EP1324984A1

EP1324984A1 - Butenolide and pentenolide derivatives as kinase inhibitors

Info

Publication number: EP1324984A1
Application number: EP01974335A
Authority: EP
Inventors: Barbara Beck; Alexander Dömling
Original assignee: Morphochem AG
Current assignee: Morphochem AG
Priority date: 2000-10-11
Filing date: 2001-10-11
Publication date: 2003-07-09
Also published as: WO2002030892A1; US20040102488A1; AU2001293869A1

Abstract

The invention relates to novel compounds of general formula (I), a method for the production thereof, prodrugs, pharmacologically acceptable salts and medicinal compositions containing the same as active ingredients, and the use of said compounds as kinase inhibitors.

Description

BUTENOLIDE AND PENTENOLIDE DERIVATIVES AS KINASE INHIBITORS

The present invention describes new butenolide and pentenolide derivatives, processes for their preparation and their use as medicaments, in particular as kinase inhibitors.

The compounds according to the invention are kinase inhibitors and therefore in a wide variety of inflammatory diseases and also diseases caused by autoimmune reactions, such as e.g. rheumatoid arthritis, asthma, MDR (multiple drug resistance), COPD (chronic obstructive pulmonary disease) and ARDS (acute respiratory distress syndrome), and also for cancer, stroke, Alzheimer's, osteoarthritis, lung disease, septic shock, angiogenesis and dermatitis and for in -vivo stimulation of nerve growth, in-vivo inhibition of scar tissue formation and / or in-vivo reduction of secondary damage of great interest. Their effect allows the use of the active substances and pharmaceutical compositions according to the invention as chemotherapeutic agents in human and veterinary medicine.

Another aspect of the present invention is to provide a new process for the preparation of these new butenolide and pentenolide derivatives, which takes place as far as possible in a multi-component reaction and is widely applicable. Multi-component reactions are used in particular in the pharmaceutical industry for the production of substance libraries to find lead structures (A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300- 3344). The present invention comprises compounds of the general formula (I):

wherein

X is an oxygen atom or a group of formula NR6;

n is 0 or 1;

U is CH or COH;

V is a group of the formula CR2R3 or U-V together is one

Group of the formula -C = CR2-;

I

Rl is an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or a heteroaryl radical;

R2 is a hydrogen atom, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical;

R3 is a hydrogen atom, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical; R4 is a hydrogen atom, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical;

R5 is a hydrogen atom, a halogen atom, a hydroxy group, an alkyl, heteroalkyl, aryl, hetero-aryl, cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical;

R6 is a hydrogen atom, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or a hetero-aralkyl radical;

or R2 and R3 or R2 and R4 together form part of a cycloalkyl, heterocycloalkyl, aralkyl or one

Are heteroaralkyl ring systems;

or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof.

In the present invention, terms or parts of terms are defined as follows in the description, claims, and summary:

The term alkyl refers to a saturated or at least partially unsaturated (ie, for example alkenyl or alkynyl), straight-chain or branched hydrocarbon group which has 1 or 2 to 20 carbon atoms, preferably 1 or 2 to 12 carbon atoms, particularly preferably 1 or has 2 to 6 carbon atoms, for example the methyl, ethyl, isopropyl, isobutyl, tert-butyl, n-hexyl, 2, 2-dimethylbutyl, n-octyl, allyl, isoprenyl or hex-2-enyl group.

The term heteroalkyl refers to an alkyl group as defined above, in which one or several carbon atoms (eg the saturated or unsaturated chain) are replaced by at least one oxygen, nitrogen, phosphorus or sulfur atom (preferably oxygen or nitrogen), for example an alkyloxy group such as methoxy or ethoxy, or a methoxymethyl, nitrile , Methylcarboxyalkyl ester, carboxy alkyl ester or 2,3-dioxyethyl group. The term heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B. acyl, acyloxy, carboxyalkyl, carboxyalkyl esters, for example methyl carboxyalkyl ester, carboxyalkylamide, alkoxycarbonyl or alkoxycarbonyloxy.

The term cycloalkyl or cyclo refers to a saturated or partially unsaturated cyclic group which has one or more rings with altogether 3 to 14 carbon atoms, preferably 3, 4, 5 or 6 to 10 carbon atoms, e.g. the cyclopropyl, cyclohexyl, tetralin or cyclohex-2-enyl group.

The term heterocycloalkyl or heterocyclo refers to a cycloalkyl group as defined above, in which one or more carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom and can be used, for example, for the piperidine, morpholine, N-methylpiperazine or N-phenylpiperazine group.

The term aryl or Ar refers to an aromatic group with one or more rings with a total of 5 to 14 carbon atoms, preferably 5 or 6 to 10 carbon atoms, for example a phenyl, naphthyl, 2-, 3- or 4-methoxyphenyl- , 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxyphenyl group. The term heteroaryl refers to an aryl group as defined above, in which one or more carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom, for example the 4-pyridyl, 2-imidazolyl, 3- Pyrazolyl and isoquinolinyl group.

The terms aralkyl or heteroaralkyl refer to groups which, according to the above definitions, encompass both aryl or heteroaryl as well as alkyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl ring systems, e.g. the tetrahydroisoquinolinyl, benzyl, 2- or 3-ethyl-indolyl or 4-methylpyridino group.

The terms alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl according to the above definitions also refer to groups in which one or more hydrogen atoms of such groups by fluorine, chlorine, bromine or iodine atoms or OH SH, NH ₂ or N0 ₂ groups are replaced. These terms also refer to groups which are substituted with unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups.

Compounds of formula (I) may contain one or more centers of chirality due to their substitution. The present invention therefore encompasses both all pure enantiomers and all pure diastereomers, and also their mixtures in any mixing ratio, and also all tautomers of the compounds described. Compounds of the general formula (I) in which X is an oxygen atom are preferred.

Further preferred are compounds of the general formula (I) wherein X is a group of the formula NR6.

Also preferred are compounds of the general formula (I) in which U is CH.

Also preferred are compounds of the general formula (I) in which U is COH.

Also preferred are compounds of the general formula (I) in which n is 0.

Compounds of the general formula (I) in which n is 1 are further preferred.

Again preferred are compounds of the general formula (I) in which U-V together are a group of the formula -C = CR2-.

Also preferred are compounds of the general formula (I), where R5 is not a nitrile group or a group of the formula R'S0 ₂ -, where R 'is an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Is aralkyl or a heteroaralkyl radical.

