Novel oxazolidinone derivatives with cyclic amidoxim or cyclic amidrazone and containing them pharmaceutical compositions

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is oxazolidinone of general formula , where values of radicals are given in invention formula, and pharmaceutical antibiotic composition, which includes as active ingredient novel oxazolidinone derivative, its hydrate, solvate, isomer or pharmaceutically acceptable salt.

EFFECT: compounds are characterised by wide antibacterial spectrum and high antibacterial activity against gram-positive and gram-negative resistant bacteria, low toxicity and can be applied as antibiotic.

7 cl, 3 tbl, 106 ex

 

The technical field to which the invention relates

The present invention relates to new derivatives of oxazolidinone represented by chemical formula 1, in particular to the new derivative oxazolidinone containing cyclic group amidoxime or cyclic amerzone.

[Chemical formula 1]

The present invention also relates to antibiotic pharmaceutical compositions comprising as an effective ingredient new derivative oxazolidinone represented by chemical formula 1, their prodrugs, hydrates, solvate, isomers, or pharmaceutically acceptable salt.

The level of technology

Since the discovery of penicillin by pharmaceutical companies around the world have developed numerous antibiotics, including β-lactam antibiotics against bacterial infections, sulfonamides, tetracyclines, aminoglycosides, macrolides, quinolones, glycopeptides, and other similar drugs. And, in addition, as a result of improper application or use of antibiotics continuously new resistant to antibiotics, bacteria or multiresistant bacteria. As a consequence, there is growing global concern about these problems. International microbiological community concerned shall eat, as the development of resistance to antibiotics in the near future may be a wide spread of new resistant bacteria, which do not interfere with any actions currently used antibiotics.

In General, bacterial pathogens can be divided into gram-positive or gram-negative bacteria. In particular, are very important gram-positive bacteria, for example,Staphylococcus,Enterococcus,,Streptococcus,and acid-fast bacteria. This is because, after they appear in the hospital environment, they are difficult to destroy and they tend to become untreatable resistant bacteria. Such resistant bacteria include methicillin-resistantStreptococcus(MRSA), methicillin-resistant coagulase-negativeStreptococcus(MRCNS), penicillin-resistantStreptococcus pneumoniae, multidrug-resistantEnterococcus faeciumor other similar bacteria.

For effective clinical treatment of gram-positive bacteria are often used glycopeptides antibiotic vancomycin. However, vancomycin exhibits different types of toxicity and, since the emergence of vancomycin-resistantEnterococcus,(VRE) in the 1990s, constantly appear bacteria that are resistant to vancomycin and other antibiotics on the basis of glycopeptides.

And in respect of such ant is biotikos, as β-lactams, quinolones and macrolides used to treat infections of the upper respiratory tract caused by specific gram-negative bacteria, includingHaemophilus influenzae(H. influenzaeandMoraxella catarrhalis(M. catarrhalis)appear resistant bacteria, such as hinolan-resistantStaphylococcus aureus(QRSA). Therefore, at present, studies on the development of new antibiotics.

Accordingly, in order to fundamentally solve the problem of antibiotic resistance, it is necessary to create antibiotics with a new chemical structure and the new mechanism of destruction of microbes. In this regard, since in 1984 was first reported by DuPont about the antibiotic with a new chemical structure based on oxazolidinone (European Paten Publication No. 127902), many pharmaceutical companies have developed and synthesized a number of derivatives oxazolidinone.

These derivative oxazolidinone are new synthetic antibiotics can be administered orally. Antibiotics based on oxazolidinone are completely different from the classical antibiotics chemical basis. Because they inhibit the initial stage of protein synthesis, they are exceptional antibacterial activity against bacteria resistant to antibiotics, in particular graphological the different bacteria, such as methicillin-resistantStaphylococcus aureus(MRSA), methicillin-resistantStaphylococcusepidermidis(MRSE), chinolin-resistantStaphylococcus aureus(QRSA), vancomycin-resistantEnterococcus,(VRE), and multidrug-resistantMycobacterium tuberculosis(MDRTB).

As examples of compounds of oxazolidinone, including oxazolidinone ring, in patent documents US Patent Nos. 4948801, 4461773, 4340606, 4476136, 4250318 and 4128654 described derivatives of 3-phenyl-2-oxazolidinone having one or two Deputy (deputies), and in patent document EP 0312000, publicationsJ. Med. Chem.32, 1673(1989),J. Med. Chem.33, 2569 (1990),TetrahedronLett. 45,123(1989) and other similar publications described derivative of 3-[(monosubstituted)phenyl]-2-oxazolidinone represented by the chemical formula A.

[Chemical formula A]

And derivative oxazolidinone represented by chemical formula B and the chemical formula C were synthesized by the company Pharmacia & decision Upjohn (patent documents WO 93/23384, WO 95/14684 and WO 95/07271). The compound of chemical formula B, "linezolid", is the first antibiotic based on oxazolidinone, approved by the Department for quality control of food and drug administration (FDA), and it is sold on the market under the trade name zyvox for oral administration and injection. However, most synthetic compounds oxazolidinone feature is described by a number of disadvantages, limiting their application, such as toxicity, low efficacy ofin vivoand low solubility. As linezolid, its solubility in water is only about 3 mg/ml, which limits its use for injection.

[Chemical formula B]

[Chemical formula C]

In the patent document WO 93/09103 disclosed phenyl derivative oxazolidinone having a heterocyclic ring, including pyridine, thiazole, indole, oxazole, China and so forth, in the 4-position of the phenyl group. But the substituents of the heterocyclic ring are only simple alkyl group or amino group, and the activity of these derivatives is not low.

To solve these problems in the patent document WO 01/94342 disclosed phenylpropane oxazolidinone with different derivatives of pyridine or phenyl in the 4-position of the phenyl group. Synthetic compounds have a wide spectrum of antibacterial action and high antibacterial activity. Despite the fact that compounds of oxazolidinone with different derivatives of pyridine in 4-position of the phenyl group oxazolidinone, have a wider spectrum of antibacterial action and high antibacterial activity compared with linezolid, however great nstwo of them have a solubility in water of 30 μg/ml or less, and so they have limited use in the preparation of injectables.

TR-700 and TR-701, represented by the chemical formula D, developed by Dong-A Pharmaceutical and license them recently sold the company Trius Therapeutics. TR-701 is a prodrug TR-700, and this tool is now at stage II clinical trials. The problem of solubility in the case of TR-700 is solved by the formation of a prodrug TR-701, and TR-700 has antibacterial activity, superior antibacterial activity of linezolid. However, the connection has higher toxicity (cytotoxicity, properties in relation to monoamine oxidase, myelosuppression, and so on)than linezolid, and therefore it is expected that it will have a lot of limitations.

[Chemical formula D]

Based on the above, we can conclude that it is not found the connection that has a significantly higher antibacterial activity, satisfactory solubility and lower toxicity.

Description of the invention

The problem solved by the invention

The authors of the present invention have synthesized new derivatives of oxazolidinone with the purpose of reception of antibiotics, have significantly higher antibacterial activity compared to exist is their antibiotics, and having a higher solubility for easier preparation of these oral and injectable drugs. It was confirmed that the new derivative oxazolidinone according to the present invention have a significantly higher antibacterial activity and significantly improved spectrum antibacterial action.

In particular, the cyclic connection amidoxime or cyclic hamidrasha provided by the present invention, has not yet been investigated. While cyclic amidoxime or amerson are relatively well-known compounds, cyclic connection amidoxime or cyclic hamidrasha disclosed in the present invention, is practically unknown. Introduction cyclic form results in a significantly improved absorption capacity and allows to obtain a Sol having an appropriate basicity, resulting in greatly increased solubility in water. Increased solubility allows production of injection preparations without the use of prodrugs and with low toxicity.

Accordingly, the present invention is the development of new derivatives oxazolidinone, in particular new compounds of oxazolidinone with a group of cyclic amidoxime or group of cyclic hamidrasha with the in order to improve their solubility, and development of methods for their preparation.

Another objective of the present invention is the development of antibiotic pharmaceutical compositions comprising as active ingredient new derivative oxazolidinone, their prodrugs, hydrates, solvate, isomers, or pharmaceutically acceptable salt.

New derivatives of oxazolidinone according to the present invention can be used for the treatment of nosocomial pneumonia, community-acquired pneumonia, complicated skin infections and skin structure, uncomplicated infections of the skin and skin structures, or infections caused by bacteria resistant to antibiotics, in particular septicemia caused by vancomycin-resistantEnterococcus faecium(VRE) or linezolid-resistantEnterococcus faecalisor for combination therapy of diseases associated with gram-negative bacteria.

The solution

Next will be described embodiments of the present invention.

The present invention relates to new derivatives of oxazolidinone represented by chemical formula 1, in particular new compounds of oxazolidinone with a group of cyclic amidoxime or group of cyclic amerzone. The present invention also relates to pharmaceutical antibiotic HDMI the Nations, comprising as active ingredient new derivative oxazolidinone represented by chemical formula 1, its prodrug, hydrate, MES, isomer or pharmaceutically acceptable salt.

[Chemical formula 1]

in chemical formula 1,

R1represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl;

Y represents-O - or-N(R2)-;

R2represents hydrogen, cyano, (C1-C6)alkyl, (C3-C6-cycloalkyl, -(CH2)mOC(=O)R11, -(CH2)mC(=O)R12, -(CH2)mC(=S)R12or-SO2R13where alkyl, R2may be optionally substituted with one or more substituent (substituents), selected from the group consisting of (C2-C6)alkenyl, (C2-C6)quinil, halogen, halogen(C1-C6)alkyl, (C1-C6)alkyl(C2-C6)quinil, hydroxyl, (C3-C6)cycloalkyl and cyano;

R11-R13independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)-quinil or (C1-C6)alkylsulphonyl, where alkyl, alkoxy, or amino, R11-R13can be optionally substituted with one ilible Deputy (deputies), selected from halogen, amino, hydroxyl, cyano, (C1-C6)alkyl, (C1-C6)-alkylcarboxylic and hydroxy(C1-C6)alkyl;

m represents an integer from 0 to 2;

X1and X2independently represent hydrogen or fluorine;

P represents-O-, -NH-, or five-membered aromatic heterocycle with the following structure

Q is hydrogen, -C(=O)R3, -C(=S)R4, -C(=O)NR5R6, -C(=S)NR5R6or five-membered aromatic heterocycle with a structure selected from the following structures:

R3and R4independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C6)alkenyl or (C2-C6)-quinil;

R5and R6independently represent hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl or (C2-C6)alkenyl;

R7represents hydrogen, halogen, (C1-C6)alkyl or (C3-C6-cycloalkyl; and

alkyl, R3-R7may be optionally substituted with one or more substituent (substituents), selected from the group consisting of hydroxyl, cyano, halogen, (C1-C6)-alkylcarboxylic and amino.

Used herein, the term "alkyl" includes the em linear and branched structures. For example, the term "(C1-C6)alkyl" includes all possible positional and geometric isomers, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl and other similar alkali.

The term "(C3-C6)cycloalkyl" includes all possible positional and geometric isomers, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and other similar cycloalkyl.

The term "(C2-C6)alkenyl" includes all possible positional and geometric isomers, such as vinyl, propenyl, 1 - and 2-butenyl, pentenyl, and other such alkenyl.

The term "(C2-C6)quinil" includes all possible positional and geometric isomers, such as acetylenyl, propargyl, 1-PROPYNYL, 2-pentenyl, and other similar alkinyl.

Derivative oxazolidinone according to the present invention can be represented by the chemical formula 2 or 3:

[Chemical formula 2]

[Chemical formula 3]

In chemical formulas 2 and 3, R2X1X2P and Q are the same as in chemical formula 1.

More preferably, derived oxazolidinone according to the present invention include compounds represented by chemical formulas 4-9:

[Henichesk the I formula 4]

[Chemical formula 5]

[Chemical formula 6]

[Chemical formula 7]

[Chemical formula 8]

[Chemical formula 9]

In chemical formula 4-9,

R2represents hydrogen, cyano, (C1-C6)alkyl, (C3-C6-cycloalkyl,

-(CH2)mOC(=O)R11, -(CH2)mC(=O)R12, -(CH2)mC(=S)R12or-SO2R13where alkyl, R2may be optionally substituted with one or more substituent (substituents), selected from the group consisting of (C2-C6)alkenyl, (C2-C6)quinil, halogen, halogen(C1-C6)alkyl, (C1-C6)alkyl(C2-C6)quinil, hydroxyl, (C3-C6)cycloalkyl and cyano;

R11-R13independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C3-C6)cycloalkyl, or (C1-C6-alkylsulphonyl, where alkyl, alkoxy or amino, R11-R13can be optionally substituted with one or more substituent (substituents), selected from halogen, amino, hydroxyl, cyano, (C1-C6)alkyl, (C 1-C6)alkylcarboxylic and hydroxy(C1-C6)alkyl;

m represents an integer from 0 to 2;

P represents-O-, -NH - or five-membered aromatic heterocycle with the following structure

Q is hydrogen, -C(=O)R3, -C(=S)R4, -C(=O)NR5R6, -C(=S)NR5R6or five-membered aromatic heterocycle with a structure selected from the following structures

R3and R4independently represent hydrogen, (C1-C6)alkyl or (C1-C6)alkoxy;

R5and R6independently represent hydrogen or (C1-C6)alkyl; and

alkyl, R3-R6may be optionally substituted with one or more substituent (substituents), selected from the group consisting of hydroxyl, cyano, halogen, (C1-C6)-alkylcarboxylic and amino.

Examples of new derivatives oxazolidinone according to the present invention include the following compounds, but the scope of the present invention is not restricted by them:

New derivatives of oxazolidinone according to the present invention are cyclic group amidoxime or group of cyclic amerzone and can be prepared in the form of prodrugs, hydrates, solvate, isomers or pharmaceutically acceptable salts, in order to improve absorption in the body, or to increase the solubility. Therefore, prodrugs, hydrates, solvate, isomers or pharmaceutically acceptable salts are also included in the scope of the present invention.

New derivatives of oxazolidinone according to the present invention can be converted into pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts join acid", suitable for the introduction of compounds of this invention and they include methanesulfonate, aconsultant, fumarate, succinate, hydrochloride, citrate, malate, tartrate and (less preferably) the hydrobromide, phosphate, sulfate and other salts. In addition, the corresponding basic salt includes, for example, salt of an alkali metal (e.g. sodium salt) or salt of the alkaline earth metal (for example, a salt of calcium or magnesium), salts of organic amine (e.g. triethylamine, research, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, N,N-dibenzylamine and Tris(2-hydroxyethyl)amine), or amino acids (for example, N-methyl-d-glutamine and Liz is on). Salt may include one or more cation (cation or anion (anion) depending on the number of charged groups (groups) and the valency of the corresponding cation (cation or anion (anion). Preferred pharmaceutically acceptable basic salt is sodium salt. However, in order to facilitate the selection of salt during its preparation, may be preferred salt is less soluble in the selected solvent.

Derived oxazolidinone of the present invention may be present either in the form of MES, for example in the form of a hydrate, or not in solvated form. The solvate of the derivative of oxazolidinone according to the present invention include all pharmaceutically active solvated forms.

Derivative oxazolidinone of the present invention can be introduced in the form of a prodrug that is transformed into the human or animal with the formation of the active ingredient of the present invention. The prodrug can be formed by introducing a specific group or substituent that is able to modify or improve the physical and/or pharmacological properties of the parent compound. Examples of prodrugs include esters of the compounds of the present invention and their pharmaceutically acceptable salts, which can be subjected to hydrolysis in vivo.

is the art there are known various types of forms of prodrugs. For example, see the following publications:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p.309-396, edited by K. Widder, et al. (Academic press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs ", by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al.,Journal of Pharmaceutical Sciences, 77, 285 (1988); and

e) N. Kakeya, et al.,Chem. Pharm. Bull., 32, 692 (1984).

Examples of prodrugs in accordance with the present invention include the following compounds.

As shown in the above examples, phosphonate or acetyl group can be attached at the hydroxyl group, so that after the introduction of the prodrug is transformed into the active form. As an option, can be attached amino acid or may be formed carbonate form. The form of prodrugs are used mainly in cases of relatively low solubility or low absorption capacity. The use of prodrugs in addition to improving the solubility and absorption can lead to improved absorption, distribution, metabolism and excretion (ADME) and PK profile.

The compound of the present invention has a chiral center at position C-5 ring oxazolidinone. Preferred diastereoisomer of a derivative oxazolidinone according to the present invention before the submitted chemical formula 1. Compared with the epimer represented by chemical formula 1b, it shows superior properties in respect of monoamine oxidase.

[Chemical formula 1b]

In the case of using a mixture of epimeres relative to the chiral center oxazolidinone, in order to achieve comparable pharmacological effect as compared to the case when using only one mirror isomer, it is possible to adjust the amount of the share of enantiomers or diastereomers).

In addition, some compounds of the present invention, depending on their Deputy (deputies) may have another chiral center. All optical isomers, diastereomers and mixtures, having antibacterial activity, are included in the scope of the present invention. A method of obtaining optically active forms (for example, recrystallization, chiral synthesis, enzymatic separation, biotransformation or separation of mixtures using chromatography) and method of measurement of antibacterial activity are known in this technical field.

As compounds represented by chemical formula 1 or their salts can tautomerizations, and even if only one of the possible tautomers shown in chemical formulas or schemes of reactions in the description of the application, the present invention covers all t is atomary, having antibacterial activity, and is not limited to the tautomeric form shown in chemical formulas or schemes reactions.

In addition, the compound of the present invention can exhibit polymorphism. Therefore, all polymorphic compounds having antibacterial activity, are included in the scope of the present invention.

New derivatives of oxazolidinone according to the present invention can be obtained by using alternative methods, depending on what they have deputies. For example, they can be obtained according to the methods described in the examples in figures 1-6. Methods of preparation, are given in figures 1-6 are examples only, and they can be easily modified by experts in this field, depending on the particular substituents. Accordingly, examples of the ways in schemes 1-6 do not limit the method of obtaining compounds of oxazolidinone of the present invention. Unless otherwise stated, the definitions for the substituents in the schemes of the reactions are the same as in chemical formula 1.

Derivative oxazolidinone chemical formula 1 according to the present invention can be synthesized using various methods of synthesis, depending on X1X2, Y, P and Q. the Characteristic methods of synthesis when X1is a fluorine atom (F), and X 2is a hydrogen atom (H), are given as examples in schemes 1-5. And case when both X1and X2are H or F, are given by way of example in scheme 6.

The syntheses of compounds of cyclic hamidrasha, when Y is a nitrogen atom (N-R2), methods of synthesis in the case when P is NH, are cited as examples in figures 1 and 2, the method of synthesis in the case when P is an aromatic heterocycle (e.g., triazole), cited as an example in figure 3, and the case when P is an atom of oxygen (O), cited as an example in figure 4. In addition, the method of synthesis of compounds of cyclic amidoxime, when Y is O, cited as an example in scheme 5.

According to scheme 1, 3,4-diplomarbeit interacts with ethanolamine obtaining compound I. After protection of the alcohol and amine groups consistently withtert-butyldimethylsilyl (TBS) andtert-butyloxycarbonyl (boc) (compound II), the nitro-group is reduced to an amine using Pd/C (compound III). Attach benzyloxycarbonyl group (cbz) using benzylchloride (Cbz-Cl) to give compound IV. Compound IV interacts with (R-glycidyl-butyrate and n-butyllithium (n-BuLi) with the formation of a chiral compound V. Compound V is reacted with methanesulfonamide (Ms-Cl) (connect the tion VI), and then with sodium azide (NaN3) (compound VII). After transformation of the azide group in the amine using Pd/C in an atmosphere of hydrogen gas, you'll join a group of cbz using Cbz-Cl with the formation of compound VIII. Compound VIII is treated with hydrochloric acid to remove the protective group (boc and tbs) to obtain compound IX, which interacts with methanesulfonanilide (Ms-Cl) with the formation of compound X. the interaction of the compound X with hydrazine and then interaction with triethylorthoformate network connection cyclic hamidrasha XII. After removal of the cbz group from compound XII (compound XIII), it can be entered a number of groups Q. in Addition, after removal of the formyl group can be introduced by a number of groups R2. Specific examples described upon receipt of the connection.

[Diagram 1]

According to scheme 2, in the case where Q is an aromatic heterocycle, containing no carbonyl group in compound VI is first injected group P and Q. the Reaction aminoisoquinoline shown as an example in scheme 2. Compound VI interacts with aminoisoquinoline with the amino group protected by a boc group, with the formation of compound XIV. Removal of boc and tbs groups with hydrochloric acid gives compound XV, subsequent metilirovanie and then the reaction is Oia with hydrazine led to the formation of compound XVII, which interacted with triethylorthoformate with the formation of cyclic compounds amerzone. After removal of the formyl group was introduced various R2group. Specific examples described upon receipt of the connection.

[Scheme 2]

According to scheme 3, the case when P is an aromatic heterocycle, divided into 1) when Q is H and 2) when Q is Deputy other than H. First, for compounds in which Q is H, azide compound (compound VII) interacts with 2.5-norbornadiene with the formation of the triazole compound (compound XVIII). Removal of boc and tbs groups with hydrochloric acid gives compound XIX. Metilirovanie (compound XX), treatment with hydrazine and then with triethylorthoformate network connection cyclic amerzone. Compounds in which Q is Deputy other than H, can be obtained as follows; connection XXI dichloropyridazine receive, as shown by the reaction dailybased and acid chloride. The interaction of the amine XIII and dailydata XXI gives the intermediate connection of cyclic hamidrasha, which after removal of the formyl groups have different R2groups. Specific examples described upon receipt of the connection.

[Scheme 3]

The case when P is an atom of oxygen (O), and Q is H, given by way of example in scheme 4. The compound in which P is O, and Q is an aromatic heterocycle, can be synthesized according to scheme 2. For compounds in which Q is H, the implementation of the protection of the alcohol group of compound V using benzoyl gives compound XXII. Removal of boc and tbs protective group with hydrochloric acid (compound XXIII) and metilirovanie gives compound XXIV, which interacts with the hydrazine with the formation of compound XXV. During the reaction with hydrazine discovered that benzoline group is removed. The connection of hydrazine reacts with triethylorthoformate with the formation of cyclic compounds amerzone. After removal of the formyl group enter the different R2group. Specific examples described upon receipt of the connection.

