Histone deacetylase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), having histone deacetylase (HDAC) enzyme inhibiting action, stereoisomers, hydrates, solvates and pharmaceutically acceptable salts thereof, compounds of formula (II), compounds selected from a list, a method of producing compounds of formula (I), a pharmaceutical composition, an inhibition method and methods of treating using compounds of formula (I). In formulae

and

R denotes substituted or unsubstituted groups selected from (C6-C10)aryl, (C3-C12)cycloalkyl, heteroaryl, (C6-C10)aryl (C1-C6)alkyl and heterocyclyl; where the heterocyclyl hereinafter is a 5-10-member ring radical which consists of carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen and sulphur, and heteroaryl hereinafter is an aromatic heterocyclyl, and each aryl, cycloalkyl, heteroaryl, arylalkyl and heterocyclyl can be substituted with one or more substitutes selected from halogens, including fluorine, chlorine, bromine, iodine, (C1-C6)alkyl, (C1-C6)alkoxy, (C6-C10)aryl, halogen(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy, -O-(C3-C12)cycloalkyl, -O-CH2-(C3-C12)cycloalkyl, hydroxyl, NRaRb and ORa, where Ra and Rb independently denote (C1-C6)alkyl and aryl; R1 denotes (C6-C10)aryl; R2 and R3 independently denote hydrogen, (C1-C6)alkyl, -COOR5, -CONR5R6, -CH2NR5R6, -CH2CH2NR5R6, -CH2CH2OH or -CH2OH; provided that one of R5 or R6 is hydrogen or unsubstituted alkyl, the other is neither hydrogen nor unsubstituted alkyl; R5 and R6 independently denote hydrogen, (C1-C6)alkyl, (C3-C12)cycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl, which can be unsubstituted or substituted; or R5 and R6 can be combined to form a saturated or unsaturated 3-8-member ring having 0-2 heteroatoms, including N, O or S; where the heteroaryl hereinafter is a 5-10-member ring radical consisting of carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen and sulphur, and each alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl can be substituted with one or more substitutes selected from halogen, including chlorine, fluorine, bromine or iodine,(C1-C6)alkoxy and NRaRb; R4 denotes OH, (C6-C10)aryl, ortho-substituted aniline or amino (C6-C10) aryl, which can be optionally substituted with one or more groups selected from halogens, including fluorine, chlorine, bromine, iodine, hydroxyl, amino groups or (C6-C10)aryl; X denotes -NR7-, -CONR7- or -N R7CO; R7 denotes hydrogen or (C1-C6)alkyl; Y denotes (C6-C10)aryl or (C6-C10)aryl(C2-C6)alkenyl; m is an integer from 0 to 1; n is an integer from 0 to 1; o is an integer from 0 to 7; and p is an integer from 0 to 1.

EFFECT: improved method.

 

The scope of the invention

The described compounds of formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, geometric isomers, polymorphs, hydrates, solvate, intermediate compounds, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs.

In the description disclosed a method of obtaining said new stilbenoids compounds of formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvate, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs.

Disclosed in the description of the compounds are inhibitors discontinuties (HDAC), and stop the cell growth of neoplastic cells, thus inhibiting proliferation. They can be used as therapeutic agents for diseases involving cell growth, such as malignant tumors, autoimmune diseases, skin diseases, infections, etc.

Background of the invention

Regulation of transcription is a key event in cell differentiation, proliferation and apoptosis. Activation of transcription of genes determines the assignment of cells, and for this reason, the transcription is tightly regulated by a variety of factors. One of its PE ulatory mechanisms, involved is the alteration of the tertiary structure of DNA, which affects the transcription factors to their target DNA regions. Nucleosomal integrity is regulated by the state of acetylation of nuclear histones, the result is the resolution of transcription.

Consider what kinds of regulation of transcription factor included changes in the structure of chromatin. Change the affinity of proteins to histone coiled DNA in the nucleosome changes the structure of chromatin. I believe that hypoallergeni histones have a greater affinity to DNA and form a tightly associated complex DNA-histone, and make DNA available for transcription regulation. Status of histone acylation is controlled by a balance of activities distancedistance (NAT) and discontinuties (HDAC).

The first allocation discontinuties from crude cell extracts was described in 1964, but the molecular characterization of the isoforms of the enzyme was carried out only recently. Inhibitors discontinuties (HDAC) are tinchebray responsible for dezazetilirovanie residues of N-acetyl-lysine in histone and nonhistone protein substrates. HDAC person is classified according to two different classes: HDAC and sirtuins as well. HDAC divided into two subclasses on the basis of their relationship with discontinuation yeast: RPD 3 (class I includes HDAC 1, 2, 3, 8 and 11) and Hda 1 (to the ACC II includes HDAC 4, 6, 7, 9 and 10). All of these HDAC have greatly transformed the zinc-dependent catalytic domain. There is increasing evidence that the acetylation status of proteins, and thus the HDAC family, plays a crucial role in the modulation of several biological processes, including transcription and cell cycle.

Recently it was found that the HDAC inhibitors stop the cell growth and apoptosis in some types of cancer cells, including colorectal cancer, T-cell lymphoma and erythroleukemia cells (M. Paris,et al.,J. Med. Chem., 2008,51, 1505-1529).

It was found that the HDAC inhibitor MG3290 is a potent, selective for fungi by potentiation some azole antifungal agents on the speciesAspergillusandCandidaincludingC. glabrataand it was also found that it potentiates the azole-resistant mutant ofC. glabrata(WO 2008/021944 and US 2008/0139673).

Assuming that apoptosis is a critical factor in the progression of cancer, HDAC inhibitors are promising agents for cancer therapy as effective inducers of apoptosis.

Recently suberoylanilide acid (SAHA) was released as an anticancer agent for the treatment of cutaneous T-cell lymphoma (CTCL), and it is known as an inhibitor of HDAC. Identified several structural classes of HDAC inhibitors, an overview is given in Marks, P.A.et al.,J. Natl. Cancer Inst., 2000,i> 92, 1210-1215. More specifically, in patent publications WO 98/55449 and US 5369108 reported alkanoyloxy with HDAC-inhibitory activity. Other compounds that can inhibit the activity of HDAC are trichostatin A (TSA), PXD101, troponin (TPX), sodium butyrate (NaB), sodium valproate (VPA), peptides containing cyclic hydroxamic acid (CHAP), depsipeptide FK-228, MGCD0103 and MS-275 can suppress these genes, resulting in antiproliferative effectsin vitroand anticancer effectsin vivo.

1) InWO 2001038322disclosed are compounds and methods for inhibition of enzyme activity discontinuties, which have the following formulas I and II.

,

where Cy is cycloalkyl, aryl, heteroaryl or heterocyclyl, any of which may be optionally substituted; L2represents C1-C6rich alkylene or C1-C6albaniles where alkylen or albaniles may be optionally substituted; Ar is aralen where specified arisen may be optionally additionally substituted. Y2represents a chemical bond or a saturated alkylene with normal or branched chain, which may be optionally substituted; Z is selected from the group consisting of aniline, pyridyl, thiadiazolyl and-O-M, M is H. L3selected from the group, with the standing of C 1-C6alkylene or C1-C6Alcanena where alkylen or albaniles may be optionally substituted; Y3represents C2-C3albaniles or C2-C3akinyan;

2) InUS 6624197 B1disclosed class of diphenylethylene formula A

,

where R represents hydrogen or-CO2Z, Z represents hydrogen or a cation; and R1, R2and R3each independently represent H, -OH or-OR4where R4represents a normal or branched alkyl with 1-12 carbon atoms; provided that when R is hydrogen and R2=R3=-OMe, then R1is not-OH. The configuration at the double bond may be E/Z. Also proposed a class of Starinov formula B;

,

where R5represents hydrogen or methyl; R6and R7independently represent hydrogen or OMe; R8represents hydrogen or hydroxy. The configuration at the double bond may be E/z Proposed pharmaceutical compositions of compounds of formula A or B for the treatment of diabetes, comprising a therapeutically effective amount of compounds in a physiologically acceptable carrier. Also proposed is a method of treatment of diabetes, including the state oral administration to a subject suffering from a diabetic condition, a therapeutically effective the th number of the compounds of formula A or B.

3) InUS 20050038125the described method of treatment and/or prevention of disorders with elevated levels of PGE2(such as arthritis, fibromyalgia, and pain) and/or LTB4(such as asthma, allergies, arthritis, fibromyalgia and inflammation), including introduction to the mammal an effective amount of pterostilbene component (PS component), pharmaceutically acceptable salts PS component or precursor of PS component, where PS component has the formula C.

,

in which R1, R2and R3independently selected from hydrogen, C1-50hydrocarbide, C1-50substituted hydrocarbide, C1-50heterodidaskalia, C1-50substituted heterodidaskalia; and where at least one of R1and R2is not hydrogen.

4) InUS 2004/0077726reveals some of the active compounds of carbamino acid, which inhibit HDAC activity and have the following formula D,

,

in which A represents an aryl group; Q1represents a covalent bond or an aryl leader group; J represents sulfonamidnuyu linker selected from: -S(=O)2NR1- , and-NR1S(=O)2-; R1represented by the Deputy in sulfonamide; and Q2is an acid leader group; provided that when J is-S(=O)2NR 1-Q1represents aryl leader group; and their pharmaceutically acceptable salt, solvate, amides, esters, ethers, chemically protected forms, and prodrugs. Described pharmaceutical compositions comprising such compounds, and their use for the inhibition of the proliferative state. Also described are the compounds of formula E in which Q1represents a covalent bond, J is-NR1SO2-, Q2represents a phenylene-meta-TRANS-ethylene. RBrepresents fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, amino, dimethylamino, diethylamino, morpholino, acetamido, nitro and phenyl, m is an integer from 0 to 4.

5) InWO 2008/054154disclosed naphthalenemethanamine derived as HDAC inhibitors of the formula 1a-1d, in which R1represents a substituted or unsubstituted alkyl group with one or more substituents.

Short description

New substituted inhibitors HDAC of formula (I)

their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvate, intermediate compounds, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs

in which the configuration at the double bond may be E/Z;

R represents substituted or unsubstituted groups selected from aryl, cycloalkyl, heteroaryl, arylalkyl, arylalkyl, arylalkyl, heterocyclyl, heteroallyl, heteroallyl and heteroallyl;

R1represents a substituted or unsubstituted group selected from aryl and heteroaryl groups;

R2and R3independently represent hydrogen, alkyl, -COOR5, -CONR5R6, -CH2NR5R6, -CH2CH2NR5R6, -CH2CH2OR5, -CH2OR5, -CH2OCONR5R6and-CH2NR5COR6; in which one of R2or R3is hydrogen or unsubstituted alkyl, the other is not hydrogen or unsubstituted alkyl;

R5and R6independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, arylalkyl, arylalkyl, heteroaryl, heteroaromatic, heteroallyl and heteroallyl, or R5or R6can be combined with the formation of a 3-8-membered ring having 0-2 heteroatoms, such as N, O or S;

R4is OR7, aryl, ortho-substituted aniline, aminoaryl and aminoglutaric, which may be further substituted where R 7is hydrogen, -COR8substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; where R8represents substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl and heterocyclyl; X represents-O-, -NR7-, -CONR7-, -NR7SO2-, -SO2NR7-, -SO2O -,-SO2-, -CH2NR7-, -NR7CONR7- , and-NR7CO-;

Y is aryl, arylalkyl and heteroaryl;

m is an integer from 0-3; n is an integer from 0-1; o is an integer from 0 to 7; and p is an integer from 0-1,

provided that if n, o and p=0, then m=0-1; and

provided that if n=1, o=3 to 7, and p=0, then m=0-1; and

provided that if n, o and p=1, then m=0-1.

Brief description of figures

Fig. 1 shows the effectiveness of compound 105 model xenograft HCT-116.

Detailed description

The new compounds of formula (I)

,

their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvate, intermediate compounds, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs,

in which the configuration at the double bond may be E/Z;

R represents substituted or unsubstituted groups selected from aryl, cycloalkyl, heteroaryl, arylalkyl is a, arylalkyl, arylalkyl, heterocyclyl, heteroallyl, heteroallyl and heteroallyl;

R1represents a substituted or unsubstituted group selected from aryl and heteroaryl;

R2and R3independently represent hydrogen, alkyl, -COOR5, -CONR5R6, -CH2NR5R6, -CH2CH2NR5R6, -CH2CH2OR5, -CH2OR5, -CH2OCONR5R6and-CH2NR5COR6; in which one of R2or R3is hydrogen or unsubstituted alkyl, the other is not hydrogen or unsubstituted alkyl;

R5and R6independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, arylalkyl, arylalkyl. heteroaryl, heteroaromatic, heteroallyl and heteroallyl; or R5and R6can be combined with the formation of saturated or unsaturated 3-8-membered ring having 0-2 heteroatoms, such as N, O or S;

R4is OR7, aryl, ortho-substituted aniline, aminoaryl and aminoglutaric, which may be further substituted; and where R7is hydrogen, -COR8, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; where R8is it is certainly substituted alkyl, aryl, heteroaryl and heterocyclyl;

X represents-O-, -NR7-, -CONR7-, -NR7SO2-, -SO2NR7-, -SO2O -,-SO2-, -CH2NR7-, -NR7CONR7- , and-NR7CO-;

Y is aryl, arylalkyl and heteroaryl;

m is an integer from 0-3; n is an integer from 0-1; o is an integer from 0 to 7; and p is an integer from 0-1,

when the groups R, R1, R5, R6, R7and R8are substituted, the substituents, which may be one or more selected from a halogen, such as fluorine, chlorine, bromine, iodine; hydroxy; nitro; cyano; oxo (=O); thioxo (=S); azido; nitroso; amino; hydrazino; formyl; alkyl; alkoxy; aryl; halogenoalkanes group, such as trifluoromethyl, tribromoethyl, trichloromethyl; halogenoalkane, including-OCH2Cl; Allakaket, including benzyloxy, venlafaxi; cycloalkyl; -O-cycloalkyl; aryl; alkoxy; heterocyclyl: heteroaryl; alkylamino; -O-CH2-cycloalkyl; -COORa; -C(O)Rb; -C(S)Ra: -C(O)NRaRb; -NRaC(O)NRbRc; -N(Ra)SORb; -N(Ra)SO2Rb; -NRaC(O)ORb; -NRaRb; -NRaC(O)Rb-; NRaC(S)Rb-; -SONRaRb-; -SO2NRaRb-; -ORa; -ORaC(O)ORb-; -OC(O)NRaRb; OC(O)Ra; -OC(O)NRaRb-; -RaNRbRc; R aORb-; -SRa; -SORaand-SO2Ra; Ra, Rband Rceach independently represents a hydrogen atom; substituted or unsubstituted groups selected from alkyl; aryl; arylalkyl; cycloalkyl; heterocyclyl; heteroaryl and heteroallyl;

the deputies, in turn, further substituted by halogen, such as fluorine, chlorine, bromine and iodine; hydroxy; nitro; cycloalkyl; cyano; azido; nitroso, amino, hydrazino, formyl; alkyl; halogenoalkanes group, such as trifluoromethyl and tripometer;

provided that if n, o and p=0, then m=0-1; and

provided that if n=1, o=3 to 7, and p=0, then m=0-1; and

provided that if n, o and p=1, then m=0-1.

The term "alkyl" refers to aliphatic hydrocarbon groups with normal or branched chain having the specified number of carbon atoms that are attached to the remainder of the molecule is a single atom. Examples of such alkyl groups include, but without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.

The term "aryl" refers to aromatic radicals having from 6 to 14 carbon atoms, such as phenyl, naphthyl, biphenyl, indanyl, substituted or unsubstituted Allenby groups such as phenylene, biphenylene, naftilan, antracene, phenanthrolin and indaniel.

The term "arylalkyl" refers to Ari who enoy group, directly related to the alkyl group, examples of such arylalkyl groups include, but are not limited to, benzyl and phenethyl.

The term "heterocyclyl" refers to a stable 3 to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For the purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic systems of rings and nitrogen atoms, phosphorus, ogorode, oxygen or sulfur in the heterocyclic ring radical may be optionally oxidized to various oxidation States. In addition, the nitrogen atom may be optionally quaternion; and the ring radical may be partially or fully saturated. Examples of such heterocyclic ring radicals include, but are not limited to, azetidine, acridines, benzodioxolyl, benzodioxane, benzofuranyl, carbazolyl, cinnoline, DIOXOLANYL, indolizinyl, naphthyridine, peligrosamente, phenazines, phenothiazines, phenoxazines, phthalazine, pyridyl, pteridinyl, purinol, hintline, honokalani, chinoline, ethenolysis, tetrazolyl, imidazolyl, tetrahydroisoquinoline, piperidinyl, piperazinil, homopiperazine, 2-oxoazetidin, azepine, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazinyl, Piri is idini, pyridazinyl, oxazolyl, oxazolidinyl, thiazolyl, indanyl, isoxazolyl, isoxazolidine, thiazolyl, thiazolyl, diazolidinyl, isothiazolin, hinokitiol, isothiazolinones, indolyl, isoindolyl, indolinyl, isoindolyl, octahedrally, activitiesunder, hinely, ethanolic, decahydroquinoline, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, thienyl, morpholinyl, thiomorpholine, sulfoxide of thiomorpholine, furyl, tetrahydrofuryl, tetrahydropyranyl, bromanil and isopropanol. Heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the formation of stable patterns.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical as defined above. Heteroaromatic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the formation of stable patterns.

The term "heteroaromatic" refers to heteroaryl ring radical as defined above directly associated with the alkyl group. Heteroarylboronic radical may be attached to the main structure at any carbon atom alkyl groups.

The term "cycloalkyl" refers to non-aromatic mono - or polycyclic the Russian ring system of about 3 to 12 carbon atoms. Examples cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and examples of the polycyclic rings include perhydroanthracene, adamantly and norbornyl groups, bridged cyclic groups or spirobicyclic group, for example, Spiro[4.4]-non-2-yl.

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a double bond carbon-carbon bonds, which may be normal or branched chain of from about 2 to 10 carbon atoms, and examples alkenyl groups include, but without limitation, ethynyl, 1-propenyl, 2-propenyl, ISO-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

The term "arylalkyl" refers to an aromatic ring radical directly linked with alkenylphenol group. The aryl radical may be attached to the main structure at any carbon atom alkenylphenol group. Examples of such arylalkyl groups include, but without limitation, phenylethenyl and phenylpropenal.

The term "heteroaromatic" refers to heteroaryl ring radical directly linked with alkenylphenol group. Heteroaryl radical may be attached to the main structure at any carbon atom alkenylphenol group. Examples of such arylalkyl groups include, but without limitation, ti is dipropenyl, IntelliPoint, pyridinemethanol and IntelliPoint.

The term "alkoxy" refers to an alkyl group attached via an oxygen atom to the remainder of the molecule. Representative examples of such groups include, but without limitation, -OCH3and-OC2H5.

The term "aryloxy" refers to an aryl group attached through an oxygen atom to the remainder of the molecule. Representative examples of such groups include, but without limitation, -O-phenyl, and-O-biphenyl.

The term "alkylamino" refers to an alkyl group, as defined above, attached via the amino group to the remainder of the molecule. Representative examples of such groups include, but without limitation, -NHCH3and-N(CH3)2.

The term "quinil" refers to hidrocarburos group with a normal or branched chain, having at least one triple bond of carbon-carbon and containing carbon atoms in the range of 2-12 atoms. Representative examples of such groups include, but are not limited to, ethinyl, PROPYNYL and butynyl.

The term "arylalkyl" refers to an aromatic ring radical directly linked with alkenylphenol group. The aryl radical may be attached to the main structure at any carbon atom alkenylphenol group.

The term "heteroarylboronic" refers to the heteroaryl radical, directly is knitted with alkenylphenol group. Heteroaryl radical may be attached to the main structure at any carbon atom alkenylphenol group.

Further, the compound of formula (I) can be its derivatives, analogs, tautomeric forms, stereoisomers, geometric isomers, a polymorph, solvate, intermediate compounds, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs.

Pharmaceutically acceptable solvate may be hydrates or include other crystallization solvents, such as alcohols.

Compounds disclosed in the description may be in the shape of an E or Z geometric isomers, and in some cases can also present their mixtures. When in formula I contains two or more double bonds, it can lead to more than two geometric isomers, and in such cases, the invention encompasses all isomers.

It is clear that the compounds included in the family of compounds of formula (I)are isomeric forms including tautomers and stereoisomers (diastereoisomers, enantiomers and geometric isomers in a configurational isomers, E or Z or a mixture of isomers (E or Z). It is also clear that some isomeric forms, like the diastereomers, enantiomers and geometric isomers can be separated by experts in the field of physical and/or chemical method is mi.

Compounds disclosed in the description, may exist as single stereoisomers, racemates or mixtures of antimirov and/or diastereomers. All such stereoisomers, racemates and mixtures thereof are considered as included in the scope of the described subject matter.

The phrase "pharmaceutically acceptable" refers to compounds or compositions that are physiologically tolerable and do not usually give an allergic or similar untoward reactions, including, but without limitation, upset stomach, or dizziness, when administered to a mammal.

Pharmaceutically acceptable salts include salts derived inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn; salts of organic bases such as N,N'- diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine and thiamine, guanidine, diethanolamine, α-phenethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperazine and the like, ammonium salts or substituted ammonium salts of aluminum. Salts also include salts of amino acids such as glycine, alanine, cysteine, cystine, lysine, arginine, phenylalanine, guanidine, etc. If it is profitable, the salts may include an additive, acid salts are sulfates, nitrates, phosphates, perchlorates, borates, hydrogenogenic, acetates, tartratami, Malea is s, citrate, succinate, palmoate, methansulfonate, tozilaty, benzoate, salicylates, hydroxynaphthoate, bansilalpet, ascorbate, glycerophosphate and Ketoglutarate.

In the description disclosed are prodrugs of compounds of formula (I)that with the introduction of undergoing chemical transformation due to metabolic processes before becoming active substances. In General, such prodrugs can be functional derivatives of the compounds according to the invention, which can easily becomein vivoin connection according to the invention.

"Prodrug" denotes a compound that is capable of becomingin vivometabolic means (i.e., by hydrolysis, recovery or oxidation) in the compound of formula (I). For example, the ester prodrug of compounds of formula (I)containing a hydroxyl group may be converted by hydrolysisin vivoin the parent molecule.

Disclosed active compounds can also be prepared in any solid or liquid form, for example, the connection may be in crystalline form, amorphous form and may have any particle size. Further, particles connections can be mikronizirovanny or neionizirovanny, or may be agglomerated, prepared in the form of granules, powders, oils, oil suspensions or any other form of solid or liquid physical and the political forms.

Also in the description of the disclosed pharmaceutical compositions containing one or more compounds of General formula (I)defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvate in combination with conventional used in pharmaceutical carriers, diluents and the like, useful for the treatment and/or prevention of proliferative disorders.

The pharmaceutical composition may be in a commonly used form, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavoring agents, sweeteners, etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to obtain injectable solutions or suspensions. The composition can be obtained by methods known in this field. Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage in the range described above. Suitable routes of administration include systemic injection, such as oral, or parent the General, such as percutaneous, intramuscular, intravenous and subcutaneous administration. Thus, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to obtain capsules, tablets, powders, syrups, solutions, suspensions and the like. If desired, the pharmaceutical composition may contain additional components, such as flavors, sweeteners, excipients and the like. For parenteral administration the compounds can be combined with sterile aqueous or organic media to form solutions or suspensions for injection. For example, can be applied solutions in sesame oil or oil of groundnuts, aqueous propylene glycol and the like, as well as aqueous solutions of water-soluble pharmaceutically acceptable additive salts of acids, salts of the compounds with the alkaline or alkaline earth metals. Solutions for injection, thus obtained, can then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly.

The compounds of formula (I) can also be entered in the form of a pharmaceutical composition in a pharmaceutically acceptable carrier, preferably formulated for oral administration.

Compounds disclosed in the description, can also be polymorphism. The invention further include the AET different polymorphs of the compounds. The term "polymorph" refers to the specific crystalline state of matter with defined physical properties, such as x-ray diffraction, infrared spectra, melting point, and the like.

This invention, in addition to the above compounds, covers the use of homologues and analogues of such compounds. In this context, the homologues are molecules having substantial structural similarity with the above-described compounds and analogs are molecules that have significant biological resemblance whatever to the structural similarity.

The term "inhibitor discontinuties used to identify compounds that can interact with discontinuedrate and to inhibit its activity, more specifically the enzyme activity. Inhibition of enzyme activity discontinuties means less ability discontinuties to the removal of acetyl groups from histone. Preferably, such inhibition is specific, that is, the inhibitor discontinuties reduces the ability discontinuties to the removal of acetyl groups from histone at a concentration that is lower than the concentration of inhibitor required to achieve another, not related biological effect.

The term "histand acetylase" and "HDAC" refers to one of the families of enzymes, which remove acetyl groups from residues ε-amino groups of lysine at the N end of the histone. Unless the context otherwise indicated, the term "histone" means any histony protein, including H1, H2A, H2B as well as, N3, N4 and N5, any species. HDAC proteins person or gene products include, but without limitation, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10. Discontinuties can also be produced from a protozoal or fungal source.

The invention also provides a method of treating cancer in a patient, comprising introducing a therapeutically effective amount of the compounds of formula (I).

The present invention provides a method of treating disorders caused by, associated or accompanied by disorders of cell proliferation and/or angiogenesis, comprising introducing a therapeutically effective amount of the compounds of formula (I).

The disorder is a proliferative disorder or selected from the group consisting of cancer, inflammatory/immune disorders, fibrocycstic diseases (e.g., liver fibrosis), diabetes, autoimmune diseases, chronic and acute neurodegenerative diseases, Huntington's disease and infectious diseases, but not limited to the above.

Compounds disclosed in the description, is used for the treatment or prevention of cancer. Cancer can switch the th solid tumor or hematologic malignancy status.

The present invention provides a method of treatment of a disorder, disease or condition that can be treated by inhibition of HDAC enzymes, including the introduction of a therapeutically effective amount of the compounds of formula (I).

The invention provides a method of treating cancer in a patient, comprising introducing a therapeutically effective amount of the compounds of formula (I). Cancer can be a malignant hematological status, and this form of hematological malignant condition selected from the group consisting of b-cell lymphoma, T-cell lymphoma and leukemia. In the case of solid tumors tumor selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, cancer of the head, neck cancer, cancer of the nose, stomach cancer, rectal cancer, pancreatic cancer and brain cancer.

The term "therapeutically effective amount" or "effective amount" means a quantity sufficient for the beneficial actions or achieve the desired result. An effective amount can be entered for one or more injections. An effective amount is usually sufficient to facilitate, improve, stabilize, reversing, slowing or delaying the progression of the disease condition.

In another aspect, the compound can be introduced combined Ter the Pia and the combination of compounds of formula (I) with one or more separate agents, not limited to such targets as HDAC, methyltransferase DNA kinase heat shock proteins (e.g., HSP90) and other metalloprotease matrix.

"Combination therapy" includes the introduction of the considered compounds in combination with other biologically active ingredients (such as, but without limitation, various antineoplastics agents) and non-drug therapies (such as, but without limitation, surgery or radiation therapy). Compounds disclosed in the description, can be used in combination with other pharmaceutically active compounds, preferably from the reinforcing effect of the compounds of the invention. Connections can be introduced simultaneously or sequentially with treatment with other medicines.

In another aspect of the considered compounds can be combined with antineoplastics agents (e.g. small molecules, monoclonal antibodies, antimuslim RNA and fusion proteins)that inhibit one or more biological targets. This combination may enhance therapeutic efficacy compared to the efficiency achieved only one of the agents, and may prevent or delay the emergence of resistant variants.

In another aspect of the considered compounds can be combined with antifungal agents (azole), which inhibit one or more biological targets. This combination may enhance therapeutic efficacy compared to the efficiency achieved only one of the agents, and may prevent or delay the emergence of resistant variants.

Compounds of the invention is administered in combination with chemotherapeutic agents. Chemotherapeutic agents comprise an extensive area of therapeutic treatment of cancer. These agents are administered at different stages of the disease with the aim of reducing tumors, destruction of the remaining cancer cells after surgery, induction of remission, maintenance of remission and/or attenuation of symptoms related to cancer or its treatment.

It is implied that the term "subject"used in the description, includes all mammals and, in particular, of the person needing treatment. therapeutically effective amount will vary depending on the subject and subjected to the treatment of painful conditions, mass and age of the subject, the severity of the disease condition, the particular selected compounds of formula (I), dosing regimen to be followed, schedule of administration, route of administration and the like, all of the above can easily be determined by the average expert in the field.

