Thiazole derivatives

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

 

The technical field to which the invention relates.

The present invention relates to compounds having inhibitory effect on the kinase 5 (ALK5), similar to the activin receptor, which is a receptor for TGF-P type I. the Present invention also relates to a catalyst for the growth of hair follicle cells, stimulate hair growth and remedy for hair growth, each of which contains a functional ALK5 inhibitor as an active ingredient.

Description of the prior art,

Transforming growth factor-β (TGF-β), and activin, BMP and such is a molecular structural unit relating to the superfamily of TGF-β. There are 2 different transmission signals of the receptor for TGF-β (type I and type II), both of which have, in their respective cell area serine/trionychinae. After the unification of TGF-β to its receptor receptor type I fosfauriliruetsa receptor type II and, thus, is activated so that the signal is passed to the kernel by the way Smad.2/3 or path TAB/TAK.

It was obvious that TGF-β exerts a sufficiently large number of physiological effects, and as one of such influences, as is well known, TGF-β has the property of accumulation of extracellular matrix in tissues by stimulating the production of suppression and destruction of proteins, which shall constitute the extracellular matrix (Massague, Annu Rev. Cell Biol. 6, 597-641 (1990)). Thus, prolonged excessive production of TGF-β and activation of the transmission system can cause a variety of fibrotic diseases. For example, in the case of the kidney has been shown that TGF-β is deeply involved in fibrosis or glomerulonephritis in renal diseases such as glomerulonephritis or diabetic nephropathy (Okuda et al., J. Clin. Invest. 86, 453-462 (1990), and in the case of the liver, it has been shown that TGF-β promotes the production of extracellular matrix in neverending cells and then participates in the occurrence of hepatic fibrosis and cirrhosis (Barnard et al., Biochim. Biophys. Acta 1032, 79-87 (1990)). In addition, one of the reasons for such incurable diseases as pulmonary fibrosis or proliferative vitreoretinopathy, accompanied by significant fibrosis is the accumulation of extracellular matrix due to the increased functions of TGF-β.

It was reported that the ALK5 inhibitor suppresses the accumulation of extracellular matrix caused by TGF-β, by blocking the signals of TGF-β/Smads (Grygieiko et al., J. Am. Soc. Nephrol. 13 (Abst Iss), 5A (F-FC022), 2002), so consider that this inhibitor is useful as a pharmaceutical product for the treatment or prevention of various diseases associated with fibrosis of the kidneys, liver or lungs, etc.

On the other hand, it is known that TGF-β exerts a significant growth inhibitory activity against various cleto is, such as epithelial cells, cells of the vascular endothelium, gametocyte or lymphocytes (Soma et al., J. Invest. Dermatol. 111, 948-954 (1998)). As for the hair follicles, it was reported that overexpression of TGF-β induces growth inhibition/apoptosis of hair follicle cells, and then the hair cycle is shifted from during which hair to telogen, and thus, it became apparent that TGF-β is deeply involved in the progression of baldness (Foitzik et al., FASEB J. 14, 752-760 (2000)).

However, research has not fully proved, what is the transmission of signals from receptor of TGF-β in the first place involved in the growth inhibition/apoptosis of hair follicle cells, and, thus, has not yet been reported in the prevention/treatment effect alopecia, which is based on the blockade of signals of TGF-β/Smad-induced inhibitor of ALK5.

Although substances that have an inhibitory effect on such activin receptor kinase 5 (ALK5), which is a receptor of TGF-β type I described in WO 00/61576A, WO 01/7273A, WO 01/62756A, WO 02/40468A, WO 03/87304A and the like, the connection thiazolidinedione in accordance with the present invention was not disclosed.

In addition, although imidazoline compound with a structure similar to the connection structure in accordance with the present invention it is well known from WO 99/03837A, WO 96/03387A, WO 03/62215A, WO 01/85723A, WO 01/44203A, JP 2001163861A, JP 07112975A, U.S. patent No. 6770663, WO 04/005264A and the like, the b inhibitory effect of these compounds against such activin receptor kinase 5 (ALK5) has not yet been reported.

Description of the invention

The aim of the present invention is the provision of a stimulator of hair growth or remedies for hair growth, which is based on the provision of inhibitory substances against ALK5, which is a receptor of TGF-β type I and his new action.

As a result of various studies to solve these problems, the authors of the present invention found that the ALK5 inhibitor inhibits the suppression of growth of hair follicle cells through TGF-β, and then also discovered that a certain type of a new group of compounds inhibits ALK5 and, in addition, found an intermediate connection to obtain the above group of compounds for the implementation of the present invention.

Thus, the present invention provides a derivative of thiazole represented by the formula (I)

or its pharmaceutically acceptable salt, where:

X1and X2differ from each other and represent a sulfur atom or a carbon atom;

R1represents a phenyl group;

phenyl group substituted by 1 to 5 members selected from the group consisting of halogen atoms, alkyl groups having 1-6 carbon atoms, alkoxygroup having 1-6 carbon atoms, hydroxy-group, fenilalanina having 7-12 carbon atoms, and alkylamino having 1-6 carbon atoms;

phenyl group fused with a 5-7 membered heteroaromatic or non-aromatic ring having at least one heteroatom selected from the group consisting of N, O and S;

pyridyloxy group;

pinolillo group;

izohinolinove group or

pyridyloxy group fused with a 5-7 membered heteroaromatic ring having at least one heteroatom selected from the group consisting of N, O and S;

R2represents a hydrogen atom, halogen atom, alkyl group having 1-6 carbon atoms, alkyl group having 1-6 carbon atoms, substituted by 1-5 halogen atoms, alkoxygroup having 1-6 carbon atoms, alkanoyloxy group having 1-6 carbon atoms, or a hydroxyalkyl group having 1-5 carbon atoms; and

A represents a group represented by the formula

or

where:

R3represents a hydrogen atom;

the hydroxy-group;

alkyl group having 1-6 carbon atoms;

phenylalkyl group having 7-12 carbon atoms; or

phenylalkyl group having 7-12 carbon atoms, substituted by a hydroxy-group, alkoxygroup having 1-6 carbon atoms, alkoxygroup having 1-6 carbon atoms, substituted alkoxygroup having 1-6 carbon atoms, or alkoxy what oppai, having 1-6 carbon atoms, substituted alkylamino having 1-6 carbon atoms,

R4represents a phenyl group;

phenyl group substituted by 1 to 5 members selected from the group consisting of halogen atoms, alkyl groups having 1-6 carbon atoms, alkoxygroup having 1-6 carbon atoms, carbamoyl group and cyanopropyl;

a hydrogen atom;

alkyl group having 1-12 carbon atoms;

alkenylphenol group having 2-12 carbon atoms;

cycloalkyl group having 3-7 carbon atoms;

alkyl group having 1-12 carbon atoms, substituted alkoxygroup having 1-6 carbon atoms, hydroxy-group, alkoxylalkyl having 8-12 carbon atoms, telemedicine group, toluensulfonate or morpholinopropan;

alkyl group having 1-6 carbon atoms, substituted by 1-5 halogen atoms;

cycloalkyl group having 3-9 carbon atoms, substituted oxopropoxy;

tetrahydropyranyloxy group;

4-piperidinyloxy group;

piperidinyloxy group, a substituted alkyl group having 1-6 carbon atoms, or tert-butoxycarbonyl group;

cyclohexanone-2'-(1,3-DIOXOLANYL) group;

pyrrolidin-2-he-5-ilen group;

the group represented by the formula-Y1-Z1-NR5-Z2-Y2-R6 ,

where:

Y1and Y2the same or different from each other and represent a simple bond or alkilinity group having 1-12 carbon atoms;

R5represents a hydrogen atom or alkyl group having 1-12 carbon atoms;

Z1and Z2the same or different from each other and represent a simple bond;

alkylenes group having 1-7 carbon atoms;

-CO-;

-CO2-;

-SO2or

-OCO-, and

R6is

cycloalkyl group having 3-7 carbon atoms;

alkyl group having 1-6 carbon atoms, substituted by 1 to 3 halogen atoms;

alkenylphenol group having 2-6 carbon atoms;

alkylamino group having 2-6 carbon atoms;

the amino group;

the amino group substituted by 1-2 groups selected from the group consisting of alkyl groups having 1-6 carbon atoms, cycloalkyl group having 3-7 carbon atoms, and tert-butoxycarbonyl group;

piperidinium;

piperidinyloxy group;

piperidinyloxy group, a substituted alkyl group having 1-6 carbon atoms;

pyrrolidinyloxy group;

piperazinilnom group;

piperazinilnom group, a substituted alkyl group having 1-6 carbon atoms;

morpholinopropan;

the hydroxy-group;

alkoxygroup having 1 to 6 atoms of carbon is a;

alkoxygroup having 1-6 carbon atoms, substituted hydroxy-group or alkoxygroup having 1-6 carbon atoms;

oxetan-2-ilen group;

tetrahydropyranyloxy group;

tetrahydropyranyloxy group;

a hydrogen atom;

phenyl group;

phenyl group substituted by alkoxygroup having 1-4 carbon atoms; or

group which forms a ring when attaching to the nitrogen atom of the above formula; or

the group represented by the formula Y3-CO-R41,

where:

Y3represents a simple bond or alkilinity group having 1-7 carbon atoms,

R41is

the hydroxy-group;

alkoxygroup having 1-6 carbon atoms;

piperidinium;

piperazine-1-ilen group, a substituted alkyl group having 1-6 carbon atoms, morpholinoethyl group having 5-10 carbon atoms, or acylaminoalkyl group having 2-14 carbon atoms;

or

morpholinopropan.

Another variant of implementation of the present invention is an inhibitor of ALK5, which contains the above-described thiazolidinedione derivative or its pharmaceutically acceptable salt as an active ingredient.

In addition, another variant of implementation of the present invention is a means for the growth of the hair to the e contains as an active ingredient a substance for inhibiting the function of ALK5, involved in signal transduction of TGF-β, and thus, the present invention provides an entirely new concept, in which the mechanism of action differs from the mechanism of action of the usual remedies for hair growth.

In addition, another variant of implementation of the present invention is an intermediate compound to obtain a compound represented by the formula (I)where the part corresponding to those of formula (I)represents a group as described below

where X3represents a hydrogen atom or a halogen atom.

Preferred compounds of formula (I) in accordance with the present invention include a compound, where R2represents a hydrogen atom, halogen atom, alkiline group having 1-6 carbon atoms, or Elgiloy group having 1-6 carbon atoms, substituted by 1-5 halogen atoms, preferably a compound where R2represents alkiline group having 1-6 carbon atoms, or triptorelin group, and more preferably a compound where R2represents a methyl group or triptorelin group.

Preferred are compounds where R1represents a phenyl group fused with a 5-7 membered heteroaromatic or non-aromatic ring, terrasim at least 1 heteroatom, selected from the group consisting of N, O and S. Preferred compounds where X1represents a sulfur atom and X2represents a carbon atom.

Although used in the present description, the term "remedy for hair growth" means a pharmaceutical product or a quasi drug, which is used for the purpose of inducing hair growth, stimulate hair growth or prevent hair loss, it is required that this term was understood in a broad sense and should not be used exclusively in any one sense. When the remedy for hair growth according to the present invention is used as a pharmaceutical product, it can be used to relieve or prevent, for example, focal alopecia or pattern baldness male pattern, but the use of tools for hair growth according to the present invention is not limited to this.

The present invention shows that a substance that inhibits the function of ALK5, acts as a facilitating or a prophylactic against hypofunction of hair follicle cells.

A substance that inhibits the function of ALK5 is a substance that inhibits the phosphorylation Samd2 and Smad3, when the signal is transmitted from the receptor of TGF-β, and, for example, illustrative compounds described in claims 1 to 6 formulas of the present invention. PQS is lku the above described mechanism of action can completely inhibit the effect of suppressing growth provided TGF-β against hair follicle cells, which are cells that produce keratin hair, it is anticipated that this substance is effective against symptoms that facilitated or prevented normal remedy for hair growth.

In addition, it is also expected that this substance has a synergistic effect in combination with other hair growth stimulants or drugs for hair growth, with a different efficiency.

Although the remedy for hair growth in accordance with the present invention can be introduced in different doses and in various dosage forms depending on the nature of the substances, it is preferable that the substance was applied topically or administered orally due to the need for prolonged administration. Not all such dosage can uniformly be expressed in digital terms. However, with respect to compounds 1-202 and 228-249, it may be necessary to introduce from about 0.0001 to 10 wt.% these substances, preferably from 0.001 to 5 wt.% these substances, and more preferably from 0.001 to 1 wt.% these substances in the form of a lotion, ointment or gel for external use, or, alternatively, it may be necessary to introduce about 1-100 mg/kg of this compound in the form of a powdered drug or capsules for oral administration. Described to enter the composition can be obtained by using conventional methods of obtaining preparative forms.

Dosage form tools for hair growth in accordance with the present invention are not specifically limited to a specific form, but in the case of the preparation for external use tool for hair growth, containing the ALK5 inhibitor, such as any of the compounds 1-202 and 228-249, as an active ingredient, preferably provided in the form of water-soluble composition. In General to obtain such water-soluble composition can be used various additives (humectants, thickeners, preservatives, antioxidants, perfumes and dyes and so on)used for the manufacture of medicines, quasi drugs, or cosmetics. Remedy for hair growth in accordance with the present invention may be provided, for example, in the form of a composition for hair care, such as medicine for hair, hair oil, mousse or hair gel composition for washing hair, such as shampoo or means for rinsing the hair, or alternatively, as the ointment.

When the remedy for hair growth in accordance with the present invention are presented in the form of liquid medicines, the ALK5 inhibitor, such as any of the compounds 1-202 and 228-249, respectively, is combined with purified water, a suitable buffer solution such as phosphate buffer, physiological with is the combat solution, such as saline solution, ringer's solution or the solution Loka, ethanol, glycerin, and commonly used surface-active agent, to obtain drugs in the form of a sterilized aqueous solution, a nonaqueous solution, suspension, liposomes or emulsions. This drug is topically applied in the form of liquid medication to the scalp. In this case, the liquid drug can be directly applied to the hairy skin of the head or it can be applied using injection nozzle for spraying.

When the remedy for hair growth in accordance with the present invention are presented in the form of a semi-solid preparation, the ALK5 inhibitor, such as any of the compounds 1-202 and 228-249, can be mixed with fat, fatty oil, lanolin, vaseline, paraffin, wax, cream, resin, plastic, glycols, higher alcohol, glycerin, water, emulsifiers, suspendresume agents or similar substances, and then topically applied as a medicinal product for external use, such as an ointment or cream.

When the remedy for hair growth in accordance with the present invention are presented in the form of a solid preparation, the ALK5 inhibitor, such as any of the compounds 1-202 and 228-249, can appropriately be mixed with a suitable additive for obtaining a medicinal product for external p is imeneniya, such as powdered drug or composition in the form of powder, or alternatively the inhibitor, if required, can be dissolved or suspended in a solvent to obtain a solid composition for application to the hairy scalp.

Further, in the case of oral administration the ALK5 inhibitor, such as any of the compounds 1-202 and 228-249, can be mixed with pharmaceutically acceptable carriers (excipients, binding agents, disintegrants, fragrances and emulsifiers, etc.), diluent, solubilizers agent or similar substance, and thus obtained pharmaceutical product is preferably provided in the form of tablets, capsules, granules, powder preparation, syrup, suspension, solution or similar form which can be obtained in accordance with the usual method.

In the present invention, the halogen atom is a fluorine atom, chlorine atom, bromine atom or iodine atom.

An alkyl group having 1-6 carbon atoms, means a saturated alkyl group with a linear or branched chain having 1-6 carbon atoms, and includes, for example, methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, sec-boutelou group, n-pentelow group, isopentyl group,neopentyl group, tert-pentelow group and n-hexoloy group.

Alkoxygroup having 1-6 carbon atoms, means alkoxygroup with a linear or branched chain having 1-6 carbon atoms, and includes, for example, a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, pentyloxy and hexyloxy.

Fenilalanina from 7-12 carbon atoms means fenilalanina having 7-12 carbon atoms, and includes, for example, benzyloxy and penetrometry.

Alkylamino having 1-6 carbon atoms, means mono - or dialkylamino with a linear or branched chain having 1-6 carbon atoms, and includes, for example, methylaminopropyl, ethylamino and N,N-dimethylaminopropyl.

Phenyl group fused with a 5-7 membered heteroaromatic or non-aromatic ring having at least one heteroatom selected from the group consisting of N, O and S, includes, for example, benzothiazolyl group, benzoxazolyl group and benzo(1,3)dioxolo group.

Peregrina group fused with a 5-7 membered heteroaromatic ring having at least one heteroatom selected from the group consisting of N, O and S, includes, for example, pyrazolopyrimidine group, imidazopyridine group triazolopyridine group.

Alcoolica group having 1-6 carbon atoms, means alkanoyloxy group with a linear or branched chain having 1-6 carbon atoms, and includes, for example, formyl group, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, valerino group, hexanoyl group and pivaloyl group.

Hydroxylysine group having 1-5 carbon atoms, means hydroxyalkyloxy group with a linear or branched chain having 1-5 carbon atoms, and includes, for example, hydroxymethylene group, 1-hydroxyethylene group and 2-hydroxyethyloxy group.

Fenilalanina group of 7-12 carbon atoms means phenylalkyl group having 7-12 carbon atoms, and includes, for example, benzyl group and fenetylline group.

An alkyl group having 1-12 carbon atoms, means a saturated alkyl group with a linear or branched chain, having 1 to 12 carbon atoms, and includes, for example, methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, 1-ethylpropyl group, n-hexoloy group and n-dodecyloxy group.

Alchemilla group having 2-12 carbon atoms, means alkenylphenol group with a linear or branched chain having 2 to 12 carbon atoms, and includes, for example the EP, the vinyl group, 1-propenyloxy group, allyl group, Isopropenyl group, butenyloxy group, isobutylene group, hexenyl group and dodecenyl group.

Cycloalkyl group of 3-7 carbon atoms means cycloalkyl group having 3-7 carbon atoms, and includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group and tsiklogeksilnogo group.

Alkoxylalkyl having 8-12 carbon atoms, means fenilalanina having 8-12 carbon atoms, in which the benzene ring is substituted by alkoxygroup, and includes, for example, 4-methoxybenzyloxy and 4-methoxyphenoxy.

Cycloalkyl group of 3-9 carbon atoms, substituted oxopropoxy means cycloalkyl group having 3-9 carbon atoms, substituted oxopropoxy in the ring, and includes, for example, 4-oxocyclohexyl group.

Tetrahydropyranyl group includes, for example, 2-tetrahydropyranyloxy group, 3-tetrahydropyranyloxy group and 4-tetrahydropyranyloxy group.

Allenova group having 1-12 carbon atoms, means alkylenes group with a linear or branched chain, having 1 to 12 carbon atoms, and includes, for example, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, HEXAMETHYL the new group and dodecanethiol group.

Allenova group having 1-7 carbon atoms, means alkylenes group with a linear or branched chain having 1 to 7 carbon atoms, and includes, for example, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group and heptamethine group.

Alchemilla group having 2-6 carbon atoms, means alkenylphenol group with a linear or branched chain having 2 to 6 carbon atoms, and includes, for example, vinyl group, 1-propenyloxy group, allyl group, Isopropenyl group, butenyloxy group, isobutylene group and hexenyl group.

Alchemilla group having 2-6 carbon atoms, means alkylamino group with a linear or branched chain having 2 to 6 carbon atoms, and includes, for example, etinilnoy group, 1-propenyloxy group and 2-propenyloxy group.

Piperidinyl group includes, for example, 2-piperidinyloxy group, 3-piperidinyloxy group and 4-piperidinyloxy group.

Pyrrolidinyl group includes, for example, 2-pyrrolidinyl group, 3-pyrrolidinyloxy group and 4-pyrrolidinyloxy group.

Piperazinilnom group includes, for example, 2-piperazinilnom group and 3-personilnya group.

Tetrahydrofuranyl group includes, for example, 2-tetrahydropyranyloxy gr the foam and 3-tetrahydropyranyloxy group.

Phenyl group substituted by alkoxygroup having 1-4 carbon atoms, includes, for example, 4-metoksifenilny group.

Morpholinoethyl group having 5-10 carbon atoms, means an alkyl group with a linear or branched chain having 1-6 carbon atoms, substituted morpholinopropan, and includes, for example, morpholinomethyl group, 1-morpholinoethyl group and 2-morpholinoethyl group.

Acylaminoalkyl group having 2-14 carbon atoms, means an alkyl group with a linear or branched chain having 1-6 carbon atoms, a substituted mono - or dialkylamino with a linear or branched chain, and includes, for example, N-methylaminomethyl group, N-ethylaminomethyl group, N,N-dimethylaminomethylene group and N,N-dimethylaminoethyl group.

An alkyl group having 1-6 carbon atoms, substituted by 1-5 halogen atoms, means a saturated alkyl group with a linear or branched chain having 1-6 carbon atoms, and includes, for example, chloromethylene group, triptorelin group and panafcortelone group.

In addition, the pharmaceutically acceptable salt is a salt with an alkaline metal, alkaline earth metal, ammonium, alkylammonium or similar connection, or, alternatively, a salt with inorganic acid or organic acid is one. Examples of the above salts include sodium salt, potassium salt, calcium salt, ammonium salt, an aluminium salt, salt of triethylamine, acetate, propionate, butyrate, formate, triptorelin, maleate, tartrate, citrate, stearate, succinate, ethylsuccinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, aconsultant, 2-hydroxyethanesulfonic, bansilalpet, paratoluenesulfonyl, lauryl, malate, aspartate, glutamate, adipat, salt with cysteine, salt with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, salt with acrylic polymer and salt with carboxyvinyl polymer.

The best way of carrying out the invention

Connection in accordance with the present invention can be synthesized, for example, by the method described below. Thus, the reaction of a combination of compounds represented by formula (a)

(where R1has the above significance, with a compound represented by the formula (b)

(where X1X2and R2have the same meanings as above and X represents halogen atom) can be used in a solvent in the presence of a catalyst, such as tetrakis(triphenylphosphine)palladium, and base, synthesizing the compound of the present invention, before the purposes of the formula (C)

(where X1X2, R1and R2have the same meanings as described above).

In addition, the compound (C) can oxidize, for example, a method in which compound (C) is subjected to contact with the palladium (II) chloride in dimethyl sulfoxide, or a method in which compound (C) is subjected to contact with potassium permanganate in acetone solution buffer, synthesizing the compound of the present invention, represented by formula (d)

(where X1X2, R1and R2have the same meanings as described above).

In addition, the interaction of the compounds represented by formula (e)

R4-CHO(e)

(where R4has the above meaning), ammonium acetate can be carried out in a solvent, synthesizing the compound of the present invention, represented by formula (f)

(where X1X2, R1, R2and R4have the same meanings as described above).

Alternatively, the connection in accordance with the present invention can also be synthesized, for example, in the following way. That is, the interaction of the compounds presented is of formula (g)

(where R3has the above significance, with a compound of the above formula (d) and ammonium acetate can be carried out in a solvent, synthesizing the compound of the present invention, represented by formula (f)

(where X1X2, R1, R2and R4have the same meanings as described above).