[Diagram 4]

Method for the synthesis of compounds of cyclic amidoxime, in which Y is O, cited as an example in scheme 5. Depending, P-Q is OH, or is not, the cases are divided into 1) and 2).

1) If P-Q is OH, P and Q groups give compound VI in accordance with schemes 1-4 with the formation of compound XXVI, which is treated with hydrochloric acid to remove the boc and tbs groups, receiving XXVII. Compound XXVII is subjected to the reaction of Mitsunobu with hydroxyphthalimide obtaining compounds XXVIII. Remove phthalimide with hydrazine and then interaction with triethylorthoformate network connection cyclic amidoxime.

2) When P-Q is OH, alcohol group oxazolidinones parts must be protected with benzoline group (compound XXIII). The reaction Mitsunobu with hydroxyphthalimide gives compound XXIX. Remove phthalimide with hydrazine and then reaction with triethylorthoformate network connection cyclic amidoxime. And again, the benzene group is removed during the reaction with hydrazine. Connection cyclic amidoxime can also be obtained by reaction with triethylorthoformate.

[Map 5]

The cases when X1is F, and X2is H, have been described in schemes 1-5. According to scheme 6, the compound in which both X1and X2are H or F, can be synthesized in the same manner as in schemes 1-5, with the only difference that in the source material, use 4-ftorirovannom or 3,4,5-tri-ftorirovannom.

*[Scheme 6]

Compositions of the present invention can be in the appropriate form for oral administration (for example, in the form of tablets, lozenges, hard or soft capsules, the crystals, aqueous or oil suspensions, emulsions, dispersible powder or granules, syrup or elixir), in the appropriate form for topical administration (for example, in the form of a cream, ointment, gel, aqueous or oil solution or suspension), in the appropriate form for ocular injection, in the appropriate form for administration by inhalation (for example, in the form of fine powder or a liquid aerosol), in the appropriate form for administration by insufflation (for example, in the form of a fine powder), or in the appropriate form for parenteral administration (for example, in the form of water or oil sterile solution for intravenous, subcutaneous, sublingual or intramuscular injection, or rectal suppository).

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may additionally include (i.e. can be prepared in dosage form together with one or more known drug(s)selected from used in medicine antibacterial agents (for example, β-lactam, macrolide, quinolone or aminoglycoside) and anti-inflammatory drugs (for example, an antifungal triazole or amphotericin b), or may be introduced in combination with one or more known drug (means). For selenitireducens effect of the composition can optionally contain carbapenem, for example, Meropenem or imipenem. In addition, the compounds of the present invention can be introduced in combination or prepared in the form of a dosage form together with increasing bactericidal permeability protein (BPI) or the inhibitor of the pump, in order to increase the activity against gram-negative bacteria and bacteria resistant to antibiotics.

Compounds of the present invention can be introduced in combination or prepared in the form of a dosage form together with vitamin such as vitamin B such as vitamin B2, vitamin B6 or vitamin B12, and folic acid. In addition, the compounds of the present invention can be introduced in combination or prepared in the form of a dosage form together with an inhibitor of cyclooxygenase (COX), in particular, COX-2 inhibitor. In addition, the compounds of the present invention can be introduced in combination or prepared in the form of a dosage form together with an antibacterial agent active against gram-positive bacteria or gram-negative bacteria.

Compositions of the present invention can be prepared by using a widely used well-known pharmaceutical AIDS. Accordingly, the composition is intended for oral administration may include, for example, one or more coloring emesto, sweetener, flavoring and/or antiseptic. Preferably, the pharmaceutical composition for intravenous infusion could include, for example, to improve stability) suitable bactericide, antioxidant, reducing agent, or a substance enhancing excretion.

Composition for oral administration may be in the form of hard gelatin capsules are prepared by mixing the active ingredient with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules are prepared by mixing the active ingredient with water or oil, such as peanut oil, liquid paraffin or olive oil.

Water suspension typically includes one or more suspendisse tool (means), for example, sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum or gum Arabic, or dispersing or wetting agent (means), for example, lecithin, condensation products of oxide alkylene with a fatty acid (for example, polyoxyethylenated), a condensation product of ethylene oxide with long chain aliphatic alcohol, for example, heptadecafluorooctane, the condensation product of ethylene oxide with a partial ester, p is obtained from a fatty acid and exit, for example, monooleate of polyoxyethylenesorbitan, the condensation product of ethylene oxide with a partial ester derived from fatty acids and anhydride exit, for example, monooleate of polyethylenimine, in addition to the active ingredient in the form of fine powder. The aqueous suspension may optionally include one or more antiseptic (antiseptics) (for example, ethyl or propylp-hydroxybenzoate), antioxidant (antioxidants) (e.g., ascorbic acid), coloring agent (tools), flavor (flavors), and/or sweetening agents (sweeteners) (e.g., sucrose, saccharin or aspartame).

Oily suspension can be prepared by suspension of the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or mineral oil (e.g., liquid paraffin). Oily suspension may additionally include a thickener, for example, beeswax, paraffin wax or cetyl alcohol. In addition, can be added to the above-mentioned sweetener or flavoring to obtain a composition for oral administration having good taste. The composition may be subjected to canning by adding an antioxidant such as ascorbic acid.

Dispersible powder or granule suitable for the sentence is the service water suspension by adding thereto water, in addition to the active ingredient include dispersing or wetting agent, suspendisse tool and one or more antiseptic (antiseptics). Examples of appropriate dispersing or wetting means and suspendida means previously described. In addition, the composition may include an auxiliary substance, such as a sweetener, flavoring and coloring agent.

For more information on medicinal forms can be found in the monograph Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.2 (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The amount of active ingredient is mixed with one or more auxiliary substance (substances), for the preparation of dosage forms of single dose may vary of course, depending on the subject, which requires the introduction of this dose, and specific way of introduction. For example, a dosage form for oral administration may include, in most cases, from 50 mg to 5 g of the compound as an active ingredient together with a corresponding number of auxiliary tools (content may vary in the range from about 5 to 98% of the total weight of the composition). Usually a single dose may include from about 200 mg to 2 g of active ingredient. For more information on the method of administration and schemes can be found in monog is the her Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.3 (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

A suitable pharmaceutical composition of the present invention is a dosage form dose suitable for oral administration, e.g. tablet or capsule, comprising from 0.1 mg to 1 g, preferably 100 mg to 1 g, the compounds of the present invention. In particular, preferred is a tablet or capsule, comprising from 50 mg to 800 mg of the compound of the present invention.

In addition, the pharmaceutical compositions of the present invention can be a pharmaceutical form suitable for intravenous, subcutaneous or intramuscular injection, for example, injection, comprising from 0.1% weight/volume to 50% weight/volume (1 mg/ml to 500 mg/ml) of the compound of the present invention.

Each patient the compound of the present invention can be administered intravenously, subcutaneously or intramuscularly, for example, at a dose of from 0.1 mg/kg to 20 mg/kg / day. The corresponding composition is administered one to four times per day. In another embodiment, the compound of the present invention is administered in a dose of from 1 mg/kg to 20 mg/kg / day. The dose for intravenous, subcutaneous or intramuscular injection may be injected by bolus injection. Alternatively, the dose for intravenous administration can be a continuous injection in those who tell some period of time. In addition, each patient can be entered day dose for oral administration, which is roughly equivalent to a one-day dose for parenteral administration. The corresponding composition is administered one to four times per day.

Compared with linezolid that comes on the market firm Pfizer, derived oxazolidinone of the present invention show antibacterial activity at much lower concentrations against a variety of bacteria that are resistant to existing antibiotics, including gram-positive bacteria, such asStaphylococcus aureus,Enterococcus faecalisand so on, and gram-negative bacteria such asHaemophilus influenzae,Moraxella catarrhalisand so forth, in particular, the high antibacterial activity against linezolid-resistantEnterococcus faecalis.

The implementation of the invention

Next will be described examples and experiments. However, the following examples and experiments are only for purpose of illustration, and should not be construed as limiting the scope of the present invention.

[Synthesis example 1] Getting connectionI

After dissolving 3,4-deformirovannoe (158 g of 0.99 mol) in acetonitrile (800 ml) and added ethanolamine (117 g, 1.9 mol), the mixture was stirred for 4 hours at which ipacarai under reflux. The reaction solution was cooled to room temperature, concentrated under reduced pressure, triturated with diethyl ether, and filtered to obtain yellowconnection I(199 g, 0,99 mol, 100%).

1H NMR (400 MHz, chloroform-d1) δ of 7.97 (d, 1H, J=8,8 Hz), 7,87 (DD, 1H, J1=to 11.6 Hz, J2=2,4 Hz), of 6.65 (t, 1H, J=8,8 Hz), 5,10-4,87 (users, 1H), 3,97-a 3.83 (m, 2H), 3,43-3,37 (m, 2H).

[Synthesis example 2] the connectionII

The connection I(100 g, 0.5 mol),tert-butyldimethylsilyl (TBS-Cl, 97 g of 0.65 mol) and imidazole (51 g, 0.75 mol) was dissolved in dichloromethane (700 ml) at 0°C. after slowly warming to room temperature and was stirred overnight. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate and washed with 0,5h. HCl, washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtain compound with tbs group attached to alcohol. This compound was dissolved in THF (500 ml) and was added 1.2 equivalent of Boc2O and 0.1 equivalent of 4-dimethylaminopyridine (DMAP). After stirring for 3 hours at room temperature was added ammonia water (30 ml). On the Le stirring for 20 minutes the solution was concentrated under reduced pressure. The concentrate was again dissolved in ethyl acetate, then washed with 0,5h. HCl, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtainthe compound (II).

1H NMR (600 MHz, chloroform-d1) δ 8,06-7,98 (m, 1H), 7,95 (DD, 1H, J1=10,2 Hz, J2=2,4 Hz), EUR 7.57 (t, 1H, J=7.8 Hz), 3,80 (t, 2H, J=5.4 Hz), to 3.73 (t, 2H, J=4,8 Hz)of 1.42 (s, 9H), 0,81 (s, 9H), of 0.01 (s, 6H).

[Synthesis example 3] the connectionIII

Compound II(92 g, 0.22 mol) was dissolved in methanol (600 ml) and after addition of Pd/C (6 g) was stirred for 4 hours in an atmosphere of hydrogen supplied from a cylinder. The reaction mixture was filtered through celite and concentrated under reduced pressure to quantitatively obtaincompound III(86 g) as a colourless oil.

1H NMR (400 MHz, chloroform-d1) δ of 6.99 (t, 1H, J=12.0 Hz), 6,44-6,30 (m, 2H), 3,81-3,63 (m, 4H), 3,63-to 3.52 (m, 2H), 1,50 (s, 3H), of 1.35 (s, 6H), 0,86 (s, 9H), of 0.03 (s, 6H).

[Example of synthesis 4] the connectionIV

Compound III(86 g, 0.22 mol) was dissolved in dichloromethane (300 ml). After adding aqueous 1N. NaOH solution (300 ml)was slowly added dropwise with stirring, benzylchloride (Cbz-Cl, 38 ml, 0.7 mol). After stirring for 1 hour at room temperature the organic layer was separated, washed twice with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure to quantitatively obtaincompounds IV(116 g) as a yellow oil.

1H NMR (600 MHz, chloroform-d1) δ 7,44-to 7.32 (m, 6H), 7,18 (t, 1H, J=8.1 Hz), of 6.96 (d, 1H, J=8,4 Hz), 6,84-6,66 (users, 1H), 5,20 (s, 2H), 3,82-3,63 (m, 2H), 3,63-to 3.58 (m, 2H)and 1.51 (s, 3H), of 1.35 (s, 6H), 0,86 (s, 9H), of 0.02 (s, 6H).

[Synthesis example 5] Getting connectionV

Compound IV(116 g, 0.22 mol) was dissolved in THF (400 ml) and after slowly adding dropwise at -78°C n-utility (2,5M solution inn-hexane, 90 ml, 0.23 mol) was stirred for 20 minutes. After adding (R)-glycidylether (31.5 ml, 0.23 mol) and subsequent stirring for 3 hours with slow warming to room temperature, brought the solution to pH ~6 using an aqueous solution of ammonium chloride and concentrated under reduced pressure. The concentrate was dissolved in a solution of 80% ethyl acetate/hexane, then washed with water and saturated aqueous solution of sodium chloride (brine), dried using anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was separated using column chromatography, using a solution of 40% of those who acetate/hexane, obtainingconnection V(45 g, 0,093 mol, 42%) as a colourless oil.

1H NMR (600 MHz, CDCl3) δ 7,50-of 7.48 (m, 1H), 7,30-7,28 (m, 1H), 7,17-7,16 (m, 1H), 4,74-4,70 (m, 1H), 4,03-was 4.02 (m, 1H), 3,98 (m, 2H, in), 3.75 (m, 3H), of 3.65 (m, 2H)and 1.51 (s, 3H), of 1.36 (s, 6H), of 0.85 (s, 9H), of 0.02 (s, 6H).

[Example of synthesis 6] the connectionVI

Connection V(45 g, 0,093 mol) was dissolved in dichloromethane (300 ml) and after addition sequentially triethylamine (26 ml, 0,186 mol) dropwise and methanesulfonanilide (MsCl, 10.9 ml, 0.14 mol) at 0°C was stirred for 20 minutes. After heating to room temperature and then stirring for 1 hour, the solution was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, then washed with 0,5h. HCl, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate and concentrated under reduced pressure to obtaincompounds VI(50 g, 0,089 mol, 96%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ 7,46 (DD, 1H, J1=to 11.6 Hz, J2=2,4 Hz), 7,29 (m, 1H), 7,13 (m, 1H), 4,94-4,88 (m, 1H), 4,50-4,39 (m, 2H), 4,12 (m, 1H), 3,92 (m, 1H), and 3.72 (m, 2H), 3,64-3,62 (m, 2H), is 3.08 (s, 3H), 1,49 (s, 3H), of 1.34 (s, 6H), or 0.83 (s, 9H), 0.00 to (s, 6H).

[Synthesis example 7] the connectionVII

Compound VI(50 g, 0,089 mol) RA is tarali in DMF (200 ml) and after addition of NaN 3(7,16 g, 0.11 mol) was stirred for 3 hours at 80°C. the Solution was cooled to room temperature, diluted with ethyl acetate, then washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate and concentrated under reduced pressure to quantitatively obtaincompounds VII(47 g, 0,089 mol) as a colorless oily solid.

1H NMR (600 MHz, CDCl3) δ of 7.48 (DD, J1=8,2 Hz, J2=1,4 Hz) 7,30 (m, 1H), 7,16 (m, 1H), 4,81-rate 4.79 (m, 1H), 4.09 to 4,08 (m, 1H), 3,86 (m, 1H), 3,74 (m, 2H), 3,62-3,59 (m, 1H)and 1.51 (s, 3H), of 1.36 (s, 6H), of 0.85 (s, 9H), of 0.02 (s, 6H).

[Example of synthesis 8] the connectionVIII

Compound VII(47 g, 0,089 mol) was dissolved in methanol (400 ml) and after addition of Pd/C (3.5 g) was stirred for 4 hours in an atmosphere of hydrogen supplied from a cylinder. The solution was filtered through celite and concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (130 ml) and, after addition of aqueous 1N. NaOH solution (130 ml)was slowly added dropwise under stirring Cbz-Cl (15,5 ml, 0.11 mol). After stirring for 2 hours at room temperature the organic layer was separated, washed with water and saturated aqueous solution of sodium chloride (RA is Sola), was dried with anhydrous sodium sulfate, concentrated under reduced pressure and separated using column chromatography, using a solution of 20% ethyl acetate/hexane, to obtaincompounds VIII(50.5 g, 0,082 mol, 92%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ 7,46-the 7.43 (m, 1H), was 7.36-7,35 (m, 1H), 7,31 (s, 6H), 7,11 (m, 1H), 5,09 (s, 2H), and 4.75 (m, 1H), 4,01 (t, 1H, J=8,4 Hz), 3,76-to 3.50 (m, 1H), 1,49 (s, 3H), of 1.34 (s, 6H), or 0.83 (s, 9H), of 0.01 (s, 6H).

[Synthesis example 9] Getting connectionIX

Compound VIII(50.5 g, 0,082 mol) was dissolved in dichloromethane (100 ml), after addition of 4n. HCl solution in dioxane (130 ml) was stirred for 3 hours at room temperature and then concentrated under reduced pressure to quantitatively obtainconnection IX(36 g, 0,082 mol) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ of 7.69 (t, 1H, J=6.0 Hz), 7,44-7,40 (m, 1H), 7,32 (s, 6H), 7,09-7,07 (m, 1H), to 6.88 (t, 1H, J=9,2 Hz), to 5.03 (s, 2H), 4,71-and 4.68 (m, 1H), 4,08-a 4.03 (m, 2H), to 3.73 at 3.69 (m, 1H), 3,60 is 3.57 (m, 3H), 3,39-to 3.34 (m, 2H), 3,18 is 3.15 (m, 2H).

[Synthesis example 10] the connectionXII

Connection IX(36 g, 0,082 mol) was dissolved in dichloromethane (300 ml), and after slowly adding dropwise sequentially triethylamine (34,5 ml, 0,245 mol) and methanesulfonamide (MsCl, and 9.5 ml, 0,123 mol) at 0°C was stirred for 10 minutes. The solution was heated to anatoy temperature, was stirred for 2 hours, diluted with dichloromethane, then washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid substance was washed with the solvent of diethyl ether and filtered to obtainconnection X(30.5 g, 0,063 mol, 77%) as a white solid.

Connection X(20 g 0,042 mol) was added to ethanol (100 ml) and after addition of hydrazine monohydrate (H2NNH2-H2O, 50 ml) was stirred for 2 hours at 60°C. the Solution was concentrated under reduced pressure to obtaincompounds XI(17,4 g 0,042 mol) in the form of oil.

Compound XI(17,4 g 0,042 mol) was added to acetic acid (200 ml) and after adding triethylorthoformate (100 ml) was boiled under reflux for 8 hours. The solution is kept under reduced pressure, dissolved in dichloromethane, then washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was separated using column chromatography, using a solution of 5% met the Nol/dichloromethane, obtainingcompounds XII(5.8 g, 0,013 mol, 31%) as a white solid.

1H NMR (600 MHz, CDCl3) δ=charged 8.52 (s, 1H), 7,55-7,53 (m, 1H), 7,30-7,28 (m, 6H), 7,19-to 7.18 (m, 1H), 7,11-was 7.08 (m, 1H), 6,86 (s, 1H), 5,27 (t, J=6 Hz, 1H), to 5.08 (s, 2H), 4,77 (m, 1H), 4,03-4,00 (m, 1H), 3,97 (t, J=4,8 Hz, 2H), 3,81 is 3.76 (m, 1H), 3,70 (t, J=5,1 Hz, 2H), 3,65-of 3.60 (m, 1H), 3,59-of 3.54 (m, 1H).

[Synthesis example 11] Get connectionXIII

Compound XII(5 g, to 0.011 mol) was dissolved in methanol (100 ml) and after addition of Pd/C (0.5 g) was stirred for 4 hours in an atmosphere of hydrogen supplied from a cylinder. The solution was filtered through celite and concentrated under reduced pressure to obtaincompounds XIII(3.2 g, 0,010 mol, 91%) as an oily solid.

1H NMR (600 MHz, DMSO-d6) δ=8,43 (s, 1H), 7,65-7,63 (m, 1H), 7,40 and 7.36 (m, 2H), 7,12 (s, 1H), 4,65-to 4.62 (m, 1H), 4.09 to 4,06 (m, 1H), 3,89-3,86 (m, 1H), 3,85 (t, J=5,1 Hz, 2H), 3,70 (t, J=4,8 Hz, 2H), 2,88-to 2.85 (m, 1H), 2,82-and 2.79 (m, 1H).

[Example of synthesis of 12] Get connectionXV

Boc-3-aminoethoxy (1.22 g, 6.6 mmol) was dissolved in DMF (40 ml) and after addition of 50% NaH (0.32 g, 6.6 mmol) was stirred for 30 minutes. After slowly adding dropwisecompounds VI(3.6 g, 6.6 mmol)dissolved in DMF (10 ml), the solution was stirred at 80°C for 4 hours. The solution was cooled to room temperature, diluted with ethyl acetate, washed twice with POM is using water, was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtaincompounds XIV(4,16 g, 6.4 mmol).

Compound XIV(4,16 g, 6.4 mmol) was dissolved in dichloromethane (20 ml), after addition of 4n. HCl solution in dioxane (20 ml) was stirred overnight at room temperature, concentrated under reduced pressure and triturated with a solvent diethyl ether with gettingcompounds XV(2.2 g, 6.2 mmol, 94%) as a white solid.

1H NMR (600 MHz, DMSO-d6) δ 8,39 (d, J=2.2 Hz, 1H), 7,52 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,18 (DD, J1=8,4 Hz, J2=1.8 Hz, 1H), 7,10 (t, J=9,3 Hz, 1H), 6,00 (d, J=2.2 Hz, 1H), a 4.86 (m, 1H), 4,11 (t, J=9 Hz, 1H), 3,80-3,19 (m, 7H).

[Example of synthesis 13] Get connectionXIX

Compound VII(0,613 g, 1.2 mmol) was dissolved in dioxane (10 ml), after addition of 2.5-norbornadiene (0.6 ml, 6 mmol) was stirred for 4 hours at boiling under reflux and cooled to room temperature. The solution was concentrated under reduced pressure, dissolved in dichloromethane, washed with water and dried using sodium sulfate to obtaincompounds XVIII(triazole, 98%)which was treated with hydrochloric acid as in synthesis example 9, to obtain thecompound XIX(0.35 g, 1.1 mmol, 92%).