Representative compounds include:/p>

1. N-Cyclopropyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

2. N-Methyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

3. N,N-Dimethyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

4. 2-Phenyl-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

5. N-Cyclopropyl-2-(thiophene-2-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

6. N-Cyclopropyl-2-phenyl-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

7. N-Cyclopropyl-2-(4-triptoreline)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

8. N-Cyclopropyl-2-(pyridin-3-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

9. N-Cyclopropyl-2-(4-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

10. N-Cyclopropyl-2-(2-chlorophenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

11. N-Cyclopropyl-2-(2-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

12. N-Cyclopropyl-2-(3-chlorophenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

13. N-Cyclopropyl-2-[benzodioxol-5-yl]-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

14. N-Cyclopropyl-2-(4-were)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

15. N-Morpholino-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyl the but)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

16. N-Morpholino-2-(2-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

17. N-Morpholino-2-(3-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

18. N-Thiomorpholine-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

19. N-Cyclooctyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

20. N-Cyclopropyl-2-(3-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

21. N-Cyclopropyl-2-(3-forfinal)-3-(4-((lE)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

22. N-Isopropyl-2-(3-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

23. N-Isopropyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

24. N-Isopropyl-2-(3,4-differenl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

25. N-Cyclopropyl-2-(3-fluoro-4-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

26. N-Isopropyl-2-(3-fluoro-4-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

27. N-Cyclopropyl-2-(3,4-differenl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

28. 2-(4-Forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

29. 2-(4-Forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-phenylacetamide;

30. N-Pyrrolidino-2-(4-fluoro who enyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

31. N-Cyclopropyl-2-(4-Cyclopropylmethoxy)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

32. N-Cyclopropyl-2-(4-benzyloxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

33. N-Cyclopropyl-2-(4-cyclopentylacetyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

34. N-(4-Terbisil)-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

35. N-Cyclopropyl-2-(2,4-acid)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

36. N-Cyclopropyl-2-(3,4-acid)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

37. N-Cyclopropyl-2-(indol-3-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

38. N-Cyclopropyl-2-(thiophene-3-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

39. N-Cyclopropyl-3-(4-forfinal)-2-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

40. N-Cyclopropyl-3-(4-forfinal)-2-(3-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

41. N-Cyclopropyl-2-(3-cyclopropylmethoxy)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

42. 2-(3-Cyclopropylmethoxy)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-phenylacetamide;

43. N-Cyclopropyl-2-(3-cyclopentylacetyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

44. 2-(3-Cyclopentylacetyl)-3-(4-(1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-phenylacetamide;

45. N-Cyclopropyl-2-(biphenyl-4-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

46. 2-(4-Cyclopropylmethoxy)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-phenylacetamide;

47. N-Cyclopropyl-3-(3,4-acid)-2-(3-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

48. N-Cyclopropyl-3-(4-methoxyphenyl)-2-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

49. N-Cyclopropyl-3-(4-cyclopropylmethoxy)-2-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

50. N-Cyclopropyl-3-(4-cyclopentylacetyl)-2-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

51. N-Cyclopropyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)but-2-ename;

52. 2-[4-(Dimethylamino)phenyl]-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-cyclopropylamine;

53. N-Cyclopropyl-3-(4-forfinal)-2-(4-(3-(hydroxyamino)-3-oxopropyl)phenyl)acrylamide;

54. N-Cyclopropyl-2-(4-forfinal)-3-(3-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;

55. 3-(4-((1E)-3-(Cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)phenyl)-N-hydroxyacetamido;

56. 3-(4-((1E)-3-(Cyclopropylamino)-2-phenylprop-1-EN-1-yl)phenyl)-N-hydroxyacetamido;

57. 3-(4-((1E)-2-(3-Cyclopentylacetyl)-3-(cyclopropylamino)prop-1-EN-1-yl)phenyl)-N-hydroxyacetamido;

58. 3-(4-((1E)-2-(3-Chlorophenyl)-3-(cyclopropylamino)prop-1-EN-1-yl)phenyl)-N-hydroxyaryl the MFA;

59. N-Cyclopropyl-3-(4-(3-(2-aminophenylamino)-3-oxoprop-1-EN-1-ylphenyl)-2-(4-forfinal)acrylamide;

60. 3-(4-((1E)-3-(2-Aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(4-forfinal)-N,N-dimethylacrylamide;

61. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(4-(trifluoromethyl)phenyl)acrylamide;

62. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(pyridin-3-yl)acrylamide;

63. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(2-chlorophenyl)acrylamide;

64. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-[benzodioxol-5-yl]acrylamide;

65. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(2-forfinal)acrylamide;

66. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(3-chlorophenyl)acrylamide;

67. (E)-N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(4-were)acrylamide;

68. N-Morpholino-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(4-forfinal)acrylamide;

69. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(3-methoxyphenyl)acrylamide;

70. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-phenylacrylate;

71. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(thiophene-2-yl)acrylamide;

72. N-Morpholino-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl-2-(2-forfinal)acrylamide;

73. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(3,4-differenl)acrylamide;

74. N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(3,4-acid)acrylamide;

75. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

76. 6-((1E)-3-(4-(3-(N,N-Dimethylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

77. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(2-chlorophenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

78. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

79. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-[benzodioxol-5-yl]-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

80. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-chlorophenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

81. 6-((1E)-3-(4-(3-Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

82. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-enyl)phenyl)acrylamide)-N-hydroxyhexanoic;

83. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(thiophene-2-yl)-3-oxoprop-1-enyl)phenyl)acrylamide)-N-hydroxyhexanoic;

84. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

85. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-methoxyphenyl)-3-about soprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

86. 6-((1E)-3-(4-(3-Morpholino)-2-(4-forfinal)-3-oxoprop-1-enyl)phenyl)acrylamide)-N-hydroxyhexanoic;

87. 6-((1E)-3-(4-(3-(Morpholino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

88. 6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-fluoro-4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxyhexanoic;

89. 4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

90. 4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(2-chlorophenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

91. 4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-chlorophenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

92. 4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

93. 4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

94. 4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(thiophene-2-yl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

95. 4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

96. 4-(((lE)-3-(4-(3-(Morpholino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

97. 4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-methoxyphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

98. 4-(((1E)-3-(4-((Morpholino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;

99. 4-(3-(Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;

100. 4-(3-(Cyclopropylamino)-2-(4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;

101. 4-(3-(Cyclopropylamino)-2-(3-methoxyphenyl)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;

102. 4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;

103. 4-(3-(Cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;

104. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)benzamide;

105. (E)-N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

106. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-triptoreline)-3-oxoprop-1-EN-1-yl)benzamide;

107. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)benzamide;

108. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3-methoxyphenyl)-3-oxoprop-1-EN-1-yl)benzamide;

109. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

110. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

111. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(1,3-benzodioxol-5-yl)-3-oxoprop-1-EN-1-yl)benzamide;

112. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-chlorophenyl)-3-oxoprop-1-EN-1-yl)benzamide;

113. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(thiophene-2-yl)-3-oxoprop-1-EN-1-yl)benzamide;

114. N-(2-AMINOPHENYL)-4-(3-(cyclopropyl the Mino)-2-(3-chlorophenyl)-3-oxoprop-1-EN-1-yl)benzamide;

115. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3,4-differenl)-3-oxoprop-1-EN-1-yl)benzamide;

116. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)benzamide;

117. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-chloro-4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

118. N-(2-AMINOPHENYL)-4-(3-(phenylamino)-2-(3,4-acid)-3-oxoprop-1-EN-1-yl)benzamide;

119. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3,4-acid)-3-oxoprop-1-EN-1-yl)benzamide;

120. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2,4-acid)-3-oxoprop-1-EN-1-yl)benzamide;

121. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-naphthyl)-3-oxoprop-1-EN-1-yl)benzamide;

122. N-(2-AMINOPHENYL)-4-(3-phenylamino-2-(2,4-acid)-3-oxoprop-1-EN-1-yl)benzamide;

123. N-(2-Amino-4-forfinal)-4-(2-(4-forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;

124. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-3-oxo-2-(1H-indol-3-yl)prop-1-EN-1-yl)benzamide;

125. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-3-oxo-2-biphenyl-4-yl-prop-1-EN-1-yl)benzamide;

126. 4-(2-(4-Forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)-N-(2-hydroxyphenyl)benzamide;

127. N-(2-AMINOPHENYL)-4-[3-(cyclopropylamino)-3-oxo-2-pyridin-3-yl-prop-1-EN-1-yl]benzamide;

128. N-(2-AMINOPHENYL)-4-(2-(4-hydroxyphenyl)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;

129. N-(2-AMINOPHENYL)-4-(2-(2,6-differenl)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)Ben is amide;

130. N-(2-AMINOPHENYL)-4-(2-(2,5-differenl)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;

131. N-(2-AMINOPHENYL)-4-(2-(4-forfinal)-3-(isopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;

132. N-(2-N-(4-Aminobiphenyl-3-yl)-4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)benzamide;

133. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-were)-3-oxoprop-1-EN-1-yl)benzamide;

134. N-(2-AMINOPHENYL)-4-(3-(methylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

135. (Z)-N-(2-AMINOPHENYL)-4-(2-(4-forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;

136. N-(2-AMINOPHENYL)-4-[2-(4-forfinal)-3-morpholine-4-yl-3-oxoprop-1-EN-1-yl]benzamide;

137. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

138. N-(2-AMINOPHENYL)-3-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

139. N-(2-AMINOPHENYL)-4-(3-(phenylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

140. 4-[3-Amino-2-(4-forfinal)-3-oxoprop-1-EN-1-yl]-N-(2-AMINOPHENYL)benzamide;

141. N-(2-AMINOPHENYL)-4-(2-(4-cyclopentylacetyl)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;

142. N-(2-AMINOPHENYL)-4-(2-(4-cyclopropylmethoxy)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;

143. N-(2-AMINOPHENYL)-4-(3-(benzylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;

144. N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)benzamide;

145. 4-(3-(Cyclopropylamino)-2-(4-ftoh the Nile)-3-oxoprop-1-EN-1-yl)-N-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)benzyl)benzamide;

146. 4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)-N-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)benzyl)benzamide;

147. 4-(3-(Cyclopropylamino)-2-[benzodioxol-5-yl]-3-oxoprop-1-EN-1-yl)-N-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)benzyl)benzamide;

148. 4-(3-(Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

149. 4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

150. 4-(3-(Cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

151. 4-(3-(Cyclopropylamino)-2-(2-chlorophenyl)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

152. 4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

153. 4-(3-(Cyclopropylamino)-2-(3-chlorophenyl)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

154. 4-(3-(Cyclopropylamino)-2-(4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

155. 4-(3-(Cyclopropylamino)-2-(2-chloro-4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

156. 4-(3-(Cyclopropylamino)-2-(3-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

157. 4-(3-(Cyclopropylamino)-2-[benzodioxol-5-yl]-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

158. 4-(3-(Cyclopropylamino)-2-(4-triptoreline)-3-oxop the p-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

159. 4-(3-(Cyclopropylamino)-2-(3,4-differenl)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;

160. 4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide;

161. 4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)-N-(6-hydroxyamino)-6-oxohexyl)benzamide;

162. 4-(3-(Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide;

163. 4-(3-(Cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide;

164. 4-(3-(Cyclopropylamino)-2-(3-forfinal)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide;

165. N-(4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)-N-hydroxyacetanilide and

166. N-(2-AMINOPHENYL)-4-((4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzamide.

Also, a method for producing compounds of formula (I), in which all groups defined previously, is shown in the following scheme 1.

This method of obtaining compounds of formula (I)in which R2=COOH, involves the following stages:

A) Condensation of compounds of formula 1a with the compound of the formula 1b in acetic anhydride in the presence of organic base to obtain the compounds of formula 1c, in which R3=H or unsubstituted alkyl, R, R1X, Y, m, n, o, and p are defined previously;

p> B) 1) the Reaction of compounds of formula 1c with an agent activating the acid, such as hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt) and the like, and amine other5R6obtaining the compounds of formula 2a in which R, R1X, Y, m, n, o, and p are defined previously.

2) the Reaction of compounds of formula 1c with a suitable agent, activating carboxylic acid, and a base with a receiving anhydridein situthat is, the restoration of suitable regenerating agent, gives compound of formula 2b, in which R, R1, R3X, Y, m, n, o, and p are defined previously.

3) Oxidation 2b suitable oxidizing agent, giving the corresponding aldehyde, which, on reduction aminating HNR5R6gives the compound of formula 2c, in which R, R1X, Y, m, n, o, and p are defined previously.

C) Hydrolysis of compounds of formula 2a or 2b or 2c base with obtaining the appropriate acid. The combination of the acid with an activating agent, such as EDCI, HOBt, and the like, in the presence of an appropriate amine R4NH2obtaining compounds of General formula (I), or the reaction of compounds of formula 2a or 2b or 2c with R4NH2in the presence of a base to obtain the compounds of General formula (I)in which R, R1, R2, R3, R4, R5, R6X, Y , n, o, and p are defined previously.

The description also suggests a method for obtaining compounds of formula (I) from compounds of formula (II), in which, when one of R2or R3is hydrogen or unsubstituted alkyl, the other is not hydrogen or unsubstituted alkyl, R4, R3, R2, R1, R, X, Y, m, n, o, and p are defined previously.

The same method is followed in the synthesis of compounds of formula (I)in which R2=H or unsubstituted alkyl, and R3=COOH, accordingly choosing acids and carbonyl compounds used in the stages A-C of the above synthesis scheme.

All of the above alternative reactions can be conducted at temperatures from 0°C to room temperature and duration of reaction may vary from 2 to 24 hours.

Received pharmaceutically acceptable salts of compounds of formula (I). Additive salts of the acids obtained by treatment with acids such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluensulfonate acid, methanesulfonate acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, be solarhoowa acid, tartaric acid and the like, in solvents such as ethyl acetate, ether, alcohols, acetone, tetrahydrofuran (THF), dioxane, etc. you can Also apply a mixture of solvents.

The following examples are presented for illustrative purposes only, and therefore they should not be construed as limiting the scope of invention.

Example 1:

Synthesis of N-cyclopropyl-2-(4-forfinal)-3-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide.

Stage-I

Obtain methyl(E)-3-(4-formylphenyl)acrylate

A suspension of (E)-3-(4-formylphenyl)acrylic acid (2 g, 10.5 mmol) in methanol (30 ml) is cooled to 5°C, and then added with stirring a concentrated H2SO4(3 ml) and heated at 60°C for 2 hours. The solvent is removed by evaporation, and the compound obtained 15 minutes, stirred with water (100 ml). Precipitated solid white color is filtered off, washed with water (300 ml) and dried to obtain the pure product (1.9 g, yield 86%).

Stage-II

Obtaining 2-(4-forfinal)-3-(4-((E)-3-methoxy-3-oxoprop-1-EN-1-yl)phenyl)acrylic acid

A mixture of 4-florfenicol acid (2.5 g, 13,2 mmol) and methyl(E)-3-(4-formylphenyl)acrylate (2,03 g, 13,2 mmol) under stirring dissolved in acetic ang is drida (8 ml). To this mixture add diisopropylethylamine (DIPEA) (3.4 ml, of 19.7 mmol) and stirred for 2 hours at 30°C. after completion of the reaction (see on TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and set the pH is equal to 1, using diluted HCl (1:1). The aqueous layer was extracted with ethyl acetate (2×150 ml). The combined ethyl acetate layer was washed with water until neutral wash water and dried over anhydrous Na2SO4. The ethyl acetate layer is evaporated to dryness with getting sticky connections and then triturated with cold dichloromethane (DCM) to obtain the solid white color. The obtained solid is filtered off and dried in vacuum, obtaining mentioned in the title compound (2 g, yield 47%).

Stage-III

Obtaining methyl-3-(E)(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylate

A mixture of 2-(4-forfinal)-3-(4-((E)-3-methoxy-3-oxoprop-1-EN-1-yl)phenyl)acrylic acid (to 0.23 g, 0.71 mmol) and cyclopropylamine (0.03 g, of 0.60 mmol), EDCl (0.27 g, 1.4 mmol), HOBt (0.10 g, 0.71 mmol) with stirring dissolved in N,N-dimethylformamide (DMF) (6 ml). With constant stirring, the reaction mixture was dropwise added triethylamine (TEA) (0.75 ml, 36 mmol) and stirred her at 30°C for 2 hours. Then the reaction mixture was diluted with ethyl acetate and posledovatel is but washed with water (3×50 ml) and saturated salt solution (3×50 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving a pure compound (0.25 g, yield 96%).

Stage-IV

Obtaining N-cyclopropyl-2-(4-forfinal)-3-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide

Hydroxylamine hydrochloride (0,86 g, 12.3 mmol) in methanol (3 ml) is mixed with KOH (0,69 g, 12.3 mmol) in methanol (3 ml) at 0°C and treated with ultrasound for 2 minutes, the obtained white precipitate is filtered off. The filtrate is added to methyl-3-(E)(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylate (0.25 g, of 0.68 mmol) in DCM (1.5 ml) and the mixture stirred for 30 minutes at room temperature. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (2×150 ml). The ethyl acetate layer dried over anhydrous Na2SO4and concentrate, getting sticky compound which is triturated with DCM (15 ml). The obtained solid pale brown color is filtered off and washed with DCM (3×5 ml), getting mentioned in the title compound (0.07 g, yield 28%).1H NMR (DMSO-d6) δ (ppm): 0,49-of 0.53 (2H, DD, -CH2), and 0.61-0,66 (2H, m, -CH2), 2,72-2,77 (1H, m, -CH), 6,38-6.42 per (1H, d, =CH), 7,00-7,02 (2H, d, Ar-H), 7,16-7,27 (5H, m, Ar-H and =CH), 7,33-the 7.43 (3H, m, Ar-H and =CH), 7,81-of 7.82 (1H, d, -NH), 9,04 (1H, s, -OH), of 10.73 (1H, s, -NH). MC m/z: 367,1 (M++1).

The following compounds were obtained in accordance with the methodology, preveden the th in Example 1.

Example No.StructureAnalytical data
21H NMR (DMSO-d6) δ (ppm): to 2.66 (3H, s, -CH3), 6,38-6.42 per (1H, d, =CH), 6,99-7,01 (2H, d, Ar-H), 7,21-7,27 (4H, m, Ar-H), 7,33-7,37 (1H, d, =CH), 7,34-the 7.43 (4H, m, Ar-H, =CH-NH), 9,03 (1H, s, -OH), of 10.73 (1H, s, -NH). MS m/z: 339,1 (M++1).
31H NMR (DMSO-d6) δ (ppm): 2,9 (3H, s, -CH3), totaling 3.04 (3H, s, -CH3), 6,39-to 6.43 (1H, d, =CH), 6,69 (1H, s, =CH), 7,10 for 7.12 (2H, d, Ar-H), 7,20-7,22 (2H, d, Ar-H), 7,29-7,33 (1H, d, =CH), 7,29-the 7.43 (4H, m, Ar-H), 9,03 (1H, s, -OH), of 10.73 (1H, s, -NH). MS m/z: 353,1 (M++1).

41H NMR (DMSO-d6) δ (ppm): 6,37-6,41 (1H, d, =CH), 6,94-to 7.00 (3H, m, Ar-H), 7,17-7,19 (2H, d, Ar-H), 7,33-7,42 (8H, m, Ar-H, =CH, -NH2), 9,04 (1H, s, -OH), of 10.73 (1H, s, -NH). MS m/z: 309,1 (M++1).
51H NMR (DMSO-d6) δ (ppm): 0,52-of 0.53 (2H, t, -CH2), 0,63-0,66 (2H, m, -CH2 ), 2,74 was 2.76 (1H, m, -CH), 6,41-of 6.45 (1H, d, -CH), 6,94-to 6.95 (1H, d, Ar-H),? 7.04 baby mortality-7,06 (1H, t, Ar-H), 7,14-to 7.15 (2H, d, Ar-H), 7,24 (1H, s, =CH), 7,37-7,41 (1H, d, =CH), 7,43 was 7.45 (2H, d, Ar-H, to 7.59-to 7.61 (1H, d, Ar-H), 7,98-to 7.99 (1H, d, -NH), and 9.1 (1H, s, -OH), and 10.8 (1H, s, -NH). MS m/z: 355,1 (M++1).
61H NMR (DMSO-d6) δ (ppm): 0,51-of 0.53 (2H, t, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,74 was 2.76 (1H, m, -CH), 6,37-6,41 (1H, d, =CH), 6,99-7,01 (2H, d, Ar-H), 7,16-of 7.23 (3H, m, Ar-H and

=CH), 7,35-7,37 (6H, m, =CH and Ar-H), 7,79 (1H, s, -NH), 9,05 (1H, s, -OH), a 10.74 (1H, s, -NH). MS m/z: 349,1 (M++1).
71H NMR (DMSO-d6) δ (ppm): 0,52-of 0.53 (2H, t, -CH2), 0,63-0,66 (2H, t, -CH2), 2,74 was 2.76 (1H, m, -CH), 6,39-to 6.43 (1H, d, =CH), 6,99-7,01 (2H, d, Ar-H), 7,33-7,40 (6H, m, Ar-H and =CH), 7,72-7,74 (2H, d, Ar-H), 8,03-of 8.04 (1H, d, -NH), and 9.1 (1H, s, -OH), of 10.73 (1H, s, -NH). MS m/z: 417,1 (M++1).
81H NMR (DMSO-d6) δ (ppm): 0,52-of 0.53 (2H, t, -CH2), of 0.64 to 0.65 (2H, t, -CH2), 2,75 was 2.76 (1H, m, -CH), 6,39-to 6.43 (1H, d, =CH), 6,99-7,01 (2H, d, Ar-H), 7,34-the 7.43 (5H, m, Ar-H and =CH), to 7.59-to 7.61 (1H, d, Ar-H), 8,05-of 8.06 (1H, t, NH), compared to 8.26-of 8.27 (1H, d, Ar-H), 8,53-8,55 (1H, m,, Ar-H), and 9.1 (1H, s, -OH), of 10.76 (1H, is, -NH). MS m/z: 350,1 (M++1).

91H NMR (DMSO-d6) δ (ppm): 0,49-0,50 (2H, d, -CH2), and 0.62 to 0.63 (2H, m, -CH2), 2,72-to 2.74 (1H, m, -CH), of 3.78 (3H, s, -CH3), 6,37-6,41 (1H, d, =CH), 6,93-to 6.95 (2H, d, Ar-H), 7.03 is-was 7.08 (4H, m, Ar-H), 7,19 (1H, s, =CH), 7,34-7,39 (3H, m, =CH and Ar-H), 7,66-to 7.67 (1H, d, -NH), and 9.1 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 379,1 (M++1).
101H NMR (DMSO-d6) δ (ppm): 0,51 (2H, m, -CH2), and 0.62-of 0.64 (2H, m, -CH2), 2,71 was 2.76 (1H, m, -CH), 6,38-6.42 per (1H, d, =CH), 6,94-of 6.96 (2H, d, Ar-H), 7,12-7,14 (1H, d, Ar-H), 7,31-of 7.55 (7H, m, Ar-H and =CH), 7,82-7,83 (1H, d, -NH) to 9.32 (1H, s, -OH), of 10.76 (1H, s, -NH). MS m/z: 383,1 (M++1).
111H NMR (DMSO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), 0,63-0,66 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), 6,38-6.42 per (1H,

d, =CH), 7,01-7,03 (2H, d, Ar-H), 7,12-7,44 (8H, m, Ar-H and =CH), 7,97-7,98 (1H, d, -NH), 9,05 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 367,1 (M++1).
12/td> 1H NMR (DMSO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), 0,63-0,66 (2H, m, -CH2), 2,74 was 2.76 (1H, m, -CH), 6,38-6.42 per (1H, d, =CH), 7,00-7,02 (2H, d, Ar-H), 7,09-7,10 (1H, d, Ar-H), 7,19 (1H, s, =CH), 7,28 (1H, s, Ar-H), 7,34 (1H, s, Ar-H), 7,38-7,44 (4H, m, Ar-H and =CH), 7,94 (1H, d, -NH) 9,05 (1H, s, -OH), a 10.74 (1H, s, -NH). MS m/z: 383,1 (M++1).
131H NMR (DMSO-d6) δ (ppm): 0,50 (2H, m, -CH2), and 0.61 to 0.63 (2H, m, -CH2), 2,73-to 2.74 (1H, m, -CH), equal to 6.05 (2H, with,-CH2), 6,38-6.42 per (1H, d, =CH), 6,58-6,60 (1H, d, Ar-H), of 6.68 (1H, s, Ar-H), 6.90 to-6,92 (1H, d, Ar-H), 7,05-7,07 (2H, d, Ar-H), 7.23 percent (1H,

s, =CH), 7,34-7,41 (3H, d, Ar-H and =CH), to 7.61(1 H, d, NH), 9,05 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 393,1 (M++1).
141H NMR (DMSO-d6) δ (ppm): 0,49 (2H, m, -CH2), and 0.61 to 0.63 (2H, m, -CH2), of 2.33 (3H, s, -CH3), by 2.73 (1H, m, -CH), 6,37-6,41 (1H, d, =CH), 7,02-7,03 (4H, m, Ar-H), 7,17-7,19 (3H, m, Ar-H and =CH), 7,33-7,37 (3H, m, Ar-H and =CH), 7,69 (1H, d, -NH), 9,05 (1H, s, -OH), of 10.73 (1H, s, -NH). MS m/z: 363,1 (M++1).
151H NMR (DMSO-d6) δ (ppm): of 3.56 (8H, Morpholine-H), 6,39 is 6.4 (1H, d, =CH), was 6.73 (1H, s, =CH), 7,10 for 7.12 (2H, d, Ar-H), 7,19-of 7.23 (2H, t, =CH and Ar-H), 7,29-to 7.32 (3H, t, Ar-H), 7,39-7,41 (2H, d, Ar-H). MS m/z: 397,2 (M++1).
161H NMR (DMSO-d6) δ (ppm): to 3.58 (8H, Morpholine-H), 6,39-to 6.43 (1H, d, =CH), 6,93 (1H, s, =CH), 7,10 for 7.12 (2H, d, Ar-H)

7,21-7,26 (2H, q, Ar-H), 7,30-to 7.35 (2H, q, Ar-H), 7,40-7,46 (3H, d, =CH and Ar-H). MS m/z: 397,2 (M++1).
171H NMR (DMSO-d6) δ (ppm): 3,55 (8H, Morpholine-H), 3,68 (3H, s, -CH3), 6,39-to 6.43 (1H, d, =CH), of 6.71 (1H, s, =CH), 6,80-6,83 (2H, t, Ar-H), 6,91-6,94 (1H, q, Ar-H), 7,14-7,16 (2H, d, Ar-H), 7,27-7,31 (1H, t, Ar-H), 7,35-7,42 (3H, t, =CH and Ar-H), 9,06 (1H, s, -OH), a 10.74 (1H, s, -NH). MS m/z: 409,4 (M++1).
181H NMR (DMSO-d6) δ (ppm): 2,58 (4H, m, -CH2), with 3.79 (4H, m, -CH2), 6,39-to 6.43 (1H, d, =CH), to 6.75 (1H, s, =CH), 7,10 for 7.12 (2H, d, Ar-H), 7,19-of 7.23 (2H, m, Ar-H), 7,29-to 7.32 (3H, m, Ar-H and =CH), 7,39-7,41 (2H, d, Ar-H). MS m/z: 413,1 (M++1).