For example, the residues can have the following meanings:

R2 hydrogen, aryl such as phenyl, heteroaryl R3 hydrogen, aryl such as phenyl, heteroaryl

R4 aryl such as phenyl, heteroaryl, methyl R5: hydrogen, aryl such as phenyl, butenyl, fluoro-, chloro- or methoxyphenyl

Examples of pharmacologically acceptable salts of the compounds of the formula (I) are salts of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid acid, maleic acid and salicylic acid. Compounds of formula (I) can be solvated, in particular hydrated. The hydration can e.g. occur during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I).

The pharmaceutical compositions according to the present invention contain at least one compound of the formula (I) as active ingredient and optionally excipients and / or adjuvants.

The pro-drugs, which are also the subject of the present invention, contain a compound of formula (I) and at least one pharmacologically acceptable protective group which is split off under physiological conditions, e.g. an alkoxy, aralkyloxy, acyl or acyloxy group, e.g. an ethoxy, benzyloxy, acetyl or acetyloxy group.

A compound of formula (I) or a pro-drug thereof can be used to inhibit kinases or to treat and / or prevent diseases mediated by kinase activity. In particular, the compounds according to the invention can be used in a wide variety of inflammatory diseases and by autoimmune reactions diseases such as rheumatoid arthritis, asthma, MDR (multiple drug resistance), COPD (chronic obstructive pulmonary disease) and ARDS (acute respiratory distress syndrome), as well as cancer, stroke, Alzheimer's disease, osteoarthritis, lung disease, septic shock, angiogenesis and dermatitis and for in vivo stimulation of nerve growth, in vivo inhibition of scar tissue formation and / or in vivo reduction of secondary damage. Their effect allows the use of the active substances and pharmaceutical compositions according to the invention as chemotherapeutic agents in human and veterinary medicine.

The therapeutic use of the compounds of formula (I), their pharmacologically acceptable salts or solvates and hydrates as well as formulations and pharmaceutical compositions is also within the scope of the present invention.

The present invention also relates to the use of these active compounds for the production of medicaments for the prevention and / or treatment of diseases which are mediated by kinase activity. In general, compounds of formula (I) are administered using known and acceptable modes, either individually or in combination with any other therapeutic agent. Such therapeutically useful agents can be administered in one of the following ways: orally, for example as dragées, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, for example as an injectable solution; rectally as suppositories; by inhalation, for example as a powder formulation or spray, transdermally or intranasally. For the production of such tablets, pills, semi-solids, coated tablets, dragees and hard gelatin capsules, the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic medicament carriers, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, dry skimmed milk and the like For the production of soft capsules, drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols can be used. For the production of liquid solutions and syrups, drug carriers such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerin, vegetable oils, petroleum, animal or synthetic oils can be used. For suppositories, drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols can be used. Compressed gases suitable for this purpose, such as oxygen, nitrogen and carbon dioxide, can be used for aerosol formulations. The pharmaceutically usable agents can also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for changing the osmotic pressure, buffers, coating additives and antioxidants.

Combinations with other therapeutic agents can include other agents that are commonly used to prevent and / or treat diseases mediated by kinase activity.

According to the invention, compounds of the formula (I) in which X is an oxygen atom can be prepared by reacting compounds of the general formulas (II), (III) and (IV),

the residues are as defined above.

According to the invention, compounds of the formula (I) in which X is a group of the formula NR6 can be prepared by reacting compounds of the general formulas (II), (III) (IV) and (V).

The described procedure runs in two steps. The first step corresponds to a Passerini or Ugi reaction and the second step to an intramolecular Horner-Wittig-Emmons reaction. The two steps of the process can be carried out either separately or in a one-pot reaction.

If the reactions described above are carried out with the exclusion of 0 ₂ (for example under an N ₂ or argon atmosphere), compounds of the formula (VI) are obtained:

If the reactions described above are carried out in the presence of 0 ₂ , compounds of the general formula (VII) are obtained if neither R2, R3 nor R6 is a hydrogen atom:

In the case of R6 = H, the corresponding dihydropyridines are formed, which are also the subject of the present invention.

If R2 is a hydrogen atom and n is 1, compounds of the general formula (VIII) are obtained in the reactions described above:

The reactions in aprotic solvents such as, for. B. dimethoxyethane, acetonitrile, dichloromethane, chloroform, toluene, benzene, diethyl ether or tetrahydrofuran, preferably carried out in ethers.

The reactions are further preferred in a temperature range from -80 to 120 ° C, more preferably from - 10 to 70 ° C, more preferably from 0 ° C to 25 ° C.

The second step is particularly preferred in the presence of alkali salts such as. B. LiCl, LiBr, Cs ₂ C0 ₃ or K ₂ C0 ₃ performed with lithium salts such as. B. LiCl are particularly preferred.

Furthermore, the second step of the reaction is alternatively or additionally in the presence of a base such as. B. sodium hydride, potassium tert-butoxide, n-butyllithium,

Lithium diisopropylamide, potassium carbonate / 18-crown-6, potassium hexamethyldisilazide (KHDMS) / 18-crown-6, triethylamine, diisopropylethylamine (DIPEA), diazabicycloundecene (DBU) or 4-dimethylaminopyridine (DMAP) or diazabicyclonones (DBN); preferably carried out a tertiary, basic amine.

Examples

Proton and carbon NMR spectra were measured in the specified solvent using a Mercury 400 spectrometer. The chemical shifts (δ) are given in ppm with respect to TMS as the internal standard. The electrospray ionization mass spectra (ESI) were recorded with an MSD (Hewlett-Packards HPLC 1100 supported electrospray MS instrument). The observed m / z ratios are given as [M + H] ⁺ or [M + Na] ⁺ signals. The products were purified by preparative chromatography with silica gel and ethyl acetate as the eluent. The purity was determined using a Hewlett-Packard LC 1100 system (YMC column, 2 mm x 50 mm, 2 μm ODSA, 220 and 254 nm; 0.6 ml / min., 6 min. Gradient from 90% H ₂ 0 to 10 % H ₂ 0 (0.5% CH ₃ COOH) vs. CH ₃ CN.). The retention time t _R in min. indicated at the wavelength 254 nm.

General work regulations:

General rule of the Passerini reaction:

2 mmol of the aldehyde (III) are suspended in 4 ml of diethyl ether and 2 mmol of the phosphonoacetic acid (IV) are added. The reaction mixture is allowed to stir for five minutes at room temperature. Now 2 mmol of the isocyanide (II) are added and the reaction mixture is stirred overnight at room temperature. The solvent is then removed on a rotary evaporator.

General regulation of the Ugi reaction: 2 mmol of the aldehyde (III) are dissolved in 4 ml of dichloromethane and 2 mmol of the amine (V) are added. 500 mg of 4 Å molecular sieve are added to this reaction mixture and the mixture is stirred at RT overnight. The molecular sieve is filtered off and the solution is concentrated. The residue is taken up in 2 ml of methanol and 2 mmol of the phosphonoacetic acid (IV) and 2 mmol of the isocyanide (II) are added. The reaction mixture is stirred overnight at room temperature. The solvent is drawn off and the Ugi product is purified by column chromatography.

