Method of modulating transporters of atp-binding cassette

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

 

Cross-reference to related applications

According to section 35, United States Code, section 119, this application claims priority under provisional patent application U.S. No. 60/582676 filed June 24, 2004 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", provisional application for U.S. patent No. 60/630127, filed November 22, 2004 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", provisional application for U.S. patent No. 60/635674, filed December 13, 2004 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", provisional application for U.S. patent No. 60/658219 filed March 3, 2005 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", and provisional application for U.S. patent No. 60/661311 filed March 11, 2005 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", the full content of each of the above applications are included in this description by reference.

The technical field to which the invention relates.

The present invention relates to modulators, transporters ATP-binding cassette ("ABC") or their fragments, including the cystic fibrosis transmembrane conductance regulator ("CFTR"), containing compositions and methods for their preparation. The present invention also relates to methods of treating diseases mediated by the ABC Transporter, using such modulators.

Background of invention

ABC Transport is Thera are a family of membrane proteins, transporters, which regulate the transport of a large number of pharmacological agents, potentially toxic drugs and xenobiotics, as well as anions. ABC Transporters are homologous membrane proteins that bind and use of cellular adenosine triphosphate (ATP) due to their specific activities. Some of these conveyors are disclosed as protein resistance to multiple drugs (like glycoprotein MDR1-P or protein resistance to numerous drugs, MRP1), which protects malignant cancer cells from chemotherapeutic agents. Currently identified 48 ABC transporters and on the basis of their identity sequences and functions, they are divided into 7 families.

ABC Transporters regulate many important physiological functions in the body and provide protection against harmful compounds present in the environment. As a result, they represent an important potential target for drugs in the treatment of diseases associated with defects in the conveyor, preventing transport of the drug from the target cell and interference in other diseases in which modulation of the activity of the ABC Transporter may be useful.

One member of the family of ABC is ransporters, usually associated with disease, is a camp/ATP-mediated transmembrane protein that functions anionic "channel, CFTR. CFTR is expressed in many cell types, including adsorption and secretory epithelial cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In the epithelial cells of the normal functioning of CFTR is important to maintain the transport of the electrolyte throughout the body, including the tissue of the respiratory tract and tissue of the digestive tract. CFTR consists of approximately 1480 amino acids that encode a protein Supplement tandem repeat transmembrane domains, and each contains six transmembrane helices and nucleotidase domain. Two transmembrane domain linked to a large polar regulatory (R)domain with multiple phosphorylation sites that regulate channel activity and cell transport.

Encoding CFTR gene has been identified and sequenced (see Gregory R.J. et al., 347:382-386 (1990); Rich D.P. et al., Nature, 347:358-362 (1990); J.R. Riordan et al., Sience, 245:1066-1073 (1989)). The defect in this gene causes mutations in CFTR, leading to cystic fibrosis ("CF"), the most common lethal genetic disease in humans. Cystic fibrosis affects approximately one out of every 2,500 children in the United States. Of the total U.S. population down is about 10 million people contain one copy of the defective gene without obvious pathological effects. In contrast, individuals with two copies associated with CF gene suffer from debilitating and detrimental effects of CF, including chronic lung disease.

In patients with cystic fibrosis mutations in CFTR, endogenous expressed in respiratory epithelium, leading to reduced apical secretion of anions, causing an imbalance in the transport of ions and fluids. The resulting decrease in the transport of anions contributes to increased accumulation of mucus in the lung and associated microbial infections, which, ultimately, are the cause of death of patients with CF. In addition to respiratory disease, patients with CF suffer from gastrointestinal problems and pancreatic insufficiency, resulting, if left untreated, is death. In addition, most men with cystic fibrosis are infertile and women with cystic fibrosis decreases fertility. In contrast to the severe effects of the two copies associated with the CF gene, individuals with one copy of the CF associated gene exhibit increased resistance to cholera and dehydration caused by diarrhea, which may explain the relatively high frequency of the CF gene in the population.

By sequencing of the CFTR gene CF-chromosomes revealed many diseases caused by mutations (Cutting G.R. et al., Nture, 346:366-369 (1990); Dean M. et al., Cell, 61:863-870 (1990); and Kerem B-s, et al., Science 245:1073-1080 (1989); Kerem B-s, et al., Proc. Natl. Acad. Sci. USA, 87:8447-8451 (1990)). Currently identified more than 1,000 diseases caused by mutations in the CF gene (http://www.genet.sikkids.on.ca/cftr/). The most common mutation is a deletion of phenylalanine at position 508 amino acid sequence of CFTR, and it is usually denoted as ΔF508-CFTR. This mutation occurs in approximately 70% of cases of cystic fibrosis and is associated with severe diseases.

The deletion of residue 508 in ΔF508-CFTR prevents protein formed from correct folding. This leads to the inability of the mutant protein to exit the ER and directed transport in the cytoplasmic membrane. As a result, the number of channels present in the membrane is much less than that observed in cells expressing CFTR wild type". In addition to the deterioration of the directed transport, the mutation leads to the discovery of defective membrane channel. Joint reduced the number of channels in the membrane and the opening of the defective channel leads to reduced transport of anions through the epithelium, leading to defective transport of ions and fluids (Quinton P.M., FASEB J., 4:2709-2727 (1990)). Research, however, showed that reduced the number of ΔF508-CFTR in the membrane are functional, although to a lesser extent than CFTR "di the CSO type" (Dalemans et al., Nature Lond., 354:526-528 (1991); Dennung et al., see above; Pasyk Foskett, J. Cell. Biochem., 270:12347-12350 (1995)). In addition to ΔF508-CFTR, another disease caused by mutations in CFTR, which lead to defective directed transport, defective synthesis and/or the opening of a defective membrane channel can be adjusted in the direction of increase or decrease due to changes in the secretion of anions and weakening of progression and/or severity of the disease.

Although CFTR transports many molecules in addition to the anions, it is clear that this role (transport anions) performs one important element in the transport of ions and water across the epithelium. Other elements include the epithelial Na+channel, ENaC, Na+/2Cl-/K+-cotransporter, Na+-K+-ATPase pump and+-channels basolateral membrane, which are responsible for the inclusion of chloride into the cell.

These elements work together to achieve directed transport through the epithelium due to their selective expression and localization in the cell. Adsorption of chloride occurs through the coordinated activity of ENaC and CFTR present in the apical membrane, and Na+-K+-ATPase pump and Cl-channels expressed on basolateral the cell surface. Secondary active transport of chloride from luminaries area leads to the accumulation of intracellular x is orida, which then can passively removed via Cl--channels, resulting in transport of the infection. The system of Na+/2Cl-/K+-cotransporter, Na+-K+-ATPase pump and basolateral membrane To+channels on basolateral surface and CFTR in luminale region coordinate the chloride secretion through CFTR in luminale area. As the water, probably, she never actively transported, its flow through the epithelium depends on very small transepithelial osmotic gradients generated by the large flow of sodium and chloride.

In addition to cystic fibrosis, modulation of CFTR activity may be useful in the case of other diseases, indirectly caused by mutations in CFTR, such as secretory disease and other diseases associated with protein folding mediated CFTR. They include, but are not limited to, chronic obstructive pulmonary disease (COPD), a disease of "dry eyes" and Sjogren syndrome. COPD is characterized by respiratory failure that progresses and is not fully reversible. Respiratory failure is caused by hypersecretion of mucus, emphysema and bronchiolitis. Activators of mutant CFTR or CFTR wild type" provide for the possible treatment of mucus hypersecretion and impaired clearance of ciliated epithelium, which is common in COPD. Concrete is, increasing the secretion of anions due to CFTR may facilitate the transport of liquid to the surface of the respiratory tract for the hydration of mucus and to optimize the viscosity pricelearn fluid. This should lead to increased clearance of ciliated epithelium and reduce symptoms associated with COPD. The disease is dry eye is characterized by a decrease in the allocation of tear fluid and atypical of the tear film lipid, protein and mucinosa profiles. There are many causes of disease "dry eyes", some of which are age, Lasik eye surgery, arthritis, drug therapy, chemical/thermal burns, allergies and diseases such as cystic fibrosis and Sjogren syndrome. Increasing the secretion of anions due to CFTR must strengthen the transport fluid from the corneal endothelial cells and secretory glands around the eye, to improve corneal hydration. This should help to reduce the symptoms associated with the disease "dry eyes". Sjogren syndrome is an autoimmune disease in which the immune system affects vlagopoulos glands throughout the body, including the eyes, mouth, skin, tissue of the respiratory tract, liver, vagina, and rectum. Symptoms include sickness "dry eye", a disease of the mouth and vagina, as well as the lungs. Disease targetbase with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis/dermatomyositis. I believe that the defective transport protein causes the disease, treatment options are limited. Modulators of CFTR activity can be hydrated different organs affected by the disease, and to help mitigate associated with disease symptoms.

As discussed above, I believe that the deletion of residue 508 in ΔF508-CFTR prevents the produced protein from the correct folding, leading to the inability of this mutant protein to exit the ER and directed transport in the cytoplasmic membrane. As a result, the plasma membrane contains an insufficient number of Mature protein and significantly reduced the chloride transport in epithelial tissues. In fact, it is shown that this cellular phenomenon of defective ER-processing of ABC transporters at the expense of the ER mechanism is the main basis not only for CF disease, but also for a large number of other "isolated" and hereditary diseases. There are two ways, according to which the function may be disrupted ER-mechanism: or due to loss of communication with the ER-export of proteins, which leads to degradation or due to ER-accumulation of these defective, abnormal folding of proteins [Aridor M. et al., Nature Med.,5(7), 745-751 (1999); B.S. Shastry et al., Neurochem. International,43, 1-7 (2003); Rutishauer J. et al., Swiss Me Wkly, 132, 211-222 (2002); Morello J.P. et al., TIPS,21, 466-469 (2000); P. Bross et al., Human Mut.,14, 186-198 (1999)]. Diseases associated with the first class of the dysfunction of the ER, are cystic fibrosis (due to abnormal folding ΔF508-CFTR, as discussed above), hereditary emphysema (due to α1-antitripsin; not Piz variants), hereditary hemochromatosis; deficiencies of coagulation-fibrinolysis, such as protein deficiency, hereditary angioedema type 1; deficits in the processing of lipids, such as familial hypercholesterolaemia, chylomicronemia type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysaccharidosis (due to lysosomal enzymes processing), a disease Sandhoff/Tea-Sachs (due to β-hexosaminidase), a disease of crigler/Najjar syndrome type II (due to UDP-glucuronyl-seatransport), polyendocrinopathy/hyperinsulemia, diabetes mellitus (due to insulin receptor), microsomia of Larona (caused by hormone receptor growth), the deficit teleoperated, primary hypoparathyroidism (due preproparathyroid hormone), melanoma (due to tyrosinase). Diseases associated with the second class of violation of ER functions are glycans CDG type 1, hereditary emphysema (due to α1-antitripsin; PiZ-is version), congenital hyperthyroid, osteopathies (due procollagen type I, II, IV), hereditary hypofibrinogenemia (due to fibrinogen), adrenocorticotropic hormone deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neurophysiology DI (due to vasopressinergic hormone/V2-receptor), nephrogenic DI (due to aquaporin II), the syndrome Charcot-Marie-Toot (due to peripheral myelin protein 22), a disease of Pelizaeus-Merzbacher; neurodegenerative diseases as Alzheimer's disease (due to β and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear, the disease Peaks; some neurological disorders, such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonica dystrophy, as well as lobkovice encelopathy, such as a hereditary disease of Creutzfeldt-Jakob disease (due to defective processing of prion protein), Fabry disease (due to lysosomal α-galactosidase a) and the syndrome of Straussler-Sheinker (caused by the defect processing Prp).

In addition to the high level of regulation of CFTR activity, reduced the secretion of anions at the expense of CFTR modulators may be useful for treatment of ecretary diarrhea, in the case of which the epithelial transport of water is dangerous increases in the activated enhance the secretion of the means of transport of chlorides. The mechanism includes an increase of camp and stimulation of CFTR.

Although there are many causes of diarrhea, the main effects of diarrhoeal diseases resulting from excessive transport of chlorides, are common to all types of diarrhea and include dehydration, acidosis, poor growth and death.

Acute and chronic diarrhea represent a significant health problem in many areas of the world. Diarrhea is a significant factor in poor nutrition, and the leading cause of death (5000000 deaths per year in children aged less than five years.

Secretory diarrhea are also dangerous condition in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory intestinal disease (IBD). 16 million travelers to developing countries from industrialized countries find diarrhea and the severity and number of cases of diarrhea vary from country to country and region travel.

Diarrhea in farm and domestic animals, such as cows, pigs and horses, sheep, goats, cats and dogs, is a major cause of death of these animals. Diarrhea may occur olubugo significant changes such as detachable or physical action, as well as in response to a variety of bacterial or viral infections and usually manifests in the first five hours of the life of the animal.

The most common cause diarrhea bacteria is enterotoxigenic E. coli (ETEC)with polesny antigen C. Conventional viral causes of diarrhoea are rotavirus and coronavirus. Other infectious agents are, among others, cryptosporidia, giardia lamblia and Salmonella.

The symptoms of rotavirus infection include the excretion of liquid fekalii, dehydration and weakness. Coronavirus provokes even more severe disorder in newborn animals and causes a higher rate of death than rotavirus infection. Often, however, young animal can be infected with more than one virus or just a combination of viral and bacterial organisms. It is dangerous increases the severity of the disease.

There is therefore a need in the modulators of the activity of the ABC Transporter containing compositions that can be used to modulate activity of the ABC Transporter in the cytoplasmic membrane of a mammal.

There is a need for methods of treatment of diseases mediated by the ABC Transporter, using such modulators of the activity of the ABC Transporter.

There is a red is a need for methods of modulating activity of an ABC Transporter in ex vivo cytoplasmic membrane of a mammal.

There is a need for modulators of CFTR activity, which can be used to modulate the activity of CFTR in the plasma membrane of a mammal.

There is a need for methods of treating diseases mediated CFTR using such modulators of CFTR activity.

There is a need for methods of modulating CFTR activity in ex vivo cytoplasmic membrane of a mammal.

A brief description of the invention

Now found that the compounds according to this invention and containing their pharmaceutically acceptable compositions are useful as modulators of the activity of the ABC Transporter. These compounds correspond to General formula (I):

or their pharmaceutically acceptable salts, where R1, R2, R3, R4, R5, R6, R7and Ar1in General and in classes and subclasses described below.

These compounds and pharmaceutically acceptable compositions are useful to treat or ameliorate the severity of a number of diseases, disorders or conditions including, but not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; deficiencies of coagulation-fibrinolysis, such as protein deficiency, hereditary angioedema type 1; deficits in the processing of lipids, such as familial hypercholesterolaemia, x is lumichrome type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysacharides, disease sandhof/Tay-Sachs disease criglernajjar Najjar syndrome type II, polyendocrinopathy/hyperinsulemia, diabetes, macrosomia of Larona, the deficit teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, hereditary emphysema, congenital hyperthyroid, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Toot disease Pelizaeus-Merzbacher; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, side amyotrophies sclerosis, progressive supranuclear, the disease Peak; heavy polyglutamine neurological disorders such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonica dystrophy, as well as lobkovice encephalopathy, such as nasledstvenna disease Creutzfeldt-Jakob disease, Fabry disease, syndrome Straussler-Sheinker, COPD, disease, dry eye syndrome and Sjogren's syndrome.

Detailed description of the invention

I. General description of the compounds of the invention

The present invention relative to the tsya to compounds of formula (I), useful as modulators of the activity of the ABC-Transporter:

or their pharmaceutically acceptable salts, where:

Ar1means a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, where the abovementioned ring optionally condensed with a 5 to 12-membered monocyclic or bicyclic, aromatic, partially unsaturated or saturated ring, where each ring contains 0-4 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, where Ar1has m substituents, each independently selected from-WRW;

W stands for a bond or optionally substituted (C1-C6)alkylidene chain, where up to two methylene groups of the residue W optionally and independently replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR', -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r NR'-, -NR'r NR'r CO-, -NR'r CO-, -S-, -SO-, -SO2-, -NR'-, -SO2NR'-, -NR'r SO2- or-NR'r SO2NR'-;

RWindependent means R', halogen, NO2CN, CF3or OCF3;

m is 0-5;

each of R1, R2, R3, R4and R5independent means-X-RX;

X is a bond or optionally substituted (C1-C6)alkylidene chain, where up to two methylene groups of the residue X is optional and illegal the performance of replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR', -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r NR'-, -NR'r NR'r CO-, -NR'r CO-, -S-, -SO-, -SO2-, -NR'-, -SO2NR'-, -NR'r SO2- or-NR'r SO2NR'-;

RXindependent means R', halogen atom, NO2CN, CF3or OCF3;

R6means a hydrogen atom, CF3, -OR', -SR', or optionally substituted C1-6aliphatic group;

R7means a hydrogen atom or a C1-6aliphatic group, optionally substituted-S-RX;

R' is independently selected from a hydrogen atom or an optionally substituted group selected from (C1-C6)aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen atoms, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen atoms, oxygen, or sulfur; or two available radical R', taken together with the atom(atoms), with which(whom) they are bound, form an optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur.

According to EcoForum other options implementation provides the compounds of formula (I):

or their pharmaceutically acceptable salts, where:

Ar1means a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, where the abovementioned ring optionally condensed with a 5 to 12-membered monocyclic or bicyclic, aromatic, partially unsaturated or saturated ring, where each ring contains 0-4 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, where Ar1has m substituents, each independently selected from-WRW;

W stands for a bond or optionally substituted (C1-C6)alkylidene chain, where up to two methylene groups of the residue W optionally and independently replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR', -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r NR'-, -NR'r NR'r CO-, -NR'r CO-, -S-, -SO-, -SO2-, -NR'-, -SO2NR'-, -NR'r SO2-, -NR'r SO2NR'-;

RWindependent means R', halogen atom, NO2CN, CF3or OCF3;

m is 0-5;

each of R1, R2, R3, R4and R5independent means-X-RX;

X is a bond or optionally substituted (C1-C6)alkylidene chain, where up to two methylene groups of the residue X optionally and independently replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR', -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r NR'-, -NR'r NR'r CO-, -NR'r CO-, -S-, -SO-, -SO2-, -NR'-, -SO2NR'-, -NR'r SO2- or-NR'r SO2NR'-;

RXindependent means R', halogen atom, NO2CN, CF3or OCF3;

R6means a hydrogen atom, CF3, -OR', -SR', or optionally substituted (C1-C8)aliphatic group;

R7means a hydrogen atom or (C1-C6)aliphatic group, optionally substituted-S-RX;

R' is independently selected from a hydrogen atom or an optionally substituted group selected from (C1-C8)aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen atoms, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen atoms, oxygen, or sulfur; or two available radical R', taken together with the atom(atoms), with which(whom) they are bound, form an optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen atoms, oxygen, or the minimum level;

provided that:

i) when R1, R2, R3, R4, R5, R6and R7mean hydrogen, then Ar1is not phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-were, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2-Bromphenol, 4-Bromphenol, 4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5-dicarbonitrile, 2,4-dimetilfenil, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro-4-were, 3-carboxyphenyl, 2-florfenicol, 3-florfenicol, 3-cryptomaterial, 3-ethoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 3,4-dimetilfenil, 2-ethylphenyl or 4-ethoxycarbonylphenyl;

ii) when R1, R2, R3, R5, R6and R7mean hydrogen and R4means a methoxy group, then Ar1is not 2-florfenicol or 3-florfenicol;

iii) when R1, R3, R4, R5, R6and R7mean hydrogen, R2means 1,2,3,4-tetrahydroisoquinoline-1-ylsulphonyl, then Ar1is not 3-cryptomaterial;

iv) when R1, R2, R3, R4, R5and R7mean hydrogen, R6means methyl, then Ar1is not phenyl;

v) when R1, R4, R5, R6and R7mean hydrogen, R2and R3taken together, mean methylendioxy, then Ar1is not 4-chlorophenyl, bromperidol, 4-nitrophenyl, 4-carbomethoxyamino, 6-ethoxybenzothiazole-2-yl, 6-carbomethoxyamino-2-yl, 6-halogenation-2-yl, 6-nitrobenzothiazole-2-yl or 6-thiocyanomethyl-2-yl;

vi) when R1, R4, R5, R6and R7mean hydrogen, R2and R3taken together, mean methylendioxy, then Ar1not a 4-substituted phenyl, where the above-mentioned Deputy is-SO2OtherXX, RXXmean 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl;

vii) when R1, R2, R3, R4, R5, R6and R7mean hydrogen, then Ar1is not thiazol-2-yl, 1H-1,2,4-triazole-3-yl or 1H-1,3,4-triazole-2-yl;

viii) when R1, R2, R3, R5, R6and R7mean hydrogen and R4means CF3, OMe, a chlorine atom, SCF3or OCF3then Ar1is not 5-methyl-1,2-oxazol-3-yl, thiazol-2-yl, 4-florfenicol, pyrimidine-2-yl, 1-methyl-1,2-(1H)-pyrazole-5-yl, pyridin-2-yl, phenyl, N-Mei-2-yl, imidazol-2-yl, 5-Mei-2-yl, 1,3-oxazol-2-yl or 1,3,5-(1H)-triazole-2-yl;

ix) when R1, R2, R3, R4, R5, R6and R7each means a hydrogen atom, then Ar1is not pyrimidine-2-yl, 4,6-dimethylpyrimidin-2-yl, 4-methoxy-6-methyl-1,3,5-triazine-2-and the Ohm, 5-bromopyridin-2-yl, pyridin-2-yl or 3,5-dichloropyridine-2-yl;

x) when R1, R2, R3, R4, R5and R7each means a hydrogen atom, R6means hydroxyl, then Ar1is not 2,6-dichloro-4-aminosulphonylphenyl;

xi) when R2or R3means optionally substituted N-piperazin, N-piperidyl or N-morpholinyl, then Ar1is optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl or indazole;

xii) when R2means optional substituted cyclohexylamine, then Ar1is optionally substituted by phenyl, pyridium or thiadiazolyl;

xiii) Ar1is optionally substituted by tetrazolyl;

xiv) when R2, R4, R5, R6and R7each means a hydrogen atom and R1and R3both mean CF3, chlorine, methyl or methoxy group, then Ar1not a 4,5-dihydro-1,3-thiazol-2-IOM, Tizol-2-yl or [3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl]phenyl;

xv) when R1, R4, R5, R6and R7each means a hydrogen atom, and Ar1means thiazol-2-yl, then neither R2or R3is not isopropyl, chlorine or CF3;

xvi) when Ar1means 4-methoxyphenyl, 4-triptoreline, 2-forfinal, phenyl or 3-chlorophenyl, then:

a) when R1, R2, R4, R5, R6and R7each means a hydrogen atom, then R3is not a methoxy group; or

b) when R1, R3, R4, R5, R6and R7each means a hydrogen atom, then R2is chlorine; or

(C) when R1, R2, R3, R5, R6and R7each means a hydrogen atom, then R4is not a methoxy group; or

d) when R1, R3, R4, R6and R7each means a hydrogen atom and R5means ethyl, then R2is not a chlorine atom;

e) when R1, R2, R4, R5, R6and R7each means a hydrogen atom, then R3is not a chlorine atom;

xvii) when R1, R3, R4, R5, R6and R7each means a hydrogen atom and R2means CF3or OCF3then Ar1is not [3,5-bis(trifluoromethyl)-1H-pyrazole-1-yl]phenyl;

xviii) when R1, R2, R4, R5, R6and R7each means a hydrogen atom and R3means a hydrogen atom or CF3then Ar1is not phenyl, substituted-och2CH2by phenyl, -och2CH2-(2-cryptomaterial), -co2CH2-(6,7-dimethoxy-1,2,3,4-tetrahydro the isoquinoline-2-yl) or substituted 1H-pyrazole-3-yl;

and

xix) excluding the following two connections:

2. Connections and definitions

Compounds of the present invention include compounds described in General above and further illustrated by the classes, subclasses and types disclosed in this description. As used in this specification, the following definitions apply, unless otherwise specified.

The term "ABC Transporter", as used herein, means a protein ABC Transporter or a fragment comprising at least one binding domain, where the above-mentioned protein or its fragment is in vivo or in vitro. The term "binding domain"as used herein, means the domain of the ABC-Transporter, which can communicate with the modulator; see, for example, T.C. Hwang et al., J. Gen. Physiol.,111(3), 477-490 (1998).

The term "CFTR"as used in this description, means the cystic fibrosis transmembrane conductance regulator or a mutation capable of regulator activity, including, but without limitation, ΔF508-CFTR and G551D-CFTR (see, for example, http://www.genet.sickkids.on.ca/cftr/ against CFTR-mutation).

The term "modulating"as used in this description means increases or decreases due to a measurable amount.

For the purposes of the present invention, the chemical elements are identified in accordance with the tvii with the periodic table of elements, the CAS version, Handbook of Chemistry and Physics, 75th extra edition. Additionally, General principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito, 1999, and in "March''s Advanced Organic Chemistry", 5th edition, edited by M.B. Smith and J. March, John Wiley and Sons, new York, 2001, the full contents of which are incorporated in this description by reference.

As described herein, the compounds according to the invention can be optionally substituted by one or more substituents, as illustrated above, or presented as examples of particular classes, subclasses and types according to the invention. It should be clear that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Usually, the term "substituted", which is preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise specified, optionally substituted group may contain a substituent in any position group which may be substituted, and, when more than one position in any given structure may be substituted by more than one Deputy, selected from the specified group, this Deputy may be either the same, or in any other position. Combinations of substituents represented by the s according to the present invention, preferred are those which lead to the formation of a stable or chemically possible connections. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions permitted upon receiving the detection and preferably their conversion, purification, and use for one or more of the purposes disclosed in this description. According to some variants of implementation, stable or chemically feasible compound is a compound which does not substantially altered when kept at a temperature of 40°C or below, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term "aliphatic" or "aliphatic group", as used herein, means a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or which contains one or more elements of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more elements of unsaturation, but which is not aromatic (also referred to in this description as "carbocycle", "cyclea efficiency" or "cycloalkyl"), which has a link with the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. According to some variants of implementation, aliphatic groups contain 1-10 aliphatic carbon atoms. According to other variants of implementation, aliphatic groups contain 1-8 aliphatic carbon atoms. According to still other variants of implementation, aliphatic groups contain 1-6 aliphatic carbon atoms and, according to still other variants of implementation, aliphatic groups contain 1-4 aliphatic carbon atoms. According to some variants of implementation, the term "cycloaliphatic" (or "carbocycle" or "cycloalkyl"refers to monocyclic (C3-C8the hydrocarbon or bicyclic or tricyclic (C8-C14the hydrocarbon that is completely saturated or that contains one or more elements of unsaturation, but which is not aromatic, that has a link with the rest of the molecule, where any individual ring in the above-mentioned bicyclic ring system is a 3-7-membered. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkeline, alkinyl the group and their "hybrids", such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicycloalkyl (for example, decalin), bridging bicycloalkyl, such as norbornyl or [2,2,2]bicycloalkyl, or break tricyclohexyl, such as substituted.

The term "heteroaromatics", as used herein, means an aliphatic group in which one or two carbon atoms, independently, substituted by one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon. Heteroaromatics residues can be substituted or unsubstituted, branched or unbranched, cyclic or alicyclic and include "heterocyclic", "heterocyclyl", "heterocyclizations" or "heterocyclic" group.

The term "heterocycle", "heterocyclyl", "geterotsiklicheskikh" or "heterocyclic"as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring system in which one or more ring members are an independently selected heteroatom. According to some variants of the implementation of the "heterocycle", "heterocyclyl", "geterotsiklicheskikh" or "heterocyclic" includes from three to fourteen ring members, where one or more members of the ring who represent a heteroatom, independently selected from atoms of oxygen, sulfur, nitrogen or phosphorus and each ring in the system is a 3-7-membered.

The term "heteroatom" means one or more atoms of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus or silicon; and stereoselectivity form of any basic nitrogen or a substituted nitrogen heterocycle, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

The term "unsaturated"as used herein, means that the residue contains one or more elements of unsaturation.

The term "alkoxy" or "thioalkyl", as used herein, refers to an alkyl group as defined above, associated with the main carbon chain through an oxygen atom ("alkoxy") or sulfur atom ("thioalkyl").

The terms "halogenations and halogenoalkane" means aliphatic or alkoxygroup, as the case may be, substituted by one or more halogen atoms. The term "halogen" means F, Cl, Br or I. Examples halogenations groups include-CHF2, -CH2F, -CF3, -CF2or perhalogenated, such as-CF2CF3.

The term "aryl", used individually or as part of a larger remnant, as in "aralkyl", "arakaki or "aryl which calcule", refers to monocyclic, bicyclic and tricyclic ring systems, comprising a total of five to fourteen ring members, where at least one ring in the system is aromatic and where each ring in the system is a 3-7-membered. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" also refers to a heteroaryl ring systems, as specified in this description below.

The term "heteroaryl used individually or as part of a larger remnant, as in "heteroalkyl" or "heteroaromatic", refers to monocyclic, bicyclic and tricyclic ring systems, comprising a total of five to fourteen ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and where each ring in the system is a 3-7-membered. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Aryl (including aralkyl, Alcoxy, aryloxyalkyl and the like) or heteroaryl (including heteroalkyl, heteroaromatics, and the like) may contain one or more substituents. Suitable substituents at unsaturated carbon atom in the aryl is whether heteroaryl selected from a halogen atom; -Ro; -ORo; -SRo; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph), optionally substituted Ro; -O(Ph), optionally substituted Ro; -(CH2)1-2(Ph), optionally substituted Ro; -CH=CH(Ph), optionally substituted Ro; -NO2; -CN; -N(Ro)2; -NRoC(O)Ro; -NRoC(O)N(Ro)2; -NRoCO2Ro; -NRoNRoC(O)Ro); -NRoNRoC(O)N(Ro)2; -NRoNRoCO2Ro; -C(O)C(O)Ro; -C(O)CH2C(O)Ro; -CO2Ro; -C(O)Ro; -C(O)N(Ro)2; -OC(O)N(Ro)2; -S(O)2Ro; -SO2N(Ro)2; -S(O)Ro; -NRoSO2N(Ro)2; -NRoSO2Ro; -C(=S)N(Ro)2; -C(=NH)-N(Ro)2or -(CH2)0-2NHC(O)Rowhere each independent of the existing Roselected from a hydrogen atom, optionally substituted C1-6aliphatic group, an unsubstituted 5-6-membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or-CH2(Ph), or, notwithstanding the above definition, two independent existing Roin the same Deputy or different substituents, taken together with the atom(atoms), with whom(which) is associated with each group of Roform a 3-8-membered cycloalkyl, heterocyclyl, aryl or hetero is rilee ring, having 0-3 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur. Optional substituents in the aliphatic group of Rochoose from the NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, HE, (C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), (halogen-C1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above With1-4aliphatic groups of Rois unsubstituted.

