 (DD), 45,6, 20,1.

Getting 130

(4-Bromo-2-chlorophenyl)-(5-hydroxymethyl-2-methoxyphenyl)methanol (compound 530)

Connection 441 (1,05 g, 2,70 mmol) were processed as described for connection 526. Flash chromatography (ethyl acetate/petroleum ether: gradient from 25/75 to 45/55) gave specified in the header of the connection.

Getting 131

(4-Bromo-2-chlorophenyl)-(2-methoxy-5-triisopropylbenzenesulfonyl)methanol (compound 531)

Connection 530 (766 mg, 2.14 mmol) were processed as described for connection 527. Flash chromatography (ethyl acetate/petroleum ether: gradient from 4/96 to 30/70) to give specified in the header of the connection.

Getting 132

(4-Bromo-2-chlorophenyl)-(2-methoxy-5-triisopropylbenzenesulfonyl)methanon (compound 532)

Compound 531 (710 mg, 1.38 mmol) were processed as described for connection 504. Flash chromatography (petroleum ether/ethyl acetate 3:97) gave specified in the header of the connection.

Getting 133

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(2-methoxy-5-triisopropylbenzenesulfonyl)methanon (533)

Connection 532 (449 mg, 0.87 mmol) and 2,4-diptiranjan (0,12 ml, to 1.14 mmol) were processed as described in the receive connection 529. Flash chromatography (ethyl acetate/petroleum ether: gradient from 10/90 to 25/75) to give specified in the header of the connection.

Example 235

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-5-hydroxymethyl-2-methoxyphenyl)methanon (compound 335)

Connection 533 (163 mg, 0.29 mmol) was treated as described for connection 331. Flash chromatography (ethyl acetate/petroleum ether: gradient from 50/50 to 75/25) gave specified in the header of the connection.

13C NMR (CD3OD) δ 196,0, 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, 112,6 (DD)105,7 (DD), 64,5, of 56.4.

Example 236

3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzyloxy ether acetic acid (compound 336)

To a solution of compound 335 (45 mg, 0.11 mmol), Et3N (46 μl, 0.34 mmol) and DMAP (3 mg) in CH2Cl2(5 ml) was added Ac2O (13 μl, 0.13 mmol) at room temperature. The solution was stirred at room temperature for 0.5 hours. Then the reaction solution was washed H2O and saturated aqueous NaHCO3, dried over MgSO4and concentrated in vacuum. The residue was purified by chromatography (ethyl acetate/petroleum ether 1:4), obtaining specified in the connection header.

13C NMR (CDCl3) δ 193,1, to 170.9, 158,9 (DD), 158,2, was 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, (DD), 104,9 (DD), 65,6, 56,0, 21,0.

Example 237

N-tert-Butoxy-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzamide (compound 337)

To a mixture of compound 437 (51 mg, 0.12 mmol), O-tert-butylhydroxytoluene (31 mg, 0.24 mmol), N-methylmorpholine (26 mg, 0.24 mmol) and 1-hydroxybenzotriazole (16 mg, 0.12 mmol) in CH2Cl2(5 ml) was added EDCI (30 mg, 0.16 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 6 hours and then extinguished H2O. the Aqueous phase was extracted five times CH2Cl2. The combined organic phases were dried over MgSO4and concentrated in vacuum. The residue was purified using flash chromatography (ethyl acetate/petroleum ether 2:1), obtaining specified in the connection header.

13C NMR (DMSO-d6) δ to 191.6, 164, 8mm, 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), of 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-dipertanyakan)benzoyl]-N-methoxy-4-methylbenzamide (compound 338)

Compound 424 (50 mg, 0.12 mmol) and the hydrochloride of N-methylhydroxylamine (21 mg, 0.25 mmol) was treated as described for connection 337. Flash chromatography (ethyl acetate/petroleum ether: gradient from 67/33 to 100/0) to give specified in the header of the connection.

13C NMR (DMSO-d6) δ 194,5, 158,8 (DD), 155,8 (DD), 149,5, 140,1, 139,5, 133,8, 133,7, 11,2, 129,4, 128,8, 126,9, 126,5 (DD), 126,2, of 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-dipertanyakan)benzoyl]-4-methylbenzamide (compound 339)

Compound 424 (100 mg, 0.25 mmol) and O-butylhydroxytoluene (63 mg, 0.50 mmol) were processed as described for connection 337. Flash chromatography (ethyl acetate/petroleum ether: gradient from 20/80 to 60/40) to give specified in the header of the connection.

13C NMR (CDCl3) δ 195,4, 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), of 124.1 (DD), to 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-dipertanyakan)benzoyl]-N-cyclohexylmethoxy-4-methylbenzamide (compound 340)

Compound 424 (50 mg, 0.12 mmol) and O-cyclohexylhydroxylamine (42 mg, 0.25 mmol) was treated as described for connection 337. Flash chromatography (ethyl acetate/petroleum ether: gradient from 67/33 to 100/0) to give specified in the header of the connection.

1H NMR (CDCl3) δ 8,68 (Sirs, 1H), 7,72 (width, 1H), 7,66 (Sirs, 1H), 7,43-7,28 (m, 3H), 7,00-PC 6.82 (m, 3H), 6.75 in (DD, 1H), 5,94 (Sirs, 1H), 3,80 (d, 2H), 2,44 (c, 3H), 1,89-of 1.56 (m, 6H), 1,35-of 1.09 (m, 3H), 1,07 is 0.84 (m, 2H).

Example 241

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2-methylthiazole-4-ylethoxy)benzamide (compound 341)

Compound 424 (50 mg, 0.12 mmol) and O-(2-methylthiazole-4-ylmethyl)hydroxylamine (36 mg, 0.25 mmol) education is atively as well as described for connection 337. Flash chromatography (ethyl acetate/petroleum ether: gradient from 67/33 to 100/0) to give specified in the header of the connection.

1H NMR (CDCl3) δ 10,0-9,0 (Sirs, 1H), 7,76 (DD, 1H), to 7.67 (d, 1H), 7,42-7,30 (m, 3H), 7,15 (c, 1H), 7,00-6,84 (m, 3H), 6.75 in (DD, 1H), 5,98 (Sirs, 1H), 5,04 (c, 2H), 2,64 (c, 3H), 2,45 (c, 3H).

Example 242

N-Benzyloxy-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 342)

Compound 424 (100 mg, 0.25 mmol) and O-benzylhydroxylamine (80 mg, 0.50 mmol) were processed as described for connection 337. Flash chromatography (ethyl acetate/petroleum ether: gradient from 80/20 to 60/40) to give specified in the header of the connection.

13C NMR (CDCl3) δ 195,3, is 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), of 124.1 (DD), to 116.2, 112,8, 111,7 (DD), 105,0 (DD), 78,5, 20,4.

Example 243

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(4-methoxybenzyloxy)-4-methylbenzamide (compound 343)

Compound 424 (100 mg, 0.25 mmol) and O-(4-methoxybenzyl)hydroxylamine (65 mg, 0.34 mmol) were processed as described for connection 337. Flash chromatography (ethyl acetate/petroleum ether: gradient from 80/20 to 60/40) to give specified in the header of the connection.

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 (�d), 105,0 (DD), 78,0, 55,3, 20,4.

Example 244

N',N'-Dimethylhydrazide 3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoic acid (compound 344)

Compound 424 (50 mg, 0.12 mmol) and N,N-dimethyl (19 μl, 0.25 mmol) was treated as described for connection 337. Flash chromatography (ethyl acetate/petroleum ether: gradient from 67/33 to 80/20) gave specified in the header of the connection.