General regulation of the Horner-Wittig-Emmons ring closure:

The reaction is optionally carried out under a nitrogen atmosphere. 1.5 mmol of the Passerini or Ugi product prepared above are dissolved in 60 ml of THF, mixed with 4.5 mmol of dry lithium chloride and 5 min. stirred at 0 ° C, whereby the salt dissolves completely. 15 mmol of triethylamine are added dropwise to this solution and a further 15 min. stirred at 0 ° C. The reaction mixture is then allowed to warm to room temperature and stirred for a further 4 h. The reaction mixture is filtered through a layer of silica gel and washed with 180 ml of ethyl acetate. The solvent is drawn off and the residue is recrystallized from ethyl acetate.

General regulations for the one-pot reaction of the Passerini variant:

The reaction is optionally carried out under a nitrogen atmosphere. 2 mmol of the aldehyde (III) are suspended in 4 ml of THF. 2 of the phosphonoacetic acid (IV) are added to this solution and 5 min. stirred at RT, giving a clear solution. To this Solution 2 mmol of the isocyanide (II) are added and the reaction mixture is stirred overnight at room temperature. 60 ml of THF and 4.5 mmol of lithium chloride are added to the reaction mixture and 5 min. stirred at 0 ° C. After the salt is completely dissolved, 15 mmol of triethylamine are slowly added dropwise and the mixture is stirred at 0 ° C. for a further 15 min. The solution is allowed to warm to RT and stirred for a further 4 h. The reaction mixture is filtered through a layer of silica gel and washed with 180 ml of ethyl acetate. The solvent is drawn off and the residue is recrystallized from ethyl acetate.

General regulations for the one-pot reaction of the Ugi variant:

The reaction is optionally carried out under a nitrogen atmosphere. 2 mmol of the aldehyde (III) are dissolved in 4 ml of dichloromethane and 2 mmol of the amine (V) are added. 500 mg of 4A molecular sieve are added to this reaction mixture and the mixture is stirred at RT overnight. The molecular sieve is filtered off and the solution is concentrated. The residue is taken up in 2 ml of methanol and 2 mmol of the phosphonoacetic acid (IV) and 2 mmol of the isocyanide (II) are added. The reaction mixture is stirred overnight at room temperature. The solvent is stripped off and the residue is taken up in 60 ml of THF, 4.5 mmol of lithium chloride are added and the mixture is stirred for 5 min. stirred at 0 ° C. After the salt is completely dissolved, 15 mmol of triethylamine are slowly added dropwise and the mixture is stirred at 0 ° C. for a further 15 min. The solution is allowed to warm to RT and stirred for a further 4 h. The reaction mixture is filtered through a layer of silica gel and washed with 180 ml of ethyl acetate. The solvent is drawn off and the residue is recrystallized from ethyl acetate. Example 1: Preparation of 5-oxo-3-phenyl-2, 5-dihydrofuran-2-carboxylic acid tert-butylamide

Molecular formula: Molar weight:

Yield:

HPLC-S (ESI-TOF): t _R , _{2S4 nm} = 3,359 min; m / z = 260 [M + H] ⁺ ; 282 [M + Na] ⁺

^ -NMR (CDC1 ₃ , 400 MHz): δ = 7.74 (m, 2H, al, a2, aromatic),

7.46 (m, 3H, bl, b2, c, aromatic), 6.31 (s, IH, (C) CH (CO)),

6.19 (broad s, IH, NH), 5.79 (s, IH, (C = 0) CH (C-O)), l, 29 (s, 9H, 3CH3)

¹³ C-NMR (CDC1 ₃ , 100 MHz): δ = 171.71 (CO), 165.68 (CO), 163.76 (CO), 131.68 (2CH, aromatic), 129.37 (C, aromatic), 128.61 (2CH, aromatic), 128.52 (CH, aromatic),

113.05 (C = CH (CO)), 81.40 ((CO) CH-O), 51, 92 ((CH) (Phe) C = CH), 28.38 (3CH3, tBu)

Example 2: Preparation of 3- (4-hydroxyphenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid (7-isopropyl-l, 4a-dimethyl-

1, 2, 3, 4, 4a, 9, 10, 10a-octahydro-phenanthrene-l-ylmethyl) -amide Molecular formula: C ₃ ιH ₃₇ N0 ₄ molecular weight: 487, 64 g / mol

HPLC-MS (ESI-TOF): t _R = 4.204 min; m / z = 642 [M + H]

Example 3: Preparation of 3-biphenyl-4-yl-5-oxo-2, 5-dihydro-furan-2-carboxylic acid benzhydryl-amide

Molecular formula: C ₃ oH ₂₃ N0 ₃ molecular weight: 445.52 g / mol

HPLC-MS (ESI-TOF): t _R = 4.070 min; m / z = 468 [M + Na]

Example 4: Preparation of 2-hydroxy-5-oxo-3, -diphenyl-2, 5 -dihydro-furan-2-carboxylic acid cyclohexylamide Molecular formula: C ₂₃ H ₂₃ N0 ₄ molecular weight: 377.44 g / mol

HPLC-MS (ESI-TOF): t _R = 3.764 min; m / z = 378 [M + H] ⁺ ; 400 [M + Na] ⁺

Example 5: Preparation of [(5-oxo-3-phenyl-2, 5-dihydro-furan-2-carbonyl) amino] acetic acid tert-butyl ester

Molecular formula: Cι ₇ H ₁₉ N0 ₅ molecular weight: 317.34 g / mol

HPLC-MS (ESI-TOF): t _R = 3.449 min; m / z = 340 [M + Na] ⁺

Example 6: Preparation of [(2-hydroxy-5-oxo-3,4-diphenyl-2,5-dihydro-furan-2-carbonyl) -amino] acetic acid tert-butyl ester

Molecular formula: C23H23NOS molecular weight: 409.44 g / mol

HPLC-MS (ESI-TOF): t _R = 3.693 min; m / z = 432 [M + Na]

Example 7: Preparation of [(2-hydroxy-5-oxo-3,4-diphenyl-2,5-dihydro-furan-2-carbonyl) amino] phenyl acetic acid tert-butyl ester

Molecular formula: C ₂₉ H ₂ 7 0 ₆ molecular weight: 485.54 g / mol

HPLC-MS (ESI-TOF): t _R = 3.970 min; m / z = 486 [M + H] ^{4 "} ; 50! [M + Na] ⁺

Example 8: Preparation of [(5-oxo-3, 4-diphenyl-2, 5-dihydro-furan-2-carbonyl) amino] phenyl acetic acid tert-butyl ester