Aliphatic or heteroaromatics group or non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents at the saturated carbon atom aliphatic or heteroaromatics group or non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon atoms of aryl or heteroaryl group and additionally include the following: =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where each R* is independently selected from a hydrogen atom or optionally substituted C1-6aliphatic group. Optional substituents in the case of the aliphatic group of R* are selected from NH2, NH(C1-4aliphatic groups who), N(C1-4aliphatic group)2, halogen atom, With1-4aliphatic group, HE, (C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), (halogen-C1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above With1-4aliphatic groups of R*is unsubstituted.

Optional substituents at the nitrogen atom non-aromatic heterocyclic ring are selected from-R+, -N(R+)2, -C(O)R+, -CO2R*, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)N(R+)2or-NR+SO2R+where R+means a hydrogen atom, optionally substituted C1-6aliphatic group, optionally substituted phenyl, optionally substituted-O(Ph), optionally substituted-CH2(Ph), optionally substituted -(CH2)1-2(Ph), optionally substituted-CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring containing one to four heteroatoms independently selected from oxygen atoms, nitrogen or sulfur, or, notwithstanding the above definition, two independent existing R+in the same Deputy or different substituents, taken together with the atom (atoms), with the cat the eye(which) is associated with each group of R +form a 3-8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur. Optional substituents in the aliphatic group or the phenyl ring of R+choose from the NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen atom, With1-4aliphatic group, HE, (C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), (halogen-C1-4aliphatic group) or a halogen-C1-4aliphatic group, where each of the above With1-4aliphatic groups of R+is unsubstituted.

The term "alkylidene chain" refers to a linear or branched carbon chain, which may be fully saturated or comprises one or more elements of unsaturation and has two point of attachment to the rest of the molecule. The term "spirocyclohexane" refers to a carbocyclic ring, which may be fully saturated or comprises one or more elements of unsaturation and has two seats attach to the same carbon atom of the ring to the rest of the molecule.

As detailed above, in some embodiments, the implementation of two independent existing Ro(or +or any other variable, defined in this description), taken together with the atom (atoms), with whom(which) is associated with each variable, form a 3-8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur. Specific rings that are formed when the combined two existing independent Ro(or R+or any other variable, defined in this description), together with the atom(atoms), with whom(which) is associated with each variable, include, but are not limited to, the following: a) two independent existing Ro(or R+or any other variable, defined in this specification)that are linked to the same atom, taken together with that atom to form a ring, for example, N(Ro)2where both existing Rotaken together with the nitrogen atom, form a piperidine-1-ilen, piperazine-1-ilen, or morpholine-4-ilen group; and b) two independent existing Ro(or R+or any other variable, defined in this specification)that are associated with different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group substituted with two available ORo:these two existing R otaken together with the oxygen atoms to which they are linked, form a condensed 6-membered oxygen-containing ring:. It should be taken into account, which can be obtained from many other rings, when two independent existing Ro(or R+or any other variable, defined in this description) together with the atom(atoms), with whom (which) is associated with each variable, and that the examples detailed above do not limit the scope of the invention.

Communications Deputy, for example, bicyclic ring system, as shown below, means that the Deputy can be attached to any substitutable ring atom in any ring of the bicyclic ring system:

Unless otherwise stated, also imply that the patterns presented in this description, include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, (Z)- and (E)-isomers on double bond and conformation of (Z)- and (E)-isomers). Therefore, single stereochemical isomers as well as mixtures of enantiomers, diastereomers and geometric (conformational) isomers of the compounds according to the present invention I is completed in the scope of this invention. Unless otherwise stated, all tautomeric forms of the compounds according to the present invention are included in the scope of this invention. For example, when R5in the compounds of formula (I) means a hydrogen atom, the compounds of formula (I) may exist as tautomers:

Additionally, unless otherwise stated, also imply that presented in this description of the structure include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having these structures, except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon13With or14C-enriched carbon are included in the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

3. Description of examples of connections

In some embodiments, implementation of the present invention Ar1choose from:

where the ring And1is a 5-6-membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen atoms, oxygen, or sulfur; or

And1and a2together represent 8-14-membered aromatic, bicyclic or tricyclic aryl ring, where each number is CH contains 0-4 heteroatoms, independently selected from nitrogen atoms, oxygen or sulfur.

In some embodiments, implementation And1means optionally substituted 6-membered aromatic ring having 0-4 heteroatoms, where the above-mentioned heteroatom means nitrogen. In some embodiments, implementation And1means optionally substituted phenyl. Or a1means optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl. Or a1means optionally substituted pyrazinyl or triazinyl. Or a1means optionally substituted pyridyl.

In some embodiments, implementation And1means optionally substituted 5-membered aromatic ring having 0-3 heteroatoms, where the above-mentioned heteroatom means nitrogen, oxygen or sulfur. In some embodiments, implementation And1means optionally substituted 5-membered aromatic ring having 1-2 nitrogen atom. In one embodiment, A1means optionally substituted 5-membered aromatic ring, other than thiazolyl.

In some embodiments, implementation And2means optionally substituted 6-membered aromatic ring having 0-4 heteroatoms, where the above-mentioned heteroatom means nitrogen. In some embodiments, implementation And2means optionally substituted phenyl. Or a 2means optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl.

In some embodiments, implementation And2means optionally substituted 5-membered aromatic ring having 0-3 heteroatoms, where the above-mentioned heteroatom means nitrogen, oxygen or sulfur. In some embodiments, implementation And2means optionally substituted 5-membered aromatic ring having 1-2 nitrogen atom. In some cases, implement And2means optionally substituted pyrrolyl.

In some embodiments, implementation And2means optionally substituted 5 to 7-membered, saturated or unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen atoms, sulfur or oxygen. Examples of such rings include piperidyl, piperazin, morpholinyl, thiomorpholine, pyrrolidine, tetrahydrofuranyl etc.

In some embodiments, implementation And2means optionally substituted, 5-to 10-membered, saturated or unsaturated carbocyclic ring. In one embodiment, A2means optionally substituted, 5-to 10-membered, saturated carbocyclic ring. Examples of such rings include cyclohexyl, cyclopentyl etc.

In some embodiments, the implementation of the ring And2choose from:

where the ring And2condensed with ring And1on two adjacent atoms of the ring.

In other embodiments, the implementation of the W means the communication means or optionally substituted C1-6alkylidene chain, where one or two methylene groups are optionally and independently replaced by O, NR', S, SO, SO2or COO, CO, SO2NR', NR'r SO2C(O)NR', NR'r C(O), OC(O), OC(O)NR', and RWmeans R' or halogen. In other embodiments, the implementation of each WRWindependent means-From1-C3alkyl, C1-C3perhalogenated, -O(C1-C3alkyl), -CF3, -OCF3, -SCF3, -F, -Cl, -Br, or-COOR', -COR', -O(CH2)2N(R')(R'), -O(CH2)N(R')(R'), -CON(R')(R'), -(CH2)2OR', -(CH2)OR', optionally substituted aromatic monocyclic or bicyclic ring, optionally substituted arylsulfonyl, optionally substituted 5-membered heteroaryl ring, -N(R')(R'), -(CH2)2N(R')(R') or -(CH2)N(R')(R').

In some embodiments, the implementation of m is 0 or m is 1, or m is 2. In some embodiments, the implementation of m is equal to 3. In other embodiments, the implementation of m is equal to 4.

In one embodiment, the implementation of whom tvline R 5means X-RX. In some embodiments, the implementation of R5means hydrogen or R5means optionally substituted C1-8aliphatic group. In some embodiments, the implementation of R5means optionally substituted C1-4aliphatic group, or R5means benzyl.

In some embodiments, the implementation of R6means a hydrogen atom, or R6means optionally substituted C1-8aliphatic group. In some embodiments, the implementation of R6means optionally substituted C1-4aliphatic group. In some other embodiments, implementation of R6means -(O-C1-4aliphatic group) or -(S-C1-4aliphatic group). Preferably, R6means-OMe or SMe. In some other embodiments, implementation of R6means CF3.

In one embodiment according to the present invention R1, R2, R3and R4simultaneously denote hydrogen. In another embodiment, R6and R7both simultaneously represent hydrogen.

In another embodiment according to the present invention R1, R2, R3, R4and R5simultaneously denote hydrogen. In another embodiment according to the present invention R1, R2, R3, R45and R6simultaneously denote hydrogen.

In another embodiment according to the present invention R2means X-RXwhere X means SO2NR'and RXmeans R'; i.e., R2means-SO2N(R')2. In one embodiment, two R', taken together, optionally form a substituted 5-7-membered ring, having 0-3 additional heteroatoms selected from nitrogen atoms, oxygen, or sulfur; or R1, R3, R4, R5and R6simultaneously denote hydrogen, and R2means SO2N(R')2.

In some embodiments, implementation of the X means a bond or optionally substituted C1-6alkylidene chain, where one or two non-adjacent methylene groups are optionally and independently replaced by O, NR', S, SO2or COO, CO, and RXmeans R' or halogen. In other embodiments, the implementation of each of the XRXindependent means-From1-3alkyl, -O(C1-3alkyl), -CF3, -OCF3, -SCF3, -F, -Cl, -Br, HE, -COOR', -COR', -O(CH2)2N(R')(R'), -O(CH2)N(R')(R'), -CON(R')(R'), -(CH2)2OR', -(CH2)OR', optionally substituted phenyl, -N(R')(R'), -(CH2)2N(R')(R') or -(CH2)N(R')(R').

In some embodiments, the implementation of R7means a hydrogen atom. In some other embodiment, R7means a linear or branched C 1-4aliphatic group.

In some embodiments, the implementation of RWselected from the group consisting of a halogen atom, ceanography, CF3, CHF2, OCHF2Me,

Et, CH(Me)2, CHMeEt, n-propyl, tert-butyl, OMe, OEt, OPh,

O-ftoheia, O-dipthera, O-methoxyphenyl, O-tolila,

O-benzyl, SMe, SCF3, SCHF2, SEt, CH2CN, NH2, NHMe, N(Me)2, NHEt,

N(Et)2C(O)CH3C(O)Ph, C(O)NH2, SPh, SO2(aminopyridine),

SO2NH2, SO2Ph, SO2NHPh, SO2-N-morpholino, SO2-N-pyrrolidyl,

N-pyrrolyl, N-morpholino, 1 piperidyl, phenyl, benzyl,

(cyclohexylethylamine)methyl,

4-methyl-2,4-dihydropyrazol-3-one-2-yl, benzimidazole-2-yl,

furan-2-yl, 4-methyl-4H-[l,2,4]triazole-3-yl,

3-(4'-chlorophenyl)-[l,2,4]oxidiazol-5-yl, NHC(O)Me, NHC(O)Et,

NHC(O)Ph, NHSO2Me, 2-indolyl, 5-indolyl, -CH2CH2OH, -OCF3,

O-(2,3-dimetilfenil), 5-methylphenyl, -SO2-N-piperidyl,

2-tolila, 3-tolila, 4-tolila, O-butyl, NHCO2C(Me)3, CO2C(Me)3,

Isopropenyl, n-butyl, O-(2,4-dichlorophenyl), NHSO2PhMe,

O-(3-chloro-5-trifluoromethyl-2-pyridyl), phenylhydroxylamine,

2,5-dimethylpyrrole, NHCOCH2C(Me)3, O-(2-tert-butyl)phenyl,

2,3-dimetilfenil, 3,4-dimetilfenil, 4-hydroxymethylene,

4-dimethylaminophenyl, 2-triptoreline,

3-triptoreline the sludge, 4-trifloromethyl, 4-cyanomethylene,

4-isobutylphenyl, 3-pyridyl, 4-pyridyl, 4-isopropylphenyl,

3-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,

4-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-ethoxyphenyl,

3-ethoxyphenyl, 4-ethoxyphenyl, 2-methylthiophenyl,

4-methylthiophenyl, 2,4-acid, 2,5-acid,

2,6-acid, 3,4-acid,

5-chloro-2-methoxyphenyl, 2-OCF3-phenyl, 3-trifloromethyl,

4-trifloromethyl, 2-phenoxyphenyl, 4-phenoxyphenyl,

2-fluoro-3-methoxyphenyl, 2,4-dimethoxy-5-pyrimidyl,

5-isopropyl-2-methoxyphenyl, 2-ftoheia, 3-ftoheia,

4-ftoheia, 3-cyanophenyl, 3-chlorphenyl, 4-chlorphenyl,

2,3-dipthera, 2,4-dipthera, 2,5-dipthera,

3,4-dipthera, 3,5-dipthera, 3-chloro-4-ftoheia,

3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl,

3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-ethoxycarbonylphenyl,

4-ethoxycarbonylphenyl, 3-isopropoxycarbonyl,

3-acetamidophenyl, 4-fluoro-3-methylphenyl, 4-methanesulfonyl,

4-methanesulfonyl,

4-N-(2-N,N-dimethylaminoethyl)carbamoylmethyl, 5-acetyl-2-tanila,

2-benzothiazyl, 3-benzothiazyl, furan-3-yl, 4-methyl-2-tanila,

5-cyano-2-tanila, N'-phenylcarbamoyl-N-piperazinil, -NHCO2Et,

-NHCO2Me, N-pyrrolidinyl, -NHSO2(CH2)2 N-piperidine,

-NHSO2(CH2)2N-research, -NHSO2(CH2)2N(Me)2, COCH2N(Me)COCH2NHMe,

-CO2Et, O-propyl, -CH2CH2NHCO2C(Me)3, hydroxyl, aminomethyl,

pentile, adamantyl, cyclopentyl, ethoxyethyl, C(Me)2CH2OH,

C(Me)2CO2Et-CHOHMe, CH2CO2Et, -C(Me)2CH2NHCO2C(Me)3, (CH2)2OEt,

O(CH2)2OH, CO2Me, hydroxymethyl, 1-methyl-1-cyclohexyl,

1-methyl-l-cyclooctyl, 1-methyl-1-cycloheptyl, C(Et)2C(Me)3,

C(Et)3, CONHCH2CH(Me)2, 2-aminomethylphenol, Attila,

1-piperidinylcarbonyl, ethinyl, cyclohexyl,

4-methylpiperidine, -OCO2Me, -C(Me)2CH2NHCO2CH2CH(Me)2,

-C(Me)2CH2NHCO2CH2CH2CH3, -C(Me)2CH2NHCO2Et, -C(Me)2CH2NHCO2Me,

-C(Me)2CH2NHCO2CH2C(Me)3, -CH2NHCOCF3, -CH2NHCO2C(Me)3,

-C(Me)2CH2NHCO2(CH2)3CH3C(Me)2CH2NHCO2(CH2)2OMe, C(OH)(CF3)2,

-C(Me)2CH2NHCO2CH2-tetrahydrofuran-3-yl, C(Me)2CH2O(CH2)2OMe or

3-ethyl-2,6-dioxopiperidin-3-yl.

In one embodiment, R' represents an atom of water is kind.

In one embodiment, R' means1-C8aliphatic group, optionally substituted by up to 3 substituents selected from a halogen atom, CN, CF3, CHF2, OCF3or OCHF2where the two methylene groups of the above With1-With8aliphatic group is optionally replaced by-CO-,

-CONH(C1-C4alkyl)-, -CO2-, -OCO-, -N(C1-C4alkyl)CO2-, -O-,

-N(C1-C4alkyl)CON(Cl-C4alkyl)-, -OCON(C1-C4alkyl)-,

-N(C1-C4alkyl)CO-, -S-, -N(C1-C4alkyl)-, -SO2N(C1-C4alkyl)-,

-N(C1-C4alkyl)SO2- or-N(Cl-C4alkyl)SO2N(C1-C4alkyl)-.

In one embodiment, R' means a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, where R' is optionally substituted up to 3 substituents selected from a halogen atom, CN, CF3, CHF2, OCF3, OCHF2or1-C6of alkyl, where the two methylene groups of the above With1-C6the alkyl optionally replaced by-CO-, -CONH(C1-C4alkyl)-, -CO2-, -OCO-,

-N(C1-C4alkyl)CO2-, -O-, -N(C1-C4alkyl)CON(Cl-C4alkyl)-,/p>

-OCON(C1-C4alkyl)-, -N(C1-C4alkyl)CO-, -S-, -N(C1-C4alkyl)-,

-SO2N(C1-C4alkyl)-, N(C1-C4alkyl)SO2or

-N(Cl-C4alkyl)SO2N(C1-C4alkyl)-.

In one embodiment, R' represents an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, where R' is optionally substituted up to 3 substituents selected from halogen, CN, CF3, CHF2, OCF3, OCHF2or1-C6of alkyl, where the two methylene groups of the above With1-C6the alkyl optionally replaced by-CO-, -CONH(C1-C4alkyl)-, -CO2-, -OCO-,

-N(C1-C4alkyl)CO2-, -O-, -N(C1-C4alkyl)CON(Cl-C4alkyl)-,

-OCON(C1-C4alkyl)-, -N(C1-C4alkyl)CO-, -S-, -N(C1-C4alkyl)-,

-SO2N(C1-C4alkyl)-, N(C1-C4alkyl)SO2or

-N(Cl-C4alkyl)SO2N(C1-C4alkyl)-.

In one embodiment, two available R', taken together with the atom(s), with whom(and) they are bound, form an optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic the prioritization of the ring, having 0-4 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, where R' is optionally substituted up to 3 substituents selected from a halogen atom, CN, CF3, CHF2, OCF3, OCHF2or1-C6of alkyl, where the two methylene groups of the above With1-C6the alkyl optionally replaced by-CO-, -CONH(C1-C4alkyl)-, -CO2-, -OCO-,

-N(C1-C4alkyl)CO2-, -O-, -N(C1-C4alkyl)CON(Cl-C4alkyl)-,

-OCON(C1-C4alkyl)-, -N(C1-C4alkyl)CO-, -S-, -N(C1-C4alkyl)-,

-SO2N(C1-C4alkyl)-, N(C1-C4alkyl)SO2or

-N(Cl-C4alkyl)SO2N(C1-C4alkyl)-.

According to one variant of implementation, the present invention relates to compounds of the formulaIIAor of the formulaIIB:

According to another variant implementation, the present invention relates to compounds of the formulaIIIAformulaIIIBformulaIIICformulaIIIDor of the formulaIIIE:

where each of X1, X2, X3, X4and X5independently selected from CH or N; and X6means O, S, or NR'.

In one embodiment, the connection fo the mules IIIAformulaIIIBformulaIIICformulaIIIDor of the formulaIIIEhave y vstrechaemosti Deputy X-RXwhere y is 0-4; or y is 1; or y is equal to 2.

In some embodiments, the implementation of the formulaIIIAX1, X2, X3, X4and X5taken together with WRWand m represent optionally substituted phenyl.

In some embodiments, the implementation of the formulaIIIAX1, X2, X3, X4and X5taken together, indicate optional substituted ring selected from:

In some embodiments, the implementation of the formulaIIIBformulaIIICformulaIIIDor of the formulaIIIEX1, X2, X3, X4, X5and X6taken together with the ring And2indicate optional substituted ring selected from:

In some embodiments, the implementation of RWselected from the group consisting of halogen atom, cyano, CF3, CHF2, OCHF2, Me, Et, CH(Me)2, CHMeEt, n-propyl, tert-butyl, OMe, OEt, OPh, O-ftoheia, O-dipthera, O-methoxyphenyl, O-tolila, O-benzyl, SMe, SCF3, SCHF2, SEt, CH2CN, NH2, NHMe, N(Me)2, NHEt, N(Et)2C(O)CH3C(O)Ph, C(O)NH2, SPh, SO2(aminopyridine), SO2NH2, SO2Ph, SO2NHPh, SO2-N-morpholinopropan, SO2-N-pyrrolidyl, N-pyrrolyl, N-morpholinopropan, 1 piperidyl, phenyl, benzyl, (cyclohexylethylamine)methyl, 4-methyl-2,4-dihydropyrazol-3-one-2-yl, benzimidazole-2-yl, furan-2-yl, 4-methyl-4H-[l,2,4]triazole-3-yl, 3-(4'-chlorophenyl)-[l,2,4]oxidiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph, or NHSO2Me.

In some embodiments, implementation of the X and RXtaken together, mean Me, Et, halogen, CN, CF3HE, OMe, OEt, SO2N(IU)(forfinal), SO2-(4-methylpiperidin-1-yl) or SO2-N-pyrrolidinyl.

According to another variant implementation, the present invention relates to compounds of the formulaIVAformulaIVBor of the formulaIVC:

In one embodiment, the compounds of formulaIVAformulaIVBand the formulaIVCthey shall have vstrechaemosti Deputy X-R Xwhere y is 0-4; or y is 1; or y is equal to 2.

In one embodiment, the present invention relates to compounds of the formulaIVAformulaIVBand the formulaIVCwhere X is a bond and RXmeans a hydrogen atom.

In one embodiment, the present invention relates to compounds of the formulaIVAformulaIVBand the formulaIVCwhere the ring And2means optionally substituted, saturated, unsaturated or aromatic 7-membered ring, having 0-3 heteroatoms selected from the atoms O, S or N. Examples of the rings include azepane, 5,5-dimethylethanol etc.

In one embodiment, the present invention relates to compounds of the formulaIVBand the formulaIVCwhere the ring And2means optionally substituted, saturated, unsaturated or aromatic 6-membered ring, having 0-3 heteroatoms selected from the atoms O, S or N. Examples of the rings include piperidinyl, 4,4-dimethylpiperidine etc.

In one embodiment, the present invention relates to compounds of the formulaIVBand the formulaIVCwhere the ring And2means optionally substituted, saturated, unsaturated or aromatic 5-membered ring, having 0-3 heteroatoms selected from the atoms O, S or N.

In one embodiment, the present invention relates to compounds form the s IVBand the formulaIVCwhere the ring And2means optionally substituted 5-membered ring with one nitrogen atom, for example, pyrrolyl or pyrrolidinyl.

According to one variant of implementation of the formulaIVprovides the following connection formulaVA-1:

where each WRW2and WRW4independently selected from a hydrogen atom, CN, CF3, halogen, linear or branched C1-C6of alkyl, 3-12 membered cycloaliphatic, phenyl, C5-With10heteroaryl or3-C7heterocyclic group, where the above heteroaryl or heterocyclic group has up to 3 heteroatoms selected from the atoms O, S or N, where the above WRW2and WRW4independently and optionally substituted with up to three substituents selected from the group consisting of-OR', -CF3, -OCF3, SR', S(O)R', SO2R', -SCF3, halogen, CN, -COOR', -COR', -O(CH2)2N(R')(R'), -O(CH2)N(R')(R'), -CON(R')(R'), -(CH2)2OR', -(CH2)OR', CH2CN, optionally substituted phenyl or fenoxaprop, -N(R')(R'), -NR'r C(O)OR', -NR'r C(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R'); and

WRW5selected from the group consisting of a hydrogen atom, -OH, NH2CN, CHF2That other', N(R')2, -NHC(O)R', -NHC(O)OR', NHSO2R', -OR', CH2OH, CH2N(R')2C(O)OR', SO2Other', SO2 N(R')2or CH2NHC(O)OR'; or WRW4and WRW5taken together, form a 5-7 membered ring containing 0-3 heteroatoms selected from the atoms N, O and S, where the abovementioned ring optionally substituted with up to three substituents WRW.

In one embodiment, the compounds of formulaVA-1have vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is equal to 0.

In one embodiment, the present invention relates to compounds of the formulaVA-1where X is a bond and RXmeans a hydrogen atom.

In one embodiment, the present invention relates to compounds of the formulaVA-1where:

each WRW2and WRW4independently selected from the group consisting of a hydrogen atom, CN, CF3, halogen atom, linear or branched C1-C6of alkyl, 3-12 membered cycloaliphatic group, or phenyl, where the above WRW2and WRW4independently and optionally substituted with up to three substituents selected from the group consisting of-OR', -CF3, -OCF3, -SCF3, halogen atom, -COOR', -COR', -O(CH2)2N(R')(R'), -O(CH2)N(R')(R'), -CON(R')(R'), -(CH2)2OR', -(CH2)OR', optionally substituted phenyl, -N(R')(R'), -NR'r C(O)OR', -NR'r C(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R'); and

WRW5choose from a group, when standing from a hydrogen atom, -OH, NH2CN, other', N(R')2, -NHC(O)R', -NHC(O)OR', NHSO2R', -OR', CH2OH, C(O)OR', SO2Other' or CH2NHC(O)O-(R').

In one embodiment, the present invention relates to compounds of the formulaVA-1where:

WRW2means a phenyl ring, optionally substituted with up to three substituents selected from the group consisting of-OR', -CF3, -OCF3, SR', S(O)R', SO2R', -SCF3, halogen, CN, -COOR', -COR', -O(CH2)2N(R')(R'), -O(CH2)N(R')(R'), -CON(R')(R'), -(CH2)2OR', -(CH2)OR', CH2CN, optionally substituted phenyl or fenoxaprop, -N(R')(R'), -NR'r C(O)OR', -NR'r C(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R');

WRW4means a linear or branched C1-C6alkyl; and

WRW5means IT.

In one embodiment, each WRW2and WRW4independently chosen from-CF3or halogen atom. In one embodiment, each WRW2and WRW4independently selected from a hydrogen atom, optionally substituted linear or branched C1-C6the alkyl. In some cases, the implementation of each WRW2and WRW4independently selected from optionally substituted n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-(etoxycarbonyl)ethyl, 1,1-dimethyl-3-(tert-butoxycarbonylamino is)propyl or n-pentile.

In one embodiment, each WRW2and WRW4independently selected from optionally substituted 3-12-membered cycloaliphatic group. Examples of embodiments of such cycloaliphatic groups include cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, substituted, [2,2,2]bicycloalkyl, [2,3,1]bicycloalkyl or [3,3,1]bicycloalkyl.

In some cases, the implementation WRW2means a hydrogen atom and WRW4means a linear or branched C1-C6alkyl. In some cases, the implementation WRW4selected from methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl.

In some cases, the implementation WRW4means a hydrogen atom and WRW2means a linear or branched C1-C6alkyl. In some cases, the implementation WRW2selected from methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl or n-pentile.

In some cases, the implementation of each WRW2and WRW4means a linear or branched C1-C6alkyl. In some cases, the implementation of each WRW2and WRW4selected from methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl or pentile.

In one embodiment, WRW5selected from the group consisting of a hydrogen atom, CHF2, NH2CN, other', N(R')2CH 2N(R')2, -NHC(O)R', -NHC(O)OR', -OR', C(O)OR' or SO2Other'; or WRW5means-OR', for example, HE.

In some cases, the implementation WRW5selected from the group consisting of a hydrogen atom, NH2CN, CHF2, NH(C1-C6the alkyl), N(C1-C6alkyl)2, -NHC(O)(Cl-C6the alkyl), -CH2NHC(O)O(Cl-C6the alkyl), -NHC(O)O(Cl-C6the alkyl), -OH, -O(C1-C6the alkyl), C(O)O(Cl-C6the alkyl), CH2O(Cl-C6the alkyl or SO2NH2. In another embodiment, WRW5selected from the group consisting of-OH, OMe, NH2, -NHMe, -N(Me)2, -CH2NH2CH2OH, NHC(O)OMe, NHC(O)OEt, CN, CHF2, -CH2NHC(O)O(tert-butyl), -O-(ethoxyethyl), -O-(hydroxyethyl), -C(O)OMe or-SO2NH2.

In one embodiment, the compound of the formulaVA-1has one, preferably several, or more preferably all of the following characteristics:

i) WRW2means hydrogen;

ii) WRW4means a linear or branched C1-C6the alkyl or aliphatic monocyclic or bicyclic group; and

iii) WRW5selected from the group consisting of a hydrogen atom,

CN, CHF2, NH2, NH(C1-C6the alkyl), N(C1-C6alkyl)2,

-NHC(O)(Cl-C6the alkyl), -NHC(O)O(Cl-C6the alkyl),

-CH2C(O)O(Cl-C 6the alkyl), -OH, -O(C1-C6the alkyl), C(O)O(Cl-C6the alkyl)

or SO2NH2.

In one embodiment, the compound of the formulaVA-1has one, preferably several, or more preferably all of the following characteristics:

i) WRW2means a halogen atom, a Cl-C6alkyl, CF3, CN or phenyl, optionally substituted by up to 3 substituents selected from Cl-C4of alkyl, -O(Cl-C4the alkyl) or halogen atom;

ii) WRW4means CF3, a halogen atom, a Cl-C6alkyl or C6-C10cycloaliphatic group; and

iii) WRW5IT means, NH2, NH(Cl-C6alkyl) or N(Cl-C6alkyl).

In one embodiment, X-RXis in position 6 rhinolining rings. In some cases, the implementation of H-RXtaken together, mean Cl-C6alkyl, -O(Cl-C6alkyl), or halogen atom.

In one embodiment, X-RXis in position 5 rhinolining rings. In some cases, the implementation of H-RXtaken together, mean-IT.

In another embodiment, the present invention relates to compounds of the formulaVA-1where WRW4and WRW5taken together, form a 5-7 membered ring containing 0-3 heteroatoms selected from N, O or S, where the abovementioned ring optionally substituted up to three WRW-substituents.

