Method for preparation of phosphodiesterase-4 inhibitors

FIELD: CHEMISTRY.

SUBSTANCE: invention relates to novel method for preparation of compounds of formula IX or IXа, which implies reaction of compound of formula Va, in solvent, with compound of formula VII or formula VIIa, in the presence of palladium catalyst and phospho ligand, in the presence of amine base, resulting in compound of formula VIII or VIIIa. The method also implies reaction of compound of formula VIII or VIIIa, in solvent, with cyclopropylamine, not necessarily in the presence of catalyst. Also, invention relates to method for purification of compound of formula IX or IXa.

Va - R1 may be either С1-8alkyl, aryl or heteroaryl, not necessarily aryl- and/or С1-8alkyl-substituted; and

.

EFFECT: method for preparation of biologically useful compounds is described.

17 cl, 3 tbl, 77 ex

 

The technical field

This invention relates to a process for the preparation of inhibitors of phosphodiesterase-4. In particular, this invention relates to a method for producing compounds which are substituted by biharilal 1,8-naphthiridine-4(1H)-areas.

The level of technology

Hormones are compounds that have different effects on cellular activity. In many respects, the hormones are messengers to trigger specific cellular responses and activities. However, many of the effects caused by hormones, are not the result of actions of the hormone. On the contrary, the first hormone binds to the receptor, thereby initiating the selection of the second connection, which continues to impact on cellular activity. In such a scenario, the hormone is known as the primary messenger, and the second connection is a secondary messenger. Cyclic amp (adenosine 3',5'-cyclic monophosphate, cyclic amp or cyclic AMP") is known as a second messenger for hormones, including epinephrine, glucagon, calcitonin, corticotropin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone and vasopressin. Thus, the cyclic amp mediates the cellular response to hormones. Cyclic AMP also mediates the cellular response is different neurotransmitters.

Phosphodiesterase ("PDE") constitute a family of enzymes involved in the metabolism of 3',5'-cyclic nucleotides, transforming them into 5 nucleosideanalogue, thereby limiting the activity of CMP as a secondary messenger. Specific phosphodiesterase, phosphodiesterase-4 ("FDA", also known as "PDE-IV"), which has a high affinity and specificity to camp, PDE type IV, is particularly interesting as a potential target for developing new anti-asthmatic and anti-inflammatory compounds. It is known that FDA exists in the form of at least four isoenzymes, each of which are encoded by separate genes. I believe that all four known PDA gene products have different roles in allergic and/or inflammatory reactions. Thus, suppose that the inhibition FDA, especially specific isoforms FDA that cause adverse reactions, can favorably influence the symptoms of allergies and inflammation. It would be desirable to obtain new compounds and compositions that inhibit the activity FDA.

The main problem inhibitors FDA is a side effect in the form of vomiting, which may occur when taking multiple connection options, as described in C. Burnouf et al., ("Burnouf"), Ann. Rep. In Med. Chem.,33:91-109 (1998). B. Hughes et al., Br. J. Pharmacol.,118:1183-1191 (1996); M.J. Perry et al., Cell Biochem. iophys., 29:113-132 (1998); S.B. Christensen et al., J. Med. Chem.,41:821-835 (1998) and Burnouf described undesirable effects of varying severity caused by different compounds. As described in M.D.Houslay et al., Adv. In Pharmacol.,44:225-342 (1998) and D. Spina et al., Adv. In Pharmacol.,44:33-89 (1998), there is great interest, and conducted extensive studies of therapeutic inhibitors FDA.

In a publication of the international application WO9422852 describes quinoline as inhibitors FDA. In the published international application WO 9907704 described derivatives of 1-aryl-1,8-naphthiridine-4-it is as inhibitors FDA.

In A.H. Cook et al., J. Chem. Soc., 413-417 (1943) described the gamma Peredelkino. Other quinoline compounds described in Kei Manabe et al., J. Org. Chem.,58(24):6692-6700 (1993); Kei manabe et al., J. Am. Chem. Soc.,115(12):5324-5325 (1993) and Kei Manabe et al., J. Am. Chem. Soc.,114(17):6940-6941 (1992).

Compounds that include ring systems, described by various researchers as effective in various types of therapy and other applications. For example, in published international application WO 98/25883 described ketoenamine as inhibitors of calpain, in the publication of European patent EP 811610 and U.S. patent No. 5679712, 5693672 and 5747541 described substituted benzoylpyridine blockers of sodium channels, in U.S. patent No. 5736297 described ring system that is used as the photosensitive composition.

In U.S. patent No. 5491147, 5608070, 562297, 5739144, 5776958, 5780477, 5786354, 5798373, 5849770, 5859034, 5866593, 5891896 and publication of the international application WO 95/35283 described inhibitors FDA, which are derived trisemester aryl or heteroaryl. In U.S. patent No. 5580888 described inhibitors FDA, which are derivatives of sterile. In U.S. patent No. 5550137 described inhibitors FDA, which are derivatives of phenylenecarbonyl. In U.S. patent No. 5340827 described inhibitors FDA, which are compounds peroxycarboxylic. In U.S. patent No. 5780478 described inhibitors FDA, which are derivatives of Tetra-substituted phenyl. In the published international application WO 96/00215 described derivatives substituted oxime used as inhibitors FDA. In U.S. patent No. 5633257 described inhibitors FDA, which are compounds cyclo(alkyl and alkenyl)phenyl-alkenyl(aryl and heteroaryl).

The invention

In one aspect, this invention relates to ignoreaction process for the preparation of intermediate compounds of formula V, which are used in obtaining inhibitors of phosphodiesterase-4:

In another aspect, the invention relates to a method for producing compounds of formula IX and formula IXa, which are inhibitors of phosphodiesterase-4:

It is shown that inhibitors of phosphodiesterase-4 are useful in the treatment of mammals, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in children, chronic obstructive pulmonary disease in animals, not diabetes, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, rejection of transplants and disease graft versus host disease, hypersecretion of gastric acid caused by bacteria, fungi or viruses sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia,loss of muscle tissue, depression, memory loss, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory phenomena, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injuries, multiple sclerosis, tumour growth and cancerous invasion of normal tissues.

Detailed description of the invention

In one embodiment, the obtaining compounds of formula IX may begin with receiving the intermediate compounds of formula V:

where

-OR1is a suitable leaving group, such as described in standard texts, such as: Protective Groups in Organic Synthesis, 2ndedition, by Theodora W. Greene and Peter G M. Wust (1991) and the Protecting Group, the author Philip J, Kocienski (1994). For example, R1can be optional With1-8the alkyl, aryl, heteroaryl, where the substituents are selected from the group including aryl, C1-8alkyl;

R3is1-8the alkyl, aryl or heteroaryl, optionally mono-, di-, tri - or Tetra-substituted by halogen, B(OH)2- ≡, aryl, heteroaryl,1-10the alkyl, alkoxy, ketone, alcohol, triflate, mesilate, amidon, complex ether, ketone, acetal, phosphate, stannane, silicom, B(OR)2where R is a C1-8the alkyl or aryl;

including:

Stage A: interaction, dinucleophiles the solvent, compound f is rmula II:

where

R2each independently is a C1-8the alkyl, optionally mono - or disubstituted With1-8the alkyl, such as methyl or ethyl, or aryl such as phenyl or heteroaryl;

with the compound of the formula I in the presence of a base:

where

R4is bromine or chlorine,

obtaining the compounds of formula III.

and

Stage: interaction, dinucleophiles the solvent, the compounds of formula III with aminoguanidinium formula IV

in the presence of a base to obtain the compounds of formula V.

Definition dinucleophiles solvent on stage is the same as given above for phase A. similarly, the definition of the basis on stage is the same as described above for stage A.

At the stage And the molar ratio of base to the compound of formula I may range from about 12:1 to about 3:1. Usually use a ratio of 8:1. A ratio below 3:1 can cause trimerization of aminoacridine obtaining 1,3,5-tricarboxylate. The molar ratio of the compounds of formula I to compound of formula II may vary from 1:1 to 1:3, is typically about 1:1,5. The interaction on stage And can be carried out at a temperature of from 25 to 100°With; usually used inter is al from about 40 to about 60° With and continue the reaction until virtually complete within 2 to 18 hours, usually from 6 to 12 hours. The interaction on stage is conducted as described above.

In this embodiment has a sub-option, in which:

R1not necessarily With1-8the alkyl, aryl, heteroaryl, where the substituents are selected from the group including aryl, C1-8alkyl;

R2is stands, ethyl or phenyl;

R3is1-8the alkyl, aryl or heteroaryl, optionally mono-, di-, tri - or Tetra-substituted by halogen, B(OH)2- ≡, aryl, heteroaryl;

In this embodiment has a sub-option, in which:

R1is stands or ethyl;

R2is stands;

R3is phenyl, substituted with halogen, B(OH)2- ≡.

In this embodiment has a sub-option, in which: dinucleophiles solvent selected from dimethylformamide, dimethylacetamide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, benzene, dioxane, methylene chloride.

In the above sub-option has sub-options, which dinucleophiles solvent is acetonitrile.

In this embodiment includes a modification in which the base is selected from sodium carbonate or potassium, triethylamine, diethylamine and the base of Chenega.

In this embodiment has a sub-option is where the base is selected from sodium carbonate or triethylamine.

In this embodiment includes a modification in which the molar ratio of the compounds of formula IV to the compound of formula III is from about 2:1 to 1:2.

In the above sub-option has sub-options, in which the molar ratio of the compounds of formula IV to the compound of formula III is about 1:1.

In this embodiment includes a modification in which the molar ratio of base to the compound of formula IV is at least 1:1.

In the above sub-option has sub-options, in which the molar ratio of base to the compound of formula IV is about 1:1.

In this embodiment includes a modification in which the interaction is carried out at a temperature of from about 20 to 100°C.

In the above sub-option has sub-options, in which the reaction is carried out at a temperature of from about 40 to about 50°C.

In the second embodiment presents a method of obtaining the compounds of formula V

where

-OR1is a suitable leaving group;

R3is1-8the alkyl, aryl or heteroaryl, optionally mono-, di-, tri - or Tetra-substituted by halogen, B(OH)2- ≡ (Alcina), aryl, heteroaryl,1-10the alkyl, alkoxy, ketone, alcohol, triflate, mesilate, amidon, complex ether, ketone, acetal, phosphate, stannane, silicom, B(OR)21-8the alkyl or aryl;

including:

Stage A: interaction, dinucleophiles the solvent, the compounds of formula II:

where

R2each independently is a C1-8the alkyl, optionally mono - or disubstituted With1-8the alkyl, such as methyl or ethyl, or aryl or heteroaryl;

with the compound of the formula I in the presence of a base:

where

R4is bromine or chlorine,

obtaining the compounds of formula III.

and

Stage: interaction, dinucleophiles the solvent, the compounds of formula III with aminoguanidinium formula IV

in the presence of a base to obtain the compounds of formula V.

In this embodiment has a sub-option, in which:

R1not necessarily With1-8the alkyl, aryl, heteroaryl, where the substituents are selected from the group including aryl, C1-8alkyl;

R2is stands, ethyl or phenyl;

R3is1-8the alkyl, aryl or heteroaryl, optionally mono-, di-, tri - or Tetra-substituted by halogen, B(OH)2- ≡, aryl, heteroaryl;

In this second variant has a sub-option, in which:

R4is chlorine.

In Dan what Ohm the second option has a sub-option, where:

R1is stands or ethyl;

R2is stands;

R3is phenyl, substituted with halogen, B(OH)2- ≡.

In this second variant, the sub-option, in which: dinucleophiles solvent selected from dimethylformamide, dimethylacetamide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, benzene, dioxane, methylene chloride.

In the above sub-option has sub-options, which dinucleophiles solvent is acetonitrile.

In this second case there is a modification in which the base is selected from sodium carbonate or potassium, triethylamine, diethylamine and the base of Chenega.

In this embodiment includes a modification in which the base is selected from sodium carbonate or triethylamine.

In this second variant, the modification stage And in which the molar ratio of base to the compound of formula I is from about 12:1 to about 3:1.

In the above sub-option has sub-options stage And in which the molar ratio of base to the compound of formula I is from about 8:1 to about 3:1.

In this second variant, the modification stage And in which the molar ratio of the compounds of formula I to compound of formula II is from about 1:1 to 1:3.

In this second variant, the modification stage And, inwhich the reaction is carried out at a temperature of from about 25 to 100° C.

In this second variant, the modification stage And in which the reaction is carried out at a temperature of from about 40 to about 60°C.

In this second variant, the modification stage, in which the molar ratio of the compounds of formula IV to the compound of formula III is from about 2:1 to 1:2.

In the above sub-option has sub-options stage, in which the molar ratio of the compounds of formula IV to the compound of formula III is about 1:1.

In this second variant, the modification stage, in which the molar ratio of base to the compound of formula IV is about 1:1 or more.

In the above sub-option has sub-options stage, in which the molar ratio of base to the compound of formula IV is about 1:1.

In this second variant, the modification stage, in which the reaction is carried out at a temperature of from about 20 to 100°C.

In the above sub-option has sub-options stage, in which the reaction is carried out at a temperature of from about 40 to 50°C.

In this second variant, the sub-option, in which the interaction on stage and interaction on stage is carried out in a single reactor without purification or extraction of product stage And before step C.

In another embodiment, this invention relates to a method for inhibiting the FOSFA diesterase-4 formulas IX and IXa:

including

Stage: interaction in the solvent And the compounds of formula Va

where

-OR1is a suitable leaving group, such as described in standard texts, such as: Protective Groups in Organic Synthesis, 2ndedition, by Theodora W. Greene and Peter G.M. Wuts (1991) and Protecting Groups, by Philip J. Kocienski (1994). For example, R1can be optional With1-8the alkyl, aryl, heteroaryl, where the substituents are selected from the group including aryl, C1-8alkyl;

with the compound of the formula VII or VIIa

in the presence of palladium catalyst and phosphine ligand, an amine base to obtain the compounds of formula VIII or VIIIa

The preferred compound of formula Va, formula VIII and VIIIa, respectively, are the following connections:

For the purposes of this invention, the solvent And selected from the group including diethylaminoacetate, dimethylformamide, acetonitrile, DMSO, methylacetamide, ethers, or their mixtures. For the purposes of this invention, the phosphine ligand is chosen from the group comprising P(C1-6alkyl)3such as P(tert-butyl)3, P(Cy)3and P(tert-butyl)2 (biphenyl). For the purposes of this invention, the palladium catalyst includes a catalyst Fu (for example, P(tert-butyl)3-Pd-P(tert-butyl)3, [PdCl(allyl)]2Pd2(DBA)3and [P(tert-butyl)3PdBr]2(catalyst Johnson-Mattei). For the purposes of this invention, the amine base is a difficulty amine base, such as tert-amylamine, tert-butylamine, Isopropylamine or Diisopropylamine.

On stage With the molar ratio of compounds of formula Va to the compound of formula VII or VIIa may vary within a wide range, but, optimally, is from about 1:1.5 to 1.5:1, typically about 1:1. As a General rule, desirable, at least 1 molar equivalent of base per mole of the compounds of formula Va plus 1 molar equivalent of the base in molar equivalent of the compound of the formula VII or VIIa. The decrease of this ratio reduces output. Thus, in the above reaction, the ratio of amine base to the compound of formula Va may be of 1.2:1 or more, but is usually from 2:1 to 3.5:1. The molar ratio of palladium to the compound of formula V is from 0.05:1 to 0.10:1. If you use, for example, [PdCl(allyl)]2that contains two mole of palladium per mole of catalyst, the ratio may be from 0.025:1 to 0.05:1. The molar ratio of phosphine ligand to palladium ordinary who is from 3:1 to 5:1, often approximately 4:1. The reaction may be conducted at temperatures from 25 to 125°usually at a temperature of from 40 to 70°and runs up until the reaction is practically complete. The presence of oxygen is minimized by blowing the reaction vessel with gaseous nitrogen before adding reagents.

The product from stage cooled to a temperature of from 0 to about 5°C. Then the product from step To add 3-6 volume of anti-solvent to the volume of solvent to precipitate the compounds of formula VIII or VIIIa. For the purposes of this invention, antibacterial defined as a non-reactive solvent in which the compound of formula VIII or VIIIa precipitates.

The suspension containing the precipitated compound of formula VIII or VIIIa, filtered or centrifuged. The precipitate on a filter or a centrifuge containing a compound of the formula VIII or VIIIa, re-suspended or directly washed with Isobutanol or isopropanol to remove residual palladium. For example, the filter cake containing the compound of formula VIII or VIIIa, can be washed in situ (for example, on the filter media) from 40 to 60 volumes of Isobutanol per unit dry weight of the compounds of formula VIII or VIIIa.

Alternatively, the residual palladium can be removed by re-dissolving the compounds of formula I in C1-6Alka is Aulnay solvent (such as methanol, ethanol or propanol) and the processing of the suspension containing the compound of formula IX or IXa, activated carbon, such as Darco G-60 or Ecosorb. Then the suspension was filtered to remove the activated carbon. Obviously, it is convenient to increase the solubility of the product in alkanones the solvent by heating alkanol (for example, to a temperature of from 25 to 70° (C) either before or after contact with the product. Typically, the suspension is kept in a warm condition within 1 to 6 hours and filtered warm.

Functionally complete metamorphosis, which is attained at the stage With, is the same as in a typical reaction mix on Sonogashira. As such, the stage With an efficient one-step method combining alkyne with arylalkenes. On the other hand, stage C is different from the reaction mix by Sonogashira in several important ways. For example, the reaction mix on Sonogashira usually requires the use of copper, zinc, magnesium or zirconium reagent in addition to the palladium catalyst. The preferred copper. However, the authors of this invention have found that when combined in Sonogashira (Sonogashira, K in Metal-Catalyzed Cross-Coupling Reactions; Diederich, F and Stang, P. eds; Wiley-VCH; Weinheim, Germany, 1998, Chapter 5. Cm. also, Littke, A and Fu, G. Angew. Chem. Int. Ed. 1998, 37, No. 24, page 3387-3388; Wolfe, J. Singer, R., Yang, B. and Buchwald, S., J. Am. Chem. Soc., 1999, 121, page 9550-9561.) compounds of formula Va and fo the mules VII formed on at least 10% dimer compounds of the formula Va in the product.

In Hermann, et al (Eur. J. Chem 2000, 3679-3681) described that if the palladium catalyst is selected properly, the necessity of using copper disappears. Two such catalysts are P(Cy)3-Pd-P(Cy)3and P(tert-butyl)3-Pd-P(tert-butyl)3(catalyst Fu). Such catalysts require special treatment. On the contrary, the catalysts in accordance with this invention receive the in situ reaction of a sustainable source of palladium (such as [Pd(allyl)Cl]2with sustainable commercially available pre-Packed ligand (such as 10 wt.% three-(tert-butyl)phosphine in hexane). Moreover, by producing the catalyst in situ, this invention provides a suitable ratio of ligand/palladium, are usually not available when using commercial products.