1H NMR (600 MG IS, DMSO-d6) δ=8,18 (s, 1H), to 7.77 (s, 1H), 7,39 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,09-7,00 (m, 2H), 5,11 (m, 1H), 4,82 (d, J=4,8 Hz, 2H), 4,18 (t, J=9.0 Hz, 1H), 3,84 (m, 1H)and 3.59 (t, J=6.0 Hz, 2H), 3,19 (t, J=6.0 Hz, 2H).

[Synthesis example 14] Get connectionXXVII-b

Compound VI(12 g, 21 mmol) was dissolved in DMF (100 ml) and after addition of NaN3(1.65 g, 26 mmol) was stirred at 80°C for 3 hours. The solution was cooled to room temperature, diluted with a mixture of ethyl acetate/hexane (150 ml/30 ml), washed 3 times with distilled water (200 ml), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated using column chromatography, using a solution of 30% ethyl acetate/hexane, to obtaincompounds VII(9.6 g, 19 mmol, 89%).Compound VII(9.6 g, 19 mmol) was dissolved in methanol (120 ml), after addition of Pd/C (1 g) was stirred for 4 hours in an atmosphere of hydrogen supplied from a cylinder, and filtered through celite to obtain compounds amine (8.6 g, 95%). The amine compound (8.6 g) was dissolved in dichloromethane (120 ml) and, after addition of saturated aqueous NaHCO3(40 ml) and then add thiophosgene (1.6 ml, 21 mmol) at 0°C. was stirred for 2 hours. The organic layer was dried with sodium sulfate, drove away under reduced pressure, was dissolved in methanol (150 ml), displaced ivali during the night while boiling under reflux, concentrated under reduced pressure, and separated using column chromatography to obtaincompound XXVI-b(2.6 g, 7.6 mmol), which was treated with hydrochloric acid as in synthesis example 9, with quantitative gettingcompound XXVII-b.

1H NMR (600 MHz, CDCl3) δ=7,35 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 6,99-6,89 (m, 2H), 6,70 (t, J=9,2 Hz, 1H), is 4.93 (m, 1H), 4,10-3,91 (m, 6H), 3,88-of 3.78 (m, 3H), 3,32 (t, J=5,2 Hz, 2H).

[Synthesis example 15] Getting connectionXXVII-a

Hydrochloridecompound XXVII-a(3.4 g, 9.8 mmol, 85%) was obtained fromcompounds VIas in synthesis example 14, using Ac2O instead of thiophosgene.

1H NMR (600 MHz, DMSO-d6) δ of 7.69 (t, 1H, J=6.0 Hz), 7,46 (DD, 1H, J1=to 13.8 Hz, J2=2,4 Hz), 7,41-7,26 (m, 5H), 7.18 in-7,11 (m, 1H), 7,00 (t, 1H, J=9.6 Hz), 6,21-5,73 (m, 2H), to 5.03 (s, 2H), 4,74-of 4.66 (m, 1H), 4,07 (t, 1H, J=9.0 Hz), 3,76-3,70 (m, 1H), 3,60 (t, 2H, J=5.7 Hz), 3,42-to 3.33 (m, 2H,), 3,19 (t, 2H, J=5.7 Hz).

[Synthesis example 16] the connectionXXVIII-a

Hydrochloridecompound XXV-a(1,69 g, a 4.86 mmol), hydroxyphthalimide (0,83 g, 5,11 mmol), triphenylphosphine (1,34 g, 5,11 mmol) and triethylamine (0.7 ml, to 4.87 mmol) was added to THF (20 ml). After slowly adding dropwise with stirring aminobutiramida of azodicarboxylate (DIAD and 1.15 ml of 5.84 mmol), the solution was stirred for 3 hours at room temperature. After filtration is then the filtrate was concentrated under reduced pressure and separated using column chromatography to obtain compound XXVIII-a(1,49 g, 3,26 mmol, 88%).

1H NMR (400 MHz, CDCl3) δ=7,86 (m, 2H), 7,76 (m, 2H), 7,38 (DD, J=8,8, and 1.6 Hz, 1H), 7,00 (DD, J=8,8, and 1.6 Hz, 1H), 6,69 (t, J=6.0 Hz, 1H), 6,13 (t, J=4.0 Hz), 4.92 in (users, 1H), and 4.75 (m, 1H), 4,42 (t, J=3,6 Hz, 1H), 4.00 points (t, J=6 Hz, 1H), 3,70 (m, 2H), 3,60 (m, 1H), 3,50 (users, 2H), 2,03 (s, 3H).

LCMS: 457 (M+H+for C22H21FN4O6.

[Synthesis example 17] Getting connectionXXIII

Connection V(26 g, 0,053 mol) was dissolved in dichloromethane (180 ml) and after a slow added successively dropwise of diisopropylethylamine (DIPEA, 13 ml, 0.079 in mol) and benzoyl chloride (Bz-Cl, 7,4 ml, 0,064 mol) at 0°C was stirred for 10 minutes. After heating to room temperature, was added a small amount of DMAP and the solution was stirred for 2 hours. The solution was concentrated under reduced pressure, dissolved in ethyl acetate, sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtaincompounds XXII(31 g, 0,053 mol), which was treated with hydrochloric acid as in synthesis example 9, with quantitative gettingcompound XXIII.

1H NMR (600 MHz, DMSO-d6) δ 7,88 (d, J=7.8 Hz, 2H), 7,63 (t, 1H, =7,2 Hz), 7,46 (t, 2H, J=7,2 Hz), 7,41 (DD, 1H, J1=to 13.8 Hz, J2=2,4 Hz), 7,11 (d, 1H, J=9.0 Hz), to 6.88 (t, 1H, J=9.0 Hz), 5,02 (m, 1H), 4,54 is 4.45 (m, 2H), 4.16 the (t, 1H, J=9.0 Hz), 3,88 (m, 1H), 3,54 (t, 2H, J=6.0 Hz), of 3.13 (t, 2H, J=6.0 Hz).

Methods of synthesis of the target compounds from the intermediate compounds obtained in the examples of syntheses 1-17, are illustrated by the following examples.

[Example 1] the connection1

Compound XIII(0.1 g, 0.31 mmol)obtained in synthesis example 11, was dissolved in dichloromethane (3 ml), after adding dropwise sequentially DIPEA (0.1 ml, 0.6 mmol) and Ac2O (0.06 ml, 0.6 mmol) was stirred for 2 hours at room temperature, concentrated under reduced pressure and separated using column chromatography to obtainconnections 1(0,098 g, 0.27 mmol, 87%) as a white solid.

1H NMR (400 MHz, chloroform-d4) δ=8,54 (s, 1H), to 7.59 (DD, J=of 13.6, 2.4 Hz, 1H), 7,20 (DD, J=of 13.6, 2.4 Hz, 1H), 7,13 (t, J=8,8 Hz, 1H), to 6.88 (s, 1H), to 6.19 (t, J=6.0 Hz, 1H), to 4.81 (m, 1H), of 4.05 (t, J=8 Hz, 1H), 3,99 (t, J=4,8 Hz, 2H), of 3.80 (DD, J=8,8, 6,8 Hz, 1H), of 3.73 (t, J=4,8 Hz, 2H), 3,69 (m, 2H), 2,03 (s, 3H).

LCMS: 364 (M+H+for C16H18FN5O4.

[Example 2] the connection2

Connection 1(0.7 g, of 1.93 mmol), 4 N. hydrochloric acid, dissolved in 1,4-dioxane (3 ml, 12 mmol) and Pd/C (70 mg) was added in THF (20 ml) and was stirred for chasov in the atmosphere of hydrogen gas. The solution was filtered through celite and concentrated under reduced pressure to obtainconnection 2(0,72 g of 1.93 mmol, 100%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ=8.34 per-8,31 (m, 2H), 7,68 (DD, J=of 13.6, 2.4 Hz, 1H), 7,56 (t, J=8,8 Hz, 1H), 7,41 (DD, J=of 13.6, 2.4 Hz, 1H), amounts to 4.76 (m, 1H), 4,15 (t, J=8,8 Hz, 1H), 3,78 (m, 3H), 3.46 in (m, 2H), 3,35 (t, J=8,4 Hz, 2H), 1,83 (, 3H).

LCMS: 336 (M+H+for C15H18FN5O3.

[Example 3] the connection3

Connection 2(0.11 g, 0.34 mmol) was dissolved in methanol (3 ml), after addition of DIPEA (0.17 ml, 1 mmol) and dimethylsulfate (52 mg, 0.41 mmol) was stirred for 6 hours at room temperature and separated using column chromatography to obtaincompound 3(29 mg, 0,083 mmol, 24%) as a white solid.

1H NMR (600 MHz, chloroform-d1) δ 7,52 (DD, 1H, J1=to 13.8 Hz, J2=2,4 Hz), 7,18 to 7.62 (m, 1H), 7,10 (t, 1H, 8,4 Hz), 6.90 to (s, 1H), 6,70 (t, 1H, J=6.0 Hz), 4,82-of 4.75 (m, 1H), Android 4.04 (t, 1H, J=9.0 Hz), 3,85 (t, 2H, J=4,8 Hz), 3,82 (t, 1H, 4.8 Hz), 3,74-of 3.60 (m, 2H), 2,99 (t, 2H,, J=4,8 Hz), and 2.79 (s, 3H), 2,02 (s, 3H).

LCMS: 350 (M+H+for C16H20F1-N5O3.

[Example 4] the connection4

Connection 2(0.21 g, to 0.63 mmol) was dissolved in DMF (3 ml), after addition of DIPEA (0.17 ml, 1 mmol) and allylbromide (0.1 g, 0.8 mmol) was stirred for 6 hours at room is temperature, and separated using column chromatography to obtainconnections 4(80 mg, 0.21 mmol, 33%) as a white solid.

1H NMR (600 MHz, CDCl3) δ=7,51 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,15-to 7.09 (m, 2H), 6,92 (s, 1H), 6,18 (ushort, 1H), 6,02 (m, 1H), 5,30 with 5.22 (m, 2H), 4,79 (m, 1H), of 4.05 (t, J=9 Hz, 1H), 3,82 (t, J=4,8 Hz, 2H), 3,79-to 3.58 (m, 6H), of 3.00 (t, J=4,8 Hz, 2H), 2,03 (s, 3H).

LCMS: 376 (M+H+for C18H22F1-N5O3.

[Example 5] Getting connection5

Connection 5(34 mg, 0,091 mmol, 43%) was obtained fromcompound 2,as in example 4, using propylbromide.

1H NMR (600 MHz, CDCl3) δ=7,51 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,16-7,11 (m, 2H), 6,95 (s, 1H), 6,00 (ushort, 1H), 4,79 (m, 1H), Android 4.04 (t, J=9 Hz, 1H), 3,85 (t, J=4,8 Hz, 2H), 3,82 (d, J=2.4 Hz, 2H), 3,79-3,62 (m, 3H), of 3.13 (t, J=4,8 Hz, 2H), 2,31 (t, J=the 2.4 Hz, 1H), 2,03 (s, 3H).

LCMS: 374 (M+H+for C18H20F1-N5O3.

[Example 6] the connection6

Connection 2(30 mg, 0.08 mmol), DIPEA (66 μl, 0.40 mmol) and ethyliodide (20 μl, 0.24 mmol), was added in dichloromethane (2 ml) at 0°C and was stirred for 8 hours while boiling under reflux. The solution was concentrated under reduced pressure and separated using column chromatography to obtainconnection 6(5 mg, 0.01 mmol, 13%) as a yellow foam.

1 H NMR (400 MHz, chloroform-d4) δ=EUR 7.57 (DD, J=15 Hz, 1H), 7,18 (s, 2H), was 7.08 (s, 1H), of 6.31 (t, J=6.0 Hz, 1H), a 4.83 (m, 1H), 4,07 (t, J=8.0 Hz, 1H), 3,90 (t, J=4,2 Hz, 2H), 3,83 (DD, J=8,0, 7.2 Hz, 1H), 3,74-the 3.65 (m, 2H), 3,12 (t, J=5.4 Hz, 3H), 3,05 (sq, J=6,6 Hz, 2H), 2.06 to (s, 3H), of 1.31 (t, J=6.6 Hz, 3H).

LCMS: 364 (M+H+for C17H22FN5O3.

[Example 7] the connection7

Connection 2(0.1 g, 0.3 mmol) was dissolved in DMF (3 ml), after addition of 1 equivalent of K2CO32 equivalents of chloroacetonitrile and catalytic amount of KI was heated for 6 hours at 80°C and separated using column chromatography to obtaincompound 7(107 mg, 0,287 mmol, 96%) as a white solid.

1H NMR (600 MHz, chloroform-d1) δ 7,40 (DD, 1H, J1=13,2 Hz, J2=2,4 Hz), 7,01 (DD, 1H, J1=8,4 Hz, J2=1.2 Hz), 6,69 (t, 1H, J=9.3 Hz), 6,14 (d, 1H, J=5.4 Hz), 4,78-4,72 (m, 1H), and 4.40 (t, 2H, J=5.4 Hz), 4.00 points (t, 1H, J=9.0 Hz), 3,76-3,66 (m, 2H), 3,61 (t, 1H, J=6.0 Hz), 3,55 (t, 2H, J=5.4 Hz), 3,03 (s, 3H), 2,03 (s, 3H).

LCMS: 374 (M+H+for C17H19FN6O3.

[Example 8] the connection8

Connection 2(0.1 g, 0.3 mmol) was dissolved in DMF (3 ml) for 6 hours at 200°C after addition of 1 equivalent of K2CO3and 2 equivalents of 1,1,1-Cryptor-2-iodata and separated using column chromatography to obtainconnection 8(11 mg, was 0.026 mmol who, 9%) as a white solid.

1H NMR (600 MHz, chloroform-d1) δ 7,52 (DD, 1H, J1=to 13.8 Hz, J2=2.4 Hz), 7.18 in-7,07 (m, 2H), 6,86 (s, 1H), 6,32-6,24 (m, 1H), 4,90 was 4.76 (m, 1H), Android 4.04 (t, J=8.7 Hz), of 3.84 (t, 2H, J=4.5 Hz), 3,81 is 3.76 (m, 1H), 3,62-to 3.52 (m, 2H), 3,24 (t, 4.5 Hz), 2,02 (s, 3H).

LCMS: 418 (M+H+for C17H19F4N5O3.

[Example 9] Getting connection9

Connection 2(150 mg, 0.40 mmol), DIPEA (200 μl, 1.20 mmol) and CYANOGEN bromide (63 mg, of 0.60 mmol), was added in dichloromethane (2 ml) at 0°C and was stirred for 0.5 hour. The solution was concentrated under reduced pressure and separated using column chromatography to obtainconnection 9(25 mg, 0.07 mmol, 17%) as a white solid.

1H NMR (400 MHz, chloroform-d4) δ=7,60 (DD, J=13,2, 2.4 Hz, 1H), 7,20 (DD, J=13,2, 2.4 Hz, 1H), 7,13 (t, J=8,8 Hz, 1H), 6.89 in (s, 1H), 4,80 (m, 1H), of 4.05 (t, J=9,2 Hz, 1H), 3,85-3,61 (m, 2H), 2,03 (s, 3H).

LCMS: 361 (M+H+for C16H17FN6O3.

[Example 10] the connection10

Connection 2(5 mg, of 0.013 mmol), DIPEA (4 μl, was 0.026 mmol) and acetylchloride (1,5 ál, 0.02 mmol), was added in dichloromethane (2 ml) at 0°C and was stirred for 1.5 hours. After adding dichloromethane (30 ml), the solution was washed with saturated aqueous sodium bicarbonate solution (15 ml), sushila use of magnesium sulfate, concentrated under reduced pressure and separated using column chromatography to obtainconnection 10(2 mg, 0.004 percent mmol, 30%) as a white solid.

1H NMR (600 MHz, chloroform-d4) δ=EUR 7.57 (DD, J=13,2, 2.4 Hz, 1H), 7,20 (DD, J=a 9.6, 2.4 Hz, 1H), 7,13 (t, J=9,6, Hz, 1H), 6,85 (s, 1H), 6,03 (t, J=6.0 Hz, 1H), 4,80 (m, 1H), 4,06 (m, 2H), 3,79 (DD, J=9,0, 6,6 Hz, 2H), 3,71 (m, 2H), 3,62 (m, 1H) 2,03 (s, 3H).

LCMS: 378 (M+H+for C17H20FN5O4.

[Example 11] Get connection11

Connection 2(30 mg, 0.08 mmol), (1H-benzotriazol-1 yloxy)triprolidine hexaflurophosphate (PyBOP, 105 mg, 0.20 mmol), zanoxolo acid (14 mg, 0.16 mmol) and DIPEA (40 μl, 0.24 mmol), was added DMF (2 ml) at 0°C and stirred for 1.5 hours at room temperature. After adding dichloromethane (30 ml) the solution was washed 3 times with saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, concentrated under reduced pressure and separated using column chromatography to obtainconnection 11(5 mg, 0.01 mmol, 13%) as a white solid.

1H NMR (400 MHz, chloroform-d4) δ=to 7.61 (DD, J=13,2, 2.8 Hz, 1H), 7,25 (DD, J=13,2, 2.8 Hz, 1H), 7,13 (t, J=8,8 Hz, 1H), 6,85 (s, 1H), to 6.19 (t, J=6.0 Hz, 1H), to 4.81 (m, 1H), 4,07 (m, 2H), 3,85 (m, 3H), of 3.75 (t, J=6.0 Hz, 2H), 3,68 (m, 2H), 2,03 (s, 3H).

LCMS: 403 (M+H+for C18H19/sub> FN6O4.

[Example 12] Get connection12

Connection 2(200 mg, 0.54 mmol), PyBOP (700 mg, of 1.34 mmol), glycolic acid (82 mg, 1.07 mmol) and DIPEA (266 μl, of 1.61 mmol), was added DMF (2 ml) at 0°C and was stirred for 2 hours at room temperature. After adding dichloromethane (100 ml) the solution was washed 3 times with distilled water, dried with magnesium sulfate, concentrated under reduced pressure, and separated using column chromatography to obtaincompounds 12(83 mg, 0.21 mmol, 39%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ=of 8.25 (t, J=6 Hz, 1H), 7.62mm (DD, J=8,8, 2.4 Hz, 1H), 7,37 (t, J=8,8 Hz, 1H), 7,32 (DD, J=8,8, 2.4 Hz, 1H), 7,07 (t, J=2.0 Hz, 1H), 4,74 (m, 1H), 4,53 (t, J=6.0 Hz, 1H), 4,32 (d, J=6 Hz, 2H), 4,12 (t, J=8,8 Hz, 1H), 3,89 (t, J=4.6 Hz, 2H), 3.75 to at 3.69 (m, 3H), 3,40 (m, 2H)and 1.83 (s, 3H).

LCMS: 394 (M+H+for C17H20FN5O5.

[Example 13] Get connection13

Connection 2(35 mg, 0.09 mmol), DIPEA (45 μl, 0.28 mmol) and cyclopropanecarbonyl (13 μl, 0.14 mmol), was added in dichloromethane (3 ml) at 0°C and was stirred for 1 hour at room temperature. The solution was concentrated under reduced pressure and separated using column chromatography to obtainconnection 13(13 mg, 0.03 s mo the R, 33%) as a white solid.

1H NMR (600 MHz, DMSO-d6) δ=of 8.25 (t, J=6 Hz, 1H), 7,6 (d, J=a 13.8 Hz, 1H), 7,39 (t, J=9.0 Hz, 1H), 7,32 (d, J=a 13.8 Hz, 1H), 7,10 (m, 1H), and 4.75 (m, 1H), 4,12 (t, J=9.0 Hz, 1H), 3,90 (s, 2H), 3,74 (t, J=6,6 Hz, 1H), 3,70 (s, 2H), 3,42 (t, J=5.4 Hz, 2H), 2,69 (t, J=6.0 Hz, 1H)and 1.83 (s, 3H), of 0.85 (d, J=6.0 Hz, 3H).

LCMS: 404 (M+H+for C19H22FN5O4.

[Example 14] Get connection14

Connection 2(30 mg, 0.08 mmol), triethylamine (23 μl, 0.16 mmol) and trimethylsilyltriflate (63 μl, 0.40 mmol), was added in dichloromethane (3 ml) at 0°C and was stirred for 2 hours at room temperature. After adding dichloromethane (30 ml) the solution was washed twice with saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, concentrated under reduced pressure, and separated using column chromatography to obtainconnection 14(8 mg, 0.02 mmol, 26%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ=compared to 8.26 (t, J=6.0 Hz, 1H), 7,60 (DD, J=15,0,2,4 Hz, 1H), 7,37-7,30 (m, 2H), of 6.96 (d, J=2.0 Hz, 1H), 6,32 (s, 2H), 4,74 (m, 1H), 4,12 (t, J=8,8 Hz, 1H), 3,78-to 3.67 (m, 4H), 3,40 of 3.28 (m, 3H)and 1.83 (s, 3H).

LCMS: 379 (M+H+for C16H19FN6O4.

[Example 15] Getting connection15

The connection 15(25 mg, 0,059 mmol, 42%) was obtained fromcompound 2,as in example 6,using carbonyldiimidazole (437 mg, 2.7 mmol) and ethanolamine.

1H NMR (600 MHz, chloroform-d1) δ of 7.69 (s, 1H), 7,54 (DD, 1H, J1=13,2 Hz, J2=2,4 Hz), 7,16 (DD, 1H, J1=9,0 Hz, J2=1,8 Hz), 7,10-was 7.08 (m, 1H), 6.87 in (t, 1H, J=6.0 Hz), 6,78 (s, 1H), 6,72 (t, 1H, J=6.0 Hz), a 4.83-7,49 (m, 1H), Android 4.04 (t, 1H, J=9.0 Hz), of 3.95 (t, 2H, J=4,8 Hz), 3,84-of 3.78 (m, 1H), 3,76 (t, 2H, J=5.4 Hz), 3.72 points (t, 2H, J=4,8 Hz)to 3.67 (DD, 2H, J1=6,0 Hz, J2=4,8 Hz), 2,03 (s, 3H).