In some cases, the implementation WRW4and WRW5taken together, form an optionally substituted 5 to 7-membered, saturated, unsaturated or aromatic ring containing 0 heteroatoms. In other embodiments, implementation WRW4and WRW5taken together, form an optionally substituted 5 to 7-membered ring containing 1-3 heteroatom selected from the atoms N, O or S. In certain other embodiments, the implementation WRW4and WRW5taken together, form an optionally substituted, saturated, unsaturated or aromatic 5-7 membered ring containing 1 nitrogen atom as a heteroatom. In some other embodiments, the implementation WRW4and WRW5taken together, form an optionally substituted 5 to 7-membered ring containing 1 oxygen atom as a heteroatom.

In another embodiment, the present invention relates to compounds of the formulaV-A-2:

where:

Y represents CH2C(O)O, C(O) or S(O)2;

m is 0-4; and

X, RX, W, and RWhave the meanings as described above.

In one embodiment, the compounds of formulaVA-2have y vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, the domestic is y is equal to 0; or y is 1; or y is equal to 2.

In one embodiment, Y represents S(O). In another embodiment, Y represents C(O)Oh; or Y represents S(O)2; or Y represents CH2.

In one embodiment, m is 1 or 2; or m is 1; or m is 0.

In one embodiment, W represents a relationship.

In another embodiment, RWmeans Cl-C6aliphatic group, halogen atom, CF3or phenyl, optionally substituted Cl-C6by alkyl, halogen atom, cyano or CF3where up to two methylene groups of the above Cl-C6aliphatic group, or a Cl-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl. Examples of embodiments WRWinclude methyl, ethyl, propyl, tert-butyl or 2-ethoxyphenyl.

In another embodiment, RWin the Y-RWmeans Cl-C6aliphatic group, optionally substituted by N(R”)2where R” means a hydrogen atom, a Cl-C6alkyl, or two R”taken together form a 5-7-membered geterotsiklicheskikh ring with 2 additional heteroatoms selected from the atoms O, S or NR'. Examples of such g is of taracelov include pyrrolidinyl, piperidyl, morpholinyl or thiomorpholine.

In another embodiment, the present invention relates to compounds of the formulaV-A-3:

where:

Q means W;

RQmeans RW;

m is 0-4;

n is 0-4; and

X, RX, W, and RWhave the meanings as described above.

In one embodiment, the compounds of formulaVA-3have vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, n is 0-2.

In another embodiment, m is 0-2. In one embodiment, m is equal to 0. In one embodiment, m is 1; or m is 2.

In one embodiment, the QRQtaken together, denote a halogen atom, CF3, OCF3CN, Cl-C6aliphatic group,-Cl-C6aliphatic group, phenyl, NH(Cl-C6aliphatic group), or N(Cl-C6aliphatic group)2where the abovementioned aliphatic group and phenyl optionally substituted with up to three substituents selected from Cl-C6of alkyl, Cl-C6of alkyl, halogen atom, ceanography, HE or CF3where up to two methylene groups of the above Cl-C6aliphatic group, or a Cl-C6and the Qila optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, SOR', SO2R', -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl.

Examples of QRQinclude methyl, isopropyl, sec-butyl, hydroxymethyl, CF3, NMe2, CN, CH2CN, fluorine atom, chlorine atom, OEt, OMe, SMe, OCF3, OPh, C(O)OMe, C(O)O-iPr, S(O)Me, NHC(O)Me or S(O)2Me.

In another embodiment, the present invention relates to compounds of the formulaV-A-4:

where X, RXand RWhave the meanings as described above.

In one embodiment, the compounds of formulaVA-4have vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, RWmeans Cl-C12aliphatic group, a C5-C10cycloaliphatic or C5-C7heterocyclic ring, where the abovementioned aliphatic group, cycloaliphatic or heterocyclic ring optionally substituted with up to three substituents selected from Cl-C6of alkyl, halogen atom, ceanography, carbonyl group, HE or CF3where up to two methylene groups of the above Cl-C6aliphatic group, or a Cl-C6the alkyl is obazatelno replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl.

Examples RWinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, vinyl, cyanomethyl, hydroxymethyl, hydroxyethyl, hydroxybutyl, cyclohexyl, substituted or-C(CH3)2-NHC(O)O-T, where T means1-C4alkyl, methoxyethyl or tetrahydrofuranyl.

In another embodiment, the present invention relates to compounds of the formulaV-A-5:

where:

m is 0-4; and

X, RX, W, RWand R' have the meanings as described above.

In one embodiment, the compounds of formulaVA-5have y vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, m is 0-2; or m is 1; or m is 2.

In another embodiment, both R' means a hydrogen atom; or one of R' means a hydrogen atom and the other R' is Cl-C4alkyl, for example methyl; or both R' means Cl-C4alkyl, for example methyl.

In another embodiment, m is 1 or 2, and RWmeans halogen atom, CF3CN, Cl-C6alifaticescoe the group, O-Cl-C6aliphatic group, or phenyl, where the abovementioned aliphatic group and phenyl optionally substituted with up to three substituents selected from Cl-C6of alkyl, Cl-C6of alkyl, halogen atom, ceanography, HE or CF3where up to two methylene groups of the above Cl-C6aliphatic group, or a Cl-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl.

Examples of embodiments, RWinclude a chlorine atom, CF3, OCF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy group, ethoxypropan, propyloxy or 2-ethoxyphenyl.

In another embodiment, the present invention relates to compounds of the formulaV-A-6:

where:

the ring means a 5-7 membered monocyclic or bicyclic, heterocyclic or heteroaryl ring, optionally substituted by up to n vstrechaemosti Deputy-Q-RQ-where n is 0-4, and Q and RQhave the meanings as described above; and

Q, RQ, X, RX, W, and RWhave the meanings as described above.

In one embodiment, the connection is possible formulas VA-6have y vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, m is 0-2; or m is 0; or m is equal to 1.

In one embodiment, n is 0-2; or n is 0; or n is equal to 1.

In another embodiment, ring b means a 5-7 membered monocyclic heterocyclic ring having up to 2 heteroatoms selected from the atoms O, S or N, optionally substituted, up to n vstrechaemosti, Deputy-Q-RQ. Examples of heterocycles include N-morpholinyl, N-piperidinyl, 4-benzylpiperazine-1-yl, pyrrolidin-1-yl or 4-methylpiperidin-1-yl.

In another embodiment, ring b means a 5-6-membered monocyclic, a heteroaryl ring having up to 2 heteroatoms selected from the atoms O, S or N, optionally substituted, up to n vstrechaemosti, Deputy-Q-RQ. Such concrete rings include benzimidazole-2-yl, 5-methylfuran-2-yl, 2,5-dimethylpyrrole-1-yl, pyridine-4-yl, indol-5-yl, indol-2-yl, 2,4-dimethoxypyrimidine-5-yl, furan-2-yl, furan-3-yl, 2-Azilian-2-yl, benzothiophen-2-yl, 4-methyltin-2-yl, 5-cyanation-2-yl, 3-chloro-5-triptorelin-2-yl.

In another embodiment, the present invention relates to compounds of the formulaV-B-1:

where:

athe Q 1and Q3means N(WRW), and the other of Q1and Q3selected from O, S or N(WRW);

Q2means C(O)CH2-C(O), C(O)-CH2CH2CH2-CH2, CF2or CF2-CF2;

m is 0-3; and

X, W, RXand RWhave the meanings as described above.

In one embodiment, the compounds of formulaV-B-1have vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, Q3means N(WRW); examples WRWinclude a hydrogen atom, a C1-C6aliphatic group(Oh)1-C6aliphatic group or C(O)OS1-C6aliphatic group.

In another embodiment, Q3means N(WRW), Q2means C(O)CH2CH2-CH2and Q1means Acting

In another embodiment, the present invention relates to compounds of the formulaV-b-2:

where:

RW1means a hydrogen atom or a C1-C6aliphatic group;

each of RW3means a hydrogen atom or a C1-C6aliphatic group; or

both RW3together form3-C6cycloalkyl or heterocyclic ring having up to two heteroatoms, selected is the R from the atoms O, S or NR', where the abovementioned ring optionally substituted by up to two substituents WRW;

m is 0-4; and

X, RX, W, and RWhave the meanings as described above.

In one embodiment, the compounds of formulaV-b-2have y vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, WRW1means a hydrogen atom, a C1-C6aliphatic group(Oh)1-C6aliphatic group or C(O)OS1-C6aliphatic group.

In another embodiment, each of RW3means a hydrogen atom, a C1-C4alkyl; or both RW3taken together, form With the3-C6cycloaliphatic group, or a 5-7 membered heterocyclic ring having up to two heteroatoms selected from the atoms O, S or N, where the above-mentioned cycloaliphatic group, or a heterocyclic ring optionally substituted with up to three substituents selected from WRW1. Such concrete rings include cyclopropyl, cyclopentyl, optionally substituted piperidyl etc.

In another embodiment, the present invention relates to compounds of the formulaV-b-3:

where:

Q4means a bond, C(O), C(O)or S(O)2 ;

RW1means a hydrogen atom or a C1-C6aliphatic group;

m is 0-4; and

X, W, RWand RXhave the meanings as described above.

In one embodiment, the compounds of formulaV-b-3have vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is equal to 0.

In one embodiment, Q4means With(About); or Q4means C(O)O. In another embodiment, RW1means1-C6alkyl. Examples RW1include methyl, ethyl or tert-butyl.

In another embodiment, the present invention relates to compounds of the formulaV-b-4:

where:

m is 0-4; and

X, RX, W, and RWhave the meanings as described above.

In one embodiment, the compounds of formulaV-b-4have y vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, m is 0-2; or m is 0; or m is equal to 1.

In another embodiment, the above-mentioned cycloaliphatic ring is 5-membered ring. Or above the ring is a six-membered ring.

In another embodiment, the present invention relates to compounds of the formulaV-B-5:

where:

ring And2means phenyl or 5-6-membered heteroaryl ring, where the ring And2and condensed with him phenyl ring, together have up to 4 substituents, independently selected from WRW;

m is 0-4; and

X, W, RWand RXhave the meanings as described above.

In one embodiment, the compounds of formulaV-B-5have y vstrechaemosti Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, ring And2means optionally substituted 5-membered ring selected from pyrrolyl, furanyl, teinila, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl or triazolyl.

In one embodiment, ring And2means optionally substituted 5-membered ring selected from pyrrolyl, pyrazolyl, thiadiazolyl, imidazolyl, oxazolyl or thiazolyl. Examples of such rings include:

where the above-mentioned ring optionally substituted as described above.

In another embodiment, ring And2means optionally substituted 6-membered ring. Examples of the rings include pyridyl, pyrazinyl or triazinyl. In another embodiment, the aforementioned ring is optionally substituted feast is dilam.

In one embodiment, ring And2means phenyl.

In another embodiment, ring And2means pyrrolyl, pyrazolyl, pyridyl or thiadiazolyl.

Examples of W in the formulaV-B-5include the link, C(O), C(O)Oh or C1-C6alkylen.

Examples RWin the formulaV-B-5include cyano, halogen atom, With1-C6aliphatic group3-C6cycloaliphatic group, aryl, 5-7 membered heterocyclic ring having up to two heteroatoms selected from the atoms O, S or N, where the abovementioned aliphatic group, phenyl and heterocyclic ring is independently and optionally substituted with up to three substituents selected from C1-C6of alkyl, O-C1-C6of alkyl, halogen atom, ceanography, HE or CF3where up to two methylene groups of the above With1-C6aliphatic group or1-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl.

In one embodiment, the present invention relates to compounds of the formulaV-B-5-a:

where:

G4means a hydrogen atom, atom g is lagena, CN, CF3, CHF2CH2F, optionally substituted C1-C6aliphatic group, aryl-C1-C6alkyl or phenyl, where G4optionally substituted by up to 4 substituents WRW; where up to two methylene groups of the above With1-C6aliphatic group or1-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-.

G5means a hydrogen atom or optionally substituted C1-C6aliphatic group;

where the above-mentioned indole ring system is optionally optionally substituted by up to 3 substituents, independently selected from WRW.

In one embodiment, the compounds of formulaV-B-5-ahave y occurrence Deputy X-RXwhere y is 0-4. In one embodiment, y is 0; or y is 1; or y is equal to 2.

In one embodiment, G4means a hydrogen atom. Or G5means a hydrogen atom.

In another embodiment, G4means a hydrogen atom, and G5means1-C6aliphatic group, where the above-mentioned aliphatic group optionally substituted C1-C6by alkyl, halogen atom, cyano or CF3where up to two metrenome the groups above With 1-C6aliphatic group or1-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl.

In another embodiment, G4means a hydrogen atom, and G5means cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyanomethyl, methoxyethyl, CH2C(O)OMe, (CH2)2-NHC(O)O-tert-butyl or cyclopentyl.

In another embodiment, G5means a hydrogen atom, and G4means a halogen atom, a C1-C6aliphatic group, or phenyl, where the abovementioned aliphatic group, or phenyl optionally substituted C1-C6by alkyl, halogen atom, cyano or CF3where up to two methylene groups of the above With1-C6aliphatic group or1-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl.

In another embodiment, G5means a hydrogen atom, and G4means halogen atom, CF3, etoxycarbonyl, tert-butyl, 2-ethoxyphenyl, 2-ethoxyphenyl, (4-C(O)NH(CH2)2-NMe2)phenyl, 2-methoxy-4-chlorophenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-acid, sec-butylaminoethyl, ethyl, tert-butyl or piperidine-1-ylcarbonyl.

In another embodiment, G4and G5both are hydrogen, and the nitrogen atom of the above indole ring is substituted With1-C6aliphatic group, C(O)(C1-C6aliphatic group) or benzyl, where the abovementioned aliphatic group or benzyl optionally substituted C1-C6by alkyl, halogen atom, cyano or CF3where up to two methylene groups of the above With1-C6aliphatic group or1-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, -NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl.

In another embodiment, G4and G5both are hydrogen, and the nitrogen atom of the above indole ring is substituted with acyl, benzyl, C(O)CH2N(Me)C(O)CH2NHMe or etoxycarbonyl.

In another embodiment, the present invention relates to compounds of the formulaI':

or their pharmaceutically acceptable salts,

where R1, R 2, R3, R4, R5, R6, R7and Ar1have the meanings as described above for compounds of the formulaI.

In one embodiment, each of R1, R2, R3, R4, R5, R6, R7and Ar1in the compounds of the formulaI'independently has a value, as described above, for any embodiments of the compounds of the formulaI.

Specific compounds according to the present invention are compounds presented in table 1, below.

Table 1
Conn.No.Name
1N-[5-(5-chloro-2-methoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
2N-(3-methoxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
3N-[2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
4N-(2-morpholinoethyl)-4-oxo-1H-quinoline-3-carboxamide
5N-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
6N-[3-(hydroxymethyl)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
7N-(4-benzoylamine 2.5-dioxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
8N-(3-amino-4-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
94-oxo-N-(3-sulfamoylbenzoyl)-1H-quinoline-3-carboxamide
101,4-dihydro-N-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-4-oxoindole-3-carboxamide

N-[1-[2-[methyl(2-methylaminomethyl)amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
114-oxo-N-[2-[2-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide
12N-[2-(4-dimethylaminophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
13N-(3-cyano-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-
carboxamid
14methyl ester [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-tert-butylphenyl]aminoarabinose acid
15N-(2-methoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
1 4-oxo-N-(2-propylphenyl)-1H-quinoline-3-carboxamide
17N-(5-amino-2-propoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
18N-(9H-fluoren-1-yl)-4-oxo-1H-quinoline-3-carboxamide
194-oxo-N-(2-chinolin)-1H-quinoline-3-carboxamide
20N-[2-(2-methylphenoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide
214-oxo-N-[4-(2-pyridylsulfonyl)phenyl]-1H-quinoline-3-carboxamide
22N-(1',2'-dihydrospiro[cyclopropane-1,3'-[3H]indol]-
6'-yl)amide of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid
23N-[2-(2-ethoxyphenyl)-5-hydroxy-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
244-oxo-N-(3-pyrrolidin-1-ylsulphonyl)-1H-quinoline-3-carboxamide
25N-[2-(3-acetylaminophenol)phenyl]-4-oxo-1H-quinoline-3-carboxamide
264-oxo-N-[2-(1-piperidyl)phenyl]-1H-quinoline-3-carboxamide
27
282-methoxyethylamine ether [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
291-isopropyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
30methyl ester of [2-isopropyl-5-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
314-oxo-N-(p-tolyl)-1H-quinoline-3-carboxamide
32N-(5-chloro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
33N-(1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
34N-[4-(1,1-diethylpropion)-2-fluoro-5-hydroxyphenyl]-4-hydroxyquinolin-3-carboxamide
351,4-dihydro-N-(2,3,4,5-tetrahydro-5,5-dimethyl-1H-benzo[b]azepin-8-yl)-4-oxoindole-3-carboxamide
36N-(2-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
37N-(1H-indol-7-yl)-4-oxo-1H-quinoline-3-carb is camid
38N-[2-(1H-indol-2-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
39tert-butyl ether [3-[(2,4-dimethoxy-3-chinolin)carbylamine]-4-tert-butylphenyl]aminoarabinose acid

40N-[2-(2-hydroxyethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
41N-(5-amino-2-propylphenyl)-4-oxo-1H-quinoline-3-carboxamide
42N-[2-[[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-4-oxo-1H-quinoline-3-carboxamide
43N-[2-(3-ethoxyphenyl)-5-hydroxy-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
44N-(2-methylbenzothiazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
45N-(2-cyano-3-forfinal)-4-oxo-1H-quinoline-3-carboxamide
46N-[3-chloro-5-(2-morpholinosydnonimine)phenyl]-4-oxo-1H-quinoline-3-carboxamide
47N-[4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
48N-(5-chloro-2-forfinal)-4-oxo-1H-quinoline-3-carboxamide
49N-[2-(2,6-acid)phenyl]-4-oxo-1H-quinoline-3-carboxamide
504-oxo-N-(2,4,6-trimetilfenil)-1H-quinoline-3-carboxamide
516-[(4-methyl-1-piperidyl)sulfonyl]-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
52N-[2-(m-tolyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
534-oxo-N-(4-pyridyl)-1H-quinoline-3-carboxamide
544-oxo-N-(8-thia-7,9-diazabicyclo[4.3.0]Nona-2,4,6,9-tetraen-5-yl)-1H-quinoline-3-carboxamide
55N-(3-amino-2-methoxy-5-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
561,4-dihydro-N-(1,2,3,4-tetrahydro-6-hydroxynaphthalene-7-yl)-4-oxoindole-3-carboxamide
57N-[4-(3-ethyl-2,6-dioxo-3-piperidyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
58N-[3-amino-4-(triptoreline)phenyl]-4-ox who-1H-quinoline-3-carboxamide
59N-[2-(5-isopropyl-2-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
60tert-butyl ester [4-isopropyl-3-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
61N-(2,3-dimetilfenil)-4-oxo-1H-quinoline-3-carboxamide
624-oxo-N-[3-(triptoreline)phenyl]-1H-quinoline-3-carboxamide
63N-[2-(2,4-differenl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
644-oxo-N-(2-oxo-1,3-dehydrobenzperidol-5-yl)-1H-quinoline-3-carboxamide
654-oxo-N-[5-(3-pyridyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
66N-(2,2-debtorrent[1,3]dioxol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
676-ethyl-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
68methyl ester of 3-[2-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]benzoic acid

69N-(3-amino-4-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
704-oxo-N-[2-(4-pyridyl)phenyl]-1H-quinoline-3-carboxamide
71isopropyl ester 3-[2-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]benzoic acid
72N-(2-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
734-oxo-N-(2-phenyl-3H-benzoimidazol-5-yl)-1H-quinoline-3-carboxamide
744-oxo-N-[5-(trifluoromethyl)-2-pyridyl]-1H-quinoline-3-carboxamide
754-oxo-N-(3-chinolin)-1H-quinoline-3-carboxamide
76N-[2-(3,4-differenl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
77N-(5-fluoro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
784-oxo-N-(2-sulfamoylbenzoyl)-1H-quinoline-3-carboxamide
79N-[2-(4-fluoro-3-were)phenyl]-4-oxo-1H-quinoline-3-carboxamide
80N-(2-methoxyphenyl)-4-oxo-1H-shall inolin-3-carboxamide
814-oxo-N-(3-propionylcarnitine)-1H-quinoline-3-carboxamide
82N-(4-diethylamino-2-were)-4-oxo-1H-quinoline-3-carboxamide
83N-[2-(3-cyanophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
84N-(4-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
85N-[2-(3,4-dichlobenil)phenyl]-4-oxo-1H-quinoline-3-carboxamide
86N-[4-[2-(aminomethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
874-oxo-N-(3-phenoxyphenyl)-1H-quinoline-3-carboxamide
88tert-butyl ether [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
89N-(2-cyano-5-were)-4-oxo-1H-quinoline-3-carboxamide
904-oxo-N-(2-tert-butylphenyl)-1H-quinoline-3-carboxamide
91N-(3-chloro-2,6-diethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
92N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
93N-[2-(5-cyano-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
94N-(5-amino-2-were)-4-oxo-1H-quinoline-3-carboxamide
95N-(2-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide
96N-[3-(cyanomethyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
97N-[2-(2,4-dimethoxypyrimidine-5-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
98N-(5-dimethylamino-2-propylphenyl)-4-oxo-1H-quinoline-3-carboxamide
994-oxo-N-(4-pentylphenol)-1H-quinoline-3-carboxamide
100N-(1H-indol-4-yl)-4-oxo-1H-quinoline-3-carboxamide
101N-(5-amino-2-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide

102N-[2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
1036-fluoro-N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
104N-(2-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
1051,4-dihydro-N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-oxoindole-3-carboxamide
106N-(2-cyano-4,5-acid)-4-oxo-1H-quinoline-3-carboxamide
107tert-butyl ester of 7-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid
108tert-butyl ether 4,4-dimethyl-7-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1,2,3,4-tetrahydroquinolin-1-carboxylic acid
109N-(1-acetyl-2,3,4,5-tetrahydro-5,5-dimethyl-1H-benzo[b]azepin-8-yl)-1,4-dihydro-4-oxoindole-3-carboxamide
110N-[4-(cyanomethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
1114-oxo-N-[2-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide
1126 ethoxy-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carbox the MFA
113N-(3-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
114tert-butyl ester [4-(2-ethoxyphenyl)-3-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
115N-[2-(2-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
1165-hydroxy-N-(1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
117N-(3-dimethylamino-4-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
118N-[2-(1H-indol-5-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
119ethyl ester of [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
120N-(2-methoxy-5-were)-4-oxo-1H-quinoline-3-carboxamide
121N-(3,4-dichlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
122N-(3,4-acid)-4-oxo-1H-quinoline-3-carboxamide
123N-[2-(3-furyl)phenyl]-4-oxo-1H-Hino is in 3-carboxamide
1246-fluoro-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
125N-(6-ethyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
126N-[3-hydroxy-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
127ethyl ester of [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-tert-butylphenyl]aminoarabinose acid
1281,6-dimethyl-4-oxo-N-(2-phenylphenyl)-1H-quinoline-3-carboxamide

129methyl ester [2-ethyl-5-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
1304-hydroxy-N-(1H-indol-6-yl)-5,7-bis(trifluoromethyl)quinoline-3-carboxamide
131N-(3-amino-5-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
132N-(5-acetylamino-2-ethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
133N-[3-chloro-5-[2-(1-piperidyl)ethylsulfonyl]phenyl]-4-about the co-1H-quinoline-3-carboxamide
134N-[2-(4-methylsulfinylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
135N-(2-benzo[1,3]dioxol-5-ylphenyl)-4-oxo-1H-quinoline-3-carboxamide
136N-(2-hydroxy-3,5-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
1376-[(4-forfinal)methylsulfanyl]-N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
138N-[2-(3,5-differenl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
139N-[2-(2,4-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
140N-(4-cyclohexylphenol)-4-oxo-1H-quinoline-3-carboxamide
141ethyl ester of [2-methyl-5-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
1424-oxo-N-(2-Deut-butylphenyl)-1H-quinoline-3-carboxamide
143N-(2-fluoro-5-hydroxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
144N-(3-GI is roxiprin)-4-oxo-1H-quinoline-3-carboxamide
145ethyl ester of 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-4-carboxylic acid
1464-oxo-N-(1,7,9-diazabicyclo[4.3.0]Nona-2,4,6,8-tetraen-5-yl)-1H-quinoline-3-carboxamide
147N-[2-(4-pertenece)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
1484-oxo-N-[5-(1-piperidinylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
149N-(3-acetylamino-4-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
1504-oxo-N-[4-[2,2,2-Cryptor-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-1H-quinoline-3-carboxamide
151N-[2-(4-methyl-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
1524-oxo-N-(2-oxo-3H-benzoxazol-6-yl)-1H-quinoline-3-carboxamide
153N-[4-(1,1-diethyl-2,2-dimethylpropyl)-2-fluoro-5-hydroxyphenyl]-4-hydroxyquinolin-3-carboxamide
154N-[3,5-bis(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
155 4-oxo-N-(2-pyridyl)-1H-quinoline-3-carboxamide
1564-oxo-N-[2-[2-(triptoreline)phenyl]phenyl]-1H-quinoline-3-carboxamide

157N-(2-ethyl-5-methylaminophenol)-4-oxo-1H-quinoline-3-carboxamide
1584-oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
159methyl ether [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]aminoarabinose acid
160N-(3-amino-4-propylphenyl)-4-oxo-1H-quinoline-3-carboxamide
161N-[3-(2-ethoxyethoxy)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
162N-(6-methoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
163N-[5-(aminomethyl)-2-(2-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
1644-oxo-N-[3-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide
1654-oxo-N-(4-sulfamoylbenzoyl)-1H-quinoline-3-carboxamide
166methyl ester 4-[2-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]benzoic acid
167N-(3-amino-4-were)-4-oxo-1H-quinoline-3-carboxamide
1684-oxo-N-(3-pyridyl)-1H-quinoline-3-carboxamide
169N-(1-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
170N-(5-chloro-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
171N-[2-(2,3-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
172N-(2-(benzo[b]thiophene-2-yl)phenyl)-1,4-dihydro-4-oxoindole-3-carboxamide
173N-(6-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
174N-[2-(5-acetyl-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
175N-(1'-acetyl-1',2'-dihydrospiro[cyclopropane-1,3'-
3H-indol]-6'-yl)amide of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid
1764-oxo-N-[4-(triptoreline)phenyl]-1H-quinoline-3-carboxamide
177N-(2-butoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
1784-oxo-N-[2-(2-tert-butylphenoxy)phenyl]-1H-quinoline-3-carboxamide
179N-(3-carbamoylmethyl)-4-oxo-1H-quinoline-3-carboxamide
180N-(2-ethyl-6-were)-4-oxo-1H-quinoline-3-carboxamide
1814-oxo-N-[2-(p-tolyl)phenyl]-1H-quinoline-3-carboxamide
182N-[2-(4-forfinal)phenyl]-4-oxo-1H-quinoline-3-carboxamide
183tert-butyl ester of 7-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1,2,3,4-tetrahydroquinolin-1-carboxylic acid
184N-(1H-indol-6-yl)-4-oxo-2-(trifluoromethyl)-1H-quinoline-3-carboxamide
185N-(3-morpholinosydnonimine)-4-oxo-1H-quinoline-3-carboxamide
186N-(3-cyclopentyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide

187N-(1-acetyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carbox the ID
188ethyl ester of 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-5-carboxylic acid
189N-(4-benzyloxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
190N-[2-(3-chloro-4-forfinal)phenyl]-4-oxo-1H-quinoline-3-carboxamide
1914-oxo-N-(5-chinolin)-1H-quinoline-3-carboxamide
192N-(3-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
193N-(2,6-dimethoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
194N-(4-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide
195N-(5-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
196N-[5-(3,3-dimethylbutylamino)-2-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
1974-oxo-N-[6-(trifluoromethyl)-3-pyridyl]-1H-quinoline-3-carboxamide
198N-(4-forfinal)-4-oxo-1H-quinoline-3-carboxamide
199 N-[2-(o-tolyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2001,4-dihydro-N-(1,2,3,4-tetrahydro-1-hydroxynaphthalene-7-yl)-4-oxoindole-3-carboxamide
201N-(2-cyano-3-were)-4-oxo-1H-quinoline-3-carboxamide
202N-[2-(5-chloro-2-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
203N-(1-benzyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
204N-(4,4-DIMETHYLPROPANE-7-yl)-4-oxo-1H-quinoline-3-carboxamide
205N-[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
206N-[2-(2,3-dimethylphenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
207ethyl ester of 2-[6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indol-3-yl]acetic acid
208N-[4-(2-substituted)-5-hydroxy-2-were]-4-oxo-1H-quinoline-3-carboxamide
209N-[4-(hydroxymethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2102,4-dimethoxy-N-(2-phenylphenyl)quinoline-3-carboxamide
211N-(2-methoxy-5-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
212N-[3-(3-methyl-5-oxo-1,4-dihydropyrazol-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
213N-[2-(2,5-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
214N-(3-methylsulfonylamino)-4-oxo-1H-quinoline-3-carboxamide
2154-oxo-N-phenyl-1H-quinoline-3-carboxamide
216N-(3H-benzimidazole-2-yl)-4-oxo-1H-quinoline-3-carboxamide
217N-(1H-indazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
2186-fluoro-N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide

221
2194-oxo-N-pyrazin-2-yl-1H-quinoline-3-carboxamide
220N-(2,3-dihydroxy-4,6-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
methyl ester [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-propylphenyl]aminoarabinose acid
222N-(3-chloro-2-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide
223N-[2-(4-methylsulfinylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2244-oxo-N-[4-[2-[(2,2,2-TRIFLUOROACETYL)aminomethyl]phenyl]phenyl]-1H-quinoline-3-carboxamide
225ethyl ester of [2-isopropyl-5-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
2264-oxo-N-(4-propylphenyl)-1H-quinoline-3-carboxamide
227N-[2-(3H-benzimidazole-2-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
228N-[2-(hydroxyphenylethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
229N-(2-methylsulfinylphenyl)-4-oxo-1H-quinoline-3-carboxamide
230N-(2-methyl-1H-indol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
231methyl ester of 3-[4-hydroxy-2-[(4-ACS who-1H-quinoline-3-yl)carbylamine]-5-tert-butylphenyl]benzoic acid
232N-(5-acetylamino-2-propylphenyl)-4-oxo-1H-quinoline-3-carboxamide
233N-(1-acetylindole-6-yl)-4-oxo-1H-quinoline-3-carboxamide
2344-oxo-N-[5-(trifluoromethyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
235N-(6-isopropyl-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
2364-oxo-N-[4-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide
237N-[5-(2-methoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
238tert-butyl ether 7'-[(4-oxo-1H-quinoline-3-ylcarbonyl)amino]Spiro[piperidine-4,4'(1'H)-quinoline]-2',3'-dihydrocarvone acid
239methyl ester [4-isopropyl-3-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
240N-(2-benzyloxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
2414-oxo-N-(8-chinolin)-1H-quinoline-3-carboxamide
242N-(5-AMI is o-2,4-dichlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
243N-(5-acetylamino-2-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
2444-oxo-N-(6,7,8,9-tetrahydro-5H-carbazole-2-yl)-1H-quinoline-3-carboxamide
245N-[2-(2,4-dichlorophenoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide
246N-(3,4-dimetilfenil)-4-oxo-1H-quinoline-3-carboxamide

2474-oxo-N-[2-(2-phenoxyphenyl)phenyl]-1H-quinoline-3-carboxamide
248N-(3-acetylamino-4-were)-4-oxo-1H-quinoline-3-carboxamide
249methyl ester [4-ethyl-3-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
250N-(5-acetylamino-2-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
251isobutyl ether [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
252N-(2-benzoylphenyl)-4-oxo-1H-quinoline-3-carboxamide
2534-oxo-N-[2-[3-(triptoreline)phenyl]phenyl]-1H-quinoline-3-carboxamide
2546-fluoro-N-(5-fluoro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
255N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-6-pyrrolidin-1-ylsulphonyl-1H-quinoline-3-carboxamide
256N-(1H-benzotriazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
257N-(4-fluoro-3-were)-4-oxo-1H-quinoline-3-carboxamide
258N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide
2594-oxo-N-(3-sec-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
260N-(5-amino-2-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
261N-[2-(3,4-dimetilfenil)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2621,4-dihydro-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]thiazin-6-yl)-4-oxoindole-3-carboxamide
263N-(4-bromo-2-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
N-(2,5-dioxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
265N-(2-benzoylphenyl)-4-oxo-1H-quinoline-3-carboxamide
266N-[5-hydroxy-4-tert-butyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2674-oxo-N-(4-phenoxyphenyl)-1H-quinoline-3-carboxamide
2684-oxo-N-(3-sulfamoyl-4-tert-butylphenyl)-1H-quinoline-3-carboxamide
269ethyl ester [4-isopropyl-3-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
270N-(2-cyano-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
271N-(3-amino-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
272N-[3-(2-morpholinosydnonimine)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
273tert-butyl ether [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]aminoarabinose acid
2744-oxo-6-pyrrolidin the-1-ylsulphonyl-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
2754-benzyloxy-N-(3-hydroxy-4-tert-butylphenyl)quinoline-3-carboxamide
276N-(4-morpholinomethyl)-4-oxo-1H-quinoline-3-carboxamide

277N-[2-(3-forfinal)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2784-oxo-N-[2-[3-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide
279N-[2-(2-methylsulfinylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2804-oxo-N-(6-chinolin)-1H-quinoline-3-carboxamide
281N-(2,4-dimetilfenil)-4-oxo-1H-quinoline-3-carboxamide
282N-(5-amino-2-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
283N-[2-(3-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
284N-(1H-indazol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
285N-[2-(2,3-differenl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2861,4-dihydro-N-(1,2,3,4-tetrahydronaphthalen-5-yl)-4-oxoindole-3-carboxamide
287N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)phenyl]-5-hydroxy-4-oxo-1H-quinoline-3-carboxamide
288N-(5-fluoro-2-methoxycarbonylamino-3-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
289N-(2-fluoro-4-were)-4-oxo-1H-quinoline-3-carboxamide
290N-[2-(3-isopropylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
291N-(2-chloro-5-hydroxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
292N-(5-chloro-2-phenoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
2934-oxo-N-[2-(1H-pyrrol-1-yl)phenyl]-1H-quinoline-3-carboxamide
294N-(1H-indol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
2954-oxo-N-(2-pyrrolidin-1-ylphenyl)-1H-quinoline-3-carboxamide
2962,4-dimethoxy-N-(2-tert-butylphenyl)quinoline-3-carbox the MFA
297N-[2-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
298ethyl ester of [2-ethyl-5-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
2994-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide
300N-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide
301N-[4-(4-methyl-4H-1,2,4-triazole-3-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
302N-[2-[4-(hydroxymethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
303N-(2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-oxo-1H-quinoline-3-carboxamide
304tert-butyl ester [4-(2-ethoxyphenyl)-3-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenylmethyl]aminoarabinose acid
305N-[2-(4-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide

306N-[2-(3-ethoxyphenyl)is enyl]-4-oxo-1H-quinoline-3-carboxamide
307N-[2-(3-chlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
308N-[2-(cyanomethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
309N-(3-ethanolic)-4-oxo-1H-quinoline-3-carboxamide
3104-oxo-N-(4-sec-butylphenyl)-1H-quinoline-3-carboxamide
311N-[2-(5-methyl-2-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
312N-[2-(2,4-acid)phenyl]-4-oxo-1H-quinoline-3-carboxamide
313N-[2-(2-forfinal)phenyl]-4-oxo-1H-quinoline-3-carboxamide
314N-(2-ethyl-6-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
315N-(2,6-dimetilfenil)-4-oxo-1H-quinoline-3-carboxamide
316N-(5-acetylamino-2-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
317N-(2,6-dichlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
3184-oxo-N-[3-[2-(1-Pieper is DIL)ethylsulfonyl]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide
3196-fluoro-N-(2-fluoro-5-hydroxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
3204-oxo-N-(2-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
321N-[2-(4-benzylpiperazine-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
322N-(2-ethyl-6-second-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
323methyl ester [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
324N-(4-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
325N-(2,6-diethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
326N-[2-(4-methylsulfinylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
327N-[5-(2-ethoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
328N-(3-acetylphenyl)-4-oxo-1H-quinoline-3-carboxamide
329N-[2-(o-tolyl)benzoxazol-5-yl]-4-oxo-1H-quinoline-3-to Roxane
330N-(2-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
331N-(2-carbamoylethyl)-4-oxo-1H-quinoline-3-carboxamide
332N-(4-ethynylphenyl)-4-oxo-1H-quinoline-3-carboxamide
333N-[2-[4-(cyanomethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
334tert-butyl ether 7'-[(4-oxo-1H-quinoline-3-ylcarbonyl)amino]Spiro[piperidine-4,4'(1'H)-1-acetylcholin]-2',3'-dihydrocarvone acid
335N-(2-carbarnoyl-5-were)-4-oxo-1H-quinoline-3-carboxamide
336N-(2-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
337N-(5-hydroxy-2,4-di-tert-butylphenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide

338N-(3-methyl-1H-indol-4-yl)-4-oxo-1H-quinoline-3-carboxamide
339N-(3-cyano-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
340N-(methylsulfonylamino-4-propylphenyl)-4-oxo-1H-quinoline-3-carboxamide
341neopentylene ether [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
342N-[5-(4-isopropylphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
343N-[5-(isobutylamino)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
344N-[2-(2-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
3456-fluoro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
3464-oxo-N-phenyl-7-(trifluoromethyl)-1H-quinoline-3-carboxamide
347N-[5-[4-(2-dimethylaminoethanol)phenyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
348N-[2-(4-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
3494-oxo-N-(2-phenylsulfonyl)-1H-quinoline-3-carboxamide
350N-(1-naphthyl)-4-oxo-1H-quinoline-3-carboxamide
351N-(5-ethyl-1H-indol-6-yl)-4-oxo-1H-hee is Olin-3-carboxamide
352tert-butyl ester 2-[6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indol-3-yl]ethylaminoethanol acid
353tert-butyl ether [3-[(4-oxo-1H-quinoline-3-yl)carbylamine]-4-tert-butylphenyl]aminoarabinose acid
354N-[2-[(cyclohexylethylamine)methyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide
355N-[2-(2-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
356N-(5-methylamino-2-propylphenyl)-4-oxo-1H-quinoline-3-carboxamide
357N-(3-isopropyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
3586-chloro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
359N-[3-(2-dimethylaminoethylmethacrylate)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
360N-[4-(deformedarse)phenyl]-4-oxo-1H-quinoline-3-carboxamide
361N-[2-(2,5-acid)phenyl]-4-oxo-1H-quinoline-3-carboxamide
N-(2-chloro-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
363N-[2-(2-fluoro-3-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
364N-(2-methyl-8-chinolin)-4-oxo-1H-quinoline-3-carboxamide
365N-(2-acetylphenyl)-4-oxo-1H-quinoline-3-carboxamide

3664-oxo-N-[2-[4-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide
367N-[2-(3,5-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
368N-(3-amino-4-propoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
369N-(2,4-dichloro-6-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide
370N-(3-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
3714-oxo-N-[2-(trifloromethyl)phenyl]-1H-quinoline-3-carboxamide
372N-[2-(4-methyl-1-piperidyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
373N-indan-4-yl-4-oxo-1H-quinoline-3-carboxamide
3744-hydroxy-N-(1H-indol-6-yl)-2-methylsulfonylamino-3-carboxamide
3751,4-dihydro-N-(1,2,3,4-tetrahydronaphthalen-6-yl)-4-oxoindole-3-carboxamide
3764-oxo-N-(2-phenylbenzoxazole-5-yl)-1H-quinoline-3-carboxamide
3776,8-debtor-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
378N-(3-amino-4-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
379N-[3-acetylamino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
380N-(2-ethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
3814-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
382ethyl ester of [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-propylphenyl]aminoarabinose acid
383N-(3-ethyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
384 N-[2-(2,5-differenl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
385N-[2-(2,4-divergence)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
386N-(3,3-dimethylindoline-6-yl)-4-oxo-1H-quinoline-3-carboxamide
387N-[2-methyl-3-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
3884-oxo-N-[2-[4-(triptoreline)phenyl]phenyl]-1H-quinoline-3-carboxamide
389N-(3-benzoylphenyl)-4-oxo-1H-quinoline-3-carboxamide
390N-[3-(aminomethyl)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
391N-[2-(4-isobutylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
392N-(6-chloro-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
393N-[5-amino-2-(2-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
3941,6-dimethyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide

395N-[4-(1-substituted)-2-fluoro-5-hydroxyphenyl]-4-hydroxyquinolin-3-carboxamide
396tetrahydrofuran-3-ymetray ether [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
3974-oxo-N-(4-phenylphenyl)-1H-quinoline-3-carboxamide
3984-oxo-N-[2-(p-tolilsulfonil)phenyl]-1H-quinoline-3-carboxamide
399N-(2-isopropyl-5-methylaminophenol)-4-oxo-1H-quinoline-3-carboxamide
400N-(6-morpholino-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
401N-[2-(2,3-dimetilfenil)phenyl]-4-oxo-1H-quinoline-3-carboxamide
4024-oxo-N-(5-phenyl-2-pyridyl)-1H-quinoline-3-carboxamide
403N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)phenyl]-4-hydroxyquinolin-3-carboxamide
404N-[5-(2,6-acid)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
405N-(4-chlorophenyl)-4-oxo-1H-hin the Lin-3-carboxamide
4066-[(4-forfinal)methylsulfanyl]-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
407N-(2-fluoro-5-hydroxy-4-tert-butylphenyl)-5-hydroxy-4-oxo-1H-quinoline-3-carboxamide
408N-(3-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
409N-(5-dimethylamino-2-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
4104-oxo-N-[2-(4-phenoxyphenyl)phenyl]-1H-quinoline-3-carboxamide
4117-chloro-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
412ethyl ester of 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-7-carboxylic acid
4134-oxo-N-(2-phenoxyphenyl)-1H-quinoline-3-carboxamide
414N-(3H-benzimidazole-5-yl)-4-oxo-1H-quinoline-3-carboxamide
415N-(3-hydroxy-4-tert-butylphenyl)-4-methoxyquinoline-3-carboxamide
416propyl ether [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-the l)carbylamine]phenyl]propyl]aminoarabinose acid
417N-(2-(benzo[b]thiophene-3-yl)phenyl)-1,4-dihydro-4-oxoindole-3-carboxamide
418N-(3-dimethylaminophenyl)-4-oxo-1H-quinoline-3-carboxamide
419N-(3-acetamidophenyl)-4-oxo-1H-quinoline-3-carboxamide
420ethyl ester of 2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propanoic acid
421N-[5-methoxy-4-tert-butyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
422N-(5,6-dimethyl-3H-benzoimidazol-2-yl)-4-oxo-1H-quinoline-3-carboxamide
423N-[3-(2-ethoxyethyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
424N-[2-(4-chlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
425N-(4-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide

N-(m-tolyl)-4-oxo-1H-quinoline-3-carboxamide
426N-(4-chloro-5-hydroxy-2-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
427 tert-butyl ester 5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid
428N-(3-hydroxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
429N-[3-amino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
430N-(2-isopropyl-6-were)-4-oxo-1H-quinoline-3-carboxamide
431N-(3-AMINOPHENYL)-4-oxo-1H-quinoline-3-carboxamide
432N-[2-(4-isopropylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
433N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
434N-(2,5-dimetilfenil)-4-oxo-1H-quinoline-3-carboxamide
435N-[2-(2-pertenece)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
436N-[2-(3,4-acid)phenyl]-4-oxo-1H-quinoline-3-carboxamide
437N-benzo[1,3]dioxol-5-yl-4-oxo-1H-quinoline-3-carboxamide
438 N-[5-(deformity)-2,4-di-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
439N-(4-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
440N-(2,2,3,3-titrator-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4-dihydro-4-oxoindole-3-carboxamide
441N-[3-methylsulfonylamino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
4424-oxo-N-[3-(1-piperidinylcarbonyl)phenyl]-1H-quinoline-3-carboxamide
4434-oxo-N-cinoxacin-6-yl-1H-quinoline-3-carboxamide
444methyl ester 5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-tert-butylbenzoic acid
445N-(2-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
446N-(1,1-dioxobenzo-6-yl)-4-oxo-1H-quinoline-3-carboxamide
447N-(3-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide
4484-oxo-N-(4-tert-butylphenyl)-1H-quinoline-3-carboxamide
449
450N-[4-(1-hydroxyethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
451N-(4-cyano-2-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
4524-oxo-N-(4-vinylphenol)-1H-quinoline-3-carboxamide
453N-(3-amino-4-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
454N-(2-methyl-5-phenylphenyl)-4-oxo-1H-quinoline-3-carboxamide
455N-[4-(1-substituted)phenyl]-4-oxo-1H-quinoline-3-carboxamide
4564-oxo-N-[3-(trifloromethyl)phenyl]-1H-quinoline-3-carboxamide
457N-(4-morpholinomethyl)-4-oxo-1H-quinoline-3-carboxamide
458N-[3-(2-hydroxyethoxy)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide

459N-(o-tolyl)-4-oxo-1H-quinoline-3-carboxamide
460butyl ester of [2-methyl-2-[4-[(4-oxo-1-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
4614-oxo-N-(2-phenylphenyl)-1H-quinoline-3-carboxamide
462N-(3-dimethylamino-4-propylphenyl)-4-oxo-1H-quinoline-3-carboxamide
463N-(4-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
4645-hydroxy-N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
465tert-butyl ester of [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-tert-butylphenylmethyl]aminoarabinose acid
466N-(2,6-diisopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
467N-(2,3-dihydrobenzofuran-5-yl)-4-oxo-1H-quinoline-3-carboxamide
4681-methyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
4694-oxo-N-(2-phenylphenyl)-7-(trifluoromethyl)-1H-quinoline-3-carboxamide
4704-oxo-N-(4-phenylsulfanyl)-1H-quinoline-3-carboxamide
471methyl ester [3-[(4-oxo-1H-quinoline-3-yl)carbylamine]4-propylphenyl]aminoarabinose acid
472ethyl ester [4-ethyl-3-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
4731-isopropyl-4-oxo-N-(2-tert-butylphenyl)-1H-quinoline-3-carboxamide
474N-(3-methyl-2-oxo-3H-benzooxazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
475N-(2,5-dichloro-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
476N-(2-cyano-5-hydroxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
477N-(5-fluoro-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide
4784-oxo-N-(3-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
479N-(1H-indol-6-yl)-5-methoxy-4-oxo-1H-quinoline-3-carboxamide
4801-ethyl-6-methoxy-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
481N-(2-naphthyl)-4-oxo-1H-quinoline-3-carboxamide
482ethyl ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]amino is aravinou acid
483N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)phenyl]-4-hydroxyquinolin-3-carboxamide
484N-(3-methylamino-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
485N-(3-dimethylamino-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide

In another embodiment, the present invention relates to compounds useful as intermediates for the synthesis of compounds of the formulaI. In one embodiment, such compounds correspond to the formulaAs-I:

or their salts;

where:

G1means a hydrogen atom, R', C(O)R', C(S)R', S(O)R', S(O)2R', Si(CH3)2R', P(O)(OR')3P(S)(OR')3or B(OR')2;

G2means a halogen atom, CN, CF3, isopropyl or phenyl, where the above isopropyl or phenyl optionally substituted by up to 3 substituents, independently selected from WRWwhere W and RWhave the meanings as described above for formula I and its embodiments;

G3means isopropyl or3-C10cycloaliphatic ring, where the above G3optionally substituted by up to 3 substituents, independently selected from WRWwhere W R Whave the meanings as described above for formula I and its embodiments;

provided that when G1means a methoxy group, G3means tert-butyl, G2is not 2-amino-4-methoxy-5-tert-butylphenyl.

In one embodiment, the present invention relates to compounds of formula a-I, provided that when G2and G3every means tert-butyl, G1is not a hydrogen atom.

In another embodiment, the implementation of:

G1means a hydrogen atom;

G2means a halogen atom or isopropyl, where the above isopropyl optionally substituted by up to 3 substituents, independently selected from R'; and

G3means isopropyl or3-C10cycloaliphatic ring, where the above G3optionally substituted by up to 3 substituents, independently selected from R';

In another embodiment, the implementation of:

G1means a hydrogen atom;

G2means a halogen atom, preferably a fluorine atom; and

G3means3-C10cycloaliphatic ring, where the above G3optionally substituted by up to 3 substituents, independently selected from methyl, ethyl, propyl or butyl.

In another embodiment, the implementation of:

G1means a hydrogen atom;

G2means CN, the atom is alogena or CF 3; or

G3means isopropyl or3-C10cycloaliphatic ring, where the above G3optionally substituted by up to 3 substituents, independently selected from R'.

In another embodiment, the implementation of:

G1means a hydrogen atom;

G2means phenyl, optionally substituted by up to 3 substituents, independently selected from-O-C1-C4of alkyl, CF3, halogen atom or CN; and

G3means isopropyl or3-C10cycloaliphatic ring, where the above G3optionally substituted by up to 3 substituents, independently selected from R'.

Examples G3include optionally substituted cyclopentyl, cyclohexyl, cycloheptyl or substituted. Or G3means branched C3-C8aliphatic chain. Examples G3include isopropyl, tert-butyl, 3,3-dieselpro-3-yl or 3,3-diethyl-2,2-dimethylpropyl-3-yl.

In another embodiment, the implementation of:

G1means a hydrogen atom;

G2means tert-butyl; and

G3means tert-butyl.

In another embodiment, the present invention relates to a compound of the formulaA-II:

or salts thereof, where:

G4means a hydrogen atom, a halogen atom, CN, CF3, CHF2CH2F, optional Zam is placed With 1-C6aliphatic group, aralkyl or phenyl ring, optionally substituted by up to 4 substituents WRW;

G5means a hydrogen atom or optionally substituted C1-C6aliphatic group;

assuming that both G4and G5, are not simultaneously hydrogen;

where the above-mentioned indole ring is additionally optionally substituted by up to 3 substituents, independently selected from WRW.

In one embodiment, G4means a hydrogen atom. Or G5means a hydrogen atom.

In another embodiment, G4means a hydrogen atom, and G5means1-C6aliphatic group, where the above-mentioned aliphatic group optionally substituted C1-C6by alkyl, halogen, cyano or CF3where up to two methylene groups of the above With1-C6aliphatic group or1-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-C4alkyl.

In another embodiment, G4means a hydrogen atom, and G5means cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-Buti is, cyanomethyl, methoxyethyl, CH2C(O)OMe, (CH2)2-NHC(O)O-tert-butyl or cyclopentyl.

In another embodiment, G5means a hydrogen atom, and G4means a halogen atom, a C1-C6aliphatic group, or phenyl, where the abovementioned aliphatic group, or phenyl optionally substituted (replaced)1-C6by alkyl, halogen atom, cyano or CF3where up to two methylene groups of the above With1-C6aliphatic group or1-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-With4alkyl.

In another embodiment, G5means a hydrogen atom, and G4means a halogen atom, etoxycarbonyl, tert-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C(O)NH(CH2)2-NMe2, 2-methoxy-4-chlorophenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-acid, sec-butylaminoethyl, ethyl, tert-butyl or piperidine-1-ylcarbonyl.

Associated with the formula A-II of the embodiment, the nitrogen atom of the above indole ring is substituted With1-C6aliphatic group, C(O)(C1-C6aliphatic group) or benzyl, where the abovementioned aliphatic g is the SCP or benzyl optionally substituted (replaced) 1-C6by alkyl, halogen atom, cyano or CF3where up to two methylene groups of the above With1-With6aliphatic group or1-C6the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'r CO2-, -O-, -NR'r CONR'-, -OCONR'-, -NR'r CO-, -S-, -NR'-, -SO2NR'-, NR'r SO2- or-NR'r SO2NR'-. In another embodiment, the above-mentioned R' means1-With4alkyl.

In another embodiment, the nitrogen atom of the above indole ring is substituted with acyl, benzyl, C(O)CH2N(Me)C(O)CH2NHMe or etoxycarbonyl.

4. General scheme of synthesis

Compounds according to the present invention is easily produced using methods known in this field. Illustrated following methods are examples of methods for producing compounds according to the present invention.

The diagram below illustrates the synthesis of acid - precursor compounds according to the present invention.

Synthesis of acid-precursorsP-IV-A, P-IV-BorP-IV-C

a) (CO2Et)2CH2; (b) (CO2Et)2CH=CH(OEt); (c) CF3CO2H, PPh3, CCl4Et3N; d) MeI; (e) PPA or diphenyl ether; (f) NaOH.

Synthesis of acid-precursorsP-IV-A, P-IV-BorP-IV-C

a) AcONH4; (b) EtOCHC(CO2Et)2, 130OC; (C) Ph2O, ∆T; d) I2, EtOH; (e) NaOH.

Synthesis of acid-precursorsP-IV-A, P-IV-BorP-IV-C

a) POCl3; (b) R ONa; (c) n-BuLi, ClCO2Et; (d) NaOH.

Synthesis of amine-predecessorP-III-A:

and (CH3)2SO4; (b) K3Fe(CN)6, NaOH, H2O; c) HNO3H2SO4; d) RCOCH3, MeOH, NH3; e) H2the Raney Nickel.

Synthesis of amine-predecessorP-IV-A:

a) HNO3, HOAc; b) Na2S2O4, THF/H2O; (C) H2Pd/C.

Synthesis of amine-predecessorP-V-A-1:

a) KNO3H2SO4; (b) NaNO2H2SO4-H2O; c) NH4CO2H, Pd-C; (d) R X; e) NH4CO2H, Pd-C.

Synthesis of amine-predecessorP-V-A-1:

a) SO2Cl2, R2=Cl; b) R2OH, R2=alkyl; (C) NBS, R1=Br; (d) ClCO2R, TEA; (e) HNO3H2SO4; (f) a base; (g) ArB(OH)2, R1=Br; h) [H]; i) R X, R1=Br; j) ClCF2CO2Me; (k) [H]; l) [H].

Synthesis of amine-predecessorP-V-A-1:

The) KNO 3; (b) [H]; c) KNO3; d) AcCl; (e) [H]; f) i) NaNO2; (ii) H2O; g) HCl.

Synthesis of amine-predecessorP-V-A-1:

a) HNO3H2SO4; (b) [H]; (c) protection; (d) R CHO; (e) removing protection; (f) [H]; g) Na2S, S, H2O; h) nitration; (i) (Boc)2O; j) [H]; k) RX; 1) [H]; PG=protective group.

Synthesis of amine precursorP-V-A-1orP-V-A-2:

a) Br2; (b) Zn(CN)2Pd(PPh)3; (C) [H]; d) BH3; (e) (Boc)2O; f) [H]; (g) (H2SO4H2O; h) R X; i) [H]; j) LiAlH4.

Synthesis of amine precursorP-V-A-1orP-V-A-2:

a)(i) NaNO2, HCl; (ii) Na2SO3, CuSO4, HCl; (b) NH4Cl; (C) [H].

Synthesis of amine-predecessorP-V-A-1:

a) CHCl2OMe; (b) KNO3H2SO4;) Desiccator; (d) Fe.

Synthesis of amine-predecessorP-V-A-3:

Ar=aryl or heteroaryl

a) nitration; (b) ArB(OH)2Pd; (c) BH3; (d) (Boc)2O.

Synthesis of amine-predecessorP-V-In-1:

a) AcCl; (b) DEAD; (C) AlCl3; d) NaOH.

Synthesis of amine-predecessorP-V-In-1:

a) ClCH2COCl; (b) []; c) protection; (d) [H];

PG=protective group.

Synthesis of amine-predecessorP-V-In-1:

a) HSCH2CO2H; (b) [H].

Synthesis of amine-predecessorP-V-b-2:

a) AlCl3; (b) [H]; (c) (i) R1R2CHCOCH2CH2Cl; (ii) NaBH4; (d) NH2OH; (e) DIBAL-H; f) nitration; (g) protection; (h) [H];

PG=protective group.

Synthesis of amine-predecessorP-V-b-3:

a) nitration; (b) defence; (C) [H].

PG=protective group.

Synthesis of amine-predecessorP-V-B-5:

a) when X=Cl, Br, I: RX, K2CO3, DMF or CH3CN; when X=OH: RX, TFFH, DIEA, THF; (b) H2Pd-C, EtOH or SnCl2·2H2O, EtOH or SnCl2·2H2O, DIEA, EtOH.

Synthesis of amine-predecessorP-V-B-5:

a) RCOCl, Et3N, CH2Cl2; (b) n-BuLi, THF; (C) NaBH4, AcOH; (d) KNO3H2SO4; (e) DDQ, 1,4-dioxane; (f) NaNO2, HCl, SnCl2·2H2O, H2O; g) MeCOR, EtOH; (h) PPA; (i) LiAlH4, THF or H2, Raney Ni, EtOH or MeOH.

Synthesis of amine-predecessorP-V-B-5:

a) NaNO2, HCl, SnCl2·2H2O, H2O; (b) RCH2COR, AcOH, EtOH; (c) H3PO4, toluene; (d) H2Pd-C, EtOH.

Synthesis of amine-predecessorR-V-B-5:

a) NaNO2, HCl, SnCl2·2H2O, H2O; (b) RCH2SON, AcOH, EtOH; (c) H3PO4, toluene; (d) H2Pd-C, EtOH.

Synthesis of amine-predecessorR-V-B-5:

a) RX (X=Br, I), triflate zinc, TBAI, DIEA, toluene; (b) H2, Raney Ni, EtOH or H2Pd-C, EtOH or SnCl2·2H2O, EtOH; (c) ClSO2NCO, DMF, CH3CN; (d) Me2NH, H2CO., AcOH; (e) MeI, DMF, THF, H2O; f) MNu (M=Na, K, Li; Nu=nucleophile).

Synthesis of amine-predecessorR-V-B-5:

a) HNO3H2SO4b) Me2NCH(OMe)2, DMF; (c) H2, Raney Ni, EtOH.

Synthesis of amine-predecessorR-V-B-5:

a)when PG=SO2Ph: PhSO2Cl, Et3N, DMAP, CH2Cl2; when PG=Ac: AcCl, NaHCO3CH2Cl2; (b) when R=RCO: (RCO)2O AlCl3CH2Cl2; when R=Br: Br2, AcOH; (c) HBr or HCl; (d) KNO3H2SO4; (e) MnO2CH2Cl2or DDQ, 1,4-dioxane; (f) H2, Raney Ni, EtOH.

Synthesis of amine-predecessorR-V-B-5:

a) NBS, DMF; (b) KNO3H2SO4; (c) HC=CSiMe3Pd(PPh3)2Cl2, CuI, Et3N, toluene, H2O; d) CuI, DMF; e) H2, Raney Nickel, MeOH.

Synthesis of amine-predecessorR-V-a-3orR-V-A-6:

Ar=aryl or heteroaryl;

a) ArB(OH)2Pd(PPh3)4, K2CO3H2O, THF or ArB(OH)2Pd2(dba)3, P(tBu)3, KF, THF.

Synthesis of amine-predecessorR-V-a-4:

R=CN, CO2Et; a) MeI, NaOtBu, DMF; (b) HCO2K, Pd-C, EtOH or HCO2NH4Pd-C, EtOH.

Synthesis of amine-predecessorR-V-a-4:

a) ArBr, Pd(OAc)2PS-PPh3, K2CO3, DMF.

Synthesis of amine-predecessorR-V-b-4:

a) H2Pd-C, MeOH.

Synthesis of amine-predecessorR-V-b-4:

a) NaBH4, MeOH; (b) H2Pd-C, MeOH; (c) NH2OH, pyridine; (d) H2Pd-C, MeOH; (e) Boc2O, Et3N, MeOH.

The synthesis of compounds of the formulaI

a) Ar1R7NH, binder, base, solvent. The examples used conditions: HATU, DIEA; BOP, DIEA, DMF; HBTU, Et3N, CH2Cl2; PFPTFA, pyridine.