In addition, the connection in accordance with the present invention can also be synthesized, for example, in the following way. That is, the compound represented by formula (C)

(where X1X2, R1and R2have the same meanings as described above)can be, for example, be hydrated by treatment with a sulfate mercury (II) and sulfuric acid in a solvent, synthesizing the compound of the present invention, represented by formula (h) or (i)

(where X1X2, R1and R2have the same meanings as above), or a mixture of compounds of the above formula (h) and the above formula (i). Further, the compound of formula (h) or formula (i) or a mixture of compounds of formulae (h) and (i) can, for example, be treated with sodium nitrite in aqueous hydrochloric acid to obtain the compound represented by formula (j) or fo is mulloy (k)

(where X1X2, R1and R2have the same meanings as above), or a mixture of compounds of the above formulas (j) and (k) and, further, to handle compound represented by the formula (e)

R4-CHO(e)

(where R4has the above meaning), and ammonium acetate in a solvent. Then, the resulting composition restore triethylphosphite or similar compound, optionally in a solvent, to obtain the compounds of the present invention, represented by formula (f)

(where X1X2, R1, R2and R4have the same meanings as described above).

Connection in accordance with the present invention can also be synthesized, for example, in the following way. That is, using a method in which the compound represented by the formula (l)

R1-CH2CO2H(l)

(where R1has the above meaning), is subjected to the interaction with N,O-dimethylhydroxylamine through gelegenheid acid in which rastvoritele or condensed with N,O-dimethylhydroxylamine in the presence of a condensing agent, such as hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, receiving the compound represented by formula (m)

(where R1has the above meaning), and then the compound represented by formula (n)

(where R2has the above meaning and X' represents a halogen atom or a hydrogen atom) is subjected to interaction with a base, such as n-utility in the solvent. The resulting anion can be given the opportunity to interact with the compound of the above formula (m) to obtain the compounds of the present invention, represented by formula (o)

(where R1and R2have the same meanings as described above). Further, the compound of formula (o) can be halogenate the copper bromide (II) in a solvent to obtain compounds of the present invention, represented by formula (p)

(where R1and R2have the same meanings as above and X represents halogen atom). Then, the compound represented by formula (b), provide an opportunity to interact with the compound represented by the formula (q)

(where R4has the above meaning), in a solvent to obtain compounds according to the present image is the shadow, represented by formula (r)

(where R1, R2and R4have the same meanings as described above). In addition to the compound represented by formula (r), provide an opportunity to interact with the compound represented by formula (s)

R3-X(s)

(where R3has the above meaning and X represents a halogen atom), in a solvent in the presence of a base such as sodium hydride, and then it is possible to synthesize the compound of the present invention, represented by formula (t) or formula (u)

(where R1, R2, R3and R4have the same meanings as above), or a mixture of compounds of the above formula (t) and (u).

Connection in accordance with the present invention can also be synthesized by the interchange of R1, R2, R3and R4in the compounds of the present invention, obtained in the ways described.

Examples of the base used for the above reactions are: salt of alkali metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, diminati, guy is reed sodium, amide and sodium tert-butylcalix; amines, such as triethylamine, Diisopropylamine, pyrrolidine and piperidine; sodium acetate and potassium acetate. As the reaction solvent can be used a solvent which is inert during the reaction, and it includes water; alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol; ethers such as dioxane and tetrahydrofuran; dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform, acetone and acetic acid.

EXAMPLES

The present invention will now be described in more detail with reference to examples and sample tests.

Example 1

The synthesis of compound 217

The triethylamine (25 ml), tetrakis(triphenylphosphine)palladium (642 mg, and 5 itinerant(1,3)dioxol (1,79 g) are added to a solution of 2-iodine-4-methylthiazole (2.50 g) in acetonitrile (50 ml) and the mixture is then stirred for 4 hours at boiling under reflux. After evaporation of the solvent the residue is purified column flash chromatography on silica gel using a mixed solvent of ethyl acetate, chloroform and hexane, obtaining specified in the title compound (2.38 g).

1H-NMR (300 MHz, CDCl3) δ ppm: 2.49 USD (3H, d, J=0.9 Hz), 6,01 (2H, s), for 6.81 (1H, d, J=8.1 Hz), 6,91 (1H, d, J=0.9 Hz), 7,01 (1H, d, J=1.6 Hz), 7,13 (1H, DD, J=8,1, 1,6 Hz); TPL: 111,5-112,0°C.

The palladium (II) chloride (139 mg) are added to a solution of compound 217 (1,91 g) in dimethyl sulfoxide (13 ml) and the mixture is then stirred for 3 h at 125°C. the resulting solution was diluted with ethyl acetate and then filtered, the resulting solution was sequentially washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The resulting residue is purified column flash chromatography on silica gel using a mixed solvent of ethyl acetate and hexane, obtaining specified in the title compound (960 mg).

1H-NMR (300 MHz, CDCl3) δ ppm: 2,52 (3H, d, J=0.9 Hz), 6,09 (2H, c), to 6.88 (1H, d, J=8.7 Hz), 7,40 (1H, d, J=0.9 Hz), of 7.48-rate of 7.54 (2H, m); TPL: 131, 5mm-132,5°C.

Example 3

Synthesis of compound 8

Ammonium acetate (1.50 g) are added to a solution of compound 203 (893 mg) and 4-cyanobenzaldehyde (510 mg) in acetic acid (40 ml) and the mixture is then stirred for 4 hours at boiling under reflux. After evaporation of the solvent, the solution is neutralized aqueous ammonia and extracted twice with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The resulting residue is purified by recrystallization from methanol and chloroform to obtain specified in the title compound (575 mg).

1H-NMR (300 MHz, DMSO-d6δ ppm: a 2.36 (3H, c)6,10 (2H, c), 7,06 (1H, d, J=7,6 Hz), 7,20 (1H, c), 7,55 (1H, userd, J=7,6 Hz), 7,73 (1H, users), of 7.97 (2H, d, J=8,3 Hz), compared to 8.26 (2H, d, J=8,3 Hz), of 13.05 (1H, users).

Example 4

Synthesis of compound (9)

Potassium hydroxide (584 mg) are added to a solution of compound 8 (575 mg) in tert-butanol (100 ml) and the mixture is then stirred overnight while boiling under reflux. After evaporation of the solvent, the solution is diluted with ethyl acetate and washed with water. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The obtained residue is recrystallized from methanol to obtain specified in the header of the compound (556 mg).

1H-NMR (300 MHz, DMSO-d6) δ ppm: a 2.36 (3H, c), 6,10 (2H, c), 7,05 (1H, d, J=8.1 Hz), 7,18 (1H, c), 7,42 (1H, users), 7,58 (1H, userd, J=8.1 Hz), of 7.75 (1H, users), 7,94-8,08 (3H, m), 8,15 (2H, d, J=8,2 Hz), 12,87 (1H, users); TPL: 276,0-277,0°C.

Example 5

Synthesis of compound 213

(1) thionyl chloride (39,6 g) and a drop of dimethylformamide are added to a solution of benzo(1,3)dioxol-5-luxusni acid (30.0 g) in toluene (200 ml) and the mixture is then stirred for 2.5 h at 60°C, after removal of the solvent receive crude benzo(1,3)dioxol-5-ilocationid. A solution of sodium hydroxide (20,0 g) in water (150 ml) are added to a solution of the hydrochloride of N,O-dimethylhydroxylamine (19.5 g) in toluene (200 ml) at 0°C, then add Aut crude benzo(1,3)dioxol-5-ilocationid and the mixture is then stirred for 3 hours The reaction mixture is extracted with toluene and dried over anhydrous magnesium sulfate, then the solvent is evaporated to obtain crude 2-benzo(1,3)dioxol-5-yl-N-methoxy-N-methylacetamide (35.4 g).

1H-NMR (200 MHz, CDCl3) δ ppm: 3,19 (3H, c)to 3.64 (3H, c)to 3.67 (2H, c), of 5.82 (2H, c), of 6.71-6,83 (3H, m).

(2) 2.6m solution of n-utility in hexane (34 ml) was added dropwise to a solution of 4-methylthiazole (8.0 g) in tetrahydrofuran (150 ml) at -70°C and the mixture is stirred for 30 minutes Then added dropwise a solution of 2-benzo(1,3)dioxol-5-yl-N-methoxy-N-methylacetamide (20,0 g) in tetrahydrofuran (20 ml) and the mixture stirred for 1 h the resulting solution, to which is added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate after drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The resulting residue is purified column flash chromatography on silica gel using a mixed solvent of ethyl acetate and hexane, to obtain 2-benzo(1,3)dioxol-5-yl-1-(4-methylthiazole-2-yl)ethanone (19.3 g).

1H-NMR (300 MHz, CDCl3) δ ppm: 2,56 (3H, d, J=0.9 Hz), 4,34 (2H, c), to 5.93 (2H, c), 6,76 (1H, d, J=7.8 Hz), to 6.80 (1H, DD, J=7,8, and 1.6 Hz), 6,86 (1H, d, J=1.6 Hz), 7,25 (1H, q, J=0.9 Hz).

(3) Bromide copper (II) (24,7 g) is added to a stirred solution of 2-benzo(1,3)dioxol-5-yl-1-(4-methylthiazole-2-yl)ethanone (19.3 g) in ethyl acetate (200 ml) and chloroform (200 ml) and the mixture is stirred in ECENA 3 hours boiling under reflux. After filtration of the reaction mixture the solvent is evaporated. The resulting residue is purified column flash chromatography on silica gel using a mixed solvent of ethyl acetate and chloroform, obtaining specified in the connection header (8,96 g).

1H-NMR (300 MHz, CDCl3) δ ppm: 2,54 (3H, d, J=0.9 Hz), 5,95 of 5.99 (2H, m), of 6.75 (1H, d, J=8.1 Hz), 6,78 (1H, c), to 7.09 (1H, DD, J=7,9, 1.9 Hz), 7,21 (1H, d, J=1.9 Hz), 7,32 (1H, q, J=0.9 Hz).

Example 6

Synthesis of compound 20

1-Acetylpyridine (1.63 g) are added to a solution of compound 213 (1,83 g) in acetonitrile (20 ml) and the mixture is stirred for 16 hours at the boil under reflux. After evaporation of the solvent, the solution was diluted with chloroform and then washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The obtained residue elute mixed solvent of chloroform and hexane through NH-silica gel (Chromatorex, produced by Fuji Silysia Chemical LTD.) column flash chromatography. The remainder of the eluate is recrystallized from a mixed solvent of ethyl acetate and hexane to obtain specified in the title compound (590 mg).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 2,09 (3H, c), of 2.34 (3H, d, J=0.9 Hz), 6,07 (2H, c), 6,98 (1H, d, J=8,2 Hz), 7,13 (1H, d, J=0.9 Hz), was 7.45 (1H, DD, J=8,2) and 1.7 Hz), 7,78 (1H, d, J=1.7 Hz), to 11.28 (1H, users), 11,76 1H, users); TPL: 169,0-173, 0mm°C.

Example 7

Synthesis of compound 19

Concentrated sulfuric acid (0,58 ml) are added to a mixed solution of compound 20 (578 mg) with methanol (10 ml) and water (10 ml) and the mixture stirred for 3 h at boiling under reflux. It added to an aqueous solution of potassium hydroxide to make the reaction solution alkaline, and then the resulting solution was extracted 3 times with chloroform. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The obtained residue elute mixed solvent of methanol and chloroform through NH-silica gel column flash chromatography. The remainder of the eluate is recrystallized from a mixed solvent of chloroform and hexane to obtain specified in the title compound (260 mg).

1H-NMR(300 MHz, CDCl3) δ ppm: 2,39 (3H, d, J=0.9 Hz), 6,00 (2H, c), 6,60 (1H, d, J=0.9 Hz), at 6.84 (1H, d, J=7.9 Hz), to 7.15 (1H, DD, J=7,9) and 1.7 Hz), 7,19 (1H, d, J=1.7 Hz); TPL: 205,5-208,0°C.

Example 8

Synthesis of compound 21

n-butyl chloride (36 μl) are added to a solution of compound 19 (70 mg) in pyridine (0.7 ml) and the mixture is stirred for 2.5 h at room temperature. After diluting the reaction mixture with ethyl acetate, the resulting mixture was washed successively with saturated aqueous dissolve the ohms of sodium bicarbonate and brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The resulting residue is purified through NH-silica gel column flash chromatography, using as solvent chloroform, obtaining specified in the title compound (84 mg).

1H-NMR (300 MHz, DMSO-d6) δ ppm: of 0.93 (3H, t, J=7,3 Hz), and 1.63 (2H, kW, J=7,3, 7,3 Hz), 2,28-to 2.41 (5H, m), 6,07 (2H, c), 6,98 (1H, d, J=8.1 Hz), 7,12 (1H, c), 7,46 (1H, userd, J=8.1 Hz), 7,79 (1H, users), 11,25 (1H, users), 11,78 (1H, users).

Example 9

Synthesis of compound 135

A solution of ammonium acetate (4,20 g) in methanol (55 ml) was added to a solution of compound 203 (1.50 g) and 4-(1,3-dioxo-1,3-dihydroindol-2-yl)Butyraldehyde (1.78 g) in tetrahydrofuran (55 ml) and the mixture is stirred for 2.5 h while boiling under reflux. After evaporation of the solvent, the solution was diluted with chloroform and then washed with saturated aqueous sodium carbonate. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The resulting residue is purified column flash chromatography on silica gel using a mixed solvent of methanol and chloroform, obtaining specified in the title compound (970 mg).

1H-NMR(300 MHz, DMSO-d6) δ ppm: 2,05-2,10 (2H, m), 2,32 (3H, d, J=0.8 Hz), 2,70 (2H, t, J=7,7 Hz), 3,70 (2H, t, J=6.8 Hz), the 6.06 (2H, c), 6,98 (1H, d, J=8,2 Hz), 7,07 (1H, is, J=1.1 Hz), 7,46 (1H, DD, J=8,2, 1.9 Hz), to 7.77-to 7.84 (5H, m), 12,19 (1H, c).

Example 10

Synthesis of compound 29

Hydrazinoacetate (984 mg) are added to a solution of compound 135 (928 mg) in ethanol (50 ml) and the mixture stirred for 3 h at boiling under reflux. After evaporation of the solvent the residue is purified column chromatography on NH-silica gel using a mixed solvent of methanol and chloroform, obtaining specified in the title compound (458 mg).

1H-NMR (200 MHz, CDCl3) δ ppm: 1,90 (2H, TT, J=6,4, 6.4 Hz), 2,43 (3H, d, J=0.9 Hz), 2,84-a 3.01 (4H, m), of 5.99 (2H, c), 6,69 (1H, d, J=0.9 Hz), at 6.84 (1H, d, J=8.1 Hz), 7,26 (1H, DD, J=8,1) and 1.7 Hz), 7,38 (1H, d, J=1.7 Hz).

Example 11

Synthesis of compound 30

Hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54 mg) are added to a solution of compound 29 (80 mg), butyric acid (25 mg) and monohydrate of 1-hydroxybenzotriazole (38 mg) in dimethylformamide (0.8 ml) and the mixture is stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and brine. After drying the organic layer over magnesium sulfate the solvent is evaporated. The obtained residue elute mixed solvent of methanol and chloroform column of chromatogr is via on NH-silica gel. The remainder of the eluate is recrystallized from a mixed solvent of ethyl acetate and hexane to obtain specified in the title compound (18 mg).

1H-NMR (300 MHz, CDCl3) δ ppm: to 0.96 (3H, t, J=7.4 Hz), 1.69 in (2H, kW, J=7,4, 7,4 Hz), 1,80-of 1.94 (2H, m), 2,22 (2H, t, J=7.4 Hz), a 2.45 (3H, d, J=0.9 Hz), and 2.79 (t, J=6.2 Hz), 3,40 (2H, TD, J=6,2, 5,9 Hz), of 5.99 (2H, c), 6,03 (1H, users), 6,72 (1H, c), 6,87 (1H, d, J=8.1 Hz), 7,39 (1H, userd, J=8.1 Hz), 7,55 (1H, users); TPL: 134,0-139,0°C.

Example 12

Synthesis of compound 31

Compound 29 (100 mg) and acetic acid (51 ml) are added to a solution of formaldehyde (72 mg) in tetrahydrofuran (2 ml) and the mixture stirred for 30 min at room temperature. The reaction mixture, which is added to triacetoxyborohydride sodium (248 mg), stirred for 16 hours To the reaction mixture an aqueous solution of sodium bicarbonate and the mixture extracted twice with ethyl acetate. After drying the combined organic layers over magnesium sulfate the solvent is evaporated. The resulting residue is purified column flash chromatography on NH-silica gel using a mixed solvent of methanol and chloroform, obtaining specified in the title compound (74 mg).

1H-NMR (200 MHz, DMSO-d6) δ ppm: 1,82 (2H, TT, J=7,7, 6.9 Hz), of 2.15 (6H, c), of 2.28 (2H, t, J=6.9 Hz), 2,35 (3H, d, J=0.9 Hz), to 2.66 (2H, t, J=7,7 Hz), 6,07 (2H, c), of 6.99 (1H, d, J=8.1 Hz), to 7.09 (1H, d, J=0.9 Hz), 7,46 (1H,userd, J=8.1 Hz), of 7.75 (1H, users), of 12.33 (1H, users).

Example 13

Synthesis of compound 167

Ammonium acetate (4,20 g) are added to a mixed solution of compound 203 (1.50 g) and methyl-6-oxohexanoate (1,38 g) with tetrahydrofuran (20 ml) and methanol (10 ml) and the mixture is stirred for 4 hours at boiling under reflux. After evaporation of the solvent, the solution was diluted with chloroform and washed with saturated aqueous sodium carbonate. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The resulting residue is purified column flash chromatography on NH-silica gel using a mixed solvent of methanol and chloroform, obtaining specified in the title compound (797 mg).

1H-NMR (300 MHz, CDCl3) δ ppm: 1,67-1,90 (4H, m), 2,39 (2H, t, J=6.9 Hz), 2,43 (3H, d, J=1.1 Hz), of 2.81 (2H, t, J=7.2 Hz), of 3.69 (3H, c), 6,00 (2H, c), 6,69 (1H, users), 6,86 (1H, d, J=8.1 Hz), 7,17-7,37 (2H, m); TPL: 158,0-159,0°C.

Example 14

Synthesis of compound 41

An aqueous solution (10 ml) of sodium hydroxide (227 mg) are added to a solution of compound 167 (767 mg) in methanol (25 ml) and the mixture stirred for 1 h at boiling under reflux. The resulting solution was neutralized 2n. a solution of hydrochloric acid and then extracted twice with chloroform. After drying the organic the Loya over anhydrous magnesium sulfate the solvent is evaporated to obtain specified in the title compound (790 mg).

1H-NMR (300 MHz, CDCl3) δ ppm: 1,82 (2H, m), is 2.05 (2H, m), 2,42 (3H, c), of 2.53 (2H, t, J=6.8 Hz), or 3.28 (2H, t, J=7.8 Hz), 6,03 (2H, c), 6,89 (1H, d, J=0.9 Hz), 6.89 in (1H, d, J=8.1 Hz), 7,14 (1H, d, J=1.7 Hz), 7,20 (1H, DD, J=for 8.1 and 1.7 Hz).

Example 15

Synthesis of compound 42

Hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (69 mg) are added to a solution of compound 41 (120 mg), n-Propylamine (21 mg) and monohydrate of 1-hydroxybenzotriazole (49 mg) in N,N-dimethylformamide (1.2 ml) and the mixture is stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and brine. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The resulting residue is purified column flash chromatography on silica gel using a mixed solvent of ethyl acetate and methanol, to obtain specified in the title compound (51 mg).

1H-NMR (300 MHz, CDCl3) δ ppm: of 0.91 (3H, t, J=7,3 Hz)and 1.51 (2H, kW, J=7,3, 7,3 Hz), 1,69 is 1.91 (4H, m), and 2.27 (2H, t, J=6.4 Hz), 2,44 (3H, d, J=0.9 Hz), 2,84 (2H, t, J=6,7 Hz), 3,21 (2H, TD, J=7,3, 6,1 Hz), USD 5.76 (1H, users), 6,00 (2H, c)of 6.71 (1H, d, J=0.9 Hz), 6,86 (1H, d, J=8.1 Hz), 7,33 (1H, userd, J=8.1 Hz), the 7.43 (1H, users).

Example 16

Synthesis of compound 45

Thionyl chloride (0.3 ml) are added to a solution of compound 41 (131 mg) in chlorofo the IU (1 ml) and the mixture is stirred for 2.5 h while boiling under reflux. After evaporation of the solvent from the reaction mixture there was added 28% aqueous ammonia and the resulting mixture is extracted twice with chloroform. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The resulting residue is purified column flash chromatography on silica gel using a mixed solvent of methanol and chloroform, obtaining specified in the title compound (42 mg).

1H-NMR(300 MHz, DMSO-d6) δ ppm: 1,48-of 1.75 (4H, m), is 2.09 (2H, t, J=7.2 Hz), 2,34 (3H, d, J=1.0 Hz), of 2.64 (2H, t, J=7.5 Hz), 6,07 (2H, c), 6,72 (1H, users), of 6.99 (1H, d, J=8,2 Hz), to 7.09 (1H, d, J=1.0 Hz), 7,26 (1H, users), to 7.50 (1H, DD, J=8,2) and 1.7 Hz), 7,82 (1H, d, J=1.7 Hz), 12,21 (1H, users).

Example 17

Synthesis of compound 216

(1) Trimethylsilylacetamide (106 ml), copper iodide (I) (0,948 g) dichloride and bis(triphenylphosphine)palladium (II) (1.75 g) are added to 6-bromobenzimidazole (53,3 g) in triethylamine (260 ml) and the mixture is stirred for 2.5 h at 80°C. After evaporation of the solvent, the resulting residue loaded onto a short column (silicagel; hexane:ethyl acetate=2:1) for elution. The remainder of the eluate is recrystallized from a mixed solvent of hexane-ethyl acetate followed by obtaining 6-trimethylsilylamodimethicone (20,0 g) as a colorless powder (TPL: 104,5-105,0°C). Repeatedly subjecting the filtrate recrystallization (n-hexane-utilized the t), receive secondary crystals (12.1 g), tertiary crystals (9,68 g) and Quaternary crystals (4.61 in) as colorless powder.

1H-NMR (300 MHz, CDCl3) δ ppm: 0,27 (9H, c), 7,60 (1H, DD, J=8,5, and 1.6 Hz), with 8.05 (1H, DD, J=8,5, 0.6 Hz), of 8.09 (1H, DD, J=1,6, 0.6 Hz), 9,03 (1H, c).

(2) potassium Carbonate (29,7 g) are added to a solution of 6-trimethylsilylamodimethicone (45,1 g) in methanol (600 ml) and the mixture stirred for 1.5 h at room temperature. The reaction solution is filtered and then the resulting mixture was sequentially washed with methanol and ethyl acetate. The filtrate is concentrated, added water and then extracted with ethyl acetate. The organic layer, washed with brine, dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (hexane:ethyl acetate=4:1→1:1) to obtain 6-ethynylbenzoate (30.0 g) as a pale yellow solid (TPL: 47,5-49,0°C).

1H-NMR (300 MHz, CDCl3) δ ppm: 3,16 (1H, c), 7,63 (1H, DD, J=8,4, and 1.6 Hz), 8,08 (1H, DD, J=8,5, 0.6 Hz), 8,11 (1H, d, J=1.4 Hz), 9,04 (1H, c)

(3) Triethylamine (280 ml) and tetrakis(triphenylphosphine)palladium (6.8 g) are added to a solution of 6-ethynylbenzoate (29.5 g) and 2-iodine-4-methylthiazole (45,9 g) in acetonitrile (600 ml) under nitrogen atmosphere. The resulting solution was heated at the boil under reflux in the course is e 5 h under nitrogen atmosphere. After evaporation of the solvent the residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1→1:1) to obtain specified in the connection header (41,2 g) as a pale yellow powder (TPL: 116,0-117,0°C).