Molecular formula: C ₂₉ H ₂ 7 0 ₅ molecular weight: 469.54 g / mol

HPLC-MS (ESI-TOF): t _R = 4.003 min; m / z = 492 [M + Na] ⁺ Example 9: Preparation of 5-oxo-3,4-diphenyl-2,5-dihydrofuran-2-carboxylic acid tert-butyl amide

Molecular formula: C ₂₁ H ₂ ιN0 ₃ molecular weight: 335.41 g / mol

Yield: 36% of theory

HPLC-MS (ESI-TOF): t _R = 3,659 min; m / z 336 [M + H] 35Ϊ [M + Na] ⁺

^ -NMR (CDC1 ₃ , 400 MHz): δ = 7.29 (m, 10H, CH aromatic), 6.08 (broad s, IH, NH), 5.63 (s, IH, (CO) CH (O)), l, 19 (s, 9H, 3x CH3)

¹³ C-NMR (CDC1 ₃ , 100 MHz): δ = 171.76 (CO), 163.59 (CO), 158.13 (CO), 130.37 (CH, aromatic), 130.27 (C, aromatic), 129.26 (CH, aromatic), 128.89 (CH, aromatic), 128.82 (CH, aromatic), 128.46 (CH, aromatic), 128.40 (CH, aromatic), 125.7 ((Phe) C (CH) or ((Phe) C (CO) butenolide ring), 81.02 ((CO) CH (O)), 51.87 (C (Me) 3, tBu), 28.40 (3CH3, tBu)

Example 10: Preparation of 3-naphthalin-2-yl-5-oxo-2, 5-dihydrofuran-2-carboxylic acid allylamide Molecular formula: Molar weight:

Yield:

HPLC-MS (ESI-TOF): t _R 3. 356 min; m / z = 294 [M + H] 316

[M + Na] ⁺

^X H-NMR (CDC1 ₃ , 400 MHz): δ = 8.39 (s, IH, CH aromatic),

7.95 (d, IH, CH aromatic), 7.88 (d, IH, CH aromatic),

7.8 (d, IH, CH aromatic) 7.73 (dd, IH, CH aromatic),

7.55 (qd, 2H, 2x CH aromatic), 6.68 (broad s, IH, NH), 6.44 (s, IH, (CO) CH (O)), 6.05 (s, IH, (C) = CH (CO) ), 5.75 (m, IH,

(CH2 = CH (CH2)), 5.15 (t, 2H, CH2 = CH), 3.89 (dm, IH, IH from (CH) CH2 (NH)), 3.75 (dm, IH, IH from (CH) CH2 ( NH))

¹³ C-NMR (CDCI3, 100 MHz): δ = 171.82 (CO), 165.22 (CO), 165.01 (CO), 134.68 (C, aromatic), 132.86 (C, aromatic), 132.55 (C, aromatic), 130.13 (CH, aromatic), 129.30 (CH, aromatic), 128.47 (CH, aromatic), 128.23 (CH, aromatic), 127.66 (CH, aromatic), 126.95 (CH, aromatic), 126.26 (CH, aromatic), 124.49 ( CH = CH2), 117.16 (CH2 = CH),

112.95 (C-CH (CO)), 81.16 ((CO) CH-O), 41.80 (CH2)

Example 11: Preparation of 3-biphenyl-4-yl-5-oxo-2, 5-dihydrouran-2-carboxylic acid butylamide Molecular weight formula: Yield:

HPLC-MS (ESI-TOF) 3,352 min; m / z = 294 [M + H] ⁺ ; 316

[M + Na] ⁺

^ -NMR (CDC1 ₃ , 400 MHz): δ = 7.86 (d, 2H, al, a2, aromatic) 7.68 (d, 2H, bl, b2, aromatic), 7.6l (d, 2H, cl, c2 aromatic) , 7.46 (t, 2H, dl, d2, aromatic), 7.39 (t, IH, e aromatic), 6.64 (broad s, IH, NH), 6.34 (s, IH, (C) CH (CO)) 5.93 ( s, IH, (C = 0) CH (C-0)), 3.29 (m, IH, (CH2) CH2 (NH)) 3.15 (m, IH, (CH2) CH2 (NH)), 1.45 (td, 2H, CH2CH2CH2), 1.28 (m 2H, CH3CH2), 0.87 (t, 3H, CH3).

¹³ C-NMR (CDC1 ₃ 100 MHz): δ = 171.93 (CO), 165.08 (CO), 164.89 (C, aromatic), 144.54 (C, aromatic), 139.65 (C, aromatic), 129.20 (CH, aromatic) , 128.88 (CH, aromatic), 128.10 (CH, aromatic), 127.93 (CH, aromatic), 112.49 (C = CH (CO)), 81.15 ((CO) CH-O), 39.28 ((CH2) CH2 (NH )), 31.14 ((CH2) CH2 (CH2)), 19, 85 ((CH3) CH2), 13.57 (CH3).

Example 12: Preparation of 3 - {[3- (4-hydroxyphenyl) -5-oxo-2, 5-dihydro-furan-2-carbonyl] -amino} -propionic acid tert-butyl ester Molecular formula: Molecular weight: Yield:

Look :

HPLC-MS (ESI-TOF): t _R = 3,110 min; m / z = 370 [M + Na] ⁺

^X H-NMR (DMSO, 400 MHz): δ = 8.78 (s, IH, OH), 7.58 (d, 2H, 2x CH aromatic), 6.81 (d, 2H, 2x CH aromatic), 6.55 (s, IH, (CO) (CO) CH (CO)), 5.93 (s, IH, (C) = CH (CO)), 3.29 (m, 2H, (CH2) CH2 (NH)), 2.48, 2.27 (m , 2H, ((CO) CH2 (CH2)), 1.37 (s, 9H, 3xCH3 tBu)

¹³ C-NMR (DMSO, 100 MHz): δ = 172.95 (CO), 170.30 (CO), 165.1l (CO), 163.52 (CO), 160.58 (C (OH), aromatic), 129.52 (2x CH, aromatic ), 120.14 (IC, aromatic), 115.60 (2x CH, aromatic), 110.56 (C = CH (CO)), 80.36 ((CO) CH (O)), 35.10 (CH2), 34.28 (CH2), 27.66 ( 3CH3, tBu)

Example 13: Preparation of 4-naphthalin-2-yl-6-oxo-6H-pyran-2-carboxylic acid tert-butylamide

Molecular formula: C ₂ oH ₁₉ N0 ₃ molecular weight: 321.38 g / mol

HPLC-MS (ESI-TOF): t _R = 3.747 min; m / z = 282 [M-C0 ₂ + H]