13C NMR (DMSO-d6) δ 194,7, 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), USD 114.9, 112,0 (DD), 111,9, 105,1 (DD), 46,1, 19,6.

Example 245

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-morpholine-4-ylbenzene (compound 345)

Compound 424 (50 mg, 0.12 mmol) and the hydrochloride of N-aminomorpholine (35 mg, 0.25 mmol) was treated as described for connection 337. Flash chromatography (ethyl acetate/petroleum ether: gradient from 67/33 to 100/0) to give specified in the header of the connection.

13C NMR (DMSO-d6) δ 194,5, 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-dipertanyakan)benzoyl]-N-hydroxy-4-methylbenzamide (compound 346)

Compound 424 (202 mg, 0.50 mmol) and O-[(dimethyl-tert-butyl)silyl]hydroxylamine (148 mg, 1.01 mmol) were processed as described for connection 337. Flash chromatog afia (ethyl acetate/petroleum ether: gradient from 67/33 to 100/0) to give specified in the header of the connection.

13C NMR (DMSO-d6) δ to 194.6, 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, of 124.1 (DD), 114,8, 111,9 (DD), 111,8, 105,0 (DD), 19,6.

Getting 134

Methyl ester of 4-(4-bromo-2-chlorobenzoyl)-3-methylbenzoic acid (compound 534)

Methyl ester of 4-iodine-3-methylbenzoic acid (0,83 g, 3.00 mmol) and compound 440 (0.75 g, 3.00 mmol) were processed as described for connection 525. Flash chromatography (ethyl acetate/petroleum ether 1:15) gave specified in the title compound as a white solid.

Getting 135

Methyl ester 4-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-3-methylbenzoic acid (compound 535)

Connection 534 (184 mg, 0.50 mmol) and 2,4-diptiranjan (of 0.066 ml of 0.65 mmol) were processed as described for connection 529. Flash chromatography (ethyl acetate/petroleum ether: gradient from 0/100 to 20/80) gave specified in the header of the connection.

Example 247

4-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-3-methylbenzamide (compound 347)

A mixture of compound 535 (127 mg, 0.30 mmol) and K2CO3(63 mg, 0.45 mmol) in ethanolamine/CH3CN 1:1 (4 ml) was stirred at room temperature for 18 hours. Then the reaction mixture was poured into H2O and was extracted three times with ethyl acetate. The combined organic phases are washed with saline,dried over MgSO 4and concentrated in vacuum. The residue was purified by chromatography (ethyl acetate/petroleum ether 5:1), obtaining specified in the title compound as a yellow solid.

13C NMR (CD3OD) δ 197,7, 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), for 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-dipertanyakan)phenyl]-[5-(3-hydroxypropyl)-2-were]metano (compound 348)

Compound 495 (0,132 g, 0.27 mmol) was dissolved in anhydrous 1,4-dioxane (1.5 ml) in a vessel with a screw cap in an argon atmosphere. Added three(2-furyl)phosphine (0,013 g, 0.05 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0,007 g 0,008 mmol) and was shaken. Added (E)-3-(tri-n-botillo)prop-2-EN-1-ol (0.104 g g, 0.3 mmol) and the reaction mixture was heated in an argon atmosphere at 100°C for 16 hours on a vibrating machine. To the reaction mixture was added CH3CN, and the solution was washed three times with petroleum ether. Phase of acetonitrile was concentrated in vacuo and purified using flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 1:3→3:1 as eluent. This gave specified in the title compound as a yellow oil.

Example 249

Methylether 4-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}thiophene-3-carboxylic acid (compound 349)

The reaction was carried out similarly as described for connection 120, using methyl ether 4-aminothiophene-3-carboxylic acid (0.5 mmol) and compound 439 (0.5 mmol). Purification was performed using flash chromatography to obtain specified in the connection header in the form of foam.

13C NMR (CDCl3) δ 195,6, 164, 8mm, 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-dipertanyakan)benzoyl]-N-furan-2-ylmethyl-4-methylbenzamide (compound 350)

The reaction was carried out similarly as described for connection 120, using furan-2-ylmethylamino (0.5 mmol) and compound 439 (0.5 mmol). Purification was performed using flash chromatography to obtain specified in the connection header in the form of 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), to 116.2, 112,8, 111,6 (DD), 110,5, to 107.8, 105,0 (DD), 37,0, 20,4.

Example 251

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-(3-methoxyphenyl)-4-methylbenzamide (compound 351)

The reaction was carried out similarly as described for connection 120, using 3-methoxybenzylamine (0.5 mmol) and compound 439 (0.5 mmol). Purification was performed using flash chromatography to obtain specified in the connection header in the form of foam.

13C NMR (CDCl3) δ 195,5, 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), of 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

Methyl ester 2-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}benzoic acid (compound 352)

The reaction was carried out similarly as described for connection 120, using methyl ester of 2-aminobenzoic acid (0.5 mmol) and compound 439 (0.5 mmol). Purification was performed using flash chromatography to obtain specified in the connection header in the form of foam.

13C NMR (CDCl3) δ 195,6, 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

Methyl ester of 3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}thiophene-2-carboxylic acid (compound 353)

The reaction was carried out similarly as described for connection 120, using methyl ether 3-aminothiophene-2-carboxylic acid (1.0 mmol) and compound 439 (0.5 mmol). Purification was performed using flash chromatography to obtain specified in the connection header in the form of foam.

13C NMR (DMSO-d6) δ 194,2, 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, of 124.1 (DD), 121,9, 114,8, 112,0 (DD), 111,9, 105,0 (DD), 52,1, 19,7.

P the emer 254

4-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}thiophene-3-carboxylic acid (compound 354)

To a suspension of compound 349 (75 mg, 0.14 mmol) in methanol (5 ml) was added water (0.5 ml) and then lithium hydroxide (17 mg, 0.7 mmol). Next, the mixture is stirred at the boil under reflux for 30 minutes. The reaction mixture was acidified (pH 5) by slow addition of HCl (1N.), and then was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum to obtain specified in the connection header in the form of solids.

13C NMR (DMSO-d6) δ for 194.3, 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-dipertanyakan)benzoyl]-4-methylbenzylamino}benzoic acid (compound 355)

The reaction was carried out similarly as described for connection 354 using the connection 352 (0.5 mmol). Specified in the title compound was obtained as a solid substance.

13C NMR (DMSO-d6) δ for 194.3, 169,9, of 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.

Getting 136

2-{3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-4-motive is solumina}benzoyl chloride (compound 536)

To a suspension of compound 355 (68 mg, 0.13 mmol) in toluene (2 ml) was added thionyl chloride (19 μl, 0.26 mmol) and then boiled under reflux for 2 hours. The reaction mixture was concentrated in vacuum to obtain specified in the title compound without any further purification.

Example 256

3-[2-Chloro-4-(2,4-dipertanyakan)benzoyl]-N-[2-(2-hydrooximethylcarbamil)phenyl]-4-methylbenzamide (compound 356)

The reaction was carried out similarly as described for obtaining compound 120, using 2-aminoethanol (0.26 mmol) and compound 536 (0.13 mmol). Purification was performed using flash chromatography to obtain specified in the connection header in the form of foam.

13C NMR (CDCl3) δ 195,8, 169,9, 164, 8mm, 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), of 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

(2-Hydroxyethyl)amide 3-{3-[2-[chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}thiophene-2-carboxylic acid (compound 357)

To a solution of compound 353 (124 mg, 0.23 mmol) in acetonitrile (2.0 ml) and 2-aminoethanol (0,50 ml) was added K2CO3(50 mg, 0.36 mmol) and was stirred for 18 hours at room temperature. The reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined and concentrated on a Sealy is agile in vacuum. Purification was performed using flash chromatography, elwira mixtures of MeOH/DCM to obtain specified in the connection header.