1H-NMR (200 MHz, CDCl3) δ ppm: of 2.51 (3H, d, J=0.9 Hz), of 6.96 (1H, d, J=0.9 Hz),7,71 (1H, DD, J=8,4, 1.8 Hz), to 8.12 (1H, d, J=7.9 Hz), to 8.20 (1H, d, J=1,8 Hz), 9,07 (1H, c)

Example 18

Synthesis of compound 204

Potassium permanganate (49,3 g) are added to a mixed solution of compound 216 (40,0 g), acetone (3.0 l)-buffer* (1.8 l) and the mixture stirred for 30 min at room temperature. The reaction solution is cooled on ice and after slow addition of sodium nitrite (20.7 g) added dropwise 10% sulfuric acid (210 ml). After stirring the resulting solution for 30 minutes while cooling on ice, the supernatant is extracted with chloroform and the aqueous layer was additionally extracted with chloroform. The combined organic layer was washed with saturated aqueous sodium bicarbonate and then dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1→1:1) to obtain the specified title compound (30.1 g) as a pale yellow powder (TPL: 134,5-135,5C).

Buffer*: sodium Hydrogen carbonate (6.8 g) bezvadny magnesium sulfate (68,0 g), dissolved in water (3.0 l).

1H-NMR (300 MHz, CDCl3) δ ppm: of 2.51 (3H, d, J=0.8 Hz), was 7.45 (1H, d, J=0.8 Hz), 8,16 (1H, DD, J=8,5) and 1.7 Hz), compared to 8.26 (1H, DD, J=8,5, 0.6 Hz), 8,64 (1H, DD, J=1,7, 0.6 Hz), 9,23 (1H, c).

Example 19

Synthesis of compound 16

Ammonium acetate (321 mg) are added to a solution of compound 204 (200 mg) and cyanobenzaldehyde (109 mg) in acetic acid (8.0 ml) and the mixture is stirred for 2 hours at boiling under reflux and for 14 h at room temperature. The reaction solution loaded with water and neutralize 28% aqueous ammonia. The resulting solution was extracted twice with chloroform, and after drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The obtained residue was washed with chloroform and the crystals are filtered with obtaining specified in the title compound (138 mg) as a colorless powder (TPL: 295,0-295,5°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), from 7.24 (1H, c), of 8.00 (2H, d, J=8.5 Hz), 8,10-of 8.37 (4H, m), 8,86 (1H, users), 9,48 (1H, c), 13,33 (1H, users).

Example 20

Synthesis of compound 50

The hydrogen peroxide solution (1,56 ml) are added to a suspension of compound 16 (130 mg) and potassium carbonate (148 mg) in dimethyl sulfoxide (5,2 ml) and the mixture stirred for 1 h at 100°C. the resulting suspension allow to cool to room temperature, to ablaut water and then precipitated crystals are filtered out. The crystals are purified column chromatography on silica gel (chloroform:methanol=100:0→90:10) and then recrystallized (chloroform-methanol-n-hexane) to obtain specified in the connection header (75,4 mg) as a pale yellow powder (TPL: >300°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 7,22 (1H, c), 7,44 (1H, users), 8,00-to 8.20 (7H, m), 8,87 (1H, users), for 9.47 (1H, c), 13,15 (1H, users).

Example 21

Synthesis of compound 71

(1) 1,02M solution diisobutylaluminium in toluene (27 ml) is added dropwise to a solution of tert-butoxycarbonylamino (2.00 g) in toluene (40 ml) at -70°C and the mixture stirred for 1 h the Reaction solution, to which is added methanol (10 ml) at -70°C, quenched, and then leave at room temperature. After diluting the reaction solution with ethyl acetate, the resulting solution was washed with 1N. aqueous solution of hydrochloric acid. The organic layer was washed with brine, filtered through celite, dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=60:40→30:70) to give tert-butyl(2-oxoethyl)carbamate (895 mg) as a colourless oil.

1H-NMR (300 MHz, CDCl3) δ ppm: of 1.46 (9H, c), 4,05-4,11 (2H, m), is 5.18 (1H, c), to 9.66 (1H, c).

(2) the Solution aceta is and ammonium (811 mg) in methanol (5.0 ml) are added to a solution of compound 204 (300 mg) and tert-butyl(2-oxoethyl)carbamate (294 mg) in tetrahydrofuran (10 ml) and the mixture stirred for 2 h at room temperature. The reaction solution, to which is added a saturated aqueous sodium hydrogen carbonate solution, neutralized and then extracted twice with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=40:60→20:80) to obtain the specified title compound (291 mg) as a pale yellow amorphous substance.

1H-NMR (300 MHz, CDCl3) δ ppm: for 1.49 (9H, c), is 2.44 (3H, d, J=0.9 Hz), 4,43 (2H, d, J=6,1 Hz), from 5.29 (1H, users), 6,76 (1H, c), 7,86 (1H, DD, J=8,5, 1.8 Hz), 8,18 (1H, d, J=8,4 Hz), 8,55 (1H, users), 9,04 (1H, c).

Example 22

Synthesis of compound 70

4h. Hydrogen chloride/dioxane (1.0 ml) are added to a solution of compound 71 (100 mg) in chloroform (10 ml) and the mixture stirred for 1.5 h at room temperature. The solvent is evaporated and then the residue is recrystallized (methanol-diethyl ether) to obtain the specified title compound (80 mg) as a pale brown powder (TPL: 229,0-233,0°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 2,37 (3H, d, J=0.9 Hz), 4,16-of 4.25 (2H, m), 7,22 (1H, d, J=0.9 Hz), 8,08 (1H, DD, J=8,6, 1.8 Hz), 8,18 (1H, d, J=8.5 Hz), at 8.60 (3H, usher.), of 8.90 (1H, d, J=0.9 Hz), for 9.47 (1H, c).

Example 23

Synthesis of compound 72

A solution of ammonium acetate (of 5.40 g) in methanol (50 ml) was added to the solution with the unity 204 (2.00 g) and (1,3-dioxo-1,3-dihydroindol-2-yl)acetaldehyde (2.00 g) in tetrahydrofuran (70 ml) and the mixture is stirred for 3.5 h at room temperature. The reaction solution, to which is added a saturated aqueous sodium hydrogen carbonate solution, neutralized and then extracted 3 times with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=40:60→20:80), (chloroform:methanol=95:5) and (chloroform:ethyl acetate=35:65) to obtain the specified title compound (1.9 g) as a pale yellow powder (TPL: 250,5-255,0°C).

1H-NMR (300 MHz, CDCl3) δ ppm: 2,44 (3H, d, J=0.8 Hz), to 5.08 (2H, c), 6,74 (1H, users), 7,71-7,94 (6H, m), 8,16 (1H, d, J=8.5 Hz), 9,03 (1H, c).

Example 24

Synthesis of compound 105

(1) Hydrazinoacetate (2,12 g) are added to a suspension of compound 72 (1.88 g) in ethanol (45 ml) and the mixture stirred for 24 h at room temperature. Methanol and chloroform added to the reaction solution for the complete dissolution of the contained sediment. After adding NH-silica gel in the resulting solution, the solvent is evaporated. The residue is purified column chromatography on NH-silica gel (chloroform:methanol=95:5) and then column chromatography on silica gel (chloroform:methanol=90:10→chloroform:methanol:ammonia= 100:1:1) to obtain the free form of compound 70 (761 mg) as a pale yellow amorphous substance.

1H-NMR (300 MHz, CDCl3) δ ppm: 2,44 (3H, the, J=1.1 Hz), of 4.12 (2H, c), of 6.73 (1H, usher.), 7,87 (1H, DD, J=8,5) and 1.7 Hz), 8,17 (1H, DD, J=8,5, 0.5 Hz), of 8.47 (1H, usher.), 9,03 (1H, c).

(2) Butyrylcholine (of 0.21 ml) was added dropwise into a solution of the free form of compound 70 (600 mg) and triethylamine (370 mg) in chloroform (15.0 ml) under cooling on ice. After stirring for 30 minutes under ice cooling, the reaction solution loaded with water and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. After purification of the residue column chromatography on silica gel (ethyl acetate→chloroform:methanol=90:10) purified substance is recrystallized (ethyl acetate-hexane) to obtain the specified title compound (441 mg) as a yellow powder (TPL: 190,0-191,0°C.

1H-NMR (300 MHz, DMSO-d6) δ ppm: to 0.89 (3H, t, J=7.4 Hz), 1,47-of 1.64 (2H, m), and 2.14 (2H, t, J=7.5 Hz), was 2.34 (3H, c), 4,36 (2H, d, J=5.6 Hz), to 7.15 (1H, d, J=0.9 Hz), 8,08 (1H, c)to 8.14 (1H, d, J=8.5 Hz), a 8.34 (1H, t, J=5,1 Hz), cent to 8.85 (1H, c), 9,43 (1H, c), 12,72 (1H, c).

Example 25

Synthesis of compound 88

Compound 72 (100 mg) are added to a suspension of sodium hydride (13 mg) in N,N-dimethylformamide (2.0 ml) under ice cooling and the mixture is stirred for 10 minutes the resulting suspension, which adds methyliodide (0,14 ml) under ice cooling, stirred for 1.5 hours under ice cooling. The reaction solution, to the which add the brine, extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. After purification of the residue column chromatography on silica gel (ethyl acetate) purified substance is recrystallized (ethyl acetate-hexane) to obtain the specified title compound (35 mg) as a colorless powder (TPL: 257,0-259,5°C).

1H-NMR (300 MHz, CDCl3) δ ppm: 2,28 (3H, d, J=0.9 Hz), the 3.65 (3H, c), is 5.06 (2H, c), 6,60 (1H, d, J=0.9 Hz), 7,56 (1H, DD, J=8,4, 1.7 Hz), 7,72-to 7.93 (4H, m), 8,11 (1H, d, J=1.6 Hz), 8,23 (1H, d, J=8.5 Hz), which is 9.09 (1H, c).

The filtrate is concentrated to obtain 2-(4-benzothiazol-6-yl-1-methyl-5-(4-methylthiazole-2-yl)-1H-imidazol-2-ylmethyl)isoindole-1,3-dione (15 mg), as represented by the following formula, in the form of a colorless, amorphous substance.

1H-NMR (300 MHz, CDCl3) δ ppm: 2,54 (3H, d, J=1.1 Hz), a 3.87 (3H, c), of 5.05 (2H, c), to 6.95 (1H, d, J=0.9 Hz), 7,52 (1H, DD, J=8,5) and 1.7 Hz), 7,72-to 7.93 (4H, m), of 7.96 (1H, DD, J=8,5, 0.6 Hz), 8,17 (1H, DD, J=1,7, 0.5 Hz), 8,93 (1H, c).

Example 26

Synthesis of compound 89

Hydrazinoacetate (290 mg) are added to a suspension of compound 88 (328 mg) in methanol (5.0 ml) and the mixture stirred for 3 h at room temperature. The reaction solution was diluted with water and extracted twice with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The remainder of the sight of the with column chromatography on silica gel (chloroform:methanol =90:10→chloroform:methanol:ammonia=100:10:1) to obtain the specified title compound (166 mg) as a colorless powder (TPL: USD 183.0-184,5°C).

1H-NMR (300 MHz, CDCl3) δ ppm: a 2.36 (3H, d, J=0.9 Hz), 3,52 (3H, c)4,06 (2H, c), is 6.61 (1H, d, J=0.9 Hz), 7,56 (1H, DD, J=8,5, and 1.6 Hz), 8,10 (1H, DD, J=1,6, 0.5 Hz), compared to 8.26 (1H, DD, J=8,4, 0.5 Hz), 9,10 (1H, c).

Example 27

Synthesis of compound 90

Butyrylcholine (0.06 ml) is added dropwise to a solution of compound 89 (159 mg) and triethylamine (101 mg) in chloroform (5.0 ml) under cooling with ice. After stirring for 1 h under ice cooling, the reaction solution loaded with water and twice extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. After purification of the residue column chromatography on silica gel (chloroform:methanol=9:1) and then column chromatography on NH-silica gel (ethyl acetate) purified substance is recrystallized (ethyl acetate-hexane) to obtain the specified title compound (137 mg) as a colorless powder (TPL: 212,5-213,5°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: to 0.88 (3H, t, J=7.4 Hz), 1,47-to 1.63 (2H, m), 2,09-to 2.18 (5H, m), 3,47 (3H, c), to 4.46 (2H, d, J=5.8 Hz),? 7.04 baby mortality (1H, d, J=0.9 Hz), to 7.64 (1H, DD, J=8,5) and 1.7 Hz), 8,17 (1H, DD, J=8,5, 0.5 Hz), a 8.34 (1H, DD, J=1,7, 0.5 Hz), 8,46 (1H, ushort, J=5.6 Hz), 9,49 (1H, c).

Example 28

Synthesis of compound 95

(1) Butyrylcholine (4.6 ml) is added dropwise to a solution of 2-(methylamino)ethanol (3.0 g) and triethylamine (11,0 ml) in chloroform (30 ml) while cooling Edom. The mixture is stirred for 20 minutes under cooling with ice and then add water. The mixture is extracted twice with chloroform. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:3→1:4 and then (chloroform:methanol=9:1) to give N-(hydroxyethyl)-N-methylbutylamine (2.8 g) as a pale yellow oil.

1H-NMR (300 MHz, CDCl3) δ ppm: 0,91-1,02 (3H, m), 1,58-to 1.77 (2H, m), 2.26 and is 2.46 (2H, m), 2,96 and of 3.07 (3H, 2c), 3,47, and of 3.56 (2H, 2T, J=5.7 Hz), of 3.78 (2H, t, J=5,1 Hz).

(2) Reagent dessa-Martin (1.9 grams) are added to a solution of N-(hydroxyethyl)-N-methylbutylamine (600 mg) in dichloromethane (6.0 ml) and the mixture stirred for 1.5 h at room temperature. The solvent is evaporated to obtain crude crystals of N-methyl-N-(2-oxoethyl)butylamide without purification. To a solution of N-methyl-N-(2-oxoethyl)butylamide and connections 204 (301 mg) in tetrahydrofuran (15 ml) add a solution of ammonium acetate (820 mg) in methanol (5.0 ml) and the mixture is stirred for 14 h at room temperature. The reaction solution is neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted twice with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on NH (hexane:ethyl acetate=35:65→chloroform:methanol=95:5) and then recrystallized (ethyl acetate-hexane) to obtain the specified title compound (233 mg) as a pale yellow powder (TPL: 175,0-175,5°C).

1H-NMR(300 MHz, DMSO-d6) δ ppm: 0,87-and 0.98 (3H, m), 1,48-to 1.67 (2H, m), 2.26 and is 2.44 (5H, m), 2,90, and of 3.07 (3H, 2c), 4,63 (2H, c), to 7.15 (1H, m), 8,03-8,19 (2H, m), 8,84 (1H, m), 9,44 (1H, d, J=1.2 Hz), 12,67 and 12.84 (1H, 2 user.).

Example 29

Synthesis of compound 96

(1) 1,02M solution diisobutylaluminium (16 ml) in toluene are added dropwise to a solution of (2-oxopyrrolidin-1-yl)acetate (1.01 g) in toluene (10 ml) at -78°C and the mixture stirred for 1 h, the Reaction solution is quenched with methanol at -78°C, then diluted with 1N. aqueous solution of hydrochloric acid and allowed to warm to room temperature with stirring. The reaction solution is filtered through celite and then the filtrate is dried. The residue is purified column chromatography on silica gel (chloroform:methanol=95:5→90:10 to obtain 2-oxopyrrolidin-1-ylacetamide (120 mg) as a colourless oil.

1H-NMR (300 MHz, CDCl3) δ ppm: 2,04-of 2.20 (2H, m), 2,46 (2H, t, J=8,2 Hz), 3,47 (2H, t, J=8,2 Hz), 4,17 (2H, c), being 9.61 (1H, c).

(2) a Solution of ammonium acetate (640 ml) in methanol (5.0 ml) are added to a solution of 2-oxopyrrolidin-1-ylacetamide (120 mg) and compound 204 (230 mg) in tetrahydrofuran (10 ml) and the mixture stirred for 1.5 h at room temperature. The reaction solution is neutralized with a saturated aqueous solution of sodium bicarbonate and then twice extracted with chloroform. P is after drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on NH-silica gel (ethyl acetate→chloroform:methanol=90:10) and then recrystallized (chloroform-ethyl acetate-hexane) to obtain the specified title compound (161 mg) as a colorless powder (TPL: of 209.5-210,5°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 1,90-of 2.05 (2H, m), 2,25 is 2.33 (2H, m), 2,33 (3H, c), of 3.43 (2H, t, J=7.2 Hz), 4,50 (2H, c), to 7.15 (1H, d, J=1.1 Hz), 8,08 (1H, users), 8,13 (1H, d, J=8,4 Hz), 8,81 (1H, users), 9,43 (1H, c), 12,82 (1H, user.).

Example 30

Synthesis of compound 197

(1) Oxazolidin-2-he (331 mg) are added to a suspension of sodium hydride (181 mg) in N,N-dimethylformamide (5.0 ml) under ice cooling and the mixture is stirred for 20 minutes To the resulting suspension is added dropwise a solution of 2-pomatoceros (1,11 g) in N,N-dimethylformamide (3.0 ml) under ice cooling and the mixture is then stirred for 1 h at room temperature. The reaction solution was diluted with ethyl acetate and washed twice with brine. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:3) to give 3-(2-benzyloxyethyl)oxazolidin-2-she (281 mg) as a colourless oil.

1H-NMR (300 MHz, CDCl3) δ ppm: 3.46 in-to 3.52 (2H, m), 3,63-and 3.72 (4H, m), 4,25-4,34 (2H, m), a 4.53 (2H, c), 7,27-7,40 (5H, m).

(2) 20% palladium Hydroxide (138 mg) are added to a solution of 3-(2-benzyloxyethyl)oxazolidin-2-she (278 mg) in methanol (10 ml) and the mixture stirred for 2 h at room temperature in a hydrogen atmosphere. The reaction solution is filtered through celite and then the solvent is evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol=90:10) to give 3-(2-hydroxyethyl)oxazolidin-2-she (144 mg) as a colourless oil.

1H-NMR (200 MHz, CDCl3) δ ppm: to 2.29 (1H, usher.), 3,39-3,47 (2H, m), 3,64-of 3.77 (2H, m), 3,78-to 3.89 (2H, m), 4,30-4,43 (2H, m).

(3) Reagent dessa-Martin (516 mg) are added to a solution of 3-(2-hydroxyethyl)oxazolidin-2-she (144 mg) in dichloromethane (5.0 ml) and the mixture stirred for 1 h at room temperature. The solvent is evaporated to obtain crude crystals (2-oxoacridine-3-yl)acetaldehyde without purification. To a suspension of (2-oxoacridine-3-yl)acetaldehyde and connection 204 (286 mg) in tetrahydrofuran (10 ml) add a solution of ammonium acetate (771 mg) in methanol (5.0 ml) and the mixture is stirred for 2 weeks at room temperature. The reaction solution is neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted twice with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified colonoscopy because it allows the Noah chromatography on NH-silica gel (chloroform→chloroform:methanol=95:5) and then recrystallized (methanol-ethyl acetate-hexane) to obtain the specified title compound (149 mg) as a colorless powder (TPL: 232,0-233,0°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 3,60-3,68 (2H, m), 4,28 is 4.36 (2H, m), of 4.49 (2H, c), 7,16 (1H, d, J=0.9 Hz), 8,08 (1H, usher.), to 8.14 (1H, d, J=8,4 Hz), 8,83 (1H, usher.), 9,44 (1H, c), 12,93 (1H, usher.).

Example 31

Synthesis of compound 138

A solution of ammonium acetate (5.35 g) in methanol (40 ml) are added to a solution of acylglycerol (45% aqueous solution of 2.36 g) and compound 204 (2.0 g) in tetrahydrofuran (60 ml) and the mixture stirred for 12 h at room temperature. The resulting solution was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=5:5→3:7→1:9) and then column chromatography on NH-silica gel (chloroform:methanol=50:1), followed by recrystallization (ethyl acetate-hexane) to obtain the specified title compound (1.01 g) as a colorless powder (TPL: 238,5-239,0°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: to 1.37 (3H, t, J=7,1 Hz), 2,31 (3H, c), and 4.40 (2H, q, J=6.8 Hz), 7,24 (1H, c), 8,03 (1H, d, J=8.7 Hz), 8,14 (1H, d, J=8.5 Hz), a total of 8.74 (1H, c), 9,48 (1H, c), 14,02 (1H, c).

Example 32

The synthesis of compound 82

Compound 138 (700 mg) are added to a suspension of sociallyengaged (134 mg) in tetrahydrofurane (30 ml) at-40°C, the mixture is stirred until until the temperature reaches 0°C and further stirred for 30 min at 0°C. the resulting solution was loaded 2n. aqueous solution of hydrochloric acid and stirred for 5 minutes the Solution is diluted with ethyl acetate and sequentially washed with saturated aqueous sodium bicarbonate and brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol=20:1→10:1) and recrystallized (chloroform-methanol-hexane) to obtain the specified title compound (309 mg) as a pale orange powder (TPL: 222,0-223,0°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 2,34 (3H, d, J=0.8 Hz), a 4.53 (2H, c), of 5.50 (1H, users), to 7.15 (1H, d, J=0.9 Hz), 8,05-8,18 (2H, m), 8,87 (1H, users), 9,43 (1H, c), 12,80 (1H, usher.).

Example 33

Synthesis of compound 198

Utilizationa (57 mg) are added to a suspension of compound 82 (239 mg), copper chloride (I) (7 mg) and pyridine (1.0 ml) in toluene (2.0 ml) and the mixture stirred for 2 h at 50°C. To the resulting solution was added water and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol=30:1) and paracrystal soviat (ethyl acetate-hexane) to obtain the specified title compound (151 mg) as a colorless powder (TPL: 144, 0mm-145,0°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: was 1.04 (3H, t, J=7.2 Hz), was 2.34 (3H, c), 2,99-of 3.12 (2H, m), 5,04 (2H, c), 7,18 (1H, d, J=0.8 Hz), 7,34 (1H, ushort, J=5.7 Hz), 8,03-to 8.20 (2H, m), of 8.90 (1H, users), to 9.45 (1H, c), 13,06 (1H, users).

Example 34

Synthesis of compound 81

(1) 1,02M solution diisobutylaluminium in toluene (23,4 ml) is added dropwise to a solution of 5-propertyeditors-2-she (1.50 g) in toluene (30 ml) for 50 min at -70°C. in a nitrogen atmosphere and the mixture is stirred for 1 h at -70°C. the Reaction solution was quenched with methanol (3.0 ml) at -70°C. and then left at room temperature. After adding 10% aqueous citric acid solution, the reaction solution is stirred for 5 minutes and Then the resulting solution was extracted with ethyl acetate and the organic layer washed with brine. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated and then the residue is purified column chromatography on silica gel (hexane:ethyl acetate=90:10→80:20) to give 5-propellerdriven-2-ol (440 mg) as a colourless oil.

1H-NMR (300 MHz, CDCl3) δ ppm: 0,9-0,98 (3H, m), 1,29-2,21 (7H, m), 2,45-of 2.56 (1H, m), 3,94-4.26 deaths (1H, m), 5,41-the ceiling of 5.60 (1H, m).

(2) a Solution of ammonium acetate (1.98 g) in methanol (18 ml) are added to a solution of compound 204 (741 mg) and 5-propellerdriven-2-ol (435 mg) in tetrahydrofuran (25 ml) and the mixture is PE is amerivault for 13 h at room temperature. After dilution with ethyl acetate to the reaction solution was sequentially washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (ethyl acetate→chloroform:methanol=40:1). The purified substance was dissolved in methanol, to which is added 4n. a solution of hydrogen chloride/ethyl acetate. After evaporation of the solvent the resulting material is recrystallized (methanol-ethyl acetate) to obtain the specified title compound (165 mg) as colorless powder.