304 [M-CO ₂ + Na] ⁺

Example 14: Preparation of 4-er-butyl-6-oxo-6H-pyran-2-carboxylic acid tert-butylamide

Molecular formula: C ₁₄ H ₂₁ N0 ₃ molecular weight: 251.33 g / mol

HPLC-MS (ESI-TOF): t _R = 3.424 min; m / z = 212 [M-CO ₂ + H] ⁺ ; 234 [M-CO ₂ + Na] ⁺

Example 15: Preparation of 4- (4-fluoro-phenyl) -6-oxo-6H-pyran-2-carboxylic acid tert-butylamide

Molecular formula: Cι ₆ H _ls FN0 ₃ molecular weight: 289.31 g / mol

HPLC-MS (ESI-TOF): t _R = 3.471 min; m / z = 250 [M-CO ₂ + H] ⁺ ; 272 [M-CO ₂ + Na] ⁺ Example 16: Preparation of 4-biphenyl-4-yl-6-oxo-6H-pyran-2-carboxylic acid tert-butylamide

Molecular formula: C ₂₂ H ₂₁ NO ₃ molecular weight: 347.42 g / mol

HPLC-MS (ESI-TOF): t _R = 3.863 min; m / z = 308 [M-CO ₂ + H] ⁺ ; 330 [M-CO ₂ + Na] ⁺

Example 17: Preparation of 4- (3-hydroxyphenyl) -6-oxo-6H-pyran-2-carboxylic acid tert-butylamide

Molecular formula: C _1S H ₁₇ N0 ₄ molecular weight: 287.32 g / mol

HPLC-MS (ESI-TOF): t _R = 3.275 min; m / z = 248 [M-CO ₂ + H] ⁺ ; 270 [M-CO ₂ + Na] ⁺ Example 18: Preparation of 3-oxo-5, 6, 7, 8-tetrahydro-3H-isochromene-1-carboxylic acid tert-butylamide

Molecular formula: C ₁₄ H ₁₉ Nθ ₃ molecular weight: 249.31 g / mol ^Λ a-

HPLC-MS (ESI-TOF): t _R = 3.191 min; m / z = 210 [M-CO ₂ + H] ⁺ ; 232 [M-CO ₂ + Na] ⁺

Example 19: Preparation of 3-oxo-9, 10-dihydro-3H-2-oxaphenanthrene-1-carboxylic acid tert-butylamide

Molecular formula: C ₁₈ H ₁₉ N0 ₃ molecular weight: 297.36 g / mol

HPLC-MS (ESI-TOF): t _R = 3.582 min; m / z = 258 [M-CO ₂ + H] ⁺ ; 280 [M-CO ₂ + Na] ⁺

Example 20: Preparation of 6-oxo-3,4-diphenyl-6H-pyran-2-carboxylic acid tert-butylamide Molecular formula: C ₂₂ H ₂ ιN0 ₃ molecular weight: 347.42 g / mol

HPLC-MS (ESI-TOF): t _R 3.687 min; m / z = 308 [M-CO ₂ + H] 330

[M-CO ₂ + Na] ⁺

Example 21: Preparation of 3,4-bis (4-methoxyphenyl) -6-oxo-6i 6-pyran-2-carboxylic acid tert-butylamide

Molecular formula: C ₂ H ₂₅ 0 ₅ molecular weight: 407.47 g / mol

HPLC-MS (ESI-TOF): t _R = 3.627 min; m / z = 368 [M-CO ₂ + H] ⁺ ; 390 [M-CO ₂ + Na] ⁺

Example 22: Preparation of 5-oxo-3-phenyl-2, 5-dihydrofuran-2-carboxylic acid {[2- (3H-isoindol-l-yl) ethyl carbamoyl] methyl} amide Molecular formula: C ₂₃ H ₂₁ N ₃ O Molecular weight: 403, 44 g / mol

HPLC-MS (ESI-TOF): t _R = 3.249 min; m / z = 404 [M + H] ⁺ ; 426 [M + Νa] ⁺

Example 23: Preparation of 5-oxo-3-phenyl-2, 5-dihydrofuran-2-carboxylic acid butylamide

Molecular formula: C ₁₅ Hι ₇ Ν0 ₃ molecular weight: 259.31 g / mol

HPLC-MS (ESI-TOF): t _R = 3.320 min; m / z = 260 [M + H] ⁺ ; 282 [M + Na] ⁺

Example 24: Preparation of 5-oxo-3-phenyl-2, 5-dihydrofuran-2-carboxylic acid benzhydryl amide

Molecular formula: C ₂₄ H ₁₉ N0 ₃ molecular weight: 369.42 g / mol

HPLC-MS (ESI-TOF): t _R = 3.625 min; m / z = 370 [M + H] ⁺ ; 392 [M + Na] ⁺

Example 25: Preparation of 5-oxo-3-phenyl-2, 5-dihydrofuran-2-carboxylic acid benzylamide

Molecular formula: Cι ₈ H ₁₅ θ ₃ molecular weight: 293.33 g / mol

HPLC-MS (ESI-TOF) 3.311 min; m / z = 294 [M + H] ⁺ ; 316

[M + Na] ⁺

Example 26: Preparation of 3-biphenyl-4-yl-5-oxo-2, 5-dihydro-furan-2-carboxylic acid cyclohexylamide

Molecular formula: C ₂₃ H ₂₃ N0 ₃ molecular weight: 361.44 g / mol

HPLC-MS (ESI-TOF): t _R 3.788 min; m / z = 362 [M + H] 384

[M + Na] ⁺ Example 27: Preparation of 3-biphenyl-4-yl-5-oxo-2, 5-dihydro-furan-2-carboxylic acid tert-butylamide

Molecular formula: C ₂₁ H ₂₁ N0 ₃ molecular weight: 335.41 g / mol

HPLC-MS (ESI-TOF): t _R = 3.688 min; m / z = 336 [M + H] ⁺ ; 35E [M + Na] ⁺

Example 28: Preparation of 3-biphenyl-4-yl-5-oxo-2, 5-dihydro-furan-2-carboxylic acid benzylamide

Molecular formula: C ₂ H ₁₉ N0 ₃ molecular weight: 369.42 g / mol

HPLC-MS (ESI-TOF): t _R = 3.712 min; m / z = 370 [M + H] ⁺ ; 392 [M + Na] ⁺ Example 29: Preparation of 3- (4-nitro-phenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid benzhydryl-amide

Molecular formula: C ₂₄ H ₁₈ N ₂ 0 ₅ molecular weight: 414.42 g / mol

HPLC-MS (ESI-TOF): t _R = 3.866 min; m / z = 415 [M + H]

Example 30: Preparation of 4- (3-cyano-phenyl) -6-oxo-6H-pyran-2-carboxylic acid tert-butylamide