13C NMR (DMSO-d6) δ 193,8, 163,5, 161,5, 158,2 (DD), 155, 2mm (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), byr111.4, 104,5 (DD), 58,8, 41,3, 19,2.

Getting 137

3-(2-Chloro-4-nitrobenzoyl)-4-methylbenzonitrile (compound 537)

In a dry flask was loaded 3-iodine-4-methylbenzonitrile (5,15 g of 21.2 mmol) and subjected to evaporation, and then filled with argon, and this process was repeated twice. Added anhydrous THF (15 ml)and the solution was cooled to -35°C; then slowly added isopropylaniline a (10.6 ml, 2,0M in diethyl ether, 21 mmol) over 20 minutes, keeping the temperature below -35°C. After complete addition, the reaction mixture was stirred at -35°C for 30 minutes. Was added dropwise THF solution of ZnCl2(3,61 g of 26.5 mmol, 1,0M) for 20 minutes. The reaction mixture was stirred at 0°C for 20 minutes; then added 2-chloro-4-nitrobenzoate (4.9 g, of 22.3 mmol) and Cu(OAc)2(85 mg, 0.42 mmol)and the reaction mixture was left to warm to room temperature. After 16 hours the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in Vacu the IU to obtain the crude product. The crude product was purified using flash chromatography using EtOAc/petroleum ether (40-60) 1:6, then 1:4 as eluent to obtain specified in the title compound as a yellow solid.

Getting 138

3-(4-Amino-2-chlorobenzoyl)-4-methylbenzonitrile (compound 538)

A mixture of compound 537 (1,05 g, 3,49 mmol) and chloride dihydrate tin (of 3.31 g, 17,46 mmol) in absolute ethanol (20 ml) was boiled under reflux. After 90 minutes the solution was cooled to room temperature and then poured into a mixture of ice/water NaOH(7h.)/EtOAc. The aqueous phase is once again was extracted with EtOAc, then DCM. The organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using EtOAc/petroleum ether 1:2 as eluent to obtain specified in the title compound as a yellow solid.

Getting 139

3-[2-Chloro-4-4-fluoro-2-methylphenylimino)benzoyl]-4-methylbenzonitrile (connection 539)

In a vessel with screw cap (8 ml) was loaded connection 538 (100 mg, of 0.37 mmol) in 1,4-dioxane (2 ml), 2-bromo-5-vtortola (55 μl, 0.44 mmol), Cs2CO3(169 mg, 0.52 mmol), Pd2(dba)3(9 mg, 0,009 mmol) and rac-BINAP (9 mg, 0.014 mmol). The tube was closed with a rubber cap was purged with argon for 5 minutes, the click was stirred at 100°C for 18 hours. The reaction mixture was left to cool to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted two more times with EtOAc. The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using chromatography, elwira EtOAc/petroleum ether 1:3 with obtaining specified in the title compound as light brown oil.

Example 258

[2-Chloro-4-(4-fluoro-2-methylphenylimino)phenyl]-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]metano (compound 358)

In a vessel with a screw cap with a magnetic stirrer was loaded connection 539 (100 mg, 0.26 mmol), TBAF·H2O (41 mg, 0.13 mmol) and TMSN3(105 μl, 0.80 mmol) and THF (0.3 ml)and the resulting mixture was heated with vigorous stirring at 85°C for 18 hours. The reaction mixture was left to cool to room temperature and then poured in a mixture of HCl (1N.) and EtOAc. The aqueous phase is once again was extracted with EtOAc. The combined organic phases are washed with saline, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using chromatography, elwira DCM/MeOH/CH3COOH 100:2,5:0,25 obtaining specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ 193,9, 159,5 (d), 154,8, 151,1, 140,7, 139,4, 136,2 (d), 134,4, 134,3, 132,1, 128,5, 127, (d), 126,4, of 124.7, the level of 121.8, 117,4 (d), 114,1, 113,5 (d), 111,1, 19,5, 17,6.

Getting 140

(5-Bromo-2-were)-(2-chloro-4-nitrophenyl)methanon (compound 540)

In a dry flask was loaded with 4-bromo-2-iodine-1-methylbenzol (6.85 g, and 23.1 mmol) and the flask was evaporated, and then filled with argon, and this process was repeated twice. Added anhydrous THF (20 ml)and the solution was cooled to -35°C; then slowly added isopropylaniline (11.5 ml, 2,0M in diethyl ether, 23 mmol) in 40 minutes, keeping the temperature below -35°C. After complete addition, the reaction mixture was stirred at -35°C for 30 minutes. Was added dropwise a solution of ZnCl2in THF (3,93 g of 28.9 mmol, 0,7M) for 20 minutes. The reaction mixture was stirred at 0°C for 20 minutes; then added 2-chloro-4-nitrobenzoate (5,33 g, and 24.2 mmol) and Cu(OAc)2(92 mg, 0.46 mmol)and the reaction mixture was left to warm to room temperature. After 16 hours the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4) filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography using EtOAc/petroleum ether 1:14 as eluent to obtain specified in the title compound as a nearly white solid.

Getting 141

(4-Amino-2-chlorophenyl)-(5-bromo-2-were)methanon (compound 541)

The reaction was carried out similarly as described for connection 538 using the connection 540 (5,64 mmol) as the nitro compounds. Purification was performed using flash chromatography to obtain specified in the title compound as a yellow solid.

Getting 142

(5-Bromo-2-were)of 2-chloro-4-(2-nitrophenylamino)phenyl]metano (compound 542)

To a solution of compound 541 (1.42 g, 4,37 mmol) and 1-fluoro-2-nitrobenzene (0,42 ml, 4.0 mmol) in DMSO (10 ml) was slowly added tert-piperonyl potassium (992 mg, 8,84 mmol) under stirring. After 20 hours at room temperature the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using chromatography, elwira EtOAc/petroleum ether 1:8 with obtaining specified in the title compound as an orange solid.

Getting 143

[4-2-Aminophenylamino)-2-chlorophenyl]-(5-bromo-2-were)methanon (connection 543)

The reaction was carried out similarly as described for connection 538 using the connection 542 (2.36 mmol) as the nitro compounds. Cleaning the implementation of the Yali using flash chromatography to obtain specified in the title compound as a yellow solid.

Getting 144

[4-(2-Aminophenylamino)-2-chlorophenyl]-(2-methyl-5-trimethylsilylethynyl)methanon (compound 544)

In a vessel with screw cap (8 ml) was loaded anhydrous the degassed triethylamine (3.0 ml) and a magnetic stirrer in an argon atmosphere. To the vessel was added the compound 543 (200 mg, 0.48 mmol), Pd2(dba)3(9.0 mg, 0.01 mmol), triphenylphosphine (13 mg, 0,048 mmol), CuI (2 mg) and amenitieseven (66 μl, 0.48 mmol)and the reaction mixture was heated with vigorous stirring at 90°C for 20 hours. The cooled reaction mixture was filtered through Decalite and concentrated in vacuum. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=5:95-30:70) as eluent and obtaining specified in the title compound as a yellow foam.

Example 259

[4-(2-Aminophenylamino)-2-chlorophenyl]-(5-ethinyl-2-were)methanon (compound 359)

A mixture of compound 544 (59 mg, 0.14 mmol) and K2CO3(28 mg, 0.20 mmol) in methanol (1.0 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum to obtain specified in the connection header without any complement the school clean.