1H-NMR (300 MHz, DMSO-d6) δ ppm: 0,82-to 0.96 (3H, m), 1,25-for 1.49 (4H, m), 1.70 to of 2.09 (2H, m), 2,33-2,48 (3H, m), 2,90 be 3.29 (2H, m), 3,51 (1H, m), 7,37 (1H, c), to 7.84 (1H, DD, J=8,5, 1.8 Hz), 8,29 (1H, d, J=8.5 Hz), 8,61 (1H, d, J=1.7 Hz), 9,58 (1H, c).

Example 35

Synthesis of compound 201

Reagent dessa-Martin (400 mg) are added to a solution of the free form of compound 81 (342 mg) in dichloromethane (7.0 ml) and the mixture stirred for 2 h at room temperature. In the reaction solution is added water and extracted with chloroform. After washing the organic layer with brine resulting material is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=1:1→3:7→1:9) and then recrystallized (tracecut-hexane) to obtain the specified title compound (225 mg) as a colorless powder (TPL: 145,0-146,0°C).

1H-NMR (300 MHz, CDCl3) δ ppm: of 0.93 (3H, t, J=7.4 Hz), 1,58-1,71 (2H, m)2,44 (3H, d, J=0.9 Hz), of 2.44-2.50 (2H, m), 2.95 and-3,11 (4H, m), 6,72 (1H, d, J=0.9 Hz), 7,86 (1H, DD, J=8,5, 1.8 Hz), 8,16 (1H, DD, J=8,5, 0.6 Hz), 8,48 (1H, user.), 9,03 (1H, c).

Example 36

Synthesis of compound 73

(1) Di-tert-BUTYLCARBAMATE (by 5.87 g) is added dropwise to a solution of 2-butylaminoethyl (3.00 g) in chloroform (30 ml) and the mixture stirred for 15 min at room temperature. The solvent is evaporated to obtain tert-butylmethyl(2-hydroxyethyl)carbamate (6,10 g) as a colourless oil.

1H-NMR (300 MHz, CDCl3) δ ppm: of 0.93 (3H, t, J=7,3 Hz), 1,22-1,56 (13H, m), up 3.22 (2H, t, J=7,3 Hz)to 3.38 (2H, t, J=5,1 Hz), 3,69-of 3.80 (2H, m).

(2) Reagent dessa-Martin (2.15 g) are added to a solution of tert-butylmethyl(2-hydroxyethyl)carbamate (1,00 g) in dichloromethane (20 ml) at room temperature and the mixture is stirred for 15 min at room temperature. After evaporation of the solvent the residue is purified column chromatography on silica gel (hexane:ethyl acetate=80:20→75:25) to give tert-butylmethyl(2-hydroxyethyl)carbamate (755 mg) as a colourless oil.

1H-NMR (300 MHz, CDCl3) δ ppm: of 0.93 (3H, t, J=7.2 Hz), 1,20-1.55V (13H, m), 3,19-to 3.36 (2H, m), 3,82 (1H, c)to 3.92 (1H, c), 9,58 (1H, c).

(3) a Solution of ammonium acetate (2.00 g) in methanol (20 ml) are added to a solution of the program 204 (750 mg) and tert-butylmethyl(2-oxoethyl)carbamate (728 mg) in tetrahydrofuran (30 ml) and the mixture stirred for 1 h at room temperature. The reaction solution was diluted with ethyl acetate and then washed sequentially with water and brine. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=80:20→50:50) to obtain the specified title compound (865 mg) as a colorless amorphous substance.

1H-NMR (300 MHz, DMSO-d6) δ ppm: to 0.88 (3H, t, J=7.2 Hz), 1,20-1,59 (13H, m), of 2.34 (3H, c), 3,29 (2H, users), to 4.46 (2H, users), 7,14 (1H, c), 8,02-8,18 (2H, m), 8,86 (1H, users), 9,43 (1H, c)of 12.73 (1H, users).

Example 37

Synthesis of compound 74

Compound 73 (875 mg) in a 10% solution of hydrogen chloride in methanol (10 ml) is stirred for 4 h at room temperature. The reaction solution is stirred for 30 min at room temperature after addition of 4n. solution of hydrogen chloride in dioxane (1.0 ml). After evaporation of the solvent the residue is recrystallized (methanol-diethyl ether) to obtain the specified title compound (730 mg) as colorless powder.

1H-NMR (300 MHz, DMSO-d6) δ ppm: of 0.91 (3H, t, J=7.4 Hz), 1,31-to 1.45 (2H, m), of 1.62 and 1.75 (2H, m), of 2.38 (3H, d, J=1.1 Hz), 3.00 and is 3.15 (2H, m), 4,32-to 4.41 (2H, m), 7,25 (1H, d, J=0.9 Hz), to 8.12 (1H, DD, J=8,7, 1.8 Hz), 8,19 (1H, DD, J=8,7, 0.6 Hz), to 8.94 (1H, d, J=1.2 Hz), 9,49 (1H, c), RS 9.69 (2H, users).

Example 38

Synthesis of compound 78

(1) Di-tert-BUTYLCARBAMATE (4,17 g) are added to piperidine-4-ylmethanol (2.00 g) in a mixed solvent of ethyl acetate (20 ml) and tetrahydrofuran (10 ml) and the mixture is stirred for 22 h at room temperature. The solvent is evaporated, the residue is added ethyl acetate and sequentially washed with saturated aqueous ammonium chloride and brine. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated to obtain tert-butyl-4-hydroxyethylpiperazine-1-carboxylate (4,06 g) as a light pink oil.

1H-NMR (200 MHz, CDCl3) δ ppm: 1,02-1,82 (5H, m)of 1.46 (9H, c), 2,59-of 2.81 (2H, m), 3,43-3,59 (2H, m), as 4.02-to 4.23 (2H, m).

(2) Reagent dessa-Martin (7,89 g) are added to a solution of tert-butyl 4-hydroxyethylpiperazine-1-carboxylate (of 4.00 g) in dichloromethane (40 ml) and the mixture stirred for 1.5 h at room temperature. After dilution with ethyl acetate to the reaction solution was sequentially washed with 1% aqueous sodium hydroxide solution and brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1→1:1) to obtain tert-butyl-4-formylpiperidine-1-carboxylate (2,43 g) as a colourless oil.

1H-NMR (200 MHz, CDCl3) δ ppm: of 1.46 (9H, c), 1,38 of 1.99 (4H, m),is 2.41 (1H, m), 2,83-3,03 (2H, m), a 3.87-4,08 (2H, m), to 9.66 (1H, c).

(3) a Solution of ammonium acetate (5.35 g) in methanol (35 ml) was added to a solution of compound 204 (2.00 g) and tert-butyl-4-formylpiperidine-1-carboxylate (2,22 g) in tetrahydrofuran (70 ml) and the mixture stirred for 15 h at room temperature. After dilution with ethyl acetate to the reaction solution was sequentially washed with water and brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol=50:1→20:1) to obtain specified in the connection header (3,27 g) as a pale yellow amorphous substance.

1H-NMR (200 MHz, CDCl3) δ ppm: to 1.47 (9H, c), 1,67-2,17 (4H, m), 2,43 (3H, d, J=0.9 Hz), was 2.76-to 3.09 (3H, m), 4,13-to 4.33 (2H, m), of 6.68 (1H, c), a 7.85 (1H, DD, J=8,6, 1.5 Hz), 8,17 (1H, d, J=8,4 Hz), 8,30 (1H, c), of 9.02 (1H, c).

Example 39

Synthesis of compound 77

4h. A solution of hydrogen chloride in ethyl acetate (10.4 ml) are added to a solution of compound 78 (2.00 g) in methanol (20 ml) and the mixture stirred for 1 h at room temperature and then for 1.5 h at 50°C. After diluting the reaction solution with chloroform, the organic layer was washed with saturated aqueous sodium bicarbonate. The aqueous layer was saturated with sodium chloride and then extracted with chloroform. Unite the military organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on NH-silica gel (chloroform:methanol=50:1→20:1) and then recrystallized from ethyl acetate to obtain specified in the connection header (793 mg) as colorless powder (TPL: 199,5-200,5°C).

1H-NMR (300 MHz, CDCl3) δ ppm: 1,76-2,17 (4H, m), of 2.45 (3H, d, J=0.9 Hz), 2,72-to 2.85 (2H, m), to 3.02 (1H, m), 3,20-of 3.32 (2H, m), of 6.68 (1H, users), a 7.85 (1H, DD, J=8,5) and 1.7 Hz), 8,17 (1H, DD, J=8,5, 0.3 Hz), 8,32 (1H, usher.), 9,03 (1H, c).

Example 40

Synthesis of compound 226

(1) After adding dropwise tert-butylnitrite (1,99 g) to a suspension of 2-amino-5-methylthiazole (2.00 g) in acetonitrile (20 ml) under cooling with ice to it gradually add the copper bromide (II) (4.30 m). The resulting suspension is stirred for 3 h at 0°C. To the reaction solution was added 1N. hydrochloric acid (100 ml) and then extracted with ethyl acetate (200 ml). After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (neutral environment; hexane:ethyl acetate=80:20). to obtain 2-bromo-5-methylthiazole (1.31 g) as a yellow oil.

1H-NMR (300 MHz, CDCl3) δ ppm: 2,44 (3H, d, J=1.2 Hz), 7,25 (1H, d, J=1.1 Hz).

(2) 2,59M solution of n-utility in hexane (2,40 ml) is added dropwise to a solution of 2-bromo-5-methylthiazole (1,00 g) in tetrahydrofuran (10 is l) at -78°C and the mixture stirred for 40 min at the same temperature. To it was added dropwise a solution of iodine (1.55 g) in tetrahydrofuran (5 ml) at -78°C and the mixture is stirred for 30 min at the same temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride (20 ml)to quench the reaction, and the resulting solution was left at room temperature. In the resulting solution was added water (20 ml) and twice extracted with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium thiosulfate (50 ml) and then dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (hexane:ethyl acetate=85:15) to give 2-iodine-5-methylthiazole (764 mg) as a brown oil.

1H-NMR (300 MHz, CDCl3) δ ppm: (300 MHz, CDCl3) δ ppm: 2,47 (3H, d, J=1.2 Hz), 7,26 (1H, d, J=1.2 Hz).

(3) To a solution of 6-ethynylbenzoate (483 mg)synthesized in example 17-(2), and 2-iodine-5-methylthiazole (740 mg) in acetonitrile (10 ml), add triethylamine (15 ml) and tetrakis(triphenylphosphine)palladium (179 mg) in a nitrogen atmosphere. The resulting solution was heated to boiling under reflux for 6 h under nitrogen atmosphere. After evaporation of the solvent the residue is purified column chromatography on silica gel (hexane:ethyl acetate=85:15→50:50) to obtain the specified title compound (601 mg) as yellow powder. (TPL: 137,0-140,0°C).

1H-NMR (200 MHz, CDCl3) δ ppm: 2,53 (3H, d, J=1.1 Hz), 7,53 (1H, d, J=1.1 Hz), 7,71 (1H, DD, J=8,5, and 1.6 Hz), 8,13 (1H, DD, J=8,5, 0.6 Hz), to 8.20 (1H, DD, J=1,6, 0.5 Hz), 9,07 (1H, c).

Example 41

Synthesis of compound 227

Potassium permanganate (733 mg) is added to the compound 226 (593 mg) in a mixed solution of acetone (45,7 ml)buffer* (25,5 ml) and the mixture stirred for 30 min at room temperature. The reaction solution is cooled on ice and after slowly adding sodium nitrite (297 mg) are added dropwise 10% sulfuric acid (3.0 ml). After stirring the solution for 15 minutes while cooling on ice to the reaction solution was added chloroform (100 ml) and water (30 ml) and then the resulting solution was filtered through celite. The filtrate is separated and the aqueous layer was extracted again with chloroform (100 ml). The combined organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified double-column chromatography on silica gel (neutral; hexane:ethyl acetate=65:35→45:55), (neutral; hexane:ethyl acetate=5:95) to obtain specified in the title compound (429 mg) as a yellow powder (TPL: 154,0-155,0C).

Buffer*: sodium Hydrogen carbonate (6.8 g) and anhydrous magnesium sulfate (68,0 g)dissolved in water (3.0 l).

1H-NMR (300 MHz, CDCl3) δ ppm: to 2.65 (3H, d, J=1.1 Hz), 7,78 (1H, d, J=1.1 Hz), 8,15 (1H, DD, =8,5, the 1.7 Hz), 8,24 (1H, DD, J=8,5, 0.6 Hz), 8,63 (1H, DD, J=1,7, 0.6 Hz), which 9.22 (1H, c).

Example 42

Synthesis of compound 228

Acetaldehyde (0.15 ml) and a solution of ammonium acetate (900 mg) in methanol (10 ml) are added to a solution of compound 227 (414 mg) in tetrahydrofuran (10 ml) and the mixture is stirred for 13 h at room temperature. The reaction solution, to which is added a saturated aqueous solution of sodium bicarbonate (70 ml) for neutralization, extracted twice with ethyl acetate (150 ml). The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (ethyl acetate→chloroform:methanol=90:10) and then recrystallized (n-hexane-ethylacetate) obtaining specified in the title compound (230 mg) as a colorless powder (TPL: 210,0-211,0°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: is 2.37 (3H, c), 2,42 (3H, c), 7,44 (1H, users), 8,09-of 8.15 (2H, m), 8,78 (1H, usher.), 9,42 (1H, c), of 12.53 (1H, usher.).

Example 43

Synthesis of compound 239

(1) Imidazole (9,63 g) and chlorine-tert-butyldimethylsilyl (9,77 g) are added to a solution of 1-(2-hydroxyethyl)-2-imidazolidinone (to 7.67 g) in N,N-dimethylformamide (75 ml) and the mixture stirred for 2 h at room temperature. In the reaction solution, water is added, diluted with ethyl acetate and then organicheskikh washed with brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=35:65→0:100) to give 1-[2-(tert-butyldimethylsilyloxy)ethyl]imidazolidin-2-it (8,73 g) as a colourless solid (TPL: 53,5-to 57.0°C).

1H-NMR (200 MHz, CDCl3) δ ppm: 0,06 (6H, c)to 0.89 (9H, c), 3,30 (2H, t, J=5.3 Hz), 3,34-of 3.46 (2H, m), 3,54-the 3.65 (2H, m), 3,74 (2H, t, J=5.3 Hz).

(2) sodium Hydride (393 mg), washed twice with hexane and then added tetrahydrofuran (10 ml). The vessel is cooled in an ice bath and added dropwise 1-[2-(tert-butyldimethylsilyloxy)ethyl]imidazolidin-2-he (2.00 g) in tetrahydrofuran (10 ml), keeping the temperature inside the vessel below 10°C. After stirring the resulting solution for 15 min to it added dropwise itmean (766 μl) at the same temperature and the mixture is stirred for 20 min at room temperature. To it add water to quench the reaction, and the resulting solution was diluted with ethyl acetate. The resulting mixture was successively washed with 2n. hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:is tracecut=35:65→0:100, chloroform:methanol=4:1) to obtain a mixture of oily substances (*). All aqueous layers are combined and concentrated and the resulting residue suspended in a mixture of chloroform-methanol and the mixture is then filtered. After drying the obtained material over anhydrous magnesium sulfate the solvent is evaporated. The previously obtained residue and the mixture of oils (*) purified column chromatography on silica gel (chloroform:methanol=9:1) to give 1-(2-hydroxyethyl)-3-methylimidazolidine-2-it (907 mg) as a pale yellow oil.

1H-NMR (300 MHz, CDCl3) δ ppm: 2,80 (3H, c), 3,29 is-3.45 (6H, m), 3,74-with 3.79 (2H, m).

(3) Reagent dessa-Martin (1,094 g) are added to a solution of 1-(2-hydroxyethyl)-3-methylimidazolidine-2-it (372 mg) in chloroform (10 ml) and the mixture stirred for 1.5 h at room temperature. The reaction solution, to which is added methanol (10 ml), compound 204 (400 mg) and ammonium acetate (856 mg), stirred for 2.5 h at room temperature. After diluting the reaction solution with chloroform, the resulting solution was washed with saturated aqueous sodium bicarbonate. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified 3 times column chromatography on silica gel (chloroform:methanol=20:1→15:1), (chloroform:acetone=2:1→1:1) and column chromatography on silicagel the type NH (chloroform) and recrystallized (ethyl acetate-diethyl ether) to obtain the specified title compound (27 mg) as a colorless powder (TPL: 232,0-233,5°C).

1H-NMR (200 MHz, CDCl3) δ ppm: 2,45 (3H, d, J=0.9 Hz), and 2.83 (3H, c), 3,30-of 3.54 (4H, m), 4,47 (2H, c), of 6.75 (1H, c), 7,89 (1H, DD, J=8,6, 1.5 Hz), 8,12-8,21 (1H, m), 9,03 (1H, c).

Example 44

Synthesis of compound 240

(1) sodium Hydride (393 mg), washed twice with hexane and then added tetrahydrofuran (10 ml). The vessel is cooled in an ice bath and added dropwise a solution of the compound synthesized in example 43-(1) (2.00 g) in tetrahydrofuran (10 ml), keeping the temperature inside the vessel below 10°C. After stirring the resulting solution for 5 min thereto are added dropwise di-tert-BUTYLCARBAMATE (2,31 g) in tetrahydrofuran (10 ml) at the same temperature and the mixture is stirred for 2 h at room temperature and then for 18 h at 50°C. To the reaction mixture successively added saturated aqueous a solution of ammonium chloride and ethyl acetate, and after washing the organic layer with brine and drying over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain tert-butyl-3-[2-(tert-butyldimethylsilyloxy)ethyl]-2-Oxymetazoline-1-carboxylate (1.54 g) as a colorless powder (TPL: 35,5-45,5°C).

1H-NMR (300 MHz, CDCl3) δ ppm: 0,05 (6H, c)to 0.89 (9H, c)of 1.53 (9H, c)to 3.35 (2H, t, J=5,2 Hz), 3,48-3,55 (2H, m), 3,71-with 3.79 (4H, m).

(2) 1.0m solution of fluoride, Tetra-n-butylamine in tetrahydrofuran (4,35 ml) was added to a solution of tert-butyl 3-[2-(tert-butyldimethylsilyloxy)ethyl]-2-Oxymetazoline-1-carboxylate (1.50 g) in tetrahydrofuran (15 ml) and the mixture stirred for 1 h at room temperature. To the reaction solution was added methanol (1 ml) and the solvent is evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol=20:1→10:1) to give tert-butyl 3-(2-hydroxyethyl)-2-Oxymetazoline-1-carboxylate (940 mg) as a colourless oil.

1H-NMR (200 MHz, CDCl3) δ ppm: 1,39 is 1.58 (9H, m), 3.27 to 3,86 (8H, m).

(3) Reagent dessa-Martin (1.47 g) are added to a solution of tert-butyl 3-(2-hydroxyethyl)-2-Oxymetazoline-1-carboxylate (800 mg) in chloroform (8 ml) and the mixture stirred for 1 h at room temperature. The reaction mixture was diluted with ethyl acetate, filtered through celite and the filtrate is evaporated solvent. The residue, to which is added tetrahydrofuran (30 ml), methanol (15 ml), compound 204 (1.0 g) and ammonium acetate (2.14 g), stirred for 16 h at room temperature. After diluting the reaction solution with chloroform, the resulting solution was washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with chloroform. After joining integrally the layers together and drying over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol=40:1→20:1) to obtain tert-butyl-3-[5-benzothiazol-6-yl-4-(4-methylthiazole-2-yl)-1H-imidazol-2-ylmethyl]-2-Oxymetazoline-1-carboxylate (983 mg) as a pale yellow amorphous substance.

1H-NMR (300 MHz, CDCl3) δ ppm: for 1.49 (9H, c), is 2.44 (3H, d, J=0.9 Hz), 3,50-to 3.58 (2H, m), 3,76-a-3.84 (2H, m), 4,58 (2H, c), 6,76 (1H, c), 7,88-of 7.96 (1H, m)to 8.14 (1H, d, J=8.7 Hz), 9,03 (1H, c).

(4) 4h. a solution of hydrogen chloride in ethyl acetate (4,03 ml) was added to a solution of tert-butyl 3-[5-benzothiazol-6-yl-4-(4-methylthiazole-2-yl)-1H-imidazol-2-ylmethyl]-2-Oxymetazoline-1-carboxylate (800 mg) in methanol (8 ml) and the mixture stirred for 18 h at room temperature. After diluting the reaction solution with chloroform, the resulting solution was washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with chloroform. After combining the organic layers together and drying over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol=20:1→10:1) and recrystallized (chloroform-ethyl acetate) to obtain the specified title compound (393 mg) as colorless powder (TPL: 236,0-237,0°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 3,23-of 3.32 (2H, m), 3,40-of 3.48 (2H, m), 4,35 (2H, c), 6,53 (1H, c), 7,16 (1H, d, J=0.9 Hz), 8,10-8,17 (2H, m), 8,86 (1H, users), 9,44 (1H, c), 12,83 (1H, users).

Example 45

Synthesis of compound 242

(1) Sulfuric acid (2,86 ml) and water (6 ml) are successively added to a solution of chromium oxide (VI) in water (3 ml) under cooling with ice. The resulting solution was added dropwise to a solution of 2-hydroxyatomoxetine (1,00 g) in acetone (22 ml) under ice cooling while maintaining the internal temperature below 20°C and the mixture stirred for 2 h at room temperature. To it was added 2-propanol to repay the reaction, the resulting solution was diluted with ethyl acetate and filtered through celite. The filtrate is washed with brine and the aqueous layer was extracted with ethyl acetate. After combining the organic layers together and drying over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (neutral; chloroform:methanol=9:1→4:1) to obtain oxetan-2-carboxylic acid (83 mg) as a pale yellow oil.

1H-NMR (200 MHz, CDCl3) δ ppm: 2,70-2,90 (1H, m), 3,01-is 3.21 (1H, m), 4,68-to 4.87 (2H, m), 5,19 (1H, DD, J=9,2, 6,6 Hz).

(2) the Hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (167 mg) are added to a solution of compound 70 (301 mg), oxetan-2-carboxylic acid (74 mg) and monohydrate of 1-hydroxybenzotriazole (118 mg) in N,N-dimethylformamide (1.5 ml) and the mixture is stirred during the course the e 3 h at room temperature. After diluting the reaction mixture with chloroform, the mixture was washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with chloroform. After combining the organic layers and dry over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol=30:1→15:1) and recrystallized (chloroform-ethyl acetate) to obtain the specified title compound (265 mg) as a colorless powder (TPL: 224,5-226,5°C).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 2,52-2,63 (1H, m), 2,86-of 3.00 (1H, m), of 4.38-of 4.67 (4H, m), 4,99 (1H, DD, J=9,0, 6.5 Hz), to 7.15 (1H, d, J=0.9 Hz), 8,03-8,17 (2H, m), charged 8.52 (1H, t, J=5.8 Hz), 8,87 (1H, c), 9,44 (1H, c), 12,72 (1H, c).

The compounds listed in table 1, receive, using the methods of examples 1-48, using appropriate substances.

Example 46

Synthesis of compound 250

(1) tert-Butylnitrite (679 mg) is added dropwise to a solution of 2-amino-4-cryptomaterial (1,00 g) in acetonitrile (10 ml) under cooling with ice and then gradually add iodide copper (I) - (1.25 g). The reaction mixture was stirred for 2 h at 0°C, then loaded 1H. hydrochloric acid (100 ml) and extracted twice with ethyl acetate (100 ml). The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The remainder of cidaut column chromatography on silica gel (hexane:ethyl acetate=80:20) to give 2-iodine-4-cryptomaterial (747 mg) as a brown solid (TPL: in 35.5 to 36.0°C).