Stage D: the interaction in the solvent, the compounds of formula VIII with cyclopropylamino, optionally in the presence of phosphite or other catalysts.

For the purposes of this invention, the solvent is defined as including arcanely solvent, such as1-4alcoholnye solvents methanol, ethanol, propanol and butanol, and triptorelin, or mixtures thereof. Can also be used acetonitrile. For the purposes of this invention, the catalyst includes butylphosphate (BuO)3P), pyridine-N-oxides, trialkylated, zinc chloride, magnesium chloride, t is flat magnesium, triplet scandium, triplet lanthanum, triplet ytterbium, dichloride titanocene or dichloride zirconocene. It should be noted that for the purposes of this invention, the term "catalyst" means a reagent, which accelerates the reaction, even when present in large than the classic "catalytic" amounts.

The molar ratio of cyclopropylamine to the compound of formula VII or VIIIa is usually more than 1:1, often of 1.1:1 or more. The decrease in the specified ratio reduces output. The ratio of catalyst to compound of formula VIII or VIIIa typically ranges from 0.025:1 to 0.075:1, often about 0.05:1 or, perhaps, from 0.10:1 to 1:1 or more. When using magnesium chloride typical ratio of catalyst to compound of formula VIII or VIIIa is from 0.9:1 to 1:1,5. The reaction can be conducted at a temperature of from about 40 to about 60°usually at a temperature of 55-60°and it is held up until the interaction is almost complete. The presence of oxygen is minimized by blowing the reaction vessel with gaseous nitrogen before adding reagents. For optimum results it is desirable to stage D when Kf is equal to or below 3000 hours/million

The product from step D is cooled to a temperature of from 0 to about 30°With, usually to room temperature. The solvent is then replaced by Antibacterials (antibacterial), for example, viparita the receiving solvent followed by the addition of excess understories. For the purposes of this invention, antibacterial In is defined as a solvent in the reaction product (in this case, the compound of formula (IX), 3-6 volumes understories on the amount of solvent added to the product from step C for the deposition of compounds of formula VIII or VIIIa. For the purposes of this invention, antibacterial defined as a non-reactive solvent, in which is deposited the compound of formula VIII or VIIIa.

To remove impurities, the suspension containing the precipitated compound of formula VIII or VIIIa, washed with a solvent such as water, acetonitrile, isopropylacetate, ethyl acetate, tetrahydrofuran, ethanol, propanol and butanol. Then the solvent is removed, for example, filtration and vacuum drying. Filtered the compound of formula VIII or VIIIa may be mixed with the solvent transformations, such as dry ethanol, methanol, triptorelin, N-methylpyrrolidone, methyl tert-butyl ether or mixtures thereof, optionally heated and maintained at a temperature of from 40 to 50°With, before, until, at least 95% of the compound of formula VIII or VIIIa not the desired shape. The solvent is then becoming removed, for example, filtration or centrifugation, and the obtained product is dried in vacuum. The required amount of solvent transformations should be sufficient for the suspension or dissolution of the compounds is of formula VIII or VIIIa.

The term "aryl", unless otherwise indicated, includes systems with multiple rings, as well as systems with a single ring, such as, for example, phenyl or naphthyl.

The term "hetero", unless otherwise indicated, includes one or more O, S or N atoms. For example, heteroseksualci and heteroaryl include a system of rings that contain one or more O, S or N atoms in the ring, including mixtures of these atoms. The heteroatoms to replace the carbon atoms in the ring. Thus, for example, heterocycles5alkyl represents a 5-membered ring containing from 5 to 0 carbon atoms.

Examples of heteroaryl include, for example, pyridinyl, chinoline, ethenolysis, pyridazinyl, pyrimidinyl, pyrazinyl, honokalani, furyl, benzofuran, dibenzofuran, thienyl, benzothiazyl, pyrrolyl, indolyl, pyrazolyl, indazoles, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

The compounds described above, may include one or more centers of asymmetry and, thus, may have the diastereomers and optical isomers. The invention includes all such possible diastereomers as well as their racemic mixtures, their almost pure separated enantiomers, all possible geometric isomers, and their salts.

The implementation of this invention is illustrated by examples inhibit the s phosphodiesterase-4, which can be obtained by applying the present invention.

Dosage of from about 0.001 mg/kg to about 140 mg/kg of body weight per day is used for the treatment of such conditions as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in children, chronic obstructive pulmonary disease in animals, no diabetes, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and disease graft versus host disease, hypersecretion of gastric acid caused by bacteria, fungi or viruses sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle loss is Kani, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative diseases with inflammation, Parkinson's disease, Alzheimer's disease, spinal cord injury, grass heads, multiple sclerosis, tumour growth and cancerous invasion of normal tissues that respond to the inhibition FDA, or, alternatively, from 0.05 mg to about 7 g per patient per day. For example, inflammation can be treated effectively by the introduction of from about 0.01 mg to 50 mg of compound per kilogram of body weight per day, or, alternatively, from about 0.5 mg to about 2.5 g per patient per day. Further, it is clear that inhibiting PDE compounds in accordance with this invention can be administered in prophylactically effective amounts to prevent the above conditions.

The amount of active ingredient that may be combined with a carrier to obtain a standard dosage forms, varies depending on subject to treatment of the patient and way of doing. For example, the preparative form for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, combined with an appropriate and convenient amount of carrier which may vary from about 5 to about 95% by weight of the total composition. Standard dosage forms typically contain from about 0.01 mg to eye is about 1000 mg of the active ingredient, usually 0.01, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg

It is clear that the specific dose level for a particular patient will depend upon such factors as the age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs and the severity of a particular subject to treatment of disease.

The examples below are intended to illustrate certain preferred variants of the present invention and do not limit the invention.

Compounds in accordance with this invention can be obtained by the following methods. The substituents are the same as in the formula I, unless otherwise specified.

The intermediate compounds of formula V

NAPHTHYRIDIN 1

Stage 1: Ethyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

A mixture of ethyl-2-chloronicotinamide (commercially available or obtained by the method described in J. Het. Chem., 30, 855, 1993) (1 equiv.) triethylamine (4 EQ.) and ethyl 3,3-diethylaminoacetate (1.5 EQ.) in acetonitrile (0,5M) is refluxed for 3 h, cooled to a temperature of 40-50°and type 3-bromaniline (1 EQ.). The reaction mixture is boiled with the reverse was built in the ICOM during the night, cooled to room temperature, diluted with water (2 volumes). The product distinguish filtration and washed with water, ether or acetonitrile-water (1:1).

1H NMR (Acetone-d6) (1,32 (t, 3H), 4,29 (square, 2H), 7,54-7,63 (m, 2H), 7,69 (DD, 1H), 7,78 (DD, 1H), to 7.93 (s, 1H), 8,66-8,71 (m, 3H).

NAPHTHYRIDIN 2

Ethyl-1-(3-acetildenafil)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

According to the method of obtaining naphthyridine 1, but replacing 3-acetyltyrosine 3 bromaniline receive specified in the header of naphthyridin 2.

1H NMR (CDCl3) (of 1.42 (t, 3H), 3,19 (s, 1H), 4,20 (square, 2H), 7,42-7,46 (m, 2H), 7,53-to 7.59 (m, 2H), to 7.67 (dt, 1H), 8,64 (DD, 1H), 8,86 (s, 1H), 8,83 (DD, 1H).

NAPHTHYRIDIN 3

Ethyl-1-(3-cyanophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

According to the method of obtaining naphthyridine 1, but replacing 3-cyanoaniline 3 bromaniline receive specified in the header of naphthyridin 3.

1H NMR (DMSO-d6) (of 1.27 (t, 3H), 4,23 (square, 2H), EUR 7.57 (DD, 1H), 7,80 (t, 1H), of 7.96-of 8.04 (m, 2H), to 8.20 (t, 1H), 8,61 (DD, 1H), 8,86 (DD, 1H), to 8.70 (s, 1H).

NAPHTHYRIDIN 4

Ethyl-1-(4-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

According to the method of obtaining naphthyridine 1, but replacing 4-bromoaniline 3 bromaniline receive specified in the header of naphthyridin 4.

1H NMR (DMSO-d6) (1.26 in (t, 3H), 4,22 (square, 2H), 7,54-to 7.59 (m, 3H), 7,78 (l, 2) - Rev.), 8,61 (DD, 1H), 8,63 (s, 1H), 8,68 (DD,1H).

NAPHTHYRIDIN 5

Ethyl-1-(2-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

According to the method of obtaining naphthyridine 1, but replacing 2-bromoaniline 3 bromaniline receive specified in the header of naphthyridin 5.

1H NMR (DMSO-d6) (1.26 in (t, 3H), 4,23 (square, 2H), 7,53 to 7.62 (m, 3H), of 7.75 (DD, 1H), 7,78 (DD, 1H), 8,61 (s, 1H), 8,63 (DD,1H), 8,68 (DD, 1H).

NAPHTHYRIDIN 6

Ethyl-1-(2-tert-butylphenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

According to the method of obtaining naphthyridine 1, but replacing 1-bromo-2-tert-butylaniline 3 bromaniline receive specified in the header of naphthyridin 6.

1H NMR (DMSO-d6) (1,08 (s, N), 1,25 (t, 3H), 4,22 (square, 2H), 7,30-7,40 (m, 2H), 7,50-7,56 (m, 2H), 7,73 (DD, 1H), 8,59 (s, 1H), to 8.62 (DD, 1H), 8,70 (DD, 1H).

NAPHTHYRIDIN 7

Ethyl-1-(3-phenylboric acid)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

According to the method of obtaining naphthyridine 1, but replacing 3-aminophenylamino acid 3-bromaniline receive specified in the header of naphthyridin 7.

1H NMR (DMSO-d6) (1.26 in (t, 3H), 4,22 (square, 2H), 7,56 (match triplets, 2H), 7,60 (d, 1H), 7,87 (c, 1H), 7,94 (d, 1H), 8,24 (s, 2H, exchangeable), 8,61 (d,1H), to 8.62 (s, 1H), 8,68 (d, 1H).

Compounds inhibitors of PDE-4

The following are examples of compounds inhibitors of PDE-4, which can be p is obtained by methods described below. It should be noted that the number of formulas used in schemes 1-12 and descriptions of these schemes should not be confused with the numbers of the formulas used elsewhere in the bid. Compounds in examples 1-13 receive with the use of naphthyridine 1.

Scheme 1

In the first method described in scheme 1 below, appropriately substituted derivative ethyl-2-chloronicotinamide formula II is subjected to interaction with 1.5 equivalents of triethylorthoformate and 5 equivalents of acetic anhydride at a temperature of 130°and after removal of the volatile components of the crude 2-chloronicotinoyl formula III immediately subjected to interaction with 1.2 equivalents of the appropriately substituted halogenosilanes formula IV, such as, for example, 3-bromaniline, in a halogenated hydrocarbon solvent such as methylene chloride, at a temperature of from 0°C to room temperature. After the necessary reaction time ranging from 2 to 24 hours, the resulting 3-killingest formula V is obtained by evaporation of the solvent and further purified by chromatography on silica gel or by crystallization from a suitable solvent.

Alternatively, the compound of formula V can be used in the next stage without further purification. The cyclization of the compounds of formula V to 1-halogenared-1,4-dihydro[1,8]nafti the one-4-one of the carboxylate of the formula VI is carried out by treatment of a small excess of a strong base, such as an alkali metal hydride, e.g. sodium hydride, in a suitable solvent, such as tetrahydrofuran, at an initial temperature of 0°With heating to room temperature, if necessary to complete the process. The product of formula VI is isolated in crude form by dilution with large volumes of water followed by filtration or extraction into a suitable organic solvent, such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product may be further purified by chromatography on silica gel, crystallization or prolonged stirring in a suitable solvent followed by filtration.

Thus obtained product of formula VI can be hydrolyzed to the corresponding carboxylic acid derivative in the basic conditions using an aqueous solution of an alkaline base such as an alkali carbonate or, preferably, sodium hydroxide or potassium, with an organic co-solvent, such as tetrahydrofuran or primary, secondary or tertiary alkanol, such as methanol or ethanol, or a mixture thereof, at temperatures from room temperature to the boiling temperature under reflux, for a suitable period of time. The obtained carboxylic acid release neoc is on the form, followed by acidification using an aqueous solution of an inorganic acid, such as hydrochloric, sulphuric or other acid, and filtration or extraction into a suitable organic solvent, such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. Further, the product can be purified by chromatography on silica gel, crystallization or prolonged stirring in a suitable solvent followed by filtration.

Then the carboxylic acid is transformed into the corresponding analogue of primary, secondary, or tertiary amide of the formula VII by any common method, well-known specialist in the field of organic chemistry, preferably through the initial conversion into a mixed anhydride by treatment of a small excess, for example, 1.25 equivalent, corresponding alkylphosphonate, such as ethyl - or isobutylparaben, in the presence of a larger excess, for example, 2.5 equivalents, of a tertiary organic amine such as triethylamine or N,N-diisopropylethylamine, in an organic solvent, such as tetrahydrofuran, at low temperature, preferably 0°during from 30 minutes to 3 hours. Then add an excess, usually 5 or more equivalents of the appropriate primary or secondary amine or an aqueous solution of ammonium hydroxide, and the resulting reaction mixture is maintained at is the temperature from 0° With up to room temperature within a reasonable period of time, usually 1 to 24 hours.

Then the desired amide of formula VII is isolated in crude form by precipitation with water and filtration or extraction into an appropriate organic solvent, such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. Further, the product can be purified by chromatography on silica gel, crystallization or prolonged stirring in a suitable solvent followed by filtration. If the amide group is a 2,6-dichloropyridine-4-yl, used another method in which the anion of 4-amino-3,5-dichloropyridine is formed at a low temperature, preferably at 0°using a strong alkali hydride such as sodium hydride, in a solvent such as tetrahydrofuran, and it is subjected to the interaction with the acid chloride of carboxylic acid (after hydrolysis of ester of the formula (VI), obtained by a suitable known method, typically from oxalicacid activated catalytic amount of N,N-dimethylformamide in a solvent such as tetrahydrofuran.

Amides of General formula VII in turn the products of formula I by interaction with the appropriately substituted aryl or heteroaryl boric acid or boric EF the RA of formula VIII in the presence of a catalyst based on a transition metal, such as TRANS-dibromobis(triphenylphosphine)palladium (II) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), in a suitable solvent or mixture of solvents, preferably 1:1 mixture of toluene and ethanol, in the presence of an excess of an aqueous solution of an alkaline base such as sodium carbonate, at a suitable temperature, preferably from 50 to 100°C, for a suitable period of time, from 0.5 to 48 hours.

The resulting reaction product is then isolated in crude form by precipitation with water and filtration or extraction into a suitable organic solvent, such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can then be purified by chromatography on silica gel, crystallization or prolonged stirring in a suitable solvent followed by filtration.

The compounds of formula I can also be obtained by the coupling of compounds of formula VII with an appropriately substituted aryl - or heteroarylboronic formula IX using a catalyst based on a transition metal, such as TRANS-dibromobis(triphenylphosphine)palladium (II) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)in the presence of copper compounds (I), such as copper iodide, in a suitable solvent such as N,N-dimethy is formamid, at a temperature of from 50 to 100°C for from 2 to 24 hours. The reaction product is carried out as described above.

Alternatively, the ester of formula VI can be converted into an ester of formula X interaction with the appropriately substituted boronic acid or boronic ester, or with an appropriately substituted derivative of stannane, in the above-described conditions, and the ester can be hydrolyzed and converted into an amide of formula I.

Boric acid of formula VIII or the corresponding boronic esters are usually obtained from commercial sources. If necessary, they can be easily derived from the corresponding halides by metallation of n-butyllithium with subsequent interaction with trialkylborane, or using the classic methods of combining catalyzed by the transition metal, with the use of tibarenians ether. Stannane formula IX is obtained from the corresponding halides first by metallation using n-utility, then the addition of chloride of anti.

Scheme 1

In an alternative method of preparing compounds of formula I, is shown in scheme 2 below, amide of formula VII can be converted to the corresponding boronic ester of formula XI by treatment with excess tibarenians ether in the presence of inorganic salts, such as acetate feces is I, in the presence of a catalyst based on a transition metal, such as TRANS-dibromobis(triphenylphosphine)palladium (II) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), in a solvent such as N,N-dimethylformamide, at a temperature of from 50 to 100°C for from 1 to 48 hours. The borate of the formula XI can be isolated by precipitation with water and filtration or extraction into an appropriate organic solvent, such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The resulting product may be further purified by chromatography on silica gel, crystallization or prolonged stirring in a suitable solvent followed by filtration.

Alternatively, the borate of the formula XI can be used in situ in the reaction medium without selection and are subject to interaction with a small excess of the appropriately substituted aryl - or heteroarylboronic formula XII in the presence of a catalyst based on a transition metal, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), in a suitable solvent or mixture of solvents, preferably 1:1 mixture of toluene and ethanol, in the presence of an excess of an aqueous solution of an alkaline base such as sodium carbonate, at a suitable temperature, preferably from 50 to 100°With, during the s a suitable period of time from 0.5 to 48 hours.

The reaction product of formula I is then isolated in crude form by precipitation with water and filtration or extraction into a suitable organic solvent, such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The resulting product may be further purified by chromatography on silica gel, crystallization or prolonged stirring in a suitable solvent followed by filtration.

Scheme 2

In the third method for the synthesis of compounds of formula I in accordance with this invention (scheme 3), intermediate nicotinergic formula III is subjected to interaction with appropriately obtained diaryl - or heteroelement formula XIII under the conditions described above, to obtain compounds of formula XIV, which cyclist interaction with a strong base such as sodium hydride, as described above, obtaining a complex ester of the formula X, which is converted into a compound of formula I by hydrolysis and formation of amide, as described above.

Scheme 3

Derivatives, diaryl - or heteroarylboronic formula XIII will receive as shown in figure 4. Appropriately substituted unilibro acid of formula XV is subjected to a combination of aniu with an appropriately substituted aryl - or heteroarylboronic formula XII in the presence of a catalyst based on a transition metal as described above, obtaining compounds of formula XIII used in scheme 3.

Scheme 4

Bromopyridine intermediate compound, substituted in position 2 by nucleophiles carbon-based formula XVII, in which R8selected from R2groups, which are linked by carbon-carbon pyridine, will receive as shown in scheme 5. Bromopyridine intermediate compounds obtained from dihalogenide formula XVI by treatment of the corresponding solution of the Grignard reagent, in the presence of a catalyst based on a transition metal, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloro Nickel (II), in a solvent such as tetrahydrofuran, at temperatures from -10°C to room temperature, and the reaction mixture is treated by well-known methods to give the desired product.

Scheme 5

Haloperidole intermediate compounds of the formula XVIII, in which the substituent in position 2 is alkoxygroup OR9receive from dihalogenide formula XVI by substitution of the appropriate alkali alkoxide, as shown in scheme 6. The reaction is carried out in a solvent such as N,N-dimethylformamide, at a temperature of from 0°C to room temperature, and at the completion of the reaction products are isolated and purified by classical methods.