1H NMR (DMSO-d6) δ (ppm): 1,45-1,68 (14H, m, -CH2), 3,88-to 3.89 (1H, m, -CH), 6,38-6.42 per (1H, d, =CH), 7,01-7,03 (2H, d, Ar-H), 7,19-of 7.24 (5H, m, Ar-H and =CH), 7,33 (1H, s, =CH), 7,38-7,40 (2H, d, Ar-H), 7,55-EUR 7.57 (1H, d, NH), 9,05 (1H, s, -OH), of 10.73 (1H, s, -NH). MS m/z: 437,1 (M++1).
19
201H NMR (DMSO-d6) δ (ppm): 0.50 to 0,57 (2H, m, -CH2), and 0.62-of 0.64 (2H, m, -CH2), 2,73-to 2.74 (1H, m, -CH), 3,70 (3H, s, -OCH3), 6,38-6.42 per (1H, d, =CH), 6,70 (2H, m, Ar-H), 6,93-to 6.95 (1H, d, Ar-H), 7,02? 7.04 baby mortality (2H, d, Ar-H), 7,24 (1H, s, =CH), 7,28-7,38 (4H, m, Ar-H and =CH), of 7.70 (1H, d, -NH) 9,06 (1H, s, -OH), a 10.74 (1H, s, -NH). MS m/z: 379,4 (M++1).
211H NMR (DMSO-d6) δ (ppm): 0,51-of 0.53 (2H, m, -CH2), 0,62 is 0.65 (2H, m, -CH2), 2,73 was 2.76 (1H, m, -CH), 6,38-6.42 per (1H,

d, =CH), of 6.96-7,02 (4H, m, Ar-H), 7,20-of 7.23 (1H, t, Ar-H), 7,29 (1H, s, =CH), 7,34-7,38 (1H, d, =CH), 7,39 was 7.45 (3H, m, Ar-H), 7,88-7,89 (1H, d, -NH), 9,06 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 367,0 (M++1).
221H NMR (DMSO-d6) δ (ppm): 1,10-of 1.11 (6H, d, -CH3), 3,94-4,01 (1H, m, -CH), 6,39-to 6.43 (1H, d, =CH), 6,98? 7.04 baby mortality (4H, m, Ar-H), 7,19-of 7.23 (1H, t, Ar-H), 7,30 (1H, s, =CH), 7,34-7,46 (4H, m,=CH and Ar-H), to 7.59-to 7.61 (1H, d, -NH), 9,06 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 369,0 (M++1).
231H NMR (DMSO-d6) δ (ppm): 1,09-of 1.11 (6H, d, -CH3), 3,94-Android 4.04 (1H, m, -CH), 6,38-6.42 per (1H, d, =CH), 7,01-7,03 (2H, d, Ar-H), 7,20-7,28 (5H, m, Ar-H and =CH), 7,34-7,40 (3H, m, =CH and Ar-H), 7,52-rate of 7.54 (1H, d, -NH), 9,29 (1H, s, -OH), 10,75

(1H, s, -NH). MS m/z: 369,2 (M++1).
241H NMR (DMSO-d6) δ (ppm): 1,09-of 1.11 (6H, d, -CH3), 3.95 to as 4.02 (1H, m, -CH), 6,39-to 6.43 (1H, d, =CH), 6,98-7,05 (3H, m, Ar-H), 7,22-7,27 (1H, t, Ar-H), 7,35-of 7.48 (5H, m, =CH and Ar-H), EUR 7.57-to 7.59 (1H, d, -NH), 9,06 (1H, s, -OH), of 10.76 (1H, s, -NH). MS m/z: 387,0 (M++1).
251H NMR (DMSO-d6) δ (ppm): from 0.50 to 0.56 (2H, m, -CH2), and 0.62 to 0.63 (2H, m, -CH2), 2,73-to 2.74 (1H, m, -CH), 3,86 (3H, s, -OCH3), 6,38-6.42 per (1H, d, =CH), 6,88-6,92 (1H, d, Ar-H), of 6.96-7,06 (4H, m, Ar-H and =CH), 7,14-to 7.18 (1H, m, Ar-H), 7,26 (1H, s, =CH), 7,34-7,41 (2H, m, Ar-H), 7,73-7,74(1H, d, -NH), 9,06 (1H, s, OH), of 10.76 (1H, s, -NH). MS m/z: 397,0 (M++1).

26 1H NMR (DMSO-d6) δ (ppm): 1,08-1,09 (6N, d, -CH3), 3,86 (3H, s, -OCH3), 3,97-a 4.03 (1H, m, -CH), 6,38-6.42 per (1H, d, =CH), 6,91-7,06 (4H, m, Ar-H and =CH), 7,15-7,20 (1H, m, Ar-H), 7,27 (1H, s, =CH), 7,34-7,39 (1H, m, Ar-H), 7,41 was 7.45 (2H, m, Ar-H), 7,53-of 7.55 (1H, d, -NH), 9,05 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 399,1 (M++1).
271H NMR (DMSO-d6) δ (ppm): 0,49-0,52 (2H, m, -CH2), and 0.61-of 0.64 (2H, m, -CH2), 2,72 was 2.76 (1H, m, -CH), 6,38-6.42 per (1H, d, =CH), of 6.96 (1H, d, Ar-H), 7,01-7,03 (2H, d, Ar-H), 7,22-7,27 (1H, m, Ar-H), 7,34-to 7.35 (2H, d, Ar-H and =CH), 7,38-7,47 (3H, m, Ar-H and-CH), 7,80-7,81 (1H, d, -NH), 9,06 (1H, s, -OH), of 10.76 (1H, s, -NH). MS m/z: 385,1 (M++1).

281H NMR (DMSO-d6) δ (ppm): 6,39-to 6.43(1H, d, =CH), 7,00-7,06 (3H, m, Ar-H and-NH), 7.18 in-7,26 (5H, m, Ar-H and-NH), 7,31-to 7.35 (1H, d, =CH), 7,39-the 7.43 (2H, t, Ar-H), 7,47 (1H, s, =CH), 9,06 (1H, s, -OH), of 10.76 (1H, , -NH). MS m/z: 327,0 (M++1).
291H NMR (DMSO-d6) δ (ppm): 6,40-6,44 (1H, d, =CH), 7,06-7,22 (3H, m, Ar-H), 7,24 was 7.45 (10H, m, Ar-H and =CH), to 7.67-of 7.69 (2H, m, Ar-H), the remaining 9.08 (1H, d, -NH), of 10.01 (1H, s, OH), 10,78 (1H, s, -NH). MS m/z: 403,1 (M++1).
30 1H NMR (DMSO-d6) δ (ppm): is 1.81 (4H, m, -CH2), 3,38 is 3.40 (4H, m, -CH2), 6,38-6.42 per (1H, d, =CH), PC 6.82 (1H, s, =CH), 7,09-7,11 (2H, d, Ar-H), 7,17-7,22 (2H, d, Ar-H), 7,27-7,31 (2H, m, Ar-H), 7,35-7,42 (3H, m, Ar-H, =CH), 9,05 (1H, s, -OH), of 10.76 (1H, s, -NH). MS m/z: 381,1 (M++1).

311H NMR (DMSO-d6) δ (ppm): 0,49-of 0.51 (2H, m, -CH2), or 0.57 to 0.63 (6H, m, -CH2), 1,22 of 1.28 (1H, m, -CH), 2,73-to 2.74 (1H, m, -CH), 3,81-a 3.83 (2H, d, -CH2), 6,37-6,41 (1H, d, =CH), 6.90 to-6,92 (2H, d, Ar-H), 7.03 is-7,05 (4H, d, Ar-H), 7,18 (1H, s, =CH), 7,33-7,38 (3H, m, Ar-H and =CH), 7,65-7,66 (1H, d, -NH), 9,05 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 418,9 (M++1).
321H NMR (DMSO-d6) δ (ppm): 0,50 (2H, m, -CH2), and 0.62 to 0.63 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), 5,12 (2H, s, -CH2), 6,37-6,41 (1H, d, =CH), 7,00-was 7.08 (6H, m, Ar-H), 7,18 (1H, s, =CH), 7,34 and 7.36 (4H, m, Ar-H), 7,38-the 7.43 (2H, m, Ar-H and =CH), 7,46-of 7.48 (2H, m, Ar-H), 7,70-7,71 (1H, d, -NH) 9,06 (1H, s, -OH), 10,77 (1H, s, -NH). MS m/z: 454,9 (M++1).

331H NMR (DMSO-d6) δ (ppm): 0,50 (2H, m, -CH2), and 0.62 to 0.63 (2H, m, -CH2), to 1.59 (2H, t, -CH2), 1,71 (4H, m, -CH2) 1,92-of 1.93 (2H, t, -CH2), 2,73-to 2.74 (1H, m, -CH), 4,82 (1H, m, -CH), 6,37-6,41 (1H, d, =CH), 6.87 in-6,89 (2H, d, Ar-H), 7,02? 7.04 baby mortality (4H, d, Ar-H), 7,16 (1H, s, =CH), 7,33-7,38 (3H, m, Ar-H and =CH), 7,70-7,71 (1H, d, -NH), 9,05 (1H, s, -OH), a 10.74 (1H, s, -NH). MS m/z: 432,9 (M++1).
341H NMR (DMSO-d6) δ (ppm): or 4.31-to 4.33 (2H, d, -CH2), 6,39-to 6.43 (1H, d, =CH), 7,01-7,03 (2H, d, Ar-H), 7,12-7,16 (2H, t, Ar-H), 7,22-7,27 (4H, m, Ar-H), 7,29-7,34 (3H, m, Ar-H and =CH), 7,38-7,40 (2H, d, Ar-H), of 7.48 (1H, s, =CH), 8,08-8,11 (1H, t, -NH), 9,05 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 434,8 (M++1).

351H NMR (DMSO-d6) δ (ppm): 0,47-of 0.48 (2H, m, -CH2), 0,60-0,61 (2H, m, -CH2), 2,67-a 2.71 (1H, m, -CH), 3,66 (3H, s, -OCH3), with 3.79 (3H, s, -OCH3), 6,37-6,41 (1H, d, =CH), 6.48 in-6,51 (2H, DD, Ar-H), 6,63-only 6.64 (1H, d, Ar-H), for 6.81-6,83 (1H, d, Ar-H), 7,02? 7.04 baby mortality (2H, d, Ar-H), 7,27 (1H, s, =CH), 7,33-7,38 (3H, m, Ar-H and-NH), 9,04 (1H, s, -OH), 10,79 (1H, s, -NH). MS m/z: 408,9 (M++1).
361H NMR (DMSO-d6) δ (ppm): 0,50-of 0.51 (2H, m, -CH2), 0,55-of 0.56 (2H, m, -CH2), 2,71 was 2.76 (1H, m, -CH), 3,62 (3H, s, -OCH3), of 3.78 (3H, s, -OCH3), 6,38-6.42 per (1H, d, =CH), 6,66-6,70 (2H, m, Ar-H), 6,95-6,97 (1H, d, Ar-H),? 7.04 baby mortality-7,06 (2H, d, Ar-H), 7,24 (1H, s, =CH), 7,34-7,40 (3H, m, Ar-H), 7,52-7,53 (1H, d, -NH), 9,04 (1H, s, -OH), 10,75 (1H, s,-NH). MS m/z: 408,9 (M++1).

371H NMR (DMSO-d6) δ (ppm): 0,460-of 0.48 (2H, m, -CH2), 0,58-of 0.62 (2H, m, -CH2), 2,73 was 2.76 (1H, m, -CH), 6,32-6,36 (1H, d, =CH), 6,84-to 6.88 (1H, t, Ar-H), 6,95-6,97 (1H, d, Ar-H), 7,05 for 7.12 (3H, m, Ar-H), 7,28-7,33 (3H, m, Ar-H), 7,35 (1H, s, =CH), 7,40-7,42 (1H, d, Ar-H), 7,52-7,53 (1H, d, -NH), of 9.02 (1H, s, -OH), 10,70 (1H, s, -NH), 11,35 (1H, s, -NH). MS m/z: 387,9 (M++1).
381H NMR (DMSO-d6) δ (ppm): 0,51 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,73 is 2.75 (1H, m, -CH), 6,40-to 6.43 (1H, d, =CH), 6,84-6,85 (1H, d, Ar-H), 7,06-was 7.08 (2H, d, Ar-H), 7,22 (1H, s, =CH), 7,35-7,42 (4H, m, Ar-H), EUR 7.57-7,58 (1H, d, -NH), 7,72 (1H, s, Ar-H), 9,04 (1H, s, -OH), a 10.74 (1H, s, -NH). MS m/z: 354,9 (M++1).

391H NMR (DMSO-d6) δ (ppm): 0,50,-0,51 (2H, d, -CH2), and 0.61-0,66 (2H, q, -CH2), 2,73 was 2.76 (1H, q, CH), 6,46-of 6.50 (1H, d, =CH), 7,05-7,06 (4H, d, Ar-H), 7,16-to 7.18 (2H, d, Ar-H), 7,25 (1H, s, =CH), 7,45-7,49 (1H, d, =CH), 7,55-EUR 7.57 (2H, d, Ar-H), 7,81-of 7.82 (1H, d, -NH), 9,07 (1H, s, -OH), 10,78 (1H, s, -NH). MS m/z: 366,9 (M++1).
40 1H NMR (DMSO-d6) δ (ppm): 0,51-of 0.53 (2H, q, -CH2), 0,63-of 0.65 (2H, t, -CH2), 2,74 is 2.75 (1H, m, -CH), 6,40-6,44 (1H, d, =CH), 7.03 is-7,05 (4H, d, Ar-H), 7,11-7,13 (1H, d, Ar-H), 7,28 (1H, s, =CH), 7,34 (1H, s, Ar-H), 7,39 was 7.45 (2H, q, Ar-H and =CH), 7,54-7,56 (1H, d, Ar-H), 7,83-to 7.84 (1H, d, -NH), 9,07 (1H, s, -OH), of 10.73 (1H, s, -NH). MS m/z: 366,9 (M++1).

411H NMR (DMSO-d6) δ (ppm): of 0.26 to 0.28 (2H, m, -CH2), 0,49-0,51 (4H, m, -CH2), 0,63-0,66 (2H, t, -CH2), 1,11-of 1.13 (1H, m, -CH), 2,73 is 2.75 (1H, m, -CH), to 3.73 of 3.75 (2H, s, -CH2), 6,37-6,41 (1H, d, =CH), 6,67-6,70 (2H, d, Ar-H), 6,91-6,93 (1H, d, Ar-H), 7,02? 7.04 baby mortality (2H, d, Ar-H), 7.23 percent-7,29 (2H, m, =CH and Ar-H), 7,33-7,38 (3H, m, =CH and Ar-H), to 7.67-to 7.68 (1H, d, -NH), 9,04 (1H, s, -OH), of 10.73 (1H, s, -NH). MS m/z: 418,9 (M++1).
421H NMR (DMSO-d6) δ (ppm): of 0.26 to 0.28 (2H, m, -CH2), 0,49-of 0.51 (2H, m, -CH2), of 1.12 (1H, m, -CH), 3.75 to is 3.76 (2H, s, -CH2), 6,40-6,44 (1H, d, =CH), 6,78-PC 6.82 (2H, d, Ar-H), 6,93-to 6.95 (1H, d, Ar-H), 7,06-7,14 (3H, m, =CH and Ar-H), 7,30-to 7.35 (5H, m, =CH and Ar-H), 7,41-the 7.43 (2H, d, Ar-H), 7,66-to 7.68 (2H, d, Ar-H), 9,05

(1H, d, -NH), 9,88 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 454,9 (M++1).
43 1H NMR (DMSO-d6) δ (ppm): 0,50-of 0.51 (2H, d, -CH2), 0,63-of 0.65 (2H, d, -CH2), of 1.52 (2H, m, -CH2), and 1.63 (4H, m, -CH2), 1,77-to 1.79 (2H, m, -CH2), 2,73-to 2.74 (1H, m, -CH), 4,71 (1H, m, -CH), 6,38-6,41 (1H, d, =CH), is 6.61 (1H, s, Ar-H), 6,68-6,70 (1H, d, Ar-H), 6.87 in-6,89 (1H, d, Ar-H), 7,01-7,03 (2H, m, =CH and Ar-H), 7,22-7,29 (2H, m, =CH and Ar-H), 7,34-7,38 (3H, d, Ar-H), 7,70-7,71 (1H, d, -NH), 9,04 (1H, s, -OH), a 10.74 (1H, s, -NH). MS m/z: 432,9 (M++1).
441H NMR (DMSO-d6) δ (ppm): 1,51 (2H, m, -CH2), and 1.63 (4H, m, -CH2), 1,78-to 1.79 (2H, m, -CH2), to 4.73 (1H, m, -CH), 6,41-of 6.45 (1H, d, =CH), was 6.73 (1H, s, Ar-H), 6,80-for 6.81 (1H, d, Ar-H), 6.90 to-6,92 (1H, d, Ar-H), 7,06-

to 7.09 (1H, t, Ar-H), 7,11-7,13 (2H, m, =CH and Ar-H), 7,28-to 7.35 (5H, m, Ar-H), 7,41-743 (2H, d, Ar-H), to 7.67-of 7.69 (2H, d, Ar-H), 9,50 (1H, d, -NH), 9,92 (1H, s, -OH) 10,78 (1H, s, -NH). MS m/z: 468,9 (M++1).
451H NMR (DMSO-d6) δ (ppm): 0,52-of 0.53 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,73-2,78 (1H, m, -CH), 6,37-6,41 (1H, d, =CH), 7,07-to 7.09 (2H, d, Ar-H), 7.23 percent-of 7.25 (3H, m, =CH and Ar-H), 7,33-7,39 (4H, m, =CH and Ar-H), 7,46 is 7.50 (2H, t, Ar-H), 7,69-7,73 (4H, t, Ar-H), 7,89-of 7.90 (1H, d, -NH), 9,04 (1H, s, -OH) a 10.74 (1H, s, -NH). MS m/z: 424,9 (M++1).
461H NMR (DMSO-d6) δ (ppm): 0,33-0,35 (2H, m, -CH2), 0,57 is 0.59 (2H, m, -CH2), of 1.12 (1H, m, -CH), 3,83-a-3.84 (2H, s, -CH2), 6,40-to 6.43 (1H, d, =CH), 6,93-to 6.95 (2H, d, Ar-H), 7,07-7,16 (5H, m, Ar-H), 7.29 trend was 7.36 (3H, m, =CH and Ar-H), 7,41-7,43

(3H, m, =CH and Ar-H), 7,66-to 7.68 (2H, d, Ar-H), 9,05 (1H, d, -NH), 9,85 (1H, s, -OH), is 10.75 (1H, s, -NH). MS m/z: 454,8 (M++1).
471H NMR (DMSO-d6) δ (ppm): 0,50-of 0.51 (2H, m, -CH2), of 0.60 to 0.63 (2H, m, -CH2), 2,73-to 2.74 (1H, m, -CH), or 3.28 (3H, s, -OCH3), 3,70 (3H, s, -OCH3), 6,41-6,46 (2H, t, Ar-H and =CH), 6,70-6,72 (1H, d, Ar-H), 6,80-PC 6.82 (1H, m, Ar-H), 7,15-7,17 (1H, d, Ar-H), 7,28 (1H, s, =CH), 7,37-of 7.48 (3H, m, Ar-H and =CH), 7,56-7,58 (1H, d, Ar-H), 7,63-to 7.64 (1H, d, -NH), 9,05 (1H, s, -OH), and 10.8 (1H, s, -NH). MS m/z: 408,9 (M++1).
481H NMR (DMSO-d6) δ (ppm): 0,49-0,50 (2H, d, -CH2), 0,60-of 0.64 (2H, q, -CH2), 2,73 is 2.75 (1H, t, CH), of 3.69 (3H, s, -OCH3), 6,47-6,51 (1H, d, =CH), 6.75 in-6,77 (2H, d, Ar-H), 6,94-

of 6.96 (2H, d, Ar-H, 7,17-7,19 (2H, d, Ar-H), 7,24 (1H, s, =CH), 7,46 is 7.50 (1H, d, =CH), 7,56-7,58 (2H, d, Ar-H), to 7.64-the 7.65 (1H, d, -NH), 9,07 (1H, s, -OH), 10,78 (1H, s, -NH). MS m/z: to 379.2 (M++1).
491H NMR (DMSO-d6) δ (ppm): 0,32-0,34 (2H, d, -CH2), 0,41 at 0.42 (2H, m, -CH2), up 0,56 0,58 (2H, m, -CH2), of 0.64 to 0.66 (2H, t, -CH2), 1,22 (1H, m, -CH), 2,79-is 2.88 (1H, m, -CH), 3,83-of 3.85 (2H, d, -CH2), 6,45-of 6.49 (1H, d, =CH), 6,92-6,94 (2H, d, Ar-H), 7,06 (1H, s, =CH), 7,43-7,47 (3H, m, Ar-H), 7,50-7,52 (1H, d, Ar-H), EUR 7.57-to 7.59 (1H, d, Ar-H), of 8.47-8,48 (1H, s, -NH), 9,06 (1H, s, -OH), 10,77 (1H, s, -NH). MS m/z: 420,1 (M++1).
501H NMR (DMSO-d6) δ (ppm): 0,49-of 0.50 (2H, m, -CH2), 0,60-of 0.62 (2H, m, -CH2), and 1.54-of 1.56 (3H, t, -CH2), 1,64-of 1.66 (3H,

m, -CH2), 1,86-to 1.87 (2H, d, -CH2), 2,72-to 2.74 (1H, m, -CH), 4,74-of 4.75 (1H, m, -CH), 6,47-6,51 (1H, d, =CH), 6,70-6,72 (2H, d, Ar-H), 6,91-6,94 (2H, d, Ar-H), 7,17-7,19 (2H, d, Ar-H), 7.23 percent (1H, s, =CH), 7,46 is 7.50 (1H, d, =CH), 7,56-to 7.61 (3H, m, Ar-H and-NH), 9,07 (1H, s, -OH), 10,78 (1H, s, -NH). MS m/z: 433,2 (M++1).
511H NMR (DMSO-d6) δ (ppm): -0,10 (2H, m, -CH2), and 0.40 at 0.42 (2H, m, -CH2), 2,33-2,5 (1H, m, -CH), 6,46-of 6.50 (1H, d, =CH), 7,22-7,27 (2H, m, Ar-H), 7,32-7,39 (4H, m, Ar-H), 7,44-of 7.48 (1H, d, =CH), 7,52-rate of 7.54 (2H, d, Ar-H), 7,84-a 7.85 (1H, d, -NH), 9,06 (1H, s, -OH), 10,77 (1H, s, -NH). MS m/z: 381,1 (M++1).
521H NMR (DMSO-d6) δ (ppm): 0,48-0,49 (2H, d, -CH2), and 0.62 to 0.63 (2H, d, -CH2), 2,73 is 2.75 (1H, q, CH), with 2.93 (6H, s, -NCH3), 6,38-6.42 per (1H, d, =CH), 6,68-6,70 (2H, d, Ar-H), 6,95-

6,97 (2H, d, Ar-H), 7,09-7,10 (3H, d, Ar-H and =CH), 7,34-7,39 (3H, m, Ar-H and =CH), 7,53-rate of 7.54 (1H, d, -NH), 9,05 (1H, s, -OH), a 10.74 (1H, s, -NH). MS m/z: 392,1 (M++1).
531H NMR (DMSO-d6) δ (ppm): 0,50 (2H, m, -CH2), and 0.61-of 0.64 (2H, q, -CH2), and 2.26-of 2.30 (2H, t, -CH2), 2,70 is 2.75 (1H, m, -CH), 2,82-to 2.85 (2H, t, -CH2), 7,01-7,05 (6H, m, Ar-H), 7,17-7,21 (3H, t, Ar-H and =CH), 7,22-of 7.23 (1H, d, -NH), a total of 8.74 (1H, s, -OH), accounted for 10.39 (1H, s, -NH). MS m/z: 369,1 ((M++1).
541H NMR (DMSO-d6) δ (ppm): 0,51-0,52 (2H, d, -CH2), 0,62 is 0.65 (2H, t, -CH2), a 2.75-2,77 (1H, m, -CH), 6,27 of 6.31 (1H, d, =CH), 6.90 to-6,92 (1H, d, Ar-H), 7.18 in-7,29 (8H, m, Ar-H and =CH), 7,38-7,40 (1H, d, Ar-H), 7,8-7,83 (1H, d, -NH), 9,05 (1H, s, -OH), of 10.76 (1H, s, -NH). MS m/z: 367,0 (M++1).

Example 55:

Synthesis of (1E)-3-(4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)phenyl)-N-hydroxyacetamido

Stage-I

Obtaining methyl-3-(1E)(4-(2-(4-forfinal)-3-hydroxyprop-1-EN-1-yl)phenyl)acrylate

To a suspension of 2-(4-forfinal)-3-(4-(3-(E)-methoxy-3-oxoprop-1-EN-1-yl)phenyl)acrylic acid (2 g, 6.1 mmol, obtained according to the method described in Example 1, stage-II) in THF (10 ml) with constant stirring add triethylamine (0,85 ml, to 6.67 mmol) at 5°C. for 30 minutes at 5°C. to this solution is added dropwise methylchloroform (0,53 ml. to 6.67 mmol) and stirred for 30 minutes at the same temperature. To this reaction mixture under stirring once added sodium borohydride (0.9 g, 24.5 mmol) and methanol (5 ml) and the reaction mixture is stirred for 2 hours at 30°C. after completion of the reaction, the reaction mixture was diluted with ethyl acetate (300 ml) and sequentially washed with water (2×100 ml) and saturated salt solution (1×100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving the crude compound, which was purified column chromatography using 12% ethyl acetate/hexane as eluent, obtaining a pure compound in a solid white color (1.5 g, yield 79%).

Stage-II

Obtaining methyl-3-(1E)(4-(2-(4-shall terphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylate

To a suspension Harrogate pyridinium (PCC, 0.75 g, 3.5 mmol) in dichloromethane (20 ml) under stirring added dropwise a solution of methyl-3-(E)(4-(2-(4-forfinal)-3 - hydroxyprop-1-EN-1-yl)phenyl)acrylate (0.9 g, 2.9 mmol) in dichloromethane (5 ml) and the reaction mixture is stirred for 1 hour at room temperature. The reaction mass was diluted with diethyl ether (200 ml) and filtered through a layer of Celite, the filtrate is successively washed with saturated aqueous NaHCO3(3×100 ml) and water (1×100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, getting a net connection specified in the header, in the form of a solid white color (0.5 g, yield 56%).

Stage-III

Obtaining methyl-3-(1E)-(4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)phenyl)acrylate

A mixture of methyl-3-(1E)(4-(2-(4-forfinal)-3-hydroxyprop-1-EN-1-yl)phenyl)acrylate (of 0.44 g, 1.4 mmol) and cyclopropylamine (0.14 g, 2.4 mmol) was stirred with MeOH (40 ml) for 3 hours. To the reaction mixture is added sodium borohydride (0.09 g, 2.3 mmol) and stirred for 30 minutes. Then the reaction mixture was diluted with ethyl acetate (300 ml) and sequentially washed with water (2×100 ml) and saturated salt solution (1×100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, getting net connection is s, specified in the header, in the form of sticky compounds pale yellow (0.4 g, yield 80%).

Stage-IV

Receiving (1E)-3-(4-((3-(cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)phenyl)-N-hydroxyacetamido

Hydroxylamine hydrochloride (5 g, total 71.8 mmol) in methanol (20 ml) is mixed with KOH (4 g, total 71.8 mmol) in methanol (18 ml) at 0°C and 2 minutes, treated with ultrasound and filtered. The filtrate is added to methyl-3-(1E)(4-(3-(cyclopropylamino)-2-(4-forfinal)-prop-1-EN-1-yl)phenyl)acrylate (1.4 g, 4 mmol) in dichloromethane (5 ml) and add KOH (0,67 g, 12 mmol). The reaction mixture is stirred for 30 minutes at room temperature. The reaction mixture was concentrated, getting sticky connection yellow color, which is dissolved in water (200 ml) and set pH = 8 using dilute acetic acid, extracted with ethyl acetate (2×150 ml). The ethyl acetate layer dried over anhydrous Na2SO4and concentrate, receiving the crude compound, which was purified flash chromatography, using a 0.4% DCM:MeOH as eluent, getting a net connection specified in the header, in the form of a solid yellow (0.56 g, yield 40%).1H NMR (DMSO-d6) δ (ppm): 0,74-0,76 (2H, d, -CH2)to 0.85 (2H, s, -CH2), 2,73 (1H, s, -CH), 4,13 (2H, s, -CH2), 6,38-6.42 per (1H, d, =CH), of 6.96-6,98 (3H, d, Ar-H), 7.23 percent-7,28 (2H, t, Ar-H and =CH), 7,34-7,40 (5H, m, Ar-H and =CH), 9,00 (2H, d, -NH and-OH), 10,79 (1H, s, -NH). MC mz: 352,9 (M ++1).

The following compounds were obtained in accordance with the methodology described in Example 55.