1H-NMR (300 MHz, CDCl3) δ ppm: of 7.75 (1H, q, J=0.9 Hz).

(2) To a solution of 6-ethynylbenzoate (402 mg)synthesized in example 17-(2), and 2-iodine-4-cryptomaterial (708 mg) in acetonitrile (8 ml), add triethylamine (12.5 ml) and tetrakis(triphenylphosphine)palladium (151 mg) in a nitrogen atmosphere and then heated at the boil under reflux for 3 h under nitrogen atmosphere. After evaporation of the solvent the residue is purified column chromatography on silica gel (hexane:ethyl acetate=85:15→70:30) to obtain the specified title compound (573 mg) as a yellow powder (TPL: 153,0-154,0°C).

1H-NMR (300 MHz, CDCl3) δ ppm: 7,74 (1H, DD, J=8,5, and 1.6 Hz), 7,81 (1H, q, J=0.9 Hz), 8,16 (1H, DD, J=8,5, 0.6 Hz), 8,24 (1H, DD, J=1,7, 0.6 Hz), 9,11 (1H, c).

Example 47

Synthesis of compound 251

Potassium permanganate (572 mg) is added to the compound 250 (562 mg) in a mixed solution of acetone (35,9 ml)buffer* (20,0 l) and the mixture stirred for 30 min at room temperature. The reaction mixture is cooled on ice and after slowly adding sodium nitrite (234 mg) are added dropwise 10% sulfuric acid (2.4 ml). After stirring the resulting solution for 15 minutes while cooling on ice to the reaction solution was added chloroform (100 ml) and water (30 ml) and then the resulting solution was filtered through a goal is. The filtrate is separated and the aqueous layer was again extracted with chloroform (100 ml). The combined organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (neutral; hexane:ethyl acetate=50:50) to obtain the specified title compound (113 mg) as a yellow powder (TPL: 163,5 is 16.5°C).

Buffer*: sodium Hydrogen carbonate (6.8 g) and anhydrous magnesium sulfate (68,0 g)dissolved in water (3.0 l).

1H-NMR (300 MHz, CDCl3) δ ppm: 8,14-8,32 (3H, m), 8,69 (1H, m), 9,27 (1H, c).

Example 48

Synthesis of compound 244

Acetaldehyde (0.15 ml) and a solution of ammonium acetate (194 mg) in methanol (3 ml) was added to a solution of compound 251 (107 mg) in tetrahydrofuran (5 ml) and the mixture is stirred for 3.5 h at room temperature. The reaction mixture is neutralized by adding a saturated aqueous solution of sodium bicarbonate (50 ml) and twice extracted with ethyl acetate (100 ml). The organic layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=30:70→1:99) and then recrystallized (n-hexane-ethylacetate) obtaining specified in the title compound (25 mg) as colorless powder. (TPL: to 190.5-192,0°C).

1H-NMR (300 MHz, DMSO-d6 ) δ ppm: 2,40 (3H, c), 8,03 (1H, DD, J=8,6, 1.5 Hz), 8,15 (1H, d, J=8.6 Hz), a 8.34 (1H, c), 8,89 (1H, users), to 9.45 (1H, c), 12,78 (1H, usher.).