13C NMR (CDCl3) δ 195,5, 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-Aminophenylamino)-2-chlorophenyl]-(2-methyl-5-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-[1,2,3]-triazole-4-yl}phenyl)methanon (compound 360)

In a vessel with a screw cap with a magnetic stir bar was added compound 359 (25 mg, 0.07 mmol), 2-(2-azidoethoxy)tetrahydropyran (25 mg, 0.14 mmol) and EtOH (0.5 ml), then CuSO4·H2O (0.3 mg) and aqueous solution of sodium-1-ascorbate (200 μl, 0.2 mmol, 1M). The reaction mixture was stirred at room temperature for 3 hours and then at 40°C for 30 minutes. The reaction mixture was concentrated on silica gel and was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=50:50-100:0) as eluent and obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 196,1, 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-Aminophenylamino)-2-chlorophenyl]-{5-[1-(2-hydroxyethyl)-1H-[1,2,3]-triazole-4-yl]-2-were}mechanon (compound 361)

A solution of compound 360 (20 mg, of 0.038 mmol) and toluene-4-sulfonic acid (11 mg, 0,057 mmol) in MeOH (0.3 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured in with the offer of aqueous NaOH (2n.) and EtOAc. The aqueous phase was washed again EtOAc. The organic phases were combined and washed with saline, dried (MgSO4), was filtered and then purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=40:60-20:80) as eluent to obtain specified in the connection header in the form of solids.

13C NMR (DMSO-d6) δ 194,7, 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, 111,3, 59,7, 52,3, 19,3.

Getting 145

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-(2-methyl-5-trimethylsilylethynyl)methanon (compound 545)

In a vessel with screw cap (8 ml) were placed waterless the degassed triethylamine (4.0 ml) and a magnetic stirrer in an argon atmosphere. To the vessel was added the compound 495 (100 mg, 0.21 mmol), Pd2(dba)3(3.8 mg), triphenylphosphine (5.4 mg, 0.02 mmol), CuI (1 mg) and amenitieseven (29 μl, 0.21 mmol)and the reaction mixture was heated with vigorous stirring at 90°C for 20 hours. The cooled reaction mixture was filtered through Decalite and concentrated in vacuum. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=0:100-10:90) as eluent, to obtain specified in the connection header in the form of foam.

Example 262

[2-Chloro-4-(2,4-differenial the but)phenyl]-(5-ethinyl-2-were)methanon (compound 362)

A mixture of compound 545 (36 mg, 0.08 mmol) and K2CO3(17 mg, 0.13 mmol) in methanol (3.0 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=0:100-20:80) as eluent, to obtain specified in the connection header in the form of foam.

13C NMR (CDCl3) δ 195,4, 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

The hydrazide 3-[2-chloro-4-(4-forgenerating)benzoyl]-4-methylbenzoic acid (compound 363)

A mixture of compound 451 (100 mg, 0.25 mmol) and hydrazinehydrate (0,12 ml, 2.5 mmol) in methanol (5 ml) was stirred at the boil under reflux for 24 hours. The reaction mixture was concentrated on silica gel in a vacuum. The crude product was purified using flash chromatography using MeOH/DCM 2:98 as eluent to obtain specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,5, 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

The hydrazide 3-[2-chloro-4-2,4-dipertanyakan)benzoyl]-4-methylbenzoic acid (compound 364)

The mixture of compounds 423 (1,00 g, 2.4 mmol) and hydrazinehydrate (1,17 ml, 24 mmol) in methanol (40 ml) was stirred by heating under reflux in 48 hours. The reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined and concentrated in vacuum. The crude product was purified using flash chromatography with a continuous gradient, using MeOH/DCM (vol.:about.=5:95-10:90) as eluent, obtaining specified in the title compound as a yellow foam.

13C NMR (CDCl3) δ 195,5, 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-dipertanyakan)benzoyl]-4-methylbenzoyl}-4-ethyl-3-thiosemicarbazide(compound 365)

In a vessel with screw cap (8 ml) was placed isothiocyanoethane (69 μl, of 0.79 mmol), compound 364 (300 mg, to 0.72 mmol), methanol (6 ml) and a magnetic stirrer. The reaction mixture was heated with stirring at 95°C for 3 hours. The cooled reaction mixture was filtered through Decalite and concentrated in vacuum. The crude product was purified using flash chromatography using THF/petroleum ether 2:3 as eluent to obtain specified in the title compound as a yellow foam.

13C NMR (DMSO-d6) δ to 194.6, 181,3, 165,0, 158,8 (DD), 155,8 (DD), at 149.5, 140,3,139,4, 133,8, 133,8, 130,9, 129,9, 129,7, 127,7, 126,6 (DD), 126,2, of 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-dipertanyakan)phenyl]-[5-(5-ethylamino-[1,3,4]thiadiazole-2-yl)-2-were]metano (compound 366)

A mixture of compound 365 (122 mg, 0.24 mmol) and POCl3(29 μl, 0.32 mmol) in 1,4-dioxane (1.0 ml) was stirred at 95°C for 20 hours. The reaction mixture was poured into a mixture of EtOAc/saturated aqueous NaHCO3. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=20:80-50:50) as eluent to obtain specified in the title compound as a yellow solid.

13C NMR (DMSO-d6) δ 194,4, 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, of 124.1 (DD), 114,8, 112,0 (DD), 111,8, 105,0 (DD), 39,6, 19,5, 14,1.

Getting 146

3-[2-Chloro-4-2,4-dipertanyakan)benzoyl]-4-methylbenzonitrile (compound 546)

Into the flask was loaded connection 538 (500 mg, of 1.85 mmol) in toluene (10 ml), 1-bromo-2,4-differental (0.25 ml, 2.22 mmol), Cs2CO3(841 mg, at 2.59 mmol), Pd(OAc)2(8 mg, 0.04 mmol) and 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (32 mg, 0,056 mmol). The flask was purged with argon for 5 minutes, closed it, and then slowly load the Wali to 120°C. The reaction vessel was stirred at 120°C for 24 hours. The reaction mixture was left to cool to room temperature and then filtered through Decalite. Concentration in vacuo gave the crude product. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=15:85-33:67) as eluent to obtain specified in the title compound as a brown foam.

Example 267

[2-Chloro-4-(2,4-dipertanyakan)phenyl]-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]metano (compound 367)

The reaction was carried out similarly as described for connection 358 using the connection 546 (0.84 mmol) as nitrile. Purification was performed using flash chromatography to obtain specified in 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, 114,8, 112,0 (DD), 111,8, 105,0 (DD), 19,6.

Example 268

Ethyl ester of 3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-oxopropanoic acid (compound 368)

The solution ethoxycarbonylethyl potassium (136 mg, 0.80 mmol) in EtOAc (1.25 ml) was cooled to 0°C in an ice bath. To the solution was added triethylamine (279 μl, 2.0 mmol) and anhydrous magnesium chloride (91 mg, 0.96 mmol)and the mixture was stirred at 35°C for 7 h the owls. The reaction mixture was cooled to 0°C was added a solution of compound 439 (230 mg, or 0.57 mmol) in EtOAc (1 ml). The temperature was raised to room temperature and stirring continued for 18 hours. The reaction mixture was cooled to C and slowly added aqueous HCl (1.5 ml, 12%). The aqueous phase was separated and washed with EtOAc (10 ml). The organic phases were combined, washed with aqueous HCl (5 ml, 12%), aqueous NaHCO3(5 ml, 50%), water (5 ml) and brine (5 ml) and then dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified using flash chromatography using DCM/petroleum ether 2:3, then diethyl ether/petroleum ether 1:2 as eluent to obtain specified in the title compound as a yellow solid.