Example No.StructureAnalytical data
561H NMR (DMSO-d6) δ (ppm): 0,26 is 0.27 (2H, d, -CH2), from 0.37 to 0.39 (2H, d, -CH2), 2,11-2,1 (1H, m, -CH), 3,55 (2H, s, -CH2), 6,32-6,426 (1H, d, =CH), 6,62 (1H, s, =CH), 6,93-to 6.95 (2H, d, Ar-H), 7,19-7,21 (2H, d, Ar-H), 7,28-7,37 (6H, m, Ar-H and =CH), 9,01 (1H, d, -OH), 10,69 (IH, s, -

NH). MC m/z: 335,1 (M++1).
571H NMR (DMSO-d6) δ (ppm): 0,23-0,24 (2H, m, -CH2), 0,36 is 0.37 (2H, d, -CH2), 1,50-1,60 (6H, m, -CH), 1,74-1,77 (2H, t, -CH2), 2,12-of 2.16 (1H, m, -CH), of 3.54 (2H, s, -CH2), 4,68-4,70 (1H, t, CH), 6,33-6,37 (1H, d, =CH), 6,60 (1H, s, =CH), of 6.66 (1H, s, Ar-H), 6.73 x to 6.75 (1H, d, Ar-H), 6,80-6,83 (1H, DD, Ar-H), 6,95-6,97 (2H, d, Ar-H), 7,21-of 7.25 (1H, t, Ar-H), 7,30 and 7.36 (3H, t, Ar-H and =CH), 9,05 (1H, s, -OH), 10,70 (1H, s, -NH). MC m/z: 419,1 (M++1).
58 1H NMR (DMSO-d6) δ (ppm): 0,23-0,24 (2H, d, -CH2), 0,36 is 0.37 (2H, s, -CH2), is 2.09 and 2.13 (1H, s, -CH), of 3.56 (2H, s, -CH2), 6,34-6,38 (1H, d, =CH), of 6.66 (1H, s, =CH), 6,95-6,97 (2H, d, Ar-H), 7,14-to 7.15 (1H, t, Ar-H), 7,27-7,37 (6H, m, Ar-H and =CH), of 9.02 (2H, s, -OH), 10,70 (1H, s, -NH). MC m/z: 369,0 (M++1).

Example 59:

Synthesis of N-cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-ylphenyl)-2-(4-forfinal)-acrylamide

Stage-I

Obtaining 3-(1E)-(4-(3-cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1 - yl)phenyl)acrylic acid

To a solution of methyl-3-(1E)-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylate (1 g, 2.7 mmol) in methanol (20 ml) add a solution of NaOH (of 0.44 g, 4.4 mmol) in water (1 ml). The reaction mixture is stirred for 2 hours at 70°C. then the solvent is completely removed by evaporation, diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The aqueous layer was acidified to pH 2 with diluted aqueous HCl (1:1) and left to stand at 4°C for 30 minutes, the precipitated solid is filtered off and dried in vacuum, obtaining the expected product in the form of a solid white color (of 0.67 g, yield 70%).

Stage-II

Obtaining N-cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-ylphenyl)-2-(4-forfinal)-acrylamide

To a suspension of 3-(1E)-(4-(3-cyclopropylamino is)-2-(4-forfinal)-3-oxoprop-1-enyl)phenyl)acrylic acid (0.21 g, 0.6 mmol) in DMF (5 ml) is added EDCI (to 0.23 g, 1.2 mmol), HOBt (0.08 g, 0.6 mmol), o-phenylenediamine (0.06 g, 0.54 mmol), and then add triethylamine (0.25 ml, 1.8 mmol). The reaction mixture is stirred for 1 hour, after which the mixture was added to cold water (20 ml). The aqueous layer was extracted with ethyl acetate (1×150 ml), washed with water (2×50 ml) and saturated salt solution (1×100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving the crude compound. Untreated, painted yellow connection triturated with ethyl acetate (20 ml), receiving specified in the title compound in the form of solid yellow (0.06 g, yield 24%).1H NMR (DMSO-d6) δ (ppm): 0,52 (2H, m, -CH2), of 0.64 to 0.65 (2H, d, -CH2), a 2.75 (1H, m, -CH), is 4.93 (2H, s, -NH2), to 6.57 (1H, t, =CH), to 6.75 (1H, d, Ar-H), 6,82-6,86 (1H, d, =CH), 6,91 (1H, t, Ar-H), 7.03 is-7,05 (2H, d, Ar-H), 7,19-7,22 (4H, m, Ar-H), 7,29 (1H, s, =CH), 7,31-7,33 (1H, d, Ar-H), 7,43-7,47 (3H, t, Ar-H), 7,97-7,98 (1H, d, -NH), a 9.35 (1H, s, -NH). MC m/z: 442,2 (M++1).

The following compounds were obtained in accordance with the methodology described in Example 59.

Example No.StructureAnalytical data
601H NMR (DMSO-d6δ (ppm): 2,92 (3H, s, -CH3), was 3.05 (3H, s, -CH3), 4,94 (2H, s, -NH2), 6,56 return of 6.58 (1H, t, Ar-H), of 6.71 (1H, s, =CH), 6.73 x to 6.75 (1H, d, Ar-H), 6,86-of 6.90 (1H, d, =CH), 6,91-6,93 (1H, m, Ar-H), 7,14-of 7.23 (4H, m, Ar-H and =CH), 7,31-7,34 (3H, t, Ar-H), of 7.48-7,49 (3H, d, Ar-H), 9,37 (1H, s, -NH). MC m/z: 430,2 (M++1).
611H NMR (DMSO-d6) δ (ppm): 0,52 is 0.55 (2H, q, -CH2), 0,63-0,66 (2H, q, -CH2);was 2.76-2,77 (1H, m, -CH), is 4.93 (2H, s, -NH2), to 6.57 (1H, t, =CH), 6.73 x to 6.75 (1H, d, Ar-H), 6,82-6,86 (1H, d, =CH), 6,91 (1H, t, Ar-H), 7,02? 7.04 baby mortality (2H, d, Ar-H), 7,31-7,47 (7H, m, =CH and Ar-H)

7,73 to 7.75 (2H, d, Ar-H), with 8.05 (1H, s, -NH), 9,34 (1H, s, -NH). MC m/z: 492,2 (M++1).
621H NMR (DMSO-d6) δ (ppm): 0,53 (2H, m, -CH2), 0,65-0,66 (2H, d, -CH2), 2,77 (1H, m, -CH), is 4.93 (2H, s, -NH2), to 6.57 (1H, t, =CH), 6.73 x to 6.75 (1H, d, Ar-H), 6,82-6,86 (1H, d, =CH), 6.89 in-6,91 (1H, t, Ar-H), 7.03 is-7,05 (2H, d, Ar-H), 7,31-7,33 (1H, d, Ar-H), 7,41-of 7.48 (4H, m, =CH and Ar-H), 7,60 to 7.62 (1H, d, Ar-H), 8,05-of 8.06 (1H, d, Ar-H), of 8.28 (1H, s, Ar-H), 8,54-8,55 (1H, d, -NH), 9,36 (1H, s, -NH). MC m/z: 425,2 (M++1).
631H NMR (DMSO-d6) δ (ppm): 0,52 (2H, m, -CH2), 0,63-of 0.65 (2H, d, -CH2), of 2.75 (1H, m, -CH), is 4.93 (2H, s, -NH2), to 6.57 (1H, t, =CH), 6.73 x to 6.75 (1H, d, Ar-H), 6,82-6,86 (1H, d,

=CH), 6,91 (1H, t, Ar-H), 6,98-7,00 (2H, d, Ar-H), 7,14-7,16 (1H, d, Ar-H), 7,31-7,34 (2H, m, =CH and Ar-H), 7,42-7,46 (5H, m, Ar-H), 7,55-EUR 7.57 (1H, d, Ar-H), to 7.84 (1H, s, -NH), a 9.35 (1H, s, -NH). MC m/z: 458,1 (M++1).
641H NMR (DMSO-d6) δ (ppm): 0,51-0,52 (2H, d, -CH2), 0,63-of 0.64 (2H, d, -CH2), a 2.75 (1H, m, -CH), is 4.93 (2H, s, -NH2), the 6.06 (2H, s, -CH2), to 6.57 (1H, t, =CH), 6,60-6,62 (1H, d, Ar-H), 6,70 (1H, s, Ar-H), 6.73 x to 6.75 (1H, d, Ar-H), 6,83-6,87 (1H, d, =CH), 6,92-6,94 (2H, d, Ar-H), 7,09-7,11 (2H, d, Ar-H), 7,26 (1H, s, =CH), 7,31 (1H, d, Ar-H), 7,45-of 7.48 (3H, t, Ar-H), 7,62-7,63 (1H, d, -NH), 9,36 I (1H, s, -NH). MC m/z: 468,1 (M++1).

651H NMR (DMSO-d6) δ (ppm): 0,53 (2H, m, -CH2), of 0.64 to 0.65 (2H, d, -CH2), 2,75 was 2.76 (1H, m, -CH), is 4.93 (2H, s, -NH2); to 6.57 (1H, t, =CH), 6.73 x to 6.75 (1H, d, Ar-H), 6,82-6,86 (1H, d, =CH), 6,91 (1H, t, Ar-H), 7,05-7,07 (2H, d, Ar-H), 7,16-7,24 (3H, m, =CH and Ar-H), 7,31-7,33 (1H, d, Ar-H), 7,43-7,47 (5H, m, Ar-H), 7,97-7,98 (1H, d, -NH), a 9.35 (1H, s, -NH). MC m/z: 442,2 ((M++1).
66 1H NMR (DMSO-d6) δ (ppm): 0,53 (2H, m, -CH2), of 0.64 to 0.66 (2H, d, -CH2), 2,75 was 2.76 (1H, m, -CH), is 4.93 (2H, s, -NH2), to 6.57 (1H, t, =CH), 6.73 x to 6.75 (1H, d, Ar-H), 6,83-6,87 (1H, d, =CH), 6.89 in-6,91 (1H, t, Ar-H),? 7.04 baby mortality-7,06 (2H, d, Ar-H), 7,11-7,13 (1H, d, Ar-H), 7,21 (1H, s, =CH), 7,31-7,33 (2H, d, Ar-H), 7,42-of 7.48

(5H, m, Ar-H), of 7.96-of 7.97 (1H, d, -NH), 9,36 (1H, s, -NH). MC m/z: 458,1 (M++1).
671H NMR (DMSO-d6) δ (ppm): 0,50 (2H, m, -CH2), and 0.62-of 0.64 (2H, d, -CH2), was 2.34 (3H, s, -CH3), 2,74 is 2.75 (1H, m, -CH), 4,94 (2H, s, -NH2), to 6.57 (1H, t, =CH), 6.73 x to 6.75 (1H, d, Ar-H), for 6.81-6,85 (1H, d, =CH), 6.89 in-6,91 (1H, t, Ar-H),? 7.04 baby mortality-7,06 (4H, m, Ar-H), 7,19-7,22 (3H, t, =CH and Ar-H), 7,31-7,33 (1H, d, Ar-H), 7,41-7,47 (3H, t, Ar-H), 7,70-7,71 (1H, d, -NH), a 9.35 (1H, s, -NH). MC m/z: 438,2 ((M++1).
681H NMR (DMSO-d6) δ (ppm): 3,57 (8H, Morpholine-H), is 4.93 (2H, s, -NH2), 6,57-6,59 (1H, t, =CH), 6.73 x to 6.75 (2H, m, Ar-H and =CH), 6,83-6,87 (1H, d, =CH), 6.89 in-6,91 (1H, t, Ar-H)

7,15-7,17 (2H, d, Ar-H), 7,20-7,24 (2H, t, Ar-H), 7,31-to 7.32 (3H, d, Ar-H), 7,45-7,49 (3H, t, Ar-H), 9,37 (1H, s, -NH). MC m/z: 472,3 (M++1).
691H NMR (DMSO-d6) δ (ppm): 0,51 (2H, m, -CH2), 0,63-of 0.65 (2H, d, -CH2), 2,74 is 2.75 (1H, m, -CH), 3,71 (3H, s, -OCH3), is 4.93 (2H, s, -NH2), to 6.57 (1H, t, =CH), of 6.71-6.75 in (3H, m, Ar-H), 6,82-6,86 (1H, d, =CH), 6.89 in-6,91 (2H, m, Ar-H), 6,94-of 6.96 (2H, d, Ar-H), 7,26 (1H, s, =CH), 7,30-to 7.32 (2H, d, Ar-H), 7,42-7,47 (3H, t, Ar-H), 7,70 (1H, s, -NH), 9,36 (1 H, s, -NH). MC m/z: 454,2 (M++1).
701H NMR (DMSO-d6) δ (ppm): from 0.50 to 0.53 (2H, q, -CH2), 0,62 is 0.65 (2H, q, -CH2), 2,74-2,77 (1H, q, CH), is 4.93 (2H, s, -NH2), to 6.57 (1H, t,

=CH), 6.73 x to 6.75 (1H, d, Ar-H), for 6.81-6,85 (1H, d, =CH), 6,91 (1H, t, Ar-H), 7,02? 7.04 baby mortality (2H, d, Ar-H), 7,16-to 7.18 (2H, t, Ar-H), 7,25 (1H; s, =CH), 7,31 (1H, d, Ar-H), 7,38-7,47 (6H, m, Ar-H), 7,80-7,81 (1H, d, -NH), a 9.35 (1H, s, -NH). MC m/z: 424,1 (M++1).
711H NMR (DMSO-d6) δ (ppm): 0,53 (2H, m, -CH2), 0,66-of 0.67 (2H, d, -CH2), was 2.76-2,77 (1H, m, -CH), of 4.95 (2H, s, -NH2), to 6.58 (1H, t, =CH), 6,74-6,76 (1H, d, Ar-H), 6.89 in-6,97 (3H, m, Ar-H), 7,07 (1H, t, Ar-H), 7.18 in-7,19 (2H, d, Ar-H), 7,26 (1H, s, =CH), 7,32 (1H, d, Ar-H), 7,47-7,51 (3H, m, Ar-H), to 7.61-7,62 (1H, d, Ar-H), 8,01-8,02 (1H, d, -NH), 9,39 (1H, s, -NH). MC m/z: 430,3 (M++1).

721H NMR (DMSO-d6) δ (ppm): 3,59 (8H, Morpholine-H), 4,94 (2H, s, -NH2), to 6.57 (1H, t, =CH), 6.73 x to 6.75 (1H, d, Ar-H):6,83-6,87 (1H, d, =CH), 6,91 (1H, t, Ar-H), to 6.95 (1H, s, =CH), 7,14-7,16 (2H, d, Ar-H), 7,22-7,27 (2H, q, Ar-H), 7,31-7,33 (2H, d, Ar-H), 7,45-7,49 (4H, t, Ar-H), 9,62 (1H, s, -NH). MC m/z: 472.0 M. (M++1).
731H NMR (DMSO-d6) δ (ppm): 0,52-of 0.54 (2H, t, -CH2), 0,62 is 0.65 (2H, q, -CH2), 2,73 was 2.76 (1H, q, CH), of 4.95 (2H, s, -NH2), 6,57-6,59 (1H, t, =CH), 6.73 x to 6.75 (1H, d, Ar-H), 6,85-6,91 (2H, t, =CH and Ar-H), 6,98 (1H, s, Ar-H), 7,05-7,07 (2H, d, Ar-H), 7,26 (1H, s, =CH), 7,32-of 7.48 (5H, m, Ar-H), 7,82-7,83 (1H, d, -NH), 9,41 (1H, s, -NH). MC m/z: 460,1 (M++1).

741H NMR (DMSO-d6) δ (ppm): 0.50 to 0.52 in (2H, m, -CH2), and 0.61-of 0.65 (2H, m, -CH2), 2,73-2,78 (1H, m, -CH), 3,62 (3H, s, -OCH3), of 3.78 (3H, s, -OCH3), is 4.93 (2H, s, -NH2), 6,55-6,59 (1H, t, =CH), 6,68 to 6.75 (3H, m, Ar-H), 6,82-6,86 (1H, d, =CH), 6.89 in-6,93 (1H, t, Ar-H), of 6.96-6,98 (1H, d, Ar-H), 7,08-7,10 (2H, d, Ar-H), 7,25 (1H, s, =CH), 7,30-to 7.32 (1H, d, Ar-H), 7,43-7,47 (3H, m, Ar-H), 7,54 (1H, d, -NH), a 9.35 (1H, s, -NH). m/z: (M+1)+=483,9.

Example 75:

Synthesis of 6-(3-(1E)-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acre is lamido)-N-hydroxysuccinimide

Stage-I

Obtaining methyl-6-(3-(1E)-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)hexanoate

To a suspension of 3-(1E)-(4-(2-(4-forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylic acid (obtained in accordance with the procedure described in Example 59, phase-I) (0.35 g, 1 mmol) in DMF (15 ml) is added EDCI (0,83 g, 2 mmol), HOBt (of 0.13 g, 1 mmol), methyl-6-aminocaproate (0.16 g, 0.9 to mmol), and then add triethylamine (0.4 ml, 3 mmol). The reaction mixture is stirred for 2 hours, after which the mixture was added to cold water (50 ml). The aqueous layer was extracted with ethyl acetate (1×150 ml), washed with water (2×50 ml) and saturated salt solution (1×100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving the crude compound. The crude compound, painted in yellow, washed with a mixture of ethyl acetate/hexane (0,5/9,5; 2×20 ml), getting mentioned in the title compound in the form of a solid yellow color (0.25 g, yield 52%).

Stage-II

Getting 6-(3-(1E)-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide

Hydroxylamine hydrochloride (0,63 g, 9 mmol) in methanol (3 ml) is mixed with KOH (0.51 g, 12.3 mmol) in methanol (3 ml) at 0°C and 2 minutes of clicks is anywayt ultrasound, the obtained white precipitate is filtered off. The filtrate is added to methyl-6-(3-(E)-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)hexanoate (0.24 g, 0.5 mmol) in DCM (1.5 ml) and the mixture is stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (1×200 ml). The ethyl acetate layer washed with water (100 ml), dried over anhydrous Na2SO4and concentrate, getting sticky compound, which is then triturated with DCM (15 ml)to give a solid. The obtained solid is filtered off and washed with DCM (5 ml), getting mentioned in the title compound (0.075 g, yield 32%).1H NMR (DMSO-d6) δ (ppm): 0,51 (2H, m, -CH2), and 0.62-of 0.64 (2H, t, -CH2), 1,24 (2H, m, -CH2), 1,40-1,49 (4H, m, -CH2), 1,91-of 1.93 (2H, d, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,12-3,13 (2H, d, -CH2), 6,53-to 6.57 (1H, d, =CH), 6,99-7,01 (2H, d, Ar-H), 7.18 in-7,22 (4H, m, Ar-H), 7,27 (1H, s, =CH), 7,28-to 7.32 (1H, d, =CH), 7,37-7,39 (2H, d, Ar-H), 7,82-7,83 (1H, d, -NH), of 8.06 (1H, s, -NH), 8,67 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 480,3 (M++1).

The following compounds were obtained in accordance with the methodology described in Example 75.

Example No.StructureAnalytical data
76 1H NMR (DMCO-d6) δ (ppm): 1,24-of 1.26 (2H, m, -CH2), 1.41 to to 1.45 (2H, m, -CH2), 1,47-is 1.51 (2H, m, -CH2), 1,92-of 1.95 (2H, t, -CH2), only 2.91 (3H, s, -CH3), totaling 3.04 (3H, s, -CH3), 3,11 -, and 3.16, (2H, q, -CH2) 6,54 return of 6.58 (1H, d, =CH), 6,69 (1H, s, =CH), 7,10 for 7.12 (2H, d, Ar-H), 7.18 in-7,22 (2H, t, =CH, Ar-H), 7,29-7,34 (3H, m, Ar-H), 7,40-7,42 (2H, d, Ar-H), 8,06-8,08 (1H, t, NH), 8,67 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 496,2 (M++1).
771H NMR (DMCO-d6) δ (ppm): 0.50 to 0.52 in (2H, t, -CH2), and 0.62-of 0.64 (2H, t, -CH2), 1,25-1,50 (6H, m, -CH2),

1,91-of 1.93 (2H;t, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,12-3,14 (2H, d, -CH2), 6,53-to 6.57 (1H, d, =CH), 6,94-of 6.96 (2H, d, Ar-H), 7,14-to 7.15 (1 H, d, Ar-H), 7,28-to 7.35 (2H, t, =CH, Ar-H), 7,38-7,40 (2H, t, Ar-H), 7,54-of 7.55 (2H, t, =CH and Ar-H), 7,55-EUR 7.57 (1H, d, Ar-H), of 7.82 (1H, d, -NH), with 8.05 (1H, t, NH), 8,67 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 496,2 (M++1).
781H NMR (DMCO-d6) δ (ppm): 0.50 to 0.52 in (2H, t, -CH2), of 0.64 to 0.65 (2H, t, -CH2), 1,24-1,25 (2H, m, -CH2), of 1.40-1.50 (4H, m, -CH2), 1,91-of 1.95 (2H, t, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,12-3,13 (2H, d, -CH2), 6,53-to 6.57 (1H, d, =CH), 7,02? 7.04 baby mortality (1H, d, Ar-H), 7,14-of 7.23 (4H, m, Ar-H)

7,28-to 7.32 (1H, d, =CH), 7,37-the 7.43 (4H, m, Ar-H and =CH), of 7.96-of 7.97 (1H, d, -NH), of 8.06 (1H, t, NH), 8,66(1H,with,-OH), 10,34 (1H, s, -NH). MC m/z: of 480.2 (M++1).
791H NMR (DMCO-d6) δ (ppm): 0.50 to 0.52 in (2H, t, -CH2), and 0.61 to 0.63 (2H, t, -CH2), 1,24 (2H, m, -CH2), 1,43-1,49 (4H, m, -CH2), 1,91-of 1.93 (2H, t, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,12-3,14 (2H, d, -CH2), the 6.06 (2H, s, -CH2), 6,54-of 6.61 (2H, q, =CH and Ar-H), of 6.68 (1H, s, Ar-H), 6,91-6,93 (1H, d, Ar-H), 7,05-7,07 (2H, d, Ar-H), 7,24 (1H, s, =CH), 7,29-7,33 (1H, d, =CH), 7,38-7,40 (2H, d, Ar-H), 7,60 (1H, s, -NH), of 8.06 (1H, s, -NH), 8,67 (1H, s, -OH), 10,33 (1H, s, -NH). MC m/z: 506,2 (M++1).

801H NMR (DMCO-d6) δ (ppm): 0,52 (2H, s, -CH2), 0,63-of 0.65 (2H, t, -CH2), 1,24-of 1.26 (2H, m, -CH2), 1,41 of 1.50 (4H, m, -CH2), 1,91-of 1.95 (2H, t, -CH2), is 2.74 (1H, m, -CH), 3,12-3,14 (2H, d, -CH2), 6,54 return of 6.58 (1H, d, =CH), 7,00-7,02 (2H, d, Ar-H), 7,09-7,11 (1H, d, Ar-H), 7,19 (1H, s, =CH), 7,29-7,33 (2H, t, =CH and Ar-H), 7,38-7,44 (4H, m, Ar-H), 7,94-of 7.95 (1H, d, -NH), 8,04-with 8.05 (1H, d, -NH), 8,67 (1H, s, -OH), 10,33 (1H, s, -NH). MC m/z: 496,1 (M++1).
811H NMR (DMCO-d6) δ (ppm): 0,49-0,50 (2H, d, -CH2), and 0.62 to 0.63 (2H, d, -CH2), 1,24-1,25 (2H, m, -CH2), 1,40-1,49 (4H, m, -CH2), 1,91-of 1.95 (2H, t, -CH2), was 2.34 (3H, s, -CH3), 2,74 was 2.76 (1H, m, -CH), 3,12-

3,14 (2H, d, -CH2), 6,53-to 6.57 (1H, d, =CH), 7,01-7,05 (4H, t, Ar-H), 7.18 in-7,20 (3H, d, Ar-H and =CH), 7,28-to 7.32 (1H, d, =CH), 7,34 and 7.36 (2H, d, Ar-H), 7.68 per-of 7.69 (1H, d, -NH), with 8.05 (1H, s, -NH), 8,67 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 476,2 (M++1).
821H NMR (DMCO-d6) δ (ppm): 0,51 (2H, s, -CH2), 0,63-of 0.64 (2H, d, -CH2), 1,23-1,25 (2H, m, -CH2), of 1.40 to 1.48 (4H, m, -CH2), 1,91-of 1.93 (2H, t, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,12-3,13 (2H, d, -CH2), 6,52-6,56 (1H, d, =CH), 6,99-7,01 (2H, d, Ar-H), 7,15-7,16 (2H, d, Ar-H), 7,22 (1H, s, =CH), 7,27-7,31 (1H, d, =CH), 7,33-7,39 (5H, m, Ar-H), 7,78-7,79 (1H, d, -NH), with 8.05 (1H, s,

-NH), 8,67 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 462,4 (M++1).
831H NMR (DMCO-d6) δ (ppm): 0,52-of 0.53 (2H, t, -CH2), of 0.64 to 0.66 (2H, t, -CH2), 1,24 (2H, m, -CH2), 1,41-1,49 (4H, m, -CH2), 1,92-of 1.93 (2H, t, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,13-3,14 (2H, d, -CH2), 6,56 to 6.0 (1H, d, =CH), 6,94-to 6.95 (1H, m, Ar-H), 7,05-7,06 (1H, t, Ar-H), 7,14-7,16 (2H, d, Ar-H), 7,24 (1H, s, =CH), to 7.32 and 7.36 (1H, d, =CH), 7,42-7,44 (2H, d, Ar-H), 7,60-to 7.61 (1H, d, Ar-H), 7,80 (1H, s, -NH), of 7.96-7,98 (1H, d, -NH), 8,66 (1H, s, -OH), 10,33 (1H, s, -NH). MC m/z: 468,2 (M++1).
841H NMR (DMCO-d6) δ (ppm): 0,49-of 0.51 (2H, q, -CH2), and 0.62-of 0.64 (2H, d, -CH2),

1,24-1,25 (2H, m, -CH2), 1,43-1,49 (4H, m, -CH2), 1,93-of 1.95 (2H, m, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,12-3,14 (2H, d, -CH2), of 3.78 (3H, s, -OCH3), 6,53-to 6.57 (1H, d, =CH), 6,93-of 6.96 (2H, t, Ar-H), 7.03 is-to 7.09 (4H, m, Ar-H), 7,20 (1H, s, =CH), 7,29-7,33 (1H, d, =CH), was 7.36-7,38 (2H, d, Ar-H), 7,66 (1H, s, -NH), 8,05-of 8.06 (1H, d, -NH), 8,68 (1H, s, -OH), 10,35 (1H, s, -NH). MC m/z: 492,5 (M++1).
851H NMR (DMCO-d6) δ (ppm): 0.50 to 0.52 in (2H, t, -CH2), 0,63-of 0.65 (2H, q, -CH2), 1,24-1,25 (2H, m, -CH2), 1,43-1,49 (4H, m, -CH2), was 1.94 (2H, m, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,12-3,14 (2H, d, -CH2), 3,71 (3H, s, -OCH3), 6,54 return of 6.58 (1H, d, =CH), 6,70-of 6.73

(2H, t, Ar-H), 6,93-to 6.95 (1H, d, Ar-H), 7.03 is-7,05 (2H, d, Ar-H), 7,25-7,38 (5H, m, =CH and Ar-H), of 7.69 (1H, s, -NH), and 8.6 (1H, s, -NH), 8,68 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 492,0 (M++1).
861H NMR (DMCO-d6) δ (ppm): 1,24 (2H, m, -CH2), 1,42-1,49 (4H, m, -CH2), 1,92-of 1.95 (2H, t, -CH2), 3,12-3,14 (2H, d, -CH2), of 3.56 (8H, Morpholine-H), 6,54 return of 6.58 (1H, d, =CH), 6,74 (1H, s, =CH), 7,11-7,13 (2H, t, Ar-H), 7,19-7,24 (2H, t, Ar-H), 7,30-7,34 (3H, m, Ar-H and =CH), 7,40-7,42 (2H, d, Ar-H), 8,06-of 8.09 (1H, t, NH), 9,01 (1H, s, -OH), 10,35 (1H, s, -NH). MC m/z: 510,0 (M++1).

871H NMR (DMCO-d6) δ (ppm): 1,24-of 1.26 (2H, m, -CH2), 1,41-is 1.51 (4H, m, -CH2), 1,91-of 1.95 (2H, t, -CH2), 3,12-3,14 (2H, d, -CH2), to 3.58 (8H, Morpholine-H), 6,54 return of 6.58 (1H, d, =CH), 6,93 (1H, s, =CH), 7,11-7,13 (2H, d, Ar-H), 7,21-7,26 (2H, m, Ar-H), 7,30-7,34 (2H, q, Ar-H and =CH), 7,40 was 7.45 (3H, m, Ar-H), 8.07-a 8,08 (1H, d, -NH), 8,67 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 510,0 (M++1).
881H NMR (DMCO-d6) δ (ppm): 0,50-of 0.51 (2H, t, -CH2), and 0.62-of 0.64 (2H, t, -CH2), 1,24-1,25 (2H, m, -CH2), 1,42-1,49 (4H, m, -CH2), 1,91-of 1.93 (2H, m, -CH2), 2,74 was 2.76 (1H, m, -CH), 3,12-3,14 (2H, d, -CH3), 3,86 (3H, s, -OCH3), 6,55-6,59 (1H, d, =CH), 6,93

is the (2H, m, Ar-H),? 7.04 baby mortality-7,07 (2H, d, Ar-H), 7,18 (1H, t, Ar-H), 7,26 (1H, s, =CH), 7,30-7,34 (1H, d, =CH), 7,42-7,44 (2H, d, Ar-H), 7,81-of 7.82 (1H, d, -NH), 8.07-a 8,08 (1H, d, -NH), 8,67 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 510,2 (M++1).