The synthesis of compounds of the formulaI'

R5=aliphatic group: a) R5X (X=Br, I), Cs2CO3, DMF.

The synthesis of compounds of the formulaV-B-5

a) NaOH, THF; b) HNR2, HATU, DIEA, DMF.

The synthesis of compounds of the formulaV-B-5

WRW=aryl or heteroaryl: (a) ArB(OH)2, (dppf)PdCl2, K2CO3, DMF.

The synthesis of compounds of the formulaV-a-2andformulaV-A-5

a) SnCl2·2H2O, EtOH; (b) PG=Boc: TFUCK, CH2Cl2; (c) CH2O NaBH3CN, CH2Cl2, MeOH; (d) RXCl, DIEA, THF or RXCl, NMM, 1,4-dioxane or RXCl, CH2Cl2, DMF; e) R R ' NH, LiClO4CH2Cl2, iPrOH.

The synthesis of compounds of the formulaV-b-2

a) when PG=Boc: TFUCK, CH2Cl2; when PG=Ac: NaOH or HCl, EtOH or THF.

The synthesis of compounds of the formulaV-a-2

a) when PG=Boc: TFUCK, CH2Cl2.

a) when PG=Boc: TFUCK, CH2Cl2; (b) ROCOCl, Et3N, DMF.

The synthesis of compounds of the formulaV-A-4:

a) when PG=BOC: TFUCK, CH2Cl2; (b) when RW=CO2R: ROCOCl, DIEA, MeOH

In the diagrams above, used the radical R denotes Deputy, for example, RWas defined in the description above. The person skilled in the art will understand that the path of synthesis, suitable for various deputies, according to the present invention are such that the reaction conditions and the stages do not cause modifications available in mind deputies.

5 Application finished dosage form and introduction

Pharmaceutically acceptable composition

As discussed above, the present invention relates to compounds that are useful as modulators of ABC transporters and, therefore, useful in the treatment of diseases, disorders or conditions such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; deficiencies of coagulation-fibrinolysis, such as protein deficiency, hereditary angioedema type 1; deficits in the processing of lipids, such as familial hypercholesterolaemia, chylomicronemia type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysacharides, disease sandhof/Tay-Sachs disease crigler-The Najjar syndrome type II, polyendocrinopathy/hyperinsulemia, diabetes, macrosomia of Larona, the deficit teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroid, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Toot disease Pelizaeus-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, side amyotrophies sclerosis, progressive supranuclear, Olesen Peak; heavy polyglutamine neurological disorders such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonica dystrophy, as well as lobkovice encephalopathy, such as nasledstvenna disease Creutzfeldt-Jakob disease (caused by a defect in the processing of prion protein), Fabry disease, syndrome Straussler-Sheinker, COPD, disease, dry eye or Sjogren syndrome.

Accordingly, according to another aspect of the present invention provides pharmaceutically acceptable compositions, where the compositions contain any of the compounds as described herein, and optionally a pharmaceutically acceptable carrier, adjuvant or excipient. According to some variants of implementation, these compositions optionally optionally contain one or more additional therapeutic agents.

You should also take into account that some of the compounds according to the present invention can exist in free form for treatment, or where appropriate, in the form of their pharmaceutically acceptable derivative or prodrug. In accordance with the present invention, pharmaceutically acceptable derivative or prodrug includes, but is not limited to, the pharmaceutical is Ki acceptable salt, esters, salts of such esters, or any other adduct or derivative which(which), after administration to a patient in need this, is able to give, directly or indirectly, connection, any otherwise described herein, or a metabolite or residue.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the medical health assessment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and consistent with the ratio of acceptable benefit/risk. The term "pharmaceutically acceptable salt" means any non-toxic salt or salt of ester compounds according to the present invention, which, after administration to a recipient, is capable to give, directly or indirectly, a compound according to the present invention or its active against inhibiting metabolite or residue.

Pharmaceutically acceptable salts are well known in this field. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in J. Pharmaceutical Sciences,66, 1-19 (1977), included in this description by reference. Pharmaceutically acceptable salts of the compounds according to the present invention include salts derived from under Odesa inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic additive salts of acids are salts formed by the amino group with inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in this field, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonic, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include salts of Molochny the metals, alkaline earth metal, ammonium and N+(C1-4alkyl)4. According to the present invention also provides for the quaternization of any basic nitrogen-containing groups of the compounds disclosed in this description. Soluble or dispersible in water or oil products can be obtained by quaternization. Examples of salts of alkaline or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and the like. Additionally, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations, Quaternary ammonium and amine formed using counterions such as halide ion, hydroxyl ion, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

As described above, the pharmaceutically acceptable composition according to the present invention additionally contain a pharmaceutically acceptable carrier, adjuvant or excipient, which, as used herein, includes any and all solvents, diluents, or other liquid filler, auxiliary dispersion or suspension means, surface active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, depending on the wish which specific dosage forms. In Remington''s Pharmaceutical Sciences, sixteenth edition, E.W. Martin (Mack Publishing Co, Easton, Pa, 1980) describes the different media used in the preparation of pharmaceutically acceptable compositions, and known methods for their preparation. Except when any usual the carrier medium is incompatible with the compounds according to the invention, such as causing undesirable biological effect or otherwise interacting in a hurtful manner with any other component (components) pharmaceutically acceptable compositions, suggest that its use is included in the scope of this invention. Some examples of substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as preteenslut, intrigejosa, kalogeropoulos, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, blackspanielgallery with polyethylene and polyoxypropyleneamine blocks, lanolin, sugar, such as actose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients such as cocoa butter and candle waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as etiloleat and tillaart; agar; buferiruemoi agents, such as magnesium hydroxide and the hydroxide aluminum; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and the composition may contain coloring agents, agents that promote the release coating agents, sweeteners, taste and flavouring agents, preservatives and antioxidants, in accordance with the assessment of the manufacturer.

The use of compounds and pharmaceutically acceptable compositions

According to still another aspect, the present invention relates to a method for the treatment of conditions, diseases and disorders, which involved a lot of activity is ü ABC Transporter, for example, CFTR. According to some variants of implementation, the present invention relates to a method of treatment of a condition, illness or impairment, which involved the lack of activity of the ABC Transporter, including the introduction of the compositions containing the compound of formula (I), to a subject, preferably a mammal in need of such treatment.

According to some variants of implementation, the present invention relates to a method of treating cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; deficiencies of coagulation-fibrinolysis, such as protein deficiency, hereditary angioedema type 1; deficits in the processing of lipids, such as familial hypercholesterolaemia, chylomicronemia type 1, abetalipoproteinemia; diseases lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysacharides, disease sandhof/Tay-Sachs disease criglernajjar Najjar syndrome type II, polyendocrinopathy/hyperinsulemia, diabetes, macrosomia of Larona, the deficit teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroid, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Toot disease Pelizaeus-Merzbacher; naradah neratinib diseases, such as Alzheimer's disease, Parkinson's disease, side amyotrophies sclerosis, progressive supranuclear, the disease Peak; heavy polyglutamine neurological disorders such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonica dystrophy, as well as gurkovich encephalopathies, such as nasledstvenna disease Creutzfeldt-Jakob disease (caused by a defect in the processing of prion protein), Fabry disease, syndrome Straussler-Sheinker, COPD, disease, dry eye or Sjogren syndrome; stage including the introduction of the above to a mammal an effective amount of a composition containing the compound according to the present invention.

According to an alternative preferred variant implementation, the present invention relates to a method of treating cystic fibrosis, comprising the stage of introduction of the above to a mammal an effective amount of a composition containing the compound according to the present invention.

According to the present invention, "effective amount" of a compound or farmatsevticheskii acceptable composition is an amount effective to treat or ameliorate the severity of one or more diseases, such as cystic fibrosis, inherited the Naya emphysema, hereditary hemochromatosis; deficiencies of coagulation-fibrinolysis, such as protein deficiency, hereditary angioedema type 1; deficits in the processing of lipids, such as familial hypercholesterolaemia, chylomicronemia type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysacharides, disease sandhof/Tay-Sachs disease criglernajjar Najjar syndrome type II, polyendocrinopathy/hyperinsulemia, diabetes, macrosomia of Larona, the deficit teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroid, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Toot disease Pelizaeus-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, side amyotrophies sclerosis, progressive supranuclear, the disease Peak; heavy polylaminate neurological disorders such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonica dystrophy, as well as lobkovice encephalopathy, such as nasledstvenna disease Creutzfeldt-Jakob disease (caused by the defect is of rocessing prion protein), Fabry disease, syndrome Straussler-Sheinker, COPD, disease, dry eye or Sjogren syndrome.

Compounds and compositions in accordance with the method according to the present invention, may be administered using any amount and any route of administration effective for the treatment or attenuation of the severity of one or more diseases, such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; deficiencies of coagulation-fibrinolysis, such as protein deficiency, hereditary angioedema type 1; deficits in the processing of lipids, such as familial hypercholesterolaemia, chylomicronemia type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysacharides, disease sandhof/Tay-Sachs, disease criglernajjar Najjar syndrome type II, polyendocrinopathy/hyperinsulemia, diabetes, macrosomia of Larona, the deficit teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroid, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Toot disease Pelizaeus-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, side amyotrophies sclerosis, the program is shirouma supranuclear, the disease Peaks; heavy polyglutamine neurological disorders such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonica dystrophy, as well as lobkovice encephalopathy, such as nasledstvenna disease Creutzfeldt-Jakob disease (caused by a defect in the processing of prion protein), Fabry disease, syndrome Straussler-Sheinker, COPD, disease, dry eye or Sjogren syndrome.

In accordance with one embodiment, compounds and compositions according to the present invention are useful to treat or ameliorate the severity of cystic fibrosis patients, in which case apparent residual CFTR activity in the apical membrane of respiratory and nerespectarea epithelium. The presence of residual CFTR activity in the epithelial surface can be easily determined using known in the field methods, for example, the standard electrophysiological, biochemical or histochemical methods. Using these methods identify CFTR activity using in vivo or ex vivo electrophysiological methods, by measuring the concentrations of Cl-in the sweat or saliva, or ex vivo biochemical or histochemical methods, by controlling the cell surface density. Using such methods,the residual CFTR activity can be easily identified in heterozygous or homozygous patients for a variety of different mutations, including homozygous or heterozygous patients with the most common mutation, ΔF508.

In accordance with another embodiment, compounds and compositions according to the present invention are useful to treat or ameliorate the severity of cystic fibrosis in patients who have induced or increased residual CFTR activity using pharmacological methods or gene therapy. Such methods increase the amount of CFTR located on the cell surface inducyruya, thus missing still CFTR activity in a patient or increasing the existing level of residual CFTR activity in a patient.

In accordance with one embodiment, compounds and compositions according to the present invention are useful to treat or ameliorate the severity of cystic fibrosis in patients with certain genotypes that exhibit residual CFTR activity, as, for example, mutations of class III (impaired regulation or the opening of membrane channels), mutations of class IV (altered conductance), or mutations of class V (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis Transmembrane Conductance Regulator Defects and Opportunities of Therapy”, Current Opinion in Pulmonary Medicine,6, 521-529 (2000)). Other genotypes in patients who exhibit residual CFTR activity, include patients homozygous for one of these classes is or heterozygous with any other class of mutations, including mutation class I mutation class II or mutation, for which there is no classification.

In accordance with one embodiment, compounds and compositions according to the present invention are useful to treat or ameliorate the severity of cystic fibrosis in patients with certain clinical phenotypes, such as moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of the epithelium. Such phenotypes include patients exhibiting pancreatic insufficiency, or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the excretory vessel, or with mild lung disease.

Exactly the required amount varies from subject to subject, depending on the type, age and General condition of the subject, the severity of the infection, the particular agent, its mode of administration and the like. Compounds according to the invention is preferably used to produce the drug in a single dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form"as used herein, refers to a physically discrete unit of the corresponding agent subjected to the treatment of the patient. However, it should be clear that su is total daily dose of the compounds and compositions according to the present invention should be defined by the regular physician, within the medical health assessment. The specific effective dose for any particular patient or organism will depend on a number of factors including the disorder that should be treated, and the severity of this violation, the activity is specifically used compounds used concrete composition; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound; the duration of the treatment; drugs used in combination or simultaneously with the specific connection, and the like factors well known in medicine. The term "patient", as used herein, means an animal, preferably a mammal, and highly preferably, human.

Pharmaceutically acceptable compositions according to this invention it is possible to introduce people and other animals orally, rectally, parenterally, intracisternally, vnutrivaginalno, administered intraperitoneally, locally (powders, ointments or drops), buccal, in the form of oral or nasal spray, or the like, depending on severity of infection that should be treated. In accordance with some variants of implementation, the compounds according to the invention can be administered orally or parenterally what about at a dose from about 0.01 mg/kg to about 50 mg/kg and preferably, from about 1 mg/kg to about 25 mg/kg, per body weight of the patient per day, once or several times per day, to achieve the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in this field, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, glycols and sorbitane esters of fatty acids, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants, such as wetting, emulsifying agents and suspendresume agents, sweeteners, flavorings and fragrances.

Injectable preparations, for example, sterile injectable aqueous or oily suspe the Ziya, can be obtained according to the prior art, using suitable dispersing agents or wetting and suspendresume agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable fillers and solvents that can be used are water, ringer's solution, according to the US Pharmacopoeia, and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as solvent or suspendida environment. For this purpose, can be used any tasteless non-volatile oils, including synthetic mono - or diglycerides. In addition, in preparations for injection use fatty acids such as oleic acid.

Injectable compositions can be sterilized, for example, by filtration through a retaining bacteria filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile environment for injection before use.

With the aim of prolonging the effect of the compounds according to the present invention, it is often desirable to slow the abs is rblu compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water-solubility. The absorption rate of the connection then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral forms introduced the connection will be terminated by dissolution or suspendirovanie compounds in the oil filler. Injectable forms depot is obtained by creating a matrix for microencapsulation connection from biorazlagaemykh polymers, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the specific polymer used, it is possible to control the rate of release of connection. Examples of other biorazlagaemykh polymers include poly(complex orthoevra) and poly(anhydrides). Injectable depot composition is also obtained by incorporating the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal injection are preferably suppositories which can be obtained by mixing the compounds according to this invention with suitable, does not cause irritation of the excipients or carriers such as cocoa butter, polietilen the Col or candle wax, which are solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, (C) humectants, such as glycerol, d) dezintegriruetsja agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) slow dissolving agents, such as paraffin, f) absorption accelerators such as Quaternary ammonium compounds, g) wetting, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the x of the mixture. In the case of capsules, tablets and pills dosage form may also include buferiruemoi agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like. Solid dosage forms as tablets, pills, capsules, pills and granules can be obtained with the applied coatings and shells, such as intersolubility shell or other coatings well known in the field of pharmaceutical preparations. They may not necessarily contain opalescent components and can also be of such composition that releases only the active ingredient (the active ingredients) or preferably in a particular part of the gastrointestinal tract, optionally, in a delayed manner. Examples of input structures, which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

The active compounds also can be the in microencapsulating form with one or more excipients, as specified above. Solid dosage forms as tablets, pills, capsules, pills and granules can be obtained with the applied coatings and shells, such as intersolubility shell, coating controlled-release and other coatings well known in the field of pharmaceutical preparations. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also include, as is the case in normal practice, additional substances other than inert diluents, such as, for tabletting lubricants and other excipients for tableting, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also include buferiruemoi agents. They may not necessarily contain opalescent components and can also be of such composition that releases only the active ingredient (the active ingredients) or preferably in a particular part of the gastrointestinal tract, optionally, in a delayed manner. Examples of input structures, which can be used include polymeric substances and waxes.

Dosage forms for local or transdermal in which edenia compounds according to the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, dosage forms for inhalation or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic composition, ear drops and eye drops are also considered as included in the scope of the present invention. Additionally, according to the present invention assumes the use of transdermal patches, which have the added advantage in relation to the implementation of controlled delivery of compounds into the body. Such dosage forms are produced by dissolution or distribution of the compound in a suitable medium. Can also be used amplifiers absorption to increase flow connection through the skin. Speed can be controlled, or by controlling the speed of the membrane or by dispersing the compound in a polymer matrix or gel.

As, in General, described above, the compounds according to the invention are useful as modulators of ABC transporters. So, not wanting to resort to any particular theory, the compounds and compositions are particularly useful in the treatment or alleviation of the severity of the diseases, conditions or disorders where hyperactivity or inactively ABC transporters the being is local to the disease, condition or violation. When hyperactivity or inactively ABC-Transporter involved in the particular disease, condition or violation of, the disease, condition or disorder can also be called as "mediated by the ABC Transporter disease, condition or disorder". Accordingly, according to another aspect, the present invention relates to a method of treating or alleviating the severity of the diseases, conditions or disorders where hyperactivity or inactively ABC-Transporter involved in a painful state.

The active compounds used according to the present invention as modulators of ABC Transporter may be determined in accordance with methods generally described in the field and in the examples of this specification.

You should also take into account that the compounds and pharmaceutically acceptable compositions according to the present invention can be used in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be introduced simultaneously with, before or after one or more other desired therapeutics or therapeutic procedures. The particular combination of therapies (therapeutic agent or procedure) for use in case of combined modes are chosen based on compatibility as emich therapeutics and/or procedures and the desired therapeutic effect. You should also take into account that in the case of therapies used, you can achieve desired effect for the same disorder (for example, proposed in the invention compound may be introduced concurrently with another agent used to treat the same disorder), or you can achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a specific disease or condition, known as "suitable for the disease or condition that is being treated."

According to one variant of implementation, the additional agent selected from a mucolytic agent, bronchodilatory agent, antibiotic, anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound according to the present invention, or food agent.

The amount of additional therapeutic agent in the compositions according to the present invention should be not more than the amount that should be generally introduced into the composition containing such a therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent disclosed in which x in the present compositions is from about 50% to 100%, in the calculation of the amount normally present in a composition containing such an agent as the sole therapeutically active agent.

Compounds according to the present invention or containing pharmaceutically acceptable compositions can be introduced into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular implants, stents and catheters. Accordingly, the present invention, in accordance with another aspect, relates to a composition for coating an implantable means including a connection according to the present invention, as described above, and according to the classes and subclasses specified in the description, and the media, which is suitable for coating the above implantable device. According to still another aspect, the present invention relates to implantable device coated when using the composition containing the compound according to the present invention, as described above, and according to the classes and subclasses specified in the description, and the media, which is suitable for coating the above implantable device. Suitable coatings and conventional receiving implantable devices coated with the coating described in the patents SSA, 5886026 and 5304121. Coatings are typically biocompatible polymeric materials, such as hydrogel polymer polymethylsiloxane, polycaprolactone, polyethylene glycol, polyacrylic acid, copolymer of ethylene and vinyl acetate, and mixtures thereof. The coating optionally can be further protected using a suitable applied top coating of Versiliana, polysaccharides, polyethylene glycol, phospholipids or combinations thereof, to impart the characteristics of a controlled release composition.

Another aspect of the invention relates to the modulation of the activity of the ABC Transporter in a biological sample or in a patient (e.g., in vitro or in vivo) method, which includes the introduction of the patient or contact with the above-mentioned biological sample compounds of formula (I) or a composition containing the above compound. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts of them.

Modulation of the activity of the ABC-Transporter, for example, CFTR, in a biological sample suitable for a variety of purposes that are known to the specialist in this area is. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena and comparative evaluation of new modulators of ABC transporters.

According to another another variant implementation, the method of modulation of the activity of anion channel in vitro or in vivo, provides for the inclusion of a stage of contacting the above-mentioned channel with a compound of formula (I). According to preferred variants of implementation, the anion channel is a chloride channel or a bicarbonate channel. According to another preferred options for implementation, the anion channel is a chloride channel.

According to alternative implementation, the present invention relates to a method of increasing the number of functional ABC transporters in the cell membrane, including the stage of contacting the above-mentioned cells with the compound of the formula (I). The term "functional ABC Transporter"as used in this description, means the ABC-Transporter, which has a transport activity. According to preferred variants of implementation, the above functional ABC Transporter CFTR is.

According to another preferred variant implementation, the activity of the ABC-Transporter is determined by measuring the transmembrane potential is and voltage. To measure the voltage potential across the membrane in a biological sample, you can use any of the known in the field of methods, such as optical analysis of transmembrane potential, or other electrophysiological methods.

In the case of optical analysis of transmembrane potential use potentialcustomers FRET sensors described by Gonzalez and Tsien (see J.E. Gonzalez and R.Y. Tsien “Voltage sensing by fluorescence resonance energy transfer in single celles”, Biophys. J.,69(4), 1272-1280 (1995); and J.E. Gonzalez and R.Y. Tsien “Improved indicators of cell membrane potential that use fluorescence energy transfer”, Chem. Biol.,4(4), 269-277 (1997)), in combination with the measuring apparatus for determining changes in fluorescence, such as the Voltage/Ion Probe Reader (VIPR) (see J.E. Gonzalez. K. Oades, et al., “Cell-based assays and instrumentation for screening ion-channel targets”, Drug Discov. Today,4(9), 431-439 (1999)).

Given potentialcustomers tests based on the change in resonant with fluorescence energy transfer (FRET) between membranectomy, potentialcustomers dye, DiSBAC2(3), and fluorescent phospholipid, CC2-DMPE, which is connected with an external "leaf" of the cytoplasmic membrane and acts as a FRET donor. Changes in transmembrane potential (Vmto cause a redistribution of the negatively charged DiSBAC2(3) in the cytoplasmic membrane and accordingly the amount of energy transmitted from 2DMPE. Changes in fluorescence emission can be controlled using the device VIPRTMII, which is an integrated liquid manipulator and fluorescent detector is designed to conduct-based cell screening using 96 - or 384-well titration microplate.

According to another aspect, the present invention relates to a kit for use in measuring the activity of a ABC Transporter or a fragment in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound of formula (I) or any of its above embodiments; and (ii) instructions for a) contacting the composition with the biological sample and b) measuring the activity of a ABC Transporter or a fragment. According to one variant of implementation, the kit further includes instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of the above ABC Transporter or a fragment in the presence of additional compounds; and (C) comparing the activity of the ABC Transporter in the presence of the additional compound with the density of the ABC Transporter in the presence of the compounds of formula (I). In preferred embodiments, the implementation of the set are used to determine the density of CFTR.

In order m is tenderly was fuller understanding of the invention, described in this description, the following examples. Assuming that these examples are for illustrative purposes only and may not be construed as limiting in any way the invention.

EXAMPLES

Example 1

General scheme for the acid components:

a) 140-150aboutWith; (b) PPA, POCl3, 70°C or diphenyl ether, 220aboutWith; (C) (i) 2n. NaOH ii) 2n. HCl.

A specific example

Diethyl ether 2-phenylaminopyrimidine acid

A mixture of aniline (25.6 g, 0.28 mol) and diethyl-2-(ethoxymethylene)malonate (62,4 g, 0.29 mol) is heated at a temperature of 140-150°C for 2 hours. The mixture is cooled to room temperature and dried under reduced pressure, getting diethyl ether 2-phenylaminopyrimidine acid in the form of a solid substance, which is used in the next stage without further purification.

1H NMR (d-DMSO) δ 11,00 (d, 1H), 8,54 (d, J=13,6 Hz, 1H), was 7.36-7,39 (m, 2H), 7,13-7,17 (m, 3H), 4,17-to 4.33 (m, 4H), 1,18-of 1.40 (m, 6H).

Ethyl ester of 4-hydroxyquinolin-3-carboxylic acid

In a three-neck flask with a capacity of 1 l, equipped with a mechanical stirrer, make diethyl ether 2-phenylaminopyrimidine acid (26,3 g, 0.1 mol), polyphosphoric acid (270 g) and phosphorylchloride (750 g). The mixture is heated at a temperature of about 70°C is stirred for 4 hours. The mixture is cooled to room temperature and filtered. The residue is treated with an aqueous solution of Na2CO3, filtered, washed with water and dried. Ethyl ester of 4-hydroxyquinolin-3-carboxylic acid obtained as a pale brown solid (15.2 g, yield 70%). The crude product used in the next stage without further purification.

A-1; 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid

Ethyl ester of 4-hydroxyquinolin-3-carboxylic acid (15 g, 69 mmol) suspended in sodium hydroxide solution (2n., 150 ml) and stirred for 2 hours at boiling temperature under reflux. After cooling, the mixture is filtered and the filtrate is acidified to pH=4 2n. HCl solution. The obtained precipitate was separated by filtration, washed with water and dried in vacuum, obtaining 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-1in the form of a dull white solid (10.5 g, yield 92%).

1H NMR (d-DMSO) δ 15,34 (s, 1H), 13,42 (s, 1H), 8,89 (s, 1H), 8,28 (d, J=8.0 Hz, 1H), 7,88 (m, 1H), 7,81 (d, J=8,4 Hz, 1H), 7,60 (m, 1H).

A specific example

A-2; 6-Fluoro-4-hydroxyquinolin-3-carboxylic acid

6-Fluoro-4-hydroxyquinolin-3-carboxylic acid (A-2) synthesized following the General scheme above, on the basis of 4-ftorhinolona. Total yield (53%).

1H-NMR (DMSO-d6): δ 15,2 (USS,1H), 8,89 (s, 1H), 7,93-a 7.85 (m, 2H), 7,80-7,74 (m, 1H).

ESI-MS: 207,9 m/z (MH+).

Example 2

2-Bromo-5-methoxybenzylamine

A mixture of 1-bromo-4-methoxy-2-nitrobenzene (10 g, 43 mmol) and Raney Nickel (5 g) in ethanol (100 ml) is stirred in hydrogen atmosphere (1 ATM.) for 4 hours at room temperature. The Raney Nickel is filtered off and the filtrate is concentrated under reduced pressure. The obtained solid is purified column chromatography, obtaining 2-bromo-5-methoxybenzylamine (7.5 g, yield 86%).

Diethyl ether 2-[(2-bromo-5-methoxybenzylamine)methylene]malonic acid

A mixture of 2-bromo-5-methoxybenzylamine (540 mg, of 2.64 mmol) and diethyl-2-(ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at 100°C for 2 hours. After cooling, the reaction mixture is recrystallized from methanol (10 ml)to give diethyl ether 2-[(2-bromo-5-methoxybenzylamine)methylene]malonic acid as a yellow solid (0.8 g, yield 81%).

Ethyl ester of 8-bromo-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Diethyl ether 2-[(2-bromo-5-methoxybenzylamine)methylene]malonic acid (9 g, and 24.2 mmol) is slowly added to polyphosphoric acid (30 g) at a temperature of 120°C. the Mixture is stirred at this temperature for 30 minutes and then cooled to room temp the atmospheric temperature. Add absolute ethanol (30 ml) and the resulting mixture is refluxed for 30 minutes. The mixture is alkalinized with an aqueous solution of sodium bicarbonate at a temperature of 25°C and extracted with EtOAc (4 x 100 ml). The organic layers are combined, dried and the solvent is evaporated, obtaining the ethyl ester of 8-bromo-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.3 g, 30%yield).

Ethyl ester of 5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A mixture of ethyl ester of 8-bromo-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.3 g, 7.1 mmol), sodium acetate (580 mg, 7.1 mmol) and 10%Pd/C (100 mg) in glacial acetic acid (50 ml) is stirred in hydrogen atmosphere (2.5 ATM.) throughout the night. The catalyst was removed by filtration and the reaction mixture is concentrated under reduced pressure. The resulting oil was dissolved in CH2Cl2(100 ml) and washed with aqueous sodium bicarbonate solution and water. The organic layer is dried, filtered and concentrated. The crude product is purified column chromatography, obtaining the ethyl ester of 5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a yellow solid (1 g, yield 57%).

A-4; 5-Methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A mixture of ethyl ester of 5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1 g, 7.1 mmol) in 10%-but the solution of NaOH (50 ml) is refluxed overnight and then cooled to room temperature. The mixture is extracted with diethyl ether. The aqueous phase is separated and acidified with concentrated HCl to pH=1-2. The obtained precipitate was separated by filtration, receiving 5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-4)(530 mg, yield 52%).

1H-NMR (DMSO) δ 15,9 (s, 1H), 13,2 (user., 1H), 8,71 (s, 1H), 7,71 (t, J=8,1 Hz, 1H), 7,18 (d, J=8,4 Hz, 1H), PC 6.82 (d, J=8,4 Hz, 1H), 3,86 (s, 3H).

ESI-MS: 219,9 m/z (MH+).

Example 3

Diethyl ether sodium salt of 2-(mercaptopropionate)malonic acid

To a suspension of NaH (60%in mineral oil, 6 g, 0.15 mol) in Et2O at room temperature is added dropwise, within 30 minutes, ethylmalonate (24 g, 0.15 mol). Then added dropwise phenylisothiocyanate (20,3 g, 0.15 mol) under stirring for 30 minutes. The mixture is refluxed for 1 hour and then stirred overnight at room temperature. The solid is separated, washed with anhydrous diethyl ether (200 ml) and dried in vacuum, obtaining diethyl ether sodium salt of 2-(mercaptopropionate)malonic acid as a pale yellow powdery substance (46 g, yield 97%).

Diethyl ether 2-(methylsulfonylmethane)malonic acid

Within 30 minutes, added dropwise methyliodide (17,7 g, 125 mmol) to a solution of diethyl ether sodium is salt-2-(mercaptopropionate)malonic acid (33 g, 104 mmol) in DMF (100 ml), cooled in an ice bath. The mixture is stirred at room temperature for 1 hour and then poured into ice water (300 ml). The obtained solid substance was separated by filtration, washed with water and dried, obtaining the diethyl ester of 2-(methylsulfonylmethane)malonic acid as a pale yellow solid (27 g, yield 84%).

Ethyl ester of 4-hydroxy-2-methylsulfonylamino-3-carboxylic acid

A mixture of diethyl ether 2-(methylsulfonylmethane)malonic acid (27 g, 87 mmol) in 1,2-dichlorobenzene (100 ml) is refluxed for 1.5 hours. The solvent is removed under reduced pressure and the oily residue is treated with hexane, obtaining a pale yellow solid, which was purified preparative HPLC, obtaining the ethyl ester of 4-hydroxy-2-methylsulfonylamino-3-carboxylic acid (8 g, yield 35%).