13C NMR (CDCl3) δ 195,2, to 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), to 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-dipertanyakan)phenyl]-[5-(4,5-dihydrooxazolo-2-yl)-2-were]metano (compound 369)

To a suspension of compound 115 (400 mg, 0.90 mmol) in DCM (4.0 ml) was added thionyl chloride (229 μl, of 3.15 mmol)and the resulting mixture was stirred at room temperature for 1 hour. Then to the reaction mixture was added a chilled water-EtOAc. The organic phase was separated, washed with brine, dried (MgSO4), Phil is trevali and concentrated in vacuum. The crude product was purified using flash chromatography with a continuous gradient using EtOAc/petroleum ether (40-60) (vol.:about.=5:95-40:60) as eluent, to obtain specified in the connection header in the form of foam.

13C NMR (CDCl3) δ 195,6, 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), for 116.2, 112,8, 111,6 (DD), 105,0 (DD), 67,7, 54,9, 20,5.

Example 270

3-{2-Chloro-4-[2-(3-ethylurea)phenylamino]benzoyl}-N-(2-hydroxyethyl)-4-methylbenzamide (compound 370)

To a solution of compound 112 (100 mg, 0.24 mmol) in anhydrous pyridine (1 ml) was added utilizationa (28 μl, 0.35 mmol) with stirring. After 1 hour the reaction mixture was poured into a mixture of EtOAc/water. The aqueous phase is once again was extracted with EtOAc. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The crude product was purified using flash chromatography with a continuous gradient, elwira EtOAc/MeOH (vol.:about.=100:0-98:2) to obtain the specified title compound as a yellow syrup.

13C NMR (DMSO-d6) δ 194,6, 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.

1. The compound of General formula I

where R1represents a halogen, With1-4alkyl or C1-4alkoxy;
R2represents odor is d, halogen;
R3represents hydrogen, or one or more Halogens;
R4represents hydrogen, halogen, R8or Y1R8;
Y1represents-NRa-;
Raand Rbare the same or different and each represents hydrogen or
With1-4alkyl;
R8represents hydrogen, C1-10alkyl;
R7represents halogen, hydroxy, trifluoromethyl, amino,
C1-6hydroxyalkyl,1-4alkoxy, C1-4alkylthio, C1-6alkylamino,
With1-4alkoxycarbonyl, -S(O)2R, -COOH, -CONH2or-NRaC(O)R', where R and R' are the same or different and each represents hydrogen or C1-3alkyl;
R5represents-COOH, Y2R9, Y2R9Y3R10With1-6alkyl-Y2R9With1-10alkyl, or unsaturated With3-8carbocyclic specified R5substituted by one or more, same or different substituents represented by R7;
R6represents hydrogen;
provided that when R5represents phenyl or1-5alkyl specified R5substituted by one or more, same or different substituents represented by R7(with the exception of three Vtorov, when R8or R6depict is to place a methyl),
with the further proviso that when R5represents-COOH, Y1can't be a-NRa-;
and with the further proviso that when R2represents hydrogen, one of R5there can be optionally substituted C1-7the alkyl or C1-7alkoxy;
Y2represents-O-, -NRa-, -NRaC(O)NRb-, -NRaC(O)-, -C(O)NRa-, -C(O)-, -NRaC(O)O-, or-OC(O)-;
R9represents a C1-10alkyloxyaryl, C1-10alkylaryl,1-10alkylsulphonyl, C1-10alkyl-dioxoimidazolidin, C1-10alkyl-oxopyrrolidin, C1-10alkylpyridine, C1-4alliteratively, saturated or unsaturated With1-4alkyl-C5-6carbocyclic, C1-10alkyl, C2-10alkenyl, saturated or unsaturated With3-8carbocyclic, morpholinyl, thiophenyl, piperazinil, dioxotetrahydrofuran, unsaturated With5-6carbocyclic-C1-10alkyl or piperazinil-C1-10alkyl, each of which is optionally substituted by one or more, same or different substituents represented by R7;
provided that, when Y2represents-O - or-NRa-, and R9represents a C1-6alkyl specified C1-6alkyl substituted by one or more, same or different substituents represented by R 7;
Y3represents-O-, -S-, -S(O)2-, -C(O)NRa-, -C(O)-, or-C(O)O-;
R10represents a C1-10alkyl, C2-10alkenyl, or tetrahydropyranyl, each of which is optionally substituted by one or more, same or different substituents represented by R7;
or its pharmaceutically acceptable salt or ester.

2. The compound according to claim 1, where R1represents methyl, ethyl, methoxy, ethoxy, bromine, fluorine or chlorine.

3. The compound according to any one of claims 1 or 2, where R2represents hydrogen, nitro, bromine, fluorine or chlorine.

4. The compound according to any one of claims 1 or 2, where R3represents hydrogen, bromine, fluorine or chlorine.

5. The compound according to any one of claims 1 and 2, where R3represents one Deputy.

6. The compound according to claim 5, where R3is in meta-position to the R4and in the para-position relative to the-NH, or where R3is in meta-position to the R4and in ortho-position to the-NH, or where R3is in ortho-position to the R4and in meta-position to the-NH.

7. The compound according to any one of claims 1 and 2, where one of R3or R4represents fluorine.

8. The compound according to any one of claims 1 and 2, where R8represents hydrogen or C1-4alkyl.

9. The compound according to any one of p is .1 and 2, where R4represents a C1-4alkyl, amino or halogen.

10. The connection according to claim 9, where R4represents methyl, ethyl, amino, bromine, fluorine or chlorine.

11. The compound according to any one of claims 1 and 2, where R7represents halogen, hydroxy, amino, -S(O)2CH3, trifluoromethyl, C1-4hydroxyalkyl,1-4alkoxy, C1-4alkylthio, C1-4alkoxycarbonyl, -COOH, or-CONH2.

12. Connection to item 11, where R7represents methoxy, ethoxy, hydroxy, methoxycarbonyl, etoxycarbonyl, amino, -COOH, fluorine, chlorine, bromine, -CONH2, methylthio, -S(O)2CH3, trifluoromethyl or hydroxymethyl.

13. The compound according to any one of claims 1 and 2, where R5is a Y2R9With1-4alkyl-Y2R9, Y2R9Y3R10With1-4alkyl, unsaturated With5-6carbocyclic-Y2R9, -COOH.

14. The connection indicated in paragraph 13, where R5is a Y2R9, Y2R9Y3R10, phenyl, methyl-Y2R9or-COOH, and R6represents hydrogen.

15. The compound according to claim 1, where R9is morpholinyl, propylsulfonyl, piperazinil, methyl, ethyl, n-propyl, n-butyl, tert-butyl, isobutyl, hexyl, isopropyl, dimethylpropyl, methyltetrahydrofuran, methylpyridine, cyclohexyl, propylaminoethyl, Benz is l, methylcyclohexyl, propylphenyl, ethylphenyl, ethylmorpholine, allyl, phenyl, methyldeoxycytidine, dioxotetrahydrofuran, were, ethylphenyl, methyldienolone, methylthiazolyl or thiophenyl.

16. The compound according to claim 1, where R10represents methyl, ethyl, or tert-butyl.

17. The compound according to any one of claims 1 and 2, where Raor Rbindependently represent hydrogen, methyl, or ethyl.