Table 1
Connection # The structural formula of the compoundSalt form, if applicableMP (°C)Data1H-NMR
Connection 1(300 MHz, DMSO-d6) δ ppm: 6,11 (2H, c), 7,07 (1H, d, J=7.9 Hz), 7,52 (1H, userd, J=7.9 Hz), to 7.61-to 7.61 (2H, m), 7,81 (1H, d, J=3,4 Hz), 7,98 (2H, d, J=8,4 Hz), of 8.27 (2H, d, and 8.4 Hz), 13,10 (1H, users)
Connection 2248,0-249,0(300 MHz, DMSO-d6) δ ppm: 6,11 (2H, c), 7,06 (1H, d, J=7.8 Hz), the 7.43 (1H, users), 7,53 (1H, userd, J=7.8 Hz), 7,60-of 7.70 (2H, m), 7,80 (1H, d, J=3.3 Hz), 7,93-8,07 (3H, m), 8,16 (2H, d, J=8,2 Hz), 12,90 (1H, users)
Connection 3(300 MHz, DM what About the-d 6) δ ppm: the 7.65 (1H, m), 7,92 (1H, d, J=3.3 Hz), 8,02 (2H, d, J=8,2 Hz), 8,08 (1H, d, J=3.3 Hz), 8,24 (1H, m), 8,46 (2H, d, J=8,2 Hz), 8,75-9,00 (2H, m)
Connection 4255,5-256,0(300 MHz, DMSO-d6) δ ppm: 7 34-7,48 {2H, m), to 7.77 (1H, d, J=3.3 Hz), 7,88-8,10 (5H, m), 8,25-to 8.40 (2H, m), a total of 8.74 (1H, d, J=4.0 Hz), 9,05 (1H, m), 13,41 (1H, users)
Connection 5(300 MHz, CDCl3) δ ppm: 1.69 in (3H, d, J=6.5 Hz), 5,19 (1H, q, J=6.5 Hz), of 6.02 (2H, c), 6,89 (1H, d, J=8,4 Hz), 7,13-of 7.23 (2H, m), 7,34 (1H, c), 7,72 (2H, d, J=8.7 Hz), of 8.04 (2H, d, J=8.7 Hz), at 10.64 (1H, users)
Connection 6140,0-148,0(300 MHz, DMSO-d6) δ ppm: 1,47 (3H, m), of 4.95 (1H, m), 5,95-6,28 (3H, m), 693 (1H, m), 7,13 was 7.45 (3H, m), 7,68 (1H, m), of 7.90-with 8.05 (3H, m), 8,15 (2H, d, J=8.1 Hz), 12,72 (1H, m)
Connection 7153,0-159,0(300 MHz, DMSO-d6) δ ppm: to 2.57 (3H, c), 6,07 (2H, c), 7,02 (1H, users), 7,25-7,47 (3H, m), 7,94-with 8.05 (3H, m), 8,17(2H, d, J=8.5 Hz), compared to 8.26 (1H, c), is 12.85 (1H, ears is .c)
Compound 8(300 MHz, DMSO-d6) δ ppm: a 2.36 (3H, c), 6,10 (2H, c), 7,06 (1H, d, J=7,6 Hz), 7,20 (1H, c), 7,55 (1H, userd, J=7,6 Hz), 7,73 (1H, users), of 7.97 (2H, d, J=8,3 Hz), compared to 8.26 (2H, d, J=8,3 Hz), of 13.05 (1H, users)
Connection 9276,0-277,0(300 MHz, DMSO-d6) δ ppm: a 2.36 (3H, c), 6,10 (2H, c), 7,05 (1H, d, J=8.1 Hz), 7,18 (1H, c), 7,42 (1H, users), 7,58 (1H, userd, J=8.1 Hz), of 7.75 (1H, users), 7,94-8,08 (3H, m), 8,15 (2H, d, J=8,2 Hz), 12,87 (1H, users)
Connection 10(300 MHz, DMSO-d6) δ ppm: 1.26 in (3H, t, J=7,6 Hz), 2,71 (2H, q, J=7,6 Hz), 6,10 (2H, c), 7,05 (1H, d, J=8.1 Hz), 7,21 (1H, c), 7,58 (1H, userd, J=8.1 Hz), 7,80 (1H, users), of 7.97 (2H, d, J=8,4 Hz), compared to 8.26 (2H, d, J=8,4 Hz), of 13.05 (1H, users)
Connection 11259,5-261,5(300 MHz, DMSO-d6) δ ppm: 1.26 in (3H, t, J=7.5 Hz), 2,71 (2H, q, J=7.5 Hz), 6,10 (2H, c), 7,05 (1H, d, J=8.1 Hz), 7,19 (1H, c), 7,42 (1H, users), to 7.59 (1H, userd, J=8.1 Hz), 7,82 (1H, is Sirs), to 7.99 (2H, d, J=8,2 Hz), of 8.04 (1H, users), of 8.15 (2H, d, J=8,2 Hz), 12,87 (1H, users)
Connection 12(300 MHz, DMSO-d6) δ ppm: 6,12 (2H, c), was 7.08 (1H, d, J=8,4 Hz), 7,49 (1H, userd, J=8,4 Hz), 7,63 (1H, users), of 7.75 (1H, c), of 7.97 (2H, d, J=8,2 Hz), of 8.25 (2H, d, J=8,2 Hz)
Connection 13273,0-275,5(300 MHz, DMSO-d6) δ ppm: 6,12 (2H, c), was 7.08 (1H, d, J=8,4 Hz), 7,38-7,53 (2H, m), 7,63 (1H, users), 7,74 (1H, c), to 7.99 (2H, d, J=8,2 Hz), of 8.04 (1H, users), 8,14 (2H, d, J=8,2 Hz), 13,03 (1H, users)
The connection 14(300 MHz, CDCl3) δ ppm: 2,74 (3H, c), 6,01 (2H, c), to 6.88 (1H, d, J=7.8 Hz), 7,14-7,24 (3H, m), of 7.70 (2H, d, J=8.7 Hz), with 8.05 (2H, d, J=8.7 Hz)
The connection 15(300 MHz, CDCl3) δ ppm: was 2.76 (3H, c), 6,01 (2H, c), 6,89 (1H, d, J=8,4 Hz), 7,15-of 7.25 (3H, m), 7,89 (2H, d, J=8.7 Hz), of 8.04 (2H, d, J=8.7 Hz)
The connection 16 295,0-295,5(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), from 7.24 (1H, c), 8 00 (2H, d, J=8.5 Hz), 8,10-of 8.37 (4H, m), 8,86 (1H, users), 9,48 (1H, s), 13,33 (1H, users)
Connection 17283,5-286,0(300 MHz, DMSO-d6) δ ppm: 2,35 (3H, c), 7,21 (1H, c), 7,34 (2H, DD, J=8,9, and 8.9 Hz), 7,98 (2H, d, J=8,3 Hz), 8,08 (2H, m), compared to 8.26 (2H, d, J=8,3 Hz), 13,20 (1H, users)
The connection 18281,0-281,5(300 MHz, DMSO-d6) δ ppm: 2,35 (3H, c), 7,19 (1H, c), 7,34 (2H, DD, J=8,6, 8.6 Hz), the 7.43 (1H, users), 7,94-8,24 (7H, m), 13,02 (1H, users)
Connection 19205,5-208,0(300 MHz, CDCl3) δ ppm: 2,39 (3H, d, J=0.9 Hz), 6,00 (2H, c), 6,60 (1H, d, J=0.9 Hz), at 6.84 (1H, d, J=7.9 Hz), to 7.15 (1H, DD, J=7,9) and 1.7 Hz), 7,19 (1H, d, J=1.7 Hz)
The connection 20169,0-173, 0mm(300 MHz, DMSO-d6) δ ppm: 2,09 (3H, c), of 2.34 (3H, d, J=0.9 Hz), 6,07 (c 2H), 6,98 (1H, d, J=8,2 Hz), 7,13 (1H, d, J=0.9 Hz), was 7.45 (1H, DD, J=8,2) and 1.7 Hz), 7,78 (1H, d, J=1.7 Hz), to 11.28 (1H, users), 11,76 (1H, users)
Connection 21(300 MHz, DMSO-d6) δ ppm: of 0.93 (3H, t, J=7,3 Hz), and 1.63 (2H, kW, J=7,3, 7,3 Hz), 2,28-to 2.41 (5H, m), 6,07 (2H, c), 6,98 (1H, d, J=8.1 Hz), 7,12 (1H, s), 7,46 (1H, userd, J=8.1 Hz), 7,79 (1H, users), 11,25 (1H, users), 11,78 (1H, users)
The connection 22223,0-225,0(300 MHz, DMSO-d6) δ ppm: a 2.36 (3H, c), between 6.08 (2H, c), 7,01 (1H, d, J=8,2 Hz), to 7.15 (1H, d, J=1.1 Hz), of 7.48-to 7.68 (4H, m), 7,83 (1H, users), of 8.09 (2H, J=8.5 Hz), 11,57 (1H, users), 12,21 (1H, users)
The connection 23(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, d, J=0.9 Hz), 3,71 (2H, c), 6,07 (2H, c), of 7.00 (1H, d, J=8,2 Hz), 7,10 (1H, d, J=0.9 Hz), 7,47 (1H, DD, J=8,2) and 1.7 Hz), of 7.75 (1H, users)
Connection 24181,0-184,0(300 MHz, DMSO-d6) δ ppm: to 0.88 (3H, t, J=7.4 Hz), and 1.54 (2H, kW, J=7,4, 7,4 Hz), 2,12 (2H, t, J=7 Hz), of 2.34 (3H, c), or 4.31 (2H, d, J=5.4 Hz), 6,07 (2H, c), of 7.00 (1H, d, J=8.1 Hz), 7,12 (1H, d, J=0.8 Hz), 7,47 (1H, users), to 7.77 (1H, users), 8,30 (1H, t, J=5.4 Hz), 12,45 (1H, users)
The connection 25217,5-219,0(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 4,55 (2H, d, J=5.4 Hz), 6,07 (2H, c), of 7.00 (1H, d, J=8.1 Hz), 7,11 (1H, c), 7,42-to 7.59 (4H, m), to 7.77 (1H,users), 7,92 (2H, d, J=8,4 Hz), 8,32 (1H, t, J=5.4 Hz), 12,51 (1H, users)
The connection 26165,5-169, 5mm(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 3,42 (2H, c), and 3.72 (3H, c), or 4.31 (2H, d, J=5.3 Hz), 6,07 (2H, c), 6,85 (2H, J=8.6 Hz), 7,01 (1H, d, J=8,2 Hz), 7,13 (1H, d, J=0.9 Hz), 7,22 (2H, J=8.6 Hz), of 7.48 (1H, DD, J=8,2, 1,7 Hz), 7,78 (1H, d, J=1.7 Hz), 8,53 (1H, t, J=5.3 Hz), 12,48 (1H, users)
Connection 27155,5-157,5(300 MHz, CDCl3) δ ppm: 2,44 (3H, d, J=0.9 Hz), only 2.91 (2H, t, J=5,9 Hz), 3,18 (2H, t, J=5,9 Hz), 6,00 (2H, c), 6,70 (1H, d, J=0.9 Hz), 6,86 (1H, d, J=8.1 Hz), 7,24 (1H, DD, J=8,1) and 1.7 Hz), was 7.36 (1H, d, J=1.7 Hz)
The connection 28148,0-10,0 (300 MHz, DMSO-d6) δ ppm.: 0,83 {3H, t, J=7.4 Hz), 1,50 (2H, kW, J=7,4, 7,4 Hz), 2,04 (2H, t, J=7.4 Hz), was 2.34 (3H, c), and 2.79 (t, J=7,3 Hz), 3,42 (2H, TD, J=7,3, 5,4 Hz), 6,07 (2H, c), of 7.00 (1H, d, J=7.9 Hz), 7,10 (1H, c), 7,51 (1H, userd, J=7.9 Hz), 7,82 (1H, users), 7,94 (1H, t, J=5.4 Hz), 12,29 (1H, users)
The connection 29(200 MHz, CDCl3) δ ppm: 1,90 (2H, TT, J=6,4, 6.4 Hz), 2,43 (3H, d, J=0.9 Hz), 2,84-a 3.01 (4H, m), of 5.99 (2H, c), 6,69 (1H, d, J=0.9 Hz), at 6.84 (1H, d, J=8.1 Hz), 7,26 (1H, DD, J=8,1) and 1.7 Hz), 7,38 (1H, d, J=1.7 Hz)
The connection 30134,5-138,5(300 MHz, CDCl3) δ ppm: to 0.96 (3H, t, J=7.4 Hz), 1.69 in (2H, kW,J=7,4, 7,4 Hz), 1,80-of 1.94 (2H, m), 2,22 (2H, t, J=7.4 Hz), a 2.45 (3H, d, J=0.9 Hz), and 2.79 (t, J=6.2 Hz), 3,40 (2H, TD, J=6,2, 5,9 Hz), of 5.99 (2H, c), 6,03 (1H, users), 6,72 (1H, c), 6,87(1H, d, J=8.1 Hz), 7,39 (1H, userd, J=8.1 Hz), 7,55 (1H, users)
The connection 31(200 MHz, DMSO-d6) δ ppm: 1,82 (2H, TT, J=7,7, 6.9 Hz), of 2.15 (6H, c), of 2.28 (2H, t, J=6.9 Hz), 2,35 (3H, d, J=0.9 Hz), to 2.66 (2H, t, J=7,7 Hz), 6,07 (2H, c), of 6.99 (1H, d, J=8.1 Hz), to 7.09 (1H, d, J=0.9 Hz), 7,46 (1H, userd J=8,1 Hz), of 7.75 (1H, users), of 12.33 (1H, users)
The connection 32(300 MHz, CDCl3) δ ppm: 1.57 in (2H, TT, J=7,4, 7,4 Hz)to 1.86 (2H, TT, J=7,4, 7,4 Hz), 2,42 (3H, d, J=0.9 Hz), 2,74-of 2.86 (4H, m)6,00 (2H, c), of 6.68 (1H, d, J=0.9 Hz), 6,85 (1H, d, J=8.1 Hz), 7,21 (1H, DD, J=8,1) and 1.7 Hz), 7,28 (1H, users)
The connection 33132,0-133,0(300 MHz, DMSO-d6) δ ppm: or 0.83 (3H, t, J=7.4 Hz), 1,38 is 1.58 (4H, m), 1.69 in (2H, TT, J=7,4, 7,4 Hz), 2,02 (2H, t, J=7.4 Hz), was 2.34 (3H, c), to 2.65 (t, J=7.5 Hz), of 3.07 (2H, TD, J=7,5, 5,4 Hz), the 6.06 (2H, c), of 6.99 (1H, d, J=8,2 Hz), to 7.09 (1H, d, J=0.9 Hz), 7,50 (1H, userd, J=8,2 Hz), to 7.77 (1H, t, J=5.4 Hz), 7,82 (1H, users), 12,20 (1H, users)
The connection 34(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, d, J=0.9 Hz), between 6.08 (2H, c), of 6.99 (1H, d, J=8,2 Hz), 7,21 (1H, d, J=0.9 Hz), of 7.48 (1H, DD, J=8,2) and 1.7 Hz), 7,60 (1H, d, J=1.7 Hz)
The connection 35199,5-200,0(300 MHz, DMSO-d6) δ ppm: to 0.89 (3H, t, J=7,3 Hz), and 1.56 (2H, kW, J=7,3, 7,3 Hz), was 2.34 (3H, c), 3,24 (2H, TD, J=7,3, 5,4 Hz), 6,07(2H, c), 6,97 (1H, d, J=8,2 Hz), 7,20 (1H, c), was 7.45 (1H, userd, J=8,2 Hz), 7,58 (1H, users), 8,42 (1H, t, J=5.4 Hz), 13,45 (1H, users)
The connection 36222,0-222,5(300 MHz, DMSO-d6) δ ppm: a 2.36 (3H, c), between 6.08 (2H, c), of 5.99 (1H, d, J=7.9 Hz), 7,12 (1H, t, J=7,3 Hz), 7,24 (1H, c), 7,37 (2H, DD, J=7,5, and 7.3 Hz), 7,47 (1H, userd, J=7.9 Hz), 7,60 (1H, users), a 7.85 (2H, J=7.5 Hz), 10,26 (1H, users), 13,68 (1H, users)
The connection 37(200 MHz, DMSO-d6) δ ppm: 2,39 (3H, d, J=1.0 Hz), of 2.81 (2H, t, J=7,1 Hz), to 3.02 (2H, t, J=7,1 Hz), 6-11 (2H, c), 7,06 (1H, d, J=8.1 Hz), 7.23 percent (1H, d, J=1.0 Hz), 7,33 (1H, DD, J=8,1, 1.5 Hz), 7,51 (1H, users)
Compound 38106,5-108,5(200 MHz, CDCl3) δ ppm: of 0.90 (3H, t, J=7,3 Hz)and 1.51 (2H, kW, J=7,3, 7,3 Hz), 2,43 (3H, d, J=1.1 Hz), to 2.66 (2H, m), 3,10 (2H, m), 3,24 (2H, TD, J=7,3, 5,4 Hz), 5,91 (1H, users), 6,00 (2H, c), of 6.71 (1H, d, J=1.1 Hz), 6,85 (1H, d, J=8.1 Hz), 7.23 percent (1H, DD, J=8,1, 1.8 Hz), 7,39 (1H, users)
Connection 39The connection 4075,0-79,0(300 MHz, DMSO-d6) δ ppm: 0,84 (3H, t, J=7,3 Hz), 1,40 (2H, kW, J=7,3, 7,3 Hz), with 1.92 (2H, TT, J=7,6, 7,6 Hz), of 2.15 (2H, t, J=7,6 Hz), was 2.34 (3H, c), of 2.64 (2H, t, J=7,6 Hz)of 3.00 (2H, dt, J=7,3, 5,4 Hz), 6,07 (2H, c), of 6.99 (1H, d, J=8.1 Hz), 7,10 (1H, c), 7,51 (1H, userd, J=8.1 Hz), 7,81 (1H, t, J=5.4 Hz), 7,83 (1H, users), 12,24 (1H, users)
The connection 41(300 MHz, CDCl3) δ ppm: 1,82 (2H, m), is 2.05 (2H, m), 2,42 (3H, c), of 2.53 (2H, t, J=6.8 Hz), or 3.28 (2H, t, J=7.8 Hz), 6,03 (2H, c), 6,89 (1H, d, J=0.9 Hz), to 6.39 (1H, d, J=8.1 Hz), 7,14 (1H, d, J=1.7 Hz), 7,20 (1H, DD, J=for 8.1 and 1.7 Hz)
The connection 42(300 MHz, CDCl3) δ ppm: of 0.91 (3H, t, J=7,3 Hz)and 1.51 (2H, kW, J=7,3, 7,3 Hz), 1,69 is 1.91 (4H, m), and 2.27 (2H, t, J=6.4 Hz), 2,44 (3H, d, J=0.9 Hz), 2,84 (2H, t, J=6,7 Hz), 3,21 (2H, TD, J=7,3,
6,1 Hz), USD 5.76 (1H, users), 6,00 (2H, c), of 6.71 (1H, d, J=0.9 Hz), 6,86 (1H, d, J=8.1 Hz), 7,33 (1H, userd, J=8.1 Hz), the 7.43(1H, users)
The connection 43(300 MHz, CDCl3) δ ppm: 1,77-of 1.97 (4H, m), 2,43 (3H, d, J=1.0 Hz), 2,48 (2H, t, J=6.3 Hz), 2,89 (2H, t, J=6,1 Hz), 6,00 (2H, c), of 6.71 (1H, d, J=1.0 Hz), 6,85(1H, d, J=7.9 Hz), 7,10 (1H, t, J=7.5 Hz), 7.24 to 7,39 (3H, m), 7,51 (2H, d, J=8,4 Hz), to 7.67 (1H, users)
The connection 44174,0-175,0(300 MHz, DMSO-d6) δ ppm; 1,52-of 1.74 (4H, m), 2,17 (2H, t, J=6,1 Hz), was 2.34 (3H, c), to 2.65 (2H, t, J=6.5 Hz), of 3.69 (3H, c), 4,18 (2H, d, J=5,9 Hz), 6,07 (2H, c), at 6.84 (2H, d, J=8,8 Hz), of 6.99 (1H, d, J=8.1 Hz), to 7.09 (1H, c), to 7.15 (2H, d, J=8,8 Hz), 7,51 (1H, userd, J=8.1 Hz), 7,83 (1H, users), to 8.25 (1H, t, J=5,9 Hz, 12,22 (1H, users)
The connection 45(300 MHz, DMSO-d6) δ ppm: 1,48-of 1.75 (4H, m), is 2.09 (2H, t, J=7.2 Hz), 2,34 (3H, d, J=1.0 Hz), of 2.64 (2H, t, J=7.5 Hz), 6,07 (2H, c), 6,72 1H, users), of 6.99 (1H, d, J=8,2 Hz), to 7.09 (1H, d, J=1.0 Hz), 7,26 (1H, users), to 7.50 (1H, DD, J=to 8.2 and 1.7 Hz), 7,82 (1H, d, J=1.7 Hz), 12,21 (1H, users)
The connection 46(300 MHz, CDCl3) δ ppm: 2,42 (3H, d, J=1,0 is C), 4,08 (2H, c), of 6.71 (1H, d, J=1.0 Hz), 7,11 (2H, DD, J=8,8, 8,8 Hz), 7,71 (2H, m)
Connection 47(300 MHz, DMSO-d6) δ ppm: to 0.88 (3H, t, J=7.4 Hz), and 1.54 (2H, kW, J=7,4, 7,4 Hz), 2,13 (2H, t, J=7.4 Hz), 2,33 (3H, c)to 4.33 (2H, d, J=5.4 Hz), 7,13 (1H, c), 7,28 (2H, DD, J=8,9, and 8.9 Hz), of 8.04 (2H, m), 8,32 (1H, t, J=5.4 Hz), to 12.58 (1H, users)
The connection 48(300 MHz, DMSO-d6) δ ppm: 2,35 (3H, d, J=0.8 Hz), 6,85 (2H, d, J=8.7 Hz), 7,14 (1H, d, J=0.9 Hz), to 7.84 (2H, d, J=8.5 Hz), to 7.93 (2H, d, J=8.5 Hz), 8,24 (2H, d, J=8.7 Hz), 9,71 (1H, c), to 12.95 (1H, c)
The connection 49>300(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 6,87 (2H, d, J=8.7 Hz), 7,14 (1H, c), 7,42 (1H, users), a 7.85 (2H, d, J=8.5 Hz), to 7.99 (2H, d, J=8,4 Hz), of 8.04 (1H, users), 8,14 (2H, d, J=8,4 Hz), 9,73 (1H, c), 12,82 (1H, users)
The connection 50>300(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 7,22 (1H, c), 7,44 (1H, users), 8,00-to 8.20 (7H, m), 8,87 (1H, users), for 9.47 (1H, c), and 13.5 (1H, users)
The connection 51210,0-211,0
The connection 52217,5-218,0
The connection 53HCl(300 MHz, DMSO-d6) δ ppm: of 1.40 (3H, t, J=7,6 Hz), 2,44 (3H, d, J=0.9 Hz), totaling 3.04 (2H, q, J=7,6 Hz), was 7.36 (1H, d, J=1.1 Hz), to 7.84 (1H, m), 8,29 (1H, m), 8,61 (1H, m), 9,58 (1H, c)
The connection 54144,5-146,0
The connection 55155,0-155,5
The connection 56to 190.5-191,0
Connection 57 (300 MHz, CDCl3) δ ppm: to 0.96 (3H, t, J=7,3 Hz), 1,39-is 1.51 (2H, m), 1,75-of 1.85 (2H, m)2,44 (3H, d, J=1.1 Hz), of 2.81 (2H, t, J=7,7 Hz), 6,69 (1H, c), 7,86 (1H, DD, J=8,5) and 1.7 Hz), 8,17 (1H, DD, J=8,5, 0.5 Hz), 8,39 (1H, c), 9,03 (1H, c)
The connection 58HCl212,0-214,5
Connection 59239,5-to 240.5
The connection 60(300 MHz, CDCl3) δ ppm: of 0.91 (3H, t, J=7,1 Hz), 1.30 and a 1.46 (4H, m), 1,74-to 1.87 (2H, m)2,44 (3H, d, J=0.8 Hz), and 2.79 (2H, t, J=7.8 Hz), 6,69 (1H, c), 7,86 (1H, DD, J=8,5) and 1.7 Hz), 8,17 (1H, d, J=8.5 Hz), scored 8.38 (1H, c), 9,03 (1H, c)
The connection 61HCl(300 MHz, DMSO-d6) δ ppm: of 1.05 (9H, c), a 2.45 (3H, c), only 2.91 (2H, c), of 7.36 (1H, c), a 7.85 (1H, m), 8,30 (1H, d, J=8.5 Hz), to 8.62 (1H, s), 9,59 (1H, c)
The connection 62 HCl207,0-212,0
Connection 63of 180.5-182,0
The connection 64129,0-130,5
The connection 65195,0-196,5
Compound 66HCl(200 MHz, DMSO-d6) δ ppm: of 0.87 (3H, t, J=7.5 Hz), a 2.01 (2H, m)2,44 (3H, d, J=0.9 Hz), 2,59 (2H, m), 3,05 (2H, m), 5,34-of 5.50 (2H, m), 7,35 {1H, d, J=0.9 Hz), 7,81 (1H, DD, J=8,6, 1.8 Hz), 8,30 (1H, d, J=8.6 Hz), 8,59 (1H, d, J=1.3 Hz), 9,58 (1H, c)
Connection 67HCl(300 MHz, DMSO-d6) δ ppm: 0,84 (3H, t, J=6,8 Hz)of 1.23 (18H, m), equal to 1.82 (2H, m)2,44 (3H, d, J=0.6 Hz), 2,98 (2H, t, J=7,6 Hz), 7,35 (1H, q, j =0.9 Hz), to 7.84 (1H, m), 8,29 (1H, d, J=8.5 Hz), 8,61 (1H, d, J=1.4 Hz), 9,58 (1H, c)
Connection 69(300 MHz, DMSO-d6) δ ppm: 2,40 (3H, d, J=0.9 Hz), 7,21 (1H, d, J=0.9 Hz), 7,50 (2H, users), 7,78 (1H, m), of 8.25 (1H, d, J=8.5 Hz), 8,54 (1H, d, J=1.4 Hz), 9,54 (1H, c)
Connection 69(300 MHz, DMSO-d6) δ ppm: 2,12 (3H, c), of 2.33 (3H, c), 7,16 (1H, d, J=1.1 Hz), 8,10-8,13 (2H, m), 8,83 (1H, users), 9,43 (1H, c), 11,37 (1H, users), a 12.03 (1H, users)
The connection 702HCl229,0-233,0(300 MHz, DMSO-d6) δ ppm: 2,37 (3H, d, J=0.9 Hz), 4,16-of 4.25 (2H, m), 7,22 (1H, d, J=0.9 Hz), 8,08 (1H, DD, J=8,6, 1.8 Hz), 8,18 (1H, d, J=8.5 Hz), at 8.60 (3H, usher.), of 8.90 (1H, d, J=0.9 Hz), for 9.47 (1H, c)
Connection 71(300 MHz, CDCl3) δ ppm: for 1.49 (9H, c), is 2.44 (3H, d, J=0.9 Hz), 4,43 (2H, d, J=6,1 Hz), from 5.29 (1H, users), 6,76 (1H, c), 7,86 (1H, DD, J=8,5, 1.8 Hz), 8,18 (1H, d, J=8,4 Hz), 8,55 (1H, users), 9,04 (1H, c)
The connection 72250,5-255,0(300 MHz, CDCl3) δ ppm: 2,44 (3H, d, J=0.8 Hz), to 5.08 (2H, c), 6,74 (1H, users), 7,71-7,94 (6H, m), 8,16 (1H, d, J=8.5 Hz), 9,03 (1H, c)
Connection 73(300 MHz, DMSO-d6) δ ppm: to 0.88 (3H, t, J=7.2 Hz), 1,20-1,59 (13H, m), of 2.34 (3H, c), 3,29 (2H, users), to 4.46 (2H, users), 7,14 (1H, c), 802-8,18 (2H, m), 8,86 (1H, users), 9,43 (1H, c)of 12.73 (1H, users)
The connection 742HCl(300 MHz, DMSO-d6) δ ppm: of 0.91 (3H, t, J=7.4 Hz), 1,31-to 1.45 (2H, m), of 1.62 and 1.75 (2H, m), of 2.38 (3H, d, J=1.1 Hz), 3.00 and is 3.15 (2H, m), 4,32-to 4.41 (2H, m), 7,25 (1H, d, J=0.9 Hz), to 8.12 (1H, DD, J=8,7, 1.8 Hz), 8,19 (1H, DD, J=8,7, 0.6 Hz), to 8.94 (1H, d, J=1.2 Hz), 9,49 (1H, c), RS 9.69 (2H, users)
Connection 75(300 MHz, DMSO-d6) δ ppm: 0,86 (3H, t, J=7.4 Hz), of 1.35 to 1.47 (2H, m), 1.77 in-to 1.87 (2H, m), 2,34 (3H, d, J=0.9 Hz), 2,44-a 2.71 (6H, m), the 6.06 (2H, c), of 6.99 (1H, d, J=8,2 Hz), to 7.09 (1H, d, J=1.1 Hz), 7,46 (1H, DD, J=8,2, 1.9 Hz), of 7.75 (1H, d, J=1,6 Hz)
The connection 762MeSO3H118,5-128,5
Connection 77199,5-200,5(300 MHz, CDCl3) δ ppm: 1,76-2,17 (4H, m), of 2.45 (3H, d, J=0.9 Hz), 2,72-to 2.85 (2H, m), to 3.02 (1H, m), 3,20-of 3.32 (2H, m), of 6.68 (1H, users), a 7.85 (1H, DD, J=8,5) and 1.7 Hz), 8,17 (1H, DD, J=8,5, 0.3 Hz), 8,32 (1H, usher.), 9,03 (1H, c)
The connection 78(200 MHz, CDCl3) δ ppm: to 1.47 (9H, c), 1,67-2,17 (4H, m), 2,43 (3H, d, J=0.9 Hz), was 2.76-to 3.09 (3H, m), 4,13-to 4.33 (2H, m), of 6.68 (1H, c), a 7.85 (1H, DD, J=8,6, 1.5 Hz), 8,17 (1H, d, J=8,4 Hz), 8,30 (1H, c), of 9.02 (1H, c)
Connection 79(300 MHz, CDCl3) δ ppm: 1,63-2,23 (8H, m), 2,43 (3H, d, J=0.9 Hz), to 2.94 (1H, m), 3.96 points-of 4.00 (4H, m), to 6.67 (1H, users), 7,86 (1H, DD, J=8,4, 1.7 Hz), 8,17 (1H, d, J=8,4 Hz), 8,31 (1H, users), 9,03 (1H, c), of 10.01 (1H, users)
The connection 80207,5-20,5
Connection 81HCl(300 MHz, DMSO-d6) δ ppm: 0,82-to 0.96 (3H, m), 1,25-for 1.49 (4H, m), 1.70 to of 2.09 (2H, m), 2,33-2,48 (3H, m), 2,90 be 3.29 (2H, m), 3,51 (1H, m), 7,37 (1H, c), to 7.84 (1H, DD, J=8,5, 1.8 Hz), 8,29 (1H, d, J=8.5 Hz), 8,61 (1H, d, J=1.7 Hz), 9,58 (1H, c)
The connection 82222,0-223,0(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, d, J=0.8 Hz), a 4.53 (2H, c), of 5.50 (1H, users), to 7.15 (1H, d, J=0.9 Hz), 8,05-8,18 (2H, m), 8,87 (1H, users), 9,43 (1H, c), 12,80 (1H, user.)
Connection 83204,5-205,0
The connection 84(300 MHz, DMSO-d6) δ ppm: 1,95-of 2.05 (2H, m), 2,34 (3H, d, J=0.6 Hz), 2,74-of 2.81 (2H, m), 3,50 (2H, t, J=6.3 Hz), and 3.72 (3H, c)to 4.41 (2H, c), 6,85-6,91 (2H, m), 7,13 (1H, d, J=1.1 Hz), 7.23 percent-7,29 (2H, m), 8,10-of 8.15 (2H, m), 8,90 (1H, c), 9,42 (1H, c), 12,51 (1H, c)
Connection 85(300 MHz, CDCl3) δ ppm: 2,1 (2H, t, J=6.0 Hz), of 2.38 (3H, c), 2,43 (3H, d, J=0.9 Hz), 2,95 (2H, t, J=7,1 Hz), 4,12-4,17 (2H, m), of 6.75 (1H, d, J=1.1 Hz), 7,27-7,31 (2H, m), 7,74-7,79 (2H, m), to 7.84 (1H, DD, J=85) and 1.7 Hz), 8,13 (1H, DD, J=8,5, 0.6 Hz), 8,43 (1H, d, J=1.4 Hz), 9,03 (1H, c)
Connection 86(300 MHz, DMSO-d6) δ ppm: 1,86-of 1.97 (2H, m), is 2.37 (3H, d, J=0.9 Hz), 2,84 (2H, t, J=7,6 Hz), 3,51 (2H, t, J=6.2 Hz), 7,20 (1H, d, J=0.9 Hz), 8,00 (1H, m), 8,18 (1H, DD, J=8,5, 0.3 Hz), 8,77 (1H, s), for 9.47 (1H, c)
Connection 87HCl(300 MHz, DMSO-d6) δ ppm: 1,58 (2H, m), a 1.88 (2H, m)2,44 (3H, d, J=0.9 Hz), 3,03 (2H, t, J=7,6 Hz), 3,24 (3H, c), 3,37 (2H, t, J=6.2 Hz), was 7.36 (1H, d, J=1.1 Hz), to 7.84 (1H, DD, J=8,5) and 1.7 Hz), 8,29 (1H, d, J=8.5 Hz), 8,61 (1H, d, J=1.2 Hz), 9,58 (1H, c)
The connection 88257,0-259,5(300 MHz, CDCl3) δ ppm: 2,28 (3H, d, J=0.9 Hz), the 3.65 (3H, c), is 5.06 (2H, c), 6,60 (1H, d, J=0.9 Hz), 7,56 (1H, DD, J=8,4, 1.7 Hz), 7,72-to 7.93 (4H, m), 8,11 (1H, d, J=1.6 Hz), 8,23 (1H, d, J=8.5 Hz), which is 9.09 (1H, c)
Connection 89 USD 183.0-184,5(300 MHz, CDCl3) δ ppm: a 2.36 (3H, d, J=0.9 Hz), 3,52 (3H, c)4,06 (2H, c), is 6.61 (1H, d, J=0.9 Hz), 7,56 (1H, DD, J=8,5, and 1.6 Hz), 8,10 (1H, DD, J=1,6, 0.5 Hz), compared to 8.26 (1H, DD, J=8,4, 0.5 Hz), 9,10 (1H, c)
Connection 90212,5-213,5(300 MHz, DMSO-d6) δ ppm: to 0.88 (3H, t, J=7.4 Hz), 1,47-to 1.63 (2H, m), 2,09-to 2.18 (5H, m), 3,47 (3H, c), to 4.46 (2H, d, J=5.8 Hz),? 7.04 baby mortality (1H, d, J=0.9 Hz), to 7.64 (1H, DD, J=8,5) and 1.7 Hz), 8,17 (1H, DD, J=8,5, 0.5 Hz), a 8.34 (1H, DD, J=1,7, 0.5 Hz), 8,46 (1H, ushort, J=5.6 Hz), 9,49 (1H, c)
Connection 91(300 MHz, CDCl3) δ ppm: 2,31 and 2.46 (3H, 2D, J=0.9 Hz), 4,96, equal to 4.97, 5,27 and 5,61 (4H, 4c), 6,61-8,29 (13H, m), 8,94 and 9,04 (1H, 2c)
The connection 92(300 MHz, CDCl3) δ ppm: 2,37 and of 2.50 (3H, 2D, J=0.9 Hz), 3.90 and 3,93 (2H, 2c), 5,12 and of 5.50 (2H, 2c), 6,60-8,27 (9H, m), 8,97 and 9,07 (1H, 2c)
Connection 93 (300 MHz, CDCl3) δ ppm: from 0.88 to 0.98 (3H, m), 1,54-of 1.73 (2H, m), 2,08-of 2.20 (2H, m), 2,39, and of 2.50 (3H, 2D, J=0.9 Hz), 4,49-of 4.57 (2H, m), 5,15 and the 5.51 (2H, 2c), 6,29 compared to 8.26 (10H, m), 8,98 and 9,07 (1H, 2c)
Connection 94(300 MHz, CDCl3) δ ppm: 0,71-of 0.94 (3H, m), 1,34-to 1.98 (4H, m), 2,38 and 2.46 (3H, 2D, J=1.1 Hz), 2,90 are 2.98 (3H, m), a 4.83 (2H, c), 5,22 and 5.55 (2H, 2c), 6,60-8,29 (9H, m), 8,97 and 9,05 (1H, 2c)
Connection 95175,0-175,5(300 MHz, DMSO-d6) δ ppm: 0,87-and 0.98 (3H, m), 1,48-to 1.67 (2H, m), 2.26 and is 2.44 (5H, m), 2,90, and of 3.07 (3H, 2c), 4,63 (2H, c), to 7.15 (1H, m), 8,03-8,19 (2H, m), 8,84 (1H, m), 9,44 (1H, d, J=1.2 Hz), 12,67 and 12.84 (1H, 2 user.)
Connection 96of 209.5-210,5(300 MHz, DMSO-d6) δ ppm: 1,90-of 2.05 (2H, m), 2,25 is 2.33 (2H, m), 2,33 (3H, c), of 3.43 (2H, t, J=7.2 Hz), 4,50 (2H, c), to 7.15 (1H, d, J=1.1 Hz), 8,08 (1H, users), 8,13 (1H, d, J=8,4 Hz), 8,81 (1H, users), 9,43 (1H, c), 12,82 (1H, user.)
Connection 97(200 MHz, CDCl3) δ ppm: 2,43 (3H, d, J=0,GZ), to 5.03 (2H, c), 6,00 (2H, c), of 6.71 (1H, users), 6,85 (1H, d, J=8.1 Hz), 7,16-7,40 (2H, m), 7,72-to $ 7.91 (4H, m)
Connection 98(200 MHz, DMSO-d6) δ ppm: 2,32 (3H, c), 4,88 (2H, c), 7,11 (1H, c), 7,25 (2H, t, J=8,9 Hz), 7,83-7,97 (6H, m)
Connection 99(300 MHz, DMSO-d6) δ ppm: 2,30 (3H, d, J=0.8 Hz), a 4.86 (2H, c), 6,79 (2H, d, J=8.7 Hz), 7,05 (1H, d, J=0.8 Hz), 7,71 (2H, d, J=8.5 Hz), 7,83-of 7.97 (4H, m), for 9.64 (1H, c), 12,43 (1H, s)
Connection 100(300 MHz, DMSO-d6) δ ppm: 2,33 (3H, d, J=0.8 Hz), a-3.84 (2H, c), PC 6.82 (2H, d, J=8,9 Hz), was 7.08 (1H, d, J=1.1 Hz), 7,75-to $ 7.91 (2H, m)
Connection 101135,5 to 136.5
Connection 102(200 MHz, CDCl3) δ ppm: of 2.38 (3H, c), 3,91 (3H, c), 5,03 2H, c), 5,19 (2H, c), of 6.71 (1H, usher.), 6,91 (1H, d, J=8.0 Hz), 7,15-to 7.50 (7H, m), 7.68 per-7,80 (2H, m), 7,81-to 7.93 (2H, m)
Connection 103(200 MHz, CDCl3) δ ppm: 2,42 (3H, d, J=0.9 Hz), 3,90 (3H, c), a 4.03 (2H, c), is 5.18 (2H, c), 6,69 (1H, d, J=0.9 Hz), 6,91 (1H, d, J=8,4 Hz), 7,15-of 7.48 (6H, m), 7,71 (1H, c)
The connection 104176,0-177,0(300 MHz, CDCl3) δ ppm: of 0.93 (3H, t, J=7.4 Hz), of 1.66 (2H, kW, J=7.5 Hz), of 2.21 (2H, t, J=7.5 Hz), 2,43 (3H, d, J=1.1 Hz), 3,91 (3H, c), 4,47 (2H, d, J=5,9 Hz), 5,19 (2H, c), to 6.67 (1H, t, J=6,1 Hz), was 6.73 (1H, d, J=1.1 Hz), 6,92 (1H, d, J=8,4 Hz), 7,13-of 7.48 (6H, m), a 7.85 (1H, c)
Connection 105190,0-191,0(300 MHz, DMSO-d6) δ ppm: to 0.89 (3H, t, J=7.4 Hz), 1,47-of 1.64 (2H, m), and 2.14 (2H, t, J=7.5 Hz), was 2.34 (3H, c), 4,36 (2H, d, J=5.6 Hz), to 7.15 (1H, d, J=0.9 Hz), 8,08 (1H, c)to 8.14 (1H, d, J=8.5 Hz), a 8.34 (1H, t, J=5,1 Hz), cent to 8.85 (1H, c), 9,43 (1H, c), 12,72 (1H, c)
The connection 106(300 MHz, CDCl3) δ ppm: 0,79 (2H, m), 1,01 (2H, m)of 1.44 (1H, m), 2,3 (3H, d, J=0.8 Hz), 4,55 (2H, d, J=5,9 Hz), to 6.75 (1H, d, J=0.8 Hz), 6,99 (1H, m), to 7.84 (1H, DD, J=8,5) and 1.7 Hz), 8,15 (1H, d, J=8,4 Hz), 8,49 (1H, users), 9,03 (1H, c)
Connection 107160,0-160,5
The connection 108199,0-200,0
Connection 109229,0-of 229.5
The connection 110172,5-173.5 metric
Connection 111212,5-213,5
The connection 112156,5-161,0
Connection 113 (300 MHz, CDCl3) δ ppm: 1,21-1,90 (10H, m), 2,17 (1H, m)2,44 (3H, d, J=0.9 Hz), a 4.53 (2H, d, J=5,9 Hz), is 6.54 (1H, t, J=5.6 Hz), 6,76 (1H, d, J=0.9 Hz), 7,86 (1H, DD, J=8,5) and 1.7 Hz), 8,16 (1H, d, J=8,4 Hz), charged 8.52 (1H, users), 9,03 (1H, s)
The connection 114of 211.5-212,5
Connection 115150,0-150,5
The connection 116200,5-205,5
Connection 117204,0-205,5
The connection 118200,5-203,5
Connection 119 (200 MHz, CDCl3) δ ppm: of 1.36 (9H, c), 2,43 (3H, d, J=0.9 Hz), is 2.88 (3H, c), 3,90 (2H, c), 4,60 (2H, d, J=6.2 Hz), to 6.75 (1H, d, J=0.9 Hz), 7,10 (1H, t, J=5.7 Hz), 7,87 (1H, DD, J=8,6, 1.5 Hz), 8,14 (1H, d, J=8,4 Hz), 8,51 (1H, c), of 9.02 (1H, c)
Connection 120214,5-215,0
Connection 121(200 MHz, CDCl3) δ ppm of 1.36 (9H, c), 2,42 (3H, d, J=0.9 Hz), 3,85 (2H, d, J=5.7 Hz), 4,59 (2H, d, J=5.7 Hz), of 5.55 (1H, c), 6,74 (1H, d, J=0.9 Hz), EUR 7.57 (1H, c), 7,81 (1H, DD, J=8,4, 1.8 Hz), to 8.12 (1H, d, J=8,8 Hz), to 8.41 (1H, d, J=1.3 Hz), of 9.02 (1H, c)
The connection 122215,0-218,5
Connection 123134,0-135,5
The connection 124223,5-224,0/td>
Connection 125186,5-190,0
Connection 126193,0-194,0
Connection 127154,5-155,5
Connection 128174,0-175,0
Connection 129197,0-197,5
The connection 130to 185.0-185,5
Connection 131 to 185.0-185,5
Connection 132(200 MHz, CDCl3) δ ppm: 2,42 (3H, d, J=0.7 Hz), up 3.22 (2H, t, J=6.8 Hz), is 4.15 (2H, t, J=6.8 Hz), 6,00 (2H, c), 6,69 (1H, c), 6,85 (1H, d, J=8.1 Hz), 7,19-of 7.25 (2H, m), 7,69-7,87 (4H, m)
Connection 133(200 MHz, CDCl3) δ ppm: to 1.16 (3H, t, J=7.5 Hz), and 2.26 (2H, q, J=7.5 Hz), a 2.45 (3H, d, J=0.9 Hz), 3,03-3,14 (2H, m), of 3.73-of 3.85 (2H, m), 6,34 (1H, usher.), to 6.75 (1H, d, J=1.3 Hz), 7,94 (1H, DD, J=8,4, 1.8 Hz), 8,18 (1H, d, J=8,4 Hz), at 8.60 (1H, usher.), 9,03 (1H, c)
Connection 134(200 MHz, CDCl3) δ ppm: 1,80 for 2.01 (2H, m), 2,10 (3H, c), the 2.46 (3H, d, J=1.3 Hz), 2,80-of 2.93 (2H, m), 3,35-3,51 (2H, m), 5,96 (1H, users), 6,76 (1H, c), 8,02 (1H, d, J=8,8 Hz), 8,17 (1H, d, J=8,8 Hz), 9,01 (1H, c)
Connection 135(300 MHz, DMSO-d6) δ ppm: 2,05-2,10 (2H, m), 2,32 (3H, d, J=0.8 Hz), 2,70 (2H, t, J=7,7 Hz), 3,70 (2H, t, J=6.8 Hz), the 6.06 (2H, c), 6,98 (1H, d, J=8,2 Hz), 7,07 (1H, d, J=1.1 Hz), 746 (1H, DD, J=8,2, 1.9 Hz), to 7.77-to 7.84 (5H, m), 12,19 (1H, c)
Connection 136(300 MHz, CDCl3) δ ppm: 1,81 of-1.83 (4H, m), 2,43 (3H, d, J=0.9 Hz), 2,87 (2H, m), of 3.78 (2H, t, J=6.8 Hz), 6,01 (2H, c), 6,69 (1H, c), 6,87 (1H, d, J=8.1 Hz), 7,21-7,24 (2H, m), 7,69-7,86 (4H, m)
Connection 137(300 MHz, DMSO-d6) δ ppm: to 1.35 (3H, t, J=7,1 Hz), was 2.34 (3H, c), 4,37 (2H, q, J=7,1 Hz)6,09 (2H, c), of 7.00 (1H, d, J=8.1 Hz), 7,22 (1H, c), 7,47 (1H, d, J=8,4 Hz), 7,58 (1H, m), 13,73 (1H, users)
Connection 138238,5-239,0(300 MHz, DMSO-d6) δ ppm: to 1.37 (3H, t, J=7,1 Hz), 2,31 (3H, c), and 4.40 (2H, q, J=6.8 Hz), 7,24 (1H, c), 8,03 (1H, d, J=8.7 Hz), 8,14 (1H, d, J=8.5 Hz), a total of 8.74 (1H, c), 9,48 (1H, c), 14,02 (1H, c)
Connection 139(200 MHz, DMSO-d6) δ ppm: 2,32 (3H, c), 7,13 (1H, d, J=0.9 Hz), 8,00-8,18 (2H, m), 8,82 (1H, d, J=1.3 Hz), 9,40 (1H, c)
The connection 140 of 209.5-212,5
Connection 141(300 MHz, CDCl3) δ ppm: 2,43 (3H, d, J=0.9 Hz), 2,79-of 2.86 (2H, m), 3,05-3,11 (2H, m), 3,74 (3H, c), 6,00 (2H, c), 6,70 (1H, users), 6,86 (1H, d, J=8.1 Hz), 7,17-7,40 (2H, m)
Connection 142168,5-170,5
Connection 143(300 MHz, DMSO-d6) δ ppm: of 2.38 (3H, c), and 2.83 (2H, t, J=7,3 Hz), totaling 3.04 (2H, t, J=7,3 Hz), 7,22 (1H, c), of 7.97 (1H, m), 8,21 (1H, d, J=8.7 Hz), the rate of 8.75 (1H, c), 9,49 (1H, c)
Connection 144208,0-209,0
Connection 145217,5-218,0
Connection 146 196,5-197,0
Connection 147201,5-202,0
Connection 148179,0-180,0
Connection 149163,5-164,0
Connection 15078.5 to 82,5
Connection 151114,0-119,0
Connection 152171,0-173, 0mm
Connection 153 188,0-189,0
Connection 154(300 MHz, DMSO-d6) δ ppm: 1.32 to-2,08 (6H, m), and 2.14 (3H, c), of 2.34 (3H, c), 2,69-2,99 (8H, m), 3,66 (1H, m), 4,25 (1H, m), 7,13 (1H, c), 8,06-8,17 (2H, m), 8,91 (1H, s), 9,43 (1H, c), 12,51 (1H, c)
Connection 155201,0-201,5
Connection 156(300 MHz, CDCl3) δ ppm: 2.23 to 2.25 (6H, 2c), 2,44 (5H, m), 2,80 and 2.86 (2H, m), 3.00 and 3,03 (3H, 2c), 3,18 (2H, m), 3,39 and 3,55 (2H, m), 6,70 (1H, m), of 7.90 (1H, m), 8,15 (1H, d, J=8.5 Hz), 8,33 and 8.75 (1H, m), 9,01 (1H, c), 10,95 (1H, m)
Connection 157164,5-166,0
Connection 158169, 5mm-172,0
Connection 159(300 MHz, DMSO-d6) δ ppm: 2,34 (9H, m), 2,59 (2H, m), with 2.93 (2H, m), 3,19 (2H, m), 353 (4H, m), 7,14 (1H, d, J=1.1 Hz), 7,89 (1H, m), 8,13 (2H, m), of 8.92 (1H, users), 9,43 (1H, c), 12,54 (1H, c)
The connection 160(200 MHz, CDCl3) δ ppm: 2,44 (3H, c), 2,84 (2H, c), 3,01 and of 3.07 (3H, 2c), 3,17 (2H, m), 3.30, and of 3.32 (3H, 2c), 3,50-the 3.65 (4H, m), 6,74 (1H, c), of 7.90 (1H, m)to 8.14 (1H, d, J=8.6 Hz), 8,61 (1H, users), 9,01 (1H, c)
Connection 161216,5-218,0
Connection 162(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), and 2.83 (2H, m), 2,95 (2H, m), 3.46 in-to 3.58 (8H, m), 7,13 (1H, d, J=0.9 Hz), 8,10 (1H, m)to 8.12 (1H, m), 8,88 (1H, users), 9,43 (1H, s), 12,55 (1H, c)
Connection 163199,0-199,5
Connection 164144,5-145,0
Connection 165(300 MHz, CDCl3) δ ppm: 2,09-and 2.14 (2H, m), 2,43 (3H, d, J=0.9 Hz), 2,43-2,49 (2H, m), 2,84 (2H, t, J=7.5 Hz), to 3.09 (3H, c), 6,01 (2H, c), 6,69 (1H, c), 6,87 (1H, d, J=8.1 Hz), 7,19 (1H, d, J=8.1 Hz), 7,26 (1H, m)
The connection 166HCl(200 MHz, CDCl3) δ ppm: 1,99-to 2.18 (2H, m), 2,31 (2H, t, J=6.8 Hz), 2,43 (3H, d, J=0.9 Hz), 2.77-to of 2.97 (5H, m), from 6.22 (1H, m), 6,74 (1H, d, J=0.9 Hz), 7,9) (1H, DD, J=8,8, 1.8 Hz), 8,13 (1H, d, J=8,8 Hz), 8,56 (1H, users), 9,01 (1H, c)
Connection 167158,0-159,0
Connection 168(300 MHz, CDCl3) δ ppm: 1.70 to at 1.91 (4H, m), 2.40 a (2H, m), 2,43 (3H, d, J=0.9 Hz), 2,84 (2H, t, J=7,1 Hz), 6,72 (1H, users), of 7.90 (1H, m), 8,16 (H, d, J=8.5 Hz), of 9.02 (1H, c)
Connection 169(300 MHz, DMSO-d6) δ ppm: 1,52-of 1.65 (2H, m), 1,76-1,89 (2H, m), is 2.30 (2H, t, J=7,3 Hz), 2,43 (3H, d, J=0.9 Hz), 2,95 (2H, t, J=7,1 Hz), 7,31 (1H, d, J=0.9 Hz), 7,88 (1H, DD, J=8,6, 1.5 Hz), of 8.27 (1H, d, J=8,4 Hz), with 8.33 (1H, c), 8,65 (1H, c), of 9.56 (1H, c)
Connection 170(300 MHz, DMSO-d6) δ ppm: 1,52-to 1.79 (4H, m), 2,11 (2H, t, J=7,3 Hz), 2,34 (3H, d, J=0.9 Hz), 2,69 (2H, t, J=7.5 Hz), 6,72 (1H, users), 7,13 (1H, d, J=1.1 Hz), 7,27 (1H, users), to 8.12 (2H, users), of 8.90 (1H, users), 9,42 (1H, c), 12,51 (1H, users)
Connection 171(300 MHz, DMSO-d6) δ ppm: of 0.82 (3H, t, J=7.4 Hz), of 1.39 (2H, m), 1,55-of 1.73 (4H, m), 2,12 (2H, t, J=7.2 Hz), 2,33 (3H, c), 2,69 (2H, t, J=7.5 Hz), 2,99 (2H, m), 7,13 (1H, c), to 7.77 (1H, ushort, J=5.6 Hz), 8,13 (2H, m), of 8.90 (1H, users), 9,43 (1H, c), 12,49 (1H, users)
Connection 172HCl105,0-117,5
Connection 173/td> 140,0-to 140.5
Connection 174(300 MHz, DMSO-d6) δ ppm: 2,35 (3H, d, J=0.9 Hz), 4,30 (2H, d, J=5.6 Hz), 5,69 (2H, c), 6,47 (1H, t, J=5.4 Hz), 7,16 (1H, d, J=1.1 Hz), with 8.05 (1H, m), 8,15 (1H, m), 8,82 (1H, c), 9,44 (1H, c)
Connection 175189,0-191,0
Connection 176(200 MHz, CDCl3) δ ppm: 2,43 (3H, d, J=0.9 Hz), to 2.94 (6H, c), 4,51 (2H, d, J=5,9 Hz), of 5.39 (1H, m), of 6.75 (1H, d, J=1.1 Hz), 7,88 (1H, DD, J=8,6, 1.8 Hz), 8,15 (1H, d, J=8.6 Hz), 8,54 (1H, d, J=1.5 Hz), of 9.02 (1H, c)
Connection 177179,5-182,0
Connection 178178,5-1800
Connection 179to 190.5-191,5
Connection 180(330 MHz, CDCl3) δ ppm: 1,31 (9H, c)to 2.41 (3H, d, J=0.8 Hz), 4,43 (2H, users), is 4.93 (1H, users), 6,01 (1H, m), 6,74 (1H, d, J=0.9 Hz), 7,80 (1H, DD, J=8,5, 1.9 Hz), 8,11 (1H, d, J=8,4 Hz), 8,46 (1H, d, J=1.5 Hz), of 9.02 (1H, c)
Compound 181222,5-223,0
Connection 182199,0-201,0
Connection 183185,5-188,0
Connection 184(300 MHz, CDClsub> 3) δ ppm: 1,05-1,84 (10H, m), 2,39 (3H, d, J=0.8 Hz), 3,47 (1H, m), 4,60 (2H, users), of 5.39 (1H, m), of 6.75 (1H, d, J=0.9 Hz), at 6.84 (1H, m), to 7.77 (1H, m), 8,13 (1H, d, J=8.5 Hz), of 8.37 (1H, d, J=1.7 Hz), 9,05 (1H, c)
Connection 185205,5-206,0
Connection 186207,0-209,0
Compound 187USD 183.0-184,0
Connection 188202,0-204,0
(decomp.)
Compound 189200,5-201,0
Connection 190180,0-181,0
Connection 191(300 MHz, CDCl3) δ ppm: 2,44 (3H, d, J=0.9 Hz), 2,50 (1H, t, J=2.5 Hz), 4,50 (2H, d, J=6,1 Hz), 4,74 (2H, d, J=2.5 Hz), 5,79 (1H, t, J=6,1 Hz), to 6.75 (1H, c), a 7.85 (1H, DD, J=8,5) and 1.7 Hz), 8,16 (1H, d, J=8.5 Hz), 9,04 (1H c)