A-16; 2-Methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Ethyl ester of 4-hydroxy-2-methylsulfonylamino-3-carboxylic acid (8 g, 30 mmol) is refluxed in a solution of NaOH (10%, 100 ml) for 1.5 hours. After cooling, the mixture is acidified with concentrated HCl to pH=4. The obtained solid substance was separated by filtration, washed with water (100 ml) and Meon (100 ml)to give 2-methylsulfanyl-4-oxo-1,-dihydroquinoline-3-carboxylic acid ( A-16) as a white solid (6 g, yield 85%).

1H-NMR (CDCl3) δ 16,4 (users, 1H), 11,1 (users, 1H), 8,19 (l,

J=8 Hz, 1H), with 8.05 (d, J=8 Hz, 1H), to 7.84 (t, J=8, 8 Hz, 1H), 7,52 (t, J=8 Hz, 1H), 2,74 (s, 3H).

ESI-MS: 235,9 m/z (MH+).

Example 4

a) PPh3Et3N, CCl4, CF3CO2H; (b) diethylmalonate; (C) T~200OC; d) 10% NaOH.

2,2,2-Cryptor-N-phenylacetonitrile

The mixture Ph3P (138,0 g, 526 mmol), Et3N (21,3 g, 211 mmol), CCl4(170 ml) and TFOC (20 g, 175 mmol) is stirred for 10 minutes in an ice bath. Add aniline (19.6 g, 211 mmol), dissolved in CCl4(20 ml). The mixture is stirred at the boiling point under reflux for 3 hours. The solvent is removed in vacuum and add hexane. Precipitation (Ph3PO and Ph3P) is filtered and washed with hexane. The filtrate is distilled under reduced pressure, getting 2,2,2-Cryptor-N-phenylacetonitrile (19 g), which is used in the next stage without further purification.

Diethyl ether 2-(2,2,2-Cryptor-1-phenyliminomethyl)malonic acid

To a suspension of NaH (3,47 g, 145 mmol, 60%in mineral oil) in THF (200 ml) add diethylmalonate (18.5 g, 116 mmol) at 0°C. the Mixture is stirred for 30 minutes at this temperature and added dropwise 2,2,2-Cryptor-N-phenylacetonitrile (19 g, 92 mmol) at a temperature of 0 is C. The reaction mixture was left to warm to room temperature and stirred over night. The mixture was diluted with CH2Cl2, washed with saturated sodium bicarbonate solution and saturated salt solution. The combined organic layers dried over Na2SO4filter and concentrate, receiving diethyl ether 2-(2,2,2-Cryptor-1-phenyliminomethyl)of malonic acid, which is used directly in the next stage without further purification.

Ethyl ester of 4-hydroxy-2-trifloromethyl-3-carboxylic acid

Diethyl ether 2-(2,2,2-Cryptor-1-phenyliminomethyl)of malonic acid is heated at a temperature of 210°C for 1 hour with continuous stirring. The mixture was purified column chromatography (petroleum ether)to give ethyl ester of 4-hydroxy-2-trifloromethyl-3-carboxylic acid (12 g, yield 24% for stage 3).

A-15; 4-Hydroxy-2-trifloromethyl-3-carboxylic acid

A suspension of ethyl ester of 4-hydroxy-2-trifloromethyl-3-carboxylic acid (5 g, 17.5 mmol) in 10%aqueous solution of NaOH is refluxed for 2 hours. After cooling, add dichloromethane, the aqueous phase is separated and acidified with concentrated HCl to pH=4. The obtained precipitate was separated by filtration, washed with water and Et2O, receiving 4-hydroxy-2-trifloromethyl the-3-carboxylic acid ( A-15) (3.6 g, yield 80%).

1H-NMR (DMSO-d6) δ 8,18-8,21 (d, J=7.8 Hz, 1H), 7,92-7,94 (d, J=8,4 Hz, 1H), 7,79-7,83 (t, J=14,4 Hz, 1H), 7,50-7,53 (t, J=15 Hz, 1H).

ESI-MS: 257,0 m/z (MH+).

Example 5

a) CH3C(O)ONH4, toluene; b) EtOCHC(CO2Et)2, 130OC; c) Ph2O; d) I2, EtOH; (e) NaOH.

3-Aminocyclopent-2-Aenon

A mixture of cyclohexane-1,3-dione (56,1 g, 0.5 mol) and AcONH4(38,5 g, 0.5 mol) in toluene is refluxed for 5 hours using the unit Dean-stark. The obtained oily layer is separated and concentrated under reduced pressure, obtaining 3-aminocyclopent-2-northward (to 49.9 g, yield 90%), which is used directly in the next stage without further purification.

Diethyl ether 2-[(3-oxocyclohexa-1 enylamine)methylene]malonic acid

A mixture of 3-aminocyclopent-2-Aenon (3,3 g, 29.7 mmol) and diethyl-2-(ethoxymethylene)malonate (6.7 g, and 31.2 mmol) is stirred at a temperature of 130°C for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil purified column chromatography (silica gel, ethyl acetate)to give diethyl ether 2-[(3-oxocyclohexa-1 enylamine)methylene]malonic acid (7.5 g, yield 90%).

Ethyl ester of 4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid

A mixture of diethyl ether 2-[(3-oxocyclohexa-1-eniami is about)methylene]malonic acid (2.8 g, 1 mmol) and diphenyl ether (20 ml) is refluxed for 15 minutes. After cooling, add n-hexane (80 ml). The obtained solid substance produce by filtration and recrystallized from methanol, obtaining the ethyl ester of 4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (1.7 g, yield 72%).

Ethyl ester of 5-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

To a solution of ethyl ester of 4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (1.6 g, 6.8 mmol) in ethanol (100 ml) is added iodine (4.8 g, 19 mmol). The mixture is refluxed for 19 hours and then concentrated under reduced pressure. The obtained solid is washed with ethyl acetate, water and acetone and then recrystallized from DMF, obtaining the ethyl ester of 5-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (700 mg, yield 43%).

A-3; 5-Hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A mixture of ethyl ester 5-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (700 mg, 3 mmol) in 10%NaOH solution (20 ml) is refluxed overnight. After cooling, the mixture is extracted with diethyl ether. The aqueous phase is separated and acidified with concentrated HCl to pH=1-2. The obtained precipitate was separated by filtration, receiving 5-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic Ki the lot ( A-3) (540 mg, yield 87%).

1H-NMR (DMSO-d6) δ 13,7 (user., 1H), 13,5 (user., 1H), and 12.6 (s, 1H), 8,82 (s, 1H), 7,68 (t, J=8,1 Hz, 1H), 7,18 (d, J=8,4 Hz, 1H), PC 6.82 (d, J=8,4 Hz, 1H).

ESI-MS: 205,9 m/z (MH+).

Example 6

a) POCl3; (b) MeONa; (C) n-BuLi, ClCO2Et; (d) NaOH.

2,4-Dichlorphenol

A suspension of quinoline-2,4-diol (15 g, of 92.6 mmol) in POCl3refluxed for 2 hours. After cooling, the solvent is removed under reduced pressure, obtaining 2,4-dichlorphenol, which is used without further purification.

2,4-Dimethoxyaniline

To a suspension of 2,4-dichlorohydrin in the Meon (100 ml) is added sodium methoxide (50 g). The mixture is refluxed for 2 days. After cooling, the mixture is filtered. The filtrate is concentrated under reduced pressure, obtaining a residue which is dissolved in water and extracted with CH2Cl2. The combined organic layers dried over Na2SO4and concentrate, receiving 2,4-dimethoxyaniline in the form of a white solid (13 g, yield 74% over 2 stages).

2,4-Dimethoxyaniline-3-ethylcarboxylate

To a solution of 2,4-dimethoxyaniline (11.5g, of 60.8 mmol) in anhydrous THF are added dropwise n-BuLi (2.5m solution in hexane, to 48.6 ml, 122 mmol) at 0°C. After stirring for 1.5 hours at a temperature of 0°C. the mixture was added to a solution of atichart is Miata in anhydrous THF, then stirred at 0°C for 30 minutes and then at room temperature overnight. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer is dried over Na2SO4and concentrated in vacuo. The resulting residue is purified column chromatography (petroleum ether/EtOAc=50/1)to give 2,4-dimethoxyaniline-3-ethylcarboxylate (9.6 g, yield 60%).

A-17; 2,4-Dimethoxyaniline-3-carboxylic acid

2,4-Dimethoxyaniline-3-ethylcarboxylate (1.5 g, 5.7 mmol) is refluxed in a solution of NaOH (10%, 100 ml) for 1 hour. After cooling, the mixture is acidified with concentrated HCl to pH=4. The obtained precipitate was separated by filtration and washed with water and diethyl ether, receiving 2,4-dimethoxyaniline-3-Karmanovo acid (A-17) as a white solid (670 mg, yield 50%).

1H-NMR (CDCl3) δ 8,01-of 8.04 (d, J=12 Hz, 1H), 7,66-7,76 (m, 2H), 7,42-7,47 (t, J=22 Hz, 2H), 4.09 to (s, 3H), of 3.97 (s, 3H).

ESI-MS: 234,1 m/z (MH+).

Commercially available acid
AcidName
A-56,8-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A-66-[(4-forfinal)methylsulfanyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-76-(4-methylpiperidin-1-sulfonyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-84-oxo-6-(pyrrolidin-1-sulfonyl)-1,4-dihydroquinoline-3-carboxylic acid
A-106-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-116 ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-124-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid
A-137-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-144-oxo-5,7-bistritei-1,4-dihydroquinoline-3-carboxylic acid
A-201-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-211-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
<> A-221,6-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-231-ethyl-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-246-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Amine components

N-1-Substituted 6-aminoindoles

Example 1

The General scheme:

a) RX (X=Cl, Br, I), K2CO3, DMF or CH3CN; (b) H2Pd/C, EtOH or SnCl2·2H2O, EtOH.

A specific example

1-Methyl-6-nitro-1H-indol

To a solution of 6-nitroindole (of 4.05 g, 25 mmol) in DMF (50 ml) add K2CO3(8,63 g, 62.5 mmol) and MeI (5,33 g, 37.5 mmol). After stirring at room temperature overnight the mixture was poured into water and extracted with ethyl acetate. The combined organic layers dried over Na2SO4and concentrated in vacuo, obtaining the product 1-methyl-6-nitro-1H-indole (4.3 g, yield 98%).

In-1; 1-Methyl-1H-indol-6-ylamine

A suspension of 1-methyl-6-nitro-1H-indole (4.3 g, 24.4 mmol) and 10%Pd/C (0,43 g) in EtOH (50 ml) is stirred in hydrogen atmosphere (1 ATM.) at room temperature over night. After filtration the filtrate is concentrated and acidified with RA is tworoom HCl-Meon (4 mol/l), getting hydrochloride of 1-methyl-1H-indole-6-ylamine (In-1) (1,74 g, yield 49%) as a gray powder.

1H-NMR (DMSO-d6): δ 9,10 (s, 2H), 7,49(d, J=8,4 Hz, 1H), 7,28 (d, J=2.0 Hz, 1H), 7,15(s, 1H), at 6.84 (d, J=8,4 Hz, 1H), 6,38 (d, J=2,8 Hz, 1H), and 3.72 (s, 3H).

ESI-MS: 146,08 m/z (MH+).

Other examples

In-2; 1-Benzyl-1H-indol-6-ylamine

1-Benzyl-1H-indol-6-ylamine (In-2) synthesized following the General scheme presented above, based on 6-nitroindole and benzylbromide. Total yield (~40%). HPLC: retention time 2,19 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 223,3 m/z (MH+).

B-3; 1-(6-Aminoindan-1-yl)alanon

1-(6-Aminoindan-1-yl)alanon (B-3) synthesized following the General scheme presented above, based on 6-nitroindole and acetylchloride. Total yield (~40%). HPLC: retention time of 0.54 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 175,1 m/z (MH+).

Example 2

Ethyl ester {[2-(tert-butoxycarbonylmethylene)acetyl]methylamino}acetic acid

To a stirred solution of (tert-butoxycarbonylmethylene)acetic acid (37 g, 0.2 mol) and Et3N (60,6 g, 0.6 mol) in CH2Cl2(300 ml) added dropwise isobutylparaben (27,3 g, 0.2 mmol) at -20°C in argon atmosphere. After the remesiana for 0.5 hours added dropwise hydrochloride ethyl ester methylaminoethanol acid (30.5 g, 129 mmol) at -20°C. the Mixture is left to warm to room temperature (about 1 hour) and quenched with water (500 ml). The organic layer is separated, washed with 10%citric acid solution, dried over Na2SO4filter and concentrate. The residue is purified column chromatography (petroleum ether/EtOAc=1:1)to give ethyl ester {[2-(tert-butoxycarbonylmethylene)acetyl]methylamino}acetic acid (12.5 g, yield 22%).

{[2-(tert-Butoxycarbonylmethylene)acetyl]methylamino}acetic acid

A suspension of ethyl ester {[2-(tert-butoxycarbonylmethylene)acetyl]methylamino}acetic acid (12.3 g, and 42.7 mmol) and LiOH (8,9 g, 214 mmol) in N2O (20 ml) and THF (100 ml) is stirred over night. The volatile solvent is removed in vacuum and the residue extracted with diethyl ether (2 times 100 ml). The aqueous phase is acidified to pH=3 with diluted HCl solution and then extracted with CH2Cl2(2 x 300 ml). The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrated in vacuo, obtaining {[2-(tert-butoxycarbonylmethylene)acetyl]methylamino}acetic acid as a colorless oil (10 g, yield 90%).

1H-NMR (CDCl3): δ 7,17 (USS, 1H), 4,14-Android 4.04 (m, 4H), 3.04 from-is 2.88 (m, 6H), 1,45-of 1.41 (m, 9H).

ESI-MS: 282,9 m/z (M+Na+).

tert-Butyl methyl ether({methyl[2-(6-nitroindole-1-yl)--oxoethyl]carbarnoyl}methyl)carbamino acid

To a mixture of {[2-(tert-butoxycarbonylmethylene)acetyl]methylamino}acetic acid (13.8 g, 53 mmol) and TFFH (21,0 g, 79.5 mmol) in anhydrous THF (125 ml) is added DIEA (27.7 ml, 159 mmol) at room temperature under nitrogen atmosphere. The solution was stirred at room temperature for 20 minutes, Add a solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 ml) and the reaction mixture is heated at 60°C for 18 hours. The solvent is evaporated and the crude mixture redistribute between EtOAc and water. The organic layer was separated, washed with water (3 times), dried over Na2SO4and concentrate. Then add diethyl ether and EtOAc. The obtained solid substance was separated by filtration, washed with diethyl ether and dried in the air, getting tert-butyl methyl ether({methyl[2-(6-nitroindole-1-yl)-2-oxoethyl]carbarnoyl}methyl)carbamino acid (6.42 per g, 30%yield).

1H-NMR (400 MHz, DMSO-d6) δ of 1.37 (m, 9H), 2,78 (m, 3H), 2.95 points (d, J=1.5 Hz, 1H), 3,12 (d, J=2.1 Hz, 2H), 4,01 (d, J=13,8 Hz, 0,6H), 4,18 (d, J=12.0 Hz, 1,4H), to 4.92 (d, J=3,4 Hz, 1,4H), to 5.08 (d, J=11,4 Hz, 0,6H), 7,03 (m, 1H), of 7.90 (m, 1H), 8,21 (m, 1H), 8,35 (d, J=3.8 Hz, 1H), 9,18 (m, 1H).

HPLC: retention time of 3.12 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: to 405.5 m/z (MH+).

In-26; tert-Butyl ether ({[2-(6-aminoindan-1-yl)-2-oxoethyl]methylcarbamoyl}methyl)methylcarbamate acid

A mixture of tert-butyl methyl ether({methyl[2-(6-neither is Rondal-1-yl)-2-oxoethyl]carbarnoyl}methyl)carbamino acid (12.4 g, of 30.6 mmol), SnCl2·2H2O (34,5 g, 153,2 mmol) and DIEA (74,8 ml, 429 mmol) in ethanol (112 ml) is heated at 70°C for 3 hours. Add water and EtOAc and the mixture is filtered through a small layer of celite. The organic layer is separated, dried over Na2SO4and concentrate, receiving tert-butyl ether ({[2-(6-aminoindan-1-yl)-2-oxoethyl]methylcarbamoyl}methyl)methylcarbamate acid (In-26) (11.4 g, quantitative yield).

HPLC: retention time 2,11 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 375,3 m/z (MH+).

2-Substituted 6-aminoindoles

Example 1

B-4-a; Hydrochloride (3-nitrophenyl)hydrazine

3-Nitrophenylamino (of 27.6 g, 0.2 mol) is dissolved in a mixture of N2O (40 ml) and 37%HCl solution (40 ml). Add a solution of NaNO2(13.8 g, 0.2 mol) in N2O (60 ml) at 0°C, then SnCl2·H2O (135,5 g, 0.6 mol) in 37%HCl solution (100 ml) at the same temperature. After stirring at 0°C for 0.5 hour, the solid is allocate by filtration and washed with water, getting hydrochloride (3-nitrophenyl)hydrazine (In-4-) (27,6 g, yield 73%).

Ethyl ester of 2-[(3-nitrophenyl)hydrazono]propionic acid

Hydrochloride (3-nitrophenyl)hydrazine (In-4-) (30,2 g, 0.16 mol) and ethyl ester of 2-oxopropanoic acid (22,3 g at 0.19 mol) is dissolved is ethanol (300 ml). The mixture is stirred at room temperature for 4 hours. The solvent is evaporated under reduced pressure, obtaining the ethyl ester of 2-[(3-nitrophenyl)hydrazono]propionic acid, which is used directly in the next stage.

B-4-b; Ethyl ester 4-nitro-1H-indole-2-carboxylic acid and ethyl ester of 6-nitro-1H-indole-2-carboxylic acid

Ethyl ester of 2-[(3-nitrophenyl)hydrazono]propionic acid obtained in the preceding stage, dissolved in toluene (300 ml). Add the PPA (30 g). The mixture is refluxed overnight and then cooled to room temperature. The solvent is removed, obtaining a mixture of ethyl ester 4-nitro-1H-indole-2-carboxylic acid and ethyl ester of 6-nitro-1H-indole-2-carboxylic acid (B-4-b) (15 g, yield 40%).

B-4; 2-Methyl-1H-indol-6-ylamine

To a suspension of LiAlH4(7,8 g, 0.21 mol) in THF (300 ml) added dropwise a mixture of ethyl ester 4-nitro-1H-indole-2-carboxylic acid and ethyl ester of 6-nitro-1H-indole-2-carboxylic acid (B-4-b) (6 g, of 25.7 mmol) in THF (50 ml) at 0°C in an atmosphere of nitrogen. The mixture is refluxed overnight and then cooled to a temperature of 0°C. To this mixture N2(7.8 ml) and 10%NaOH solution (7.8 ml) at 0°C. the Insoluble solid is removed by filtration. Fil is Rath dried over Na 2SO4filter and concentrate under reduced pressure. The crude residue is purified column chromatography, obtaining 2-methyl-1H-indol-6-ylamine (B-4) (0.3 g, yield 8%).

1H-NMR (CDCl3): δ EUR 7.57 (USS,; 1H), 7,27 (d, J=8,8 Hz, 1H), 6,62 (s, 1H), 6,51-6,53 (m, 1H), 6,07 (s, 1H), 3,59-3,25 (USS, 2H), is 2.37 (s, 3H).

ESI-MS: of 147.2 m/z (MH+).

Example 2

6-Nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid

A mixture of ethyl ester 4-nitro-1H-indole-2-carboxylic acid and ethyl ester of 6-nitro-1H-indole-2-carboxylic acid (B-4-b) (0.5 g, 2,13 mmol) in 10%NaOH solution (20 ml) is refluxed overnight and then cooled to room temperature. The mixture is extracted with diethyl ether. The aqueous phase is separated and acidified with HCl to pH=1-2. The obtained solid substance produce by filtration, obtaining a mixture of 6-nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid (0.3 g, yield 68%).

Amide 6-nitro-1H-indole-2-carboxylic acid and amide 4-nitro-1H-indole-2-carboxylic acid

A mixture of 6-nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid (12 g, 58 mmol) and SOCl2(50 ml, 64 mmol) in benzene (150 ml) is refluxed for 2 hours. The benzene and excess SOCl2removed under reduced davlantes dissolved in CH 2Cl2(250 ml). Added dropwise NH4OH (21,76 g, 0.32 mol) at 0°C. the Mixture is stirred at room temperature for 1 hour. The obtained solid substance produce by filtration, obtaining the crude mixture of amide 6-nitro-1H-indole-2-carboxylic acid and amide 4-nitro-1H-indole-2-carboxylic acid (9 g, yield 68%), which is used directly in the next stage.

6-Nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile

A mixture of amide 6-nitro-1H-indole-2-carboxylic acid and amide 4-nitro-1H-indole-2-carboxylic acid (5 g, 24 mmol) dissolved in CH2Cl2(200 ml). Add Et3N (24,24 g, 0.24 mol), then (CF3CO)2O (51,24 g, 0.24 mol) at room temperature. The mixture is stirred for 1 hour and poured into water (100 ml). The organic layer is separated. The aqueous layer was extracted with EtOAc (3 x 100 ml). The combined organic layers dried over Na2SO4filter and concentrate under reduced pressure. The crude residue is purified column chromatography, obtaining a mixture of 6-nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile (2.5 g, yield 55%).

B-5; 6-Amino-1H-indole-2-carbonitrile

A mixture of 6-nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile (2.5 g, a 13.4 mmol) and Raney Nickel (500 mg) in EtOH (50 ml) was stirred at room temperature in the atmosphere is e hydrogen (1 ATM.) within 1 hour. The Raney Nickel is filtered off. The filtrate is evaporated under reduced pressure and purified column chromatography, obtaining 6-amino-1H-indole-2-carbonitrile (B-5) (1 g, yield 49%).

1H-NMR (DMSO-d6): δ was 12.75 (USS, 1H), 7,82 (d, J=8 Hz, 1H), EUR 7.57 (s, 1H), 7,42 (s, 1H), 7,15 (l,J=8 Hz, 1H).

ESI-MS: 158,2 m/z (MH+).

Example 3

2,2-Dimethyl-N-o-tolylpropan

To a solution of o-tolylamino (21,4 g, 0.20 mol) and Et3N (of 22.3 g, 0.22 mol) in CH2Cl2add 2,2-dimethylpropionic (25,3 g, 0.21 mol) at 10°C. the Mixture is stirred over night at room temperature, washed with aqueous solution of HCl (5%, 80 ml), a saturated solution of NaHCO3and saturated salt solution, dried over Na2SO4and concentrated in vacuo, getting 2,2-dimethyl-N-o-tripropionin (35,0 g, yield 92%).

2-tert-Butyl-1H-indol

To a solution of 2,2-dimethyl-N-o-Tripropylamine (30.0 g, 159 mmol) in anhydrous THF (100 ml) was added dropwise n-BuLi (2.5 M in hexane, 190 ml) at a temperature of 15°C. the Mixture is stirred overnight at a temperature of 15°C, cooled in water bath with ice and treated with a saturated solution of NH4Cl. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2 SO4, filtered and concentrated in vacuo. The residue is purified column chromatography, obtaining 2-tert-butyl-1H-indole (23,8 g, yield 88%).

2-tert-Butyl-2,3-dihydro-1H-indol

To a solution of 2-tert-butyl-1H-indole (5.0 g, 29 mmol) in Asón (20 ml) is added NaBH4at 10°C. the Mixture is stirred for 20 min at 10°C, treated dropwise N2About under ice cooling and extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4, filtered and concentrated in vacuo, obtaining a mixture of original substances, and 2-tert-butyl-2,3-dihydro-1H-indole (4.9 g), which is used directly in the next stage.

2-tert-Butyl-6-nitro-2,3-dihydro-1H-indol

To a solution mixture of 2-tert-butyl-2,3-dihydro-1H-indole and 2-tert-butyl-1H-indole (9.7 g) in H2SO4(98%, 80 ml) is added slowly KNO3(5.6 g, and 55.7 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 1 hour, gently poured on crushed ice, alkalinized Na2CO3to pH~8 and extracted with ethyl acetate. The combined extracts washed with saturated salt solution, dried over anhydrous Na2SO4and concentrated in vacuo. The residue is purified column chromatography, obtaining 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (4.0 g, yield 32% over 2 stages).

2-Tr is t-Butyl-6-nitro-1H-indol

To a solution of 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (2.0 g, 9.1 mmol) in 1,4-dioxane (20 ml) was added DDQ at room temperature. After boiling under reflux for 2.5 hours the mixture is filtered and the filtrate concentrated in vacuo. The residue is purified column chromatography, obtaining 2-tert-butyl-6-nitro-1H-indole (1.6 g, yield 80%).

B-6; 2-tert-Butyl-1H-indol-6-ylamine

To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in Meon (10 ml) was added Raney Nickel (0.2 g). The mixture is stirred at room temperature in hydrogen atmosphere (1 ATM.) within 3 hours. The resulting mixture was filtered and the filtrate concentrated. The residue is washed with petroleum ether, receiving 2-tert-butyl-1H-indol-6-ylamine (B-6) (1.0 g, yield 89%).

1H-NMR (DMSO-d6) δ 10,19 (s, 1H), 6,99 (d, J=8,1 Hz, 1H), 6,46 (s, 1H), and 6.25 (DD, J=1,8, 8,1 Hz, 1H), 5,79 (d, J=1.8 Hz, 1H), to 4.52 (s, 2H), 1,24 (s, 9H).

ESI-MS: 189,1 m/z (MH+).

3-Substituted 6-aminoindoles

Example 1

N-(3-Nitrophenyl)-N'-proprietarytrading

A solution of sodium hydroxide (10%, 15 ml) is added slowly to a stirred suspension of the hydrochloride (3-nitrophenyl)hydrazine (In-4-) (1.89 g, 10 mmol) in ethanol (20 ml) to achieve pH=6. To the mixture is added acetic acid (5 ml), then propionic aldehyde (0.7 g, 12 mmol). After stirring for 3 hours at to the room temperature the mixture was poured into ice water and the precipitate are filtered, washed with water and dried in the air, receiving N-(3-nitrophenyl)-N'-proprietarytrading, which is used directly in the next stage.

3-Methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indol

A mixture of N-(3-nitrophenyl)-N'-proprietarytrading dissolved in 85%H3RHO4(20 ml), and toluene (20 ml) is heated at a temperature of 90-100°C for 2 hours. After cooling, the toluene is removed under reduced pressure. The oil obtained is alkalinized 10%NaOH solution to pH=8. The aqueous layer was extracted with EtOAc (3 x 100 ml). The combined organic layers are dried, introit and concentrated under reduced pressure, obtaining a mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (1.5 g, yield 86% over two stages), which is used directly in the next stage.

In-7; 3-Methyl-1H-indol-6-ylamine

A mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (3 g, 17 mol) and 10%Pd/C (0.5 g) in ethanol (30 ml) is stirred overnight in a hydrogen atmosphere (1 ATM.) at room temperature. Pd/C is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified column chromatography, obtaining 3-methyl-1H-indol-6-ylamine (In-7) (0.6 g, yield 24%).

1H-NMR (CDCl3): δ to 7.59 (USS, 1H), 7,34 (l, J=8.0 Hz, 1H), 6,77 (s, 1H), only 6.64 (s, 1H), to 6.57 (m, 1H), 3,57 (USS, 2H), 2,28 (s, 3H).

ESI-MS: of 147.2 m/z (MH+).

Example 2

6-Nitro-1H-indol-3-carbonitril

To a solution of 6-nitroindole (a 4.86 g, 30 mmol) in DMF (24.3 ml) and CH3CN (243 ml) was added dropwise a solution of ClSO2NCO (5 ml, 57 mmol) in CH3CN (39 ml) at 0°C. After complete addition, the reaction mixture is left to warm to room temperature and stirred for 2 hours. The mixture is then poured into ice water, alkalinized with saturated solution of NaHCO3to pH=7-8 and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over Na2SO4and concentrate, getting 6-nitro-1H-indol-3-carbonitrile (4.6 g, yield 82%).

In-8; 6-Amino-1H-indol-3-carbonitril

A suspension of 6-nitro-1H-indol-3-carbonitrile (4.6 g, 24.6 mmol) and 10%Pd/C (0,46 g) in EtOH (50 ml) is stirred in hydrogen atmosphere (1 ATM.) at room temperature over night. After filtration the filtrate is concentrated and the residue purified column chromatography (petroleum ether/EtOAc=3/1)to give 6-amino-1H-indol-3-carbonitrile (In-8) (1 g, yield 99%) as a pink powder.

1H-NMR (DMSO-d6): δ 11,51 (s, 1H), to 7.84 (d,J=the 2.4 Hz, 1H), 7,22 (l,J=and 8.4 Hz, 1H), 6,62 (s, 1H), 6,56 (l,J=and 8.4 Hz, 1H), 5,0 (s, 2H).

ESI-MS: 157,1 m/z (MH+).

Example 3

Dimethyl(6-nitro-1H-indol-3-ylmethyl)Amin

A solution of dimethylamine (25 g, 0.17 m is l) and formaldehyde (14.4 ml, 0.15 mol) in acetic acid (100 ml) is stirred at 0°C for 30 minutes To the resulting solution was added 6-nitro-1H-indole (20 g, 0.12 mol). After stirring for 3 days at room temperature the mixture was poured into 15%aqueous NaOH solution (500 ml) at 0°C. the Precipitate was separated by filtration and washed with water, getting dimethyl(6-nitro-1H-indol-3-ylmethyl)amine (23 g, yield 87%).

B-9-a; (6-Nitro-1H-indol-3-yl)acetonitrile

To a mixture of DMF (35 ml) and MeI (74,6 g of 0.53 mol) in water (35 ml) and THF (400 ml) is added dimethyl(6-nitro-1H-indol-3-ylmethyl)amine (23 g, 0,105 mol). Then the reaction mixture is refluxed for 10 minutes, add potassium cyanide (54.6 g, 0.84 mol) and the mixture continue to boil under reflux overnight. The mixture is then cooled to room temperature and filtered. The filtrate is washed with saturated salt solution (3 times 300 ml), dried over Na2SO4filter and concentrate. The residue is purified column chromatography, obtaining (6-nitro-1H-indol-3-yl)acetonitrile (B-9-a) (7.5 g, yield 36%).