Schemes is 6

If necessary intermediate compounds of formulas XIX or XX, in which the substituent in position 2 is a sulfide, sulfoxide or sulfon, get them as described in scheme 7. The corresponding developedin formula XVI is subjected to interaction with the corresponding toolboxitem, usually derived from the corresponding thiol or disulfide under the action of strong bases, such as alkali hydride or n-utility, in a solvent such as N,N-dimethylformamide or diethyl ether, at temperatures from -78°C to room temperature. At the completion of the reaction products of the formula XIX isolate and purify the classical methods. The resulting products can be oxidized to the corresponding sulfoxidov or sulfones of formula XX processing oxidizing agent such as oxen or organic peroxynitrate. In figure 7, R10is N or C1-6the alkyl.

Scheme 7

Getting halogencontaining intermediate compounds of formula XXII presented in figure 8, requires processing halogenopyrimidines ether of formula XXI with a solution of the corresponding Grignard reagent, in a solvent such as diethyl ether, at a temperature of from 0°C to room temperature. If the reaction is carried out for more than glutelin the th period of time or by boiling under reflux, get halogenopyrimidines formula XXIII. In schemes 8 and 9 R7is1-6the alkyl and R6is stands or ethyl.

Scheme 8

Figure 9 shows an alternative method of synthesis of certain halogenopyrimidines formula XXIII. If 2.5-dibromopyridin treated with n-butyllithium in toluene at a temperature of -78°C, followed by addition of an appropriate ketone or aldehyde, with subsequent quenching of the reaction at a temperature of -78°receive a carbinol of formula XXIII in which the carbinol group occupies position 2 of the pyridine ring. If the stage of metallation is carried out in diethyl ether, the same process yields an intermediate compound of formula XXIII in which the carbinol group occupies position 5 of the pyridine ring.

Scheme 9

R7and R8may be the same or different,

or R7or R8can be hydrogen.

Figure 10 shows the methods of synthesis of compounds of formula I in which R2is substituted by phenyl or heteroaryl. The intermediate compound of the formula I, in which R2is halogen, is subjected to the interaction with an appropriately substituted boronic acid or boronic ester of formula VII or tributylstannyl formula IX, use the Zuya one of the methods described above, to give the desired compound.

Scheme 10

Various further transformations of pre-obtained compounds of the formula I presented in scheme 11. If the aryl group is a pyridine or quinoline group, the compound can be oxidized to the corresponding nitrogen oxide processing appropriate oxidizing agent such as m-chloroperoxybenzoic acid or monoperoxyphthalic magnesium, usually applied conditions. If one or more substituents Ar group is a ketone, the compound is converted into a analog oxime by treatment with hydroxylamine in pyridine as solvent. Sulfide Deputy is easily oxidized to the corresponding sulfoxide or sulfone in the application of the appropriate amount of oxidant, such as oxen or organic peroxynitrate.

The transformation of 2-benzyloxypyridine in the corresponding 2-pyridone perform processing triperoxonane acid in a solvent such as methylene chloride, at room temperature or with slight heating. The removal of the tert-butoxycarbonyl protective group of piperazinovogo rings provide interaction with triperoxonane acid in a solvent such as 1,2-dichloroethane at the boiling point under reflux. P is imarah, where the Deputy Ar is hydroxymethylene group, it can be transformed in a similar halogenmethyl group using Tetrachloromethane in the presence trisemester phosphine, such as triphenylphosphine or divos, in a solvent such as methylene chloride. The halide may be substituted for the corresponding sodium salt sulfinol acid to obtain alkyl - or arylsulfonyl equivalent.

Scheme 11

The conversion of 1-hydroxy-1-medicalcollege derived, such as the compounds of formula XXIV in scheme 12, 1.2-dihydroxyacetone analogs of formula XXVI carried out first by dehydration using an acidic catalyst, for example, by heating in aqueous sulfuric acid, to obtain the intermediate 1-alkylvinyl the compounds of formula XXV, which is transformed into the desired diol of formula XXVI by dihydroxypropane using, for example, an oxidizing agent, such as 4-methylmorpholine N-oxide (NMO) in the presence of catalytic amounts of osmate dihydrate potassium.

Scheme 12

Examples

Examples of the present invention, shown in the following table, refer to the formula (I)

N
Table 1
ExampleRR1R2R3R4R6
1Nisopropyl3-C(O)IUNNN
2N3-C(O)IUNNN
3Nisopropyl4-n-propylNNN
4Nisopropyl3-C(O)IUNNN
5Hisopropyl2-MeNNN
6Meisopropyl4-C(O)MeNNN
9Ntertbutyl4-C(O)MeNNN
11NisopropylNNN
16Ncyclopropyl4-CH2OHNN
18Ncyclopropyl4-SEtNNN
20Ncyclopropyl4-SO2NH2NNN
21Nisopropyl3-OEtNNN
22Nisopropyl4-SMeNNN
23Nisopropyl3-C(O)IU4-OHNN
49Nisopropyl4-SO2MeNNN
52Ncyclopropyl4-SO2EtNNN
53Ncyclopropyl4-S(O)EtNNN
54Nisopropyl4-C(=NOH)MeNNN
55NisopropylN NN
56Ncyclopropyl4-CH2SO2MeNNN

Table 2
ExampleRR1π-positionR2R3R4R6n
7Hisopropyl3HHHH0
10H3HHHH0
14Hcyclopropyl3HHHH0
15Hisopropyl35-SMeHHH0
17Hcyclopropyl4HHHH0
24 Hisopropyl35-COOEtHHH0
25Hisopropyl35-CMe2OHHHH0
26Hisopropyl36-CH2CHMe2HHH0
27Hisopropyl35-C(O)MeHHH0
28Hisopropyl36-MeHHH0
30HN36-CMe2OHHHH1
32Hcyclopropyl35-SO2MeHHH0
33Hcyclopropyl24-CMe2OHHHH1
34Hcyclopropyl2-CMe 2OHHHH0
35Hcyclopropyl43-CMe2OHHHH0
36Hcyclopropyl43-CMe2OHHHH1
37Hcyclopropyl36-SO2isopropylHHH0
38Hcyclopropyl36-OMeHHH0
39Hcyclopropyl36-MeHHH0
40Hcyclopropyl36-OCH2CF3HHH0
41Hcyclopropyl35-BrHHH0
42Hcyclopropyl36-OCH2PhH HH0
43Hcyclopropyl36-C(cyclopropyl)2OHHHH0
44Hcyclopropyl35-CMe2OHHHH1
45Hcyclopropyl36-CMe2OHHHH0
46Hisobutyl36-CMe2OHHHH0
47Hcyclopropyl36-CMe2OHHH5-Br0
48Hcyclopropyl36-CMe2OHHHH0
50Hcyclopropyl36-SO2MeHHH0
51Hisopropyl35-SO2MeHH H0
59Hisopropyl3HHHH1
60H3HHHH1
61Hisopropyl35-COOEtHHH1
62Hisopropyl35-CMe2OHHHH1
63Hisopropyl36-CH2CHMe2HHH1
64Hisopropyl36-MeHHH1
65Hcyclopropyl3HHHH1
66Hcyclopropyl36-CMe2OHHHH1
67H/td> cyclopropyl4HHHH1
68Hcyclopropyl35-BrHHH1
73Hisobutyl36-CMe2OHHHH1
74Hcyclopropyl36-MeHHH1
75Hcyclopropyl36-SO2MeHHH1
76Hcyclopropyl36-CMe2OHHH5-Br1
77cyclopropyl36-CMe(CH2OH)OHHHH1

Table 3
ExampleRR1Ar R4R6
8Hisopropylindol-5-ylHH
12Hisopropylthe quinoline-3-ylHH
13Hisopropylpyrimidine-5-ylHH
19Hcyclopropyl3-thienylHH
29Hcyclopropyl1-oxidability-5-ylHH
57HcyclopropylHH
72Hisopropyl1-acidogenesis-3-ylHH

Table 4
ExampleRR1ArAr1R4R6
31NisopropylPh4-(pyridin-3-yl)N N
58Ncyclopropylpyridine-3-ylNN
69Ncyclopropylpyridine-3-ylNN
70Ncyclopropyl1-oxidability-3-ylNN
71Hcyclopropyl1-oxidability-3-ylNN

Table 5
R1R4R6Ar
cyclopropylHH
cyclopropylHH
isopropyl7-MeH
isopropylH5-Me
cyclopropylHH
cyclopropylHH
cyclopropylHH
cyclobutylH6-F
6-FH
HH
5-F4-F
isopropylHH
isopropylHH
isopropylHH
cyclopropylHH
HH
cyclopropylHH
cyclobutylHH
HH
HH

Example 1

N-Isopropyl-1-[3-(3-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: Ethyl-3-(3-bromoaniline)-2-(2-chloronicotinoyl)acrylate

A mixture of ethyl-2-chloronicotinamide (41,1 g of 180.5 mmol), triethylorthoformate (40,12 g, 271 mmol) and acetic anhydride (92,05 g, 902,5 mmol) is heated at a temperature of 130°C for 2.5 hours. Volatile components are distilled off and the residue together twice evaporated with xylene. The oily residue is dissolved in methylene chloride (250 ml) and added slowly 3-bromaniline (37,25 g, 216,6 mmol). The resulting solution was stirred at room temperature for 18 hours and the solvent is evaporated. The crude compound is used as is in the next stage.

Step 2: Ethyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-the n-3-carboxylate

The crude compound from step 1 was dissolved in tetrahydrofuran (500 ml), the solution is cooled to a temperature of 0°and portions add sodium hydride (60% dispersion in oil, 9.4 g, 235 mmol). After stirring at a temperature of 0°C for 1 hour mixture was allowed to warm to room temperature. After 2 hours the suspension add water (400 ml) and the insoluble solid is filtered and rinsed with water. When it dries, the solid is stirred in ether (150 ml) at room temperature for 24 hours and filtered to obtain specified in the connection header in the form of a cream solid.

1H NMR (Acetone-d6) (1,32 (t, 3H), 4,29 (square, 2H), 7,54-7,63 (m, 2H), 7,69 (DD, 1H), 7,78 (DD, 1H), to 7.93 (s, 1H), 8,66-8,71 (m, 3H).

Stage 3: 1-(3-Bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid

A suspension of ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate from step 2 (52,5 g 140,7 mmol) in a mixture of tetrahydrofuran (400 ml), methanol (400 ml) and 1N aqueous sodium hydroxide (280 ml) is heated at a temperature of about 50°With stirring for 20 minutes. After cooling, the mixture was diluted with water (300 ml) and add 1N aqueous HCl (325 ml). After stirring for 45 minutes the precipitate is filtered, well washed with water and dried to obtain specified in the title acid as a cream Tverdov the substance.

1H NMR (Acetone-d6) (the 7.65 (t, 1H), 7,76 (m, 2H), to 7.84 (d, 1H), to 7.99 (s, 1H), 8,87 (m, 2H), 9,01 (s, 1H).

Stage 4: N-Isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid from step 3 (26,3 g, 76 mmol) and triethylamine (23,2 g, 230 mmol) in tetrahydrofuran (1000 ml) at a temperature of 0°With add isobutylparaben (18,85 g, 138 mmol). After stirring at a temperature of 0°C for 2 hours added Isopropylamine (23 g, 390 mmol) and the mixture was allowed to warm to room temperature and stirred over night. Then the mixture is distributed between ethyl acetate and water, the organic phase is dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to obtain N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

1H NMR (Acetone-d6) (1,25 (d, 6N), 4,17 (m, 1H), to 7.59-7,63 (m, 2H), of 7.70 (d, 1H), 7,80 (d, 1H), 7,94 (s, 1H), 8,73 (m, 1H), 8,78 (d, 1H), cent to 8.85 (s, 1H), being 9.61 (ush., NH).

Stage 5: N-Isopropyl-1-[3-(3-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

A mixture of N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from step 4, 3-acetylphenylalanine acid (1.2 equiv.) TRANS-dibromobis(triphenylphosphine)palladium (II) is 0.05 equiv.) toluene (6 ml/mm is l), ethanol (2 ml/mmol) and 2M aqueous sodium carbonate (8 EQ.) refluxed for 1 hour in nitrogen atmosphere. The mixture is diluted with ethyl acetate and the organic phase is washed with water and saturated salt solution, dried and evaporated. The crude product is subjected to chromatography on silica gel, elwira gradient 20-40% ether in methylene chloride to obtain the product N-isopropyl-1-[3-(3-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (1,29 (d, 6N), to 2.65 (s, 3H), 4,28 (m, 1H), 7,47 (m, 2H), 7,55 (t, 1H), 7,65 (m, 2H), 7,80 (m, 2H), 7,95 (DD, 1H), 8,19 (USS, 1H), 8,70 (DD, 1H), 8,81 (DD, 1H), 9,05 (s, 1H), 9,65 (ush., NH).

Example 2

N-(2,6-Dichloropyridine-4-yl)-1-[3-(3-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: the Anion of 4-amino-3,5-dichloropyridine

A suspension of sodium hydride as a 60% dispersion in oil (360 mg, 9 mmol) in tetrahydrofuran (15 ml) is cooled to a temperature of 0°C. Slowly add a solution of 4-amino-3,5-dichloropyridine (978 mg, 6 mmol) in tetrahydrofuran (15 ml). The mixture was incubated at a temperature of 0°C for 2.5 hours.

Stage 2: the acid chloride of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid

A suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid from step 3 of example 1 (690 mg, 2 the mole) in tetrahydrofuran (12 ml) is cooled to a temperature of 0° With and add oxalicacid (381 mg, 3 mmol) followed by the addition of 2 drops of N,N-dimethylformamide. Then the resulting mixture was stirred at room temperature for 1 hour, then refluxed for 45 minutes and cooled to room temperature.

Stage 3: N-(2,6-Dichloropyridine-4-yl)-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

The mixture from stage 2 in the form of a brown suspension is added through a syringe to a cold suspension with stage 1. The resulting mixture was stirred at room temperature for 18 hours, quenched with aqueous saturated solution of ammonium chloride and distributed between ethyl acetate and water. The crude product after evaporation of the organic phase triturated with ether (50 ml) and filtered to obtain N-(2,6-dichloropyridine-4-yl)-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a beige solid.

1H NMR (Acetone-d6) (to 7.61-of 7.70 (m, 2H), 7,76 (d, 1H), 7,81 (d, 1H), 8,00 (s, 1H), to 8.62 (s, 2H), 8,80 (USS, 1H), 8,86 (d, 1H), 8,99 (s, 1H) 12,1 (ush., NH).

Stage 4: N-(2,6-Dichloropyridine-4-yl)-1-[3-(3-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing N-(2,6-dichloropyridine-4-yl)-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide with stage 3 N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide receive N-(2,6-d is chloropyridin-4-yl)-1-[3-(3-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (to 2.65 (s, 3H), 7,47 (d, 1H), 7,50-of 7.60 (m, 2H), of 7.70 (m, 2H), 7,82 (d, 2H), 7,98 (d, 1H), to 8.20 (s, 1H), 8,55 (s, 2H), 8,75 (USS, 1H), of 8.92 (DD, 1H), 9,14 (s, 1H) 12,08 (ush., NH).

Example 3

N-Isopropyl-1-[3-(4-n-propylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but substituting 4-n-propylaniline acid 3-acetylphenylalanine acid, get mentioned in the title compound as a white solid.

1H NMR (Acetone-d6) (0,93 (t, 3H), 1,24 (d, 6N), of 1.65 (m, 2H), 2,62 (t, 2H), 4,18 (m, 1H), 7,31 (d, 2H), 7,58-to 7.61 (m, 2H), 7.68 per-7,72 (m, 3H), 7,87 (d, 1H), 7,95 (s, 1H), 8,72 (m, 1H), 8,78 (DD, 1H), of 8.92 (s, 1H), 9,66 (ush., NH).

Example 4

N-Isopropyl-1-[3-(4-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing 4-acetylphenylalanine acid 3-acetylphenylalanine acid, receive specified in the title compound in the form of solids.

1H NMR (Acetone-d6) (1,25 (d, 6N), 2,61 (s, 3H), 4,17 (m, 1H), to 7.59 (m, 1H), of 7.70 (d, 1H), 7,76 (t, 1H), 7,92 (d, 2H), of 7.97 (d, 1H), 8.07-a 8,10 (m, 3H), 8,72 (USS, 1H), 8,78 (DD, 1H), of 8.92 (s, 1H) 9,65 (ush., NH).

Example 5

N-Isopropyl-1-[3-(2-were)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing 2-methylphenylimino acid 3-acetylphenylalanine is islote, get listed in the title compound in the form of solids.

1H NMR (Acetone-d6) (1,24 (d, 6N), to 2.35 (s, 3H), 4,17 (m, 1H), 7,27-7,34 (m, 4H), 7,56-of 7.60 (m, 2H), 7,65 (m, 2H), of 7.70 (t, 1H), total of 8.74 (m, 1H), 8,78 (DD, 1H), of 8.92 (s, 1H) for 9.64 (ush., NH).

Example 6

N-Isopropyl-N-methyl-1-[3-(4-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: N-Isopropyl-N-methyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 1, step 4, but substituting N-isopropyl-N-methylamine Isopropylamine, to obtain N-isopropyl-N-methyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of a yellow solid.

1H NMR (Acetone-d6) (exists in two rotamers of amide) (1,18 (m, 6N), 2,85 (s, 3H), of 4.05 (m, 0,5H), 4,84 (m, 0,5H), 7,49-to 7.64 (m, 3H), 7,72 (d, 1H), 7,86 (s, 1H), 8,14 (s, 1H), 8,65 (d, 2H).

Stage 2: N-Isopropyl-N-methyl-1-[3-(4-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but substituting N-isopropyl-N-methyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide with stage 1 N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide and replacing 4-acetylphenylalanine acid 3-acetylphenylalanine acid, receive N-isopropyl-N-methyl-1-[3-(4-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of a white solid.

1N I Is R (CDCl 3) (exists in two rotamers of amide) (1,23 (m, 6N), 2,62 (s, 3H), 4.00 points (m, 0,5H), 4.92 in (m, 0,5H), 7,38-of 7.55 (m, 2H), 7,63-to 7.77 (m, 5H), 8,03 (d, 2H), 8,14 (s, 0,5H), 8,21 (s, 0,5H), 8,65 (m, 1H), 8,75-8,80 (m, 1H).

Example 7

N-Isopropyl-1-[3-(pyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing pyridine-3-boronic acid 1,3-propanediylbis cyclic ether 3-acetylphenylalanine acid and replacing [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) TRANS-dibromobis(triphenylphosphine)palladium (II)receive specified in the title compound as a beige solid.

1H NMR (Acetone-d6) (1,24 (d, 6N), 4,17 (m, 1H), of 7.48 (m, 1H), 7,60 (m, 1H), 7,71 (DD, 1H), 7,78 (t, 1H), 7,95 (DD, 1H), 8,05 (USS, 1H), 8,15 (m, 1H), at 8.60 (m, 1H), 8,72 (m, 1H), 8,78 (DD, 1H), of 8.92 (s, 1H), 8,99 (USS, 1H), 9,65 (ush., NH).