Example 89:

Synthesis of 4-((3-(1E)-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide

Stage-I

Obtaining methyl-4-((3-(1E)-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)benzoate

To a suspension of (1E)-3-(4-(2-(4-forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylic acid (obtained in accordance with the procedure described in Example 59, phase-II, 0.35 g, 1 mmol) in DMF (15 ml) is added EDCI (0,83 g, 2 mmol), HOBt (of 0.13 g, 1 mmol) and cleaners containing hydrochloride salt of methyl-4-aminomethylbenzoic (0.18 g, 0.9 mmol), then add triethylamine (0.4 ml, 3 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, after which the mixture was added to cold water (50 ml). The aqueous layer was extracted with ethyl acetate (1× 150 ml) and washed with water (2×50 ml), 10% diluted HCl (50 ml) and saturated salt solution (1×100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving the crude compound (0,225 g, yield of 53.5%).

Stage-II

Getting 4-((3-(1E)-(4-(3-(Cyclops is pilipino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide

Hydroxylamine hydrochloride (0.55 g, 8 mmol) in methanol (2 ml) is mixed with KOH (0.45 g, 8 mmol) in methanol (2 ml) at 0°C and 2 minutes, treated with ultrasound, the obtained white precipitate is filtered off. The filtrate is added to methyl 4-((3-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)phenyl)acrylamide)methyl)benzoate (to 0.22 g, 0.44 mmol) in DCM (1.5 ml) and the mixture stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (1×200 ml). The ethyl acetate layer washed with water (100 ml), dried over anhydrous Na2SO4and concentrate, receiving the crude compound, followed by rubbing with DCM (15 ml). The obtained solid is filtered off and washed with DCM (5 ml), receiving specified in the header connection (0,044 g, yield 20%).1H NMR (DMSO-d6) δ (ppm): 0,51 (2H, m, -CH2), 0,62 is 0.65 (2H, m, -CH2), 2,73 is 2.75 (1H, m, -CH), 4,37-to 4.38 (2H, d, -CH2), 6,62 of 6.66 (1H, d, =CH), 7,00-7,02 (2H, d, Ar-H), 7,15-7,19 (3H, m, Ar-H), 7,21-7,27 (3H, d, Ar-H and =CH), 7,35 (2H, d, Ar-H), 7,38-7,40 (2H, m, Ar-H and NH), 7,69-7,71 (2H, d, Ar-H), 7,83-to 7.84 (1H, d, =CH), 8,63 (1H, t, NH). MC m/z: 500,1 (M++1).

The following compounds were obtained in accordance with the methodology described in Example 89.

Example No.StructureAnalytically the data
901H NMR (DMSO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), and 0.62-of 0.64 (2H, m, -CH2), 2,72 is 2.75 (1H, m, -CH), 4,40 was 4.42 (2H, d, -CH2), 6,61-of 6.65 (1H, d, =CH), 6,95-6,97 (2H, d, Ar-H), 7,14 (1H, d, =CH), 7,31-7,34 (3H, m, Ar-H and =CH), 7,38-7,44 (5H, m, Ar-H), 7,54-7,56 (1H, d, Ar-H), 7,69-7,71 (2H, d, Ar-H), 7,82-7,83 (1H, d, -NH), 8,62-8,65 (1H, t, -NH), and 9.0 (1H, s, -

OH), 11,17 (1H, s, -NH). MS m/z: 516,1 (M++1).
911H NMR (DMSO-d6) δ (ppm): 0,52 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), to 4.41 was 4.42 (2H, d, -CH2), 6,62 of 6.66 (1H, d, =CH), 7,01-7,03 (2H, d, Ar-H), 7,09-7,11 (1H, d, Ar-H), 7,19 (1H, s, =CH), 7,29-7,42 (8H, m, Ar-H and =CH), 7,69-7,71 (2H, d, Ar-H), 7,95-of 7.96 (1H, d, -NH), 8,63-8,65 (1H, t, NH), 9,01 (1H, s, -OH), 11,18 (1H, s, -NH). MS m/z: 516,2 (M++1).
921H NMR (DMSO-d6) δ (ppm): 0,49 (2H, m, -CH2), and 0.62 to 0.63 (2H, m, -CH2), of 2.33 (3H, s, -CH3), by 2.73 (1H, m, -CH), 4,40-to 4.41 (2H, d, -CH2), 6,60-only 6.64 (1H, d, =CH), 7,02? 7.04 baby mortality (4H, d, Ar-H), 7.18 in-7,20 (3H, m, Ar-H and =CH), 7,31-7,39 (4H, m, Ar-H and =CH), 7,69-7,71 (3H, m, Ar-H and-NH), 8,63 (2H, m, NH and Ar-H), 9,01 (1H, s, -OH), 11,18 (1H, s, -NH). MS

m/z: 496,2 (M++1).931H NMR (DMSO-d6) δ (ppm): 0,50 (2H, m, -CH2), 0,63-of 0.64 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), 4,40-to 4.41 (2H, d, -CH2), 6,60-only 6.64 (1H, d, =CH), 6,99-7,01 (2H, d, Ar-H), 7,14-to 7.15 (2H, d, Ar-H), 7,22 (1H, s, =CH), 7,31-7,37 (8H, m, Ar-H), 7,69-7,71 (2H, d, Ar-H and =CH), 7,78 (1H, d, -NH), 8,64 (1H, t, NH), 9,01 (1H, s, -OH), 11,l8(lH, s, -NH). MS m/z: 482,4 (M++1).941H NMR (DMSO-d6) δ (ppm): 0,52-of 0.53 (2H, m, -CH2), 0,65-0,66 (2H, m, -CH2), 2,73 is 2.75 (1H, m, -CH), 4,42-4,43 (2H, d, -CH2), 6,62 of 6.66 (1H, d, =CH), 6,94-to 6.95 (1H, d, Ar-H), 7,15-7,17 (1H, m, Ar-H), 7,24 (2H, m, Ar-H and =CH), 7,32-7,34 (1H, d, Ar-H), 7,39-7,47 (5H, m, Ar-H and =CH), 7,60-to 7.61 (1H, d, Ar-H), 7,69-7,71 (2H, d, Ar-H), to 7.99 (1H, d, -NH), 8,66-8,69

(1H, t, NH), of 9.02 (1H, s, -OH), 11,18 (1H, s, -NH). MS m/z: 488,6 (M++1).
951H NMR (DMSO-d6) δ (ppm): 0,49-of 0.50 (2H, m, -CH2), and 0.62 to 0.63 (2H, m, -CH2), 2,73 is 2.75 (1H, m, -CH), of 3.77 (3H, s, -OCH3), to 4.41 was 4.42 (2H, d, -CH2), 6,62 of 6.66 (1H, d, =CH), 6,92-to 6.95 (2H, d, Ar-H), 7,03 -7,07 (4H, m, Ar-H), 7,19 (1H, s, =CH), 7,32-7,40 (5H, m, Ar-H and =CH), 7,69-7,71 (3H, m, Ar-H and-NH), 8,65 (1H, t, NH), 9,01 (1H, s, -OH), 11,18 (1H, s, -NH). MS m//: 512,6 (M++1).
961H NMR (DMSO-d6) δ (ppm): of 3.56 (8H, m, -CH2), 4,42-4,43 (2H, d, -CH2), 6,67 to 6.75 (2H, d, =CH), 7,12-7,14 (2H, d, Ar-H), 7,22 was 7.45 (12H, m, Ar-H and =CH), 7,70-7,72 (2H, d, Ar-H), 8,65-8,67 (1H, t, NH), 9,04 (1H, s, -OH), 11,19 (1H, s, -NH). MS m/z: 530,4 (M++1).

971H NMR (DMSO-d6) δ (ppm): 0,50-of 0.51 (2H, m, -CH2), and 0.62-of 0.64 (2H, m, -CH2), 2,73 is 2.75 (1H, m, -CH), 3,70 (3H, s, -OCH3), to 4.41 was 4.42 (2H, d, -CH2), 6,61-of 6.65 (1H, d, =CH), 6,70 (3H, m, Ar-H), 7,02-7,05 (2H, d, Ar-H), 7,24 (1H, s, =CH), 7,31-7,40 (5H, m, =CH and Ar-H), 7,69 (4H, m, Ar-H and NH), 8,63 and 8.6 (1H, t, NH), 9,01 (1H, s, -OH), 11,18 (1H, s, -NH). MS m/z: 512,6 (M++1).
981H NMR (DMSO-d6) δ (ppm): to 3.58 (8H, m, -CH2), to 4.41 was 4.42 (2H, d, -CH2), 6,62 of 6.66 (1H, d, =CH), 6,93 (1H, s, =CH), 7,11-7,13 (2H, d, Ar-H), 7,21 was 7.45 (9H, m, Ar-H and =CH), 7,69-7,71 (2H, d, Ar-H), 8,64-8,67 (1H, t, NH), 10,65 (1H, s, -OH), 11,18 (1H, s, -NH). MS m/z: 529,9 (M++1).

Example 99:

Synthesis of 4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide the

Stage-I

Obtaining 3-(4-(methoxycarbonyl)phenyl)-2-(4-were)acrylic acid

A mixture of 4-methylphenylacetic acid (3 g, 20 mmol) and methyl-4-formylbenzoate (3.3 g, 20 mmol) under stirring dissolved in Ac2O (8 ml). To this mixture add diisopropylethylamine (DIPEA) (5.2 ml, 30 mmol) and stirred for 6 hours at 30°C. after the reaction is controlled by TLC using 100% ethyl acetate as eluent, the reaction mixture was poured into water and set the pH to 3 with diluted HCl (1:1). The aqueous layer was extracted with ethyl acetate (2×150 ml). The combined ethyl acetate layer was washed with water until neutral wash water and dried over anhydrous Na2SO4. The ethyl acetate layer is evaporated to dryness, getting sticky compound which is triturated with cold dichloromethane (DCM) to obtain the solid pale yellow color. It is filtered off and dried in vacuum, obtaining mentioned in the title compound (3.88 g, yield 66%).

Stage-II

Obtaining methyl-4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)benzoate

A mixture of 3-(4-(methoxycarbonyl)phenyl)-2-(4-were)acrylic acid (to 0.23 g, 0.71 mmol), cyclopropylamine (3.88 g, 13 mmol), EDCl (5 g, 26 mmol), HOBt (1.8 g, 13 mmol) in AC is shivani dissolved in N,N-dimethylformamide (DMF) (6 ml). To this reaction mixture with constant stirring dropwise added triethylamine (TEA) (5.5 ml, 39 mmol). The reaction mixture is stirred for 4 hours at 30°C. After the reaction mixture was poured into ice-cold water (150 ml), upon standing at room temperature for 1 hour, a precipitate of white color, which is filtered off and washed with hexane (100 ml), dried in vacuum, obtaining a pure compound (2.9 g, yield 66%).

Stage-III

Getting 4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)benzoic acid

To a solution of methyl-4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)benzoate (4 g, 12 mmol) in methanol (10 ml) add a solution of NaOH (1.4 g, 36 mmol) in water (1 ml). The reaction mixture for two hours refluxed at 70°C. the Solvent is removed by evaporation, poured into ice-cold water. The aqueous layer was acidified to pH 3 with citric acid and left to stand at 4°C for 30 minutes, the precipitated solid is filtered off and dried in vacuum, obtaining a solid pale yellow color (3.2 g, yield 83%).

Stage-IV

Getting 4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide

To a suspension of 4-(3-(cyclopropylamino)-2-(p-tolyl)-3-oxoprop-1-EN-1-yl)benzoic acid (0.1 g, 0.3 mmol) in DMF (3 ml) to ablaut hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium (BOP-reagent, to 0.23 g, 0.55 mmol), HOBt (0.04 g, 0.3 mmol), hydroxylamine hydrochloride (0.03 g, 0.35 mmol), then added DIPEA (0.16 ml, 0.9 mmol). The reaction mixture is stirred for 1 hour, after which the mixture was added to cold water (100 ml) and incubated for 1 hour at 0°C, there is formed a solid white color. The obtained solid is filtered off and washed with water (50 ml), dried in vacuum, obtaining mentioned in the title compound in the form of a solid white color (0,080 g, yield 77%).1H NMR (DMSO-d6) δ (ppm): 0,46-of 0.51 (2H, m, -CH2), of 0.58 to 0.60 (2H, m, -CH2), to 2.29 (3H, s, CH3), 2,69-2,70 (1H, m, -CH), for 6.81 (4H, m, Ar-H), 6,97-7,03 (3H, m, Ar-H), was 7.36-7,38 (1+1H, d, Ar-H and =CH), of 7.70 (1H, d, NH), 8,99 (1H, s, OH), 11,10 (1H, s, NH). MC m/z: sauce 337,1 (M++1).

The following compounds were obtained in accordance with the methodology described in Example 99.

Example No.StructureAnalytical data
1001H NMR (DMSO-d6) δ (ppm): 0,50 (2H, m, -CH2), and 0.62-of 0.64 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), of 3.77 (3H, s, OCH3), 6,91-6,93 (2H, d, Ar-H), 7,06 (4H, m, Ar-H), 7,20 (1H, s, =CH), 7,53 (2H, d, Ar-H), 7,71 (1H, d, NH), 9,01 (1H, s, OH), 11,13 (1H, s, NH). MC m/z: 353,1

(M++l).
1011H NMR (DMSO-d6) δ (ppm): 0,50 (2H, m, -CH2), 0,63-of 0.64 (2H, m, -CH2), 2,67-to 2.74 (1H, m, -CH), with 3.79 (3H, s, OCH3), of 6.68 (2H, m, Ar-H), 6,94 (1H, d, Ar-H), 7,06 (2H, m, Ar-H), 7.24 to 7,29 (2H, m, Ar-H and =CH), 7,53 (2H, d, Ar-H), 7,73-7,79 (1H, d, NH), 9,01 (1H, s, NH), 11,13 (1H, s, OH). MC m/z: 353,1 (M++1).
1021H NMR (DMSO-d6) δ (ppm): 0,50-0,55 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,73 is 2.75 (1H, m, -CH), 7,03 (2H, d, Ar-H), 7,14 (2H, d, Ar-H), 7.23 percent (1H, s, =CH), was 7.36 (3H, m, Ar-H), 7,51 (2H, d, Ar-H), to 7.84 (1H, d, NH), 9,01 (1H, s, OH), 11,13 (1H, s, NH). MC m/z: 323,1 (M++1).
1031H NMR (DMSO-d6) δ (ppm): 0,51-0,57 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,73 is 2.75 (1H, m, -CH), 7,05-of 7.24 (5H, m, Ar-H), was 7.36 (2H, m, =CH and Ar-H), 7,54 (2H, d, Ar-H), 7,95 (1H, d, NH), of 8.90 (1H, s, OH), 11,16 (1H, s, NH). MC m/z: 339,0 (M++1).

Example 104:

Synthesis of N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)benzamide

Stage-I

Obtaining N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)Besame is and

To a suspension of 4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)benzoic acid (0.2 g, 0.6 mmol, obtained in accordance with the procedure described in Example 99, stage I-III) in DMF (3 ml) is added EDCI (to 0.23 g, 1.1 mmol), HOBt (0.08 g, 5 mmol), o-phenylenediamine (0.08 g, 0.7 mmol), then add TEA (0,23 ml, 15 mmol). The reaction mixture is stirred for 4 hours, after which the mixture was added to cold water (100 ml) and incubated for 1 hour at 0°C, receiving solid pale yellow color. The solid is filtered off and washed with water (50 ml), dried in vacuum, obtaining specified in the header connection (0,110 g, yield 45%).1H NMR (DMSO-d6) δ (ppm): 0,51 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), of 2.33 (3H, s, -CH3), 2,67 is 2.75 (1H, m, -CH), to 4.87 (2H, s, -NH2), 6,55 return of 6.58 (1H, m, Ar-H), 6,74-6,76 (1H, m, Ar-H), 6,93-6,97 (1H, m, Ar-H),? 7.04 baby mortality (2H, d, Ar-H), 7,11 (3H, m, Ar-H), 7,19 (2H, m, Ar-H), 7,25 (1H, s, =CH), 7,76 for 7.78 (3H, m, Ar-H and-NH), to 9.57 (1H, s, -NH). MC m/z: 412,2 (M++1).

The following compounds were obtained in accordance with the methodology described in Example 104.

Example No.StructureAnalytical data
1051H NMR (DMCO-d6) δ (ppm: 0,52-of 0.58 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), to 4.87 (2H, s, -NH2), 6,55 return of 6.58 (1H, m, Ar-H), to 6.75 (1H, d, Ar-H), 6,93-6,97 (1H, m, Ar-H), 7,09-7,11 (3H, m, Ar-H), 7,19-7,24 (4H, m, Ar-H), 7,32 (1H, s, =CH), 7,79 (2H, d, Ar-H), to $ 7.91 (1H, d, -NH), 9,63 (1H, s, -NH). MS m/z: 416,1 (M++1).
1061H NMR (DMCO-d6) δ (ppm): 0,54 (2H, m, -CH2), 0,65-0,66 (2H, m, -CH2), was 2.76 (1H, m, -CH), to 4.87 (2H, s, -NH2), 6,56 (1H,

m, Ar-H), to 6.75 (1H, d, Ar-H), to 6.95 (1H, m, Ar-H), 7,09-7,11 (3H, m, Ar-H), 7,38 (2+1H, m, Ar-H and =CH), 7,74 (2H, d, Ar-H), 7,80 (2H, d, Ar-H), 8,11 (1H, d, -NH), a 9.60 (1 H, s, -NH). MS m/z: 466,1 (M++1).
1071H NMR (DMCO-d6) δ (ppm): 0,52 (2H, m, -CH2), of 0.64 to 0.66 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), a 4.86 (2H, s, -NH2), 6,55-6,59 (1H, m, Ar-H), to 6.75 (1H, d, Ar-H), 6,94-6,97 (1H, m, Ar-H), 7,08-7,10 (3H, m, Ar-H), 7,15-7,17 (2H, d, Ar-H), 7,27 (1H, s, =CH), 7,38 (3H, m, Ar-H), 7,76 (2H, d, Ar-H), of 7.90 (1H, d, -NH), 9,58 (1H, s, NH). MS m/z: 398,2 (M++1).
1081H NMR (DMCO-d6) δ (ppm): 0,51-of 0.53 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), 3,71 (3H, s, -OCH3), to 4.87 (2H, s, -NH2 ), 6,56 (1H, m, Ar-H), of 6.71-6,76 (3H, m, Ar-H), 6,93-of 6.96 (2H, m

Ar-H, 7,10-7,13 (3H, m, Ar-H), 7,28-7,33 (1+1H, Ar-H and =CH), 7,76 for 7.78 (3H, m, Ar-H and NH), to 9.57 (1H, s, -NH). MS m/z: 428,2 (M++1).
1091H NMR (DMCO-d6) δ (ppm): 0,53-of 0.58 (2H, m, -CH2), of 0.64 to 0.66 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), 4,88 (2H, s, -NH2), 6,56 (1H, m, Ar-H), to 6.75 (1H, d, Ar-H), to 6.95 (1H, m, Ar-H), 7,10-7,24 (6H, m, Ar-H and =CH), was 7.45 (2H, d, Ar-H), 7,79 (2H, s, Ar-H), of 8.06 (1H, d, -NH), a 9.60 (1H, s, -NH). MS m/z: 416,0 (M++1).
1101H NMR (DMCO-d6) δ (ppm): about 0.53-0.54 (2H, m, -CH2), 0,65-0,66 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), 4,88 (2H, s, -NH2), to 6.57 (1H, m, Ar-H), to 6.75 (1H, d, Ar-H), 6,93-of 6.99 (3H, m, Ar-H), 7,10 for 7.12 (3H, m, Ar-H), 7,21 (1 H, t, Ar-H), 7,34 (1H, s, =CH), the 7.43 (1H, s, Ar-H), 7,79 (2H, d, Ar-H), 7,97

(1H, d, -NH), a 9.60 (1H, s, -NH). MS m/z: 416,1 (M++1).
1111H NMR (DMCO-d6) δ (ppm): 0,52 (2H, m, -CH2), 0,63-of 0.64 (2H, m, -CH2 ), 2,75 was 2.76 (1H, m, -CH), 4,89 (2H, s, -NH2), the 6.06 (2H, s, -CH2), to 6.58-6,60 (2H, m, Ar-H), 6,69 (2H, m, Ar-H), 6,92-6,94 (2H, m, Ar-H), 7,15-7,17 (3H, m, Ar-H), 7,29 (1H, s, =CH), to 7.77 (1H, d, -NH), 7,79-7,81 (2H, d, Ar-H), a 9.60 (1H, s, NH). MS m/z: 441,8 (M++1).
1121H NMR (DMCO-d6) δ (ppm): 0,52 (2H, m, -CH2), of 0.64 to 0.65 (2H, m, -CH2), 2,73 is 2.75 (1H, m, -CH), 4,88 (2H, s, -NH2), 6,56 return of 6.58 (1H, m, Ar-H), 6.73 x to 6.75 (1H, d, Ar-H), 6,92-6,94 (1H, m, Ar-H),? 7.04 baby mortality-7,06 (2H, m, Ar-H), 7,09-to 7.15 (2H, m, Ar-H), 7,32-to 7.35 (1H, t, Ar-H), 7,41 was 7.45 (1H, t, Ar-H), to 7.50 (1H, s, =CH), 7,55-EUR 7.57 (1H, d, Ar-H), to 7.77-7,79 (2H, d, Ar-H)

7,93-7,94 (1H, d, -NH), 9,58 (1H, s, -NH). MS m/z: 431,8 (M++1).
1131H NMR (DMCO-d6) δ (ppm): 0,53 is 0.55 (2H, m, -CH2), of 0.66 and 0.68 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), 4,89 (2H, s, -NH2), to 6.58 (1H, m, Ar-H), 6,76 (1H, d, Ar-H), 6,94-of 6.96 (2H, d, Ar-H),? 7.04 baby mortality-7,07 (1H, m, Ar-H), 7,13 (1H, d, Ar-H), 7.24 to 7,27 (3H, m, Ar-H and =CH), 7,60-to 7.61 (1H, d, Ar-H), 7,84-7,86 (2H, d, Ar-H), 8,09-8,10 (1H, d, -NH), for 9.64 (1H, s, -NH). MS m/z: 403,8 (M++1).
1141H NMR (DMCO-d6) δ (ppm): about 0.53-0.54 (2H, m, -CH2), 0,65-0,66 (2H, m, -CH2), a 2.75 (1H, m, -CH), 4,88 (2H, s, -NH2), 6,56 (1H, m, Ar-H), 6,74-6,76 (1H, d, Ar-H), to 6.95 (1H, m, Ar-H), 7,10 for 7.12 (4H, m, Ar-H), 7,21 (1H, s, Ar-H), 7,34 (1H, s, =CH), 7,41-7,44 (2H, m, Ar-H), 7,79-7,81 (2H, d, Ar-H), 8,03-

of 8.04 (1H, d, NH), a 9.60 (1H, s, NH). MS m/z: 431,8 (M++1).
1151H NMR (DMCO-d6) δ (ppm): 0,53 (2H, m, -CH2), of 0.64 to 0.65 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), 4,88 (2H, s, -NH2), 6,57 return of 6.58 (1H, m, Ar-H), to 6.75 (1H, d, Ar-H), 6,93-6,97 (2H, m, Ar-H), 7,11-7,13 (3H, m, Ar-H), 7.23 percent-of 7.25 (1H, m, Ar-H), 7,41 was 7.45 (3H, m, Ar-H and =CH), 7,80-of 7.82 (2H, m, Ar-H), 7,88-7,89 (1H, d, NH), 9,59 (1H, s, -NH). MS m/z: 433,8 (M++1).
1161H NMR (DMCO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), of 3.78 (3H, s, -OCH3), 4,88 (2H, s, -NH2), 6,56 (1H, m, Ar-H), of 6.71-6,76 (1H, m, Ar-H), 6,93-to 6.95 (3H, m, Ar-H), 7,06-7,14 (5H, m, Ar-H), 7.23 percent (1H, s, =CH), to 7.77-7,79 (3H, m, Ar-H and-NH), 9,58 (1H, s, -NH). MS m/z:

427,9 (M++1).
1171/sup> H NMR (DMCO-d6) δ (ppm): 0,523-0,528 (2H, m, -CH2), of 0.64 to 0.65 (2H, m, -CH2), a 2.75 (1H, m, -CH), 4,88 (2H, s, -NH2), 6,56 (1H, t, Ar-H), to 6.75 (1H, d, Ar-H), to 6.95 (1H, d, Ar-H), 7,05 for 7.12 (3H, m, Ar-H), 7,19-7,24 (1+1H, m, Ar-H and =CH), EUR 7.57 (2H, t, Ar-H), 7,79-7,88 (2+1H, m, Ar-H and-NH), 9,59 (1H, , -NH). MS m/z: 449,8 (M++1).
1181H NMR (DMCO-d6) δ (ppm): to 3.64 (3H, s, -OCH3), with 3.79 (3H, s, -OCH3), 4,89 (2H, s, -NH2), 6,59 (1H, t, Ar-H), 6.75 in-6,83 (3H, m, Ar-H), 6,94-7,01 (2H, m, Ar-H), 7,07-7,14 (2H, m, Ar-H), from 7.24 (2H, d, Ar-H), 7,33 (2H, t, Ar-H), 7,39 (1 H, s, =CH), 7,69 (2H, d, Ar-H), 7,83 (2H, d, Ar-H), being 9.61 (1H, s, -NH), 9,80 (1H, s, -NH). MS m/z: 493,8 (M++1).