(300 MHz, CDCl3) δ ppm: of 0.93 (3H, t, J=7.4 Hz), 1,58-1,71 (2H, m)2,44 (3H, d, J=0.9 Hz), of 2.44-2.50 (2H, m), 2.95 and-3,11 (4H, m), 6,72 (1H, d, J=0.9 Hz), 7,86 (1H, DD, J=8,5, 1.8 Hz), 8,16 (1H, DD, J=8,5, 0.6 Hz), 8,48 (1H, user.), 9,03 (1H, c)
Connection 192HCl174,0-175,0
Connection 193161,0-162,0
Connection 194142,5-144, 0mm
Connection 195177,5-178,5
Connection 196170,5-which is 171,5
Connection 197232,0-233,0(300 MHz, DMSO-d6) δ ppm: 2,34 (3H, c), 3,60-3,68 (2H, m), 4,28 is 4.36 (2H, m), of 4.49 (2H, s), 7,16 (1H, d, J=0.9 Hz), 8,08 (1H, usher.), to 8.14 (1H, d, J=8,4 Hz), 8,83 (1H, usher.), 9,44 (1H, c), 12,93 (1H, user.)
Connection 198144, 0mm-145,0(300 MHz, DMSO-d6) δ ppm: was 1.04 (3H, t, J=7.2 Hz), was 2.34 (3H, c), 2,99-of 3.12 (2H, m), 5,04 (2H, c), 7,18 (1H, d, J=0.8 Hz), 7,34 (1H, ushort, J=5.7 Hz), 8,03-to 8.20 (2H, m), of 8.90 (1H, users), to 9.45 (1H, c), 13,06 (1H, users)
Compound 199181,5-182,0
The connection 200(300 MHz, CDCl3) δ ppm with 1.07 (3H, t, J=7.5 Hz), 1,89 (2H, m)2,44 (3H, d, J=0.9 Hz), is 3.08 (2H, m), of 4.44 (2H, d, J=6.2 Hz), vs. 5.47 (1H, m), 6,76 (1H, c), 7,83 (1H, m), 8,16 (1H, d, J=8.5 Hz), to 8.45 (1H, users), 9,04 (1H, c)
Connection 201145,0-146,0
The connection 202248,0-251,0 (decomp.)
Connection 203131, 5mm-132,5
Connection 204134,5-135,5(300 MHz, CDCl3) δ ppm: of 2.51 (3H, d, J=0.8 Hz), was 7.45 (1H, d, J=0.8 Hz), 8,16 (1H, DD, J=8,5) and 1.7 Hz), compared to 8.26 (1H, DD, J=8,5, 0.6 Hz), 8,64 (1H, DD, J=1,7, 0.6 Hz), 9,23 (1H, c)
Connection 205(300 MHz, CDCl3) δ ppm: 2,53 (3H, d, J=0.8 Hz), 6,77-6,84 (2H, m), the 7.43 (1H, d, J=0.8 Hz), 7,80-7,87 (2H, m)
The connection 20675,0-77,0
Connection 207(300 MHz, CDCl3) δ ppm: 6,09 (2H, c), 6,89 (1H, d, J=8.5 Hz), 7,51 (1H, d, J=1.7 Hz), 7,51 (1H, DD, J=8,5) and 1.7 Hz), 7,83 (1H, d, J=3.0 Hz), 8,11 (1H, d, J=3.0 Hz)
Connection 208(300 MHz, CDCl3) δ ppm: 6,11 (2H, c), of 6.90 (1H, d, J=8.7 Hz), 7,47-rate of 7.54 (2H, m), 7,72 (1H, c)
Connection 209(300 MHz, CDCl3) δ ppm: of 1.28 (3H, t, J=7,6 Hz), 2,87 (2H, arcs, J=7,6, 0.8 Hz), 6,09 (2H, c), to 6.88 (1H, d, J=8.7 Hz), 7,41 (1H, t, J=0.8 Hz), 7,49-7,53 (2H, m)
Connection 210(200 MHz, CDCl3) δ ppm: was 2.76 (3H, c), between 6.08 (2H, c), to 6.88 (1H, d, J=8.1 Hz), 7,50-EUR 7.57 (2H, m), 8,23 (1H, c)
Connection 211(300 MHz, CDCl3) δ ppm: 2,69 (3H, c), 6,11 {2H, c), of 6.90 (1H, DD, J=8,1, 0.5 Hz), 7,50-7,58 (2H, m), 8,65 (1H, c)
The connection 212(300 MHz, CDCl3) δ ppm: of 1.65 (3H, d, J=6.5 Hz), 2,71 (1H, d, J=4,8 Hz), 5,19 (1H, m)6,09 (2H, c), to 6.88 (1H, d, J=8.1 Hz), to 7.50 (1H, d, J=1.7 Hz), 7,54 (1H, DD, J=8,2) and 1.7 Hz), with 8.33 (1H, c)
Connection 213(300 MHz, CDCl3) δ ppm of 2.54 (3H, d, J=0.9 Hz), 5,95 of 5.99 (2H, m), of 6.75 (1H, d, J=8.1 Hz), 6,78 (1H, c), to 7.09 (1H, DD, J=7,9, 1.9 Hz), 7,21 (1H, d, J=1.9 Hz), 7,32 (1H, d, J=0.9 Hz)
Connection 214(300 MHz, CDCl3) δ ppm: 2,54 (3H, d, J=0.9 Hz), 3,80 (3H, c), PC 6.82 (1H, c), to 6.88 (2H, DD, J=8,9 and 2.2 Hz), 7,30 (1H, d, J=0.9 Hz), 7 59 (2H, DD, J=8,7, 2,2 Hz)
Connection 215(300 MHz, CDCl3) δ ppm: to 2.55 (3H, d, J=0.9 Hz), 6,99 (1H, c), 7,34 (1H, q, J=0.8 Hz), 7,81 (1H, DD, J=8,7, 2.0 Hz), to 8.12 (1H, d, J=8.5 Hz), 8,30 (1H, d, J=1.7 Hz), 9,04 (1H, c)
Connection 216 116,0-117,0(200 MHz, CDCl3) δ ppm: of 2.51 (3H, d, J=0.9 Hz), of 6.96 (1H, d, J=0.9 Hz), 7,71 (1H, DD, J=8,4, 1.8 Hz), to 8.12 (1H, d, J=7.9 Hz), to 8.20 (1H, d, J=1,8 Hz), 9,07 (1H, c)
Connection 217111,5-112,0
Connection 218200 MHz, CDCl3) δ ppm: 2.49 USD (3H, d, J=0.9 Hz), 5,72 (1H, usher.), of 6.73-to 6.88 (2H, m), 6.90 to (1H, d, J=0.9 Hz), 7,39-of 7.48 (2H, m)
Connection 21982,0-83,0
Connection 220(300 MHz, CDCl3) δ ppm: 6,02 (2H, c), PC 6.82 (1H, d, J=8.1 Hz), 7,03 (1H, d, J=1.7 Hz), 7,14 (1H, DD, J=8,1) and 1.7 Hz), was 7.36 (1H, d, J=3,4 Hz), to 7.84 (1H, d, J=3,4 Hz)
Connection 221(300 MHz, CDCl3) δ is d: 6,02 (2H, c), PC 6.82 (1H, d, J=8.1 Hz), 7,00 (1H, d, J=1.6 Hz), 7,13 (1H, DD, J=8,1, 1,6 Hz), 7.23 percent (1H, s)
Connection 222(300 MHz, CDCl3) δ ppm: to 1.32 (3H, t, J=7.5 Hz), 2,84 (2H, arcs, J=7,5, and 0.9 Hz), 6,01 (2H, c), for 6.81 (1H, DD, J=8,1, 0.3 Hz), 6,91 (1H, t, J=0.9 Hz), 7,01 (1H, DD, J=1,7, 0.3 Hz), 7,13 (1H, DD, J=8,1) and 1.7 Hz)
Connection 223(300 MHz, CDCl3) δ ppm: 2,73 (3H, c), of 5.99 (2H, c), is 6.78 (1H, d, J=8.1 Hz), of 6.99 (1H, d, J=1.7 Hz), to 7.09 (1H, DD, J=8,1) and 1.7 Hz), 7,32 (1H, c)
Connection 224(300 MHz, CDCl3) δ ppm: 2,75 (3H, c), 6,01 (2H, c), for 6.81 (1H, d, J=8.1 Hz), 7,02 (1H, d, J=1.7 Hz), 7,13 (1H, DD, J=8,1, 1,6 Hz), 7,76 (1H, c)
Connection 225(300 MHz, CDCl3) δ ppm: 1,67 (3H, d, J=6.5 Hz), 2,86 (1H, m), 5,16 (1H, m), of 5.99 (2H, c), 6,79 (1H, d, J=8.1 Hz), 7,00 (1H, d, J=1.7 Hz), 7,10 (1H, DD, J=8,1, 1,6 Hz), 7,44 (1H, c)
Connection 226 137,0-140,0(300 MHz, CDCl3) δ ppm: 2,53 (3H, d, J=1.1 Hz), 7,53 (1H, d, J=1.1 Hz), 7,71 (1H, DD, J=8,5, and 1.6 Hz), 8,13 (1H, DD, J=8,5, 0.6 Hz), to 8.20 (1H, DD, J=1,6, 0.5 Hz), 9,07 (1H, c)
Connection 227154,0-155,0(300 MHz, CDCl3) δ ppm: to 2.65 (3H, d, J=1.1 Hz), 7,78 (1H, d, J=1.1 Hz), 8,15 (1H, DD, J=8,5) and 1.7 Hz), 8,24 (1H, DD, J=8,5, 0.6 Hz), 8,63 (1H, DD, J=1,7, 0.6 Hz), which 9.22 (1H, c)
Connection 228210,0-211,0(300 MHz, DMSO-d6) δ ppm: is 2.37 (3H, c), 2,42 (3H, c), 7,44 (1H, users), 8,09-of 8.15 (2H, m), 8,78 (1H, usher.), 9,42 (1H, c), of 12.53 (1H, user.)
Connection 229273,0-275,0 (decomp.)
Connection 230263,0-268,0 (decomp.)
Connection 231 144, 0mm-145,0
Connection 232215,5-218,5
Connection 233146,5-148,0
Connection 234129,5-131,0
Connection 235158,0-159,5
Connection 236HCl(300 MHz, DMSO-d6) δ ppm: 2,39 (3H, d, J=1.1 Hz), 3,34-to 3.49 (4H, m), 3,54-3,63 (4H, m), 5,27 (2H, c), 7,29 (1H, d, J=1.1 Hz), 7,95 (1H, DD, J=8,5, 1.9 Hz), 8,23 (1H, DD, J=8,5, 0.5 Hz), 8,73 (1H, d, J=1.9 Hz), 9,52 (1H, c)
Connection 237HCl1190-124,0
Connection 2382390-239,5
Compound 239232,0-233,5
Connection 240236,0-237,0
Connection 241220,5-222,0
Connection 242224,5-226,5
Connection 243253,0-255,0 (decomp.)
Connection 244 to 190.5-192,0(300 MHz, DMSO-d6) δ ppm: 2,40 (3H, c), 8,03 (1H, DD, J=8,6, 1.5 Hz), 8,15 (1H, d, J=8.6 Hz), a 8.34 (1H, c), 8,89 (1H, users), to 9.45 (1H, c), 12,78 (1H, user.)
Connection 245(200 MHz, CDCl3) δ ppm: for 1.49 (9H, c), and 4.40 (2H, d, J=6.2 Hz), 5,32 (1H, t, J=5.7 Hz), the 7.65 (1H, c), to 7.84 (1H, DD, J=8,4, 1.3 Hz), 8,19 (1H, d, J=8,8 Hz), of 8.90 (1H, d, J=1.3 Hz), 9,06 (1H, c)
Connection 2462HCl(300 MHz, DMSO-d6) δ ppm: 4,17-to 4.28 (2H, m), of 8.06 (1H, DD, J=8,5, 1.8 Hz), to 8.20 (1H, d, J=8.5 Hz), 8,43 (1H, d, J=0.9 Hz), 8,67 (2H, users), 8,93 (1H, d, J=1.7 Hz), 9,49 (1H, c)
Connection 247(300 MHz, DMSO-d6) δ ppm: 3,37 (3H, c), 3,90 (2H, c), to 4.46 (2H, d, J=5.8 Hz), 8,00 (1H, DD, J=8,6, and 1.6 Hz), 8,16 (1H, d, J=8.5 Hz), 8.34 per-8,39 (2H, m), 8,83 (1H, d, J=1.4 Hz), 9,46 (1H, c), 12,92 (1H, users)
Connection 248(300 MHz, DMSO-d6) δ ppm: a 1.01 (3H, t, J=7,1 Hz), 3.00 and-3,11 (2H, m), 4,33 (H, d, J=5.8 Hz), between 6.08 (1H, t, J=5.5 Hz), 6,37 (1H, t, J=5.6 Hz), 8,01 (1H, DD, J=8,6, and 1.6 Hz), 8,16 (1H, d, J=8.5 Hz), of 8.37 (1H, c), 8,84 (1H, d, J=1.2 Hz), 9,46 (1H, c), 12,93 (1H, users)
Compound 249(300 MHz, CDCl3) δ ppm: 1,72-1,89 (4H, m), 2,38-2,52 (1H, m), 3.33 and-of 3.46 (2H, m), 3.96 points-4,06 (2H, m), 4,58 (2H, d, J=5.8 Hz), 6,74 (1H, ushort, J=5,1 Hz), to 7.61 (1H, c), 7,81 (1H, DD, J=8,5) and 1.7 Hz), 8,16 (1H, d, J=8.5 Hz), 8,65 (1H, users), 9,06 (1H, c)
Connection 250153,0-154,0(300 MHz, CDCl3) δ ppm: 7,74 (1H, DD, J=8,5, and 1.6 Hz), 7,81 (1H, q, J=0.9 Hz), 8,16 (1H, DD, J=8,5, 0.6 Hz), 8,24 (1H, DD, J=1,7, 0.6 Hz), 9,11 (1H, c)
Connection 251163,5-164,5(300 MHz, CDCl3) δ ppm: 8,14-8,32 (3H, m), 8,69 (1H, m), 9,27 (1H, c)