LCMS: 423 (M+H+for C18H23FN6O5.

[Example 16] the connection16

The connection 16(15 mg, to 0.032 mmol, 25%) was obtained fromcompound 2,as in example 15, using carbonyldiimidazole and diethanolamine.

1H NMR (600 MHz, DMSO-d6) δ 7,70 to 7.62 (m, 1H), 7,37-7,30 (m, 2H), and 7.1 (s, 1H), 4,81 was 4.76 (m, 1H), 4,45-and 4.40 (m, 2H), 4,14 (t, 1H, J=9.0 Hz), 4,01-of 3.94 (m, 2H), 3,82-of 3.78 (m, 4H), 3,55 (d, 2H, J=4,8 Hz), 3,48-of 3.42 (m, 1H), 3,42-3,38 (m, 2H), 3,20-and 3.16 (m, 2H), was 1.94 (s, 3H), of 1.29 (t, 2H, J=7,2 Hz).

LCMS: 467 (M+H+for C20H27FN6O6.

[Example 17] Getting connection17

Connection 17(31 mg, of 0.075 mmol, 88%) was obtained fromcompound 2,as in example 11, using DIPEROXY acid.

1H NMR (600 MHz, chloroform-d1) δ to 7.61 (DD, 1H, J1=13,2 Hz, J2=3.0 Hz), 7,22 (DD, 1H, J1=9,0 Hz, J2=2,4 Hz), 7,14 (t, 1H, J=9.0 Hz), 6.90 to (s, 1H), 6,77 (t, 1H, J=53,4 Hz), 6,04 (t, 1H, J=6.3 Hz), a 4.83-rate 4.79 (m, 1H), 4,08 (t, 2H, J=4,8 Hz), of 4.05 (t, 1H, J=9.0 Hz), 3,88-of 3.80 (m, 1H), 3,78 (t, 2H, J=4,8 Hz in ), 3.75-of 3.69 (m, 1H), 3,69-of 3.60 (m, 1H), 203 (C, 3H).

LCMS: 414 (M+H+for C17H18F3N5O4.

[Example 18] the connection18

Connection 2(35 mg, 0.09 mmol), DIPEA (45 μl, 0.28 mmol) and methanesulfonamide (11 μl, 0.14 mmol), was added in dichloromethane (3 ml) at 0°C and was stirred for 1 hour at room temperature. The solution was concentrated under reduced pressure and separated using column chromatography to obtainconnection 18(13 mg, 0.03 mmol, 33%) as a white solid.

1H NMR (600 MHz, DMSO-d6) δ=compared to 8.26 (t, J=5.4 Hz, 2H), to 7.61 (d, J=a 13.8 Hz, 1H), 7,43 (t, J=9.6 Hz, 1H), 7,33 (d, J=9.6 Hz, 1H), 7,21 (s, 1H), and 4.75 (m, 1H), 4,13 (t, J=8,4 Hz, 1H), 3,84 (s, 1H), 3,74 (t, J=8,4 Hz, 1H), of 3.56 (s, 2H), 3,41 (t, J=5.4 Hz, 2H), 2,98 (s, 3H)and 1.83 (s, 3H).

LCMS: 414 (M+H+for C16H20FN5O5S.

[Example 19] Getting connection19

Connection 2(30 mg, 0.08 mmol), DIPEA (66 μl, 0.40 mmol) and methylisothiocyanate (6 μl, 0.24 mmol), was added in dichloromethane (2 ml) at 0°C and was stirred for 12 hours. The solution was concentrated under reduced pressure and separated using column chromatography to obtainconnection 19(17 mg, 0.03 mmol, 38%) as a white solid.

1H NMR (600 MHz, chloroform-d4) δ=7,78 (s, 1H), 7,58 (DD, J=13,2, 2.4 Hz, 1H), 7,21 (DD, J=13,2, 2.4 Hz, 1H), 13th (t, J=8,4 Hz, 1H), 6,86 (s, 1H), 5,96 (t, J=6.0 Hz, 1H), 4,80 (m, 1H), 4,59 (t, J=5.4 Hz, 2H), of 4.05 (t, J=7.5 Hz, 1H), 3,81-of 3.77 (m, 3H), 3,71 (m, 1H), 3,65 (m, 1H), 3,20 (d, J=4,8 Hz, 1H), 2,03 (s, 3H).

LCMS: 409 (M+H+for C17H21FN6O3S.

[Example 20] Get connection20

Connection 2(50 mg, 0.13 mmol), triethylamine (55 μl, 0,39 mmol) and amidosulfonic (145 μl, 0.26 mmol), was added in dichloromethane (3 ml) at 0°C and was stirred for 12 hours at room temperature. After adding dichloromethane (30 ml) the solution was washed twice with saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, concentrated under reduced pressure, and separated using column chromatography to obtainconnection 20(5 mg, 0.01 mmol, 10%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ=compared to 8.26 (t, J=4,8 Hz, 1H) 7,60 (DD, J=13,2, 2.4 Hz, 1H), 7,42 (t, J=8,8 Hz, 1H), 7,32 (DD, J=13,2, 2.4 Hz, 1H), 7,12 (s, 1H), 7,05 (s, 2H), 4,74 (m, 1H), 4,12 (t, J=9,2 Hz, 1H), 3,81 (t, J=5,2 Hz, 2H), to 3.73 (DD, J=9,2, 6.4 Hz, 1H), 3,50-to 3.38 (m, 4H)and 1.83 (s, 3H).

LCMS: 414 (M+H+for C15H19FN6O5S.

[Example 21] Get connection21

Connection 2(50 mg, 0.13 mmol), triethylamine (36 μl, 0.26 mmol) and dimethylaminomethylene (16 μl, 0.15 mmol), was added in DMF (1 ml) at 0°C and stirred in ECENA 12 hours at room temperature. After adding dichloromethane (30 ml), the solution was washed twice with saturated aqueous sodium bicarbonate solution (10 ml), dried with magnesium sulfate, concentrated under reduced pressure, and separated using column chromatography to obtainconnection 21(6 mg, 0.01 mmol, 10%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ=a 7.62 (DD, J=13,2, 2.4 Hz, 1H), 7,19 (DD, J=13,2, 2.0 Hz, 1H), 7,12 (t, J=8,8 Hz, 1H), 6,94 (s, 1H), 6,00 (t, J=6.0 Hz, 1H), 4,80 (m, 1H), of 4.05 (t, J=8,8 Hz, 1H), 3,85 (t, J=4.4 Hz, 2H), 3,79 (DD, J=8,8 that 6.8 Hz, 1H), 3,71-of 3.60 (m, 4H), 3,03 (s, 6H), 2,03 (s, 3H).

LCMS: 443 (M+H+for C17H23FN6O5.

[Example 22] the connection22

The connection 22(36 mg, of 0.085 mmol, 78%) was obtained fromcompound 2,as in example 11.

1H NMR (400 MHz, DMSO-d6) δ=compared to 8.26 (t, J=6.0 Hz, 1H), 7,50 (d, J=a 13.8 Hz, 1H), 7,37 (t, J=9.0 Hz, 1H), 7,24 (d, J=9.0 Hz, 1H), 5,86 (s, 1H), 5,61 (m, 1H), 4.72 in (m, 1H), 4,11 (m, 1H), and 3.72 (m, 1H), 3,41-to 3.35 (m, 2H), is 3.08 (m, 2H,), of 2.86 (m, 2H)and 1.83 (s, 3H), of 1.31 (s, 3H), 1,24 (s, 3H).

LCMS: 422 (M+H+for C19H24FN5O5.

[Example 23] Get connection23

Connection 2(30 mg, 0.08 mmol), PyBOP (105 mg, 0.20 mmol), Boc-Gly-OH (28 mg, 0.16 mmol) and DIPEA (40 μl, 0.24 mmol), was added DMF (2 ml) at 0°C and was stirred for 1.5 hours at room temperature. After adding dichloromethane is (30 ml), the solution was washed 3 times with distilled water (10 ml), dried with magnesium sulfate, concentrated under reduced pressure, separated using column chromatography, and after adding 4n hydrochloric acid dissolved in 1,4-dioxane (3 ml)was stirred for 0.5 hour. The product was concentrated under reduced pressure to obtaincompounds 23(10 mg, 0.02 mmol, 29%).

1H NMR (400 MHz, DMSO-d6) δ=8,29 (t, J=6 Hz, 1H), 8,10 (s, 3H), a 7.62 (DD, J=15,0, 2.4 Hz, 1H), 7,40 (t, J=8,8 Hz, 1H), 7,34 (DD, J=15,0, 2.4 Hz, 1H), 7,20 (s, 1H), 4,74 (m, 1H), 4,13 (t, J=8,8 Hz, 1H), 3,99-of 3.94 (m, 3H), 3,74 (t, J=4.0 Hz, 2H), 3,42 (t, J=4,8 Hz, 2H)and 1.83 (s, 3H).

LCMS: 393 (M+H+for C17H21FN6O4.

[Example 24] Get connection24

Connection 24(200 mg, 0.48 mmol, 34%) was obtained fromcompound 2,as in example 7, using ethylbromoacetate.

1H NMR (600 MHz, chloroform-d1) δ to 7.50 (DD, 1H, J1=to 13.8 Hz, J2=2,4 Hz), 7,13 (DD, 1H, J1=9,0 Hz, J2=2,4 Hz), 7,10 (t, 1H, J=8,4 Hz), 6.89 in (s, 1H), 6,70 (t, 1H, J=6.0 Hz), 4,82-rate 4.79 (m, 1H), 4,25-is 4.21 (m, 2H), Android 4.04 (t, 1H, J=9.0 Hz), of 3.84 (t, 2H, J=4, 2 Hz), 3,82-of 3.80 (m, 1H), of 3.77 (s, 2H), 3,66 (t, 2H, J=4,2 Hz), 3,24 (t, 2H, J=4, 2 Hz), 2,02 (s, 3H).

LCMS: 422 (M+H+for C19H24FN5O5.

[Example 25] Get connection25

Connection 24(100 mg, 0.24 mmol) was dissolved in methanol (2 ml), the settlement of the E. adding ammonia water (0.5 ml) was stirred for overnight at 100°C. in a sealed tube, concentrated under reduced pressure, and separated using column chromatography to obtaincompounds 25(20 mg, 0,051 mmol, 21%).

1H NMR (400 MHz, DMSO-d6) δ of 8.25 (t, 1H, J=5.6 Hz), 7,56 (d, 1H, 14,0 Hz), 7,83-7,26 (m, 2H), 7,21-was 7.08 (m, 2H), 6,91 (s, 1H), 4.75 V-4,71 (m, 1H), 4,11 (t, 1H, J=9.0 Hz), 3,82 at 3.69 (m, 3H), 3,50 is 3.40 (m, 2H), and 3.31 (s, 2H), 3,03 (t, 2H,, J=4.4 Hz)and 1.83 (s, 3H).

LCMS: 393 (M+H+for C17H21FN6O4.

[Example 26] Get connection26

Connection 24(100 mg, 0.24 mmol) was dissolved in methanol (20 ml), after addition of a solution of hydroxylamine in methanol (20 ml) (obtained by adding 2.4 g of KOH to 2.4 g NH2OH-HCl and then filtered) was stirred overnight at room temperature, concentrated under reduced pressure, and separated using column chromatography to obtainconnection 26(22 mg, 0,054 mmol, 23%).

1H NMR (600 MHz, DMSO-d6) δ 8,30-to 8.20 (m, 1H), 7,35-7,25 (m, 1H), 7,10-7,00 (m, 1H), 6.87 in (s, 1H), 5,33 is 5.28 (m, 1H), 4,71-to 7.64 (m, 1H), 4,11 (t, 2H, J=9.0 Hz), Android 4.04 (t, 2H, J=8,4 Hz), 3,17 (s, 2H), 2.91 in (t, 2H, J=6.6 Hz)and 1.83 (, 1H).

LCMS: 409 (M+H+for C17H21FN6O5.

[Example 27] Get connection27

Connection 24(110 mg, 0.26 mmol) was dissolved in THF (10 ml) and after addition of 2M solution of LiBH4(0.2 ml, 0.4 mmol) was stirred for 3 hours at room temperature the round. After adding a small amount of water, the solution was separated using column chromatography to obtainconnection 27(24 mg, 0,063 mmol, 29%) as a pale yellow solid.

1H NMR (600 MHz, chloroform-d1) δ rate of 7.54 (DD, 1H, J1=to 13.8 Hz, J2=2,4 Hz), 7,16 (DD, 1H, J1=9,0 Hz, J2=2,4 Hz), 7,12 (t, 1H, J=8,4 Hz), 6.90 to (s, 1H), 5,98 (t, 1H, J=6.0 Hz), to 4.87 (m, 1H), of 4.05 (t, 1H, J=9.0 Hz), of 3.97 (m, 2H), 3,85 (t, 2H, J=4, 2 Hz), 3,82-3,6 (m, 3H), of 3.07 (t, 2H, J=4,2 Hz)to 3.00 (m, 2H,), 2,04 (s, 3H).

LCMS: 380 (M+H+for C17H22FN5O4.

[Example 28] Get connection28

Compound XXVIII-a(0,22 g, 0.49 mmol) and hydrazine (monohydrate, 1 ml) was dissolved in methanol (10 ml)was stirred for 2 hours at boiling under reflux, and concentrated under reduced pressure and after adding triethylorthoformate (5 ml) and acetic acid (5 ml) was stirred for 4 hours at boiling under reflux. The solution was concentrated under reduced pressure and separated using column chromatography to obtainconnection 28(32 mg, 0.10 mmol, 20%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ=of 8.25 (t, J=6 Hz, 1H), 7,60 (DD, J=14,0, 2.4 Hz, 1H), 7,46 (s, 1H), 7,38 (t, J=8,8 Hz, 1H), 7,31 (DD, J=9,2, 2.0 Hz, 1H), 4,74 (m, 1H), 4,12 (t, J=9,2 Hz, 1H), Android 4.04 (t, J=3,6 Hz, 2H), 3.75 to to 3.67 (m, 3H), to 3.41 (t, J=5.6 Hz, 2H)and 1.83 (s, 3H).

LCMS: 337 (M+H+for C 15H17FN4O4.

[Example 29] Getting connection29

Connection 2(100 mg, 0.27 mmol) was dissolved in chloroform (3 ml) and after adding a saturated aqueous solution of NaHCO3(3 ml) and then add thiophosgene (0,021 ml) at 0°C was stirred for 30 minutes. The organic layer was separated, and was added ammonia water (1 ml). The solution was diluted with THF (10 ml) and kept under reduced pressure, removing half the amount of the solvent. After adding ammonia water (2 ml), the solution was stirred over night at room temperature. The solution is kept under reduced pressure and triturated with ethyl ether to obtainconnection 29(80 mg, 0.20 mmol, 74%) as a white solid.

1H NMR (600 MHz, DMSO-d6) δ of 8.27 (t, 1H, J=4,8 Hz), 7,98 (s, 1H), 7.62mm (DD, 1H, J1=to 13.8 Hz, J2=2,4 Hz), to 7.59-7,46 (m, 1H), 7,42 (t, 1H, J=9.0 Hz), 7,34 (d, 1H, J=9.0 Hz), 7,16 (s, 1H), 7,51-6,89 (users, 2H), 4,79-4,69 (m, 1H), 4,37 (t, 2H, J=4, 2 Hz), 4,13 (t, 1H, J=9.6 Hz), 3,79-3,70 (m, 3H), 3.42 points (t, 2H, J=4,8 Hz), 3,38-3,29 (m, 1H)and 1.83 (s, 3H).

LCMS: 395 (M+H+for C16H19FN6O3S.

[Example 30] Get connection30

Connection 2(100 mg, 0.27 mmol) was dissolved in chloroform (3 ml), after addition of saturated aqueous NaHCO3(3 ml) and then add thiophosgene (0.01 ml) at 0°C was stirred for 30 minutes. The organic layer was separated, kept under reduced pressure, and after adding methanol (5 ml) was stirred overnight at room temperature. The solution is kept under reduced pressure and separated using column chromatography to obtainconnection 30(31 mg, 0.20 mmol, 74%) as a white solid.

1H NMR (600 MHz, DMSO-d6) δ of 7.60 (DD, 1H, J1=13,2 Hz, J2=1.2 Hz), 7,25-to 7.18 (m, 1H), 7,16 (t, 1H, J=8,4 Hz), of 6.96 (s, 1H), 6,51 (users, 1H), 4,86-rate 4.79 (m, 1H), with 4.64-of 4.54 (m, 2H), 4,19 (s, 3H), 4,06 (t, 1H, J=9.0 Hz), 3,88 is 3.76 (m, 3H), 3,74-3,66 (m, 2H), 2,03 (s, 3H).

LCMS: 410 (M+H+for C17H20FN5O4S.

[Example 31] Get connection31

The connection 31(26 mg, 0.061 mmol, 32%) was obtained fromcompound 2,as in example 30, using ethanol instead of methanol.

1H NMR (600 MHz, DMSO-d6) δ of 7.60 (d, J=12.0 Hz), 7.24 to to 7.18 (m, 1H), 7,15 (t, 1H, J=8,4 Hz), 6,97 (s, 1H), 6,32 (users, 1H), 4,88 was 4.76 (m, 1H), 4.75 in with 4.64 (m, 2H), with 4.64-4.53-in (m, 2H), 4,06 (t, 1H, J=8,4 Hz), 3,88-of 3.77 (m, 3H), 3,74-of 3.60 (m, 2H), 2,03 (s, 3H), of 1.46 (t, 3H, J=6.6 Hz).

LCMS: 424 (M+H+for C18H22FN5O4S.

[Example 32] Get connection32

The connection 32(23 mg, 0,052 mmol, 22%) was obtained fromcompounds 2,as in example 30, using ethylene glycol instead of methanol.

1H NMR (600 MHz, chloroform-d1) δ a 7.62 (DD, 1H, J1=of 12.6 Hz, J2=1.8 Hz), of 7.23-7,19 (m, 1H), 7,18 (t, 1H, 9.0 Hz), 7,06 (s, 1H), 6.42 per (t, 1H, J=6.6 Hz), 4,96-4,86 (users, 1H), 4,86-of 4.77 (m, 1H)and 4.65 (t, 2H, J=3.6 Hz), 4,59 (t, 2H, J=4,8 Hz), 4,07 (t, 1H, 9.0 Hz), 3,98-to 3.89 (m, 2H), 3,88-with 3.79 (m, 3H), 3.72 points-of 3.65 (m, 2H), 2,03 (s, 3H).

LCMS: 440 (M+H+for C18H22FN5O5S.

[Example 33] Get connection33

The connection 33(16 mg, being 0.036 mmol, 35%) was obtained fromcompounds 2,as in example 30, using aminoethanol instead of methanol.

1H NMR (600 MHz, DMSO-d6) δ of 8.28 (t, 1H, J=5.4 Hz), to 7.67-7,58 (m, 1H), 7,43 (t, 1H, J=9.0 Hz), 7,38-7,31 (m, 1H), 7,20 (s, 1H), 4,08 (t, 1H, J=5.4 Hz), 4,78-4,70 (m, 1H), 4,39 (t, 2H, J=4,8 Hz), 4,13 (t, 1H, J=9.0 Hz), 3,81-3,75 (m, 2H), to 3.58 (t, 2H, J=4, 2 Hz), 3,53 (t, 2H, J=5.7 Hz), 3,42 (t, 2H, J=5.4 Hz)and 1.83 (s, 3H).

LCMS: 439 (M+H+for C18H23FN6O4S.

[Example 34] Get connection34

Connection 2(50 mg, 0.13 mmol) was dissolved in ethanol (5 ml) and after addition of DIPEA (of 0.03 ml, 0.2 mmol), NaF (7 mg, 0,17 mmol) and utilitiesman is 0.019 ml, 0.16 mmol) was stirred over night at room temperature. The solution is kept under reduced pressure and separated using column chromatography to obtainconnection 34(10 mg, of 0.025 mmol, 19%) as a white solid.

1H NMR (600 MHz, CDCl3) δ=a 7.62 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,25-7,21 (m, 2H), 7,16 (t, J=8,4 Hz, 1H), 6,94 (s, 1H), 5,93 (ushort, 1H), to 4.81 (m, 1H), 4,73 (t, J=5,2 Hz, 2H), 4,06 (t, J=8,8 Hz, H), 3,83-3,62 (m, 5H), of 2.81 (s, 3H), 2,03 (s, 3H).

LCMS: 394 (M+H+for C17H20FN5O3S.

[Example 35] Get connection35

The connection 35(35 mg, 0,086 mmol, 65%) was obtained fromcompounds 2,as in example 6, using carbonyldiimidazole and ethanol.

1H NMR (600 MHz, CDCl3) δ=7,58-7,56 (m, 1H), 7,19-to 7.18 (m, 1H), 7,13-7,10 (m, 1H ), 6,92 (s, 1H), 6,21 (m, 1H), 4,80 (m, 1H), 4,33-4,32 (m, 2H), 4,06-a 4.03 (m, 1H), 3,99 (m, 2H), 3,81-of 3.77 (m, 3H), 3,71-3,66 (m, 2H), 2,03 (s, 3H), to 1.38 (t, J=6.3 Hz, 3H).

LCMS: 407 (M+H+for C18H22FN5O5.

[Example 36] Get connection36

The connection 36(14 mg, 0,034 mmol, 74%) was obtained fromcompound 2,as in example 11, using pyruvic acid.

1H NMR (600 MHz, DMSO-d6) δ of 8.27 (t, J=6.0 Hz, 1H) to 7.61 (DD, J1=13,2 Hz, J2=3.0 Hz, 1H), 7,40 (t, J=9.0 Hz, 1H), 7,33 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), 7,18 (s, 1H), 4,74 (m, 1H), 4,13 (t, J=9 Hz, 1H), 3,90 (t, J=4,8 Hz, 2H), of 3.77-and 3.72 (m, 3H), 3,42-3,30 (m, 2H), 2,33 (s, 3H)and 1.83 (s, 3H).