In-9; (6-Amino-1H-indol-3-yl)acetonitrile

A mixture of (6-nitro-1H-indol-3-yl)acetonitrile (B-9-a) (1.5 g, to 74.5 mmol) and 10%Pd/C (300 mg) in EtOH (50 ml) was stirred at room temperature in hydrogen atmosphere (1 ATM.) within 5 hours. Pd/C is removed by filtration and the filtrate volume is more, receiving (6-amino-1H-indol-3-yl)acetonitrile (In-9) (1.1 g, yield 90%).

1H-NMR (DMSO-d6): δ 10,4 (USS, 1H), 7,18 (d, J=8,4 Hz, 1H), 6,94 (s, 1H), of 6.52 (s, 1H), 6.42 per (DD, J=8,4, 1.8 Hz, 1H), amounts to 4.76 (s, 2H), 3,88 (s, 2H).

ESI-MS: 172,1 m/z (MH+).

Example 4

tert-Butyl ether [2-(6-nitro-1H-indol-3-yl)ethyl]carbamino acid

To a solution of (6-nitro-1H-indol-3-yl)acetonitrile (In-9) (8.6 g, 42.8 mmol) in anhydrous THF (200 ml) is added 2M solution of a complex of borane-dimethyl sulfide in THF (214 ml, 0.43 mol) at 0°C. the Mixture is refluxed overnight under nitrogen atmosphere. The mixture is then cooled to room temperature and add a solution of (BOC)2(14 g, 64,2 mmol) and Et3N (89,0 ml, 0.64 mol) in THF. The reaction mixture was allowed to mix overnight and then poured into ice water. The organic layer is separated and the aqueous phase extracted with EtOAc (3 x 200 ml). The combined organic layers washed with water and saturated salt solution, dried over Na2SO4filter and concentrate under reduced pressure. The crude product is purified column chromatography, obtaining tert-butyl ether [2-(6-nitro-1H-indol-3-yl)ethyl]carbamino acid (5 g, yield 38%).

10; tert-Butyl ether [2-(6-amino-1H-indol-3-yl)ethyl]carbamino acid

A mixture of tert-butyl methyl ether [2-(6-neither the ro-1H-indol-3-yl)ethyl]carbamino acid (5 g, 16.4 mmol) and Raney Nickel (1 g) in EtOH (100 ml) was stirred at room temperature in hydrogen atmosphere (1 ATM.) within 5 hours. The Raney Nickel is filtered off and the filtrate is evaporated under reduced pressure. The crude product is purified column chromatography, obtaining tert-butyl ether [2-(6-amino-1H-indol-3-yl)ethyl]carbamino acid (10) (3 g, yield 67;).

1H-NMR (DMSO-d6) δ 10,1 (users, 1H), 7,11, (d, J=8,4 Hz, 1H), 6,77-of 6.73 (m, 2H), 6,46 (d, J=1.5 Hz, 1H), 6,32 (DD, J=8,4, and 2.1 Hz, 1H), to 4.62 (s, 2H), 3,14-is 3.08 (m, 2H), 2,67-2,62 (m, 2H), of 1.35 (s, 9H).

ESI-MS: 275,8 m/z (MH+).

Example 5

The General scheme

a) RX (X=Br, I), triflate zinc, TBAI, DIEA, toluene; (b) H2, Raney Ni, EtOH or SnCl2·2H2O, EtOH.

A specific example

3-tert-Butyl-6-nitro-1H-indol

To a mixture of 6-nitroindole (1 g, 6, 2 mmol), zinc triflate (of 2.06 g, 5.7 mmol) and TBAI (1.7 g, 5,16 mmol) in anhydrous toluene (11 ml) is added DIEA (1.47 g, to 11.4 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 10 min at a temperature of 120°C, then add tert-butylbromide (0,707 g, 5,16 mmol). The resulting mixture was stirred for 45 min at a temperature of 120°C. the Solid is filtered off, the filtrate is concentrated to dryness and purified column chromatography on silica gel (petroleum ether/EtOAc=20:1), p is the best 3-tert-butyl-6-nitro-1H-indole as a yellow solid (0.25 g, yield 19%).

1H-NMR (CDCl3): δ 8,32 (d, J=2.1 Hz, 1H), 8,00 (DD, J=2,1, 14.4 Hz, 1H), a 7.85 (d, J=8.7 Hz, 1H), 7,25 (s, 1H), of 1.46 (s, 9H).

B-11; 3-tert-Butyl-1H-indol-6-ylamine

A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 13.7 mmol) and Raney Nickel (0.5 g) in ethanol was stirred at room temperature in hydrogen atmosphere (1 ATM.) within 3 hours. The catalyst is filtered off and the filtrate concentrated to dryness. The residue is purified column chromatography on silica gel (petroleum ether/EtOAc=4:1)to give 3-tert-butyl-1H-indol-6-ylamine (B-11) (2.0 g, yield 77,3%) as a gray solid.

1H-NMR (CDCl3): δ 7,58 (m, 2H), 6.73 x (d, J=1.2 Hz, 1H), 6,66 (s, 1H), to 6.57 (DD, J=0,8, 8.6 Hz, 1H), 3,60 (USS, 2H), of 1.42 (s, 9H).

Other examples

B-12; 3-Ethyl-1H-indol-6-ylamine

3-Ethyl-1H-indol-6-ylamine (B-12) synthesized following the General scheme above, on the basis of 6-nitroindole and ethylbromide. Total yield (42%).

HPLC: retention time of 1.95 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 161,3 m/z (MH+).

B-13; 3-Isopropyl-1H-indol-6-ylamine

3-Isopropyl-1H-indol-6-ylamine (B-13) synthesized following the General scheme above, on the basis of 6-nitroindole and isopropylidene. Total yield (17%).

HPLC: retention time of 2.06 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 175,2 m/z (MH+).

B-14; 3-sec-Butyl-1H-indol-6-ylamine

3-sec-Butyl-1H-indol-6-ylamine (B-14) synthesized following the General scheme above, on the basis of 6-nitroindole and 2-bromobutane. Total yield (20%).

HPLC: retention time 2,32 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 189,5 m/z (MH+).

B-15; 3-Cyclopentyl-1H-indol-6-ylamine

3-Cyclopentyl-1H-indol-6-ylamine (B-15) synthesized following the General scheme above, on the basis of 6-nitroindole and itselemental. Total yield (16%).

HPLC: retention time 2,39 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 201,5 m/z (MH+).

B-16; 3-(2-Ethoxyethyl)-1H-indol-6-ylamine

3-(2-Ethoxyethyl)-1H-indol-6-ylamine (B-16) synthesized following the General scheme above, on the basis of 6-nitroindole and 1-bromo-2-ethoxyethane. Total yield (15%).

HPLC: retention time of 1.56 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 205,1 m/z (MH+).

B-17; Ethyl ester (6-amino-1H-indol-3-yl)acetic acid

Ethyl ester (6-amino-1H-indol-3-yl)acetic acid (B-17) synthesized following the General scheme above, on the basis of 6-nitroindole and ethyl ether Vodokanal acid. About the d output (24%).

HPLC: retention time of 0.95 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 219,2 m/z (MH+).

4-Substituted 6-aminoindoles

2-Methyl-3,5-dinitrobenzoic acid

To a mixture of HNO3(95%, 80 ml) and H2SO4(98%, 80 ml) is added slowly 2-methylbenzoic acid (50 g, and 0.37 mol) at 0°C. After complete addition, the reaction mixture is stirred for 1.5 hours, keeping the temperature below 30°C, poured into ice water and stirred for 15 minutes the precipitate is separated by filtration and washed with water, obtaining 2-methyl-3,5-dinitrobenzoic acid (70 g, yield 84%).

Ethyl ester of 2-methyl-3,5-dinitrobenzoic acid

A mixture of 2-methyl-3,5-dinitrobenzoic acid (50 g, 0.22 mol) in SOCl2(80 ml) is refluxed for 4 hours and then concentrated to dryness. Add CH2Cl2(50 ml) and EtOH (80 ml). The mixture is stirred at room temperature for 1 hour, poured into ice water and extracted with EtOAc (3 x 100 ml). The combined extracts are washed with saturated solution of Na2CO3(80 ml), water (2 times 100 ml) and saturated salt solution (100 ml), dried over Na2SO4and concentrate to dryness, obtaining the ethyl ester of 2-methyl-3,5-dinitrobenzoic acid (50 g, yield 88%).

Ethyl ester of 2-(2-dimethylaminovinyl)for 3,5-dinitrobenzoic acid

A mixture of ethyl ester of 2-methyl-3,5-dinitrobenzoic acid (35 g, 0.14 mol) and dimethoxyphenylethylamine (32 g, 0.27 mol) in DMF (200 ml) is heated at a temperature of 100°C for 5 hours. The mixture is then poured into ice water. The precipitate was separated by filtration and washed with water, obtaining the ethyl ester of 2-(2-dimethylaminovinyl)for 3,5-dinitrobenzoic acid (11.3 g, yield 48%).

B-18; Ethyl ester of 6-amino-1H-indole-4-carboxylic acid

A mixture of ethyl ester of 2-(2-dimethylaminovinyl)for 3,5-dinitrobenzoic acid (11.3 g, 0,037 mol) and SnCl2(83 g of 0.37 mol) in ethanol is refluxed for 4 hours. The mixture is concentrated to dryness, the residue poured into water and alkalinized with saturated solution of Na2CO3to pH=8. The precipitate is filtered off and the filtrate is extracted with ethyl acetate (3 times 100 ml). The combined extracts washed with water (2 times 100 ml) and saturated salt solution (150 ml), dried over Na2SO4and concentrate to dryness. The residue is purified column chromatography on silica gel, obtaining the ethyl ester of 6-amino-1H-indole-4-carboxylic acid (18) (3 g, yield 40%).

1H-NMR (DMSO-d6) δ 10,76 (users, 1H), 7,11-7,14 (m, 2H), for 6.81-PC 6.82 (m, 1H), 6,67 of 6.68 (m, 1H), 4,94 (users, 2H), 4,32-of 4.25 (q, J=7.2 Hz, 2H), 1,35 to 1.31 (t, J=7,2, 3H).

ESI-MS: 205,0 m/z (MH+).

5-Substituted 6-am is noonday

Example 1

The General scheme

A specific example

1-Fluoro-5-methyl-2,4-dinitrobenzene

To a stirred solution of HNO3(60 ml) and H2SO4(80 ml), cooled in an ice bath was added 1-fluoro-3-methylbenzo (27.5 g, 25 mmol) at such a speed that the temperature did not exceed 35°C. the Mixture is left to mix for 30 min at room temperature and poured into ice water (500 ml). The precipitate (a mixture of desired product and 1-fluoro-3-methyl-2,4-dinitrobenzene, approximately 7:3) is separated by filtration and purified by recrystallization from 50 ml of diisopropyl ether, receiving 1-fluoro-5-methyl-2,4-dinitrobenzene in the form of a white solid (18 g, yield 36%).

[2-(5-fluoro-2,4-dinitrophenyl)vinyl]dimethylamine

A mixture of 1-fluoro-5-methyl-2,4-dinitrobenzene (10 g, 50 mmol), dimethoxyphenylethylamine (11.9 g, 100 mmol) and DMF (50 ml) is heated at a temperature of 100°C for 4 hours. The solution is cooled and poured into water. The red precipitate was separated by filtration, sufficiently washed with water and dried, obtaining [2-(5-fluoro-2,4-dinitrophenyl)vinyl]dimethylamine (8 g, yield 63%).

B-20; 5-fluoro-1H-indol-6-ylamine

A suspension of [2-(5-fluoro-2,4-dinitrophenyl)vinyl]amine (8 g of 31.4 mmol) and Raney Nickel (8 g) in EtOH (80 ml) is stirred in the atmosphere is e hydrogen (40 psi) at room temperature for 1 hour. After filtration the filtrate is concentrated and the residue purified by chromatography (petroleum ether/EtOAc=5/1)to give 5-fluoro-1H-indol-6-ylamine (B-20) as a brown solid (1 g, yield 16%).

1H-NMR (DMSO-d6): δ 10,56 (USS, 1H), 7,07 (d, J=12 Hz, 1H), 7,02 (m, 1H), of 6.71 (d, J=8 Hz, 1H), 6,17 (s, 1H), 3,91 (USS, 2H).

ESI-MS: to 150.1 m/z (MH+).

Other examples

B-21; 5-Chloro-1H-indol-6-ylamine

5-Chloro-1H-indol-6-ylamine (B-21) synthesized following the General scheme above, on the basis of 1-chloro-3-methylbenzene. Total yield (7%).

1H-NMR (CDCl3): δ a 7.85 (USS, 1H), 7,52 (s, 1H), 7,03 (s, 1H), 6,79 (s, 1H), 6,34 (s, 1H), 3,91 (USS, 2H).

ESI-MS: 166,0 m/z (MH+).

B-22; 5-Trifluoromethyl-1H-indol-6-ylamine

5-Trifluoromethyl-1H-indol-6-ylamine (B-22) synthesized following the General scheme above, on the basis of 1-methyl-3-cryptomelane. Total yield (2%).

1H-NMR (DMSO-d6): 10,79 (USS, 1H), 7,55 (s, 1H), 7,12 (s, 1H), 6,78 (s, 1H), 6,27 (s, 1H), 4.92 in (s, 2H).

ESI-MS: 200,8 m/z (MH+).

Example 2

1-Benzazolyl-2,3-dihydro-1H-indol

To a mixture of DMAP (1.5 g), benzosulfimide (24 g, 136 mmol) and 2,3-dihydro-1H-indole (14,7 g, 124 mmol) in CH2Cl2(200 ml) added dropwise Et3N (19 g, 186 mmol) in water bath with ice. After soversheni is added, the mixture is stirred at room temperature overnight, washed with water, dried over Na2SO4and concentrated to dryness under reduced pressure, obtaining 1-benzazolyl-2,3-dihydro-1H-indole (30,9 g, yield 96%).

1-(1-Benzazolyl-2,3-dihydro-1H-indol-5-yl)alanon

To a stirred suspension of AlCl3(144 g of 1.08 mol) in CH2Cl2(1070 ml) is added acetic anhydride (54 ml). The mixture is stirred for 15 minutes added dropwise a solution of 1-benzazolyl-2,3-dihydro-1H-indole (46,9 g, 0.18 mol) in CH2Cl2(1070 ml). The mixture is stirred for 5 hours and quenched by slow addition of crushed ice. The organic layer is separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers washed with saturated aqueous NaHCO3and saturated salt solution, dried over Na2SO4and concentrated in vacuo, obtaining 1-(1-benzazolyl-2,3-dihydro-1H-indol-5-yl)alanon (42.6 g, yield 79%).

1-Benzazolyl-5-ethyl-2,3-dihydro-1H-indol

To stir magnetic stirrer TFOC (1600 ml) for 1 hour at a temperature of 0°C. add sodium borohydride (64 g, 1,69 mol). To the mixture is added dropwise a solution of 1-(1-benzazolyl-2,3-dihydro-1H-indol-5-yl)ethanone (40 g, 0.13 mol) in TFOC (700 ml) for 1 hour. The mixture is stirred overnight at a temperature of 25°C, diluted with H2About (1600 ml) and alkalinized granules hydroxide hydroxide is I at a temperature of 0°C. The organic layer is separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate under reduced pressure. The residue is purified column chromatography on silica gel, receiving 1-benzazolyl-5-ethyl-2,3-dihydro-1H-indole (16.2 g, yield 43%).

5-Ethyl-2,3-dihydro-1H-indol

A mixture of 1-benzazolyl-5-ethyl-2,3-dihydro-1H-indole (15 g, 0.05 mol) in HBr (48%, 162 ml) is refluxed for 6 hours. The mixture is alkalinized with a saturated solution of NaOH to pH=9 and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over Na2SO4and concentrate under reduced pressure. The residue is purified column chromatography on silica gel, receiving 5-ethyl-2,3-dihydro-1H-indole (2.5 g, yield 32%).

5-Ethyl-6-nitro-2,3-dihydro-1H-indol

To a solution of 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 17 mmol) in H2SO4(98%, 20 ml) is added slowly KNO3(1.7 g, 17 mmol) at 0°C. After complete addition, the mixture is stirred at a temperature of 0-10°C for 10 min, gently poured on ice, alkalinized with NaOH solution to pH=9 and extracted with ethyl acetate. The combined extracts washed with saturated salt solution, dried over Na2SO4and concentrate to dryness. The rest of cleansing the t column chromatography on silica gel, receiving 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, yield 58%).

5-Ethyl-6-nitro-1H-indol

To a solution of 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 9.9 mmol) in CH2Cl2(30 ml) is added MnO2(4 g, 46 mmol). The mixture is stirred at room temperature for 8 hours. The solid is filtered off and the filtrate is concentrated to dryness, obtaining the crude 5-ethyl-6-nitro-1H-indole (1.9 g, quantitative yield).

B-23; 5-Ethyl-1H-indol-6-ylamine

A suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney Nickel (1 g) was stirred in hydrogen atmosphere (1 ATM.) at room temperature for 2 hours. The catalyst is filtered off and the filtrate concentrated to dryness. The residue is purified column chromatography on silica gel, receiving 5-ethyl-1H-indol-6-ylamine (B-23) (760 mg, yield 48%).

1H-NMR (CDCl3) δ of 7.90 (users, 1H), 7,41 (s, 1H), 7,00 (s, 1H), 6,78 (s, 2H), to 6.39 (s, 1H), 3,39 (users, 2H), 2.63 in (kV, J=7.2 Hz, 2H), 1,29 (t, J=6.9 Hz, 3H).

ESI-MS: owed 161.1 m/z (MH+).

Example 3

2-Bromo-4-tert-butylbenzylamine

To a solution of 4-tert-butylbenzylamine (447 g, 3 mol) in DMF (500 ml) added dropwise NBS (531 g, 3 mol) in DMF (500 ml) at room temperature. After complete addition, the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with water, saturated salt solution, dried over Na 2SO4and concentrate. The crude product is directly used in the next stage without further purification.

2-Bromo-4-tert-butyl-5-nitrophenylamino

2-Bromo-4-tert-butylbenzylamine (162 g, 0.71 mol) are added dropwise to H2SO4(410 ml) at room temperature, obtaining a clear solution. The obtained clear solution is then cooled to a temperature in the range from -5°C to -10°C. added dropwise a solution of KNO3(82.5 g, 0.82 mol) in H2SO4(410 ml), maintaining the temperature in the range from -5 to -10°C. After complete addition, the reaction mixture is poured into ice water and extracted with EtOAc. The combined organic layers washed with 5%solution of Na2CO3and saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography (EtOAc/petroleum ether=1/10)to give 2-bromo-4-tert-butyl-5-nitrophenylamino in the form of a yellow solid (152 g, yield 78%).

4-tert-Butyl-5-nitro-2-trimethylsilylethynyl

To a mixture of 2-bromo-4-tert-butyl-5-nitrophenylamino (27,3 g, 100 mmol) in toluene (200 ml) and water (100 ml) under nitrogen atmosphere add Et3N (27.9 ml, 200 mmol), Pd(PPh3)2Cl2(2,11 g, 3 mmol), CuI (950 mg, 0.5 mmol) and trimethylsilylacetamide (21.2 ml, 150 mmol). The reaction mixture is heated at 70°C in tightly closed is Albe for 2.5 hours, cooled to room temperature and filtered through a small layer of celite. The filter cake was washed with EtOAc. The combined filtrate was washed with 5%solution of NH4OH and water, dried over Na2SO4and concentrate. The crude product is purified column chromatography (0-10% EtOAc/petroleum ether)to give 4-tert-butyl-5-nitro-2-trimethylsilylethynyl in the form of a brown viscous liquid (25 g, yield 81%).

5-tert-Butyl-6-nitro-1H-indol

To a solution of 4-tert-butyl-5-nitro-2-trimethylsilylmethylamine (25 g, 86 mmol) in DMF (100 ml) under nitrogen atmosphere add CuI (8,2 g, 43 mmol). The mixture is heated at a temperature of 135°C in a sealed flask overnight, cooled to room temperature and filtered through a small layer of celite. The filter cake was washed with EtOAc. The combined filtrate is washed with water, dried over Na2SO4and concentrate. The crude product is purified column chromatography (10-20% EtOAc/hexane)to give 5-tert-butyl-6-nitro-1H-indole as a yellow solid (12.9 g, yield 69%).

In-24; 5-tert-Butyl-1H-indol-6-ylamine

The Raney-Nickel (3 g) are added to 5-tert-butyl-6-nitro-1H-indole (14,7 g, 67 mmol) in methanol (100 ml). The mixture is stirred in hydrogen atmosphere (1 ATM.) at 30°C for 3 hours. The catalyst is filtered off. The filtrate is dried over Na2SO4 and concentrate. The crude viscous dark brown oil is purified column chromatography (10-20% EtOAc/petroleum ether)to give 5-tert-butyl-1H-indol-6-ylamine (In-24) as a gray solid (11 g, yield 87%).

1H-NMR (300 MHz, DMSO-d6): δ 10,3 (USS, 1H), 7,2 (s, 1H), 6,9 (m, 1H), and 6.6 (s, 1H), 6,1 (m, 1H), 4,4 (USS, 2H)and 1.3 (s, 9H).

Example 4

5-Methyl-2,4-dinitrobenzoic acid

To a mixture of HNO3(95%, 80 ml) and H2SO4(98%, 80 ml) is added slowly 3-methylbenzoic acid (50 g, and 0.37 mol) at 0°C. After complete addition, the mixture is stirred for 1.5 hours, keeping the temperature below 30°C. the Mixture is then poured into ice water and stirred for 15 minutes the Precipitate was separated by filtration and washed with water, getting a mixture of 3-methyl-2,6-dinitrobenzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, yield 84%). To a solution of the mixture in EtOH (150 ml) added dropwise SOCl2(53,5 g, 0.45 mol). The mixture is refluxed for 2 hours and concentrated to dryness under reduced pressure. The residue is dissolved in EtOAc (100 ml) and extracted with a 10%solution of Na2CO3(120 ml). It was found that the organic layer contains ethyl ester 5-methyl-2,4-dinitrobenzoic acid, while the water layer contains 3-methyl-2,6-dinitrobenzoic acid. Organic the sky layer is washed with saturated salt solution (50 ml), dried over Na2SO4and concentrate to dryness, obtaining the ethyl ester of 5-methyl-2,4-dinitrobenzoic acid (20 g, yield 20%).

Ethyl ester of 5-(2-dimethylaminovinyl)-2,4-dinitrobenzoic acid

A mixture of ethyl ester 5-methyl-2,4-dinitrobenzoic acid (39 g, 0.15 mol) and dimethoxyphenylethylamine (32 g, 0.27 mol) in DMF (200 ml) is heated at a temperature of 100°C for 5 hours. The mixture is then poured into ice water. The precipitate was separated by filtration and washed with water, obtaining the ethyl ester of 5-(2-dimethylaminovinyl)-2,4-dinitrobenzoic acid (15 g, yield 28%).

B-25; Ethyl ester of 6-amino-1H-indole-5-carboxylic acid

A mixture of ethyl ester 5-(2-dimethylaminovinyl)-2,4-dinitrobenzoic acid (15 g, 0.05 mol) and Raney Nickel (5 g) in EtOH (500 ml) is stirred in hydrogen atmosphere (50 psi) at room temperature for 2 hours. The catalyst is filtered off and the filtrate concentrated to dryness. The residue is purified column chromatography on silica gel, obtaining the ethyl ester of 6-amino-1H-indole-5-carboxylic acid (B-25) (3 g, 30%yield).

1H-NMR (DMSO-d6) δ is 10.68 (s, 1H), to 7.99 (s, 1H), 7,01-7,06 (m, 1H), 6,62 (s, 1H), 6,27-6,28 (m, 1H), 6,16 (s, 2H), 4,22 (kV, J=7.2 Hz, 2H), 1.32 to of 1.27 (t, J=7.2 Hz, 3H).

Example 5

1-(2,3-Dihydroindol-1-yl)alanon

To a suspension of NaHCO3(504 g, 6.0 mol) and 2,3-dihydro-1H-indole (60 g, 0.5 to the ol) in CH 2Cl2(600 ml), cooled on a water bath with ice, added dropwise acetylchloride (78,5 g, 1.0 mol). The mixture is stirred at room temperature for 2 hours. The solid is filtered off and the filtrate is concentrated, obtaining 1-(2,3-dihydroindol-1-yl)alanon (82 g, yield 100%).

1-(5-Bromo-2,3-dihydroindol-1-yl)alanon

To a solution of 1-(2,3-dihydroindol-1-yl)ethanone (58,0 g, 0.36 mol) in acetic acid (3000 ml) add Br2(87,0 g, 0.54 mol) at 10°C. the Mixture is stirred at room temperature for 4 hours. The precipitate was separated by filtration, obtaining the crude 1-(5-bromo-2,3-dihydroindol-1-yl)alanon (100 g, yield 96%), which is used directly in the next stage.

5-Bromo-2,3-dihydro-1H-indol

A mixture of crude 1-(5-bromo-2,3-dihydroindol-1-yl)ethanone (100 g, 0.34 mol) in HCl (20%, 1200 ml) is refluxed for 6 hours. The mixture is alkalinized solution of Na2CO3to pH=8,5-10 and then extracted with ethyl acetate. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate under reduced pressure. The residue is purified column chromatography on silica gel, receiving 5-bromo-2,3-dihydro-1H-indole (37 g, yield 55%).

5-Bromo-6-nitro-2,3-dihydro-1H-indol

To a solution of 5-bromo-2,3-dihydro-1H-indole (45 g, 0,227 mol) in H2SO4(98%, 200 ml) is added slowly KNO3(23,5 g, 0.23 mol) at 0°C. After complete addition, the mixture is stirred at a temperature of 0-10°C for 4 hours, gently poured on ice, alkalinized solution of Na2CO3to pH=8 and extracted with ethyl acetate. The combined organic extracts washed with saturated salt solution, dried over Na2SO4and concentrate to dryness. The residue is purified column chromatography on silica gel, receiving 5-bromo-6-nitro-2,3-dihydro-1H-indole (42 g, yield 76%).

5-Bromo-6-nitro-1H-indol

To a solution of 5-bromo-6-nitro-2,3-dihydro-1H-indole (20 g, was 82.3 mmol) in 1,4-dioxane (400 ml) was added DDQ (30 g, 0.13 mol). The mixture is stirred at a temperature of 80°C for 2 hours. The solid is filtered off and the filtrate concentrated to dryness. The residue is purified column chromatography on silica gel, receiving 5-bromo-6-nitro-1H-indole (7.5 g, yield 38%).

In-27; 5-Bromo-1H-indol-6-ylamine

A mixture of 5-bromo-6-nitro-1H-indole (7.5 g, and 31.1 mmol) and Raney Nickel (1 g) in ethanol is stirred in hydrogen atmosphere (1 ATM.) at room temperature for 2 hours. The catalyst is filtered off and the filtrate concentrated to dryness. The residue is purified column chromatography on silica gel, receiving 5-bromo-1H-indol-6-ylamine (In-27) (2 g, 30%yield).

1H-NMR (DMSO-d6): δ 10,6 (s, 1H), 7,49 (s, 1H), 6,79-7,02 (m, 1H), 6,79 (who, 1H), 6,14-6,16 (m, 1H), to 4.81 (s, 2H).

7-Substituted 6-aminoindoles

3-Methyl-2,6-dinitrobenzoic acid

To a mixture of HNO3(95%, 80 ml) and H2SO4(98%, 80 ml) is added slowly 3-methylbenzoic acid (50 g, and 0.37 mol) at 0°C. After complete addition, the mixture is stirred for 1.5 hours, keeping the temperature below 30°C. the Mixture is then poured into ice water and stirred for 15 minutes the Precipitate was separated by filtration and washed with water, getting a mixture of 3-methyl-2,6-dinitrobenzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, yield 84%). To a solution of the mixture in EtOH (150 ml) added dropwise SOCl2(53,5 g, 0.45 mol). The mixture is refluxed for 2 hours and concentrated to dryness under reduced pressure. The residue is dissolved in EtOAc (100 ml) and extracted with a 10%solution of Na2CO3(120 ml). It was found that the organic layer contains ethyl ester 5-methyl-2,4-dinitrobenzoic acid. The aqueous layer was acidified with HCl to pH=2~3, and the obtained precipitate was separated by filtration, washed with water and dried in the air, getting 3-methyl-2,6-dinitrobenzoic acid (39 g, yield 47%).

Ethyl ester of 3-methyl-2,6-dinitrobenzoic acid

A mixture of 3-methyl-2,6-dinitrobenzoic acid (39 g, 0.15 mol) and SOCl2(80 ml) is refluxed for 4 cha is impressive. The excess SOCl2removed under reduced pressure and the residue is added dropwise to a solution of EtOH (100 ml) and Et3N (50 ml). The mixture is stirred at 20°C for 1 hour and concentrated to dryness. The residue is dissolved in EtOAc (100 ml), washed with a solution of Na2CO3(10%, 2 x 40 ml), water (2 times 50 ml) and saturated salt solution (50 ml), dried over Na2SO4and concentrate, getting ethyl ester of 3-methyl-2,6-dinitrobenzoic acid (20 g, yield 53%).

Ethyl ester of 3-(2-dimethylaminovinyl)-2,6-dinitrobenzoic acid

A mixture of ethyl ester of 3-methyl-2,6-dinitrobenzoic acid (35 g, 0.14 mol) and dimethoxyphenylethylamine (32 g, 0.27 mol) in DMF (200 ml) is heated at a temperature of 100°C for 5 hours. The mixture is then poured into ice water, the precipitate was separated by filtration and washed with water, obtaining the ethyl ester of 3-(2-dimethylaminovinyl)-2,6-dinitrobenzoic acid (25 g, yield 58%).