1191H NMR (DMCO-d6) δ (ppm): 0,514-0,518 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,761-2,769 (1H, m, -CH), 3,63 (3H, s, -OCH3), of 3.77 (3H, s, -OCH3), to 4.87 (2H, s, -NH2), to 6.57 (1H, t, Ar-H), 6,67-6,76 (3H, m, Ar-H), 6,93-6,97 (2H, m, Ar-H), 7,11-to 7.15 (3H, m, Ar-H), 7,29 (1H, s, =CH), 7,62-7,63 (1H, t, NH), 7,78-7,80 (2H, d, Ar-H), 9,58 (1H, s, -NH). MS m/z: 457,9 (M++1).
1201H NMR (DMCO-d6) δ (ppm): 0,48 (2H, m, -CH2), and 0.61 to 0.63 (2H, m, -CH2), 2,70-a 2.71 (1H, m, -CH), to 3.67 (3H, s, -OCH3), with 3.79 (3H, s, -OCH3), to 4.87 (2H, s, -NH2), 6,51 (1H, is, Ar-H), to 6.57 (1H, t, Ar-H), of 6.65 (1H, s, Ar-H), 6,76 (1H, d, Ar-H), PC 6.82 (1H, d, Ar-H), to 6.95 (1H, t, Ar-H), 7,12-7,13 (3H, m, Ar-H), 7,32 (1H, s, =CH), the 7.43 (1H, t, NH), to 7.77 (2H, d, Ar(H)to 9.57 (1H, s, -NH). MS m/z:

457,9 (M++1).
1211H NMR (DMCO-d6) δ (ppm): 0,53 (2H, m, -CH2), of 0.65 (2H, m, -CH2), 2,80 (1H, m, -CH), 4,84 (2H, s, -NH2), 6,54-6,56 (1H, t, Ar-H), 6,72-of 6.73 (1H, d, Ar-H), 6,93-6,97 (1H, t, Ar-H), 7,07 for 7.12 (3H, m, Ar-H), 7,25-7,27 (2H, m, Ar-H), 7,42 (1H, s, =CH), 7,53 (1H, m, Ar-H), 7,71-7,76 (3H, m, Ar-H), to $ 7.91-to 7.93 (4H, d, Ar-H and-NH), 9,52 (1H, s, -NH). MS m/z: 447,9 (M++1).
1221H NMR (DMCO-d6) δ (ppm): 3,71 (3H, s, -OCH3), 3,81 (3H, s, -OCH3), 4,89 (2H, s, -NH2), 6,52-6,60 (2H, d, Ar-H), 6,69 (1H, s, Ar-H), 6.75 in-6,77 (1H, d, Ar-H), 6.90 to-6,92 (1H, d, Ar-H), 6,94-6,98 (1H, t, Ar-H), 7,05-was 7.08 (1H, t, Ar-H), 7,12-7,14 (1H, d, Ar-H), 7.23 percent-of 7.24 (2H, d, Ar-H), 7,29-7,33 (2H, t, Ar-H), the 7.43 (1H, s, =CH), 7,66-to 7.68 (2H, d, Ar-H)

7,80-of 7.82 (2H, d, Ar-H), a 9.60 (1H, s, -NH), 9,67 (1H, s, -NH). MS m/z: 493,8 ((M++1).
123 1H NMR (DMCO-d6) δ (ppm): 0,53 (2H, m, -CH2), of 0.64 to 0.65 (2H, m, -CH2), was 2.76-2,77 (1H, m, -CH), to 5.21 (2H, s, -NH2), of 6.31-6,34 (1H, t, Ar-H), of 6.49-of 6.52 (1H, d, Ar-H),? 7.04 baby mortality-7,05 (1H, t, Ar-H), 7,09-7,11 (2H, d, Ar-H), 7,19-7,24 (4H, m, Ar-H), 7,32 (1H, s, =CH), 7,78-7,80 (2H, d, Ar-H), of 7.90-to $ 7.91 (1H, d, Ar-H), of 9.51 (1H, s, -NH). MS m/z: 433,8 (M++1).
1241H NMR (DMCO-d6) δ (ppm): 0,47-0,49 (2H, m, -CH2), and 0.61 to 0.63 (2H, m, -CH2), 2,75 was 2.76 (1H, s, -CH), 4,84 (2H, s, -NH2), 6,76 (1H, t, Ar-H), 6.89 in (1H, d, Ar-H), of 6.99 (3H, m, Ar-H), 7,08-7,10 (2H, d, Ar-H), 7,20-7,22 (2H, d, Ar-H), 7,32-7,33 (1H, d, Ar-H), 7,40-7,44 (2H, t, Ar-H and =CH), 7,62-to 7.64 (1H, d, Ar-H), 7,70-

7,72 (2H, d, Ar-H), of 9.55 (1H, s, -NH), 11,38 (1H, s, -NH). MS m/z: 436,9 (M++1).
1251H NMR (DMCO-d6) δ (ppm): 0,54 is 0.55 (2H, m, -CH2), 0,66-of 0.67 (2H, m, -CH2), 2,78-and 2.79 (1H, m, -CH), a 4.86 (2H, s, -NH2), 6,56-to 6.57 (1H, t, Ar-H), 6.73 x to 6.75 (1H, d, Ar-H), to 6.95 (1H, t, Ar-H), 7,09-7,11 (1H, d, Ar-H), 7,17-7,19 (2H, d, Ar-H), 7.24 to 7,26 (2H, d, Ar-H), 7,31 (1H, s, =CH), 7,38-7,40 (1H, d, Ar-H), 7,46 is 7.50 (2H, t, Ar-H), 7,70-7,74 (4H, m, Ar-H), 7,78-7,80 (2H, d, Ar-H), 7,99-of 8.00 (1H, d, -NH), 9,59 (1H, s, -NH). MS m/z: 473,9 (M++1).
126 1H NMR (DMCO-d6) δ (ppm): 0,53 (2H, m, -CH2), of 0.64 to 0.65 (2H, m, -CH2), was 2.76-2,77 (1H, m, -CH), 6,79-for 6.81 (1H, t, Ar-H), 6.89 in-6,91 (1H, d, Ar-H), 7,00? 7.04 baby mortality (1H, t, Ar-H), 7,11-7,13 (2H, d, Ar-H), 7,19-7,24 (4H,

m, Ar-H), 7,32 (1H, s, =CH), 7,58-of 7.60 (1H, d, Ar-H), to 7.77-7,79 (2H, d, Ar-H), to 7.93-7,94 (1H, d, Ar-H), 9,49 (2H, s, -NH and-OH). MS m/z: 416,8 (M++1).
1271H NMR (DMCO-d6) δ (ppm): 0,54 (2H, m, -CH2), 0,66-of 0.67 (2H, m, -CH2), 2.77-to 2,78 (1H, m, -CH), is 4.93 (2H, s, -NH2), 6,56-6,59 (1H, t, Ar-H), 6,74-6,76 (1H, d, Ar-H), 6,93-6,97 (1H, t, Ar-H), 7,09-7,11 (3H, m, Ar-H), 7,40 was 7.45 (2H, m, Ar-H and =CH), to 7.61-7,63 (1H, d, Ar-H), 7,79-7,81 (2H, d, Ar-H), 8,12-8,13 (1H, d, Ar-H), of 8.27 (1H, s, Ar-H), 8,54-8,55 (1H, d, -NH), to 9.57 (1H, s, -NH). MS m/z: 398,9 (M++1).
1281H NMR (DMCO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), and 0.62-0,66 (2H, m, -CH2), 2,73-2,77 (1H, m, -CH), 4,88 (2H, s, -NH2), 6,55 return of 6.58 (1H, t, Ar-H), 6.75 in-6,77 (3H, d, Ar-H), 6,94-of 6.96 (3H, d, Ar-H), 7,11-7,13

(3H, t, Ar-H), 7,19 (1H, s, =CH), to 7.67-to 7.68 (1H, d, Ar-H), to 7.77-7,79 (2H, d, Ar-H), to 9.57 (2H, s, -NH and OH). MS m/z: 413,9 (M+ +1).
1291H NMR (DMCO-d6) δ (ppm): 0,52-of 0.54 (2H, m, -CH2), 0,65 is 0.67 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), 4,89 (2H, s, -NH), to 6.57 (1H, t, Ar-H), 6,74-6,76 (1H, m, Ar-H), to 6.95 (1H, t, Ar-H), 7,11-to 7.18 (5H, m, Ar-H), 7,51 (1H, m, Ar-H), to 7.64 (1H, s, =CH), 7,82-to 7.84 (2H, d, Ar-H), 8,24 is 8.25 (1H, d, -NH), 9,62 (1H, s, -NH). MS m/z: 433,8 (M++1).
1301H NMR (DMCO-d6) δ (ppm): about 0.53-0.54 (2H, m, -CH2), 0,63-0,66 (2H, m, -CH2), a 2.75-2,77 (1H, m, -CH), 4,89 (2H, s, -NH2), 6,55 return of 6.58 (1H, t, Ar-H), 6,74-6,76 (1H, d, Ar-H), 6,93-6,97 (1H, t, Ar-H), 7.03 is-7,06 (1H, t, Ar-H), 7,11-7,17 (3H, m, Ar-H), 7,28-7,31 (2H, t,

Ar-H), 7,54 (1H, s, =CH), 7,82-to 7.84 (2H, d, Ar-H), 8,08-of 8.09 (1H, d, -NH), being 9.61 (1H, s, -NH). MS m/z: 433,8 (M++1).
1311H NMR (DMCO-d6) δ (ppm): 1,11 (6H, s, -CH3), 3,96-was 4.02 (1H, m, -CH), 4,88 (2H, s, -NH2), 6,55 return of 6.58 (1H, t, Ar-H), 6,74-6,76 (1H, d, Ar-H), 6,93-6,97 (1H, d, Ar-H), 7,11-7,13 (3H, d, Ar-H), 7.18 in-7,26 (4H, m, Ar-H), 7,33 (1H, s, =CH), 7,63-the 7.65 (1H, d, Ar-H), 7,79-7,81 (2H, d, Ar-H), 9,58 (1H, s, -NH). MS m/z: 417,9 (M++1).
132 1H NMR (DMCO-d6) δ (ppm): about 0.53-0.54 (2H, m, -CH2), 0,65-0,66 (2H, m, -CH2), was 2.76-2,77 (1H, m, -CH), 4,08 (2H, s, -NH2), 6,83-6,85 (1H, d, Ar-H), 7,11-7,13 (2H, d, Ar-H), 7,21-of 7.25 (5H, m, Ar-H), 7,31-7,33 (2H, m, Ar-H), was 7.36-7,40 (2H, m, Ar-H), of 7.48 (1H, s, =CH), 7,52-rate of 7.54 (2H, d, Ar-H), 7,82-to 7.84 (2H, d, Ar-H), 7,92-to 7.93

(1H, d, Ar-H), 9,68 (1H, s, -NH). MS m/z: 491,8 (M++1).
1331H NMR (DMCO-d6) δ (ppm): 0,50-of 0.51 (2H, m, -CH2), 0,63-0,66 (2H, m, -CH2), of 2.08 (3H, s, -CH3), 2,73 was 2.76 (1H, s, -CH), to 4.87 (2H, s, -NH2), 6,55 return of 6.58 (1H, t, Ar-H), 6.73 x to 6.75 (1H, d, Ar-H), 6,93-of 6.96 (1H, t, Ar-H), 7,01-7,03 (3H, m, Ar-H), 7,09-7,11 (1H, d, Ar-H), 7,21-7,24 (1H, m, Ar-H), 7,30 (2H, m, Ar-H), 7,41 (1H, s, =CH), 7,70-7,76 (3H, m, Ar-H and NH), of 9.55 (1H, s, -NH). MS m/z: 411,9 ((M++1).
1341H NMR (DMCO-d6) δ (ppm): of 2.68 (3H, s, -CH3), to 4.87 (2H, s, -NH2), 6,55-6,59 (1H, t, Ar-H), 6,74-6,76 (1H, d, Ar-H), 6,93-6,97 (1H, t, Ar-H), 7,08 for 7.12 (3H, d, Ar-H), 7,22-7,28 (4H, m, Ar-H and =CH), 7,49-7,51 (2H, d, Ar-H), 7,78-7,80 (2H, d, Ar-H), 9,58 (1H, s, -NH). MS m/z: 390,2 (M++1).

135 1H NMR (DMCO-d6) δ (ppm): 0,42 (2H, m, -CH2), 0,66-of 0.67 (2H, m, -CH2), 2,80-of 2.81 (1H, m, -CH), to 4.92 (2H, s, -NH2), 6,59-6,62 (1H, t, Ar-H), 6,78-to 6.80 (1H, d, Ar-H), of 6.96-7,00 (1H, t, Ar-H), 7,12 (1H, s, =CH), 7,16-to 7.18 (1H, d, Ar-H), 7,25-7,29 (2H, t, Ar-H), to 7.59-to 7.61 (4H, d, Ar-H), 7,97-7,99,(2H, d, Ar(H)8,59 at 8.60 (1H, d, Ar-H), RS 9.69 (1H, s, -NH). MS m/z: 4l6,2 (M++1).
1361H NMR (DMCO-d6) δ (ppm): to 3.58 (8H, s, -CH2), 4,88 (2H, s, -NH2), to 6.58 (1H, t, Ar-H), 6.75 in-6,77 (1H, d, Ar-H), for 6.81 (1H, d, Ar-H):to 6.95 (1H, t, Ar-H), 7,11 (1H, d, Ar-H), 7,20-7,22 (3H, m, Ar-H), 7,24 (1H, s, =CH), 7,30-7,34 (2H, m, Ar-H), 7,82-to 7.84 (2H, d, Ar-H), being 9.61 (1H, s, -NH). MS m/z: 446,2 (M++1).

1371H NMR (DMCO-d6) δ (ppm): to 0.67 (2H, m, -CH2), 0,82-0,85 (2H, m, -CH2), 2,73-2,77 (1H, m, -CH), the 4.90 (2H, s, -NH2), 6,59-6,62 (1H, t, Ar-H), 6,78-to 6.80 (1H, d, Ar-H), of 6.96-7,00 (1H, t, Ar-H), 7,07-to 7.09 (4H, d, Ar-H), 7,15-7,17 (1H, d, Ar-H), 7,26 (1H, s, =CH), 7,28-7,29 (2H, d, Ar-H), 7,86-7,87 (1H, d, Ar-H), 7,98-of 8.00 (2H, d, Ar-H), 9,73 (1H, s, -NH). MS m/z: 416,0 (M++1).
1381H NMR (DMCO-d6) δ (ppm): 0,49-of 0.53 (2H, m, -CH2), and 0.62-0,66 (2H, m, -CH2), 2,74-2,78 (1H, m, -CH), to 4.87 (2H, s, -NH2), 6,57-6,60 (1H, t, Ar-H), 6,76-6,7 (1H, d, Ar-H), 6,95-6,98 (1H, t, Ar-H), 7,01-7,02 (1H, d, Ar-H), 7,10 for 7.12 (1H, d, Ar-H), 7,13-7,22 (4H, m, Ar-H), 7,27-7,30 (1H, t, Ar-H), 7,35 (1H, s, =CH), 7,75-7,81 (2H, d, Ar-H), 7,84-7,86 (1H, d, Ar-H), 9,58 (1H, s, -NH).

MS m/z: 416,0 (M++1).
1391H NMR (DMCO-d6) δ (ppm): 4,89 (2H, s, -NH2), 6,55-to 6.57 (1H, t, Ar-H), 6,60-6,62 (1H, d, Ar-H), 6,78-to 6.80 (1H, d, Ar-H), of 6.99 (2H, t, Ar-H), 7,12-7,14 (2H, m, Ar-H), 7,20-7,37 (6H, m, Ar-H), 7,46 (1H, s, =CH), 7,69-7,71 (2H, d, Ar-H), 7,83-a 7.85 (2H, d, Ar-H), 9,62 (1H, s, -NH), 10,07 (1H, s, -NH). MS m/z: 452,0 (M++1).
1401H NMR (DMCO-d6) δ (ppm): to 4.87 (2H, s, -NH2), to 6.57 (1H, t, Ar-H), 6,74-6,76 (1H, d, Ar-H), to 6.95 (1H, t, Ar-H), 7,10 for 7.12 (4H, m, Ar-H), 7,22-7,24 (4H, m, Ar-H and NH2), 7,38 (1H, s, -NH2), to 7.50 (1H, s, =CH), 7,79-7,81 (2H, d, Ar-H), 9,58 (1H, s, -NH). MS m/z: 376,0 (M++1).
1411H NMR (DMCO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), of 0.64 to 0.65 (2H, m, -CH2), to 1.59 (2H, m, -CH2), 1,72 (4H, m, -CH2),

1,92-of 1.93 (2H, m, -CH2), 2,74 was 2.76 (1H, m, -CH), a 4.83-4,88 (3H, t, -NH2and-CH), to 6.57 (1H, t, Ar-H), 6,74-6,76 (1H, d, Ar-H), 6,88-of 6.90 (2H, d, Ar-H), to 6.95 (1H, t, Ar-H),? 7.04 baby mortality-7,06 (2H, d, Ar-H), 7,12-7,14 (3H, m, Ar-H), 7,22 (1H, s, =CH), 7,78-7,80 (3H, t, Ar-H and-NH), 9,58 (1H, s, -NH). MS m/z: 482,1 (M++1).
1421H NMR (DMCO-d6) δ (ppm): 0,32-0,33 (2H, d, -CH2), 0,51-0,52 (2H, d, -CH2), 0,57 is 0.59 (2H, d, -CH2), 0,63-of 0.65 (2H, d, -CH2), 1,22-1,25 (1H, m, -CH), 2,75-2,78 (1H, m, -CH), 3,82-a 3.83 (2H, d, -CH2), 4,88 (2H, s, -NH2), to 6.57 (1H, t, Ar-H), 6,74-6,76 (1H, d, Ar-H), 6,91-to 6.95 (3H, m, Ar-H),? 7.04 baby mortality-7,06 (2H, d, Ar-H), 7,11-7,14 (3H, m, Ar-H), 7.23 percent (1H, s, =CH), 7,74-7,79, (3H, m, Ar-H and-NH), 9,58 (1H, s, -NH). MS m/z: 468,1 (M++1).

1431H NMR (DMCO-d6) δ (ppm): 4,36-4,37 (2H, d, -CH2), 4,88 (2H, s, -NH2), 6,55-6,59 (1H, t, Ar-H), 6,74-6,76 (1H, d, Ar-H), 6,93-6,97 (1H, t, Ar-H), 7,11-7,13 (3H, d, Ar-H), 7.24 to to 7.35 (9H, m, Ar-H), 7,53 (1H, s, =CH), 7,79-7,81 (2H, d, Ar-H), 8.17-a to 8.20 (1H, t, NH), 9,58 (1H, s, -NH). MS m/z: 466,0 (M++1).

Example 144:

Synthesis of N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-enyl)benzamide

Stage-I

Obtaining methyl-3-(4-(2-(4-forfinal)-3-hydroxyprop-1-EN-1-yl)phenyl)benzoate

To with whom spencie 2-(4-forfinal)-3-(4-(methoxycarbonyl)phenyl)acrylic acid (3 g, 10 mmol) (obtained in accordance with the procedure described in Example 99, stage-I) in THF (30 ml) with constant stirring add triethylamine (1.5 ml, 12 mmol) at 5°C. To this solution is added dropwise methylchloroform (0,86 ml, 12 mmol) at 5°C and stirred for 30 minutes at the same temperature. To this reaction mixture in one step add borohydride sodium (1.5 g, 40 mmol) and dropwise methanol (20 ml)and the reaction mixture is stirred for 1 hour at 30°C. after completion of the reaction, the reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (100 ml) and saturated salt solution (100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving the crude compound. The crude product is purified column chromatography using 10% ethyl acetate/hexane as eluent, to obtain a pure compound in a solid white color (1.4 g, yield 51%).

Stage-II

Obtaining methyl-4-(2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzoate

Chlorproma pyridinium (PCC) (1.12 g, 5.2 mmol) dissolved in dichloromethane (20 ml). With constant stirring, added dropwise a solution of methyl-3-(4-(2-(4-forfinal)-3-hydroxyprop-1-EN-1-yl)phenyl)benzoate (to 1.14 g, 4 mmol) in dichloromethane (4 ml) and the reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is diluted with diet the gross ether (100 ml) and filtered through Celite; the filtrate was washed with saturated aqueous NaHCO3(2×100 ml) and water (100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, getting clean is mentioned in the title compound in the form of a solid white color (of 0.58 g, yield 53%).

Stage-III

Obtaining methyl-4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)benzoate

A mixture of methyl-4-(2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzoate (0,568 g, 2 mmol) and cyclopropylamine (0.17 g, 3 mmol) is stirred with MeOH (50 ml) for 3 hours. The reaction mixture was added NaBH4(0,114 g, 3 mmol) and stirred for 30 minutes. Then the reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (3×50 ml) and saturated salt solution (100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving net specified in the title compound in the form of sticky compounds pale yellow (0.51 g, yield 76%).

Stage-IV

Getting 4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)benzoic acid

To a solution of methyl-4-((4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzoate (0.5 g, 1.5 mmol) in methanol (10 ml) add a solution of NaOH (0,088 g, 3.8 mmol) in water (0.5 ml). The reaction mixture is refluxed for 1 hour at 70°C. the Solution is tel removed by evaporation, and the residue poured into ice water. The aqueous layer was acidified to pH 3 with citric acid, the precipitated solid is filtered off and dried in vacuum, obtaining a solid pale yellow color (0.4 g, yield 77%).

Stage-V

Obtaining N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-enyl)benzamide

To a solution of 4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)benzoic acid (0.4 g, 1.3 mmol) in DMF (5 ml) is added EDCI (0,49 g, 2.6 mmol), HOBt (0,175 g, 1.3 mmol) and TEA (0.54 ml, 3.9 mmol), then added o-phenylenediamine (0,280 g, 2.6 mmol). The reaction mixture is stirred for 2 hours at room temperature, after which the residue is poured into water and extracted with ethyl acetate (300 ml) and washed with water (3×50 ml) and saturated salt solution (100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving the crude compound. The compound obtained purified flash chromatography using 15% ethyl acetate/hexane as eluent, the pure fraction is evaporated, getting mentioned in the title compound (0,040 g, yield 9%).1H NMR (DMSO-d6) δ (ppm): 0.24 to 0.25 in (2H, m, -CH2), from 0.37 to 0.39 (2H, m, -CH2), 2,13-and 2.14 (1H, m, -CH), of 3.57 (2H, s, -CH2), a 4.86 (2H, s, -NH2), 6,55-6,59 (1H, t, Ar-H), 6,70 (1H, s, =CH), 6,74-6,76 (1H, d, Ar-H), 6,93-to 6.95 (1H, t, Ar-H), 7,02? 7.04 baby mortality (2H, m, Ar-H), 7,10 for 7.12 (1H, d, Ar-H), 7,16-7,26 (4H, m, Ar-H), 7,74-7,76 (2H, d, Ar-H)9,52 (1H, s, -NH). MC m/z: 402,2(M ++1).

Example 145:

Synthesis of 4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)-N-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)benzyl)benzamide

Stage-I

Obtaining methyl-3(4-((4-((1E)-3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamido)methyl)phenyl)acrylate

To a suspension of 4-((1E)-3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzoic acid (0.3 g, 0.9 mmol, obtained in accordance with the procedure described in Example 99, phase-III) in DMF (5 ml) is added EDCI (0.35 g, 1.8 mmol), HOBt (0.12 g, 0.9 mmol), methyl-4-aminomethylated (0,237 g, 1.1 mmol), then add the triethylamine (0.4 ml, 3 mmol). The reaction mixture is stirred for 8 hours, after which the mixture was poured into cold water (100 ml), the obtained white precipitate is filtered off, washed with water (1×150 ml), dried in vacuum, obtaining mentioned in the title compound in the form of a solid yellow (0.4 g, yield 87%).

Stage-II

Getting 4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)-N-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)benzyl)benzamide

Hydroxylamine hydrochloride (0.5 g, 7.2 mmol) in methanol (2 ml) is mixed with KOH (0.4 g, 7.2 mmol) in methanol (2 ml) at 0°C and 2 minutes, treated with ultrasound, the obtained white precipitate is filtrowa. The filtrate is added to methyl 3-(4-((4-(1E)-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)benzamido)methyl)phenyl)acrylate (0.20 g, 0.4 mmol) in DCM (1.5 ml) and the mixture is stirred for 30 minutes at room temperature. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml). Layers of ethyl acetate, washed with water (100 ml), dried over anhydrous Na2SO4and concentrate, receiving the crude compound which was triturated with DCM (15 ml)to give a solid, which is filtered off and washed with DCM (5 ml), receiving specified in the header connection (0,050 g, yield 25%).1H NMR (DMSO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), 4,43-of 4.44 (2H, d, -CH2), 6,39-to 6.43 (1H, d, =CH), 7,05-7,07 (2H, d, Ar-H), 7,16-7,22 (4H, m, Ar-H), 7,29-to 7.32 (3H, m, Ar-H and =CH), 7,40-7,44 (1H, d, =CH), 7,49-7,51 (2H, d, Ar-H), 7.68 per-of 7.70 (2H, d, Ar-H), 7,89-of 7.90 (1H, d, -NH), 9,00 (2H, m, NH and OH), of 10.73 (1H, s, NH). MC m/z: 498,1 (M+-1).

The following compounds were obtained in accordance with the methodology described in Example 145.

Example No.StructureAnalytical data
1461H NMR (DMCO-d6) δ (ppm): 0,51 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,74 1H, m, -CH), 4,42 (2H, s, CH2), to 6.43 (1H, d, =CH), 7,05 (2H, d, Ar-H), 7,14 (2H, d, Ar-H), 7,24 (1H, s, =CH), 7,30 (2H, d, Ar-H), was 7.36 (3H, m, Ar-H), 7,38 (1H, d, =CH), 7,49 (2H, d, Ar-H), 7,66 (2H, d, Ar-H), 7,87 (1H, d, -NH), 8,99 (2H, m, NH and OH), is 10.75 (1H, s, NH). MS m/z: 480,1 (M++1).
1471H NMR (DMCO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), of 0.64 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), of 4.44 (2H, s, CH2), equal to 6.05 (2H, s, -CH2), 6,46 (1H, d, =CH),

6,61 of 6.66 (2H, m, Ar-H), 6,91-6,93 (1H, d, Ar-H), 7,14-7,16 (2H, d, Ar-H), 7,27 (1H, s, =CH), 7,34 and 7.36 (2H, d, Ar-H), 7,43-7,46 (1H, d, =CH), 7,55-7,56 (2H, d, Ar-H), 7.68 per-of 7.70 (2H, d, Ar-H), 7,80 (1H, s, NH), 9,04 (2H, t, NH and OH), is 10.75 (1H, s, NH). MS m/z: 525,8 (M++1).

Example 148:

Synthesis 4-3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide

Stage-I

Obtaining 4-((4-3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)benzamido)methyl)benzoic acid

To a solution of methyl ester of 3-(4-((2-(4-were)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)phenyl)benzoic acid (0.26 g, 0.5 mmol, obtained by analogy with the method described in Example 145, phase-II with suitable reactive substances) is methanol (10 ml) add a solution of NaOH (0.06 g, 1.6 mmol) in water (0.5 ml). The reaction mixture is stirred for 3 hours at 70°C. the Solvent is completely removed by evaporation, diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The aqueous layer was acidified to pH 3 with diluted aqueous HCl (1:1) and left to stand for 30 minutes at 4°C, the precipitated solid is filtered off and dried in vacuum, obtaining a solid yellow (0,22 g, yield 88%).

Stage-II

Obtaining 4-3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide

To a suspension 4-3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-enyl)benzoic acid (0,22 g, 0.5 mmol) in DMF (5 ml) is added EDCI (0.4 g, 0.9 mmol), HOBt (0.06 g, 0.5 mmol), hydroxylamine hydrochloride (0.05 g, 0.7 mmol), and then add triethylamine (0.25 ml, 1.4 mmol). The reaction mixture is stirred for 1 hour, after which the mixture was added to cold water (20 ml). Upon standing at room temperature for 10 minutes, a precipitate, which is filtered off, washed (20 ml) with water and dried in vacuum, obtaining mentioned in the title compound (0.14 g, yield 61%).1H NMR (DMSO-d6) δ (ppm): 0,51 (2H, m, -CH2), and 0.62-of 0.64 (2H, m, -CH2), 2,32 (3H, s, -CH3), 2,74 is 2.75 (1H, m, -CH), of 4.45 (2H, d, -CH2), 7,02 (2H, s, Ar-H), 7,06 (2H, d, Ar-H), 7,18 (2H, d, Ar-H), 7,22 (1H, s, =CH), 7,33 (2H, d, Ar-H), to 7.67-to 7.77 (4H, m, Ar-H), 7,78 (1H, d, NH), of 9.02 (2H, m, NH and OH), 11,17 (1H, s, NH). MC m/z:470,4 (M ++1).

The following compounds were obtained in accordance with the methodology described in Example 148.

Example No.StructureAnalytical data
1491H NMR (DMCO-d6) δ (ppm): 0,51 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), of 4.45 (2H, d, -CH2), 7,06 (2H, d, Ar-H), 7,14 (2H, d, Ar-H), 7,25 (1H, s, =CH), 7,32-7,37 (5H, m, Ar-H) 7,66-of 7.69 (4H, m, Ar-H), 7,88 (1H, d, NH), of 9.02 (2H, m, NH and OH), 11,17 (1H, s, NH). MS m/z: 456,2 (M++1).
1501H NMR (DMCO-d6) δ (ppm): 0,52 (2H, m, -CH2), of 0.64 to 0.65 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), of 4.45 (2H, d, -CH2), 7,08-7,22 (5H, m, Ar-H), 7,33 (2H, d, Ar-H and =CH), the 7.43 (2H, d, Ar-H)

to 7.67-of 7.70 (4H, m, Ar-H), of 8.06 (1H, d, NH), 9,04 (2H, 1, OH), 11,18 (1H, s, NH). MS m/z: 472,1 (M+-1).
151'H NMR (DMCO-d6) δ (ppm): 0,51-0,52 (2H, m, -CH2), 0,63-of 0.64 (2H, m, -CH2), 2,73-to 2.74 (1H, m, -CH), of 4.45(2H, d, -CH2), 7,02 (2H, d, Ar-H), 7,11-7,13 (1H, d, Ar-H), 7,32 (3H, m, Ar-H), 7,41 (1H, t, Ar-H), 7,47 (1H, s, =CH), 7,54 (1H, d, Ar-H), to 7.68 (4H, m, Ar-H), 7,92-to 7.93 (1H, d, NH), 9,03 (2H, m, OH), 11,17 (1H, s, NH). MS m/z: 488,0 (M+-1).
1521H NMR (DMCO-d6) δ (ppm): 0,52 (2H, m, -CH2), 0,63-of 0.64 (2H, m, -CH2), a 2.75 (1H, m, -CH), of 4.44 is 4.45 (2H, d, -CH2), 7,05 (2H, d, Ar-H), 7,17-to 7.18 (4H, d, Ar-H), 7,20-7,34 (3H, m, Ar-H and =CH), 7.68 per-7,89 (4H, m, Ar-H), 7,89 (1H, d, NH), 9,01 (2H, m, -NH and-OH), br11.01 (1H, s, -NH). MS m/z: 474,2 (M++1).