LCMS: 406 (M+H+for C18H20FN5O5.

[Example 37] Get connection37

The connection 37(13 mg, 0,033 mmol, 65%) was obtained fromcompound 2,as in example 4, using chloroacetone.

1H NMR (600 MHz, CDCl3) δ=7,52 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,15 (DD, J1=8,4 Hz, J2=2.4 Hz, 1H), 7,11 (t, J=8,4 Hz, 1H),6.89 in (C, 1H), 6,09 (ushort, 1H), 4,79 (m, 1H), Android 4.04 (t, J=9 Hz, 1H), 3,85 (t, J=4,8 Hz, 2H), 3,79-3,62 (m, 5H), of 3.12 (t, J=4,8 Hz, 2H), and 2.26 (s, 3H), 2,03 (s, 3H).

LCMS: 392 (M+H+for C18H22FN5O4.

[Example 38] Get connection38

The connection 37(7 mg, 0.018 mmol) was dissolved in dichloromethane (2 ml) and after addition of 2M solution of LiBH4was stirred for 2 hours at room temperature. After adding a small amount of water, the solution was separated using column chromatography to obtaincompound 38(3.6 mg, 0,009 mmol, 50%) as a white solid.

1H NMR (600 MHz, CDCl3) δ=rate of 7.54 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,15 (DD, J1=8,4 Hz, J2=2.4 Hz, 1H), 7,11 (t, J=8,4 Hz, 1H), 6.89 in (s, 1H), 6,09 (ushort, 1H), 4,79 (m, 1H), Android 4.04 (t, J=9 Hz, 1H), 3,85 (t, J=4,8 Hz, 2H), 3,79-3,62 (m, 5H), of 3.12 (t, J=4,8 Hz, 2H), and 2.26 (s, 3H), 2,03 (s, 3H).

LCMS: 394 (M+H+for C18H24FN5O4.

[Example 39] Get connection39

Connection 39(15 mg, 0,039 mmol, 74%) was obtained fromcompounds 2,as in example 4, using 3-chloro-2-methylpropene.

1H NMR (600 MHz, CDCl3) δ=7,51 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,15-to 7.09 (m, 2H), 6,91 (s, 1H), 6,06 (ushort, 1H), equal to 4.97 (s, 1H), is 4.93 (s, 1H), 4,79 (m, 1H), Android 4.04 (t, J=9 Hz, 1H), 3,81 (t, J=4,8 Hz, 2H), 3,78-3,61 (m, 3H), of 3.48 (s, 2H), equal to 2.94 (t, J=4,8 Hz, 2H), 2,03 (s, 3H)and 1.83 (s, 3H).

LCMS: 390 (M+H+for C19H24FN O3.

[Example 40] Get connection40

The connection 40(11 mg, or 0.027 mmol, 34%) was obtained fromcompounds 2,as in example 4, using 2,3-dichloro-1-propene.

1H NMR (600 MHz, CDCl3) δ=7,52 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,15-to 7.09 (m, 2H), 6,91 (s, 1H), 6,23 (ushort, 1H), 5,49 (s, 1H), 5,42 (s, 1H), 4,79 (m, 1H), Android 4.04 (t, J=9 Hz, 1H), 3,85 (t, J=4,8 Hz, 2H), 3,79-3,62 (m, 5H), is 3.08 (t, J=4,8 Hz, 2H), 2,03 (s, 3H).

LCMS: 410 (M+H+for C18H21ClFN5O3.

[Example 41] Get connection41

Connection 2(228 mg, of 0.68 mmol), cyclobutanone (0,076 ml of 1.02 mmol) and NaBH(OAc)3(187 mg, 0.88 mmol) was dissolved in dichloromethane (20 ml) and after adding acetic acid (1 ml) was stirred for 2 hours at room temperature. The solution was diluted with dichloromethane, then washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate, and concentrated under reduced pressure to obtainconnection 41(200 mg, 0.51 mmol, 75%) as a white solid.

1H NMR (600 MHz, CDCl3) δ=7,51 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,15-to 7.09 (m, 2H), 6,95 (s, 1H), 6,09 (ushort, 1H), 4,79 (m, 1H), a 4.03 (t, J=9 Hz, 1H), 3,82 (t, J=4,8 Hz, 2H), 3,78-3,61 (m, 3H), 3,41 (m, 1H), only 2.91 (t, J=4,8 Hz, 2H), 2.21 are 2,11 (m, 4H), 2,03 (s, 3H), 1,811,72 (m, 2H).

LCMS: 390 (M+H+for C19H24FN5O3.

[Example 42] Get connection42

The connection 42(15 mg, 0,039 mmol, 79%) was obtained fromcompounds XIIIas in example 11.

1H NMR (400 MHz, DMSO-d6) δ=8,64 (t, J=5.6 Hz, 1H), 8,42 (s, 1H), to 7.61 (DD, J1=14 Hz, J2=2.0 Hz, 1H), 7,38 (t, J=8,8 Hz, 1H), 7,33 (DD, J1=8,8 Hz, J2=2.0 Hz, 1H), 7,12 (s, 1H), 4,78 (m, 1H), 4,14 (t, J=9,2 Hz, 1H), 3,84 (t, J=4,8 Hz, 2H), 3.75 to 3,47 (m, 7H).

LCMS: 389 (M+H+for C17H17FN6O4.

[Example 43] Get connection43

Compound XIII(190 mg, 0.6 mmol) and carbonyldiimidazole (143 mg, 0.9 mmol) was dissolved in dichloromethane (5 ml) and after adding triethylamine (0.25 ml, 1.8 mmol) was stirred for 6 hours at room temperature. After distillation, 1/3 of the volume of the solution under reduced pressure was dissolved in dichloromethane (5 ml) and ethanol (10 ml)and was stirred for 36 hours at room temperature. The solution was washed with distilled water, dried with magnesium sulfate, concentrated under reduced pressure, and separated using column chromatography to obtainconnection 43(23 mg, 0,058 mmol, 29%).

1H NMR (600 MHz, DMSO-d6) δ=scored 8.38 (s, 1H), 7,56 (DD, J1=14 Hz, J2=2.0 Hz, 1H), 7,45 (ushort, 1H), 7,35-7,28 (m, 2H), 7,01 (s, 1H), 4,69 (m, 1H), 4,10 (t, J=9,2 Hz, 1H) 3,95 (square, J=6,6 Hz, 2H), 3,80-3,3 (m, 7H), of 1.09 (t, J=6.6 Hz, 3H).

LCMS: 394 (M+H+for C17H20FN5O5.

[Example 44] Get connection44

Compound XIII(190 mg, 0.6 mmol) and carbonyldiimidazole (143 mg, 0.9 mmol) was dissolved in dichloromethane (5 ml) and after adding triethylamine (0.25 ml, 1.8 mmol) was stirred for 6 hours at room temperature. After distillation, 1/3 of the volume of the solution under reduced pressure was dissolved in THF (5 ml) and ethylamine (50 mg), was stirred for 36 hours at room temperature and boiled under reflux for 2 hours. The solution was washed with distilled water, dried with magnesium sulfate, concentrated under reduced pressure and separated using column chromatography to obtainconnection 44(35 mg, 0,089 mmol, 45%).

1H NMR (600 MHz, CDCl3) δ=8,53 (s, 1H), to 7.59 (d, J=13 Hz, 1H), 7,19 (d, J=9 Hz, 1H), 7,13 (d, J=9 Hz, 1H), to 6.88 (s, 1H), 5,75 (users, 1H), 5,28 (users, 1H), to 4.81 (m, 1H), Android 4.04 (t, J=8,2 Hz, 1H), 3,98 is 3.15 (m, 9H), of 1.08 (t, J=6,6 Hz, 3H).

LCMS: 393 (M+H+for C17H21FN6O4.

[Example 45] Get connection45

The connection 45(840 mg, 2.1 mmol, 95%) was obtained fromcompounds XIIIas in example 11, using DIPEROXY acid.

1H NMR (400 MHz, DMSO-d6) δ=9,18 (t, J=5.6 Hz, 1H), 8,42 (s, 1H), to 7.61 (DD, J 1=14 Hz, J2=2.0 Hz, 1H), 7,38 (t, J=8,8 Hz, 1H), 7,32 (DD, J1=8,8 Hz, J2=2.0 Hz, 1H), 7,12 (s, 1H), of 6.26 (t, J=53 Hz, 1H) 4,82 (m, 1H), 4,16 (t, J=8,8 Hz, 1H), 3,84 (t, J=4,8 Hz, 2H), 3,80-of 3.53 (m, 5H).

LCMS: 400 (M+H+for C16H16F3N5O4.

[Example 46] Get connection46

The connection 46(750 mg, 1.8 mmol, 84%) was obtained fromconnection 45,as in example 2.

1H NMR (600 MHz, DMSO-d6) δ 9,17-of 9.30 (m, 1H), 8,43-of 8.28 (m, 1H), to 7.67 9dd, 1H, J1=to 13.8 Hz, J2=2,4 Hz), to 7.61 (t, 1H, J=9.0 Hz), 7,44 and 7.36 (m, 1H), 6,27 (9t, 1H, J=53,4 Hz), 4,85-4,80 (m, 1H), 4,19 (t, 1H, J=9.0 Hz), 3,81 of 3.75 (m, 2H), 3,38-of 3.32 (m, 2H).

LCMS: 372 (M+H+for C15H16F3N5O3.

[Example 47] Get connection47

Connection 47(16 mg, 0,037 mmol, 25%) was obtained fromconnections 46,as in example 12.

1H NMR (600 MHz, chloroform-d1) δ EUR 7.57 (DD, 1H, J1=to 13.8 Hz, J2=2,4 Hz), 7,21 (DD, 1H, J1=9,0 Hz, J2=2,4 Hz), 7,13 (t, 1H, J=9.0 Hz), of 6.96-6.90 to (m, 1H), 6,86 (s, 1H), 5,94 (t, 1H, J=54,0 Hz), 4,88 of 4.83 (m, 1H), 4,12 (t, 1H, J=9.0 Hz), 4,06 (t, 2H, J=5.4 Hz), 3,90-3,81 (m, 1H), 3,80-3,74 (m, 3H), 3,74-3,66 (m, 1H), to 3.64 (s, 2H).

LCMS: 430 (M+H+for C17H18F3-N5O5.

[Example 48] Get connection48

The connection 48(16 mg, 0.04 mmol, 61%) was obtained fromconnections 46,as in example 6.

1H NMR (600 MHz, chloroform-d ) δ of 7.48 (DD, 1H, J1=13,2 Hz, J2=2,4 Hz), of 7.23 (t, 1H, J=5.4 Hz), 7,16-was 7.08 (m, 2H), 6,94 (s, 1H), 5,94 (t, 1H, J=54,0 Hz), 4,86-4,82 (m, 1H), 4,10 (t, 1H, J=9.0 Hz), 3,88-a-3.84 (m, 1H), 3,83 (t, 2H, J=4,8 Hz), 3,78-to 3.73 (m, 1H), of 3.73-3,64 (m, 1H), to 3.02 (t, 2H, J=4,8 Hz), 3,00 vs. 2.94 (m, 3H), of 1.23 (t, 2H, 7.2 Hz).

LCMS: 400 (M+H+for C17H20F3-N5O3.

[Example 49] Get connection49

The connection 49(15 mg, 0,037 mmol, 57%) was obtained fromconnections 46,as in example 5.

1H NMR (600 MHz, CDCl3) δ 7,51 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,16-7,11 (m, 2H), of 6.96 (s, 1H), 6.89 in (ushort, 1H), 5,94 (t, J=54,0 Hz, 1H), 4,84 (m, 1H), 4,11 (t, J=9.0 Hz, 1H), 3,89-to 3.64 (m, 7H), of 3.13 (t, J=4,8 Hz, 2H), 2,31 (t, J=2.4 Hz, 1H).

LCMS: 410 (M+H+for C18H18F3-N5O3.

[Example 50] Get connection50

The connection 50(15 mg, 0,037 mmol, 68%) was obtained fromconnections 46,as in example 7.

1H NMR (600 MHz, CDCl3) δ 7,53 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,17-7,13 (m, 2H), 7,01 (ushort, 1H), of 6.96 (s, 1H), 5,94 (t, J=54,0 Hz, 1H), around 4.85 (m, 1H), 4,11 (t, J=9.0 Hz, 1H), 3,98 (s, 2H) 3,89-3,66 (m, 5H), 3.15 in (t, J=4,8 Hz, 2H).

LCMS: 411 (M+H+for C17H17F3-N6O3.

[Example 51] Get connection51

The connection 51(155 mg, 0.36 mmol, 86%) was obtained fromcompounds XIIIas in example 11, using dichloracetic acid.

1H NMR (400 M is C, DMSO-d6) δ=8,99 (t, J=6.0 Hz, 1H), 8,42 (s, 1H), to 7.61 (d, J=12 Hz, 1H), 7,38 (t, J=9.0 Hz, 1H), 7,31 (d, J=9 Hz, 1H), 7,12 (s, 1H), of 6.49 (s, 1H), to 4.81 (m, 1H), 4,16 (t, J=8,8 Hz, 1H), 3,84 (t, J=4,8 Hz, 2H), 3,74-3,66 (m, 3H), 3,55 (t, J=5,2 Hz, 2H).

LCMS: 432 (M+H+for C16H16Cl2-FN5O4.

[Example 52] Get connection52

The connection 52(250 mg, 0.6 mmol, 92%) was obtained fromcompounds XIIIas in example 11, using isoxazolidinone acid.

1H NMR (400 MHz, DMSO-d6) δ=to 9.32 (t, J=5.6 Hz, 1H), up 8.75 (d, J=1.2 Hz, 1H) 8,42 (s, 1H), 7,60 (DD, J1=14 Hz, J2=2.0 Hz, 1H), 7,38 (t, J=8,8 Hz, 1H), 7,33 (DD, J1=8,8 Hz, J2=2.0 Hz, 1H), 7,11 (d, J=1.2 Hz, 1H), 4,88 (m, 1H), 4,18 (t, J=9,2 Hz, 1H), 3,88-3,82 (m, 3H), of 3.69 (t, J=5,2 Hz, 2H), to 3.64 (t, J=5.6 Hz, 2H).

LCMS: 417 (M+H+for C18H17-FN6O5.

[Example 53] Get connection53

Compound XIII(4.5 g, 14 mmol) was dissolved in dichloromethane (75 ml) and after adding a saturated aqueous solution of NaHCO3(75 ml) and thiophosgene (1.1 ml, 14 mmol) at 0°C was stirred for 1 hour. The organic layer was dried with sodium sulfate, drove away under reduced pressure, was dissolved in methanol (120 ml)was stirred over night while boiling under reflux, and concentrated under reduced pressure, and separated using column chromatography to obtainlink the 53 (3,18 g, with 8.05 mmol, 58%) as a white solid.

1H NMR (600 MHz, CDCl3) δ=8,55 (s, 1H), 7,58 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,21 (DD, J1=9,0 Hz, J2=2.7 Hz, 1H), 7,13 (t, J=8,4 Hz, 1H), 6.89 in (s, 1H), of 6.71 (t, J=6.3 Hz, 1H), is 4.93 (m, 1H), 4,13-4,08 (m, 2H), of 4.05 (m, 1H), 4,01 (s, 3H), 3,99 (t, J=5.0 Hz, 2H), 3,90 (m, 1H), 3,74 (t, J=5.0 Hz, 2H).

LCMS: 396 (M+H+for C16H18FN5O4S.

[Example 54] connection54

The connection 54(210 mg, 0.51 mmol, 65%) was obtained fromcompound XIIIas in example 53, using ethanol instead of methanol.

1H NMR (600 MHz, CDCl3) δ=8,54 (s, 1H), 7,58 (DD, J1=14 Hz, J2=2,8 Hz, 1H), 7,21 (DD, J1=14 Hz, J2=3.8 Hz, 1H), 7,13 (t, J=8,4 Hz, 1H), to 6.88 (s, 1H), 6.75 in (t, J=6.3 Hz, 1H), 4,96 (m, 1H), 4,54-of 4.44 (m, 2H), 4.09 to as 4.02 (m, 3H), 3,98 (t, J=4,8 Hz, 2H), 3,92 (m, 1H), of 3.73 (t, J=4,8 Hz, 2H), 1,31 (t, J=7 Hz, 3H).

LCMS: 410 (M+H+for C17H20FN5O4S.

[Example 55] Get connection55

The connection 55(52 mg, 0.12 mmol, 52%) was obtained fromcompounds XIIIas in example 53, using isopropanol instead of methanol.

1H NMR (600 MHz, CDCl3) δ=8,55 (s, 1H), 7,58 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,22 (DD, J1=9,0 Hz, J2=2.7 Hz, 1H), 7,13 (t, J=8,4 Hz, 1H), to 6.88 (s, 1H), to 6.57 (t, J=6.3 Hz, 1H), 5,54 (m, 1H), is 4.93 (m, 1H), 4,12-4,06 (m, 2H), was 4.02 (m, 1H), 3,99 (t, J=4,8 Hz, 2H), 3,92 (m, 1H), of 3.73 (t, J=4,8 Hz, 2H), 1.32 to (d, J=6 Hz, 3H), 1.27mm (d, J=6 Hz, 3H).

LCMS: 424 (M+H for C18H22FN5O4S.

[Example 56] Get connection56

The connection 56(36 mg, 0,088 mmol, 57%) was obtained fromcompounds XIIIas in example 53, using ethylamine instead of methanol.

1H NMR (600 MHz, CDCl3) δ=8,54 (s, 1H), 7,58 (DD, 1H, J1=13,2 Hz, J2=the 2.4 Hz), 7,20-7,19 (m, 1H), 7,13 (t, 1H, J=9.0 Hz), to 6.88 (s, 1H), 4.92 in-4,96 (m, 1H), 4,10-4,06 (m, 3H), 3,99 (t, 2H, J=4,8 Hz), 1,44 was 1.43 (m,2H), 1,21 (t, 3H, J=7.2 Hz).

LCMS: 409 (M+H+for C17H21FN6O3S.

[Example 57] Get connection57

Compound XXVII-bgetting in synthesis example 14 was subjected to the reaction of Mitsunobu as in example 16. Then got theconnection 57(84 mg, 0.23 mmol, 31%)as in example 28.

1H NMR (600 MHz, CDCl3) δ=of 8.25 (s, 1H), 7.62mm (DD, J1=13 Hz, J2=2.0 Hz, 1H), 7,30 (t, J=9 Hz, 1H), 7,24 (DD, J1=9 Hz, J2=2.0 Hz, 1H), 6.73 x (ushort, 1H), 4,94 (m, 1H), 4,21-Android 4.04 (m, 4H), to 4.01 (s, 3H), 3,90 (t, J=4,8 Hz, 2H), 3,80 (t, J=4,8 Hz, 2H).

LCMS: 369 (M+H+for C15H17FN4O4S.

[Example 58] Get connection58

The connection 53(400 mg, 1.01 mmol) was dissolved in methanol (20 ml), after addition of 4n. HCl solution in dioxane (2 ml) and 10% Pd/C (50 mg) was stirred for 2 hours in an atmosphere of hydrogen supplied from the tank, filtered through celite, and drove away when pengendalian with quantitative getting connection 58in the form of a white solid.

1H NMR (600 MHz, CDCl3) δ=7,51 (DD, J1=14 Hz, J2=1.8 Hz, 1H), 7,16-7,10 (m, 2H), 6.89 in (s, 1H), 6,78 (ushort, 1H), is 4.93 (m, 1H), 4,10-3,98 (m, 6H), 3,88-3,81 (m, 3H), 3,32 (t, J=4,8 Hz, 2H).

LCMS: 368 (M+H+for C15H18FN5O3S.

[Example 59] Getting connection59

The connection 58(150 mg, 0.41 mmol) was dissolved in dichloromethane (5 ml), after addition of DIPEA (of 0.14 ml, 0.82 mmol) and acetoxyacetyl (of 0.066 ml, 0.61 mmol) at 0°C was stirred at room temperature for 6 hours. The solution is kept under reduced pressure and separated using column chromatography to obtainconnections 59(31 mg, of 0.066 mmol, 16%) as a white solid.

1H NMR (600 MHz, CDCl3) δ 7,58 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,22-7,11 (m, 2H), 6,83 (s, 1H), 6,69 (t, J=6.0 Hz, 1H), to 5.08 (s, 2H), 4,96 (m, 1H), 4,10-to 3.89 (m, 9H), 3,74 (t, J=4,8 Hz, 2H), measuring 2.20 (s, 3H).

LCMS: 468 (M+H+for C19H22FN5O6S.

[Example 60] Getting connection60

The connection 58(0.013 mg, 0.035 mmol) was dissolved in DMF (2 ml), after addition of DIPEA (0.01 ml, 0.07 mmol) and iodomethane (0.003 ml, 0.035 mmol) was stirred over night at room temperature, and separated using column chromatography to obtainconnection 60(3.1 mg, 0,0081 mmol, 23%) as a white solid fuel is Dogo substances.

1H NMR (600 MHz, CDCl3) δ=7,52 (DD, J1=14 Hz, J2=2.0 Hz, 1H), 7,15 (DD, J1=9 Hz, J2=2.0 Hz, 1H), 7,11 (t, J=9 Hz, 1H), 6.90 to (s, 1H), 6,76 (ushort, 1H), 4,94 (m, 1H), 4,10-of 3.85 (m, 7H), 3,82 (t, J1=4,8 Hz, 2H), 2,99 (t, J1=4,8 Hz, 2H), and 2.79 (s, 3H).

LCMS: 382 (M+H+for C16H20FN5O3S.

[Example 61] connection61

The connection 61(15 mg, of 0.038 mmol, 45%) was obtained fromconnection 58,as in example 60, using Iodate instead of iodomethane.