Molecular formula: C ₁₇ Hχ ₆ N ₂ θ ₃ molecular weight: 296.33 g / mol

HPLC-MS (ESI-TOF): t _R = 3.481 min; m / z = 257 [M-CO ₂ + H] 279 [M-CO ₂ + Na] ⁺

Example 31: Preparation of 3- (4-cyano-phenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid cyclohexylamide Molecular formula: C ₁₈ H ₁₈ N ₂ θ3 Molecular weight: 310.36 g / mol

HPLC-MS (ESI-TOF): t _R = 3.343 min; m / z = 311 [M + H] ⁺ ; 333

[M + Na] ⁺

Example 32: Preparation of 3-naphthalene-1-yl-5-oxo-2, 5-dihydro-furan-2-carboxylic acid butylamide

_Molecular formula: C _ι9 H ₁₉ N0 ₃ molecular weight: 309.37 g / mol

HPLC-MS (ESI-TOF): t _R = 3.517 min; m / z = 310 [M + H] 332 [M + Na] ⁺

Example 33: Preparation of 3 -naphthalene-1-yl-5-oxo-2, 5-dihydro-furan-2-carboxylic acid cyclohexylamide Molecular formula: C ₂₁ H ₂₁ NO Molecular weight: 335.41 g / mol

HPLC-MS (ESI-TOF) 3.638 min; m / z = 336 [M + H] ⁺ ; 35S

[M + Na] ⁺

Example 34: Preparation of 3-naphthalene-1-yl-5-oxo-2, 5-dihydro-furan-2-carboxylic acid tert-butylamide

_Molecular formula C ₁₉ H _α9 N0 ₃ molecular weight: 309.37 g / mol

HPLC-MS (ESI-TOF): t _R 3.524 min; m / z = 310 [M + H] 332

[M + Na] ⁺

Example 35: Preparation of 3-naphthalene-1-yl-5-oxo-2, 5-dihydro-furan-2-carboxylic acid benzylamide Sum formula: C ₂₂ Hι ₇ Nθ ₃ molecular weight: 343, 39 g / mol

HPLC-MS (ESI-TOF): t _R = 3.545 min; m / z = 344 [M + H] ⁺ ; 366 [M + Na] ⁺

Example 36: Preparation of 3- (4-chlorophenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid {[2- (1H-indol-3-yl) ^■ ethylcarbamoyl] methyl} - amide

Molecular formula: C ₂₃ H2oClN ₃ 0 ₄ molecular weight: 437.89 g / mol

HPLC-MS (ESI-TOF): t _R = 3.358 min; m / z = 460 [M + Na]

Example 37: Preparation of 3- (4-chlorophenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid butylamide Molecular formula: C ₁₅ H ₁₆ C1N0 ₃ molecular weight: 293, 75 g / mol

HPLC-MS (ESI-TOF) t _R = 3.453 min; m / z = 294 [M + H] 316

[M + Na] ⁺

Example 38: Preparation of 3- (4-chlorophenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid cyclohexylamide

Molecular formula: C ₁₇ H ₁₈ C1N0 ₃ molecular weight: 319.79 g / mol

HPLC-MS (ESI-TOF): t _R = 3.581 min; m / z 320 [M + H] ⁺ ; 342 [M + Na] ⁺

Example 39: Preparation of 3- (4-chlorophenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid tert-butylamide Molecular formula: C ₁₅ H _1S C1N0 ₃ molecular weight: 293.75 g / mol

HPLC-MS (ESI-TOF): t _R = 3.452 min; m / z = 294 [M + H] 316

[M + Na] ⁺

Example 40: Preparation of 3- (4-chlorophenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid allylamide

Molecular formula: C ₁ H ₁₂ ClNθ ₃ molecular weight: 277.71 g / mol

HPLC-MS (ESI-TOF) t _R = 3.252 min; m / z = 278 [M + H] 300

[M + Na] ⁺

Example 41: Preparation of 3- (4-chlorophenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid benzhydryl-amide Molecular formula: C ₂₄ H ₁₈ C1N0 ₃ molecular weight: 403, 87 g / mol

HPLC-MS (ESI-TOF): t _R 3.759 min; m / z = 404 [M + H] ⁺ ; 426

[M + Na] ⁺

Example 42: Preparation of 3- (4-chlorophenyl) -5-oxo-2, 5-dihydro-furan-2-carboxylic acid benzylamide

Molecular formula: C ₁₈ H ₁ C1N0 ₃ molecular weight: 327.77 g / mol

HPLC-MS (ESI-TOF) 3.477 min; m / z = 328 [M + H] ⁺ ; 350

[M + Na] ⁺

Example 43: Preparation of 1- (3-cyano-phenyl) -3-methyl-5-oxo-2,5-dihydro-lff-pyrrole-2-carboxylic acid (3-phenoxy-phenyl) amide Molecular formula: C2 ₅ H ₁₉ N ₃ θ ₃ Molar weight: 409.45 g / mol

HPLC-MS (ESI-TOF): t _R 3.805 min; m / z 410 [M + H] 432

[M + Na] ⁺

Example 44: Preparation of l-allyl-3-naphthalin-2-yl-5-oxo-2,5-dihydro-lH-pyrrole-2-carboxylic acid (3-benzoyl-phenyl) amide

Molecular formula: C ₁₃ H ₂₄ N ₂ 0 ₃ molecular weight: 472.55 g / mol

HPLC-MS (ESI-TOF): t _R = 3.890 min; m / z = 473 [M + H] ⁺ ; 495 [M + Na] ⁺ Example 45: Preparation of 1-cyclopropyl-3-naphthalen-2-yl-5-oxo-2, 5-dihydro-1H-pyrrole-2-carboxylic acid (pyridin-3-ylmethyl) -amide

Molecular formula: C ₂ 7H ₃ iN ₅ 0 ₃ molecular weight: 383.45 g / mol

HPLC-MS (ESI-TOF) t _R = 2.743 min; m / z = 384 [M + H] 406

[M + Na] ⁺

Example 46: Preparation of 1- {[2- (1H-indol-3-yl! Ethylcarbamoyl] methyl} -5-oxo-3,4-diphenyl-2,5-dihydro-lH-pyrrole-2-carboxylic acid allylamide

Molecular formula: C ₃₂ H ₃ oN0 ₃ molecular weight: 518.62 g / mol

HPLC-MS (ESI-TOF): t _R = 4.058 min; m / z = 568 [M + H] Example 47: Preparation of 3- (4-chlorophenyl) -1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (4-fluoro-phenyl) -5-oxo-2,5 - dihydro-lH-pyrrole -2-carboxylic acid tert-butylamide