Example 8

N-Isopropyl-1-[3-(indol-5-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing 5-indolinone acid 3-acetylphenylalanine acid, get mentioned in the title compound in the form of a whitish solid.

1H NMR (DMSO-d6) (1,20 (d, 6N), 4,10 (m, 1H), 6,47 (s, 1H), 7,38 (USS, 1H), 7,46-7,52 (m, 3H), to 7.59-7,66 (m, 2H), 7,87-to 7.93 (m, 3H), 8,72-8,81 (m, 3H), 9,67 (ush., NH), and 11.2 (ush., NH).

Example 9

N-tert-Butyl-1-[3-(4-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-of the-3-carboxamide

Stage 1: N-tert-Butyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 1, step 4, but substituting tert-butylamine Isopropylamine, to obtain N-tert-butyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of a yellow solid.

1H NMR (Acetone-d6) (the 1.44 (s, N), 7,58 to 7.62 (m, 2H), of 7.70 (DD, 1H), 7,78 (DD, 1H), 7,93 (USS, 1H), 8,72 (m, 1H), 8,77 (DD, 1H), 8,81 (s, 1H) 9,73 (ush., NH).

Stage 2: N-tert-Butyl-1-[3-(4-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing N-tert-butyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide with stage 1 N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide and replacing 4-acetylphenylalanine acid 3-acetylphenylalanine acid, receive N-tert-butyl-1-[3-(4-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide with the release of 93% in the form of a white solid.

1H NMR (Acetone-d6) (1,45 (s, N), 2,61 (s, 3H), to 7.59 (m, 1H), 7,69-7,72 (m, 1H), to 7.77 (t, 1H), 7,92-to 7.99 (m, 3H), 8.07-a 8,11 (m, 3H), 8,72 (m, 1H), 8,78 (DD, 1H), 8,91 (s, 1H), 9,79 (ush., NH).

Example 10

N-(2,6-Dichloropyridine-4-yl)-1-[3-(pyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 4 of example 2, but replacing [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), TRANS-di is rambis(triphenylphosphine)palladium (II) and substituting pyridine-3-boronic acid 1,3-propanediylbis cyclic ether 3-acetylphenylalanine acid, get listed in the title compound in the form of a transparent solid substance.

1H NMR (Acetone-d6) (of 7.48 (m, 1H), 7,68 (m, 1H), to 7.77-of 7.82 (m, 2H), 7,98 (m, 1H), 8,12-8,17 (m, 2H), 8,61 (m, 1H), to 8.62 (s, 2H), 8,80 (m, 1H), 8,88 (DD, 1H), 8,99 (USS, 1H), 9,06 (s, 1H), 12,2 (ush., NH).

Example 11

N-Isopropyl-1-{3-[4-(4-tertbutyloxycarbonyl-1-yl)phenyl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 4-tert-Butyloxycarbonyl-1-(3-bromophenyl)piperazine

To a suspension of the hydrochloride of 1-(4-bromophenyl)piperazine (103,15 g, 371,59 mmol) in acetonitrile (1.5 l) at temperature 0°C in an atmosphere of nitrogen is added a catalytic amount of 4-dimethylaminopyridine (4,54 g, 37,159 mmol) followed by the addition of triethylamine (155 ml, 1114,77 mmol) and di-tert-BUTYLCARBAMATE (121,65 g, 557,385 mmol, dissolved in a minimal amount of acetonitrile, and the resulting reaction mixture is heated to room temperature and stirred for 5.5 hours. The reaction mixture is filtered, add ethyl acetate and the organic phase is washed with 10% aqueous citric acid, water (2x) and saturated salt solution, then dried and evaporated to obtain the crude product 4-tert-butyloxycarbonyl-1-(3-bromophenyl)piperazine, which is used as such in the next stage.

Stage 2: 3-(4-tert-Butyloxycarbonyl-1-yl)-foilborne the acid

To 4-tert-butyloxycarbonyl-1-(3-bromophenyl)piperazine from step 1 (118,30 g, 346,9 mmol) in tetrahydrofuran/toluene (1/1, 1.5 l) at a temperature of -78°C in nitrogen atmosphere are added dropwise n-utility (2,5M, 160 ml, 398,9 mmol) and the resulting reaction mixture is stirred at a temperature of -78°C for 20 minutes. Added dropwise triisopropylsilyl (96,1 ml, 416,3 mmol) and the reaction mixture is heated to a temperature of 0°C and stirred for 2 hours. Add aqueous saturated ammonium chloride (400 ml), water (100 ml) and 1 equivalent of N3RHO4(20 ml) and the mixture is stirred for 15 minutes, then concentrated to a volume of approximately 200 ml (at this stage the mixture becomes bluish and sludge). The mixture is slowly diluted with heptane (800 ml) and the resulting suspension is stirred over night. The suspension is filtered, the solid is washed with heptane and dried to obtain specified in the header of boric acid.

Stage 3: N-Isopropyl-1-{3-[4-(4-tertbutyloxycarbonyl-1-yl)phenyl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) TRANS-dibromobis(triphenylphosphine)palladium (II) and substituting boric acid from stage 2 3-acetylphenylalanine acid, receive a 4-tert-butyloxycarbonyl-1-(3-bromophenyl)pieperazinove proizvodnje in the form of solids.

1H NMR (CDCl3) (1,30 (d, 6N), for 1.49 (s, N), 3,18 (m, 4H), to 3.58 (m, 4H), 4,29 (m, 1H), 6,98 (d, 2H), 7,32 (d, 1H), 7,45 (m, 1H), 7,53 (d, 2H), 7,55 to 7.62 (m, 2H), 7,72 (d, 1H), 8,70 (m, 1H), 8,82 (d, 1H), 9,07 (s, 1H), 9,68 (ush., NH).

Example 12

N-Isopropyl-1-[3-(quinoline-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-carboxamid

According to the method stage 5 of example 1, but replacing 3-henrybarnes acid 3-acetylphenylalanine acid, receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (1,29 (d, 6N), the 4.29 (m, 1H), 7,49 (m, 2H), to 7.61 (t, 1H), 7,70 for 7.78 (m, 3H), 7,86-a 7.92 (m, 2H), 8,14 (d, 1H), at 8.36 (s, 1H), 8,71 (m, 1H), 8,84 (DD, 1H), 9,10 (s, 1H), 9,19 (s, 1H) 9,67 (ush., NH).

Example 13

N-Isopropyl-1-[3-(pyrimidine-5-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-carboxamid

According to the method stage 5 of example 1, but replacing 5-pyrimidinone acid 3-acetylphenylalanine acid, receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (1,28 (d, 6N), 4,27 (m, 1H), of 7.48 (DD, 1H), 7,52 (m, 1H), 7,65 (s, 1H), 7,74 (m, 2H), 8,68 (m, 1H), 8,72 (d, 1H), 8,98 (s, 2H), 9,03 (s, 1H), which 9.22 (s, 1H) 9,62 (ush., NH).

Example 14

N-Cyclopropyl-1-[3-(pyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: N-Cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 1, stage 4, n is replacing cyclopropylamine Isopropylamine, get N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a fluffy solid.

1H NMR (Acetone-d6) (0,59 (m, 2H), 0,80 (m, 2H), 2,96 (m, 1H), to 7.59-to 7.68 (m, 2H), 7,72 (DD, 1H), 7,82 (DD, 1H), of 7.97 (s, 1H), 8,72-8,81 (m, 2H), 8,89 (s, 1H) 9,70 (ush., NH).

Stage 2: N-Cyclopropyl-1-[3-(pyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 7, but replacing N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide with stage 1 N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide receive N-cyclopropyl-1-[3-(pyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of a cream solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,78 (m, 2H), 2.91 in (m, 1H), 7,52 (m, 1H), 7,63-of 7.69 (m, 2H), 7,74 (t, 1H), of 7.97 (d, 1H), 8,07 (USS, 1H), 8,17 (d, 1H), 8,61 (m, 1H), 8,73 (DD, 1H), 8,79 (m, 1H), cent to 8.85 (s, 1H), 8,99 (USS, 1H), 9,74 (ush., NH).

Example 15

N-Isopropyl-1-[3-(5-methylthiopyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing 5-methylthiopyridine-3-boronic acid 3-acetylphenylalanine acid and replacing [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) TRANS-dibromobis(triphenylphosphine)palladium (II)receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (1,33 (d, 6N), 2,60 (s, 3H), 4,33 (m, 1H), of 7.48-7,54 m, 2H), 7,66 (m, 1H), 7,73 (t, 1H), 7,78-7,81 (m, 2H), 8,55 (s, 1H), 8,66 (s, 1H), total of 8.74 (m, 1H), 8,87 (d, 1H), which is 9.09 (s, 1H), RS 9.69 (ush., NH).

Example 16

N-Cyclopropyl-1-[3-(4-hydroxymethylene)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 14, but replacing 4-gidroksietilirovanny acid pyridine-3-boronic acid 1,3-propanediylbis cyclic ether, receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (0,71 (m, 2H), 0,89 (m, 2H), 1,88 (t, 1H), 3,03 (m, 1H), 4,78 (d, 2H), 7,43 (d, 1H), 7,46-7,52 (m, 3H), to 7.61-of 7.69 (m, 4H), 7,80 (d, 1H), 8,73 (m, 1H), 8,83 (DD, 1H), 9,10 (s, 1H), 9,82 (ush., NH).

Example 17

N-Cyclopropyl-1-[3-(pyridin-4-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method stage 5 of example 1, but replacing N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide and replacing 4-pyridineboronic acid 3-acetylphenylalanine acid, get mentioned in the title compound as a white solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,77 (m, 2H), 2,90 (m, 1H), to 7.64 (m, 1H), 7,72-7,89 (m, 4H), 8,03 (d, 1H), 8,13 (s, 1H), 8,66-8,78 (m, 4H), 8,84 (s, 1H) 9,72 (ush., NH).

Example 18

N-Cyclopropyl-1-[3-(4-ethylthiophene)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 14, but replacing 4-ethylthioxanthone acid pyridine-3-boronic acid 1,3-propanediylbis cyclic ether, receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (0,72 (m, 2H), 0,90 (m, 2H), 1,48 (t, 3H), 3,03 (m, 3H), 7,42 (d, 3H), 7,50 (m, 1H), EUR 7.57 (d, 2H), to 7.64 (s, 1H), 7,68 (t, 1H), 7,78 (d, 1H), up 8.75 (m, 1H), cent to 8.85 (d, 1H), 9,10 (s, 1H), 9,83 (ush., NH).

Example 19

N-Cyclopropyl-1-[3-(3-thienyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 14, but replacing 3-tiotemporal acid pyridine-3-boronic acid 1,3-propanediylbis cyclic ether, receive specified in the title compound in the form of solids.

1H NMR (Acetone-d6) (0,60 (m, 2H), 0,79 (m, 1H), 2,96 (m, 1H), EUR 7.57-7,72 (m, 5H), 7,92-7,98 (m, 2H), with 8.05 (s, 1H), total of 8.74 (s, 1H), 8,78 (d, 1H), 8,93 (s, 1H) 9,74 (ush., NH).

Example 20

N-Cyclopropyl-1-[3-(4-sulfamoyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: Enconomy ether 4-sulfamoylbenzoic acid

A mixture of 4-bromobenzaldehyde, tibarenians ether (1.1 EQ.), potassium acetate (3.5 equiv. and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) is 0.05 EQ.) in N,N-dimethylformamide (4 ml/mmol) is heated at a temperature of 85°C for 18 hours. After quenching with a saturated aqueous solution x is Orica ammonium mixture is distributed between ethyl acetate and water and the product from the organic phase is subjected to chromatography on silica gel, elwira mixture 1:1 of ethyl acetate and hexane to obtain 4-sulfamoylbenzoic acid pincavage ether in the form of solids.

Stage 2: N-Cyclopropyl-1-[3-(4-sulfamoyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

A mixture of N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide, Borat from phase 1 (1.2 EQ.) of palladium acetate (0.1 EQ.), triphenylphosphine (0.35 in EQ.) and 2M aqueous sodium carbonate (3.5 EQ.) in n-propanol (10 ml/mmol) is stirred at a temperature of 85°C for 1 hour. After cooling, the mixture was quenched with saturated aqueous ammonium chloride and distributed between ethyl acetate and water and the product from the organic phase is subjected to chromatography on silica gel, elwira mix 1:5:4 ethanol, ethyl acetate and methylene chloride to obtain N-cyclopropyl-1-[3-(4-sulfamoyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (Acetone-d6) (0,62 (m, 2H), 0,82 (m, 2H), 2,98 (m, 1H), 6,66 (ush., NH2), to 7.64 (m, 1H), 7,74 (m, 1H), 7,80 (t, 1H), 7,97-with 8.05 (m, 5H), 8,10 (m, 1H), 8,76 (m, 1H), 8,81 (DD, 1H), 8,97 (s, 1H), 9,77 (ush., NH).

Example 21

N-Isopropyl-1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: Ethyl 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

According to the method stage 5 of example 1, but replacing 1-(3-br mpanel)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate from step 2 of example 1, N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide and replacing 3-ethoxybenzoate acid 3-acetylbenzoic acid, get the connection ethyl 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate in the form of solids.

Stage 2: 1-[3-(3-Ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid

According to the method of stage 3 of example 1, but replacing ethyl 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate from step 1 ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate, to obtain the compound 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid, which is used in the next stage without treatment.

Stage 3: N-Isopropyl-1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

A mixture of 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid from step 2 and thionyl chloride (4 equiv.) in tetrahydrofuran (10 ml/mmol) is refluxed for 45 minutes, then evaporated. The residue is dissolved in the same volume of tetrahydrofuran, added Isopropylamine (5 EQ.) and the mixture is stirred at room temperature for 18 hours. After quenching with a saturated aqueous solution of ammonium chloride the mixture is distributed between ethyl acetate and water and the product from the organic phase is subjected to chromatography on silica gel, elwira 10% ether in methylene chloride to obtain N-isopropyl-1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carb is xamiga in the form of solids.

1H NMR (CDCl3) (1,29 (d, 6N), of 1.42 (t, 3H), 4,08 (square, 2H), 4,28 (m, 1H), 6,91 (d, 1H), 7,12 (s, 1H), 7,18 (d, 1H), 7,34 (t, 1H), 7,40 (d, 1H), 7,46 (m, 1H), 7,60-the 7.65 (m, 2H), of 7.75 (d, 1H), 8,71 (USS, 1H), 8,82 (DD, 1H), the remaining 9.08 (s, 1H), 9,70 (ush., NH).

Example 22

N-Isopropyl-1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: Ethyl 1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate

According to the method stage 5 of example 1, but replacing 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate from step 2 of example 1, N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide and replacing 4-methylthioinosine acid 3-acetylbenzoic acid, receive connection ethyl 1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate in the form of solids.

Stage 2: 1-[3-(4-Methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid

According to the method of stage 3 of example 1, but replacing ethyl 1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate from step 1 ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylate, to obtain the compound 1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid in the form of a solid substance.

Stage 3: N-Isopropyl-1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 is confident 21, but replacing 1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid, receive N-isopropyl-1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

1H NMR (Acetone-d6) (1,24 (d, 6N), 2,52 (s, 3H), 4,18 (m, 1H), 7,37 (d, 2H), 7,58 to 7.62 (m, 2H), 7,69-7,73 (m, 3H), 7,87 (d, 1H), of 7.96 (s, 1H), 8,72 (m, 1H), 8,78 (DD, 1H), 8,91 (s, 1H), 9,65 (ush., NH).

Example 23

N-Isopropyl-1-[3-(3-acetyl-4-hydroxyphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

A mixture of 5'-bromo-2'-hydroxyacetophenone, tibarenians ether (1.25 equiv.) potassium acetate (3 EQ.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) is 0.05 EQ.) in N,N-dimethylformamide (10 ml/mmol) is stirred at a temperature of 80°C for 3 hours and cooled. Add a solution of N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 1, stage 4 (0.75 EQ.) in N,N-dimethylformamide (7 ml/mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) is 0.05 EQ.) and 2M aqueous sodium carbonate (8.5 equiv.) and the resulting mixture is stirred at a temperature of 80°C for 2.5 hours. The cooled mixture is distributed between ethyl acetate and water and the product from the organic phase is subjected to chromatography on silica gel, elwira 60% ethyl acetate in Gex is obtaining specified in the title compounds as a pale yellow solid.

1H NMR (Acetone-d6) (1,24 (d, 6N), a 2.75 (s, 3H), 4,19 (m, 1H), 7,06 (d, 1H), to 7.59-7,63 (m, 2H), 7,72 (t, 1H), 7,92 (d, 1H), of 7.97 (d, 1H), 8,02 (s, 1H), with 8.33 (s, 1H), 8,73 (m, 1H), 8,78 (DD, 1H), of 8.90 (s, 1H), 9,65 (ush., NH).

Example 24

N-Isopropyl-1-[3-(5-carbamaxepine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 23, but substituting N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide 5'-bromo-2'-hydroxyacetophenone and replacing 5-bromonicotinate N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide get mentioned in the title compound as a beige solid.

1H NMR (CDCl3) (1,29 (d, 6N), of 1.40 (t, 3H), 4,28 (m, 1H), 4,42 (square, 2H), 7,45-7,51 (m, 2H), 7,68 (s, 1H), 7,71 (t, 1H), 7,80 (d, 1H), 8,49 (s, 1H), 8,59 (m, 1H), 8,82 (d, 1H), 9,03 (s, 1H), 9,07 (s, 1H), 9,23 (s, 1H) for 9.64 (ush., NH).

Example 25

N-Isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)pyridine-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 3-Bromo-5-(1-hydroxy-1-methylethyl)pyridine

To a solution of ethyl 5-bromonicotinate (1,02 g, 4.4 mmol) in diethyl ether (15 ml) at a temperature of -30°add 3M solution Metalmania bromide (4 ml, 12 mmol) in ether. The resulting slurry is then refluxed for 2 hours, then cooled and quenched with an excess of 0.5m aqueous monobasic phosphate and apredeljat between simple ether and water. The product from the organic phase is subjected to chromatography on silica gel, elwira 2:1:2 mixture of ether and pentane and saturated ammonium methylene chloride, to obtain the compound 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine as a yellow oil.

Stage 2: N-Isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)pyridine-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 24, but substituting 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine from step 1 ethyl 5-bromonicotinate get mentioned in the title compound as a yellow foam.

1H NMR (CDCl3) (1,28 (d, 6N), of 1.62 (s, 6N), 2,52 (USS, 1H), 4,25 (m, 1H), 7,41-of 7.48 (m, 2H), 7,60-to 7.68 (m, 2H), of 7.75 (d, 1H), with 8.05 (s, 1H), 8,67-8,71 (m, 3H), 8,80 (DD, 1H), 9,03 (s, 1H) 9,66 (ush., NH).