1H NMR (600 MHz, CDCl3) δ=7,51 (DD, J1=14 Hz, J2=1.8 Hz, 1H), 7,15 (DD, J1=8,4 Hz, J2=2.4 Hz, 1H), 7,11 (m, 1H), 6,92 (s, 1H), 6,77 (ushort, 1H), is 4.93 (m, 1H), 4,11-was 4.02 (m, 3H), 4,01 (s, 3H), 3,88-of 3.85 (m, 1H), 3,83 (t, J=4,8 Hz, 2H), to 3.02 (t, J=4,8 Hz, 2H), 2,98-to 2.94 (m, 2H), 1,24 (t, J=7,2 Hz, 3H).

LCMS: 396 (M+H+for C17H22FN5O3S.

[Example 62] Getting connection62

The connection 62(15 mg, 0,037 mmol, 67%) was obtained fromconnection 58,as in example 60, using allylbromide instead of iodomethane.

1H NMR (600 MHz, chloroform-d1) δ 7,51 (DD, 1H, J1=13,2 Hz, J2=1,8 Hz), to 7.15 (DD, 1H, J1=9,0 Hz, J2=2,4 Hz), 7,11 (t, 1H, 8,4 Hz), 6,92 (s, 1H), of 6.68 (t, 1H, J=6.0 Hz), between 6.08 and 5,96 (m, 1H), from 5.29 (DD, 1H, J1=10,2 Hz, J2=1,8 Hz), 5,24 (DD, 1H, J1=10,2 Hz, J2=1,8 Hz), 4,98-4,88 (m, 1H), 4,12-Android 4.04 (m, 2H), was 4.02-3,98 (m, 1H), 4,01 (s, 3H), 3,86 (DD, 1H, J1=9.6 Hz, J2=7,2 Hz), 3,82 (t, 2H, J=4,2 Hz)to 3.58(d, 2H, J=6.0 Hz), of 3.00 (t, 2H, J=4,8 Hz).

LCMS: 408 (M+H+for C18H22FN5O3S.

[Example 63] Getting connection63

Connection 63(36 mg, 0,089 mmol, 68%) was obtained fromconnection 58,as in example 60, using propylbromide instead of iodomethane.

1H NMR (600 MHz, chloroform-d1) δ 7,53 (DD, 1H, J1=to 13.8 Hz, J2=2,4 Hz), 7,16 (DD, 1H, J1=9,0 Hz, J2=2,4 Hz), 7,13 (t, 1H, 8,4 Hz), of 6.96 (s, 1H), 6,69 (t, 1H, J=6.0 Hz), 4,98-of 4.90 (m, 1H), 4,14-3,98 (m, 3H), 4,01 (s, 3H), 3,90-3,82 (m, 1H), 3,85 (t, 2H, J=6.6 Hz), 3,83 (d, 2H, J=2.4 Hz), of 3.13 (t, 2H, J=a 5.4 Hz), 2,31 (t, 1H, J=2.4 Hz).

LCMS: 406 (M+H+for C18H20FN5O3S.

[Example 64] Getting connection64

The connection 64(16 mg, of 0.038 mmol, 74%) was obtained fromconnection 58,as in example 60 using 1-bromo-2-buten instead of iodomethane.

1H NMR (600 MHz, CDCl3) δ 7,52 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,16 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), 7,12 (t, 8,4 Hz, 1H), 6,95 (s, 1H), 6,70 (t, J=6.0 Hz, 1H), 4,94 (m, 1H), 4,13 of 3.75 (m, 11H), of 3.12 (t, J=5.4 Hz, 2H), 1,87 (t, J=2,4 Hz, 3H).

LCMS: 420 (M+H+for C19H22FN5O3S.

[Example 65] Getting connection65

The connection 65(22 mg, 0,054 mmol, 64%) was obtained fromconnection 58,as in example 60, using bromoacetonitrile instead of iodomethane.

1H NMR (600 MHz, CDCl3) the 7,56 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,17 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), 7,14 (t, 8,4 Hz, 1H), of 6.96 (s, 1H), of 6.68 (t, J=6.0 Hz, 1H), 4.95 points (m, 1H), 4,12-3,86 (m, 11H)and 3.15 (t, J=5.4 Hz, 2H).

LCMS: 407 (M+H+for C17H19FN6O3S.

[Example 66] Getting connection66

Compound 66(15 mg, 0,034 mmol, 54%) was obtained fromconnection 58,as in example 60, using 2,3-dichloropropan instead of iodomethane.

1H NMR (600 MHz, CDCl3) δ 7,52 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,16 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), 7,11 (t, 8,4 Hz, 1H), 6,92 (s, 1H), 6.73 x (t, J=6.0 Hz, 1H), 5,49 (s, 1H), 5,42 (s, 1H), 4,94 (m, 1H), 4,12-a-3.84 (m, 9H), and 3.72 (s, 2H), is 3.08 (t, J=5.4 Hz, 2H).

LCMS: 442 (M+H+for C18H21ClFN5O3S.

[Example 67] Getting connection67

Connection 67(18 mg, 0,043 mmol, 84%) was obtained fromconnection 58,as in example 41, using cyclopropanecarboxaldehyde.

1H NMR (600 MHz, CDCl3) δ 7,51 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,18 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), 7,11 (t, 8,4 Hz, 1H), 7,01 (t, J=6.0 Hz, 1H), 6,91 (s, 1H), 4.95 points (m, 1H), 4,12-a 3.83 (m, 9H), of 3.13 (t, J=4,8 Hz, 2H), 2,82 (d, J=7.2 Hz, 2H), 1,08 (m, 1H), or 0.57 (m, 2H), 0,21 (m, 2H).

LCMS: 422 (M+H+for C19H24FN5O3S.

[Example 68] Getting connection68

The connection 68(19 mg, 0.045 mmol, 76%) was obtained fromconnection 58,as in PR is least 41, using cyclobutanone.

1H NMR (600 MHz, CDCl3) δ 7,51 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,16-to 7.09 (m, 2H), 6,95 (s, 1H), 6,64 (ushort, 1H), 4,94 (m, 1H), 4,11-3,98 (m, 6H), a 3.87 (m, 1H), 3,82 (t, J=4,8 Hz, 2H), 3,42 (m, 1H), only 2.91 (t, J=4,8 Hz, 2H), 2.23 to-2,12 (m, 4H), 1,81-of 1.73 (m, 2H,).

LCMS: 422 (M+H+for C19H24FN5O3S.

[Example 69] Getting connection69

Connection 69(24 mg, 0,053 mmol, 47%) was obtained fromconnection 58,as in example 60, using ethylbromoacetate instead of iodomethane.

1H NMR (600 MHz, chloroform-d1) δ 7,52 (DD, 1H, J1=13,2 Hz, J2=1,8 Hz), to 7.15 (DD, 1H, J1=9,0 Hz, J2=2,4 Hz), 7,11 (t, 1H, 8,4 Hz)6,91 (s, 1H), 6,83 (t, 1H, J=6.6 Hz), 4,98-of 4.90 (m, 1H), 4.26 deaths-is 4.21 (m, 2H), 4,13-of 3.97 (m, 3H), 4,01 (s, 3H), 3,85 (t, 2H, J=4, 2 Hz), of 3.78 (s, 2H), 3,24 (t, 2H, J=4,8 Hz), 1,03 (t, 3H, J=7.2 Hz).

LCMS: 454 (M+H+for C19H24FN5O5S.

[Example 70] Getting connection70

Connection 69(17 mg, 0,037 mmol) was dissolved in THF (2 ml) and after addition of 2M solution of LiBH4(1 ml) was stirred at room temperature for 3 hours. After adding a small amount of water, the solution was separated using column chromatography to obtainconnection 70(6.5 mg, to 0.016 mmol, 43%) as a white solid.

1H NMR (600 MHz, chloroform-d1) δ 7,53 (DD, 1H, J1=13,2 Hz, J2=1,8 Hz), 7,17 (DD, 1H, J1 =8,4 Hz, J2=2,4 Hz), 7,12 (t, 1H, 9.0 Hz), 6.90 to (s, 1H), 6.73 x (t, 1H, J=6.0 Hz), 4,98-of 4.90 (m, 1H), 4,18-Android 4.04 (m, 2H), 4.04 the-3,98 (m, 1H), 4,01 (s, 3H), of 3.96 (t, 2H, J=4,8 Hz), a 3.87 (DD, 1H, J1=9,0 Hz, J2=7,2 Hz), of 3.84 (t, 2H, J=4,8 Hz), of 3.07 (t, 2H, J=4,8 Hz)of 3.00 (t, 2H, J=4,8 Hz).

LCMS: 412 (M+H+for C17H22FN5O4S.

[Example 71] Getting connection71

Connection 71(84 mg, 0,19 mmol, 76%) was obtained fromconnection 58,as in example 60, using Bromeliaceae instead of iodomethane.

1H NMR (600 MHz, CDCl3) δ 7,51 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,16-7,07 (m, 2H), 6,91-6,89 (m, 2H), 4.95 points (m, 1H), and 4.40 (t, J=5.4 Hz, 2H) 4,13-3,86 (m, 7H), 3,83 (t, J=4,8 Hz, 2H), 3.15 in (t, J=5.4 Hz, 2H), to 3.09 (t, J=4,8 Hz, 2H), 2,10 (s, 3H).

LCMS: 454 (M+H+for C19H24FN5O5S.

[Example 72] Getting connection72

The connection 72(54 mg, 0.12 mmol, 61%) was obtained fromconnection 58,as in example 53.

1H NMR (600 MHz, DMSO-d6) δ=9,56 (t, J=6 Hz, 1H), 7.62mm (DD, J1=14 Hz, J2=2.0 Hz, 1H), 7,43 (t, J=9 Hz, 1H), 7,34 (DD, J1=9 Hz, J2=2.0 Hz, 1H), 7,17 (s, 1H), 4.92 in (m, 1H), to 4.41 (ushort, 2H), 4,17 (t, J1=9 Hz, 1H), 3,99 (s, 3H), 3,88 (s, 3H), 3,85 is 3.76 (m, 5H).

LCMS: 442 (M+H+for C17H20FN5O4S2.

[Example 73] Getting connection73

Compound XIII(223 mg, 0.69 mmol) and NaF (38 mg, 1.3 equivalent) was dissolved in ethanol (10ml) and after adding ethyldiamine (0.1 ml, 1.2 equivalent) was stirred overnight at room temperature. After distillation under reduced pressure and the mixture was dissolved in ethyl acetate, washed with brine, dried with sodium sulfate, and separated using column chromatography to obtainconnections 73(220 mg, of 0.58 mmol, 84%) as a white solid.

1H NMR (600 MHz, CDCl3) δ=charged 8.52 (s, 1H) to $ 7.91 (ushort, 1H), 7,56 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,17 (DD, J1=9,0 Hz, J2=2.7 Hz, 1H), 7,11 (t, J=8,4 Hz, 1H), 6.87 in (s, 1H), to 4.98 (m, 1H), 4,28-4,24 (m, 1H), 4,12-4,07 (m, 2H), 3,97 (t, J=4,8 Hz, 2H), 3,86-a-3.84 (m, 1H), 3,71 (t, J=4,8 Hz, 2H), 2,58 (s, 3H).

LCMS: 380 (M+H+for C16H18-FN5O3S.

[Example 74] Getting connection74

Connection 73(220 mg, of 0.58 mmol) was dissolved in methanol (10 ml) and after addition of 4M HCl solution in dioxane (1 ml) was stirred at room temperature for 2 hours, and concentrated under reduced pressure to quantitatively obtainconnection 74(240 mg) in the form of cleaners containing hydrochloride salt.

1H NMR (400 MHz, DMSO-d6) δ=10,5 (ushort, 1H), of 7.70 (d, J=14 Hz, 1H), to 7.61 (t, J=8,8 Hz, 1H), 7,42 (d, J=8,8 Hz, 1H), 5,00 (m, 1H), 4,20 (m, 1H), 3,94-of 3.78 (m, 5H), 3,62 (ushort, 2H), of 2.45 (s, 3H).

LCMS: 352 (M+H+for C15H18-FN5O2S.

[Example 75] Getting connection75

Connection 75(35 mg, 0.09 mmol, 42%) was obtained fromconnection 74,as in example 7.

1H NMR (600 MHz, CDCl3) δ=7,74 (ushort, 1H), 7,55 (DD, J1=14 Hz, J2=1.8 Hz, 1H), 7.18 in for 7.12 (m, 2H), of 6.96 (s, 1H), free 5.01 (m, 1H), 4,32 (m, 1H), 4,12-Android 4.04 (m, 2H), 3.96 points (s, 2H), 3,88-a 3.83 (m, 3H), 3.15 in (t, J=4 Hz, 2H), 2,98-to 2.94 (m, 2H), 1,24 (t, J=4,2 Hz, 2H), 2,61 (s, 3H).

LCMS: 391 (M+H+for C17H19-FN6O2S.

[Example 76] Getting connection76

The connection 76(35 mg, 0,086 mmol, 36%) was obtained fromconnection 74,as in example 12.

1H NMR (600 MHz, CDCl3) δ=7,80 (m, 1H), 7,56 (DD, J1=13 Hz, J2=2,4 Hz), 7,19-7,17 (m, 1H), 7,13-7,10 (m, 1H), 5,00-4,96 (m, 1H), 4,48 (d, J=4,2 Hz, 2H), 4,29-of 4.25 (m, 1H), 4,10-4,07 (m, 2H), of 4.05 (t, J=4,8 Hz, 2H), 3,86-a 3.83 (m, 1H), 3,74 (t, J=4,8 Hz, 2H), 3.27 to (t, J=4,8 Hz, 1H), 2,58 (s, 3H).

LCMS: 410 (M+H+for C17H20FN5O4S.

[Example 77] Getting connection77

Connection 77(350 mg, 0.84 mmol, 79%) was obtained by reactionconnectionXIII with Ph2CHCH2CH2OC(S)CHF2over night at room temperature, as described in the publication ofBioorg. Med. Chem. Lett.2006,16, 3475-3478.

1H NMR (400 MHz, CDCl3) δ=8,55 (s, 1H), 8,48 (ushort, 1H), 7,56 (DD, J1=14 Hz, J2=2.0 Hz, 1H), 7,20 (DD, J1=8,8 Hz, J2=2.0 Hz, 1H), 7,14 (t, J=8,8 Hz, 1H), 6.89 in (s, 1H), from 6.22 (t, J=56 Hz, 1H), to 5.03 (m, 1H), 4,34 (m, 1H), 4,16 (t, J=8,8 Hz, 1H), 4,06 (m, 1H), 3,99 (t, J=4,8 Hz, 2H), 3,82-to 3.73 (m, 3H).

*LCMS: 416 (M+H+for C16 H16F3N5O3S.

[Example 78] Getting connection78

Connection 77were subjected to interaction, as in example 74. Then got thethe connection 78(26 mg, 0.061 mmol, 35%)as in example 5.

1H NMR (600 MHz, CDCl3) δ=8,65 (ushort, 1H), 7,49 (DD, J1=14 Hz, J2=2.0 Hz, 1H), 7,14-7,13 (m, 2H), of 6.96 (s, 1H), from 6.22 (t, J=56 Hz, 1H), to 5.03 (m, 1H), 4,34 (m, 1H), 4,15 (t, J=8,8 Hz, 1H), Android 4.04 (m, 1H), 3,86-of 3.78 (m, 5H), 3,14 (t, J=4,8 Hz, 2H), 2,31 (t, J=1.8 Hz, 1H).

LCMS: 426 (M+H+for C18H18F3N5O2S.

[Example 79] Getting connection79

Compound VIobtained in synthesis example 6 were subjected to interaction as in synthesis example 12, using hydroxyethoxy instead of boc-aminoethoxy. Then got theconnection 79(53 mg, 0.14 mmol, 28%)as in synthesis example 10.

1H NMR (400 MHz, DMSO-d6) δ=8,71 (d, J=2 Hz, 1H), 8,42 (s, 1H), 7,65 (DD, J1=14 Hz, J2=2.0 Hz, 1H), 7,41-7,37 (m, 2H), 7,07 (s, 1H), to 6.39 (d, J=2 Hz, 1H), 5,10 (m, 1H), to 4.81 (m, 1H), 4,49 (m, 1H), 4,21 (t, J=9,2 Hz, 1H), 3,93 (m, 1H), 3,84 (t, J=5.6 Hz, 2H), 3,70 (t, J=4,8 Hz, 2H).

LCMS: 390 (M+H+for C17H16-FN5O5.

[Example 80] Get connection80

Compound VIwere subjected to interaction, as in the example 12 synthesis using boc-aminothiazol instead of boc-aminoethoxy. Then got thewith the unity 80 (26 mg, 0,064 mmol, 16%)as in synthesis example 10.

1H NMR (400 MHz, CDCl3) δ=8,55 (s, 1H), EUR 7.57 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,21 (DD, J1=9,0 Hz, J2=2.7 Hz, 1H), 7,13-was 7.08 (m, 2H), at 6.84 (s, 1H), 6,55 (d, J=3.6 Hz, 1H), 5,34 (users, 1H), equal to 4.97 (m, 1H), 4,10 (t, J=8,8 Hz, 1H), 3,99 (t, J=5.4 Hz, 2H), 3,92-with 3.79 (m, 3H), of 3.73 (t, J=5.4 Hz, 2H).

LCMS: 405 (M+H+for C17H17-FN6O3S.

[Example 81] Getting connection81

Connection 81(35 mg, 0,094 mmol, 25%) was obtained fromcompound XIX,as in synthesis example 10.

1H NMR (400 MHz, CDCl3) δ=8,49 (s, 1H), to 7.77 (d, J=1 Hz, 1H), 7,71 (s, 1H), 7,41 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,08? 7.04 baby mortality (m, 2H), at 6.84 (d, J=1 Hz, 1H), 6,86 (s, 1H), is 5.06 (m, 1H), 4,78 (d, J=4 Hz, 2H), 4,14 (t, J=8,8 Hz, 1H), 3,94-to 3.64 (m, 7H).

LCMS: 374 (M+H+for C16H16-FN7O3.

[Example 82] Getting connection82

The connection 82(84 mg, 0.24 mmol, 73%) was obtained fromconnections 81,as in example 2.

1H NMR (400 MHz, DMSO-d6) δ=of 8.37 (s, 1H), 8,19 (s, 1H), to 7.77 (s, 1H), of 7.64-7,56 (m, 2H), 7,35 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), 7,08? 7.04 baby mortality (m, 2H), by 5.18 (m, 1H), around 4.85 (d, J=5,2 Hz, 2H), 4,27 (t, J=9,2 Hz, 1H), 3,93 (m, 1H), 3,78 (ushort, 2H), 3,35 (ushort, 2H).

LCMS: 346 (M+H+for C15H16-FN7O2.

[Example 83] Getting connection83

The connection 82(62 mg, 0.16 mmol) was dissolved in methanol (5 ml) and PEFC is added 4M HCl solution in dioxane (0.1 ml), formalin (0.2 ml) and Pd/C (6 mg) was subjected to interact for 2 hours at room temperature in an atmosphere of hydrogen supplied from a cylinder. The solution was filtered through celite, was dissolved in distilled water (10 ml), neutralized, extracted with dichloromethane, dried with sodium sulfate, and concentrated under reduced pressure to obtainconnection 83(34 mg, 0,086 mmol, 54%).

1H NMR (400 MHz, CDCl3) δ=7,78 (s, 1H), of 7.75 (s, 1H), 7,39-7,00 (m, 3H), to 6.88 (s, 1H), 5,08 (m, 1H), 4,80 (d, J=4.4 Hz, 2H), 4,15 (t, J=9,2 Hz, 1H), 3,95 (m, 1H), 3,80 (t, J=4.6 Hz, 2H), 2,98 (t, J=4.6 Hz, 2H) and 2.79 (s, 3H).

LCMS: 360 (M+H+for C16H18-FN7O2.

[Example 84] Getting connection84

The connection 84(26 mg, 0,068 mmol, 74%) was obtained fromconnection 82,as in example 5.

1H NMR (400 MHz, CDCl3) δ=7,79 (s, 1H), 7,76 (s, 1H), 7,39-7,03 (m, 3H), 6,94 (s, 1H), 5,08 (m, 1H), 4,80 (d, J=3,6 Hz, 2H), 4,15 (t, J=9,2 Hz, 1H), 3,95 (m, 1H), 3,84-3,82 (m, 4H), 3,12 (ushort, 2H), 2,34 (s, 1H).

LCMS: 384 (M+H+for C18H18-FN7O2.

[Example 85] Getting connection85

Connection 85(81 mg, 0.21 mmol, 31%) was obtained fromcompounds XVas in synthesis example 10.

1H NMR (400 MHz, CDCl3) δ=8,49 (s, 1H), 8,02 (d, J=2.0 Hz, 1H), 7,54 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,17 (DD, J1=9,0 Hz, J2=2.7 Hz, 1H), was 7.08 (t, J=8,4 Hz, 1H), 6,86 (s, H), 5,86 (d, J=2.0 Hz, 1H), is 4.93 (m, 1H), 4,06 (t, J=8,8 Hz, 1H), 3,94 (t, J=5.0 Hz, 2H), a 3.87 is 3.57 (m, 5H).

LCMS: 389 (M+H+for C17H17-FN6O4.

[Example 86] Getting connection86

Connection 86(35 mg, 0,097 mmol, 71%) was obtained fromconnection 85,as in example 2.

1H NMR (600 MHz, DMSO-d6) δ=8,40 (s, 1H), 8.30 to (s, 1H), of 7.70 (d, J=13 Hz, 1H), 7,60 (t, J=8,4 Hz, 1H), 7,41 (d, J=8,4 Hz, 1H), 6,03 (s, 1H), 5,86 (d, J=2.0 Hz, 1H), 4.92 in (m, 1H), 4,20 (t, J=7.8 Hz, 1H), 3,89-to 3.36 (m, 7H).

LCMS: 361 (M+H+for C16H17-FN6O3.

[Example 87] Getting connection87

Connection 87(15 mg, being 0.036 mmol, 35%) was obtained fromconnection 86,as in example 12.