Molecular formula: C ₃ αH ₃₂ ClFN ₂ 0 ₄ molecular weight: 551.06 g / mol

HPLC-MS (ESI-TOF): t _R = 3.946 min; m / z = 427 [M + H] ⁺ ; 449 [M + Na] ⁺

Example 48: Preparation of 5- (4-but-3-enyl-2-cyclohexylcarbamoyl-1-methyl-5-oxo-2, 5-dihydro-1H-pyrrol-3-yl) -2-hydroxy-benzoic acid methyl ester

Molecular formula: C ₂₄ H ₃ oN ₂ 0 ₅ molecular weight: 426.52 g / mol

HPLC-MS (ESI-TOF): t _R = 3.556 min; m / z = 524 [M + H] ⁺ ; Example 49: Preparation of 3- (4-cyano-phenyl) -1- (3-methylbutyl) -5-oxo-2,5-dihydro-lH-pyrrole-2-carboxylic acid {[methyl- (2-pyridine -2-yl-ethyl) carbamoyl] methyl} amide

Molecular formula: C ₂₇ H _{31 5} θ ₃ molecular weight: 473.58 g / mol

HPLC-MS (ESI-TOF): t _R = 3,334 min; m / z 598 [M + H] ⁺ ; 626 [M + Na] ⁺

Example 50: Preparation of 1- (3,3-diphenyl-propyl) -3 - (4-methoxy-phenyl) -5-oxo-2,5-dihydro-lH-pyrrole-2-carboxylic acid (4-methoxy-3 -oxo-butyl) -amide

Molecular formula: C ₃₂ H ₃₄ N ₂ 0 ₅ molecular weight: 526.64 g / mol

HPLC-MS (ESI-TOF) = 3.115 min; m / z = 373 [M + H] ⁺ ; 395

[M + Na] ^{4 "}

Example 51: Preparation of 5-oxo-3-phenyl-2, 5-dihydrofuran-2-carboxylic acid cyclohexylamide

Molecular formula: C ₁₇ H ₁₉ N0 ₃ molecular weight: 285.35 g / mol

HPLC-MS (ESI-TOF): t _R = 3.472 min; m / z = 286 [M + H] ⁺ ; 30i [M + Na] ⁺

Example 52: Preparation of 5-oxo-3,4-diphenyl-2,5-dihydrofuran-2-carboxylic acid cyclohexylamide

Molecular formula: Molecular weight: Yield:

HPLC-MS (ESI-TOF): t _R = 3,732 min; m / z = 362 [M + H] ^{4 "} ; 384 [M + Na] ⁺

^ Η-NM (CDC1 ₃ , 400 MHz): δ = 7.36 (m, 10H, lOx CH aromatic), 6.30 (d, IH, NH), 5.8l (s, IH, (C = 0) CH (CO) ), 3.64 (m, IH, (CH2) 2CH (NH)), 1.89 (d, 2H, CH2), 1.67 (m, 2H, CH2), 1.58 (d, 2H, CH2), 1.26 (m, 2H, CH2), 1.12 (m, 2H , CH2)

¹³ C-NMR (CDCI ₃ , 100 MHz): δ = 171.08 (CO), 163.69 (CO), 157.97 (C, aromatic), 130.38 (C, aromatic), 130.14 (CH, aromatic), 129.25 (CH, aromatic ), 129.02 (CH, aromatic), 128.911 (CH, aromatic), 128.52 (CH, aromatic), 128.44 (CH, aromatic), 128.34 (CH, aromatic), 125.62 (CH, aromatic), 80.58 ((CO) CH -O), 48.65 (CH, cyclohexyl), 32.73 (CH2, cyclohexyl), 32.59 (CH2, cyclohexyl), 25.24 (CH2, cyclohexyl), 24.77 (CH2, cyclohexyl)

Example 53: Preparation of 2- {[4- (4-fluoro-phenyl) -5-oxo-3-thiophene-2-yl-2,5-dihydro-furan-2-carbonyl] -amino} - propionic acid tert- butyl ester

Molecular formula: Molecular weight: Yield:

HPLC-MS (ESI-TOF): t _R = 3,781 min; m / z = 454 [M + H] ^{4 "} ; 376 [M- tBu + H] ⁺ ^X H-NMR (CDCI ₃ , 400 MHz): δ = 7.76 (d, IH, (CH) CH (S)), 7.36 (m, 2H, 2x CH aromatic), 7.10 (t, 2H, 2x CH aromatic) , 7.00 (m, IH, CH aromatic), 6.89 (IH, CH aromatic) 5.71 (s, IH, (CO) CH (O)), 4.34 (q, IH, (CO) (CH3) CH (NH)) , 1.41 (broad, 3H, (CH ₃ ) CH), 1.33 (s, 9H, 3x CH3 tBu)

¹³ C-NMR (CDCI ₃ , 100 MHz): δ = 171.79 (CO), 165.90 (CO), 165.66 (CO), 151.43 (C, aromatic), 134.76 (2CH, aromatic), 132.80 (2CH, aromatic), 128.38 (ICH, aromatic), 126.18 (aromatic), 117.10 (2CH, aromatic), 83.01 ((CO) CH- O), 49.9KCH), 28.58 (3CH3), 19.02 (1CH3)

Example 54: Preparation of 2- {[4 - (3-methoxyphenyl) -5-oxo-3-phenyl-2,5-dihydro-furan-2-carbonyl] -amino} - -methylpentanoic acid methyl ester

Molecular formula: C ₂₅ H ₂₇ N0 ₆ molecular weight: 437.5 g / mol

HPLC-MS (ESI-TOF): t _R = 3,746 min; m / z = 438 [M + H] ⁺ ; 460 [M + Na] ⁺

^ ^• H-NMR (CDCI ₃ , 400 MHz): δ = 7.35 (, 6H, 6x CH aromatic), 7.25 (m IH, CH aromatic), 6.92 (m, 2-3, 2x CH aromatic), 6.68 (m , IH, NH), 5.86 (s, IH, (C = 0) CH (CO)), 4.55 (, IH, (C0) CH (CH2) (NH)), 3.69 (td, 6H, CH3-0-Phe, CH3-0-CO), 1.54 (m, 3H, CH2, CH (CH3) 2), 0.88 (m, 6H, 2CH3-0), 0.77 (2d, 6H, 2CH3)

¹³ C-NMR (CDC1 ₃ , 100 MHz): δ = 172.3 (CO), 164, 8 (CO), 159.5 (CO), 157.4 (C aromatic, C (OMe)), 130.5 (CH aromatic), 130.4 ( CH aromatic), 130.1 (C aromatic), 129.9 (C aromatic), 129.7 (CH aromatic), 129.6 (CH aromatic), 129.0 (CH aromatic), 128.4 (CH aromatic), 121.6 (CH aromatic), 115.1 (CH aromatic ), 114.41 (CH, aromatic), 80.35 ((CO) CH (0)), 55.1 (CH3 -O-CO), 52.36l (CH3-0), 50, 8 ((CO) CH (CH2) (NH )), 41.1 (CH (CH3) 2), 24.8 (CH2),