The test example 1

Test for inhibitory activity against the phosphorylation of Smad2/3

Cells A plated on the tablet and cultured overnight in medium Ham's F-12 with the addition of 10% FBS (fetal calf serum). Wednesday, replace the same medium containing compounds that do not have connected the I, after incubation for another 2 hours and to it was added TGF-β1 to bring the final concentration to 1 ng/ml and additionally incubated for 1 h After completion of the incubation medium is removed and cells are washed with PBS (phosphate buffered saline) and then are lysed by RIPA solution. The solution of cell lysates subjected thus, using antibody against Smad2/3, and then carried out the Western blotting. Using a rabbit antibody against phosphorylated serine as the primary antibodies, anti-rabbit IgG antibody labeled with HRP as the secondary antibody and detection reagents ECL Western blotting as detection reagent, measuring the magnitude of light emission, using Limi-Imager F1 (Roche Diagnostics), etc.

Following the above methods, measure the inhibitory activity of the corresponding compounds against phosphorylation of Smad2/3, caused by the stimulation of TGF-β1, and calculate IC50 values.

The results are shown in table 2.

Table 2
Connection # IC50 (nm)Connection # IC50 (nm)
The connection 5080 Connection 129107
The connection 5224Connection 17189
Connection 5745Connection 175126
The connection 6831Connection 17677
The connection 8089Connection 18638
Connection 8152Connection 19131
Connection 8399Connection 19792
Connection 8738Connection 19893
Connection 10532Compound 19970
The connection 12467Soedinenie 42

The test example 2

The test cell proliferation in hair follicles

In accordance with the method described Arase et al. (Arase et al., J Dermatol Sci 2, 66-70 (1991)), the cells of the hair follicles are extracted from human hair and are cultivated using KGM-1 (Clonetics).

After sowing follicular cells on 24-well plate and cultivation during the night environment is replaced with another medium, containing compounds that do not have a connection, and after incubation for another 2 hours and to it was added TGF-β1 to bring the final concentration to 0.1 ng/ml and additionally incubated for another 72 h For 2 h until completion of the cultivation, the medium was added reagent Alamar blue, the amount of which is added 1/10 environment, and measure the intensity of florescence environment (excitation: 544 nm, emission: 590 nm) to determine the number of living cells. The drawing shows the number of living cells when they enter one of TGF-β1 and when they are introduced simultaneously with TGF-β1 and connection, provided that the number of living cells, certain, when these cells were cultured for 72 h without the addition of TGF-β1, is taken as 100%.

Industrial applicability

Compounds in accordance with the present invention have inhibitory effect on ALK5, which is a receptor for TGF-β1 is IPA I, and they are useful as pharmaceuticals for the treatment or prevention of various diseases, such as alopecia or diabetic nephropathy associated with ALK5, a receptor of TGF-β1 type I.

1. Derived thiazole represented by the formula (I)

or its pharmaceutically acceptable salt,
where X1and X2differ from each other and represent a sulfur atom or a carbon atom;
R1represents a phenyl group;
phenyl group, substituted with 1-2 members selected from the group consisting of halogen atoms, alkoxygroup having 1-6 carbon atoms, hydroxy-group, fenilalanina having 7-12 carbon atoms;
phenyl group fused with a 5-7 membered heteroaromatic or non-aromatic ring having at least one heteroatom consisting of N, O and S;
pyridyloxy group;
R2represents a hydrogen atom, halogen atom, alkyl group having 1-6 carbon atoms, alkyl group having 1-6 carbon atoms, substituted by 1-5 halogen atoms, alkoxygroup having 1-6 carbon atoms, or a hydroxyalkyl group having 1-5 carbon atoms; and
A represents a group represented by the formula

or

where R3represents a hydrogen atom;
alkiline the group, having 1-6 carbon atoms;
phenylalkyl group having 7-12 carbon atoms; or
phenylalkyl group having 7-12 carbon atoms, substituted by a hydroxy-group, alkoxygroup having 1-6 carbon atoms, alkoxygroup having 1-6 carbon atoms, substituted alkoxygroup having 1-6 carbon atoms, or alkoxygroup having 1-6 carbon atoms, substituted alkylamino having 1-6 carbon atoms,
R4is
phenyl group substituted by 1 member selected from the group consisting of carbamoyl group and cyanopropyl;
a hydrogen atom;
alkyl group having 1-12 carbon atoms;
alkenylphenol group having 2-12 carbon atoms;
cycloalkyl group having 3-7 carbon atoms;
alkyl group having 1-6 carbon atoms, substituted alkoxygroup having 1-6 carbon atoms, hydroxy-group, alkoxylalkyl having 8-12 carbon atoms, telemedicine group, toluensulfonate or morpholinopropan;
alkyl group having 1-6 carbon atoms, substituted by 1-5 halogen atoms;
cycloalkyl group having 3-9 carbon atoms, substituted oxopropoxy;
tetrahydropyranyloxy group;
4-piperidinyloxy group;
piperidinyloxy group, substituted tert-butoxycarbonyl group;
cyclohexanone-2'-(1,3-DIOXOLANYL the left) group;
pyrrolidin-2-he-5-ilen group;
the group represented by the formula-Y1-Z1-NR5-Z2-Y2-R6,
where Y1and Y2the same or different from each other and represent a simple bond or alkilinity group having 1-12 carbon atoms;
R5represents a hydrogen atom or alkyl group having 1-12 carbon atoms;
Z1and Z2the same or different from each other and represent a simple link;
alkylenes group having 1-7 carbon atoms;
-CO-;
-CO2-;
-SO2or
-OCO-, and
R6is
cycloalkyl group having 3-7 carbon atoms;
alkyl group having 1-6 carbon atoms, substituted by 1 to 3 halogen atoms;
alkenylphenol group having 2-6 carbon atoms;
alkylamino group having 2-6 carbon atoms;
the amino group;
the amino group substituted by 1-2 groups selected from the group consisting of alkyl groups having 1-6 carbon atoms, cycloalkyl group having 3-7 carbon atoms, and tert-butoxycarbonyl group;
piperidinium;
piperidinyloxy group;
piperidinyloxy group, a substituted alkyl group having 1-6 carbon atoms;
pyrrolidinyloxy group;
piperazinilnom group;
piperazinilnom group, a substituted alkyl group having 1-6 carbon atoms;
Mor is aminogroup;
the hydroxy-group;
alkoxygroup having 1-6 carbon atoms;
alkoxygroup having 1-6 carbon atoms, substituted hydroxy-group or alkoxygroup having 1-6 carbon atoms;
oxetan-2-ilen group;
tetrahydropyranyloxy group;
tetrahydropyranyloxy group;
a hydrogen atom;
phenyl group;
phenyl group substituted by alkoxygroup having 1-4 carbon atoms; or
the group, which forms oxazolidin-2-he or imidazolidin-2-he's accession to the nitrogen atom of the above formula; or
the group represented by the formula Y3-CO-R41,
where Y3represents a simple bond or alkilinity group having 1-7 carbon atoms,
R41is
the hydroxy-group;
alkoxygroup having 1-6 carbon atoms;
piperazine-1-ilen group, a substituted alkyl group having 1-6 carbon atoms, morpholinoethyl group having 5-10 carbon atoms, or acylaminoalkyl group having 2-14 carbon atoms;
or
morpholinopropan.

2. Derived thiazole or its pharmaceutically acceptable salt according to claim 1, where R2represents a hydrogen atom, halogen atom, alkyl group having 1-6 carbon atoms, or alkyl group having 1-6 carbon atoms, substituted by 1-5 halogen atoms.

3. Derived thiazole or its pharmaceutically PR is acceptable salt according to claim 1, where R2represents an alkyl group having 1-6 carbon atoms, or triptorelin group.

4. Derived thiazole or its pharmaceutically acceptable salt according to claim 1, where R2represents a metal group or triptorelin group.

5. Derived thiazole or its pharmaceutically acceptable salt according to any one of claims 1 to 4, where R1represents a phenyl group fused with a 5-7 membered heteroaromatic or non-aromatic ring containing at least one heteroatom selected from the group consisting of N, O and S.

6. Derived thiazole or its pharmaceutically acceptable salt according to claim 1, where X1represents a sulfur atom and X2represents a carbon atom.

7. The ALK5 inhibitor containing as an active ingredient derived thiazole or its pharmaceutically acceptable salt according to claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The ALK5 inhibitor according to claim 7, which is a therapeutic agent against glomerulonephritis, diabetic nephropathy, hepatic fibrosis, cirrhosis, pulmonary fibrosis, proliferative vitreoretinopathy or alopecia or remedy for hair growth.

9. The ALK5 inhibitor according to claim 7 or 8, which is a medicinal product for external use.

10. Stimulator of proliferation of hair out what's follicles, containing the ALK5 inhibitor according to claims 1 to 6 as an active ingredient.

11. Stimulator of hair growth or remedy for hair growth, containing the ALK5 inhibitor according to claims 1 to 6 as an active ingredient.

12. Derived thiazole represented by the formula

or its pharmaceutically acceptable salt,
where X1and X2differ from each other and represent a sulfur atom or a carbon atom;
R1is
phenyl group substituted by 1 member selected from the group consisting of halogen atoms, alkoxygroup having 1-6 carbon atoms, hydroxy-group;
benzo[1,3]dioxol;
benzothiazole;
R2represents a hydrogen atom, halogen atom, alkyl group having 1-6 carbon atoms, alkyl group having 1-6 carbon atoms, substituted by 1-5 halogen atoms, alkanoyloxy group having 1-6 carbon atoms, or a hydroxyalkyl group having 1-5 carbon atoms; and
And1represents a group represented by the formula

where X3represents a halogen atom,
provided that when X1represents a sulfur atom, X2represents a carbon atom, And1representsR1is not 4-methoxyphenyl.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I: , their optical isomers or optical isomer mix, and pharmaceutically acceptable salts, where: R1 is independently selected out of group including: aryl, heteroaryl, arylcarboxyamido, heteroarylcarboxyamido, aryloxy, arylalcoxy or arylamino, and where indicated groups of aryl, aryalkyl or heteroaryl can be substituted by 0-3 substitutes R1a, where R1a is independently selected out of group including: halogen, alkyl, alkenyl, alcoxy, alcoxyalkyl, hydroxyalkyl, mono-, di- or trihalogenoalkyl, mono-, di- or trihalogenoalcoxy, mono- or disubstituted aminoalkyl, aminocarbonyl, mono- or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, etherified carboxylic acid residue, arylcarbonylamino, carbamate, R1b-aryl or R1b-heteroaryl where R1b is H, halogen, OH, amino, mono- or disubstituted amino, mono-, di- or trihalogenoalkyl, alkcoxy, mono-, di- or trihalogenoalcoxy, hydroxyalkyl; R2 is independently selected out of group including: H, OH, cyano, halogen or aryl; optionally R1 and R2 can be linked to form spirocyclyl; R3, R4, R5 and R6 are H; optionally R1 and R3 can be cyclised to form carbocycle; optionally R3 and R4 or R5 and R6 are cyclised to form bicyclic bridge system including ethylene bridge; optionally R3 and R6 are cyclised to form bicyclic bridge system including methylene or ethylene group; R7 and R8 are independently selected out of group including hydrogen, OH, C1-C8alkyl, arylalcoxy, heteroarylalcoxy; optionally R7 and R9 can be cyclised to form spirocarbocycle or spiroheterocycle; and m=0-5; where "aryl" term denotes aromatic carbocyclic groups such as phenyl, biphenyl, indenyl, naphthyl, and aromatic groups condensed with heterocycles; where "heterocycle" term denotes aromatic and non-aromatic rings including 3 to 10 atoms in the ring, 1-4 of which are heteroatom selected out of oxygen, sulfur or nitrogen; where "alkyl" term, when used separately or as suffix, denotes branched or non-branched alkyl group including 1 to 8 carbon atoms in chain; where "alkenyl" term denotes non-saturated branched or non-branched alkyl group including 2 to 12 carbon atoms in chain.

EFFECT: compounds applicable as chemokine receptor activity modulators.

15 cl, 1 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazol derivatives of general formula (I) and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and to based medicinal agent. In general formula (I) , R1 represents 1,4-dioxepanyl or tetrahydropyran-4-yl; R2 represents -N(R)-(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with one-two substitutes chosen from group, consisting of C1-C6alkyl or -NR2, or represents -(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 heteroatoms chosen of N, S or O, optionally substituted with group -(CH2)n-OH, C1-C6alkyl, C1-C6alkoxy, or represents -(CH2)n-5-or 6-merous aromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with the following group: C1-C6alkyl, C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), -CH2N(R)(CH2)2OCH3, -N(R)(CH2)2OCH3, - CH2-morpholinyl or -CH2-pyrrolidinyl or represents (CH2)n-C3-C6cycloalkyl optionally substituted with group hydroxy, or represents -N(R)-C3-C6cycloalkyl optionally substituted with group hydroxy or C1-C6alkyl, or represents phenyl optionally substituted with group C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), C1-C6alkyl, -CH2-pyrrolidine-1-yl, CH2N(R)(CH2)2OCH3 or -CH2-N(R)C(O)-(C1-C6alkyl), or represents 1,4-dioxa-8-azaspiro[4,5]decane, or 2-oxa-5-azabicyclo[2,2,1]heptane, or 1-oxa-8-azaspiro[4,5]decane, or -N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or 2-azabicyclo[2,2,2]octane; R represents hydrogen or C1-C6alkyl; n stands for 0 or 1.

EFFECT: compounds can be applied for treatment and prevention of diseases mediated by adenosine A2A and A1 receptors, eg Alzheimer's disease, some depressions, toxicomania, Parkinson's disease.

8 cl, 3 dwg, 61 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invented compounds have antagonist properties towards CB1 receptors. In formula (I) , R1 is a lower alkoxy, (lower alkyl amino)-(lower alkoxy) or -N(Ra)Rb; Ra is hydrogen, lower alkyl, carbamoyl-(lower alkyl), hydroxy-(lower alkyl), dihydroxy-(lower alkyl), lower alkynyl, lower alkoxy, (lower alkoxy)-(lower alkyl), di-(lower alkylamino)-(lower alkyl), C3-6cycloalkyl; or Ra is a phenyl-(lower alkyl) group, where the phenyl fragment can be optionally mono-substituted, independently, by lower alkyl, lower alkoxy or halogen; or Ra is a 5- or 6-member heteroaromatic ring system, containing one or two nitrogen atoms in the ring, where the said heteroaromatic ring system is bonded to the remaining part of the molecule by lower alkylene; or Ra is a 5-, 6- or 7-member saturated heterocyclic ring system, containing one nitrogen heteroatom, where the said heterocyclic ring system is optionally mono-substituted by lower alkyl; Rb is hydrogen, lower alkyl or (lower alkoxy)-(lower alkyl); or Ra and Rb together with a nitrogen atom to which they are bonded, for a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring system, optionally containing an extra heteroatom, which is chosen from nitrogen, oxygen or sulphur, where the said heterocyclic ring system is optionally mono- or disubstituted, independently, by lower alkyl, hydroxy group, hydroxy-(lower alkyl), lower alkoxy, (lower alkoxy)-(lower alkyl) group, cyano group, halogen, phenyl and/or benzyl; R2 is hydrogen or lower alkyl; R3 is phenyl, mono- or disubstituted, independently, by lower alkoxy, halogen, or perfluoro-(low alkoxy) group; and R4 is phenyl, which is mono- or disubstituted with a halogen.

EFFECT: new compounds have useful biological properties.

18 cl, 195 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds with formula I where R1, R2, R3 and Y together with a formula I residue, are compounds, chosen from a group given in the formula of invention, or to their pharmaceutically used and split esters, or to their acid-additive salts, which promote release of parathyroid hormone.

EFFECT: compounds can be used for making medicinal agents, with antagonistic properties towards calcium sensitive parathyroid gland receptor for treating diseases mediated by effect of parathyroid hormone.

7 cl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I): (I) where: R1 represents either direct or branched (C1-C7)alkyl, or (C2-C4)alkenyl; R2 represents piridinyl, thienyl, thiazol; R3 represents one or more substitutes chosen from halogen atoms and following groups; trifluoromethyl, direct or branched (C1-C6)alkyl; as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to mew compounds with formula (I), their pharmaceutical salts and ester derivatives. In general formula (I) n equals 0 or an integer from 1 to 4; Z is -(CHR8)m-, -(CH2)mO(CHR8)r-, -(CH2)mS(CHR8)r- or -(CH2)mNR9(CHR8)r-, L3 is -(CHR)S-, where R is represents hydrogen and s equals 1, Q2 is oxygen, X and Y independently represent CH or nitrogen; or -X=Y- represents sulphur, oxygen. Description of the rest of the radicals is given in the summary of invention.

EFFECT: invented compounds have inhibiting effects on PTPase.

12 cl, 3 dwg, 51 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and pharmaceutically acceptable salts. Claimed compounds have modulation effect on CB cannabinoid receptor. In the general formula (I) , R and R1 are the same or different and are phenyl optionally substituted by 1-3 substitutes Y, where Y is substitute selected out of group including chlorine, iodine, bromine, fluorine, on condition that X is not a sub-group (ii); or one of R and R1 radicals is phenyl group, while the other radical is formed or linear C2-8-alkyl group or benzyl group; X is one of the sub-groups (i) or (ii). Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim.

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds with inhibition effect on thrombocyte aggregation, their pharmaceutically acceptable salts, particularly compounds of general formula (I) (where R1 is C1-C6 alkyl etc., R2 is hydrogen, C2-C7 alkanoyl, C7-C11 arylcarbonyl, group of formula R4-(CH2)1- etc., R3 is C6-C10 aryl etc., X1, X2, X3, X4 and X5 are independently hydrogen, halogen etc., and n is an integer from 0 to 2), its pharmaceutically acceptable salts. Invention claims pharmaceutical compositions inhibiting thrombocyte activation and containing claimed compounds as agent.

EFFECT: obtaining compounds applicable as media of prevention and treatment of diseases related to thrombo- or embologenesis.

26 cl, 272 ex, 8 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: compounds of this invention possess properties of protein kinase inhibitors. In the general formula p means integer within 0 to 2; R and R1 mean O; A1 and A2 mean single bond, (C1-C6)alkyl; B2 means monocyclic or bicyclic, saturated or unsaturated heterocyclic radical including 1 to several identical or different heteroatoms, chosen among O, S, N and NR7, probably substituted with one or several identical or different substitutes.

EFFECT: inhibiting effect on protein kinase, effective application of compounds of formula for medical products.

49 cl, 1 tbl, 6 dwg, 334 ex

FIELD: chemistry.

SUBSTANCE: described are 2,6-substituted pyridine-3-carbonyl derivatives of formula (I) , in which A stands for alkandiyl, is necessary disrupted by oxygen; X stands for halogen, alkylsulfonyl with 1-6 carbon atoms; Y stands for heterocycle and, if necessary, heterocycle can contain SO2-group or oxo-group (C=O), possibly substituted by alkyl, alkoxy, alkylthio with 1-6 carbon atoms in alkyl groups; Z stands for group of formula: or . Also described are intermediate derivatives of formulas (II) and (IV) .

EFFECT: extension of range of substituted pyridylketones with herbicidal activity.

3 cl, 3 tbl, 49 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: compound of formula [I]: is described, where the ring A represents halogen substituted benzene ring; the ring B represents benzene ring substituted with two lower, 1 to 4 carbon atoms, alcoxy-groups; the ring C represents benzene ring or five-member aromatic heterocyclic ring, that may be optionally substituted with substitute as follows: carboxyl group, C1-4-alkyl group, C2-7-alkanoiloxy-C1-6-alkyl group, phenyl-C1-4-alkyl group, phenyl group, optionally substituted with carboxyl group, or oxo-group; R1 represents C1-6-alkyl group, optionally substituted with hydroxyl group, that optionally substituted with C2-20-alkanoil or C1-7-alkyl group; X1a represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X1b represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X2 represents bound, -O- or -S- ; X3 represents bound or group, formed by one hydrogen atom elimination from either straight or branched chain C1-7-alkyl, or C2-6-alkenyl group, that optionally substituted with hydroxyl or oxo-group; and Y represents optionally etherified carboxyl group; or its salt. Benzoxazepin derivatives production method, medicine based on them, and their application are also described.

EFFECT: novel compounds have high lipids-decreasing effect and are helpful as hyperlipidemia prevention and treatment medicine.

20 cl, 168 ex

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

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