Example 26

N-Isopropyl-1-{3-[6-(2-methylpropyl " pyridine-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-2-(2-methylpropyl " pyridine

To a solution of 2,5-dibromopyridine (4.5 g, 19 mmol) in tetrahydrofuran (50 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]declomycin (II) (103 mg, 0,19 mmol) and the resulting mixture is cooled to a temperature of -10°C. is added Slowly 2M solution of bromide isobutylamine in ether (12,4 ml of 24.7 mmol) and the mixture is stirred at a temperature of from -10 to 10°C for 3.5 hours. After quenching with a saturated aqueous solution of ammonium chloride, the mixture is partitioned between simple ether and the ode, and the product from the organic phase is subjected to chromatography on silica gel, elwira 10% ether in pentane to obtain compound 5-bromo-2-(2-methylpropyl)pyridine in the form of volatile oil.

Stage 2: N-Isopropyl-1-{3-[6-(2-methylpropyl " pyridine-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 24, but substituting 5-bromo-2-(2-methylpropyl)pyridine from step 1 ethyl 5-bromonicotinate receive the compound N-isopropyl-1-{3-[6-(2-methylpropyl " pyridine-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

1H NMR (CDCl3) (0,92 (d, 6N), of 1.28 (d, 6N), 2,10 (m, 1H), 2,69 (d, 2H), 4,28 (m, 1H), 7,19 (d, 1H), 7,40-7,47 (m, 2H), 7,60 (s, 1H), to 7.64 (t, 1H), 7,73 (d, 1H), 7,79 (DD, 1H), 8,68 (m, 1H), 8,77-8,83 (m, 2H), 9,05 (, 1H), 9,66 (ush., NH).

Example 27

N-Isopropyl-1-[3-(5-acetylpyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 3-Acetyl-5-bromopyridin

To a solution of ethyl 5-bromonicotinate (3,9 g of 16.9 mmol) in ether (50 ml) at a temperature of 0°add 3M bromide solution Metalmania (16,9 ml, 50.8 mmol). The obtained thick suspension is slowly heated to room temperature and after 1.5 hours it is slowly poured into an excess of 1M aqueous monobasic phosphate. The mixture is partitioned between ether and water and the product from the organic phase is subjected to chromatography on silica gel, elwira 1::2 mixture of ether, pentane and saturated ammonium methylene chloride, to obtain the compound 3-acetyl-5-bromopyridine. This technique also gives 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine as described in example 25.

Stage 2: N-Isopropyl-1-[3-(5-acetylpyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 23, but replacing 3-acetyl-5-bromopyridine with stage 1 ethyl 5-bromonicotinate receive the compound N-isopropyl-1-[3-(5-acetylpyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

1H NMR (CDCl3) (1,29 (d, 6N), 2,69 (s, 3H), 4,28 (m, 1H), of 7.48 (DD, 1H), 7,51 (d, 1H), 7,69 (s, 1H), 7,72 (t, 1H), 7,80 (d, 1H), 8,42 (s, 1H), 8,69 (m, 1H), 8,82 (d, 1H), 9,05 (s, 2H), 9,17 (s, 1H), 9,63 (ush., NH).

Example 28

N-Isopropyl-1-[3-(6-methylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-2-methylpyridin

According to the method of stage 1 of example 26, but substituting chloride Metalmania bromide isobutylamine receive connection 5-bromo-2-methylpyridine in the form of solids.

Stage 2: N-Isopropyl-1-[3-(6-methylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 24, but substituting 5-bromo-2-methylpyridine with stage 1 ethyl 5-bromonicotinate receive the compound N-isopropyl-1-[3-(6-methylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of a solid which CSOs substances.

1H NMR (CDCl3) (1,32 (d, 6N), 2,63 (m, 3H), 4,30 (m, 1H), 7,25 (d, 1H), 7,45-7,51 (m, 2H), 7,63 (s, 1H), 7,69 (t, 1H), to 7.77 (d, 1H), 7,82 (DD, 1H), 7,82 (DD, 1H), 8,72 (m, 1H), 8,78 (s, 1H), cent to 8.85 (d, 1H), remaining 9.08 (s, 1H), 9,68 (ush., NH).

Example 29

N-Cyclopropyl-1-[3-(1-oxidability-5-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-1-oxidability

To 5-bromopyrimidine (2,05 g, 12.9 mmol) in methylene chloride (25 ml) is added m-chloroperoxybenzoic acid (purity 70%, 3,17 g, 12.9 mmol) and the resulting mixture was stirred at room temperature for 5 days. Add calcium hydroxide (1 g) and after 10 minutes the mixture is filtered through celite. Product evaporation of the filtrate is subjected to chromatography on silica gel, elwira with ethyl acetate to obtain compound 5-bromo-1-oxidability in the form of a white solid.

Stage 2: N-Cyclopropyl-1-[3-(1-oxydiphenylene-5-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 24, but substituting 5-bromo-1-oxydiphenylene with stage 1 ethyl 5-bromonicotinate and replacing N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide receive the compound N-cyclopropyl-1-[3-(1-oxydiphenylene-5-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

1H NMR (CDCl3) (0,66 (m, 2H), 0,84 (m, 2H), 2,97 (m, 1H), of 7.48 (m, 1H), 7,58 (d, 1H), 7,65 (s, 1H), 7,71 (d, 1H), to 7.77 (t, 1H), 8,46 (s, 1H), at 8.60 (s, 1H), 8,68 (USS, 1H), 8,81 (DD, 1H), 8,98 (s, 1H), of 9.02 (s, 1H), 9,72 (ush., NH).

Example 30

1-{3-[6-(1-Hydroxy-1-methylethyl)-1-oxidability-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-2-(1-hydroxy-1-methylethyl)pyridine

To a suspension of 2,5-dibromopyridine in toluene (12 ml/mmol)cooled down to -78°add n-utility 2.5m in hexane (of 1.05 equiv.) and the resulting mixture is stirred in the cold for 2.5 hours. Add acetone (2 EQ.) and stirring is continued for 1.5 hours. After quenching with a saturated aqueous solution of ammonium chloride, the mixture is heated to room temperature and distributed between ethyl acetate and water. The product from the organic phase is subjected to chromatography on silica gel, elwira 20% ethyl acetate in hexane to obtain compound 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine in the form of syrup.

Stage 2: 5-Bromo-2-(1-hydroxy-1-methylethyl)pyridine N-oxide

To a solution of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from step 1 in methylene chloride (5 ml/mmol) at room temperature add m-chloroperoxybenzoic acid 70% (1.1 EQ.) and the resulting mixture was stirred at room temperature for 18 hours. Add excess hydroxydione and after 5 minutes the mixture is filtered through a layer of cellite. The crude product evaporation of the filtrate is subjected to chromatography on silica gel, elwira 80% ethyl acetate in hexane to obtain compound 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine N-oxide as a white solid.

Stage 3: 1-(3-Bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 4 of example 1, but replacing the 28% aqueous ammonium hydroxide Isopropylamine, to obtain the compound 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

Stage 4: 1-{3-[6-(1-Hydroxy-1-methylethyl)-1-oxidability-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 24, but substituting 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine N-oxide from step 2 above ethyl 5-bromonicotinate and substituting 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide get the connection 1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxidability-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (1,76 (C, 6N), of 5.83 (ush., 1H, NH), 7,50 (d, 1H), 7,55 (m, 1H), EUR 7.57 to 7.62 (m, 2H), 7,65 (m, 2H), 7,72 for 7.78 (m, 2H), 8,55 (s, 1H, HE), is 8.75 (m, 1H), 8,90 (DD, 1H), remaining 9.08 (s, 1H), 9,52 (ush., 1H, NH).

Example 31

N-Isopropyl-1-{3-[4-(pyridin-3-yl)phenyl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: N-And propyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

A mixture of N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from step 4 of example 1, tibarenians ether (1.1 EQ.), potassium acetate (3.5 EQ.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) is 0.05 EQ.) in N,N-dimethylformamide (5 ml/mmol) is stirred at a temperature of 85°C for 18 hours. Add tibarenians ether (0.4 EQ.) and palladium catalyst is 0.05 EQ.) and heating and stirring is continued for another 24 hours. After cooling, the mixture is distributed between ethyl acetate and water and the crude product from the organic phase is subjected to chromatography on silica gel, elwira 1:1 mixture of ethyl acetate and hexane. Then the product is stirred in hexane at room temperature for several hours and filtered to obtain compound N-isopropyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

Stage 2: 3-(4-Bromophenyl)pyridine

A mixture of pyridine-3-boronic acid 1,3-probandooooo cyclic ether, 4-bromobenzene (1.1 equiv.) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) is 0.05 EQ.) and 2M aqueous sodium carbonate (5 EQ.) in N,N-dimethylformamide (2 ml/mmol) is stirred at a temperature of 85°C for 4 hours. After quenching with a saturated aqueous solution of ammonium chloride, the mixture is distributed between ethyl acetate and water and the crude product from the organic phase is subjected to chromatography on silica gel, elwira 1:9 mixture of ethyl acetate and hexane to obtain compound 3-(4-bromophenyl)pyridine in the form of solids.

Stage 3: N-Isopropyl-1-{3-[4-(pyridin-3-yl)phenyl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

A mixture of borate with stage 1, 3-(4-bromophenyl)pyridine from step 2 (1.5 equiv.) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) is 0.05 EQ.) and 2M aqueous sodium carbonate (5 EQ.) in N,N-dimethylformamide (7 ml/mmol) is stirred at a temperature of 85°C for 1 hour. After cooling, the mixture is distributed between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel, elwira 7:3 mixture of ethyl acetate and methylene chloride to obtain compounds N-isopropyl-1-{3-[4-(pyridin-3-yl)phenyl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (1,30 (d, 6N), 4,25 (m, 1H), 7,35 (m, 1H), 7,39-of 7.48 (m, 2H), 7,60 to 7.75 (m, 6N), 7,80 (d, 1H), of 7.90 (d, 1H), 8,58 (d, 1H), 8,70 (m, 1H), 8,82 (d, 1H), 8,88 (s, 1H), remaining 9.08 (s, 1H), 9,68 (ush., NH).

Example 32

N-Cyclopropyl-1-[3-(5-methylsulfinylphenyl-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: N-Cyclopropyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 1 of example 31, but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]nattered is n-4-one-3-carboxamide with stage 1 of example 14 N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide, get the compound N-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

Stage 2: 3-Bromo-5-methylsulfinylphenyl

To 3,5-dibromopyridine (2,96 g, 12.5 mmol) in diethyl ether (70 ml) at a temperature of -78°add n-utility 1,6M in hexano (8.6 ml, 13.7 mmol) and the resulting mixture is stirred in the cold for 3 hours. Add dimethyl disulfide (1,12 ml, 12.5 mmol) and the mixture is heated to room temperature, then partitioned between simple ether and water. To the crude product evaporation of the organic phase added tetrahydrofuran (80 ml), methanol (20 ml), Oxon (17 g) and sufficient amount of saturated aqueous sodium bicarbonate to obtain a slightly basic environment. After stirring for 4 hours at room temperature, then add an excess of 1M aqueous sodium metabisulfite, the organic solvent is evaporated and the residue distributed between ethyl acetate and water. The crude product from the organic phase are mixed in a small volume of ethyl acetate and filtered to obtain compound 3-bromo-5-methylsulfonylamino in the form of solids.

Stage 3: N-Cyclopropyl-1-[3-(5-methylsulfinylphenyl-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 31, but substituting 3-br the m-5-methylsulfonylamino from stage 2 above 3-(4-bromophenyl)pyridine and replacing N-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide with stage 1 N-isopropyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide, get the compound N-cyclopropyl-1-[3-(5-methylsulfinylphenyl-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0,71 (m, 2H), 0,90 (m, 2H), 3,03 (m, 1H), 3,21 (s, 3H), 7,53 (m, 1H), 7,60 (d, 1H), 7,74 (s, 1H), 7,80 (t, 1H), 7,86 (d, 1H), 8,45 (m, 1H), total of 8.74 (m, 1H), 8,86 (d, 1H), which is 9.09 (s, 1H), 9,20 (d, 2H), 9,78 (ush., NH).

Example 33

N-Cyclopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-1-oxidability-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: Methyl 2-bromoisonicotinic

To a solution of 2-bromoisonicotinic acid (Chem. Pharm. Bull.,38:2446 (1990)) (2.0 g) in tetrahydrofuran (100 ml) is added an excess of ethereal diazomethane and the resulting mixture was stirred at room temperature for 1 hour. The mixture is evaporated and the product is subjected to chromatography on silica gel, elwira 1:3 mixture of ethyl acetate and hexane to obtain methyl ester 2-bromoisonicotinic acid as colorless liquid.

Stage 2: 2-Bromo-4-(1-hydroxy-1-methylethyl)pyridine

According to the method of stage 1 of example 25, but substituting methyl 2-bromoisonicotinic with stage 1 ethyl 5-bromonicotinate get the connection of 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine as a white solid.

Stage 3: 2-Bromo-4-(1-hydroxy-1-methylethyl)pyridine-N-oxide

By the method of step 2 of example 30, but substituting 2-bromo-4-(1-hydroxy-1-METI is ethyl)pyridine from step 2 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get the connection of 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine-N-oxide as a white solid.

Stage 4: N-Cyclopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-1-oxidability-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine-N-oxide from step 3 of 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-1-oxidability-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a beige solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,79 (m, 2H), 1,45 (s, 6N), 2,90 (m, 1H), 5,35 (s, 1H, HE), of 7.48 (m, 1H), to 7.64 (m, 1H), 7,72 (m, 3H), 8,11 (m, 2H), 8,30 (d, 1H), 8,72 (DD, 1H), 8,78 (m, 1H), 8,82 (s, 1H), 9,72 (ush., NH).

Example 34

N-Cyclopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)pyridine-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 2-Bromo-5-(1-hydroxy-1-methylethyl)pyridine

A solution of 2,5-dibromopyridine in diethyl ether (5 ml/mmol) cooled to a temperature of -78°and slowly add n-utility 2,5M in hexano (of 1.05 EQ.). After 2 hours of maturation on the add cold acetone (1.3 EQ.) and stirring is continued for 1 hour. The resulting mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature and partitioned between ether and water. Neojidannyy from the organic phase triturated with 1:1 ether:hexane and filtered to obtain compound 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine in the form of solids.

Stage 2: N-Cyclopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)pyridine-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine from step 1 of 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)pyridine-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0,71 (m, 2H), 0,90 (m, 2H), 1,68 (C, 6N), of 1.85 (s, 1H, HE), totaling 3.04 (m, 1H), 7,45-7,52 (m, 2H), 7,71 (t, 1H), 7,79 (d, 1H), 7,95 (DD, 1H), 8,16 (s, 1H), to 8.20 (d, 1H), 8,72 (m, 1H), 8,80-8,87 (m, 2H), 9,12 (s, 1H), 9,82 (ush., NH).

Example 35

N-Cyclopropyl-1-{3-[3-(1-hydroxy-1-methylethyl)pyridine-4-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 4-Bromo-2-(1-hydroxy-1-methylethyl)pyridine

By the method of stages 1-2 of example 33, but substituting 4-bromopicolinic acid (Aust. J. Chem.24:390 (1971)) 2-bromoisonicotinic acid in stage 1, get connection 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine as a white solid.

Stage 2: N-Cyclopropyl-1-{3-[3-(1-hydroxy-1-methylethyl)pyridine-4-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine from step 1 of 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-{3-[3-(1-hydroxy-1-metile who yl)pyridine-4-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a beige solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,78 (m, 2H), 1,48 (C, 6N), only 2.91 (m, 1H), 5,27 (s, 1H, HE), a 7.62-7,66 (m, 2H), 7,72 7,79 (m, 2H), 8,01 (m, 1H), 8,10 (s, 1H), 8,58 (d, 1H), 8,73-8,79 (m, 2H), 8,84 (s, 1H), 9,73 (ush., NH).

Example 36

Synthesis of N-cyclopropyl-1-{3-[3-(1-hydroxy-1-methylethyl)-1-oxidability-4-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 4-Bromo-2-(1-hydroxy-1-methylethyl)pyridine-N-oxide

By the method of step 2 of example 30, but substituting 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine from step 1 of example 35 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, obtain compound 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine-N-oxide as a white solid.

Stage 2: N-cyclopropyl-1-{3-[3-(1-hydroxy-1-methylethyl)-1-oxidability-4-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine-N-oxide from step 1 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-{3-[3-(1-hydroxy-1-methylethyl)-1-oxidability-4-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a beige solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,78 (m, 2H), 1,62 (C, 6N), 2,90 (m, 1H), 6,99 (s, 1H, HE), the 7.65 to 7.84 (m, 4H), 7,94 (s, 1H), 8,03 (DD, 1H), 8,15 (s, 1H), scored 8.38 (d, 1H), 8,73-8,78 (m, 2H), 8,83 (s, 1H), 9,73 (ush., NH).

Example 37

N-Cyclopropyl-1-[3-(6-isopropylacetanilide-3-yl)phenyl]-1,4-dihydro[1,]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-2-isopropylpyridine

To a mixture of 2,5-dibromopyridine (2,07 g, 8,73 mmol) and 2-propanethiol (0,97 ml, 10.4 mmol) in N,N-dimethylformamide (20 ml) at a temperature of 0°With portions added sodium hydride, 60% dispersion in oil (450 mg, 11.3 mmol). The resulting mixture was stirred at room temperature for 1 hour, then partitioned between ether and water. The crude product from the organic phase is subjected to chromatography on silica gel, elwira 10% ethyl acetate in hexane, to obtain the compound 5-bromo-2-isopropylpyridine in the form of solids.

Stage 2: 5-Bromo-2-isopropylacetanilide

To a solution of 5-bromo-2-isopropylpyridine with stage 1 (2,03 g is 8.75 mmol) in tetrahydrofuran (50 ml) and methanol (25 ml) at a temperature of 0°add Oxon (15,8 g for 25.8 mmol) and then saturated aqueous sodium bicarbonate (25 ml). The resulting mixture was stirred at room temperature for 6 hours. The mixture is quenched with aqueous sodium bicarbonate and distributed between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel, elwira 20% ethyl acetate in hexane, to obtain the compound 5-bromo-2-isopropylpiperazine in the form of a white solid.

Stage 3: N-Cyclopropyl-1-[3-(6-isopropylacetanilide-3-yl)phenyl]-1,4-dihyd what about[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 5-bromo-2-isopropylpiperazine from stage 2 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-[3-(6-isopropylacetanilide-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0,70 (m, 2H), 0,89 (m, 2H), 1.39 in (d, 6N), to 3.00 (m, 1H), 3,82 (m, 1H), 7,51 (m, 1H), 7,60 (d, 1H), 7,72 (s, 1H), 7,80 (t, 1H), 7,83 (d, 1H), 8,15-8,24 (m, 2H), 8,72 (m, 1H), 8,86 (DD, 1H), 9,03 (s, 1H), 9,10 (s, 1H), 9,82 (ush., NH).