22.8 (CH3), 21.7 (CH3)

Example 55: Preparation of 6-0xo-4-phenyl-6H-pyran-2 ^■ carboxylic acid tert-butylamide

Sum fo rme 1 C ₁₆ H ₁₇ N0 ₃ Molecular weight: 271.32 g / mol

HPLC-MS (ESI-TOF): t _R = 3.418 min; m / z = 232 [M-CO ₂ + H] 254 [M-CO ₂ + Na] ⁺

Example 56: Preparation of l-benzyl-6-oxo-4-phenyl-1,2,3, 6-tetrahydro-pyridine-2-carboxylic acid tert-butylamide Molecular weight formula: Yield:

HPLC-MS (ESI-TOF): t _R = 3. 584 min; m / z 363 [M + H] 385 [M + Na] ^{4 "}

^ -NMR (CDC1 ₃ 400 MHz): δ = 7.39 (m, 10H, lOx CH aromatic), 6.31 (s, IH, (CO) CH (C)), 5.6l (s, IH, (CO) (CH2 ) CH (N)), 4.97 (d, IH, (Phe) CH2 (N)), 4.49 (d, IH, (Phe) CH2 (N)), 4.05 (d, IH, (CH) CH2 (C)) ), 3.40 (d (CH) CH2 (C)), 2.90 (m, IH), 1.17 (s, 3H), 1.12 (s, 9H, 3x CH3 tBu))

¹³ C-NMR (CDC1 ₃ , 100 MHz): δ = 169.3 (CO), 164.5 (CO), 149.6 (C aromatic), 137.1 (C aromatic), 129.7 (CH aromatic), 129.0 (CH aromatic), 128.7 ( CH aromatic), 128.6 (CH aromatic), 128.1 (CH aromatic), 126.2 (CH aromatic), 118.8 (CH double bond), 59.7 ((CO) CH (N) (CH2)), 51.4 (C (Me) 3), 50.0 ((Phe) CH2 (N)), 30.3 ((CH) (CH2) (C)), 28.3 (3x CH3 tBu)

Example 57: Preparation of 2-hydroxy- (3-methoxy-phenyl) -5-oxo-3-phenyl -2, 5-dihydro-furan-2-carboxylic acid cyclohexylamide Molecular formula: C ₂ H ₂₅ N0 ₅ molecular weight: 407.47 g / mol

HPLC-MS (ESI-TOF): t _R = 3.736 min; m / z 408 [M + H] 430 [M + Na] ^{4 "}

Example 58: Preparation of 1-benzyl-5-oxo-3, 4-diphenyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid tert-butylamide

Molecular formula: C ₂₈ H ₂₈ N ₂ 0 ₂ molecular weight: 424.55 g / mol

HPLC-MS (ESI-TOF): t _R = 3,950 min; m / z 441 [M + H] 463 [M + Na] ⁺

^α H-NMR (CDC1 ₃ , 400 MHz): δ = 7.49 (2H, aromatic), 7.41 (2H, aromatic), 7.29 (12H, aromatic), 5.47 (d, 2H, (Phe) CH2 (N)), 4.81 (d, IH), 4.36 (d, IH), 1.58 (s, IH), 1.24 (s, IH), 0.9l (s, 9H, tBu)

Claims

Patentanspräche

1. Compounds of the general formula (I):

wherein

X is an oxygen atom or a group of formula NR6;

n is 0 or 1;

U is CH or COH;

V is a group of the formula CR2R3 or U-V together are a group of the formula -C = CR2-;

Rl is an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical;

R5 is a hydrogen atom, a halogen atom, a hydroxy group, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical;

R6 is a hydrogen atom, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical;

or R2 and R3 or R2 and R4 together are part of a cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl ring system;

2. Compounds according to claim 1, wherein X is an oxygen atom.

3. Compounds according to claim 1, wherein X is a group of formula NR6.

4. Compounds according to any one of claims 1 to 3, wherein U is CH.

5. Compounds according to any one of claims 1 to 3, wherein U is COH.

6. Compounds according to any one of claims 1 to 5, wherein n is 0.

7. Compounds according to any one of claims 1 to 5, wherein n is 1.

8. Compounds according to any one of claims 1 to 3 and 7, wherein U-V together are a group of the formula -C = CR2-,

I wherein R2 is as defined in any one of the preceding claims.

9. Pharmaceutical compositions containing a compound according to any one of claims 1 to 8 and optionally carriers and / or adjuvants.

10. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 9 for the inhibition of kinases.

11. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 9 for the treatment and / or prevention of diseases which are mediated by kinase activity.

12. Use of a compound or a pharmaceutical composition according to any one of claims 1 to 9 for the treatment and / or prevention of inflammatory diseases and diseases caused by autoimmune reactions.

13. Use of a compound or a pharmaceutical composition according to one of claims 1 to 9 for the treatment and / or prevention of rheumatoid arthritis, asthma, MDR (multiple drug resistance), COPD, ARDS, cancer, stroke, Alzheimer's, osteoarthritis, lung disease, septic shock, angiogenesis, dermatitis as well as for the in vivo stimulation of nerve growth, the in vivo inhibition of scar tissue formation and / or in vivo reduction of secondary damage.

14. A process for the preparation of compounds according to any one of claims 1-8, characterized in that

Compounds of the formulas (II), (III), (IV) and optionally (V) are reacted with one another:

the residues being as defined in any one of the preceding claims.

15. The method according to claim 14, characterized in that the reaction is carried out in an aprotic solvent.

16. The method according to any one of claims 14 or 15, characterized in that an ether is used as solvent.

17. The method according to any one of claims 14 to 16, characterized in that the reaction is carried out at a temperature of -80 to 120 ° C, in particular from 0 to 25 ° C.

18. The method according to any one of claims 14 to 17, characterized in that in a first step the compounds of the formulas II, III and IV and optionally V are reacted with one another and in a second step the reaction product from the first step in the presence of at least one alkali salt , such as a lithium salt.

19. The method according to any one of claims 14 to 18, characterized in that the second step is carried out in the presence of at least one base such as a tertiary basic amine.

20. The method according to any one of claims 14 to 19, characterized in that the reaction is carried out in the presence or with the exclusion of 0 ₂ .

21. Use of a method according to one of claims 14 to 20 for the synthesis of substance libraries.

22. Use of a method according to one of claims 14 to 20 for locating lead structures.