18. The compound according to any one of claims 1 and 2, selected from the group including
3-[2-chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-(tetrahydrofuran-2-ylmethyl)benzamide (compound 104),
3-[2-chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-N-(2-methoxyethyl)-4-methylbenzamide (compound 106),
3-[2-chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-4-methyl-N-(3-morpholine-4-ylpropyl)benzamide (compound (107),
3-[4-(2-aminophenylamino)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 112),
3-[4-(2-amino-4-brompheniramine)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 113),
3-[4-(4-bromo-2-methylphenylimino)-2-chlorobenzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 114),
3-[2-chloro-4-(2,4-dipertanyakan)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-AMINOPHENYL the Mino)-2-chlorobenzoyl]-N-(3-hydroxypropyl)-4-methylbenzamide (compound 118),
3-[2-chloro-4-(4-fluoro-2-methylphenylimino)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 119),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 120),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4,N-dimethylbenzamide (compound 121),
ethyl ester of (2-{3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}acetylamino)acetic acid (compound 122),
ethyl ester {3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methylbenzylamino}acetic acid (compound 123),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-ethyl-4-methylbenzamide (compound 126),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-isobutyl-4-methylbenzamide (compound 129),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2,2-dimethylpropyl)-4-methylbenzamide (compound 130),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(3-methoxypropyl)-4-methylbenzamide (compound 131),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-4-methyl-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide (compound 132),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-(2-dimethylaminoethyl)-4-methylbenzamide (compound 133),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-CIS-(4-hydroxycyclohexyl)-4-methylbenzamide (compound 135),
3-[2-chloro-4-(4-chloro-2-forgenerating)benzoyl]-N-TRANS-(4-hydroxycyclohexyl)-4-methylbenzamide (compound 136),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydro is setil)-4-methoxybenzamide (compound 140),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2,2-dottorati)-4-methoxybenzamide (compound 141),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-foradil)-4-methoxybenzamide (compound 142),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 143),
N-carbamoylmethyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzamide (compound 144),
N-carbamoylmethyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 145),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-foradil)-4-methylbenzamide (compound 147),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2,2,2-triptorelin)benzamide (compound 148),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-ethyl-4-methylbenzamide (compound 149),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-cyclohexylmethyl-4-methylbenzamide (compound 150),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxypropyl)-4-methylbenzamide (compound 151),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methylbenzamide (compound 152),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(1-hydroxymethylpropane)-4-methylbenzamide (compound 153),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(2,2,3,3,3-pentafluoropropyl)benzamide (compound 154),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(3-hydroxypropyl)-4-methylbenzamide (compound 155),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-g is droxi-1,1-dimethylethyl)-4-methylbenzamide (compound 156),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2-hydroxy-1-hydroxymethyl-1-methylethyl)-4-methylbenzamide (compound 157),
ethyl ester {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}acetic acid (compound 158),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(4-hydroxybutyl)-4-methylbenzamide (compound 159),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(3-hydroxy-1,1-dimethylbutyl)-4-methylbenzamide (compound 160),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methyl-N-(3-phenylpropyl)benzamide (compound 161),
(R)-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(1-hydroxymethyl-3-methylbutyl)-4-methylbenzamide (compound 162),
3-[4-(2,4-dipertanyakan)benzoyl]-N-(2-foradil)-4-methylbenzamide (compound 163),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-isopropyl-4-methylbenzamide (compound 164),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-N-(2,2-dottorati)-4-methylbenzamide (compound 166),
methyl ester 5-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}-4-oxopentanoic acid (compound 167),
N-[(2-carbamoylation)methyl]-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 168),
ethyl ester of (2-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzylamino}acetylamino)acetic acid (compound 169),
N-allyl-3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzamide (compound 170),
3-[2-chloro-4-(2,6-dipertanyakan is)benzoyl]-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 173),
3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-foradil)-4-methoxybenzamide (compound 174),
3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 175),
3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-N-(3-hydroxypropyl)-4-methoxybenzamide (compound 176),
3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxy-1,1-dimethylethyl)-4-methoxybenzamide (compound 178),
3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxy-N-(2-morpholine-4-retil)benzamide (compound 179),
3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxy-1-hydroxymethyl-1-methylethyl)-4-methoxybenzamide (compound 180),
3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-N-(2-hydroxyethyl)-4-methoxy-N-methylbenzamide (compound 181),
ethyl ester {3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzylamine}acetic acid (compound 182),
ethyl ester of (2-{3-[2-chloro-4-(2,6-dipertanyakan)benzoyl]-4-methoxybenzylamine}acetylamino)acetic acid (compound 183),
3-[2-chloro-4-(3-fluoro-2-methylphenylimino)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 186),
3-[2-chloro-4-(2-chloro-4-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 188),
3-[2-chloro-4-(4-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 190),
3-(2-chloro-4-phenyliminomethyl)-N-(2-hydroxyethyl)-4-methylbenzamide (compound 191),
3-[2-chloro-4-(3,5-dipertanyakan)benzoyl]-N - (2-hydroxyethyl)-4-methylbenzamide (compound 192),
3-[2-chloro-4-(3-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methylbenzamide (compound 193),
3-[2-chloro-4-(4-forgenerating)benzoyl]-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 194),
3-(2-chloro-4-phenyliminomethyl)-N-(2-hydroxyethyl)-4-methoxybenzamide (compound 195),
3-[2-chloro-4-(4-forgenerating)benzoyl]-N-(2,2-dottorati)-4-methoxybenzamide (compound 196),
3-[2-chloro-4-(4-forgenerating)benzoyl]-N-(2-foradil)-4-methoxybenzamide (compound 197),
3-[2-chloro-4-(4-forgenerating)benzoyl]-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 198),
N-carbamoylmethyl-3-[2-chloro-4-(4-forgenerating)benzoyl]-4-methoxybenzamide (compound 199),
3-(2-chloro-4-phenyliminomethyl)-N-(2,2-dottorati)-4-methoxybenzamide (compound 200),
3-(2-chloro-4-phenyliminomethyl)-N-(2-foradil)-4-methoxybenzamide (compound 201),
3-(2-chloro-4-phenyliminomethyl)-N-(2,3-dihydroxypropyl)-4-methoxybenzamide (compound 202),
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-methoxypropionate (compound 241),
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}propionamide (compound 242),
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-2-(2-methoxyethoxy)ndimethylacetamide (compound 243),
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-morpholine-4-ylpropionic (compound 244),
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-hydroxypropionate (compound 245,
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-2-hydroxybenzamide (compound 247),
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-2-(2,5-dioxoimidazolidin-4-yl)ndimethylacetamide (compound 248),
{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}amide
2,6-dioxotetrahydrofuran-4-carboxylic acid (compound 249),
2-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylphenylcarbinol}ethyl ester of acrylic acid (compound 250),
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-methylsulfinylpropyl (compound 251),
N-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-methanesulfonamide (compound 252),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(2-hydroxyethyl)urea (compound 260),
ethyl ester of (3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)acetic acid (compound 261),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(3-methoxyphenyl)urea (compound 262),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(3-triptoreline)urea (compound 263),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-proprotein (compound 264),
ethyl ester of 3-(3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)propionic acid (compound 265),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-cyclohex lochaven (compound 266),
1-allyl-3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}urea (compound 267),
1-benzyl-3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}urea (compound 268),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-atilmotin (compound 269),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-phenylacetone (compound 270),
1-butyl-3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}urea (compound 271),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-phenethylamine (compound 272),
methyl ester of 2-(3-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}ureido)benzoic acid (compound 273),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-Isopropylamine (compound 275),
1-{3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}-3-(4-methoxyphenyl)urea (compound 276),
benzyl ether of {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 277),
allyl ether {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 278),
ethyl ester {3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-were}carbamino acid (compound 279),
[2-chloro-4-(2,4-dipertanyakan)phenyl]-[5-(3-hydroxyethylamino)-2-were]metano (compound 281),
[2-chloro-4-(2,4-dipertanyakan)phenyl]-(3'-hydroxymethyl-4-methylbiphenyl-3 is)methanon (compound 282),
[2-chloro-4-(2,4-dipertanyakan)phenyl]-(3'-hydroxy-4-methylbiphenyl-3-yl)methanon (compound 283),
[2-chloro-4-(2,4-dipertanyakan)phenyl]-(4'-methoxy-4-methylbiphenyl-3-yl)methanon (compound 284),
N-{3'-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4'-methylbiphenyl-3-yl}ndimethylacetamide (compound 285),
[2-chloro-4-(2,4-dipertanyakan)phenyl]-[2-fluoro-5-(3-hydroxypropoxy)phenyl]metano (compound 314),
[2-chloro-4-(2,4-dipertanyakan)phenyl]-5-hydroxymethyl-2-methoxyphenyl)methanon (compound 335),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methoxybenzyloxy ether acetic acid (compound 336),
3-[2-chloro-4-(2,4-dipertanyakan)benzoyl]-4-methylbenzoic acid (compound 424).