Example 38

N-Cyclopropyl-1-[3-(6-methoxypyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-2-methoxypyridine

To a solution of 2,5-dibromopyridine (6,95 g, 29 mmol) in N,N-dimethylformamide (5 ml) is added methanol (3,56 ml) and 1M tert-piperonyl potassium (32,3 ml) and the resulting mixture was stirred at room temperature for 18 hours. The resulting suspension is quenched with saturated aqueous ammonium chloride and distributed between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel, elwira 1:9 mixture of ether and hexane, to obtain the compound 5-bromo-2-methoxypyridine in the form of oil.

Stage 2: N-Cyclopropyl-1-[3-(6-methoxypyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 5-bromo-2-methoxypyridine article is Hai 13-bromo-5-methylsulfinylphenyl, get the compound N-cyclopropyl-1-[3-(6-methoxypyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0,71 (m, 2H), 0,89 (m, 2H), 3,00 (m, 1H), 4.00 points (s, 3H), 6,85 (d, 1H), 7,44 (d, 1H), 7,50 (m, 1H), 7.62mm (s, 1H), 7,68 (t, 1H), 7,73 (d, 1H), 7,83 (DD, 1H), 8,44 (s, 1H), 8,73 (m, 1H), cent to 8.85 (DD, 1H), 9,10 (s, 1H), 9,82 (ush., NH).

Example 39

N-Cyclopropyl-1-[3-(6-methylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 5-bromo-2-methylpyridine with stage 1 of example 28 3-bromo-5-methylsulfinylphenyl receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (0,72 (m, 2H), 0,90 (m, 2H), 2,65 (s, 3H), 3,03 (m, 1H), 7,28 (d, 1H), 7,45-7,53 (m, 2H), 7,66 (s, 1H), 7,72 (t, 1H), 7,80 (d, 1H), to 7.84 (DD, 1H), 7,83 (m, 1H), 8,80 (s, 1H), 8,86 (DD, 1H), 9,11 (s, 1H), 9,82 (ush., NH).

Example 40

N-Cyclopropyl-1-{3-[6-(2,2,2-triptoreline)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-2-(2,2,2-triptoreline)pyridine

According to the method of stage 1 of example 38, but substituting 2,2,2-triptoreline methanol, by heating at a temperature of 70°C for 18 hours to obtain the compound 5-bromo-2-(2,2,2-triptoreline)pyridine in the form of oil.

Stage 2: N-Cyclopropyl-1-{3-[6-(2,2,2-triptoreline)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 5-bromo-2-(2,2,2-triptoreline)pyridine from step 1 of 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-{3-[6-(2,2,2-triptoreline)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0,72 (m, 2H), 0,90 (m, 2H), 3,03 (m, 1H), 4,85 (square, 2H), 7,00 (d, 1H), 7,43-7,53 (m, 2H), 7.62mm (s, 1H), 7,69 for 7.78 (m, 2H), 7,92 (DD, 1H), 8,42 (s, 1H), 8,73 (m, 1H), cent to 8.85 (DD, 1H), 9,10 (s, 1H), 9,80 (ush., NH).

Example 41

N-Cyclopropyl-1-[3-(5-bromopyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 3,5-dibromopyridine 3-bromo-5-methylsulfinylphenyl get mentioned in the title compound as a white solid.

1H NMR (DMSO-d6) (0,58 (m, 2H), 0,79 (m, 2H), 2,90 (m, 1H), 7,65 (m, 1H), 7,71-to 7.77 (m, 2H), 8,03 (d, 1H), 8,14 (s, 1H), 8,49 (s, 1H), total of 8.74 (USS, 1H), 8,79 (USS, 1H), 8,86 (s, 1H), 9,01 (s, 1H), 9,73 (ush., NH).

Example 42

N-Cyclopropyl-1-[3-(6-benzyloxypyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 2-Benzyloxy-5-bromopyridin

A mixture of 2,5-dibromopyridine, benzyl alcohol (1.3 EQ.), pellets of potassium hydroxide (2.4 EQ.) and dibenzo-18-crown-6 (of 0.05 EQ.) in toluene (4 ml/mmol) is refluxed with simultaneous azeotropic removal of water in the tip is of 3 hours. After evaporation of toluene, the resulting mixture was partitioned between chloroform and water. The crude product from the organic phase is recrystallized from ether - hexane to obtain compound 2-benzyloxy-5-bromopyridine in the form of solids.

Stage 2: N-Cyclopropyl-1-[3-(6-benzyloxypyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 2-benzyloxy-5-bromopyridine with stage 1 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-[3-(6-benzyloxypyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,79 (m, 2H), 2.91 in (m, 1H), 5,42 (s, 2H), 7,00 (d, 1H), 7,32-of 7.48 (m, 5H), to 7.61-7,72 (m, 3H), of 7.90 (d, 1H), to 7.99 (s, 1H), 8,14 (d, 1H), 8,59 (s, 1H), 8,73-8,84 (m, 3H), 9,73 (ush., NH).

Example 43

N-Cyclopropyl-1-{3-[6-dicyclopropyl(hydroxy)methyl-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-2-dicyclopropyl(hydroxy)methylpyridine-N-oxide

By the method of stages 1 and 2 of example 30, but replacing dicyclopropyl-ketone acetone in stage 1, get connection 5-bromo-2-dicyclopropyl(hydroxy)methylpyridine-N-oxide in the form of solids.

Stage 2: N-Cyclopropyl-1-{3-[6-dicyclopropyl(hydroxy)methyl-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]after the DIN-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 5-bromo-2-dicyclopropyl(hydroxy)methylpyridine-N-oxide from step 1 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-{3-[6-dicyclopropyl(hydroxy)methyl-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide as a white solid.

1H NMR (CDCl3) (0,52 (m, 4H), 0,70 (m, 4H), 0,76 (m, 2H), 0,89 (m, 2H), 1,35 (m, 2H), to 3.02 (m, 1H), 7,52 (m, 1H), 7,58 (m, 1H), 7.62mm (DD, 1H), 7,68 (s, 1H), 7,73-7,80 (m, 3H), 8,15 (ush., 1H, HE), 8,49 (s, 1H), 8,72 (m, 1H), cent to 8.85 (DD, 1H), which is 9.09 (s, 1H), 9,78 (ush., NH).

Example 44

N-Cyclopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxidability-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 2-Bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide

By the method of step 2 of example 30, but substituting 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine from step 1 of example 34 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get the connection of 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide as a white solid.

Stage 2: N-Cyclopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxidability-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide from step 1 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-acidophil the Jn-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0.69 (m, 2H), 0.88 to (m, 2H), and 1.63 (s, 6N), 2,20 (s, 1H, HE), 2,98 (m, 1H), 7,38-7,49 (m, 3H), 7,52 (d, 1H), of 7.70 (t, 1H), 7,98-of 8.04 (m, 2H), and 8.50 (s, 1H), 8,69 (m, 1H), 8,80 (DD, 1H), remaining 9.08 (s, 1H), 9,75 (ush., NH).

Example 45

N-Cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from step 1 of example 30 3-bromo-5-methylsulfinylphenyl receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (0,72 (m, 2H), 0,90 (m, 2H), 1,62 (C, 6N), to 3.02 (m, 1H), around 4.85 (s, 1H, HE), of 7.48-7,53 (m, 3H), 7,68 (s, 1H), 7,73 (t, 1H), 7,80 (d, 1H), 7,95 (DD, 1H), 8,72 (m, 1H), 8,81 (s, 1H), 8,86 (DD, 1H), 9,10 (, 1H), 9,78 (ush., NH).

Example 46

N-Isobutyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-(3-AMINOPHENYL)-2-(1-hydroxy-1-methylethyl)pyridine

According to the method stage 5 of example 1, but replacing 3-aminophenylamino acid 3-acetylphenylalanine acid and substituting 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from step 1 of example 30 N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide receive connection 5-(3-AMINOPHENYL)-2-(1-hydroxy-1-methylethyl)pyridine in the form of solids.

Stage 2: 1-{3-[6-(1-Hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid

By the method of stages 1-3 of example 1, but replacing 5-(3-AMINOPHENYL)-2-(1-hydroxy-1-methylethyl)pyridine 3-bromaniline with stage 1 the first stage, get the connection 1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid in the form of solids.

Stage 3: N-Isobutyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 4 of example 1, but replacing the acid from step 2 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid, and substituting isobutylamine Isopropylamine, to obtain the compound N-isobutyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of a cream solid.

1H NMR (Acetone-d6) (0,98 (d, 6N), of 1.53 (s, 6H), of 1.88 (m, 1H), 3,26 (t, 2H), 4,66 (s, 1H, HE), 7,60 (m, 1H), 7,69 (d, 1H), 7,76-7,79 (m, 2H), 7,95 (d, 1H), with 8.05 (s, 1H), 8,16 (DD, 1H), 8,73 (m, 1H), 8,79 (DD, 1H), 8,90 (, 1H), to 8.94 (s, 1H), 9,83 (ush., NH).

Example 47

N-Cyclopropyl-1-{5-bromo-3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 1-(3,5-Dibromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid

By the method of stages 1-3 of example 1, but substituting 3,5-dibromoanisole 3 bromaniline in stage 1, get the connection 1-(3,5-dibromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carbon is Oh acid in the form of a beige solid.

Stage 2: N-Cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 4 of example 1, but replacing 1-(3,5-dibromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid from step 11-(3-bromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxylic acid, and substituting cyclopropylamine Isopropylamine, to obtain the compound N-cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

Stage 3: 2-(1-Hydroxy-1-methylethyl)-5-tributylstannyl

To a suspension of 2,5-dibromopyridine in toluene (5 ml/mmol) at a temperature of -78°add n-utility 2.5m in hexane (1 equiv.) and the resulting mixture is stirred in the cold for 2.5 hours. Add acetone (1 EQ.) and the mixture is heated to a temperature of -50°where it turns into a brown solution. After cooling to -78°add n-utility (1 EQ.) together with ether (2 ml/mmol). After stirring in the cold for a further one hour add the presence of TBT chloride (1.1 EQ.) and the mixture is heated to room temperature and stirred for 2 hours. The mixture is quenched with saturated aqueous ammonium chloride and distributed between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel, elwira 1:9 mixture of ethyl acetate and hexane to obtain compound 2-(1-g is droxy-1-methylethyl)-5-tributylstannyl in the form of a colourless liquid.

Stage 4: N-Cyclopropyl-1-{5-bromo-3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

A mixture of N-cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from step 2, 2-(1-hydroxy-1-methylethyl)-5-tributylstannyl with stage 3 (1.4 equiv.) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) is 0.05 EQ.) and copper iodide (of 0.05 EQ.) in N,N-dimethylformamide (15 ml/mmol) is stirred at a temperature of 85°C for 5 hours. After cooling, the resulting mixture was distributed between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel, elwira 1:6:3 mixture of ethanol, ethyl acetate and methylene chloride to obtain compounds N-cyclopropyl-1-{5-bromo-3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0,72 (m, 2H), 0,90 (m, 2H), 1,62 (C, 6N), to 3.02 (m, 1H), amounts to 4.76 (s, 1H, HE), 7,50-7,56 (m, 2H), 7.62mm (s, 1H), 7,69 (s, 1H), of 7.90-of 7.96 (m, 2H), total of 8.74 (m, 1H), 8,79 (s, 1H), 8,86 (DD, 1H), 9,07 (s, 1H), 9,74 (ush., NH).

Example 48

N-Cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 2-(1-Hydroxy-1-methylethyl)-6-tributylstannyl

According to the method of stage 3 of example 47, but replacing the 2,6-dibromopyridine 2.5-dibromopyridin receive the compound 2-(1-hydroxy-1-methylethyl)-6-tributylstannyl.

Stage 2: N-Cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 4 of example 47, but replacing 2-(1-hydroxy-1-methylethyl)-6-tributyltinchloride with stage 1 2-(1-hydroxy-1-methylethyl)-5-tributylstannyl receive the compound N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0,72 (m, 2H), 0,90 (m, 2H), 1.61 of (C, 6N), totaling 3.04 (m, 1H), 5,13 (s, 1H, HE), 7,40 (d, 2H), 7,46-7,53 (m, 2H), 7,70-7,76 (m, 2H), a 7.85 (t, 1H), 8,13 (s, 1H), they were 8.22 (d, 1H), 8,73 (m, 1H), 8,87 (d, 1H), 9,12 (s, 1H), 9,83 (ush., NH).

Example 49

N-Isopropyl-1-[3-(4-methylsulfinylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a mixture of N-isopropyl-1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 22 in tetrahydrofuran (24 ml/mmol), methanol (12 ml/mmol) and water (12 ml/mmol) is added Oxon (2,24 EQ.) and the resulting mixture was stirred at room temperature for 2 hours. The mixture is quenched with saturated aqueous sodium bicarbonate and distributed between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel, elwira 30% ether in methylene chloride to obtain specified in the title compound as a white solid prophetic is TBA.

1H NMR (Acetone-d6) (1,25 (d, 6N), and 3.16 (s, 3H), 4,18 (m, 1H), 7,60 (m, 1H), 7,74 (d, 1H), 7,79 (t, 1H), to 7.99 (d, 1H), with 8.05 (s, 4H), of 8.09 (s, 1H), 8,72 (m, 1H), 8,78 (DD, 1H), 8,93 (s, 1H), for 9.64 (ush., NH).

Example 50

N-Cyclopropyl-1-[3-(6-methylsulfonylmethyl-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: 5-Bromo-2-methylthiopyridine

A mixture of 2,5-dibromopyridine and timelocked sodium (1.3 EQ.) in N,N-dimethylformamide (2 ml/mmol) was stirred at room temperature for 20 minutes, then cooled to a temperature of 0°C. After dilution with cold water the precipitate was filtered to obtain compound 5-bromo-2-methylthiopyridine in the form of solids.

Stage 2: N-Cyclopropyl-1-[3-(6-methylthiopyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 3 of example 32, but substituting 5-bromo-2-methylthiopyridine with stage 1 3-bromo-5-methylsulfinylphenyl receive the compound N-cyclopropyl-1-[3-(6-methylthiopyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

Stage 3: N-Cyclopropyl-1-[3-(6-methylsulfonylmethyl-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 49, but substituting N-cyclopropyl-1-[3-(6-methylthiopyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from stage 2 N-isopropyl-1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]h is pteridine-4-one-3-carboxamide, get the compound N-cyclopropyl-1-[3-(6-methylsulfonylmethyl-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide in the form of solids.

1H NMR (CDCl3) (0,66 (m, 2H), 0,84 (m, 2H), 2,97 (m, 1H), 3,26 (s, 3H), of 7.48 (m, 1H), 7,55 (d, 1H), to 7.67 (s, 1H), 7,74-7,80 (m, 2H), 8,14-8,19 (m, 2H), 8,68 (m, 1H), 8,81 (DD, 1H), 8,96 (s, 1H), 9,05 (s, 1H), 9,73 (ush., NH).

Example 51

N-Isopropyl-1-[3-(5-methylsulfinylphenyl-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 49, but substituting N-isopropyl-1-[3-(5-methylthiopyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 15 N-isopropyl-1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (1,33 (d, 6N), 3,20 (s, 3H), or 4.31 (m, 1H), 7,52 (m, 1H), 7,60 (d, 1H), 7,73 (s, 1H), 7,79 (t, 1H), 7,86 (d, 1H), 8,48 (m, 1H), 8,73 (m, 1H), 8,88 (d, 1H), remaining 9.08 (s, 1H), 9,19 (d, 2H), 9,68 (ush., NH).

Example 52

N-Cyclopropyl-1-[3-(4-ethylsulfonyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 49, but substituting N-cyclopropyl-1-[3-(4-ethylthiophene)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 18 N-isopropyl-1-[3-(4-methylthiophenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide receive specified in the title compound in the form of solids

1H NMR (CDCl3) (0,72 (m, 2H), 0,90 (m, 2H), of 1.35 (t, 3H), to 3.02 (m, 1H), 3,18 (square, 2N), of 7.48-7,56 (m, 2H), of 7.70 (s, 1H), of 7.75 (t, 1H), to 7.84 (m, 3H), 8,03 (d, 2H), 8,73 (m, 1H), cent to 8.85 (DD, 1H), 9,10 (s, 1H), 9,80 (ush., NH).

Example 53

N-Cyclopropyl-1-[3-(4-ethylsulfinyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a solution of N-cyclopropyl-1-[3-(4-ethylthiophene)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 18 in a 1:1 mixture of methylene chloride and methanol (9 ml/mmol) is added at a temperature of 0°With the uranyl monoperoxyphthalate magnesium (MMRR, a 0.5 molar equiv.) and the resulting mixture is stirred in the cold for 2 hours. The mixture is quenched with saturated aqueous sodium bicarbonate and distributed between methylene chloride and water. The crude product from the organic phase is subjected to chromatography on silica gel, elwira 90:9:1 mixture of methylene chloride, ethanol and 28% aqueous ammonium hydroxide, to obtain the specified header connection in the form of solids.

1H NMR (CDCl3) (0,68 (m, 2H), 0,85 (m, 2H)and 1.15 (m, 3H), 2,80 (m, 1H), equal to 2.94 (m, 1H), 2,98 (m, 1H), 7,45 is 7.50 (m, 2H), 7,65-7,73 (m, 4H), 7,76-of 7.82 (m, 3H), 8,71 (m, 1H), 8,83 (DD, 1H), 9,06 (s, 1H), 9,78 (ush., NH).

Example 54

N-Isopropyl-1-{3-[4-(1-oximeter)phenyl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a solution of N-isopropyl-1-[3-(4-acetylphenyl)phenyl]-1,4-dihydro[1,8]natteri the Jn-4-one-3-carboxamide from example 4 in pyridine (11 ml/mmol) at room temperature add hydroxylamine hydrochloride (2.1 EQ.) and the resulting mixture is stirred for 16 hours. The mixture is filtered through celite and the filtrate is evaporated. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium carbonate and then water, dried and evaporated. The residue is stirred in a small volume of acetone and filtered to obtain specified in the connection header in the form of solids.

1H NMR (CDCl3) (1,29 (d, 6N), and 2.27 (s, 3H), 4,30 (m, 1H), 7,39 (d, 1H), 7,46 (m, 1H), 7,56 (d, 2H), to 7.59-7,63 (m, 2H), 7,66 (d, 2H), 7,72 (d, 1H), 8,17 (s, 1H, HE), 8,69 (USS, 1H), 8,82 (d, 1H), 9,10 (s, 1H), 9,71 (ush., NH).

Example 55

N-Isopropyl-1-{3-[4-(4-piperazine-1-yl)phenyl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a solution of N-isopropyl-1-{3-[4-(4-tertbutyloxycarbonyl-1-yl)phenyl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 11 in methylene chloride (10 ml/mmol) is added triperoxonane acid (6 ml/mmol) and the resulting mixture was stirred at room temperature for 2 hours, then gently heated for 15 minutes. The mixture is evaporated and the crude product is subjected to chromatography on silica gel, elwira 9:0,9:0,1 mixture of methylene chloride, methanol and 28% aqueous ammonium hydroxide, to obtain the specified header connection in the form of solids.