1531H NMR (DMCO-d6) δ (ppm): 0,52-of 0.53 (2H, m, -CH2), 0,63-of 0.65 (2H, m, -CH2), of 2.50 (1H, m, -CH), 4,45-to 4.46 (2H, d, -CH2), 7,07-7,10 (3H, m, Ar-H), 7,19 (1H, s, =CH), 7,32-to 7.35 (3H, m, Ar-H), 7,41-7,42 (2H, m, Ar-H), to 7.67-7,72 (4H, t, Ar-H), 8,10-to 8.20 (1H, d, -NH), 8,99 (1H, s, -OH), 9,05 (1H, t, NH), 11,16 (1H, s, -NH). MS m/z: 490,1 (M++1).
1541H NMR (DMCO-d6) δ (ppm): 0,50-of 0.51 (2H, m, -CH2), and 0.61-of 0.64 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), 3,76 (3H, s, -OCH3), 4,45-to 4.46 (2H, d, -CH2), 6,91-6,93 (2H, d, Ar-H),? 7.04 baby mortality-7,10 (4H, m, Ar-H), 7,21 (1H, s, =CH), 7,33-to 7.35 (2H, d, Ar-H), to 7.67-of 7.69 (2H, d, Ar-H), 7,73-7,74 (3H, d, -NH), 8,99-9,03 (2H, m, -NH and-OH), 11,16 (1H, s, -NH). MS m/z: 486,2 (M++1).

1551H NMR (DMCO-d6) δ (ppm): 0,56 is 0.59 (2H, m, -CH2), and 0.61-0,66 (2H, m, -CH2), 2,72 was 2.76 (1H, m, -CH), of 4.44-to 4.46 (2H, d, -CH2), 7,02? 7.04 baby mortality (2H, d, Ar-H), 7,15-7,24 (2H, m, Ar-H), 7,33-to 7.35 (2H, d, Ar-H), 7,54 (1H, s, =CH), 7,56 (1H, d, Ar-H), to 7.67-7,72 (4H, t, Ar-H), a 7.85-7,86 (1H, d, -NH), 9,03-9,05 (2H, m, -NH and-OH), 11,16 (1H, s, -NH). MS m/z: 508,1 (M++1).
1561H NMR (DMCO-d6) δ (ppm): 0,52-of 0.53 (2H, m, -CH2), 0,62 is 0.65 (2H, m, -CH2), 2,73-2,77 (1H, m, -CH), 4,45-to 4.46 (2H, d, -CH2), 6,95-6,99 (2H, t, Ar-H), 7,07-to 7.09 (2H, d, Ar-H), 7.18 in-7,22 (1H, t, Ar-H), 7,32 (1H, s, =CH), 7,34 (2H, m, Ar-H), 7,38-the 7.43 (1H, m, Ar-H), to 7.67-of 7.70 (4H, m, Ar-H), to 7.93-7,94 (1H, d, -NH), 8,99-9,01 (1H, t, NH), 9,03-9,04 (1H, s, -OH), 11,16 (1H, s, -NH). MS m/z: 474,2 (M++1).

1571H NMR (DMCO-d6) δ (ppm): 0,50-of 0.51 (2H, m, -CH2), and 0.62 to 0.63 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), 4,45-4,47 (2H, d, -CH2), 6,04 (2H, s, CH2), 6,57-6,59 (1H, d, Ar-H), to 6.67 (1H, s, Ar-H), 6.89 in-6,91 (1H, d, Ar-H), 7,11-7,13 (2H, d, Ar-H), 7,26 (1H, s, =CH), 7,33-to 7.35 (2H, d, Ar-H), to 7.67-7,71 (5H, m, Ar-H and-NH), 8,99-9,03 (2H, m, -NH and-OH), 11,16 (1H, s, -NH). MS m/z: 500,3 (M++1).
158 1H NMR (DMCO-d6) δ (ppm): about 0.53-0.54 (2H, m, -CH2), of 0.64 to 0.66 (2H, m, -CH2), 2,75 was 2.76 (1H, m, -CH), of 4.44-to 4.46 (2H, d, -CH2), 7,05-7,06 (2H, d, Ar-H), 7,32 (1H, s, =CH), 7,34-7,37 (4H, t, Ar-H), to 7.67-of 7.69 (3H, d, Ar-H), 7,71-7,73 (3H, d, Ar-H), 8,08-of 8.09 (1H, d, -NH), 8,99 (1H, s, -OH), 9,01-9,04 (1H, t, NH), of 11.15 (1H, s, -NH). MS m/z: 524,2 (M++1).

1591H NMR (DMCO-d6) δ (ppm): 0,52-of 0.53 (2H, m, -CH2), 0,62 is 0.65 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), 4,45-to 4.46 (2H, d, -CH2), to 6.95 (1H, M, Ar-H), 7,08-7,10 (2H, d, Ar-H), 7,24 (1H, t, Ar-H), 7,33-to 7.35 (2H, d, Ar-H), 7,39-the 7.43 (2H, d, =CH and Ar-H), to 7.67-7,73 (4H, m, Ar-H), 7,86-7,87 (1H, d, -NH), 8,99 (1H, s, -OH), 9,01-9,04 (1H, t, NH), 11,16 (1H, s, -NH). MS m/z: 492,2 (M++1).

Example 160:

Synthesis of 4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide

Stage-I

Obtaining methyl-6-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamido)hexanoate

To a suspension of 3-(4-2-(4-forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzoic acid (0.4 g, 1.2 mmol, obtained in accordance with the procedure described in Example 99, phase-III) in DMF (5 ml) is added EDCI (of 0.47 g, 2.4 mmol), HOBt (0.17 g, 1.2 mmol), methyl-6-aminocaproate (0.27 g, 1.4 mmol), after CEG is added triethylamine (0.5 to ml, 3.6 mmol). The reaction mixture is stirred for 8 hours, after which the mixture was added to cold water (50 ml). The aqueous layer was extracted with ethyl acetate (1×150 ml), washed with water (2×50 ml) and saturated salt solution (1×100 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, receiving the crude compound, which was washed with hexane (2×20 ml), getting mentioned in the title compound in the form of a solid white color (0.5 g, yield 89%).

Stage-II

Getting 4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide

Hydroxylamine hydrochloride (0.55 g, 8 mmol) in methanol (3 ml) is mixed with KOH (0.45 g, 8 mmol) in methanol (3 ml) at 0°C and 2 minutes, treated with ultrasound, the obtained white precipitate is filtered off. The filtrate is added to methyl-6-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)benzamide)hexanoate (0.2 g, 0.4 mmol) in DCM (1.5 ml) and the mixture stirred for 30 minutes at room temperature. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate layer washed with water (100 ml), dried over anhydrous Na2SO4and concentrate, getting mentioned in the title compound (0,040 g, yield 20%).1H NMR (DMSO-d6) δ (ppm): 0,52 (2H, m, -CH2), 0,63-of 0.64 (2H, m, -CH2), 1,23 - 1,25 (2H, m, -CH2 ), 1,44 of 1.50 (4H, m, -CH2), 1,90-of 1.94 (2H, m, -CH2), 2,74 is 2.75 (1H, m, -CH), 3,17-3,19 (2H, m, -CH2),? 7.04 baby mortality (2H, d, Ar-H), 7,16-7,22 (4H, m, Ar-H), 7,28 (1H, s, =CH), 7,63 (2H, d, Ar-H), 7,89 (1H, d, NH), at 8.36 (1H, t, NH), 8,66 (1H, s, -OH), 10,32 (1H, s, NH). MC m/z: 452,2 (M+-1).

The following compounds were obtained in accordance with the methodology described in Example 160.

Example No.StructureAnalytical data
1611H NMR (DMCO-d6) δ (ppm): 0,51 (2H, m, -CH2), 0,62 is 0.65 (2H, m, -CH2), 1,23-1,24 (2H, m, CH2), 1,44-1,49 (4H, m, CH2), 1,90-of 1.92 (2H, m, CH2), 2,74 is 2.75 (1H, m, -CH), 3,16-3,18 (2H, m, CH2), 7,03 (2H, d, Ar-H), 7,14 (2H, t, Ar-H), 7,24 (1H, s, =CH), 7,37 (3H, m, Ar-H), 7,60 (2H, s, Ar-H), 7,86 (1H, d, -NH), at 8.36 (1H, t, NH), 8,66 (1H, s, -OH), 10,32 (1H, s, -NH). MC m/z: 436,2 (M++1).
1621H NMR (DMCO-d6) δ (ppm): 0,49-of 0.50 (2H, m, -CH2), and 0.62-of 0.64 (2H, m, -CH2), 1,23-1,25 (2H, m, CH2), the 1.44 to 1.48 (4H, m, CH2), 1,90-of 1.92 (2H, m, CH2), 2,32 (3H, s, CH3), 2,74 is 2.75 (1H, m, -CH), 3,17-3,18 (2H, m, CH2), 7,01-7,06 (4H, m, Ar-H), 7,17-7,21 (3H, m, Ar-H and =CH), to 7.61

(2H, d, Ar-H), 7,76 (1H, d, NH), at 8.36 (1H, t, NH), 8,67 (1H, s, -OH), 10,34 (1H, s, NH). MS m/z: 450,3 (M++1).
1631H NMR (DMCO-d6) δ (ppm): 0,52 (2H, m, -CH2), of 0.64 (2H, m, -CH2), 1,22-1,24 (2H, m, CH2), was 1.43 to 1.48 (4H, m, CH2), 1,89-of 1.93 (2H, m, CH2), 2,74 is 2.75 (1H, m, -CH), 3,15-3,17 (2H, m, CH2), 7,05 (2H, d, Ar-H), 7,12-7,21 (2H, m, Ar-H), the 7.43 (1H, s, =CH), a 7.62 (2H, d, Ar-H), 7,76 (2H, m, Ar-H), 8,03 (1H, d, NH), scored 8.38 (1H, t, NH), 8,65 (1H, s, -OH), 10,32 (1H, s, NH). MS m/z: 453,9 (M++1).
1641H NMR (DMCO-d6) δ (ppm): 0,52 (2H, m, -CH2), 0,63-of 0.64 (2H, m, -CH2), 1,24-of 1.27 (2H, m, CH2), 1,48-of 1.62 (4H, m, CH2), 1,90-of 1.94 (2H, m, CH2), 2,74 is 2.75 (1H, m, -CH), 3,15-3,17 (2H, m, CH2), to 6.95 (2H, d, Ar-H), 7,05-to 7.09 (2H, m, Ar-H), 7,11 (1H, m, Ar-H), 7,26 (1H,

s, =CH), was 7.45 (1H, m, Ar-H), to 7.64 (2H, m, Ar-H), 7,98 (1H, d, -NH), scored 8.38 (1H, t, -NH), is 8.75 (1H, s, -OH), 10,35 (1H, s, -NH). MS m/z: 453,9 (M++1).

Example 165:

Synthesis of N-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)phenyl)-N'-hydroxyacetanilide

Stage-I

Obtaining 2-(4-am is nofeel)-N-cyclopropyl-3-(4-forfinal)acrylamide

To a solution of tert-butyl 4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenylcarbamate (0.8 g, 2 mmol, obtained by analogy with the method described in Example 1, stage II-III, applying appropriate reactive substances) in dichloromethane (10 ml) add triperoxonane acid (of 0.44 ml, 6 mmol). The reaction mixture is stirred for 2 hours, after which the DCM is evaporated and diluted with ethyl acetate (100 ml) and washed with 10% sodium bicarbonate solution (3×50 ml), water (3×50 ml). The organic layer is dried over anhydrous Na2SO4and evaporated, obtaining the crude compound indicated in the title (of 0.53 g, yield 90%).

Stage-II

Getting ethyl-8-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)-8-oxooctanoate

To a suspension of 2-(4-AMINOPHENYL)-N-cyclopropyl-3-(4-forfinal)acrylamide (of 0.53 g, 1.7 mmol) in DMF (6 ml) was added BOP-reagent (1.5 g, 3.4 mmol), HOBt (0.2 g, 1.7 mmol), etilsalat (0.34 g, 1.7 mmol), and then add triethylamine (0.7 ml, 5.1 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. Upon completion the reaction mixture was added to cold water (50 ml). The aqueous layer was extracted with ethyl acetate (1×150 ml), washed with water (2×50 ml) and saturated salt solution (1×100 ml). The organic layer is dried over anhydrous Na2SO4and to the center, receiving the crude compound (0.3 g, yield 35%).

Stage-III

Obtaining N-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)phenyl)-N'-hydroxyacetanilide

Hydroxylamine hydrochloride (0,78 g, and 11.2 mmol) in methanol (2 ml) is mixed with KOH (0,63 g, and 11.2 mmol) in methanol (2 ml) at 0°C and 2 minutes, treated with ultrasound, the obtained white precipitate is filtered off. The filtrate is added to ethyl-8-(4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)-8-oxooctanoate (0.3 g, of 0.62 mmol) in methanol (1.5 ml) and the mixture is stirred for 1.5 hours at room temperature. Then the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (1×200 ml). The ethyl acetate layer washed with water (100 ml), dried over anhydrous Na2SO4and concentrate to obtain the crude compound, which was purified flash chromatography using a 1.2% MeOH/DCM as eluent is evaporated pure faction, getting mentioned in the title compound (0,056 g, yield 20%).1H NMR (DMSO-d6) δ (ppm): 0,47-of 0.51 (2H, m, -CH2), 0,60-of 0.64 (2H, m, -CH2), 1,25-of 1.29 (4H, m, -CH2), 1,48-of 1.53 (2H, m, -CH2), and 1.54-of 1.59 (2H, m, -CH2), 1,92 is 1.96 (2H, t, -CH2), 2,29 of-2.32 (2H, t, -CH2), 2,73-to 2.74 (1H, m, -CH),? 7.04 baby mortality-7,06 (6H, m, Ar-H), 7,21 (1H, s, =CH), 7,58-of 7.60 (3H, m, Ar-H and NH), 8,66 (1H, s, -NH), becomes 9.97 (1H, s, -OH), 10,34 (1H, s, -NH). MC m/z: 468,3 (M++1).

Example 166:

Synthesis of N-(2-am is nofeel)-4-((4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzamide

Stage-I

Obtaining methyl-4-((4-(3-(cyclopropyl)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzoate

To a solution of 2-(4-AMINOPHENYL)-N-cyclopropyl-3-(4-forfinal)acrylamide (0.34 g, 1.15 mmol, obtained in accordance with the procedure described in Example 165, the stage-I) in dichloromethane (25 ml) under stirring at 37°C. add methyl-4-formylbenzoate (0,185 g, 1.15 mmol). After stirring for 5 minutes to the reaction mixture add triacetoxyborohydride sodium (0.39 g, of 1.85 mmol), and then add acetic acid (0.3 ml). The reaction mixture is stirred for 8 hours at room temperature. After that the reaction mixture is treated with a system of ethyl acetate:water (1:1, 100 ml) and extracted with ethyl acetate (3×50 ml). The organic layer was washed with saturated salt solution (100 ml) and dried over anhydrous sodium sulfate and evaporated, getting mentioned in the title compound (0,42 g, yield 80%)

Stage-II

Getting 4-((4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzoic acid

To a solution of methyl-4-((4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzoate (0,42 g, 0.9 mmol) in methanol (10 ml) add a solution of NaOH (0.075 g, 18 mmol) in water (0.5 ml). The reaction mixture Ki is Atat under reflux for 1 hour at 70°C. The solvent is removed by evaporation, and the residue was poured into ice-cold water. The aqueous layer was acidified with citric acid to pH 3 and allowed to stand at 4°C for 30 minutes, the precipitated solid is filtered off and dried in vacuum, obtaining a solid pale yellow color (0,22 g, 51%yield).

Stage-III

Obtaining N-(2-AMINOPHENYL)-4-((4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzamide

To a suspension of 4-((4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzoic acid (0,215 g, 0.5 mmol) in DMF (3 ml) is added CDCl (to 0.23 g, 1.1 mmol), HOBt (0.08 g, 0.55 mmol), o-phenylenediamine (0,086 g, 0.7 mmol), then added TEA (0.2 ml, 1.5 mmol). The reaction mixture is stirred for 4 hours, after which the mixture was added to cold water (100 ml) and incubated for 1 hour at 0°C. the Resulting solid pale yellow color is filtered and washed with ethyl acetate (15 ml), dried in vacuum, obtaining specified in the header connection (0,020 g, yield 8%).1H NMR (DMSO-d6) δ (ppm): 0,46 of 0.47 (2H, m, -CH2), 0,60-of 0.62 (2H, m, -CH2), 2,70-a 2.71 (1H, m, -CH), 4,36-4,37 (2H, d, -CH2), 4,88 (2H, s, -NH2), 6,55-of 6.61 (4H, m, Ar-H and-NH), 6,76-PC 6.82 (3H, m, Ar-H), 6,93-6,94 (1H, t, Ar-H), 6,98? 7.04 baby mortality (3H, m, Ar-H), 7,06-7,17 (3H, m, Ar-H), of 7.48-to 7.50 (3H, M, Ar-H and =CH), 7,93-of 7.95 (2H, d, Ar-H and-NH), being 9.61 (1H, s, -NH). MC m/z: 521,1 (M++1).

Anticancer experimental methods

Experimental drugs were subjected to screening against cancer activity in three cell lines using five concentrici for each connection. Cell line HCT 116 (rectum), NClH460 (easy) and U251 (glioma) were kept in DMEM containing 10% fetal cow serum. 96-well microtitre the plates were inoculable cells in 100 μl of the suspension (5×104cells/ml) for 24 hours at 37°C, 5% CO2, 95% air and 100% relative humidity. Separate tablets of these cell lines was also inoculable to determine the viability of the cells before adding the compounds (T0).

The addition of experimental drugs:

After 24-hour incubation of the investigated compounds were added in 96-well plates. Each tablet contains one of the above cell lines, and the following samples were prepared three times: five different dilutions (0,01, 0,1, 1, 10 and 100 μm) of the four studied compounds, the appropriate dilution of standard cytotoxic and growth medium (untreated) wells. Compounds were dissolved in DMSO to prepare a 20 mm initial solution on the day of add medication, and were prepared as serial dilutions in complete growth medium at 2× the fortress, so that 100 μl added to the wells, and gave final concentrations (0.01, 0.1 and 1, 10 and 100 μm) in the hole. In these ASCS is egomaniac as standard drugs used SAHA.

The change in the endpoint:

For measurements of T0after approximately 24 hours after seeding cells, the tablet T0added 20 μl of a solution of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazole (MTT), and incubated 3 hours at 37°C in an incubator with CO2. Tablet containing cells and test compounds were treated in a similar way within 48 hours after incubation. After 3 hours after adding MTT contents of the wells was aspirated carefully, after which dobelli 150 μl DMSO per well. The tablets were shaken to ensure dissolution of the crystals formazan in DMSO, and read the absorbance at 570 nm (A570).

Calculate GI50, TGI and LC50:

Percentage growth (PG) was calculated in relation to control and holes zero measurement (T0as follows:

PG=(A570test-A570T0)/(A570control-A570T0)×100

(if A570test>A570T0)

PG=(A570test-A570T0)/(A570T0)×100

(if A570test<A570T0).

The values of PG was represented on a graph against the concentration of the drug in order to calculate the following: GI50is the concentration required to reduce PG 50% vs. control; TGI is the concentration required to reduce PG 100% against control, and LC50is the concentration required to reduce PG 50% FR is in T 0. (Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. (J. Immunol. Methods. 1983,65 (1-2), 55 to 63); Anne Monkset al. "Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines" (JNCI, Vol.83,No.11,1991)).

Results growth inhibition of the synthesized compounds are given in Table 1.

Screening HDAC activity:

The study of inhibition discontinuties (HDAC) with the use of the substrate Boc-Lys (Ac)-AMC: inhibition of HDAC is involved in the modulation of transcription and induction of apoptosis or differentiation of cancer cells. Fluorimetric study provides a rapid method based on fluorescence, which eliminates radioactivity, extraction or chromatography, used in traditional methods. The method is based on two stages. First fluorimetric substrate HDAC, which includes acetylated side chain of lysine, and incubated with the sample having the activity of HDAC (extract of mouse liver). Dezazetilirovanie substrate makes the sensitive substrate on the next stage; processing trypsinogen stop solution gives the fluorophore, which can easily be determined using fluorescence reader for tablets.

The study was performed in black 96-well-microplate, and the total volume for the study was 100 µl. The enzyme from rat liver (10 mg/is l) was diluted 1:6 with HDAC buffer. Prepared enzyme cocktail of 10 ál of diluted enzyme and 30 ml of buffer HDAC. To each well was added 40 μl of enzyme cocktail, and then added 10 μl of the compounds (1 μm and 10 μm) or buffer (control). The tablet was preincubator 5 minutes at 37°C. the HDAC Reaction was started by adding 50 ál of HDAC substrate Boc-Lys (Ac)-AMC (Bachem AG, Switzerland). Tablet incubated for 30 minutes at 37°C. the Reaction was stopped by adding 100 μl trypsinogen stop solution and incubated for 15-30 minutes at 37°C. Measurement of fluorescence at the wavelength of excitation of 360 nm and the wavelength of emission of 460 nm was monitored allocation of AMC. Clean the buffer and clean the substrate served as blank experiments. For selected compounds of the research in a wide concentration range: 0,001, 0,01, 0,1, 1, and 10 μm, was determined IC50(concentration inhibiting 50% of the HDAC) (Dennis Wegeneret al.,Anal. Biochem.,321, 2003, 202-208).

Results inhibition of HDAC 1 and 10 microns and values IC50shown in Table 1.

The selectivity to HDAC isoforms:

Because it is known that compounds of the type benzamido have the potential specificity to HDAC class 1, active compounds were tested for inhibitory activity is against HDAC1. The study was performed, as described previously, with the use of recombinant fermenta HDAC1 (BIOMOL. USA)following the manufacturer's instructions. To determine the values IC50compounds were investigated at five different concentrations (0,001, 0,01, 0,1, 1, and 10 μm). The results are shown in Table-2 indicate that these compounds inhibit the enzyme HDAC1 at nanomolar concentrations that are significantly lower compared to the activity of HDAC on tablets with enzyme murine liver, which indicates that the specific activity of the HDAC isoforms.

Table 2
The specific activity of the HDAC isoforms
The analyzed connectionInhibition of HDAC (IC50nm)
10577,0
107180,0
110150,0
111100,0
11249,0
11444,0
11568,0
116 60,0

Determination of acetylation of histone (H3), tubulin acetylation and induction of P21:

The levels of acetylated histone H3, acetylated tubulin and P21 were determined in the cell lysate sandwich ELISA method (Cell Signaling Technology, USA, catalog number: 7232, 7204 and 7167, respectively), following the manufacturer's instructions. Briefly, the cells of cancer of the rectum (NST, 10000/well) for 4 hours were incubated with the test compound (1 and 10 μm) or medium (control) at 37°C in an incubator with CO2. For the induction of P21 incubation lasted 18 hours. After incubation in buffer for lysis of the cells by sonication on ice prepared cell lysates. Lysates were collected after centrifugation and subjected to the ELISA procedure. 100 µl of each diluted cell lysate in dilution buffer (1:1) was added to microwells coated with a suitable breathtaking antibody, and incubated overnight at 4°C. After washing was added to 100 µl of the antibody for 1 hour at 37°C. After a second washing step was added 100 μl of HRP-linked secondary antibodies for 30 minutes at 37°C. Finally, after washing was added 100 μl of TMB substrate for 10 minutes at 37°C, after which was added 100 μl of stop solution. The absorption of each well was measured using a spectrophotometer at 450 nm (A450). Re ulitity expressed as the ratio of growth (A 450test/And450control) compared with the control, and they are presented in Table 3. In these studies tested the selected connection, and it was found that they cause acetylation of histone and tubulin and induce the expression of P21 in cancer cells of the rectum several times higher compared to the untreated control. Thus, these compounds showed good activity against HDAC in cells in addition to the activity in the selected enzyme preparations.

Table 3
The effect of HDAC inhibition in cells (acetylation of histones, acetylation of tubulin and induction of P21)
The analyzed connectionCellular effects of HDAC inhibition
(fold increase)
Acetylation of H3Acetylation μ-tubulinInduction of P21
1 mcm10 mcm1 mcm10 mcm1 mcm10 mcm
1051,24to 6.672,228,981,052,50
1210,6315,6912,0016,351,952,93
148,4615,529,0014,021,073,28

Metabolic stability in liver microsomesin vitro:

Metabolic stability is defined as the percentage of parent compound is lost over time in the presence of liver microsomes, S9 liver or hepatocytes, depending on the purpose of the study. On the basis of ideas about the metabolic stability of the newly discovered compounds, these compounds can be ranked for further research and potential drug candidates, not advanced in development due to pharmacokinetic reasons, can be lowered.

Prepare phosphate buffer (pH 7.4) and the original solutions of the investigated compounds (usually in DMSO or water). Incubate the reactions is nnow mixture, including cryopreserved liver microsomes of mouse or human (1 mg/ml), an investigational compound (50 μm) and NADPH during different periods of time, such as 10, 15, 30 and 60 minutes, or a single period of time, for example 60 minutes. The reaction starts with the addition of NADPH and stopped immediately or after 60 minutes of screening tests, or after 5, 15, 30 or 60 minutes for more accurate estimates of clearance by adding ice acetonitrile, after which the prepared samples. Determination of loss of parent compound (compared with the zero time point control and/or NADPH-control) is carried out by means of HPLC or LC-MS. Metabolism is expressed as a percentage of the studied compounds, metaboliziruyushchei after a certain time. Apply a quality criterion of the metabolic ability of microsomes is a marker response and marker substrate (e.g., testosterone) (Rodrigues, A.D., Use of in vitro human metabolism studies in drug development. An industrial perspective.Biochem. Pharm., 48(12):2147-2156, 1994). Metabolic stability is expressed as % of the compound's metabolism after 30 minutes of incubation in the presence of active microsomes. Connection with the metabolism of less than 30%, defined as highly stable. Connection with the metabolism from 30% to 60%, defined as moderately stable, and connections, showing % metabolism above 60%, defined as malastare the performance communications. It was found that some compounds are highly and moderately stable.

Anticancer activity ofin vivo:

Studies have been conducted using female Nude mice, SCID (severe combined immunodeficiency, Severe Combined Immune Deficient) aged 6-8 weeks. Mice were kept in individually ventilated cages (IVC) at constant temperature (22±3°C) and humidity (50±20%). Mice had free access to feed and water. Tumors were obtained from ATCC, USA and was supportedin vivosubcutaneous injection (s.c.) fragments of the tumor (approx. 30 mg) to healthy mice according to standard published procedures. All protocols for animal experimentation approved by the Institutional Animal Ethics Committee, ORLL, Chennai. Each experimental group consisted of 6-8 mice bearing s.c. the tumor. Tumors implanted punctures in median area, with Trocar, and tumor growth was monitored by measuring the diameters of the tumor by Vernier caliper. Tumor volume (TV) was calculated by the following formula:

TV (mm3)=L x W2×0,5,

where L and W are the largest and smallest diameters of the tumor, respectively. Processing the connection was started when the tumor was palpable (150-200 mm3).

The investigated compound was administered by oral feeding in the volume of 5-10 ml/kg of the Drug was administered once a day every day for 21 days. To ntronium the mice were injected carrier in the equivalent volume. Tumor size was measured twice a week and body weight were recorded daily before the introduction.

The effectiveness of the studied compounds (T) was estimated by calculating several parameters based on the tumor volume (TV) in relation to untreated control (C). Normal estimation parameters were T/C % [TV./TV×100] and the inhibition of tumor volume (TVI=1-T/C%). Other parameters were the relative tumor volume, percentage change in tumor volume, delay tumor and the logarithm of cell death.

Toxic effects of the treatment was evaluated by the weight loss (in %). Lethal toxicity was defined as any death in the treated group occurred before any deaths in the control group. Mice were examined daily for mortality and clinical signs of toxicity.