19. Pharmaceutical composition having the property of inhibiting the production of cytokines, including an effective amount of a compound according to any one of claims 1 to 18, or its pharmaceutically acceptable salt or ester together with a pharmaceutically acceptable carrier or excipient.

20. The compound according to any one of claims 1 to 18, having the properties of inhibitors of TNF-α or MAR-kinase RA for use as an active ingredient of a medicinal product.

21. The compound according to any one of claims 1 to 18 for receiving medicines for use as anti-inflammatory agent or anti-cancer agent.

22. The method of obtaining compounds of General structural forms of the crystals I,

where R1, R2, R3, R4, R5and R6have the meanings indicated in claim 1, comprising the following stages:
a) the conversion of compounds of General structural formula VI,

where Hal represents halogen, and R1, R5and R6have the meanings indicated in claim 1, each of which are independently protected or unprotected, in ORGANOMETALLIC intermediate connection;
b) Parametrierung specified ORGANOMETALLIC intermediate compounds in tsinkorganicheskih intermediate connection;
c) interaction of the specified tsinkorganicheskih intermediate connection galogenangidridy acid of the General structural formula V,

where R2matter specified in claim 1, protected or unprotected, in the presence of a catalyst to obtain compounds of General structural formula IV,

where R1, R2, R5and R6have the meanings indicated above, each of which are independently protected or unprotected;
e) recovery of the compounds of General structural formula IV with stage C) or (d) to the amine of General structural formula III,

where R1, R2, R5and R6have the meanings indicated above, each of which independently is adixen or unprotected;
d) the interaction of the amine of General structural formula III with stage e) with a compound of General structural formula II,

where L represents triflate or halogen, R3and R4have the meanings indicated in claim 1, each of which are independently protected or unprotected, to obtain the compounds of General structural formula I, where R1, R2, R5and R6have the meanings indicated above, each of which are independently protected or unprotected;
h) optional conversion, protection or removal of protecting one or more substituents or functional groups of R1, R2, R3, R4, R5and R6compounds of General structural formula I from step g) to obtain the corresponding compounds of General structural formula I.

23. The method of obtaining compounds of General structural formula I,

where R1, R2, R3, R4, R5and R6have the meanings indicated in claim 1, comprising the following stages:
a) the conversion of compounds of General structural formula VIIa,

where Hal represents a halogen, W is a halogen or triflate, and R2matter specified in claim 1, secured or unsecured, in ORGANOMETALLIC intermediate connection;
b) Parametrierung at asanoha ORGANOMETALLIC intermediate compounds in tsinkorganicheskih intermediate connection;
c) interaction of the specified tsinkorganicheskih intermediate connection galogenangidridy acid of the General structural formula VIII,

where R1, R5and R6have the meanings indicated in claim 1, each of which are independently protected or unprotected, in the presence of a catalyst to obtain compounds of General structural formula IIIa,

where W, R1, R2, R5and R6have the meanings indicated above, each of which are independently protected or unprotected;
(e) the interaction of compounds of General structural formula IIIa with stage C) or d) with the amine of General structural formula IIa,

where R3and R4have the meanings indicated in claim 1, each of which are independently protected or unprotected, to obtain the compounds of General structural formula I, where R1, R2, R3, R4, R5and R6have the meanings indicated above, each of which are independently protected or unprotected.

24. The method according to item 22 or 23, where the interaction at the stage C) is carried out in the presence of a salt of copper.



 

Same patents:

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to derivatives of tetrahydronaphthalene and their salts, which have antagonistic properties towards the vanilloid receptor, to their use and medicinal preparation based on them. The compounds can be used for curing and preventing diseases, related to the activity of VR1, particularly for treating acute uroclepsia, hyperactive urinary bladder, chronic pain etc. In general formula (I) X represents an alkyl with 1-6 carbon atoms, or , Y represents a single bond, or , R1, R2 and R3 independently represent hydrogen, halogen, hydroxyq, nitro, carboxyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, (C3-8cycloalkyl)amino, (C1-6alkoxy)carbonyl, sulfonamide, C1-6alkyl, optionally substituted with a cyano group or mono-, di-, or tri-halogen, C1-6alkoxy group, optionally substituted with a halogen or C1-6alkyl group, or (C1-6alkyl)thio-group, optionally substituted mono-, di- or tri-halogen; R4, R5, R6 and R7 independently represent hydrogen, alkyl with 1-6 carbon atoms or phenyl; Z1 represents hydrogen or alkyl with 1-6 carbon atoms; and Z2 represents hydrogen, halogen or alkyl with 1-6 carbon atoms.

EFFECT: obtaining tetrahydronaphthalene derivatives and its salts, with antagonistic properties towards the vanilloid receptor.

10 cl, 3 tbl, 123 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):

or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.

EFFECT: valuable medicinal properties of compounds and composition.

9 cl, 2 sch, 2 tbl, 29 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, to derivatives of 1,4-diketones, namely to novel biologically active substance -2-(2,4-dichloranilino)-1,4-bis(4-methylphenyl)-2-buten-1,4-dione of formula 1 , which possesses antimicrobial activity and can be applied in medicine.

EFFECT: obtaining novel biologically active substance which possesses antimicrobial activity.

1 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel nonsteroid synthetic derivatives with the following structures or their pharmaceutically acceptable salts:

, , ,

,

or

, which are capable of modulating the androgen receptor.

EFFECT: invention relates to pharmaceutical compositions containing said derivatives and use thereof to make nonsteroid medicinal agents for treating and/or preventing conditions or diseases such as prostate hyperplasia, prostate cancer, hirsutism, severe hormone-dependant alopecia or acne etc, resulting from antagonistic activity towards the androgen receptor.