1H NMR (CDCl3) (1,29 (d, 6N), 2,99 (m, 4H), and 3.16 (m, 4H), 4,25 (m, 1H), 6,94 (d, 2H), 7,29 (d, 1H), 7,42 (m, 1H), 7,50 (d, 2H), 7,52-7,58 (m, 2H), 7,69 (d, 1H), 8,66 (m, 1 is), 8,78 (DD, 1H), 9,04 (s, 1H), RS 9.69 (ush., NH).

Example 56

N-Cyclopropyl-1-[3-(4-methylsulfonylmethyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1:N-Cyclopropyl-1-[3-(4-bromomethylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

A mixture of N-cyclopropyl-1-[3-(4-hydroxymethylene)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 16, chetyrehpostovye carbon (2 EQ.) and dipose (0,6 molar EQ.) in methylene chloride (15 ml/mmol) was stirred at room temperature for 3 hours. The mixture was concentrated at room temperature and subjected to chromatography on silica gel, elwira 1:1 mixture of ethyl acetate and methylene chloride, to obtain the compound N-cyclopropyl-1-[3-(4-bromomethylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide.

Stage 2: N-Cyclopropyl-1-[3-(4-methylsulfonylmethyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a solution of N-cyclopropyl-1-[3-(4-bromomethylphenyl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from step 1 in N,N-dimethylformamide (20 ml/mmol) is added sodium salt methanesulfinic acid (1.3 EQ.) and the resulting mixture was stirred at room temperature for 18 hours. To the mixture is added saturated aqueous solution of ammonium chloride and ethyl acetate and the insoluble solid is filtered, well washed with the ode, hexane, ether and ethyl acetate to obtain specified in the connection header in the form of solids.

1H NMR (CDCl3) (0,72 (m, 2H), 0,89 (m, 2H), 2,85 (s, 3H), 3.04 from (m, 1H), 4,34 (s, 2H), 7,46-7,52 (m, 2H), 7,55 (d, 2H), 7,65-7,73 (m, 4H), 7,80 (d, 1H), 8,76 (m, 1H), cent to 8.85 (d, 1H), 9,12 (s, 1H), 9,82 (ush., NH).

Example 57

N-Cyclopropyl-1-[3-(1,6-dihydro-6-oxopyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a solution of N-cyclopropyl-1-[3-(6-benzyloxypyridine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 42 in 1,2-dichloroethane (25 ml/mmol) is added triperoxonane acid (1.5 ml/mmol) and the resulting mixture is stirred at a temperature of 60°C for 18 hours. Add triperoxonane acid (0.75 ml/mmol) and heating continued for another 24 hours. The cooled mixture is diluted with methylene chloride and add saturated aqueous sodium bicarbonate, which gives the precipitation of the solid, which is filtered. From the filtrate collected organic phase and evaporated to a solid substance, which combine with previously filtered solid. This mixture is subjected to chromatography on silica gel, elwira 10% methanol in methylene chloride to obtain specified in the title compound as a white fluffy solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,78 (m, 2H), 2,90 (m, N), of 6.45 (d, 1H), 7,52 (m, 1H), to 7.61-the 7.65 (m, 2H), 7,78 (d, 1H), a 7.85 (s, 1H), 7,89-to 7.93 (m, 2H), total of 8.74 (d, 1H), 8,78-8,81 (m, 2H), 9,73 (ush., NH), or NH>11 h/million

Example 58

N-Cyclopropyl-1-[[3-{5-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]pyridine-3-yl}phenyl]]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of stage 4 of example 47, but replacing N-cyclopropyl-1-[3-(5-bromopyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 41 N-cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide get mentioned in the title compound as a white solid.

1H NMR (DMSO-d6) (0,58 (m, 2H), 0,79 (m, 2H), 2.91 in (m, 1H), and 5.30 (s, 1H, HE), the 7.65 (m, 1H), 7,71-7,79 (m, 3H), 8,12 (d, 1H), 8,23 compared to 8.26 (m, 2H), 8,49 (s, 1H), up 8.75 (DD, 1H), 8,80 (m, 1H), 8,87 (s, 1H), 8,97 (m, 2H), 9,04 (s, 1H), 9,74 (ush., NH).

Example 59

N-Isopropyl-1-[3-(1-oxidability-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-isopropyl-1-[3-(pyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 7 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get mentioned in the title compound as a white solid.

1H NMR (DMSO-d6) (1,21 (d, 6N), 4,10 (m, 1H), 7,51 (t, 1H), to 7.64 (m, 1H), 7,71 to 7.75 (m, 3H), of 7.97 (m, 1H), of 8.09 (s, 1H), 8,23 (d, 1H), 8,69-8,77 (m, 3H), 8,84 (s, 1H), 9,66 (ush., NH).

Example 60

N-(2,6-Dichloropyridine-4-yl)--[3-(1-oxidability-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-(2,6-dichloropyridine-4-yl)-1-[3-(pyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 10 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get mentioned in the title compound as a white solid.

1H NMR (DMSO-d6) (7,51 (m, 1H), 7,69 for 7.78 (m, 4H), to 7.99 (DD, 1H), 8,14 (s, 1H), 8,24 (DD, 1H), to 8.70 (s, 1H), 8,73 (s, 2H), 8,84 (m, 2H), 8,99 (s, 1H), 12,05 (ush., NH).

Example 61

N-Isopropyl-1-[3-(5-carboethoxy-1-oxidability-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-isopropyl-1-[3-(5-carbamaxepine-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 24 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get mentioned in the title compound as a white solid.

1H NMR (CDCl3) (1,28 (d, 6N), of 1.40 (t, 3H), 4,28 (m, 1H), 4,43 (square, 2H), 7,49 (DD, 1H), 7,56 (m, 1H), 7,68 (s, 1H), 7,73 (d, 2H), 8,04 (s, 1H), at 8.60 (s, 1H), 8,68 (DD, 1H), 8,77 (s, 1H), 8,82 (d, 1H), 9,01 (s, 1H), being 9.61 (ush., NH).

Example 62

N-Isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)pyridine-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carbox the Ministry of foreign Affairs of example 25 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get listed in the title compound as a white solid.

1H NMR (CDCl3) (1,29 (d, 6N), 1,60 (C, 6N), 4,11 (USS, 1H), 4,23 (m, 1H), 7,42-7,51 (m, 2H), 7,58 (s, 2H), 7,65 (m, 2H), 8,28 (s, 1H), with 8.33 (s, 1H), 8,64 (m, 1H), 8,80 (d, 1H), 8,98 (s, 1H), being 9.61 (ush., NH).

Example 63

N-Isopropyl-1-{3-[6-(2-methylpropyl)-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-isopropyl-1-{3-[6-(2-methylpropyl " pyridine-3-yl]-phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 26 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get mentioned in the title compound as a white solid.

1H NMR (CDCl3) (0,98 (d, 6N), of 1.29 (d, 6N), to 2.29 (m, 1H), 2,32 (d, 2H), 4.26 deaths (m, 1H), 7,28 (d, 1H), 7,38 (d, 1H), 7,47-7,52 (m, 2H), 7,60 (s, 1H), 7,69 (m, 2H), 8,53 (s, 1H), 8,69 (m, 1H), 8,82 (DD, 1H), 9,03 (s, 1H), 9,62 (ush., NH).

Example 64

N-Isopropyl-1-[3-(6-methyl-1-oxidability-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-isopropyl-1-[3-(6-methylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 28 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get mentioned in the title compound as a white solid.

1H NMR (CDCl3) (1,32 (d, 6N), 2,60 (s, 3H), 4,30 (m, 1H), 7,35-7,45 (m, 2H), 7,50 (m, 2H), 7.62mm (s, 1H), 7,72 (d, 2H), and 8.8 (s, 1H), 8,72 (m, 1H), cent to 8.85 (DD, 2H), 9,06 (s, 1H), 9,66 (ush., NH).

Example 65

N-Cyclopropyl-1-[3-(1-oxidability-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-cyclopropyl-1-[3-(pyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 14 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get mentioned in the title compound as a white solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,78 (m, 2H), 2,90 (m, 1H), 7,52 (t, 1H), 7,65 (m, 1H), 7,72-7,76 (m, 3H), 7,98 (m, 1H), 8,10 (s, 1H), of 8.25 (d, 1H), 8,70-8,79 (m, 3H), cent to 8.85 (s, 1H), 9,72 (ush., NH).

Example 66

N-Cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 29, but substituting N-oxide of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from step 2 of example 30 5-bromo-1-oxidability get mentioned in the title compound as a white solid.

1H NMR (CDCl3) (0,66 (m, 2H), 0,85 (m, 2H), 1.70 to (C, 6N), of 2.97 (m, 1H), 7,43-7,49 (m, 2H), 7,52-7,56 (m, 2H), to 7.61 (s, 2H), 7,71-7,74 (m, 2H), 8,49 (s, 1H), 8,68 (m, 1H), 8,80 (d, 1H), of 9.02 (s, 1H), 9,74 (ush., NH).

Example 67

N-Cyclopropyl-1-[3-(1-oxidability-4-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-cyclepro the Il-1-[3-(pyridin-4-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 17 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get listed in the title compound as a white solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,79 (m, 2H), 2,92 (m, 1H), 7,62-of 7.70 (m, 2H), of 7.75 (t, 1H), 7,88 (d, 2H), 8,03 (d, 1H), 8,15 (s, 1H), 8.30 to (d, 2H), up 8.75 (d, 1H), 8,80 (m, 1H), 8,86 (s, 1H), 9,73 (ush., NH).

Example 68

N-Cyclopropyl-1-[3-(5-bromo-1-oxidability-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-cyclopropyl-1-[3-(5-bromopyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 41 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get mentioned in the title compound as a pale yellow solid.

1H NMR (DMSO-d6) (0,56 (m, 2H), 0,78 (m, 2H), 2.91 in (m, 1H), 7,65 (m, 1H), 7,71-7,74 (m, 2H), 8,02-of 8.06 (m, 2H), 8,15 (s, 1H), at 8.60 (s, 1H), 8,73-8,79 (m, 3H), 8,86 (s, 1H), 9,73 (ush., NH).

Example 69

N-Cyclopropyl-1-[[3-{5-[6-(1-hydroxy-1-methylethyl)-1-oxidability-3-yl]pyridine-3-yl}phenyl]]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-cyclopropyl-1-[[3-{5-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]pyridine-3-yl}phenyl]]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 58 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine and using 1.6 EQ. m-chloroperoxybenzoic acid, get mentioned in the title compound as a white solid.

1H NMR (DMSO-d 6) (or 0.57 (m, 2H), 0,78 (m, 2H), 2.91 in (m, 1H), 6,94 (s, 1H, HE), the 7.65 (m, 1H), 7,71-7,79 (m, 3H), of 7.97 (DD, 1H), 8,13 (d, 1H), of 8.25 (s, 1H), 8,55 (s, 1H), total of 8.74 (DD, 1H), 8,80 (m, 1H), 8,87 (s, 1H), 8,91 (, 1H), 9,00 (s, 1H), which is 9.09 (s, 1H), 9,73 (ush., NH).

Example 70

N-Cyclopropyl-1-[[3-{5-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]-1-oxidability-3-yl}phenyl]]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 69 also get mentioned in the title compound as a white solid.

1H NMR (DMSO-d6) (or 0.57 (m, 2H), 0,79 (m, 2H), 2,92 (m, 1H), 5,32 (s, 1H, HE), the 7.65 (m, 1H), 7,72-7,80 (m, 3H), 8,08-8,17 (m, 2H), 8,27 (m, 2H), 8,70-8,82 (m, 4H), 8,88 (s, 1H), 8,98 (s, 1H), 9,73 (ush., NH).

Example 71

N-Cyclopropyl-1-[[3-{5-[6-(1-hydroxy-1-methylethyl)-1-oxidability-3-yl]-1-oxidability-3-yl}phenyl]]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 69 also get mentioned in the title compound as a white solid.

1H NMR (DMSO-d6) (0,58 (m, 2H), 0,80 (m, 2H), 2,92 (m, 1H), 6,85 (USS, 1H, HE), the 7.65 (m, 1H), 7,70-7,80 (m, 3H), of 7.96 (d, 1H), 8,13 (m, 2H), 8,29 (s, 1H), 8,71-8,84 (m, 4H), 8,89 (s, 1H), of 8.92 (s, 1H), 9,73 (ush., NH).

Example 72

N-Isopropyl-1-[3-(1-acidogenesis-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-isopropyl-1-[3-(quinoline-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-ka is bocamodem from example 12 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get listed in the title compound in the form of solids.

1H NMR (CDCl3) (1,30 (d, 6N), 4,28 (m, 1H), 7,49 (DD, 1H), 7,54 (d, 1H), 7,66-a 7.85 (m, 5H), 7,92 (m, 2H), 8,69 is 8.75 (m, 2H), 8,84 (d, 1H), 8,86 (s, 1H), remaining 9.08 (s, 1H), for 9.64 (ush., NH).

Example 73

N-Isobutyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a mixture of N-isobutyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 46 13:1 methylene chloride/methanol (33 ml/mmol) at room temperature add the uranyl monoperoxyphthalate magnesium (MMRR, to 1.1 molar EQ.) and the resulting mixture was stirred at room temperature for 24 hours. The mixture is filtered through a layer of celite and the filtrate washed with aqueous sodium carbonate, then with water and dried. The crude product is subjected to chromatography on silica gel, elwira 8% ethanol in ethyl acetate, and the resulting solid is stirred at room temperature in air for several hours and filtered to obtain specified in the title compound as a pale pink solid.

1H NMR (Acetone-d6) (0,98 (d, 6N), to 1.61 (s, 6H), of 1.88 (m, 1H), 3,26 (t, 2H), 7,52 (s, 1H, HE), to 7.61 (m, 1H), 7,66 (d, 1H), to 7.77-of 7.82 (m, 2H), 7,88 (d, 1H), to 7.99 (d, 1H), 8,12 (s, 1H), 8,68 (s, 1H), 8,73 (m, 1H), 8,80 (DD, 1H), 8,93 (s, 1H), 9,81 (ush., NH).

Example 74

N-Cyclopropyl-1-[3-(6-methyl-1-oxidability-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

According to the method of example 73, but replacing N-cyclopropyl-1-[3-(6-methylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 39 N-isobutyl-1-{3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (0,72 (m, 2H), of 0.91 (m, 2H), 2,61 (s, 3H), to 3.02 (m, 1H), 7,38 (d, 1H), 7,45 (DD, 1H), 7,49-7,58 (m, 2H), 7,66 (s, 1H), to 7.75 (m, 2H), 8,61 (s, 1H), 8,72 (m, 1H), 8,87 (DD, 1H), remaining 9.08 (s, 1H), 9,78 (ush., NH).

Example 75

N-Cyclopropyl-1-[3-(6-methylsulphonyl-1-oxidability-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

To a suspension of N-cyclopropyl-1-[3-(6-methylsulfonylmethyl-3-yl)phenyl]-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 51 in methylene chloride (30 ml/mmol) is added urea-hydrogen peroxide (8 EQ.) and the resulting mixture is cooled to a temperature of 0°C. Add triperoxonane acid (4.7 equiv.) and the mixture is heated to room temperature to obtain a solution. After 18 hours, add urea-hydrogen peroxide (2.6 EQ.) and triperoxonane acid (2 EQ.) and stirring is continued for another 2 hours. The mixture is quenched with saturated aqueous sodium metabisulfite, dilute what ethylenchloride and the organic phase is washed with 1N aqueous HCl, then a saturated solution of salt and water, dried and evaporated. The crude product is subjected to chromatography on silica gel, elwira 40% toluene in acetone to obtain specified in the connection header in the form of solids.

1H NMR (CDCl3) (0,66 (m, 2H), 0,85 (m, 2H), 2,97 (m, 1H), 3,52 (s, 3H), of 7.48 (m, 1H), 7,58-the 7.65 (m, 3H), 7,72 for 7.78 (m, 2H), 8,15 (d, 1H), 8,54 (s, 1H), 8,68 (USS, 1H), 8,81 (d, 1H), 9,01 (s, 1H), 9,71 (ush., NH).

Example 76

N-Cyclopropyl-1-{5-bromo-3-[6-(1-hydroxy-1-methylethyl)-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 30, but substituting N-cyclopropyl-1-{5-bromo-3-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide from example 47 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, get mentioned in the title compound in the form of solids.

1H NMR (CDCl3) (0,71 (m, 2H), 0,90 (m, 2H), 1,75 (C, 6N), to 3.02 (m, 1H), of 7.48-of 7.60 (m, 5H), 7,73 (s, 1H), 7,88 (s, 1H), charged 8.52 (s, 1H), 8,72 (m, 1H), 8,84 (DD, 1H), 9,04 (s, 1H), 9,71 (ush., NH).

Example 77

N-Cyclopropyl-1-{3-[6-(1,2-dihydroxy-1-methylethyl)-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

Stage 1: N-Oxide of 5-bromo-2-(1-methylvinyl)pyridine

A mixture of N-oxide of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from step 2 of example 30 (1.29 g) and 25% aqueous sulfuric acid is heated pritemperature 130° With in 2 days. After cooling, the mixture was made slightly basic by the addition of 10N aqueous sodium hydroxide and distributed between ethyl acetate and water. The crude product evaporation of the organic phase is used as such in stage 2.

Stage 2: N-Oxide of 5-bromo-2-(1,2-dihydroxy-1-methylethyl)pyridine

The crude product from step 1 was dissolved in 3:1 mixture of acetone and water (16 ml) and add N-oxide 4-methylmorpholine (1 g) and the dihydrate asmita potassium (90 mg). The resulting mixture was stirred at room temperature for 3 days, then add an excess of solid sodium bisulfite and the mixture is evaporated. The residue is diluted with methylene chloride and filtered. The filtrate is evaporated and the residue is subjected to chromatography on silica gel, elwira with ethyl acetate, to obtain specified in the title compound as a white solid.

Stage 3: N-Cyclopropyl-1-{3-[6-(1,2-dihydroxy-1-methylethyl)-1-oxidability-3-yl]phenyl}-1,4-dihydro[1,8]naphthiridine-4-one-3-carboxamide

By the method of step 2 of example 32, but substituting N-oxide of 5-bromo-2-(1,2-dihydroxy-1-methylethyl)pyridine from step 2 of 3-bromo-5-methylsulfinylphenyl receive specified in the title compound in the form of solids.

1H NMR (CDCl3) (0,66 (m, 2H), 0,85 (m, 2H), 1.61 of (s, 3H), 2,78 (m, 1H, HE), of 2.97 (m, 1H), 3,90 (m, 1H), 3,97 (m, 1H), of 7.48 (m, 1H), 7,53 (m, 2H), 7,60 (m, 2H), 7,69-7,72 (m, 2H), 7,92 (s, 1H, HE), 8,49 (s, 1H), ,68 (m, 1H), 8,80 (DD, 1H), of 9.02 (s, 1H), 9,73 (ush., NH).