1H NMR (600 MHz, DMSO-d6) δ=8,39 (d, J=1.2 Hz, 1H), 7.62mm (DD, J1=14 Hz, J2=2.4 Hz, 1H), 7,38-7,33 (m, 1H), 7,07 (s, 1H), 6,56 (t, J=6 Hz, 1H), 6,00 (d, J=1.2 Hz, 1H), 4,91-to 4.87 (m, 1H), 4,54-to 4.52 (m, 1H), 4,32 (d, J=6.0 Hz, 2H), 4,18-to 4.15 (m, 1H), 3,89 (t, J=4,8 Hz, 2H), 3,83-of 3.80 (m, 1H), 3,70 (t, J=4,8 Hz, 2H), 3.46 in-of 3.43 (m, 2H).

LCMS: 419 (M+H+for C18H19-FN6O5.

[Example 88] Getting connection88

The connection 88(210 mg, 0.46 mmol, 42%) was obtained fromconnection 86,as in example 59.

1H NMR (600 MHz, CDCl3) δ=8,07 (d, 1H, J=1.8 Hz), 7,58 (DD, 1H, J1=13,2 Hz, J2=3,0 Hz), 7,21 (DD, 1H J1=8,4 Hz, J2=2,4 Hz), 7,11 (t, 1H, J=8,4 Hz), PC 6.82 (s, 1H), 5,88 (d, 1H, J=1.8 Hz), to 5.08 (s, 2H), 4,96-5,00 (m, 1H), and 4.40 (t, 1H, J=6.6 Hz), 4.09 to (t, 1H, J=9.0 Hz), was 4.02 (t, 2H, J=4,8 Hz), of 3.77-of 3.78 (m, 1H), 3,74 is 3.76 (m, 1H), 3,66-3,62 (m, 1H).

LCMS: 461 (M+H+for C20H21-FN6O6.

[Example 89] Getting connection89

Connection 89(36 mg, 0,096 mmol, 68%) was obtained fromconnection 86,as in example 3.

1H NMR (600 MHz, CDCl3) δ 8,07 (d, J=1.2 Hz, 1H), 7,51 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,15 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), 7,09 (t, 8,4 Hz, 1H), 6.89 in (s, 1H), by 5.87 (d, J=1.2 Hz 1H), equal to 4.97 (m, 1H), 4,42 (t, J=6 Hz, 1H), 4,08 (t, J=8,4 Hz, 1H), a 3.87-of 3.60 (m, 5H), 2,98 (t, J=4,8 Hz, 2H), and 2.79 (s, 3H).

LCMS: 375 (M+H+for C17H19-FN6O3.

[Example 90] Getting connection90

Connection 90(15 mg, 0,039 mmol, 45%) was obtained fromconnection 86,as in example 6.

1H NMR (400 MHz, CDCl3) δ=8,07 (d, 1H, J=1.6 Hz), 7,51 (DD, 1H, J1=to 13.6 Hz, J2=the 2.4 Hz), to 7.15 (DD, 1H, J1=9,2 Hz, J2=the 2.4 Hz), to 7.09 (t, 1H, J=8,8 Hz)6,91 (s, 1H), by 5.87 (DD, 1H, J=1.6 Hz), 4,99-is 4.93 (m, 1H), and 4.40 (t, 1H, J=6.4 Hz), 4,07 (t, 1H, J=9.0 Hz), 3,86-3,81 (m, 3H), 3,78-and 3.72 (m, 1H), 3,64 (t, 1H, J=3.2 Hz), 3,62-to 3.58 (m, 1H), 3,01 (t, 2H, J=4,8 Hz), 2.95 and (t, 2H, J=7,07 Hz)of 1.23 (t, 3H, J=7,0 Hz).

LCMS: 389 (M+H+for C18H21-FN6O3.

[Example 91] Getting connection91

Connection 91(25 mg, 0,063 mmol, 64%) was obtained fromconnection 86,as in example 5.

1H NMR (600 MHz, CDCl3) δ 8,07 (d, J=1,8 is C, 1H), 7,53 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,16 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), 7,11 (t, 8,4 Hz, 1H), 6,95 (s, 1H), by 5.87 (d, J=1.8 Hz, 1H), 4,96 (m, 1H), 4,35 (t, J=6,6 Hz, 1H), 4,08 (t, J=9 Hz, 1H), a 3.87-of 3.60 (m, 7H), of 3.13 (t, J=4,8 Hz, 2H), 2,31 (t, J=2.4 Hz, 1H).

LCMS: 399 (M+H+for C19H19-FN6O3.

[Example 92] Get connection92

The connection 92(240 mg, 0.75 mmol, 32%) was obtained fromcompound XXIII,as in synthesis example 10.

1H NMR (600 MHz, CDCl3) δ=8,55 (s, 1H), to 7.61 (DD, J1=13 Hz, J2=2.4 Hz, 1H), 7,25 (DD, J1=9,0 Hz, J2=2.7 Hz, 1H), 7,14 (t, J=8,4 Hz, 1H), 6.90 to (s, 1H), 4,79 (m, 1H), 4.04 the-3,99 (m, 5H), 3,79-to 3.73 (m, 3H), 2,58 (users, 1H).

LCMS: 323 (M+H+for C14H15-FN4O4.

[Example 93] Getting connection93

Connection 93(190 mg, of 0.65 mmol, 74%) was obtained fromconnection 92,as in example 2.

1H NMR (600 MHz, DMSO-d6) δ=7,73 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,60 (t, J=9 Hz, 1H), 7,45 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), and 4.75 (m, 1H), 4,11 (t, J=9.0 Hz, 1H), 3,88 (m, 1H), 3,78 (t, J=4,8 Hz, 2H), 3,70-3,55 (m, 2H), 3,36 (t, J=4,8 Hz, 2H).

LCMS: 295 (M+H+for C13H15-FN4O3.

[Example 94] Getting connection94

Connection 93(150 mg, 0.51 mmol) was dissolved in methanol (5 ml), formaldehyde (37% aqueous solution of 0.21 ml, 2.55 mmol) and after adding acetic key is lots one (0.03 ml, 0.51 mmol) and NaBH3CN (48 mg, 0.77 mmol) was stirred for 1 hour at room temperature. The solution is kept under reduced pressure, dissolved in dichloromethane (100 ml), sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (brine), dried using anhydrous sodium sulfate, concentrated under reduced pressure, and separated using column chromatography to obtainconnection 94(71 mg, 0.23 mmol, 45%).

1H NMR (600 MHz, DMSO-d6) δ=to 7.59 (DD, J1=to 13.8 Hz, J2=2.4 Hz, 1H), 7,33-7,30 (m, 2H), at 6.84 (s, 1H), 5,23 (t, J=5.4 Hz, 1H), 4,70 (m, 1H), 4,07 (t, J=9.0 Hz, 1H), 3,82 (m, 1H), 3,71 (t, J=4,8 Hz, 2H), 3,69-of 3.54 (m, 2H), 2,87 (t, J=4,8 Hz, 2H), 2,61 (s, 3H).

LCMS: 309 (M+H+for C14H17-FN4O3.

[Example 95] Getting connection95

Connection 95(300 mg, 0.86 mmol) was obtained from 4-fluoro-nitrobenzene according to scheme 6, as in the synthesis ofconnections 1.

1H NMR (600 MHz, CDCl3) δ=8,56 (s, 1H), 7,55 (m, 2H), 7,11 (s, 1H), 7,07 (m, 2H), 6,00 (ushort, 1H), 4,79 (m, 1H), 4,07 (t, J=9.6 Hz, 1H), was 4.02 (t, J=4,8 Hz, 2H), 3,81 (m, 1H), 3,76 (t, J=4,8 Hz, 2H), 3.72 points-3,61 (m, 2H), 2,03 (, 3H).

LCMS: 346 (M+H+for C16H19N5O4.

[Example 96] Getting connection96

Connection 96(42 mg, 0.13 mmol, 48%) was obtained fromconnection 95,in PR the least 3.

1H NMR (600 MHz, CDCl3) δ=of 7.48 (d, J=9.0 Hz, 2H), 7,22 (s, 1H), 7,02 (d, J=9.0 Hz, 2H), 5,93 (ushort, 1H), 4,77 (m, 1H), of 4.05 (t, J=9.6 Hz, 1H), 3,81 (t, J=4,8 Hz, 2H), 3,79-to 3.58 (m, 3H), 3,01 (t, J=4,8 Hz, 2H), 2,80 (s, 3H), 2,03 (s, 3H).

LCMS: 332 (M+H+for C16H21N5O3.

[Example 97] Getting connection97

Connection 97(540 mg, 1.4 mmol) was obtained from 4-fluoro-nitrobenzene according to scheme 6, as in the synthesis ofconnections 53.

1H NMR (600 MHz, CDCl3) δ=8,56 (s, 1H), 7,55 (d, J=9.0 Hz, 2H), 7,11 (s, 1H), 7,07 (d, J=9.0 Hz, 2H), 6,69 (ushort, 1H), 4,94 (m, 1H), 4,13-of 4.05 (m, 3H), 4.04 the-3,99 (m, 5H), 3,90 (m, 1H), 3,76 (t, J=4,8 Hz, 2H).

LCMS: 378 (M+H+for C16H19N5O4S.

[Example 98] Get connection98

Connection 98(160 mg, 0.44 mmol, 62%) was obtained fromconnections 97,as in example 60.

1H NMR (600 MHz, CDCl3) δ=of 7.48 (d, J=9.0 Hz, 2H), 7,21 (s, 1H), 7,02 (d, J=9.0 Hz, 2H), 6,69 (ushort, 1H), 4.92 in (m, 1H), 4,13-4,08 (m, 2H), 4,01-3,95 (m, 4H), 3,86 (m, 1H), 3,81 (t, J=4,8 Hz, 2H), 3,01 (t, J=4,8 Hz, 2H), 2,80 (, 3H).

LCMS: 364 (M+H+for C16H21N5O3S.

[Example 99] Getting connection99

Connection 99(340 mg, 0.96 mmol) was obtained from 4-fluoro-nitrobenzene according to scheme 6, as in the synthesis ofconnections 81.

1H NMR (600 MHz, CDCl3) δ=8,55 (s, 1H), 7,80 (d, J=1 Hz, 1H), of 7.75 (d, J=1 Hz, 1H), 7,40 (d, J=9.0 Hz, 2H), to 7.09 (s, 1H), 7,03 (d, J=9.0 Hz, 2H), 5,08 (m, 1H), 4,81 d, J=4 Hz, 2H), 4,17 (t, J=8,4 Hz, 1H), 4,00-of 3.97 (m, 4H), to 3.73 (t, J=4,8 Hz, 2H).

LCMS: 356 (M+H+for C16H17-N7O3.

[Example 100] Getting connection100

Connection 100(280 mg, from 0.76 mmol) was obtained from 4-peritrabecular scheme 6, as in the synthesis ofconnection 85.

1H NMR (600 MHz, CDCl3) δ=8,55 (s, 1H), of 8.06 (d, J=1.8 Hz, 1H), 7,54 (d, J=9 Hz, 2H), 7,10 (s, 1H), 7,06 (d, J=9 Hz, 2H), of 5.89 (d, J=1.8 Hz, 1H), 4,96 (m, 1H), 4,10 (t, J=9 Hz, 1H), 3,99 (t, J=4,8 Hz, 2H), with 3.89 (m, 1H), 3.75 to and 3.72 (m, 3H), 3,62 (m, 1H).

LCMS: 371 (M+H+for C17H18-N6O4.

[Example 101] Getting connection101

Connection 101(37 mg, 0.10 mmol, 68%) was obtained fromconnection 100,as in example 89.

1H NMR (600 MHz, CDCl3) δ=8,07 (s, 1H), of 7.48 (d, J=9 Hz, 2H), 7,21 (s, 1H), 7,01 (d, J=9 Hz, 2H), by 5.87 (s, 1H), 4.95 points (m, 1H), 4,40 (ushort, J=6 Hz, 1H), 4.09 to (t, J=9 Hz, 1H), 3,85 (t, J=8,4 Hz, 1H), 3,80 (t, J=4,8 Hz, 2H), with 3.89 (m, 1H), 3,76-3,59 (m, 2H), 3,00 (t, J=4,8 Hz, 2H), 2,80 (s, 3H).

LCMS: 357 (M+H+for C17H20-N6O3.

[Example 102] Getting connection102

Connection 102(24 mg, 0,069 mmol, 37%) was obtained as in example 57, fromcompound XXVII-cthat was obtained from 4-fluoro-nitrobenzene according to scheme 6, as in the example 14 synthesis.

1H NMR (600 MHz, CDCl3) δ=7,56 (s, 1H), 7,54 (d, J=9 Hz, 2H), 7,06 (d, J=9 Hz, 2H), 6,67 (ushort, 1H), is 4.93 (m, 1H), 4,21 (t, J=4,8 Hz, 2H), 4,13-4,07 (m, 3H, to 4.01 (s, 3H), 3,88 (t, J=9 Hz, 1H), of 3.77 (t, J=4,8 Hz, 2H).

LCMS: 351 (M+H+for C15H18-N4O4S.

[Example 103] Getting connection103

Connection 103(350 mg, 0.90 mmol) was obtained from 3,4,5-tri-peritrabecular scheme 6, as in the synthesis ofconnections 81.

1H NMR (600 MHz, CDCl3) δ=8,54 (s, 1H), to 7.77 (d, J=1 Hz, 1H), of 7.75 (d, J=1 Hz, 1H), 7,15 (s, 1H), 7,13 (s, 1H), 6,69 (s, 1H), 5,11 (m, 1H), 4,81 (d, J=4 Hz, 2H), 4,15 (t, J=8,8 Hz, 1H), was 4.02-3,98 (m, 3H), of 3.65 (t, J=4,8 Hz, 2H).

LCMS: 392 (M+H+for C16H15-F2N7O3.

[Example 104] connection104

The connection 104(23 mg, 0.061 mmol, 62%) was obtained fromconnection 103,as in example 83.

1H NMR (400 MHz, CDCl3) δ=7,79 (s, 1H), 7,74 (s, 1H), 7,11 (s, 1H), to 7.09 (s, 1H), 6,65 (s, 1H), 5,11 (m, 1H), 4,81 (d, J=4 Hz, 2H), 4,16 (t, J=9 Hz, 1H), 3,95 (m, 1H), of 3.73 (t, J=4,8 Hz, 2H), 2,99 (t, J=4,8 Hz, 2H).

LCMS: 378 (M+H+for C16H17-F2N7O2.

[Example 105] Getting connection105

Connection 105(640 mg, 1.6 mmol) was obtained from 3,4,5-trif-trnitrophenol scheme 6, as in the synthesis ofconnection 85.

1H NMR (400 MHz, CDCl3) δ=8,54 (s, 1H), 8,08 (d, J=1.6 Hz, 1H), 7,29 (s, 1H), 7,27 (s, 1H), of 6.71 (s, 1H), of 5.89 (d, J=1.6 Hz, 1H), 4,99 (m, 1H), 4,54 (t, J=6,4 Hz, 1H), 4,08 (t, J=9 Hz, 1H), 4.00 points (t, J=4,8 Hz, 2H), 3,90-to 3.73 (m, 2H), 3,69-3,62 (m, 3H).

LCMS: 407 (M+H+for C17H16-F2 N6O4.

[Example 106] Getting connection106

The connection 106(24 mg, 0.061 mmol, 74%) was obtained fromconnection 105,as in example 89.

1H NMR (400 MHz, CDCl3) δ=of 8.06 (d, J=1.6 Hz, 1H), 7.23 percent (s, 1H), 7,18 (s, 1H), 6,65 (s, 1H), 5,90 (d, J=1.6 Hz, 1H), 4,99 (m, 1H), 4.92 in (t, J=6,4 Hz, 1H), 4,06 (t, J=8,8 Hz, 1H), 3,89-3,61 (m, 5H), of 3.00 (t, J=4,8 Hz, 2H).

LCMS: 393 (M+H+for C17H18-F2N6O3.

[Test example 1] Measurement of antibacterial activityin vitro

For testing antibacterial activity of derivatives oxazolidinone synthesized in examples 1-106, a study was conducted activity in vitro as follows.

Antibacterial activity ofin vitroderivatives oxazolidinone example 1-106 was estimated using the method of microrasbora nutrient medium compared to growth of bacteria in the untreated control group. Determined the minimum inhibitory concentration of antibiotic at which the growth of bacteria can be Engibarov up to 90% (MIC90µg/ml). The measurement MIC90conducted c by way of microrasbora nutrient medium in accordance with the document of the Institute of clinical and laboratory standards USA [Clinical and Laboratory Standards Institute Document. (2000) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically-Fifth Edition: M7-A5. CLSI, Villanova, PA].

1) Bacteria, under uraemia test.

Antibacterial activity was determined against 14 bacterial species, including metitillinciuvstivenyStaphylococcus aureus(MSSA), metitsillinrezistentnyeStaphylococcus aureus(MRSA), vancomycinresistantEnterococcus,(VRE), intolerability and vancomycinresistantEnterococcus faecalis(LVRE),Haemophilus influenzaeandMoraxella catarrhalis(S. aureus, S. aureusMR, S. epidermidis, S. epidermidisMR, E. faecalis E. faecalisVanAE. faecalisVanA LRE. faeciumVanA, E. faecium, E. coli, P. aeruginosa, K. pneumoniae, H. influenzaeandM. catarrhalis). Results for MIC90in regard to the most important two bacteria, MRSA and LVRE, shown in table 1.

2) Preparation of the test connection

Compound (compound 1-106, that is derived oxazolidinone synthesized in examples 1-106) was dissolved in DMSO at a concentration of 10240 μg/ml and serially diluted two times with DMSO. Compound in a solution of DMSO then diluted 20 times with sterile distilled water. The final concentration of the test compound in antibacterial incubations ranged from 0,0625 up to 128 µg/ml Final concentration of DMSO, which was used as an aid, was 2.5% (by volume). Linezolid (chemical formula (B) used in the link quality comparison. The results of antibacterial activity of COI the subjects of the compounds listed in table 1.

[Chemical formula B]

8
Table 1
Antibacterial activity (MIC90µg/ml) of compounds represented by chemical formula 1
Connection.MRSA1LVRE2Connection.MRSA1LVRE2Connection.MRSA1LVRE2
Linezolid2323628720,52
1183728730,06252
2216384740,252
3283928750,252
4184028760,52
5184124770,54
62842832780,54
718 43232798>64
84164486480216
90,58451481116
104324621682232
1118472883116
12 2848416840,516
134164918850,516
142850216860,58
15485114870,58
16128>1285221688 0,58
1718530,58890,58
18416540,549028
190,545528910,58
201664564892164
2124570,25 293132
2216128580,25494164
233264590,5295116
24216600,25296216
25432610,54970,58
2616 64620,0625298116
27464630,5499232
2821664281000,532
290,54650,54101132
3014660,541020,25 4
3118670,541030,2516
32832680,252104232
332869281050,516
340,5470141060,516
3528710,5 4
1. methicillin-resistantStaphylococcus aureus
2. linezolid-resistant and vancomycin-resistantEnterococcus faecalis

As can be seen from table 1, derived oxazolidinone of the present invention showed potent antibacterial activity against some gram-positive bacteria that are resistant to existing antibiotics, such as metitsillinrezistentnyeStaphylococcus aureusand vancomycinresistantEnterococcus faecalisat much lower concentrations compared with the connection compare linezolid. Although table 1 is not shown, but they were also effective against various gram-positive bacteria, and some of them were effective against gram-negative bacteria such asHaemophilus influenzae, Moraxella catarrhalis. In particular, as they show high antibacterial activity against linezolidresistanceEnterococcus faecalisthey may be effective against intolerability of bacteria that constantly apply now.

Accordingly, it is obvious that the derivative oxazolidinone of the present invention can be used as antibiotics, with the wide spectrum of antibacterial action against gram-positive bacteria.

[Test example 2 determination of the solubility in water

Determined solubility in water methanesulfonate (MSA) of representative compounds among the derivatives of oxazolidinone chemical formula 1. Linezolid chemical formula B used in the link quality comparison. The results are shown in table 2.

Determination of solubility was performed using the method1H NMR in accordance with the following method. First, methanesulfonate (100 mg) of the compounds were added to the D2O (0.5 ml). After preparation of saturated solution by vigorous shaking for 30 minutes, the solution was filtered and took from it an aliquot of 0.3 ml was Added thereto a solution of compound comparison (0.3 ml) (In this example, tests used DMSO, diluted with D2O) with a precisely known concentration. From1H NMR spectrum of the solution was calculated by the integral ratio of the peak sample to the peak of comparison (DMSO). As the concentration of the reference solution is known, from the integral relations can be used to calculate the number of moles of the sample. Then, calculate the solubility of the sample.

Table 2
The solubility of methansulfonate in the water
ConnectionLinezolid 838994
Solubility (mg/ml)
(solubility in %)
3
(0,3%)
117
(12%)
129
(13%)
136
(14%)

As can be seen from the table, the solubility of the compounds represented by chemical formula 1, in water is more than 10%, because they can be prepared in the form of salts. In contrast, the solubility of linezolid in water is only 0.3%. In other words, the solubility of the compounds of the present invention in water up to 50 times higher than the solubility of linezolid. This advantage allows you to prepare on the basis of the compounds of the present invention antibiotics that can be administered orally or intravenously in bolus that is not feasible for linezolid. In addition, because they are effective against linezolid-resistant bacteria, and also against MRSA and VRE, based on them can be made unique in its properties antibiotics that can replace linezolid.