6 cl, 5 dwg, 3 tbl,12 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new photoinitiators, method of their obtainment, compositions hardening with irradiation, and application of those compositions in coating preparation. Invention claims photoinitiators of formulae I , where R1, R2, R3 and R4 are independently C1-C8alkyl or benzyl; or R1 and R2 together and/or R3 andR4 together are cyclohexyl; R5 is hydrogen; A is OH, Br, -O-C1-C12alkyl, -O-R7, where R7 is linear or forked C2-C21hydroxyalkyl carbon chain interrupted by 1 to 9 oxygen atoms; or -NR8R9, where R8 and R9 are independently C1-C21alkyl or C2-C4alkyl substituted by one or more OH groups; A' is -O-; X and Y are independently -OH or -N(CH3)2; n is 2; R6 is linear or forked divalent -CO-NH-(C2-C16alkylene)-(NH-CO)- radical or linear or forked -CO-NH-(C0-C9alkylene)-(NH-CO)- which can be interrupted by phenylene, or linear or forked divalent -C2-C50alkylene radical with carbon chain interrupted by 1 to 15 oxygen atoms.

EFFECT: efficient method of obtaining new organic photoinitiators.

11 cl, 20 cx

FIELD: organic synthesis.

SUBSTANCE: invention relates to synthesis of camptotecin analogues from 2'-amino-5'-hydroxypropiophnone corresponding to AB ring portion of camptotecin structure and tricyclic ketone converted into CDE ring portion in camptotecin structure. Preparation of 2'-amino-5'-hydroxypropiophnone comprises following steps: (1) preparing compound (b) by mixing compound (a), benzylation agent, and a base followed by stirring mixture obtained in solvent on heating under reflux; (2) preparing compound (c) by dropwise adding Grignard reagent to compound (b) under an inert gas atmosphere; (3) preparing compound (d) by mixing compound (c) with an oxidant and stirring resulting mixture; and (4) preparing compound (e) via catalytic reduction of compound (d) (see scheme 1 below). Intermediate compounds (c') and (d') are described. Also described is a method for preparing tricyclic ketone to provide efficient complete synthesis of camptotecin serving as starting compound for irinotecan hydrochloride and a various types of camptotecin derivatives as well as for stable preparation of camptotecin and its derivatives. Scheme 1: .

EFFECT: expanded synthetic possibilities in camptotecin derivatives series.

5 cl, 17 tbl, 33 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention proposes new compounds of the general formula (I):

wherein R1 means one or more similar or different substitutes taken among the group consisting of hydroxy-group, halogen atom including F, Cl, Br and J, (C1-C5)-alkyl, (C1-C5)-alkoxy-group under condition that when R1 means one substitute then it is in ortho-position and when R1 means above one substitute then at least one substitute at R1 is in ortho-position; R2 means halogen atom including F, Cl, Br and J, (C1-C5)-alkyl, (C1-C5)-alkoxy-group; R3 means halogen atom including F, Cl, Br and J; R6 means hydrogen atom or methyl; and its salts with pharmaceutically acceptable acids, hydrates or solvates. Compounds elicit activity against acne and acne-related diseases.

EFFECT: valuable medicinal properties of compounds.

7 cl, 4 tbl, 43 ex

The invention relates to a method for producing 2-aminobenzophenones, which are intermediate compounds in obtaining reducing cholesterol agents, which are agents for the treatment of mental disorders, and anti-inflammatory agents

The invention relates to new nitromethylene formula (I)

< / BR>
in which A represents C6-C10aryl, thienyl, benzothiazyl; X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy, or cryptometer; p is chosen from 0, 1, 2, 3, 4, or 5; Z represents a bond, -CO-NH-, SO2-NH-, a sulfur atom, sulfinyl group or a C2-C7alkenylamine radical; R1, R2, R3and E indicated in paragraph 1

The invention relates to 1-phenylalanine - new ligands of 5-HT4receptors of formula I, where R1- halogen; R2- H, C1-C4alkoxy; R3- C1-C4alkoxy, phenyl C1-C4alkoxy, where phenyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy; R2and R3together represent methylenedioxy, Ethylenedioxy; R4denotes a group of formula (a) or (b), where n = 3, 4, 5; p = 0; q = 1 or 2; R5and R6each C1-C4alkyl or together are - (CH2)4- , - (CH2)6-, - (CH2)2O(CH2)2-,

-CHR8CH2CR9R10CHR11CH2- where R8and R11each H or together are - (CH2)t- where t =1; R9- H, HE, C1-C8alkyl, C1-C4alkyloxy; R10- H, C1-C8alkyl, phenyl, - (CH2)xR12where x = 0, 1, 2, 3; R12HE, C1-C4alkyloxy, - C(O)NR13R14, - NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15, -NR13C(O)NR14R15; R13, R14, R15- independently - H, C1-C4e is phenyl optionally substituted C1-C4alkyloxy, methylendioxy, Ethylenedioxy; or R7- (CH2)z- R12where z = 2, 3

FIELD: chemistry.

SUBSTANCE: invention relates to novel anti-tumour compounds which are kahalalide F derivatives, pharmaceutical compositions containing said derivatives and their use in preparing an anti-tumour medicinal agent.

EFFECT: obtaining novel anti-tumour compounds.

4 cl, 9 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology and is a peptide which induces killer T cells ex vivo and which has an amino acid sequence as shown in one SEQ ID NOS: from 1 to 3. The disclosed peptide is used in an ex vivo agent for inducing anti-tumour immunity, in an ex vivo agent for inducing antigen-presenting cells, in an ex vivo agent which induces tumour-reactive T cells, as well as in an ex vivo pharmaceutical agent when treating or preventing tumours. The invention also relates to an antibody against the said peptide.

EFFECT: disclosed agents enable identification of glypican-3-derivative peptide, which can bond with HLA-A2, and activation of human killer T cells in order to provide an immunotherapy agent which may be effective in approximately 40% Japanese patients suffering from certain types of malignant tumours, accompanied by high level of GPC3 expression.

7 cl, 4 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pyrimidine nucleoside compound of general formula (1) , in which one of X and Y is a cyano group and the other is hydrogen; R1 is hydrogen, (R3)(R4)(R5)Si- or a carbonyl group which includes an alkyl monosubstituted with an amino group; R2 is hydrogen or (R6)(R7)(R8)Si-, provided that at least one of R1 and R2 is not hydrogen; or R1 and R2 together form a 6-member cyclic group -Si(R9)(R10)-, where each of R9 and R10 is a straight or branched alkyl; R3, R4 and R5 denote a straight or branched alkyl optionally substituted alkoxy, or cycloalkyl; R6, R7 and R8 denote a straight or branched alkyl optionally substituted alkoxy, cycloalkyl or phenyl, or to pharmacologically acceptable salts thereof. The invention also relates to a range of specific compounds of formula (1) or to their pharmacologically acceptable salts: 5'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-diethylisopropylsilyl-2'-cyano-2,-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(dimethyl-n-octylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-diethylisopropylsilyl -2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-(tert-butyldimethylsily)-2'-cyano-2'-desoxy-1-β-O-arabinofuranosylcytosine; 3'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-5'-O-(L-valyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(L-valyl)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; and 3'-O-cyclopropyl-diisopropylsilyl-2'-cyano-2'-desoxy-1-β-D- arabinofuranosylcytosine.

EFFECT: obtaining formula (1) compounds or their pharmacologically acceptable salts for preparing a medicinal agent for treating tumours.

9 cl, 20 tbl, 1 dwg, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts and esters. The disclosed compounds have inhibitory effect on cyclin-dependant kinase. In formula I R1 denotes , R3 is selected from a group consisting of H, CO2R6, C(O)R6, SO2R6 and SO2NR5R6, R5 and R6 are each independently selected from a group which includes H and (lower)alkyl, R2 is phenyl which contains one, two or three substitutes independently selected from a group which includes halogen or -O-(lower)alkyl.

EFFECT: preparation of a pharmaceutical composition which contains an effective amount of a formula I compound as an active ingredient.

6 cl, 1 tbl, 22 ex

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