Inhibitor of PDE-4, the example In

N-Cyclopropyl-1-{3-[(1-oxidability-3-yl)ethinyl]phenyl}-4-oxo-1,4-dihydro-1,8-naphthiridine-3-carboxamide (compound IX)

Stage 1:

the solvent for washing
MaterialsMMNumberMolEquivalent-tape
Ethyl ester of afterindenttrue318,332,50 kgthe 7.851,0
HCl salt of 3-bromopyridine-N-oxide210,461,82 kg8,641,1
tert-Amylamine87,17 d=0,7462.7 l45,63,0
Allylpalladium dimer365,8572 g0,22.5 mol.%
three-tert-Butylphosphine10% hexano (0.33 M)2,38 l0,810 mol.%
Diethylaminoacetate (DMAc)solvent60 l---24 about.
Waterantibacterial90 l---36 about.
n-Butanol87,6 l---35 about.

100-liter round bottom flask equipped with a reflux condenser and a device for transmission of nitrogen and download HCl salt bromopyridine-N-oxide followed by the addition of 12.5 l DMAc and cooled in an ice bath. Add pure tert-amylamine via addition funnel over 1 hour. It is noted that the addition of amine causes a slight exothermic reaction: temperature rises from 5°to 10°C. Add a solution of phosphine to obtain a light yellow homogeneous solution. Then add π-allylpalladium dimer in the form of a suspension in 1.5 liters of DMAc. The reaction is stirred at a temperature of 10°C for 30 minutes. Acetylene compound is weighed into the bottle and add 9.9 kg DMAc. This acetylene solution is added to the reaction flask. The bottle was washed with 22 kg of DMAc and it is added to the reaction mixture. Add the number of DMAc required to obtain a total volume of 60 liters of milk Obtained yellow solution is heated to a temperature of 60°S, during which he becomes homogeneous brown solution until the reaction is completed, which is determined by the absorption of acetylene compounds. The reaction mixture is cooled to a temperature of 0°before adding 90 l of water to precipitate the product from the solution. The suspension is shown that the comfort to collect the product. To remove the palladium precipitate washed 87,5 l of n-butanol on a filtering apparatus and then dried in a vacuum oven at a temperature of 50Z in a stream of nitrogen overnight to obtain a white solid, 2,68 kg, 83% yield.

NMR1H (CDCl3400MHz) δ: of 1.35 (t, J=7,1 Hz, 3H), 4,34 (sq, J=7,1 Hz, 2H), 7,28 (DD, J=8.0 a, 6,8 Hz, 1H), 7,34 (dt, J=8,0, 1.2 Hz, 1H), 7,38 (DD, J=8.0 a, 4,4 Hz, 1H), 7,49 (DDD, J=8.0 a, 2,4, 1,2, Hz, 1H), 7,58 (t, J=7.9 Hz, 1H), to 7.64 (t, J=1.8 Hz, 1H), to 7.67 (dt, J=7,6, 1.2 Hz, 1H), 8,12 (dt, J=6,5, 1.1 Hz, 1H), of 8.27 (s, 1H), 8,59 (DD, J=4,4, 1.9 Hz, 1H), 8,64 (s, 1H), total of 8.74 (DD, J=8,0, 1.9 Hz, 1H).

NMR13With (CDCl3400 MHz) δ: 14,3, 61,1, 84,7, 92,4, 112,8, 121,4, 122,7, 123,0, 123,2, 125,8, 128,3, 128,5, 129,8, 130,7, 132,5, 136,8, 139,1, 141,0, 149,0, 149,9, 152,5, 164,6, 174,5.

Also use the following method for recovering palladium:

MaterialsMMNumberMolEquivalents
Essential product411,140,718 kgthe 7.851,0
Darco G-60---0,359 kg---50 wt.%
Methanolsolvent82 l---50.

After the deposition of the water-moist filter cake is dried in a stream of nitrogen. 100 l round bottom flask equipped, dephlegmator is, stirrer and a device for transmission of nitrogen, then download the essential product and 72 l of methanol. The mixture is heated to a temperature of 60°up until solids are dissolved. The mixture is cooled to a temperature of 55°and add Darco G-60 in the form of a suspension in 6 l of methanol. The mixture is heated to a temperature of 60°C for four hours. The solution is filtered through Solka Floc warm to remove Darco. Layer Solka Floc washed with 4 l of methanol. The combined filtrates are concentrated to 25 years, at this point begins to form copious white precipitate. This suspension can be applied directly at the stage of obtaining the amide.

Stage 2:

MaterialsMMNumberMolEquivalents
The penultimate ester411,411.4 kg3,41,0
Cyclopropylamine57,10, d=0,82421 l---15 about.
(Butylphosphate250, d=0,91546 ml0,175 mol.%)*
Methanolsolvent21 l---15 about.
Isopropy the acetate antibacterial72 l------
15% aq. acetonitrilesolvent24 l---24 about.

Pass filter, 1 micron

*Parentheses around these butylphosphate mean that the experiment was performed both with and without butylphosphate.

100-liter round bottom flask equipped with a reflux condenser and a device for transmission of nitrogen and download the penultimate ether and methanol followed by the addition of cyclopropylamine. As indicated above, may be added to the catalyst or a Lewis acid. The reaction mixture is heated to a temperature of 60°until complete absorption of ether. The end of the reaction determine when the content of the broadcast will be less than 2% by HPLC. After completion the reaction mixture is cooled to a temperature of 40°and concentrated to approximately half volume. Add isopropylacetate, at the same time fending off the rest of methanol and amine. After completion of the replacement of solvents on isopropylacetate final volume of 20 L. a sample is Taken of the suspension and filtered. The precipitate was washed with 2 l of isopropylacetate and then dried in a vacuum oven at a temperature of 50°in a stream of nitrogen overnight.

72-liter round bottom flask equipped with a reflux condenser and a device for transmission and the PTA and download solid product compounds IX and 24 l of a 15% aqueous acetonitrile. The suspension is heated to a temperature of 60°C. All solids dissolved. The solution is filtered through a 1-micron pass filter, simultaneously heating a second 72-liter round-bottom flask, then cooled to a temperature of 22°C. the Suspension is filtered and the solids dried in a vacuum oven at a temperature of 50°in a stream of nitrogen overnight with getting 0,86 kg crystalline compounds IX, 60% yield.

NMR1H (CDCl3400MHz) δ: 0,61-to 0.73 (m, 2H), of 0.79 to 0.92 (m, 2H), 2.95 and-a 3.01 (m, 1H), 7,28 (DD, J=8.0 a, 6,8 Hz, 1H), 7,40 (d, J=8.0 Hz, 1H), of 7.48 (dt, J=8.0 a, 4,4 Hz, 1H), 7,49 (DDD, J=8.0 a, 2,0, 1.2 Hz, 1H), to 7.61 (t, J=8.0 Hz, 1H), to 7.64 (m, J=2.0 Hz, 1H), 7,71 (dt, J=7,6, 1.2 Hz, 1H), 8,19 (d, J=6,6 Hz, 1H), 8.34 per (s, 1H), 8,70 (DD, J=4,6, 1.8 Hz, 1H), 8,80 (DD, J=8,0, 1.9 Hz, 1H), 9,00 (s, 1H), 9,74 (USD, J=3,6 Hz, 1H).

NMR13With (CDCl3400 MHz) δ: 6,5, 22,4, 84,6, 92,5, 113,5, 121,4, 122,0, 122,9, 123,2, 125,7, 128,4, 128,6, 129,8, 130,7, 132,6, 136,4, 139,0, 140,4, 141,1, 148,0, 149,7, 153,0, 165,1, 177,1.

An alternative method, illustrating obtain the amide with the use of magnesium chloride

MaterialsMMNumberMolEquivalents
The penultimate ester411,411.0 kg2,431,0
Magnesium chloride95,22 0,231 kg2,431,0
Cyclopropylamine57,10, d=0,82410 l---10 about.
Acetonitrilesolvent30 l---30.
16 l16 about.
Watersolvent8 l---8.
Sodium citrate294,100,79 kgto 2.671,1

Pass filter, 1 micron

Process description

72-liter round bottom flask equipped with a reflux condenser and a device for transmission of nitrogen and download the penultimate ether and acetonitrile, followed by the addition of magnesium chloride and then cyclopropylamine. The reaction mixture is heated to a temperature of 60°until the completion of the intake air. The end of the reaction determine when the content of the broadcast will be less than 0.5% by HPLC. After completion the reaction mixture is cooled to a temperature of 40°and concentrated to approximately half volume. Add acetonitrile, at the same time fending off the rest of cyclopropylamine. After replacing the solvent acetonitrile final volume is 8 HP Add 8 l of water and suspend the Yu is heated to a temperature of 60° C. All solids dissolved. The solution is filtered through a 1-micron pass filter, simultaneously heating a second 22-liter round-bottom flask, then cooled to a temperature of 22°C. the Suspension is filtered and the solids dried in a vacuum oven at a temperature of 50°in a stream of nitrogen overnight with getting 0,82 kg '191, 80% output.

Stage 3: recrystallization of compound IX

MaterialsMMNumberMolEquivalents
Connection IX422,450,86 kg2,01,0
Ethanolsolvent20 l---4,3 about.

72-liter round bottom flask equipped with a reflux condenser and a device for transmission of nitrogen and load connection IX and ethanol. The suspension is heated to a temperature of 50°under stirring until complete recrystallization. Recrystallization is completed, if there is more than 95% of the forms And according to the NMR of solids or powder x-ray. The mixture is cooled to a temperature of 22°C, then filtered to collect the solid, which is dried in a vacuum oven at a temperature of 50Z in the flow of AZ is that during the night with obtaining 0,74 kg of the desired shape. Solids sieved through a 12 mesh with getting 0,719 kg fluffy solid.

Inhibitor of PDE-4, example 2

N-cyclopropyl-1-{3-[(pyridine-3-yl)ethinyl]phenyl}-4-oxo-1,4-dihydro-1,8-naphthiridine-3-carboxyamide (compound IXa)

Compound IXa receive according to the method of example 1, replacing 3-bromopyridine 3-bromopyridine-N-oxide.

Other changes or modifications which are obvious to experts in the art, without going beyond the scope of this invention. This invention is limited only by the claims.

1. The method of obtaining the compounds of formula IX or IXa:

including

stage: interaction in the solvent And the compounds of formula Va

where R1selected from C1-8of alkyl, aryl and heteroaryl, optionally substituted by aryl and/or C1-8by alkyl; and

solvent And is diethylaminoacetate, dimethylformamide, acetonitrile, DMSO, methylacetamide, ethers, or mixtures thereof,

with the compound of the formula VII or formula VIIa

in the presence of a palladium catalyst and a phosphine ligand in the presence of amine base is for obtaining the compounds of formula VIII or formula VIIIa

stage D: the interaction of the solvent Into compounds of the formula VIII or VIIIa with cyclopropylamino, optionally in the presence of a catalyst, to obtain the compounds of formula IX or IXa.

2. The method according to claim 1, in which the phosphine ligand is P(C1-6alkyl)3.

3. The method according to claim 1, wherein the palladium catalyst is chosen from the group comprising palladium catalysts selected from P(tert-butyl)3-Pd-P(tert-butyl)3, [PdCl(allyl)2Pd2(DBA)3and [P(tert-butyl)3PdBr]2.

4. The method according to claim 1, in which the molar ratio of compounds of formula Va to the compound of formula VII or VIIa is from about 1:1.5 to 1.5:1.

5. The method according to claim 1, in which the molar ratio of amine equivalents of base per mole of the compounds of formula VII or VIIa is from 2:1 to 3.5:1.

6. The method according to claim 1, in which the molar ratio of palladium catalyst to the compound of formula Va is from 0.05:1 to 0.10:1.

7. The method according to claim 1, in which stage is carried out at a temperature of from 40 to 70°C.

8. The method according to claim,1 in which the solvent is a C1-8arcanely solvent or acetonitrile.

9. The method according to claim 1, wherein the catalyst is selected from butylphosphate (BuO)3R and magnesium chloride.

10. The method according to claim 1, in which moderneurodesign of cyclopropylamine to the compound of formula VIII or VIIIa is, at least 1:1.

11. The method according to claim 1, in which stage D is carried out at a temperature of from 40 to 60°C.

12. The method according to claim 1, in which stage C and stage D is carried out in a single reactor without purification or extraction of product stage before moving on to stage D.

13. The method according to claim 1, further comprising mixing the compounds of formula IX with solvent transformation for the recrystallization of compounds of formula IX or IXa.

14. The method according to item 13, in which the solvent transformations are selected from dry ethanol, methanol, N-methylpyrrolidinone, triptoreline, methyl tert-butyl ether or mixtures thereof.

15. The method of purification of the compounds of formula IX or IXa

comprising combining the compound of formula IX or IXa with the amount of solvent transformations sufficient for suspension connection, and recrystallization of the compounds of formula IX or IXa.

16. The method according to item 15, in which the solvent transformations are chosen from dimethylformamide, dimethylacetamide, N-methylpyrrolidinone and C1-4alkanol.

17. The method according to clause 16, in which the solvent transformation contains water in an amount less than 5%.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically suitable salt or solvate thereof, where dashed line stands for additional bond, а is a number from 0 to 2, b is a number from 0 to 2, n is 2, p is 2, r is 1, М1 stands for nitrogen, М2 stands for С(R3), X stands for either a bond or alkylene group with number of carbon atoms from 1 to 6, Y stands for -С(О)- group, Z stands for a bond, or alkylene group with number of carbon atoms from 1 to 6, or alkenylene group with number of carbon atoms from 1 to 6, or -С(O)-, -CH(CN)-, -SO2- or СН2С(O)NR4- group, R1 stands for groups, R2 stands for six-membered heteroaryl ring with one or two heteroatoms chosen independently of each other from either nitrogen atom or N-O group, other atoms of the cycle being carbon, five-membered heteroaryl ring with one, two, three or four heteroatoms chosen independently of each other from nitrogen, oxygen or sulphur, other atoms of the cycle being carbon, R32 stands for substituded quinoline group, R32 stands for substituted aryl group, heterocycloalkyl group, cycloalkyl group with number of carbon atoms from 3 to 6, alkyl group with number of carbon atoms from 1 to 6, group, where the said six-membered heteroaryl ring or the said five-membered heteroaryl ring may be R6-substituted, R12 independently of others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group or fluorine atom, provided in case R12 stands for hydroxyl or fluorine the rest of R12 cannot be bonded to a nitrogen-bonded carbon atom, or two R12 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjaicent carbon atoms of the ring, R13 independently of the others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group, alcoxy group with number of carbon atoms from 1 to 6, or fluorine atom, provided in case R13 stands for hydroxyl or fluorine the rest of R13 cannot be bonded to a nitrogen-bonded carbon atom, or two R13 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjacent carbon atoms of the ring. See description for meaning of the other structural elements. Invention relates also to pharmaceutical compositions, as well as to application of compounds of formula I.

EFFECT: preparation of novel biologically active substances and pharmaceutical compositions.

20 cl, 659 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method (variants) for synthesis of racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone and its (+)-enantiomer. The first variant of method for synthesis of racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone involves step (e) and another variant involves steps (b)-(e). Method for synthesis of (+)-enantiomer involves the following steps (a)-(f): (a) interaction of 2,6-diaminopyridine with malic and sulfuric acids to form 2-amino-7-hydroxy-1,8-naphthyridine hydrosulfate that (b) is treated with phthalyl reagent in a solvent medium to form phthalimidylnaphthyridine of the formula (2): that (c) is chlorinated to form chloride of the formula (3): that (d) is reduced to hydroxyindolinone of the formula (4): that (e) is treated with 5-methyl-2-oxohexyltriphenylphosphonium halide to yield racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone that (f) is separated and final (+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone is prepared. Invention provides improving method for synthesis of 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone from 2-(7-chloro-1,8-naphthyridine-2-yl)-3-hydroxyisoindolinone-1-one based on using 5-methyl-2-oxohexyltriphenylphosphonium halide.

EFFECT: improved methods of synthesis.

13 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): that are antagonists of CRF receptors and wherein Ar means optionally substituted phenyl or monocyclic 6-membered heteroaryl comprising one heteroatom chosen from nitrogen, oxygen or sulfur atoms; R1-R4 have values given in the invention claim, or to their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of indicated compounds and to pharmaceutical compositions containing these compounds that are useful for administration to a patient suffering from diseases that are relived in therapy using antagonists of CRF receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 tbl, 17 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one isethionate salt and to its crystalline forms. These substances show properties of selective inhibitor of cyclin-dependent kinase 4 (CDK4) and can be used in treatment, for example, of inflammatory and cellular proliferative diseases. Crystalline forms of salt show powdery roentgenogram in values 2θ about 8.7, 13.5 and 17.6 (form A); 5.1, 11.8, 12.1, 12.8, 13.1 and 14.7 (form B), and 8.4, 8.9 and 21.9 (form D). Also, invention relates to methods for preparing crystalline 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one isethionate salt, to medicinal agent and its using for preparing a medicinal agent.

EFFECT: valuable medicinal and biochemical properties of compound.

23 cl, 5 tbl, 18 dwg, 12 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel compound - ((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine succinate of the formula: that possesses property of CCR-2 antagonist. Also, invention relates to a method for modulation of activity of chemokine receptors and a method for treatment, improvement, control and reducing risk of inflammatory and immunoregulatory disorder or disease, and to a method for improvement, control and reducing risk of rheumatic arthritis.

EFFECT: valuable medicinal properties of compound.

4 cl, 3 tbl, 5 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7, cycle A, cycles B, X, Y and Z have values given in the invention claims and in description of the claim, and to their pharmaceutically acceptable salts also. Proposed compound possess an antitumor activity and can be used in treatment of oncological diseases. Also, invention relates to a pharmaceutical composition based on these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

23 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes imidazoquinoline derivatives of the formula (I): wherein X represents alkyl, -CHR3-; Z represents groups -S-. -SO-, or -SO2-; R1 is chosen from group comprising alkyl and unsubstituted phenyl; R2 is chosen from group comprising hydrogen atom, alkyl, alkyl-Y-alkyl; each R3 represents hydrogen atom; Y represents -O-; n = 0. Also, invention describes a tetraimidazoquinoline derivative, pharmaceutical compositions based on thereof and a method for stimulating biosynthesis of cytokine in animal body. Proposed compounds and compositions can induce biosynthesis of different cytokines and therefore they can be used in treatment of different diseases being among them viral and tumor diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

20 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) , methods for their synthesis and their using for therapeutic treatment of the nervous system disorders associated with 5-HT-6 receptor. Invention provides synthesis of novel biologically active substances of the formula (I) and pharmaceutical compositions based on thereof used in treatment of the nervous system disorders and controlled by 5-HT-6 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

6 tbl, 82 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

Up!