[Test example 3] Cytotoxicity and inhibition of MAO (monoamine oxidase)

1) Determination of cytotoxicity by analysis using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)

Analysis using MTT is the number of the defective colorimetric determination of viable mammalian cells and cell proliferation. It is based on restoring tetrazolium salt MTT using mitochondrial succinate-dehydrogenase of viable cells with the formation of a blue product formazan. The analysis allows to evaluate cellular respiration and the amount of product formazan for living cells present in the culture. For this test the cells of the Chinese hamster ovary (CHO-K1) were obtained from the American type culture collection (ATCC (USA)). Parisienne CHO cells were isolated from the flasks with culture by treatment with a solution of trypsin-EDTA, and were sown in 96-well-microtiter plate at 5000 cells per well. After culturing for 24 hours in an incubator at 37°C and 5% CO2the cells were processed using derivatives oxazolidinone according to the present invention, synthesized in the above examples, at 7 different concentrations. After further culturing for a further 48 hours in the incubator at 37°C and 5% CO2, was added to each well 15 μl of MTT solution with a concentration of 5 µg/ml Cells additionally incubated in the incubator at 37°C and 5% CO2within about 2 hours. Then the culture medium was removed and added to each well 100 μl of DMSO solution. After shaking the microplate for 30 minutes and measuring the absorption at 550 nm using a tablet reader Spectramax plus 190 (Molecular Devices, USA). Reduced the f absorption bands, processed by the connection, in comparison with the untreated control group is a sign of decreased viability of the cells, which allows to evaluate the cytotoxicity of the compounds. After calculation of the percent absorption at different concentrations compared with the control group using the statistical data GraFit (version 5.0.12)supplied by the company Erithacus Software, has been calculated value CC50the concentration of the compounds according to the present invention, in which cell proliferation is reduced by 50%.

2) Inhibition of MAO

It is known that linezolid acts as a nonselective acting reversible inhibitor of monoamine oxidase, and can apparently interact with adrenergic or serotonergic drugs. Synthesized in examples derived oxazolidinone according to the present invention were tested for inhibition of monoamine oxidase A (MAO A) and monoamine oxidase B (MAO B). Set for the analysis of MAO-GLO was set by the company Promega (USA), and the enzymes MAO A and MAO B were purchased from the company Sigma-Aldrich (USA). From the aldehyde product obtained by the action of the enzyme MAO on the amino group of the substrate, obtain methyl ester of luciferin. Then add the reagent for the detection of luciferin for inactivation of the enzyme MAO. The esterase and Luc is Peraza, included in the reagent oxidizes luciferin, resulting emitted light. Light emission register for measuring the activity of MAO. Light emission was detected using LEADseeker instrument (Amershan Bioscience, Sweden). The MAO activity was measured in the presence of compounds according to the present invention 3.9 to 500 μm and compared with an untreated control group. Linezolid used in the link quality comparison. For measuring the activity of compounds represented by chemical formula 1, when MAO inhibition may be determined by the size of the IC50the concentration of compounds in which the enzyme activity is inhibited by 50% (This value is associated with the inhibition constant Ki). The concentration of inhibitor at which the rate of hydrolysis of the substrate is reduced by 50% (i.e. the value of the IC50) can be determined from the graph in logarithmic coordinates relative rate of hydrolysis (compared to eingeborenen control group) on the concentration of the compounds of chemical formula 1.

The effect of MAO inhibition by the compounds of chemical formula 1 was measured by determining the inhibition constants Ki.

Equation 1

Ki=IC50/{1+([S]/Km)}

In equation 1, Kmis a constant of Michaelis-Menten, that is the substrate concentration at which SC is the rate of the enzymatic reaction is half of the maximum, and IC50is the concentration of inhibitor at which the rate of hydrolysis of the substrate is reduced by 50%. The value of the IC50was determined by plotting in logarithmic coordinates relative rate of hydrolysis (compared to eingeborenen control group) on the concentration of the compounds of chemical formula 1. Used the statistical data GraFit (version 5.0.12)supplied by the company Erithacus Software.

Test results of cytotoxicity and inhibition of MAO for representative compounds of the derivatives oxazolidinone chemical formula 1, are given in table 3.

Because the connection is comparing linezolid show significant inhibitory activity against the enzymes MAO and there is a possibility that it causes toxic or other side effects, many efforts have been made to search for a connection that does not have the effect of MAO inhibition. In General, compounds based on oxazolidinone demonstrate a strong effect of inhibition of MAO that they can be used as MAO inhibitors. However, although the MAO inhibitor and may provide a therapeutic effect for those who need it, but when it is used as an antibiotic, it can lead to toxic or other side effects. Accordingly, the definition of effect in which euromania MAO for antibiotics based on oxazolidinone is certainly mandatory, and antibiotic characterized by less effect of MAO inhibition, is preferred.

Linezolid and TR-700 chemical formula D, developed by Trius Therapeutics, used as compounds of the comparison. Since TR-701 is a prodrug TR-700, used TR-700.

Table 3
Tests for cytotoxicity and inhibition of MAO
CC50(µm)MAOA (µm)MAOB (µm)
Linezolid>1307,94,3
TR-70028<2,06,1
53>1302458
83>13019207
89>1305,2>250
94>1304 176
102>1308984

As can be seen from table 3, TR-700 shows a significant amount of a cytotoxic effect and a powerful inhibitory effect on MAO A and MAO B. In contrast, most of the compounds of the present invention are safe from the point of view of cytotoxicity and are 10 times less inhibitory effect than the TR-700.

Since the compounds of the present invention exhibit high solubility and high antibacterial activity with less toxicity, they are extremely promising candidates for use as antibiotics next generation.

The present application contains subject matter related to a patent application in Korea No. 10-2008-0093712 registered by the intellectual property Office Korea on September 24, 2008, the contents of which is given here by reference.

Although the present invention is described with specific embodiments, for specialists in this field is obvious that can be done various changes and modifications without deviating from the essence and scope of the invention defined in the following claims.

About Islena applicability

As described above, the new derivative oxazolidinone of the present invention showing the spectrum of antibacterial action against resistant bacteria, including methicillin-resistantStaphylococcus(MRSA), low toxicity, and high antibacterial activity against bacteria that are resistant to existing antibiotics, such asStaphylococcus aureusandEnterococcus faecalisin particular high antibacterial activity against linezolidresistanceEnterococcus faecalis. Therefore, they can effectively be used as antibiotics 2nd generation on the basis of oxazolidinone. In addition, derivatives oxazolidinone with a group of cyclic amidoxime or group of cyclic hamidrasha according to the present invention can be easily prepared dosage form for oral administration, or injections, as they have a higher solubility in water than other existing connections oxazolidinone.

1. New derivative oxazolidinone represented by chemical formula 1, its hydrate, MES, isomer or pharmaceutically acceptable salt:

where R1represents hydrogen or (C1-C6) alkyl;
Y represents-O - or-N(R2)-;
R2represents hydrogen, cyano, (C1-C6) alkyl, (C3-C6)-the CEC is alkyl, - (CH2)mOC (=O)R11, -(CH2)mC (=O)R12, -(CH2)mC (=S)12or-SO2R13where alkyl, R2may be optionally substituted with one or more substituent (substituents), selected from the group consisting of (C2-C6) alkenyl, (C2-C6) quinil, halogen, halogen (C1-C6) alkyl, (C1-C6) alkyl (C2-C6) quinil, hydroxyl, (C3-C6)cycloalkyl and cyano; R11-R13independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C3-C6) cycloalkyl or (C1-C6) alkylsulphonyl, where alkyl, alkoxy, or amino, R11-R13can be optionally substituted with one or more substituent (substituents), selected from halogen, amino, hydroxyl, cyano, (C1-C6)alkyl, (C1-C6)alkylcarboxylic and hydroxy(C1-C6)alkyl;
m represents an integer from 0 to 2;
X1and X2independently represent hydrogen or fluorine;
R represents-O-, -NH - or five-membered aromatic heterocycle with the following structure:

Q is hydrogen, -C(=O)R3, -C(=S)R4, -C(=O)NR5R6C(=S)NR5R6or five-membered aromatic heterocycle with what structure, selected from the following structures:

R3and R4independently represent hydrogen, (C1-C6)alkyl or (C1-C6) alkoxy;
R5and R6independently represent hydrogen or (C1-C6) alkyl;
R7is hydrogen; and
alkyl, R3and R4may be optionally substituted with one or more substituent (substituents), selected from the group consisting of cyano and halogen.

2. New derivative oxazolidinone according to claim 1, which is represented by chemical formula 2 or 3, its hydrate, MES, isomer or pharmaceutically acceptable salt:


where R2, X1X2P and Q are such as defined in claim 1.

3. New derivative oxazolidinone according to claim 2, which is represented by chemical formula 4, 5, or 6, its hydrate, MES, isomer or pharmaceutically acceptable salt:

where R2represents hydrogen, cyano, (C1-C6)alkyl, (C3-C6-cycloalkyl, -(CH2)mOC (=O)R11, - (CH2)MC (=O)R12, -(CH2)mC(=S)R12or-SO2R13where alkyl, R2may be optionally substituted with one or more substituent (substituents), selected from the group consisting of (C2 -C6)alkenyl, (C2-C6)quinil, halogen, halogen(C1-C6)alkyl, (C1-C6)alkyl (C2-C6)quinil, hydroxyl, (C3-C6)cycloalkyl and cyano; R11-R13independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C3-C6) cycloalkyl, or (C1-C6-alkylaryl, and alkyl, alkoxy or amino, R11-R13can be optionally substituted with one or more substituent (substituents), selected from halogen, amino, hydroxyl, cyano, (C1-C6)alkyl, (C1-C6)alkylcarboxylic and hydroxy (C1-C6)alkyl;
m represents an integer from 0 to 2;
R represents-O-, -NH - or five-membered aromatic heterocycle with the following structure:

Q is hydrogen, -C(=O)R3, -C(=S)P4, -C(=O)NR5R6, -C(=S)NR5K6or five-membered aromatic heterocycle with a structure selected from the following structures:

R3and R4independently represent hydrogen, (C1-C6)alkyl or (C1-C6)alkoxy;
R5and R6independently represent hydrogen or (C1-C6)alkyl; and alkyl, R3and R4 may be optionally substituted with one is about or more Deputy (deputies), selected from the group consisting of cyano and halogen.

4. New derivative oxazolidinone according to claim 2, which is represented by chemical formula 7, 8 or 9, its hydrate, MES, isomer or pharmaceutically acceptable salt:

where R represents-O-, -NH - or five-membered aromatic heterocycle with the following structure:

Q is hydrogen, -C(=O)R3, -C(=S)R4, -C(=O)NR5R6C(=S)NR5R6or five-membered aromatic heterocycle with a structure selected from the following structures:

R3and R4independently represent hydrogen, (C1-C6)alkyl or (C1-C6)alkoxy;
R5and R6independently represent hydrogen or (C1-C6) alkyl; and alkyl, R3and R4may be optionally substituted with one or more substituent (substituents), selected from the group consisting of cyano and halogen.

5. New derivative oxazolidinone according to claim 3, which is selected from the following compounds, its hydrate, MES, isomer or pharmaceutically acceptable salt:






6. New derivative oxazolidinone according to claim 4, which is selected from the following compounds, its hydrate, MES, isomer or pharmaceutically acceptable salt:

7. Pharmaceutical antibiotic composition comprising as active ingredient new derivative oxazolidinone according to any one of claims 1 to 6, its hydrate, MES, isomer or pharmaceutically acceptable salt.



 

Same patents:

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention is a 6-10-member aryl selected from phenyl, naphthyl, tetrahydronaphthalenyl, indanyl or a 6-member heteroaryl containing 1-2 N atoms, selected from pyridyl or pyrimidinyl, where the aryl and heteroaryl groups can be unsubstituted or substituted with 1-3 substitutes selected from a group consisting of C3-6-cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, halogen atom, C1-7-alkyl, C1-7-alkoxy, oxazolyl, piperidin-1-yl, or C1-7-alkyl, substituted with a halogen atom, or represents phenyl, where at least one hydrogen atom is substituted with deuterium or tritium; R2 is a hydrogen atom, C1-7-alkyl or is benzyl, unsubstituted or substituted C1-7-alkoxy or halogen atom; or R1 and R2 together with a N atom with which they are bonded form 2,3-dihydroindol-1-yl or 3,4-dihydro-1quinolin-1-yl. The invention also relates to a method of producing compounds of formula and to a pharmaceutical composition having high affinity for the TAAR1 receptor.

EFFECT: compounds of formula (I), having high affinity for the TAAR1 receptor.

29 cl, 4 dwg, 1 tbl, 183 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

EFFECT: producing the compounds and compositions for preventing and treating neurological and mental disorders and diseases with involved orexin receptors.

13 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel cyanoisoquinoline derivatives of formula I , where R is selected from a group comprising hydrogen and C1-C10 alkyl, R1, R2, R3 and R4 are independently selected from a group comprising hydrogen, halogen, hydroxy, C1-C10 alkyl, substituted with 1-3 halogen atoms or C6-C14 acryl, C6-C14 aryl, -OR7, -SR7 and -SO2R7, where R7 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14 aryl, C3-C10 cycloalkyl, C6-C14 aryl and C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are optionally substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino and C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, and R5 and R6 are independently selected from a group comprising hydrogen and C1-C3 alkyl, or pharmaceutically acceptable salts thereof. The invention also relates to novel cyanoquinoline derivatives of formula II , where R31, R32, R33 and R34 are independently selected from a group comprising hydrogen, hydroxy, halogen, C1-C10 alkyl substituted with 1-3 halogen atoms or with C6-C14 aryl, C6-C14 aryl, -OR37, -SR37 and -SO2R37, where R37 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14aryl, C3-C10 aryl, C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, R35 denotes hydrogen or methyl, or pharmaceutically acceptable salts thereof. The invention also relates to specific cyanoisoquinoline compounds, a pharmaceutical composition based on the compound of formula I, a hypoxia-inducible factor (HIF) hydroxylase inhibiting method, a method of treating, preventing or slowing down development of a condition associated with hypoxia-inducible factor (HIF), a condition associated with erythropoietin (EPO), anaemia, based on use of the compound of formula I.

EFFECT: obtaining novel cyanoisoquinoline compounds having useful biological properties.

42 cl, 1 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I): wherein n means 1 or 2, X means an oxygen atom, a sulphur atom or NH, R1 means a side group of natural α-amino acid or its homologues or isomers specified in hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methyl-propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxy-ethyl, carboxymethyl, 2-carboxyethyl, carbamoyl-methyl, 2-carbamoyl ethyl a, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 3-guanidinopropan-1-yl, benzyl or 4-hydroxybenzyl, R2 means hydrogen or methyl, R3 means hydrogen, or R1 and R3 are coupled together by the group (CH2)3- or (CH2)4- and together with nitrogen and carbon atoms whereto attached form a five- or six-member ring, as well to their salts, solvates and salt solvates.

EFFECT: preparing compounds for treating and/or preventing the diseases, first of all thromboembolic diseases.

2 cl, 2 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine of formula (I) in which R1 denotes a methyl group, R2 denotes a R21NR22 group, where R21 denotes an ethyl group which is substituted with an ethoxycarbonyl group, and R22 denotes a pyridin-2-yl group, R3 denotes an n-hexyloxycarbonyl group, where at step (a) phenyldiamine of formula (II) where R1 and R2 assume values given for formula (I), which reacts with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, to obtain a product of formula (III) where R1 and R2 assume values given for formula (I), which is hydrogenated at temperature from 30 to 60°C at hydrogen pressure from 1 to 10 bar, over palladium on activated charcoal (Pd/C) in a mixture of tetrahydrofuran and water, and then, without any preliminary extraction of the hydrogenation product, the obtained compound of formula (I), in which R3 denotes hydrogen, in the presence of potassium carbonate reacts with a compound of formula (IV) R3-X (IV), where R3 assumes values given for formula (I), and X denotes a suitable splitting group.

EFFECT: simple method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine.

3 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved preparing method.

15 cl, 1 dwg, 4 tbl, 5 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).

EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.

36 cl, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes genetically modified Shigella bacteria, which have deletions or gene modifications: virG(icsA) in combination with two or more genes setAB(shET 1), senA(shET2), senB(shET2- 2), stxAB and msbB2. Obtained bacteria have three or more deletions in identified genes and can be used as vaccine strains against dysentery and diarrhea, caused by Shigella. Constructed are the following specific vaccine strains: WRSS3 (ΔsenA, ΔsenB, ΔvirG, ΔmsbB2), WRSf2G15 (ΔvirG, ΔsetAB, ΔsenA, ΔsenB, ΔmsbB2) and WRSd5 (ΔvirG, ΔstxAB, ΔsenA, ΔsenB, ΔmsbB2), on the basis of which created are immunogenic compositions, live and invasive vaccines and sets, aimed at prevention and treatment of said diseases.

EFFECT: vaccine strain by invention is safer and when used will attenuate or eliminate symptoms of high temperature and diarrhea in people.

14 cl, 12 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically dermatovenerology. Baneocin ointment is used as an agent for topical treatment of infiltrative-suppurant trichophytosis capitis for 48 hours with underlying conventional systemic antimycotic therapy. The agent shows manifested antimicrobial, anti-inflammatory, resolving and regenerative effect.

EFFECT: invention extends the range of topical products for treating infiltrative-suppurant trichophytosis capitis.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of [1,8]naphthyridine, described by formula I(a), where Z represents -NR41-; A represents phenyl; each R10, R17, R31, R33, R35 and R41 in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C1-C6haligenalkyl, phenyl, C3-C6cycloalkyl, -Ls-O-Rs, -Ls-C(O)Rs, -Ls-C(O)ORs and LE-Q-LE-(morpholine); X is selected from group, consisting of bond, -Ls-O-, -Ls-S- and -Ls-C(O)N(Rs)-; R22 is selected from group, consisting of halogen, C1-C6alkyl, phenyl, and phenyl C1-C2alkyl, and, optionally, is substituted with one R26, where R26 in each case is independently selected from group, consisting of halogen, hydroxy, nitro, C1-C6alkyl, -Ls-OSO2Rs; Y is selected from group, consisting of bond, -Ls-O-, -Ls-S(O)-, -Ls-C(O)N(R15) - and -Ls-S-, where R15 represents hydrogen; R50 represents -L1-A1, where A1 is selected from group, consisting of C1-C6alkyl and phenyl and L1 is selected from group, consisting of bond and C1-4alkylene, where A1 is optionally substituted with from one to three R30, and R30 in each case is independently selected from group, consisting of halogen, hydroxy, amino, azido, C1-C6alkyl, -Ls-O-Rs, -Ls-C(O)ORs, -LS-N(RSRS), -Ls-C(=NRs)RS', -Ls-C(O)N(RsRsO, -Ls-N(Rs)C(O)Rs', -LE-Q-LE'- (phenyl or naphthyl) and -LE-Q-LE'-(M5-M6heterocyclyl, which represents pyridine, pyrazine, pyrrolodine, furan, thiophene, piperidine); Ls in each case is independently selected from group, consisting of bond and C1-4alkylene; each RS and Rs' in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C3-6alkenyl, C1-6alkoxy, C1-6alkoxyC1-C6alkyl and C1-6alkoxycarbonylC1-C6alkyl; each LE and LE' in each case is independently selected from group, consisting of bond, C1-4alkylene, -C1-4alkylene-NC(O)-C1-4alkylene-; Q in each case is independently selected from group, consisting of bond, -O-, -N(Rs)C(O)-, -C(O)N(Rs)- and -O-SO2-; each R17 and R30 in each case is optionally independently substituted with from one to three substituent(s), selected from group, consisting of halogen and hydroxy; and each heterocyclyl group in -LE-Q-LE'-(M5-M6heterocyclyl) in each case is optionally independently substituted with at least one or two substituents, selected from group, consisting of hydrogen, hydroxy, C1-C6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, phenyloxy and phenylC1-6alkoxycarbonyl, or to their pharmaceutically acceptable salts. Invention also relates to compounds of formula II(a), pharmaceutical composition based on claimed compounds, application of claimed compounds, method of inhibition of HCV virus replication, method of treating HCV infection.

EFFECT: obtained are novel derivatives, useful in treatment of HCV infection.

FIELD: medicine.

SUBSTANCE: invention refers to compounds for treating hepatitis of formulae or wherein Ry represents alkyl or hydroxyalkyl; each Ra and Rb independently represents hydrogen, alkyl, arylalkyl or cycloalkyl; or together with nitrogen atom whereby substituted, form morpholine, piperidine or pyrrolidine; and each R2 and R3 are independently H, or R2 and R3 are bound, thereby forming a cyclic group by an alkyl, ester or carbamate bind. There are presented new biologically active compounds.

EFFECT: higher efficacy of the composition.

20 cl, 28 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: subcutaneous composition for treating microbial infection in an animal contains: a) fluorfenicol approx. 300 mg/ml; b) flunixin or one of its pharmaceutically acceptable salts approx. 16.5 mg/ml; and c) aprotonic polar solvent approx. 5 to approx. 80% specified in a group consisting of N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 2-pyrrolidone, formal glycerol and their combination. A method of treating an animal's disease specified in a group consisting of cattle respiratory disease, pig's respiratory disease, coffin rot, acute mastitis, acute epidemic conjunctivitis, metritis and enteritis in an animal involving the stage of the subcutaneous introduction of a therapeutically effective amount of said composition into the animal requiring such treatment.

EFFECT: higher clinical effectiveness in said diseases.

17 cl, 3 tbl, 7 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: during phases of regeneration and epithelisation, a wound surface is coated with a dressing impregnated with an ointment of the following composition, wt %: organic-silicon glycerohyrogel - 95.25, ciprofloxacin - 0.2, oxytocin - 4.55.

EFFECT: method provides faster regenerative processes at the II and III phases of the wound process, prevented the onset of persistent infection and purulent-septic complications, reduced length of treatment.

2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is a covalent conjugate of interferon with a polytriethylenediamine N-oxide derivative, and can be used to produce antiviral preparations, having antiviral and immunotropic activity. The compound is a novel stable antiviral interferon preparation with prolonged action.

EFFECT: owing to detoxicant and antioxidant properties of the carrier, the preparation has a wide range of pharmacological applications.

6 cl, 1 dwg, 2 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to gynecology. Simultaneously with intravenous introduction of antibacterial preparations performed is ultrasound low-frequency impact dynamically distributed on external surface of uterus area. Impact is performed with the following parameters: frequency 34-46 kHz and amplitude 4-12 mcm. Rate of dynamic distribution of impact is directly proportional to its amplitude.

EFFECT: method contributes to normal course of puerperium, prevention of local infectious complications.

2 cl, 1 dwg

Up!