The results of the study of xenograft:

Connection 105 showed good anticancer activityin vivomodel xenograft NST (rectum). Treatment of compound 105 (100 mg/kg, orally, daily for 21 days) resulted in maximum inhibition of tumor volume (TVI) 39.4% compared with control-treated media, during the course of the study (Fig. 1). Moreover, the processing of the connection has not resulted in significant loss of body weight or mortality associated with the treatment, compared to counter the LEM.

1. The compound of formula (I)

its tautomeric forms, stereoisomers, polymorphs, hydrates, solvate and a pharmaceutically acceptable salt,
in which the configuration at the double bond may be E/Z;
R represents substituted or unsubstituted groups selected from (C6-C10)aryl, (C3-C12)cycloalkyl, heteroaryl, (C6-C10)aryl(C1-C6)alkyl and heterocyclyl;
where heterocyclyl hereinafter is responsible 5-10-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, oxygen and sulfur, and heteroaryl hereinafter is responsible aromatic heterocyclyl, and each aryl, cycloalkyl, heteroaryl, arylalkyl and heterocyclyl may be substituted by one or more substituents selected from halogen, including fluorine, chlorine, bromine, iodine, (C1-C6)alkyl, (C1-C6)alkoxy, (C6-C10)aryl, halogen(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy, -O-(C3-C12)cycloalkyl, -O-CH2-(C3-C12)cycloalkyl, hydroxyl, NRaRband ORawhere Raand Rbindependently represent a (C1-C6)alkyl and aryl;
R1is a (C6-C10)aryl;
R2and R3independently depict ablaut hydrogen, (C1-C6)alkyl,
-COOR5, -CONR5R6, -CH2NR5R6, -CH2CH2NR5R6, -CH2CH2OH or
-CH2OH; provided that one of R2or R3is hydrogen or unsubstituted alkyl, the other is not hydrogen or unsubstituted alkyl;
R5and R6independently represent hydrogen, (C1-C6)alkyl, (C3-C12-cycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl which may be unsubstituted or substituted; or R5and R6can be combined with the formation of saturated or unsaturated 3-8-membered ring having 0-2 heteroatoms, including N, O or S;
heteroaryl hereinafter is responsible 5-10-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, oxygen and sulfur, and each alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroaromatic can be substituted by one or more substituents selected from halogen, chlorine, fluorine, bromine or iodine, (C1-C6)alkoxy and NRaRb;
R4is HE, (C6-C10)aryl, ortho-substituted aniline or amino (C6-C10)aryl, which may be optional is entrusted substituted by one or more groups, selected from halogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino or (C6-C10)aryl;
X represents-NR7-, -CONR7- or-NR7CO-;
R7represents hydrogen or (C1-C6) alkyl;
Y represents a (C6-C10)aryl or (C6-C10)aryl(C2-C6)alkenyl;
m is an integer from 0-1; n is an integer from 0-1; o is an integer from 0 to 7; and p is an integer from 0-1.

2. The compound according to claim 1, in which
R represents substituted or unsubstituted groups selected from (C6-C10)aryl groups, including phenyl, naphthyl and indanyl; and (C3-C12)cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl; heteroaryl groups include pyridinyl, pyridazinyl, pyrimidyl, triazinyl, pyrrolyl, indolyl, pyrazolyl, imidazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and chinoline; and (C6-C10)aryl(C1-C6)alkyl groups include benzyl and phenylethyl;
heterocyclyl groups, including benzodioxolyl, benzodioxane and benzofuranyl;
R1is (C6-C10)aryl group includes phenyl, naphthyl and indanyl;
R2and R3independently represent hydrogen, (C -C6)alkyl group, including methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl; -COOR5, -CONR5R6CH2NR5R6, -CH2CH2NR5R6, -CH2CH2HE or-CH2HE; provided that one of R2or R3is hydrogen or unsubstituted alkyl, the other is not hydrogen or unsubstituted alkyl;
R5and R6independently represent hydrogen, substituted or unsubstituted groups selected from (C1-C6)alkyl groups, including methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl; and (C3-C12)cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl; and (C6-C10)aryl groups, including phenyl, naphthyl and indanyl; and (C6-C10)aryl(C1-C6)alkyl groups, including benzyl and phenylethyl; heteroaryl groups, including pyridinyl, pyridazinyl, pyrimidyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, indolyl and chinoline; heteroarylboronic groups, including tamiltamil, pyridinylmethyl and intelliprofile; or R5and R6can be combined with the formation of saturated or unsaturated 3-8-membered ring, having the th 1-2 heteroatoms, including N, O or S;
R4is HE, (C6-C10)aryl, including phenyl, naphthyl and indanyl; ortho-substituted aniline or amino(C6-C10)aryl, which is optionally substituted;
X represents-NR7-, -CONR7- or-NR7CO-;
R7represents hydrogen or (C1-C6)alkyl;
Y represents a (C6-C10) aryl groups, including phenyl, naphthyl and indanyl; or (C6-C10)aryl(C2-C6)alkenylphenol group, including phenylethenyl and phenylpropenal.

3. The compound according to claim 1, selected from the group of compounds consisting of:
N-Cyclopropyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Methyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N, N-Dimethyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
2-Phenyl-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(thiophene-2-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-phenyl-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(4-triptoreline)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(pyridin-3-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(4-methoxyphenyl)-3-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(2-chlorophenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(2-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(3-chlorophenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-[benzodioxol-5-yl]-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(4-were)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Morpholino-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Morpholino-2-(2-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Morpholino-2-(3-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Thiomorpholine-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclooctyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(3-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(3-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Isopropyl-2-(3-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Isopropyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Isopropyl-2-(3,4-differenl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(3-fluoro-4-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Isopropyl-2-(3-fluoro-4-methoxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(3,4-differenl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
2-(4-Forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
2-(4-Forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-phenylacetamide;
N-Pyrrolidino-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(4-Cyclopropylmethoxy)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(4-benzyloxyphenyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(4-cyclopentylacetyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-(4-Terbisil)-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(2,4-acid)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(3,4-acid)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(indol-3-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(thiophene-3-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl--(4-forfinal)-2-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-3-(4-forfinal)-2-(3-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(3-cyclopropylmethoxy)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
2-(3-Cyclopropylmethoxy)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-phenylacetamide;
N-Cyclopropyl-2-(3-cyclopentylacetyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
2-(3-Cyclopentylacetyl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-phenylacetamide;
N-Cyclopropyl-2-(biphenyl-4-yl)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
2-(4-Cyclopropylmethoxy)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-phenylacetamide;
N-Cyclopropyl-3-(3,4-acid)-2-(3-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-3-(4-methoxyphenyl)-2-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-3-(4-cyclopropylmethoxy)-2-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-3-(4-cyclopentylacetyl)-2-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
N-Cyclopropyl-2-(4-forfinal)-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)but-2-enamide;
2-[4-(Dimethylamino)phenyl]-3-(4-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)-N-cyclopropylamine;
N-Cyclopropyl-3-(4-forfinal)-2-(4-(3-(hydroxyl the but)-3-oxopropyl)phenyl)acrylamide;
N-Cyclopropyl-2-(4-forfinal)-3-(3-((1E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide;
3-(4-((1E)-3-(Cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)phenyl)-N-hydroxyacetamido;
3-(4-((1E)-3-(Cyclopropylamino)-2-phenylprop-1-EN-1-yl)phenyl)-N-hydroxyacetamido;
3-(4-((1E)-2-(3-Cyclopentylacetyl)-3-(Cyclopropylamino)prop-1-EN-1-yl)phenyl)-N-hydroxyacetamido;
3-(4-((1E)-2-(3-Chlorophenyl)-3-(Cyclopropylamino)prop-1-EN-1-yl)phenyl)-N-hydroxyacetamido;
N-Cyclopropyl-3-(4-(3-(2-aminophenylamino)-3-oxoprop-1-EN-1-ylphenyl)-2-(4-forfinal)acrylamide;
3-(4-((1E)-3-(2-Aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(4-forfinal)-N,N-dimethylacrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(4-(trifluoromethyl)phenyl)acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(pyridin-3-yl)acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(2-chlorophenyl)acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-[benzodioxol-5-yl]acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(2-forfinal)acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(3-chlorophenyl)acrylamide;
(E)-N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(4-were)acrylamide;
N-Morpholino-3-(4-((1E)-3-(2-aminophen the laminitis)-3-oxoprop-1-EN-1-yl)phenyl)-2-(4-forfinal)acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(3-methoxyphenyl)acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-phenylacetamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(thiophene-2-yl)acrylamide;
N-Morpholino-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(2-forfinal)acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(3,4-differenl)acrylamide;
N-Cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-EN-1-yl)phenyl)-2-(3,4-acid)acrylamide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(N,N-Dimethylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(2-chlorophenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-[benzodioxol-5-yl]-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-chlorophenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclo is propylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(thiophene-2-yl)-3-oxoprop-1-enyl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-methoxyphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-Morpholino)-2-(4-forfinal)-3-oxoprop-1-enyl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Morpholino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
6-((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-fluoro-4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)-N-hydroxysuccinimide;
4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(2-chlorophenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-chlorophenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(thiophene-2-yl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(4-methoxyphenyl) - oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Morpholino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Cyclopropylamino)-2-(3-methoxyphenyl)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(((1E)-3-(4-(3-(Morpholino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)acrylamide)methyl)-N-hydroxybenzamide;
4-(3-(Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;
4-(3-(Cyclopropylamino)-2-(4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;
4-(3-(Cyclopropylamino)-2-(3-methoxyphenyl)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;
4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;
4-(3-(Cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)-N-hydroxybenzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)benzamide;
(E)-N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-triptoreline)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3-methoxyphenyl)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclo is propylamino)-2-(1,3-benzodioxol-5-yl)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-chlorophenyl)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(thiophene-2-yl)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3-chlorophenyl)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3,4-differenl)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-methoxyphenyl)3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-chloro-4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(phenylamino)-2-(3,4-acid)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(3,4-acid)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2,4-acid)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-naphthyl)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-phenylamino-2-(2,4-acid)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-Amino-4-forfinal)-4-(2-(4-forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-3-oxo-2-(1H-indol-3-yl)prop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-3-oxo-2-biphenyl-4-yl-prop-1-EN-1-yl)benzamide;
4-(2-(4-Forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)-N-(2-hydroxyphenyl)benzamide;
N-(2-AMINOPHENYL)-4-[3-(cyclopropylamino)-3-oxo-2-feast of the DIN-3-yl-prop-1-EN-1-yl]benzamide;
N-(2-AMINOPHENYL)-4-(2-(4-hydroxyphenyl)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(2-(2,6-differenl)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(2-(2,5-differenl)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(2-(4-forfinal)-3-(isopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-(4-Aminobiphenyl-3-yl)-4-(3-(cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-enyl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(2-were)3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(methylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;
(Z)-N-(2-AMINOPHENYL)-4-(2-(4-forfinal)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-[2-(4-forfinal)-3-morpholine-4-yl-3-oxoprop-1-EN-1-yl]benzamide;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-3-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(phenylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)benzamide;
4-[3-Amino-2-(4-forfinal)-3-oxoprop-1-EN-1-yl]-N-(2-AMINOPHENYL)benzamide;
N-(2-AMINOPHENYL)-4-(2-(4-cyclopentylacetyl)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(2-(4-cyclopropylmethoxy)-3-(cyclopropylamino)-3-oxoprop-1-EN-1-yl)benzamide;
N-(2-AMINOPHENYL)-4-(3-(benzylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)be Sumida;
N-(2-AMINOPHENYL)-4-(3-(cyclopropylamino)-2-(4-forfinal)prop-1-EN-1-yl)benzamide;
4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)-N-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-[benzodioxol-5-yl]-3-oxoprop-1-EN-1-yl)-N-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-EN-1-yl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(2-chlorophenyl)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(3-chlorophenyl)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(4-methoxyphenyl)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(2-chloro-4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(3-forfinal)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Qi is lepapillon)-2-[benzodioxol-5-yl]-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(4-triptoreline)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(3,4-differenl)-3-oxoprop-1-EN-1-yl)-N-(4-(hydroxycarbamoyl)benzyl)benzamide;
4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide;
4-(3-(Cyclopropylamino)-2-phenyl-3-oxoprop-1-EN-1-yl)-N-(6-hydroxyamino)-6-oxohexyl)benzamide;
4-(3-(Cyclopropylamino)-2-(4-were)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide;
4-(3-(Cyclopropylamino)-2-(2-forfinal)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide;
4-(3-(Cyclopropylamino)-2-(3-forfinal)-3-oxoprop-1-EN-1-yl)-N-(6-(hydroxyamino)-6-oxohexyl)benzamide;
N-(4-(3-(Cyclopropylamino)-2-(4-forfinal)-3-oxoprop-1-EN-1-yl)phenyl)-N-hydroxyacetanilide and
N-(2-AMINOPHENYL)-4-((4-(3-(cyclopropylamino)-1-(4-forfinal)-3-oxoprop-1-EN-2-yl)phenylamino)methyl)benzamide.

4. The method of obtaining the compounds of formula (I) according to claim 1 of the compounds of formula (II), in which one of R2or R3is hydrogen or unsubstituted alkyl, the other is not hydrogen or unsubstituted alkyl, and R4, R3, R2, R1, R, X, Y, m, n, o, p are defined previously

5. The compound of formula (II)or its stereoisomer, enantiomer, diastereoisomer, or a pharmaceutically acceptable whom I Sol, in which one of R2or R3is hydrogen or unsubstituted alkyl, the other is not hydrogen or unsubstituted alkyl, and R4, R3, R2, R1, R, X, Y, m, n, o, p are defined previously

6. The pharmaceutical composition capable of inhibiting discontinuation comprising the compound of formula (I) according to claim 1 or 3 as the active ingredient together with a pharmaceutically acceptable carrier, diluent, excipient or MES.

7. The pharmaceutical composition according to claim 6, where the composition is in the form of tablets, capsules, powder, syrup, solution, aerosol or suspension.

8. Method of inhibiting HDAC in a cell, comprising processing said cells an effective amount of a compound according to claim 1 or 3.

9. The method of treatment of a condition mediated by HDAC, including introduction to a subject suffering from a condition mediated by HDAC, a therapeutically effective amount of a compound according to claim 1 or 3.

10. The method of treatment and/or prevention of proliferative conditions or cancer, comprising the administration to a subject suffering from a proliferative conditions or cancer, a therapeutically effective amount of a compound according to claim 1 or 3.

11. A method of treating cancer by administration of combination of compounds according to claim 1 or 3 with other clinically relevant cytotoxic agents or N. the cytotoxic agents to the needy in the mammal.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to substrate material for complex formation and selective extraction of americium, plutonium, uranium or thorium in their cationic form, which is para-tert-butyl-calix[6]arene of formula (IIA), where R'1 R'3 and R'5, which are identical or different, each separately denotes: (i) a linear or branched C1-6alkyl deposited on a substrate, wherein one of the groups R'1 R'3 and R'5 in the compound of formula (IIA) is a group (ii); (ii) spacer-substrate, where the space is a divalent radical selected from a group comprising aryl(C1-6alkyl)aryl; and the substrate is selected from a substrate which is a copolymer of chloro- or bromo-methylstyrene and divinylbenzene. The invention also relates to a liquid membrane deposited on a substrate for complex formation or selective extraction of americium, plutonium, uranium or thorium in their cationic form, containing para-tert-butyl-calix[6]arene of formula (IA) or (IB), which is dissolved in an organic solvent, having boiling point higher than 60°C and absorbed on a substrate, which is epoxy resin, where R1, R3 and R5, which are identical or different, each separately denotes: (i) a hydrogen atom, (ii) a linear or branched C1-6alkyl.

EFFECT: obtaining novel materials.

7 cl, 8 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline form of N-[(R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide, where crystalline form represents polymorphic form IV which has roentgen powder difractogram with characteristic peaks, expressed in degrees 2θ,approximately at 4.6, 7.2, 14.6, 19.9, 23.2 and 26.5. Invention also relates to pharmaceutical composition, dosed form, method of obtaining polymorphic form IV and to method of treating disease state, mediated by MEK activity.

EFFECT: increase of target product output.

17 cl, 1 tbl, 1 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: compound is a matrix metalloproteinase or aggrecanase. The invention also relates to a pharmaceutical composition based on said compounds and a method of treating osteoarthritis, (I), where W is -C(O)-; R1 is bisphenyl, possibly containing one or more substitutes R5 and R6; and if R1 contains one or more substitutes R5 and R6, the substitutes can be identical or different; R2 is hydrogen; R3 is -CO2H, -CONHOH, -CONHR7 or -COOR7; R4 is -CONR9R10; m equals 0. The values of substitutes R5-R7, R9, R10 are as described in the claim.

EFFECT: compounds have the capacity to modulate metalloproteinase activity.

18 cl, 40 ex, 18 dwg, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to substrate material for complex formation and selective extraction of americium, plutonium, uranium or thorium in their cationic form, which is para-tert-butyl-calix[6]arene of formula (IIA), where R'1 R'3 and R'5, which are identical or different, each separately denotes: (i) a linear or branched C1-6alkyl deposited on a substrate, wherein one of the groups R'1 R'3 and R'5 in the compound of formula (IIA) is a group (ii); (ii) spacer-substrate, where the space is a divalent radical selected from a group comprising aryl(C1-6alkyl)aryl; and the substrate is selected from a substrate which is a copolymer of chloro- or bromo-methylstyrene and divinylbenzene. The invention also relates to a liquid membrane deposited on a substrate for complex formation or selective extraction of americium, plutonium, uranium or thorium in their cationic form, containing para-tert-butyl-calix[6]arene of formula (IA) or (IB), which is dissolved in an organic solvent, having boiling point higher than 60°C and absorbed on a substrate, which is epoxy resin, where R1, R3 and R5, which are identical or different, each separately denotes: (i) a hydrogen atom, (ii) a linear or branched C1-6alkyl.

EFFECT: obtaining novel materials.

7 cl, 8 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an ore processing reagent which contains alkylhydroxamic acid of formula: R-C(=O)N(R")-OM, where R denotes a straight or branched C2-C18 alkyl, R" denotes H and M denotes hydrogen, and a nonionic surfactant selected from a group comprising ethoxylated alcohols, esters, ethoxylated acids, ethoxylated (alkyl)phenols, alkanoylamides, copolymers of polyethyleneoxide and mixtures thereof, where the weight ratio of the nonionic surfactant to the alkylhydroxamic acid is between 1:20 and 1:1, as well as to methods for selective separation of impurities.

EFFECT: more efficient processing.

34 cl, 13 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel bioisosteres of actinonin of general formula (I) , as well as to pharmaceutically acceptable salts thereof and pharmaceutical compositions based on said compounds, with peptide deformylase (PDF) inhibitory activity, as well as to use of the compounds or pharmaceutical compositions based on said compounds to prepare medicinal agents. In general formula (I) R1 is a hydrogen atom, R2 is a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenyl residue, where the heteroatom is sulphur, R3 is a hydrogen atom, R4 is (C1-C6)alkyl residue, (C3-C7)cycloalkyl residue, R6 is a hydrogen atom, n is 1, 2 or 3. Values of substitute R5 are given in the formula of invention.

EFFECT: new compounds have useful biological activity.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to hydroxamate derivatives described by general formula I: , in which R1 represents H or linear C1-C6-alkyl; R2 hydrogen, С110-alkyl optionally substituted by 1-5 constituents selected from hydroxy, amino, hydroxyalkyl; C4-C9-cycloalkyl; aryl; C4-C9-heterocycloalkyl, C4-C9-heterocycloalkylalkyl containing 2 heteroatoms (nitrogen and/or oxygen); C4-C9-cycloalkylalkyl; arylalkyl; heteroarylalkyl containing 1-4 nitrogen atoms as heteroatoms; -(CH2)nC(O)R6, -(CH2)nOC(O)R6, -N(R12)C(O)-W; HONH-C(O)-CH=C(R1)arylalkyl, and (CH2)nR7; R3 and R4, identical or different, independently denote hydrogen, optionally OH-substituted C1-C6-alkyl; C(O)-O-W, or -N(R12)C(O)W; or R3 and R4 together with carbon atom, to which they are linked, represent C=O; or R2 together with carbon atom, to which it is linked, and R3 together with carbon atom, to which it is linked, can form C4-C9-heterocycloalkyl containing 2 nitrogen atoms as heteroatoms; or mixed aryl or non-aryl polyheterocyclic ring; R5 is selected from hydrogen; C1-C6-alkyl; C4-C9-cycloalkyl; C(O)-W; aryl optionally substituted by 1-2 constituents selected from halogen and hydroxyalkyl; heteroaryl containing nitrogen as heteroatom; arylalkyl; aromatic polycycle; polyheteroaryl containing 1-2 nitrogen atoms as heteroatoms and optionally substituted by 1-2 substituents selected from hydroxyalkyl, halogen, alkyl, and aryl; mixed aryl-nonaryl polyheterocycle containing nitrogen or oxygen atom as heteroatom and optionally substituted by groups -N-OH, =N-OH; n, n1, n2, and n3, identical or different, are independently selected from within a range of 0-6; X and Y, identical or different, are independently selected from hydrogen, halogen, and nitro group; or pharmaceutically acceptable salt thereof. Invention also relates to a pharmaceutical composition showing inhibitory activity toward hydroxamate derivative of general formula I in combination with one or several pharmaceutically acceptable carriers. Hydroxamate derivative of general formula I are also appropriate for treating proliferative disease and regulating p21 promoter.

EFFECT: enabled use of hydroxamate derivatives as deacetylase inhibitors.

42 cl, 6 tbl, 272 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to using dicarboxylic acids of the general formula (2): R-CONH-OH (2) wherein R means -HO-HNCO, -HO-NHCOCH-(OH)CH(OH), -HOOC-CH2CH2, -HO-OCCH=CH as inhibitors of metastasis and agents enhancing chemotherapeutic activity of antitumor preparations. Also, invention relates to a method for enhancing effectiveness of cytostatics in carrying out cytostatic chemotherapy of tumors. Method is carried out by using cytostatics in combination with derivatives of dicarboxylic acids of the formula (2). Also, invention relates to a method for inhibition of metastasizing process. Method is carried out by effect of the known cytostatics and derivatives of dicarboxylic acid of the formula (2) on tumor. Proposed substances provide enhancing antitumor and anti-metastatic activity of known cytostatics based on using derivatives of dicarboxylic acids.

EFFECT: valuable medicinal properties of agents and preparations, enhanced effectiveness of metastasizing inhibition.

4 cl, 4 dwg, 7 ex

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 is chosen from the following order: hydrogen atom, (C1-C4)-alkyl, -COOH, -COO-(C1-C4)-alkyl; R2, R3, R4 and R5 are chosen independently from the following order: hydrogen, halogen atom, (C1-C4)-alkyl-, hydroxy-group, (C1-C4)-alkoxy-group; Y means -CH2-CH2-; X means alkylene chain comprising from 4 to 10 carbon atoms that is saturated or unsaturated and can comprise one double bond, it can be branched or direct, its enantiomers, and its salts with pharmaceutically acceptable acids and bases. Also, invention relates to a pharmaceutical composition possessing inhibitory effect on histone deacetylase activity and comprising active component as compound of the formula (I) in mixture with pharmaceutically acceptable carrier, excipients or diluting agents. Invention proposes tetralone derivatives possessing antitumor activity.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

6 cl, 1 tbl, 14 ex

The invention relates to methods of producing compositions collector for flotation of minerals

The invention relates to new compounds of General formula I

< / BR>
in which R1selected from the group consisting of hydrogen, unsubstituted or optionally substituted aralkyl, unsubstituted or optionally substituted orelkinoservisa, unsubstituted or optionally substituted allyloxycarbonyl, unsubstituted or optionally substituted alkyl and hydroxyamino group; R2selected from the group consisting of hydrogen, unsubstituted or optionally substituted orelkinoservisa, unsubstituted or optionally substituted allyloxycarbonyl, aminosidine group; R3selected from the group consisting of hydrogen, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R4selected from the group consisting of unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R5and R6that may be the same or different, each independently selected from the group consisting of hydrogen, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted cycle>and R6taken together with the nitrogen atom to which they are attached, form an unsubstituted or optionally substituted heterocyclic group; R7selected from the group consisting of hydrogen, hydroxy, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R8selected from the group consisting of hydrogen, hydroxy, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl, and R9selected from the group consisting of hydrogen, hydroxy, amino and a group of the formula-X-Y, in which X is selected from the group consisting of unsubstituted or optionally substituted (C1-C6)-alkylene and unsubstituted or optionally substituted phenylene, and Y denotes a group of formula-a-b or a-B, where a is selected from the group consisting of unsubstituted or optionally substituted (C1-C6)-alkylene, imino and unsubstituted or optionally substituted (C1-C6)-alkylamino, and selected from the group consisting of hydrogen, amino, amidino, acylmethyl, unprotected or optionally protected bis (phosphono)methyl, provided that R7, R8and R are not simultaneously represent

FIELD: chemistry.

SUBSTANCE: compound is a matrix metalloproteinase or aggrecanase. The invention also relates to a pharmaceutical composition based on said compounds and a method of treating osteoarthritis, (I), where W is -C(O)-; R1 is bisphenyl, possibly containing one or more substitutes R5 and R6; and if R1 contains one or more substitutes R5 and R6, the substitutes can be identical or different; R2 is hydrogen; R3 is -CO2H, -CONHOH, -CONHR7 or -COOR7; R4 is -CONR9R10; m equals 0. The values of substitutes R5-R7, R9, R10 are as described in the claim.

EFFECT: compounds have the capacity to modulate metalloproteinase activity.

18 cl, 40 ex, 18 dwg, 6 tbl

FIELD: chemistry.

SUBSTANCE: proposed composition contains a) synthetic polymer and b) one or several compounds of formula or where R1, R2 and R3 or Y1, Y2 and Y3, or Z1, Z2 and Z3 represent, for example branched C3-C20alkyl.

EFFECT: possibility of significantly reducing blushing of polymers.

41 cl, 10 tbl, 90 ex

FIELD: polymer materials.

SUBSTANCE: invention relates to polypropylene compositions exhibiting improved ability to crystallize, high transmittance coefficient and high transparency due to a specific trimesic acid triamide present therein in amounts between 0.001 to 5% of the weight of triamide. Utilization of triamides as turbidity lowering additive for crystallizable polypropylene is described as well as novel compounds of this group, mixtures thereof, and polypropylene compositions based thereon.

EFFECT: improved physicochemical characteristics of polypropylene resins.

19 cl, 4 tbl, 4 ex

The invention relates to new compounds of formula I, where R1- H, alkyl, aryl, R2- alkyl, R3- H, halogen, the nitro-group, R4- H, alkyl, Z is alkyl, W is alkyl, alkoxy, substituted aryl, substituted heteroaryl, where the heteroatoms may be O, N, S, and substituted amino group and substituted oxygraph, X - substituted aryl or substituted heteroaryl, where the heteroatoms may be O, N, S

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and is applicable for treating rectal cancer with synchronous remote metastases. That is ensured by radiation therapy together with radio modifiers and combined with chemotherapy followed by radical resection of a primary tumour and remote metastases. The radio modifiers are presented by the intrarectal introduction of metronidazole as a part of a composite mixture containing sodium alginate and 2% dimethylsulphoxide, and also local microwave hyperthermia. The chemotherapy is presented by a two-day intensive course of chemotherapy FOLFOX6 involving high doses of platinum and 5-fluorouracil in the form of the 48-hour infusion.

EFFECT: method allows reducing total length of treatment, enabling a complete course of effective preoperative radiation chemotherapy with minimum toxicity in a relatively short time, performing earlier sphincter-preserving operations with well-timed resection of the primary tumour, regional and remote metastases ensured by implementing mechanisms, chemosensitisation and synergic effect of said radio sensitising agents.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to cell biology. Dopamine and/or its synthetic analogues, particularly substituted 3,4-dihydro-2(1H)-pyrimidinthione is applied as a cytotoxic agent having an effect on human cancer cells in culture.

EFFECT: presented substances can find application in medicine as a base for developing dosage forms used for therapy of malignant growths.

5 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having chemical structure of formula II , all salts and stereoisomers thereof, where the value of radicals D, A2 and B are as described in paragraph 1 of the claim. The invention also relates to a composition having activity as a c-kit and c-fms modulator, a method of treating a subject suffering from a disease or condition mediated by c-kit and c-fms and a kit for modulating c-kit and c-fms.

EFFECT: novel compounds which can be useful in treating c-kit-mediated diseases or conditions and/or c-fms-mediated diseases or conditions are obtained and described.

21 cl, 44 ex

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