B-19; Ethyl ester of 6-amino-1H-indole-7-carboxylic acid

A mixture of ethyl ester of 3-(2-dimethylaminovinyl)-2,6-dinitrobenzoic acid (30 g, 0,097 mol) and Raney Nickel (10 g) in EtOH (1000 ml) is stirred in hydrogen atmosphere (50 psi) for 2 hours. The catalyst is filtered off and the filtrate concentrated to dryness. The residue is purified column chromatography on silica gel, obtaining the ethyl ester of 6-amino-1H-indole-7-carbon is Oh acid ( B-19in the form of not-quite-white solid (3.2 g, yield 16%).

1H-NMR (DMSO-d6) δ 10,38 (s, 1H), 7,44-7,41 (d, J=8.7 Hz, 1H), 6,98 (t, 1H), 6,65 (s, 2H), 6,50-6,46 (m, 1H), 6,27-of 6.26 (m, 1H), 4,43 is 4.36 (q, J=7.2 Hz, 2H), 1,35 (t, J=7.2 Hz, 3H).

Phenols

Example 1

2-tert-Butyl-5-nitroaniline

To a cooled solution of sulfuric acid (90%, 50 ml) added dropwise 2-tert-butylbenzylamine (4.5 g, 30 mmol) at 0°C. Portions add potassium nitrate (4.5 g, 45 mmol) at 0°C. the Reaction mixture is stirred at a temperature of 0-5°C for 5 min, poured into ice water and then extracted three times with EtOAc. The combined organic layers washed with saturated salt solution and dried over Na2SO4. After removal of solvent the residue is purified by recrystallization, using 70% EtOH-H2Oh, getting 2-tert-butyl-5-nitroaniline (3.7 g, yield 64%).

1H-NMR (400 MHz, CDCl3): δ 7,56 (DD, J=8,7, 2.4 Hz, 1H), of 7.48 (d, J=2.4 Hz, 1H), was 7.36 (d, J=8.7 Hz, 1H), 4,17 (s, 2H), of 1.46 (s, 9H).

HPLC: retention time of 3.27 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 195,3 m/z (MH+).

S-1; 2-tert-Butyl-5-NITROPHENOL

To a mixture of 2-tert-butyl-5-nitroaniline (1,94 g, 10 mmol) in 40 ml of 15%H2SO4added dropwise a solution of NaNO2(763 mg, 11.0 mmol) in water (3 ml) at 0°C. the resulting mixture was stirred at the rate which the temperature 0-5°C for 5 minutes Excess NaNO2neutralized with urea, then add 5 ml of a mixture of H2SO4-N2On (mass./wt.=1:2) and the mixture is refluxed for 5 minutes Then add three aliquots of 5 ml of a mixture of H2SO4-N2On (mass./wt.=1:2) while boiling under reflux. The reaction mixture is cooled to room temperature and twice extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After removal of solvent the residue is purified column chromatography (0-10% EtOAc-hexane)to give 2-tert-butyl-5-NITROPHENOL (C-1-a) (1.2 g, yield 62%).

1H-NMR (400 MHz, CDCl3): δ 7,76 (DD, J=8,6, 2.2 Hz, 1H), 7,58 (d, J=2.1 Hz, 1H), 7,43 (d, J=8.6 Hz, 1H), 5,41 (s, 1H), 1,45 (s, 9H).

HPLC: retention time of 3.46 min, 10-99% CH3CN, the analysis time of 5 minutes

S-1; 2-tert-Butyl-5-aminophenol

To boiling under reflux to a solution of 2-tert-butyl-5-NITROPHENOL (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 ml) is added ammonium formate (200 mg, 3.1 mmol), then 140 mg of 10%Pd/C. Then the reaction mixture was refluxed for 30 min, cooled to room temperature and filtered through a layer of celite. The filtrate is concentrated to dryness and purified column chromatography (20-30% EtOAc-hexane)to give 2-tert-butyl-5-aminophenol (S-1) (144 mg, yield 87%).

1H-NMR (400 M is C, DMSO-d6): δ 8,76 (s, 1H), 6,74 (d, J=8,3 Hz, 1H), 6,04 (d, J=2.3 Hz, 1H), to 5.93 (DD, J=8,2, 2.3 Hz, 1H), 4,67 (s, 2H), 1.26 in (s, 9H).

HPLC: retention time of 2.26 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 166,1 m/z (MH+).

Example 2

The General scheme

a) RX (X=Br, I), K2CO3or Cs2CO3, DMF; (b) HCO2NH4or HCO2K, Pd/C, EtOH.

A specific example

1-tert-Butyl-2-methoxy-4-nitrobenzene

To a mixture of 2-tert-butyl-5-NITROPHENOL (C-1-a) (100 mg, 0.52 mmol) and K2CO3(86 mg, of 0.62 mmol) in DMF (2 ml) add CH3I (40 μl, of 0.62 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with water and extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After filtration the filtrate is evaporated to dryness, obtaining 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, yield 76%), which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ to 7.77 (t, J=4.3 Hz, 1H), of 7.70 (d, J=2.3 Hz, 1H), 7,40 (d, J=8.6 Hz, 1H), 3,94 (s, 3H), of 1.39 (s, 9H).

C-2; 4-tert-Butyl-3-methoxyaniline

To boiling under reflux to a solution of 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 0.4 mmol) in EtOH (2 ml) add potassium formate (300 mg, 3.6 mmol) in water (1 ml), then 10%Pd/C (15 mg). Then reacciona the mixture is refluxed for 60 min, cooled to room temperature and filtered through celite. The filtrate is concentrated to dryness, obtaining 4-tert-butyl-3-methoxyaniline (C-2) (52 mg, yield 72%), which is used without further purification.

HPLC: retention time to 2.29 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 180,0 m/z (MH+).

Other examples

C-3; 3-(2-Ethoxyethoxy)-4-tert-butylbenzylamine

3-(2-Ethoxyethoxy)-4-tert-butylbenzylamine (C-3) synthesized following the General scheme above, on the basis of 2-tert-butyl-5-NITROPHENOL (C-1-a) and 1-bromo-2-ethoxyethane.

1H-NMR (400 MHz, CDCl3) δ 6,97 (d, J=7.9 Hz, 1H), 6,17 (s, 1H), 6,14 (d, J=2.3 Hz, 1H), 4.00 points (t, J=5,2 Hz, 2H), 3,76 (t, J=5,2 Hz, 2H), 3,53 (kV, J=7,0 Hz, 2H), 1.27mm (s, 9H), of 1.16 (t, J=7.0 Hz, 3H).

HPLC: retention time of 2.55 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 238,3 m/z (MH+).

C-4; 2-(2-tert-Butyl-5-aminophenoxy)ethanol

2-(2-tert-Butyl-5-aminophenoxy)ethanol (C-4) synthesized following the General scheme above, on the basis of 2-tert-butyl-5-NITROPHENOL (C-1-a) and 2-bromoethanol.

HPLC: retention time of 2.08 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 210,3 m/z (MH+).

Example 3

N-(3-Hydroxyphenyl)ndimethylacetamide and 3-formelementname ether in ssnoi acid

To intensively stirred suspension of 3-aminophenol (50 g, 0.46 mol) and NaHCO3(193,2 g, 2.3 mol) in chloroform (1 l) was added dropwise chlorocatechol (46,9 g, 0.6 mol) for 30 min at 0°C. After complete addition, the reaction mixture is refluxed overnight and then cooled to room temperature. Excess NaHCO3removed by filtration. The filtrate is poured into water and extracted with EtOAc (3 x 300 ml). The combined organic layers washed with saturated salt solution (500 ml), dried over anhydrous Na2SO4and concentrate under reduced pressure, obtaining a mixture of N-(3-hydroxyphenyl)ndimethylacetamide and 3-formelementname ether acetic acid (35 g, 4:1 according to NMR analysis). The mixture is used directly in the next stage.

N-[3-(3-Methylbut-3-enyloxy)phenyl]ndimethylacetamide

Suspension of a mixture of N-(3-hydroxyphenyl)ndimethylacetamide and 3-formelementname ether acetic acid (18,12 g, 0.12 mol), 3-methylbut-3-EN-1-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph3P (31,44 g, 0.12 mol) in benzene (250 ml) is refluxed overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer separated. The aqueous phase is extracted with EtOAc (3 x 300 ml). The combined organic layers washed with saturated salt solution, dried over betw denim Na 2SO4and concentrate. The residue is purified column chromatography, obtaining N-[3-(3-methylbut-3-enyloxy)phenyl]ndimethylacetamide (11 g, yield 52%).

N-(4,4-DIMETHYLPROPANE-7-yl)ndimethylacetamide

A mixture of N-[3-(3-methylbut-3-enyloxy)phenyl]ndimethylacetamide (2.5 g, of 11.4 mmol) and AlCl3(4.52 g, to 34.3 mmol) in torbenson (50 ml) is refluxed overnight. After cooling, the reaction mixture was poured into water. The organic layer is separated and the aqueous layer was extracted with EtOAc (3 x 40 ml). The combined organic layers washed with saturated salt solution, dried over anhydrous Na2SO4and concentrated in vacuo. The residue is purified column chromatography, obtaining N-(4,4-DIMETHYLPROPANE-7-yl)ndimethylacetamide (1.35 g, yield 54%).

C-5; 3,4-Dihydro-4,4-dimethyl-2H-chromen-7-amine

A mixture of N-(4,4-DIMETHYLPROPANE-7-yl)ndimethylacetamide (1.35 g, 6.2 mmol) in 20%HCl solution (30 ml) is refluxed for 3 hours and then cooled to room temperature. The reaction mixture is alkalinized 10%aqueous NaOH solution to pH=8 and extracted with EtOAc (3 times 30 ml). The combined organic layers washed with saturated salt solution, dried over anhydrous Na2SO4and concentrate, receiving 3,4-dihydro-4,4-dimethyl-2H-chromen-7-amine (C-5) (1 g, yield 92%).

1H-NMR (DMSO-d6) δ 6.87 in (d, J=8,4 Hz, 1H), 6,07 (DD, J=8,4, 2.4 Hz, 1H), by 5.87 (d, J=2.4 Hz, 1H), and 4.75 (s, 2H, to 3.99 (t, J=5.4 Hz, 2H), 1,64 (t, J=5,1 Hz, 2H)and 1.15 (s, 6H).

ESI-MS: 178,1 m/z (MH+).

Example 4

The General scheme

X=F, Cl; a) ROH, H2SO4or MeSO3H, CH2Cl2; (b) R CO2Cl, Et3N, 1,4-dioxane or CHCl3; (c) HNO3H2SO4or KNO3H2SO4or HNO3, AcOH; (d) piperidine, CH2Cl2; (e) HCO2NH4Pd/C, EtOH or SnCl2·2H2O, EtOH or H2Pd/C, MeOH.

A specific example

2-tert-Butyl-4-terfenol

4-Terfenol (5 g, 45 mmol) and tert-butanol (5,9 ml, 63 mmol) dissolved in CH2Cl2(80 ml) and treated with concentrated sulfuric acid (98%, 3 ml). The mixture is stirred at room temperature overnight. The organic layer is washed with water, neutralized NaHCO3, dried over MgSO4and concentrate. The residue is purified column chromatography (5-15% EtOAc-hexane)to give 2-tert-butyl-4-terfenol (3.12 g, yield 42%).

1H-NMR (400 MHz, DMSO-d6): δ to 9.32 (s, 1H), 6.89 in (DD, J=11,1, 3.1 Hz, 1H), 6,84-6,79 (m, 1H), 6,74 (DD, J=8,7, 5.3 Hz, 1H), 1,33 (s, 9H).

2-tert-Butyl-4-performancebut

To a solution of 2-tert-butyl-4-terfenol (2,63 g, 15.7 mmol) and NEt3(3,13 ml of 22.5 mmol) in dioxane (45 ml) add methylchloroform (1,27 ml, 16.5 mmol). The mixture is stirred at room temperature for 1 hour. Sieges is to remove by filtration. The filtrate is then diluted with water and extracted with diethyl ether. Extract in diethyl ether, washed with water and dried over MgSO4. After removal of solvent the residue is purified column chromatography, obtaining 2-tert-butyl-4-performancebut (of 2.08 g, yield 59%).

1H-NMR (400 MHz, DMSO-d6): δ 7.24 to (DD, J=8,8, 5.4 Hz, 1H), 7,17-7,10 (m, 2H), 3,86 (s, 3H), of 1.29 (s, 9H).

2-tert-Butyl-4-fluoro-5-nitrophenylarsonic (C-7-a) and 2-tert-butyl-4-fluoro-6-nitrophenylarsonic (C-6-a)

To a solution of 2-tert-butyl-4-performancedata (1,81 g, 8 mmol) in H2SO4(98%, 1 ml) slowly add chilled mixture of H2SO4(1 ml) and HNO3(1 ml) at 0°C. the Mixture is stirred for 2 hours, until it warms up to room temperature, poured on ice and extracted with diethyl ether. Extract in diethyl ether, washed with saturated salt solution, dried over MgSO4and concentrate. The residue is purified column chromatography (0-10% EtOAc-hexane)to give 2-tert-butyl-4-fluoro-5-nitrophenylarsonic (C-7-a) (1.2 g, yield 55%) and 2-tert-butyl-4-fluoro-6-nitrophenylarsonic (C-6-a) (270 mg, yield 12%).

2-tert-Butyl-4-fluoro-5-nitrophenylarsonic (C-7-a):

1H-NMR (400 MHz, DMSO-d6): δ 8,24 (d, J=7,1 Hz, 1H), 7,55 (d, J=a 13.4 Hz, 1H), 3,90 (s, 3H), of 1.32 (s, 9H).

2-tert-Butyl-4-fluoro-6-nitrophenylacetate the t ( C-6-a):

1H-NMR (400 MHz, DMSO-d6): δ of 8.04 (DD, J=7,6, 3.1 Hz, 1H), 7,69 (DD, J=10,1, 3.1 Hz, 1H), 3,91 (s, 3H), of 1.35 (s, 9H).

2-tert-Butyl-4-fluoro-5-NITROPHENOL

To a solution of 2-tert-butyl-4-fluoro-5-nitrophenylacetate (C-7-a) (1.08 g, 4 mmol) in CH2Cl2(40 ml) is added piperidine (3,94 ml, 10 mmol). The mixture is stirred at room temperature for 1 hour and extracted with 1N. NaOH solution (3 times). The aqueous layer was acidified with 1N. HCl solution and extracted with diethyl ether. Extract in diethyl ether, washed with a saturated solution of salt, dried (MgSO4and concentrate, receiving 2-tert-butyl-4-fluoro-5-NITROPHENOL (530 mg, yield 62%).

1H-NMR (400 MHz, DMSO-d6): δ the 10.40 (s, 1H), 7,49 (d, J=6,8 Hz, 1H), 7,25 (d, J=13,7 Hz, 1H), of 1.36 (s, 9H).

C-7; 2-tert-Butyl-5-amino-4-terfenol

To boiling under reflux to a solution of 2-tert-butyl-4-fluoro-5-NITROPHENOL (400 mg, 1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) is added 5%Pd/C (260 mg). The mixture is then refluxed for 1 hour, cooled and filtered through celite. The solvent is removed by evaporation, receiving 2-tert-butyl-5-amino-4-terfenol (C-7) (550 mg, yield 83%).

1H-NMR (400 MHz, DMSO-d6): δ 8,83 (USS, 1H), 6,66(d, J=13,7 Hz, 1H), from 6.22 (d, J=8.5 Hz, 1H), 4,74 (USS, 2H), 1.26 in (s, 9H).

HPLC: retention time of 2.58 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 184,0 m/z (MH+).

Other examples

C-10; 2-tert-Butyl-5-amino-4-chlorophenol

2-tert-Butyl-5-amino-4-chlorophenol (C-10) synthesized following the General scheme above, on the basis of 4-chlorophenol and tert-butanol. Total yield (6%).

HPLC: retention time of 3.07 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 200,2 m/z (MH+).

S-13; 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol

5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (S-13) synthesized following the General scheme above, on the basis of 4-terfenol and 1-methylcyclohexanol. The overall yield (3%).

HPLC: retention time of 3.00 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 224,2 m/z (MH+).

S-19; 5-Amino-2-(3-ethylpent-3-yl)-4-terfenol

5-Amino-2-(3-ethylpent-3-yl)-4-terfenol (S-19) synthesized following the General scheme above, on the basis of 4-terfenol and 3-ethyl-3-pentanol. Total yield (1%).

S-20; 2-Substituted-5-amino-4-terfenol

2-Substituted-5-amino-4-terfenol (S-20) synthesized following the General scheme above, on the basis of 4-terfenol and adamantane-1-ol.

S-21; 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol

5-Amino-4-fluoro-2-(1-methylcyclohex the Teal)phenol ( S-21) synthesized following the General scheme above, on the basis of 4-terfenol and 1-methylcycloheptane.

S-22; 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol

5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (S-22) synthesized following the General scheme above, on the basis of 4-terfenol and 1-methylcyclopentanol.

S-23; 5-Amino-2-(3-ethyl-2,2-dimethylpentan-3-yl)-4-terfenol

5-Amino-2-(3-ethyl-2,2-dimethylpentan-3-yl)-4-terfenol (S-23) synthesized following the General scheme above, on the basis of 4-terfenol and 3-ethyl-2,2-dimethylpentan-3-ol.

Example 5

S-6; 2-tert-Butyl-4-fluoro-6-aminopenicillanic

To boiling under reflux to a solution of 2-tert-butyl-4-fluoro-6-nitrophenylphosphate (250 mg, of 0.92 mmol) and ammonium formate (250 mg, 4 mmol) in EtOH (10 ml) is added 5%Pd/C (170 mg). The mixture is then refluxed for 1 hour, cooled and filtered through celite. The solvent is removed by evaporation and the residue is purified column chromatography (0-15% EtOAc-hexane)to give 2-tert-butyl-4-fluoro-6-aminopenicillanic (S-6) (60 mg, yield 27%).

HPLC: retention time at 3.35 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 242,0 m/z (MH+).

Example 6

Methyl ester of 2,4-di-tert-butylphenyl ester of carbonic acid

Methylchloroform (58 ml, 750 mmol) are added dropwise to a solution of 2,4-di-tert-butylphenol (103,2 g, 500 mmol), Et3N (139 ml, 1000 mmol) and DMAP (3,05 g, 25 mmol) in dichloromethane (400 ml), cooled on a water bath with ice at 0°C. the Mixture is left to warm to room temperature under stirring overnight, then filtered through silica gel (approximately 1 l)using a mixture of 10% ethyl acetate-hexane (~4 l) as eluent. The combined filtrates are concentrated, obtaining the methyl ester of 2,4-di-tert-butylphenyl ester of carbonic acid as a yellow oil (132 g, quantitative yield).

1H-NMR (400 MHz, DMSO-d6): δ to 7.35 (d, J=2.4 Hz, 1H), 7,29 (DD, J=to 8.5, 2.4 Hz, 1H), 7,06 (d, J=8,4 Hz, 1H), 3,85 (s, 3H), of 1.30 (s, 9H), of 1.29 (s, 9H).

Methyl ester of 2,4-di-tert-butyl-5-nitrophenylthio ester of carbonic acid and methyl ester of 2,4-di-tert-butyl-6-nitrophenylthio ester of carbonic acid

To a stirred mixture of methyl ester of 2,4-di-tert-butylphenyl ester of carbonic acid (4,76 g, 18 mmol) in concentrated sulfuric acid (2 ml), cooled on a water bath with ice, add chilled mixture of sulfuric acid (2 ml) and nitric acid (2 ml). Adding exercise slowly so that the reaction temperature will not exceed isala 50°C. The reaction mixture was allowed to mix for 2 hours, until it warms up to room temperature. The reaction mixture was then bring in ice water and extracted with diethyl ether. A layer of diethyl ether, dried (MgSO4), concentrated and purified column chromatography (0-10% ethyl acetate-hexane), receiving a mixture of methyl ester of 2,4-di-tert-butyl-5-nitrophenylthio ester of carbonic acid and methyl ester of 2,4-di-tert-butyl-6-nitrophenylthio ester of carbonic acid in the form of a pale yellow solid (4,28 g), which are used directly in the next stage.

2,4-di-tert-Butyl-5-NITROPHENOL and 2,4-di-tert-butyl-6-NITROPHENOL

A mixture of methyl ester of 2,4-di-tert-butyl-5-nitrophenylthio ester of carbonic acid and methyl ester of 2,4-di-tert-butyl-6-nitrophenylthio ester of carbonic acid (4,2 g, 12.9 mmol) was dissolved in Meon (65 ml) and add KOH (2.0 g, 36 mmol). The mixture is stirred at room temperature for 2 hours. The reaction mixture was then acidified (pH=2-3) by adding concentrated HCl and partitioned between water and diethyl ether. A layer of diethyl ether, dried (MgSO4), concentrated and purified column chromatography (0-5% ethyl acetate-hexane)to give 2,4-di-tert-butyl-5-NITROPHENOL (1.31 g, yield 29% over 2 stages) and 2,4-di-tert-butyl-6-NITROPHENOL.

2,4-di-tert-Butyl-5-NITROPHENOL:

sup> 1H-NMR (400 MHz, DMSO-d6): δ 10,14 (s, 1H, OH), 7,34 (s, 1H), 6,83 (s, 1H), of 1.36 (s, 9H), of 1.30 (s, 9H).

2,4-di-tert-Butyl-6-NITROPHENOL:

1H-NMR (400 MHz, CDCl3): δ of $ 11.48 (s, 1H), 7,98 (d, J=2.5 Hz, 1H), 7,66 (d, J=2.4 Hz, 1H), 1,47 (s, 9H), of 1.34 (s, 9H).

S-9; 5-Amino-2,4-di-tert-butylphenol

To boiling under reflux to a solution of 2,4-di-tert-butyl-5-NITROPHENOL (1.86 g, 7.4 mmol) and ammonium formate (1.86 g) in ethanol (75 ml) add 5% of the mass. palladium-on-coal (Pd/C) (900 mg). The reaction mixture is stirred at the boil under reflux for 2 hours, cooled to room temperature and filtered through celite. Celite washed with methanol and the combined filtrates concentrated, obtaining 5-amino-2,4-di-tert-butylphenol as a gray solid (1.66 g, quantitative yield).

1H-NMR (400 MHz, DMSO-d6): δ 8,64 (s, 1H, HE), at 6.84 (s, 1H), between 6.08 (s, 1H), 4,39 (s, 2H, NH2), of 1.27 (m, 18H).

HPLC: retention time of 2.72 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 222,4 m/z (MH+).

S-8; 6-Amino-2,4-di-tert-butylphenol

A solution of 2,4-di-tert-butyl-6-NITROPHENOL (27 mg, 0.11 mmol) and SnCl2·2H2O (121 mg, 0.54 mmol) in EtOH (1.0 ml) is heated in a microwave oven at 100°C for 30 minutes the Mixture is diluted with EtOAc and water, alkalinized with saturated solution of NaHCO3and filtered through celite. The organic layer is separated and dried over Na2O 4. The solvent is removed by evaporation, getting 6-amino-2,4-di-tert-butylphenol (S-8), which is used without further purification.

HPLC: retention time is 2.74 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 222,5 m/z (MH+).

Example 7

4-tert-Butyl-2-chlorophenol

To a solution of 4-tert-butylphenol (40,0 g, 0.27 mol) and SO2Cl2(37,5 g, 0.28 mol) in CH2Cl2add Meon (9.0 g, 0.28 mol) at 0°C. After complete addition, the mixture is stirred over night at room temperature and then add water (200 ml). The resulting solution was extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue is purified column chromatography (petroleum ether/EtOAc=50:1)to give 4-tert-butyl-2-chlorophenol (47,0 g, yield 95%).

4-tert-Butyl-2-chlorineresistant

To a solution of 4-tert-butyl-2-chlorophenol (47,0 g, 0.25 mol) in dichloromethane (200 ml) was added Et3N (50.5 g, 0.50 mol), DMAP (1 g) and methylchloroform (35.4 g, 0.38 mol) at 0°C. the Reaction mixture was left to warm to room temperature and then stirred for 30 minutes, the Reaction mixture was washed with H2Oh, the organic layer dried over Na2SO4and concentrate, receiving 4-tert-butyl-2-CHLOROFORMATES arbonet (56,6 g, yield 92%), which is used directly in the next stage.

4-tert-Butyl-2-chloro-5-nitrophenylarsonic

4-tert-Butyl-2-chlorineresistant (36,0 g, 0.15 mol) is dissolved in concentrated H2SO4(100 ml) at 0°C. are added in several Portions KNO3(0,53 g, 5.2 mmol) for 25 minutes, the Reaction mixture is stirred for 1.5 hours and poured on ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers washed with aqueous solution of NaHCO3, dried over Na2SO4and concentrated in vacuo, obtaining 4-tert-butyl-2-chloro-5-nitrophenylarsonic (41,0 g), which is used without further purification.

4-tert-Butyl-2-chloro-5-NITROPHENOL

Potassium hydroxide (10.1 g, 181 mmol) are added to 4-tert-butyl-2-chloro-5-nitrophenylarsonic (40,0 g, 139 mmol) in Meon (100 ml). After 30 min, the reaction mixture is acidified with 1N. HCl solution and extracted with dichloromethane. The combined organic layers combined, dried over Na2SO4and concentrated in vacuo. The crude residue is purified column chromatography (petroleum ether/EtOAc=30:1)to give 4-tert-butyl-2-chloro-5-NITROPHENOL (23,0 g, yield 68% over 2 stages).

S-11; 4-tert-Butyl-2-chloro-5-aminophenol

To a solution of 4-tert-butyl-2-chloro-5-NITROPHENOL (12,6 g, 54,9 mmol) in Meon (50 ml) was added Ni (1.2 g). The reaction mixture is shaking in an atmosphere of hydrogen (1 ATM.) within 4 hours. The reaction mixture is filtered and the filtrate concentrated. The residue is purified column chromatography (petroleum ether/EtOAc=20:1)to give 4-tert-butyl-2-chloro-5-aminophenol (S-11) (8.5 g, yield 78%).

1H-NMR (DMSO-d6): δ was 9.33 (s, 1H), 6,80 (s, 1H), from 6.22 (s, 1H), amounts to 4.76 (s, 1H), 1,23 (s, 9H).

ESI-MS: 200,1 m/z (MH+).

Example 8

2-Substituted-4-methylphenylethylamine

Ethylchloride (of 0.64 ml, 6.7 mmol) is added dropwise to a solution of 2-substituted-4-METHYLPHENOL (1,09 g, 4.5 mmol), Et3N (1.25 ml, 9 mmol) and DMAP (catalytic amount) in dichloromethane (8 ml), cooled on a water bath with ice, at 0°C. the Mixture is left to warm to room temperature under stirring overnight, then filtered and the filtrate concentrated. The residue is purified column chromatography (10-20% ethyl acetate-hexane)to give 2-substituted-4-methylphenylethylamine in the form of a yellow oil (1,32 g, yield 94%).

2-Substituted-4-methyl-5-nitrophenylarsonic

To a chilled solution of 2-substituted-4-methylphenylethylamine (1,32 g, 4.2 mmol) in H2SO4(98%, 10 ml) in small portions add KNO3(510 mg, 5.0 mmol) at 0°C. the Mixture is stirred for 3 hours until it warms up to room temperature, poured on ice and then extracted with dichloromethane. United organically the layers are washed with a solution of NaHCO 3and saturated salt solution, dried over MgSO4and concentrate to dryness. The residue is purified column chromatography (0-10% EtOAc-hexane)to give 2-substituted-4-methyl-5-nitrophenylacetylene (378 mg, yield 25%).

2-Substituted-4-methyl-5-NITROPHENOL

To a solution of 2-substituted-4-methyl-5-nitrophenylacetate (378 mg, 1.05 mmol) in CH2Cl2(5 ml) is added piperidine (1.0 ml). The solution was stirred at room temperature for 1 hour, adsorb on silica gel under reduced pressure and purified flash chromatography on silica gel (0-15% EtOAc-hexane)to give 2-substituted-4-methyl-5-NITROPHENOL (231 mg, yield 77%).

C-12; 2-Substituted-4-methyl-5-aminophenol

To a solution of 2-substituted-4-methyl-5-NITROPHENOL (231 mg, 1.6 mmol) in EtOH (2 ml) is added 5% of the mass. palladium-on-coal (10 mg). The mixture is stirred in hydrogen atmosphere (1 ATM.) during the night, and then filtered through celite. The filtrate is evaporated to dryness, obtaining the 2-substituted-4-methyl-5-aminophenol (C-12), which is used without further purification.

HPLC: retention time 2,52 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 258,3 m/z (MH+).

Example 9

2-tert-Butyl-4-bromophenol

To a solution of 2-tert-butylphenol (250 g, 1,67 mol) in CH3CN (1500 ml) is added NBS (300 g, 1,67 mol) at room temperature. the donkey complete addition the mixture is stirred at room temperature overnight and then the solvent is removed. Add petroleum ether (1000 ml) and the resulting white precipitate is filtered off. The filtrate is concentrated under reduced pressure, obtaining the crude 2-tert-butyl-4-bromophenol (380 g), which is used without further purification.

Methyl(2-tert-butyl-4-bromophenyl)carbonate

To a solution of 2-tert-butyl-4-bromophenol (380 g, 1,67 mol) in dichloromethane (1000 ml) was added Et3N (202 g, 2 mol) at room temperature. To the above solution is added dropwise methylchloroform (155 ml) at 0°C. After complete addition, the mixture is stirred at 0°C for 2 hours, quenched with a saturated solution of ammonium chloride and diluted with water. The organic layer is separated and washed with water and saturated salt solution, dried over Na2SO4and concentrate, receiving crude methyl(2-tert-butyl-4-bromophenyl)carbonate (470 g), which is used without further purification.

Methyl(2-tert-butyl-4-bromo-5-nitrophenyl)carbonate

Methyl(2-tert-butyl-4-bromophenyl)carbonate (470 g, 1,67 mol) is dissolved in concentrated H2SO4(1000 ml) at 0°C. are added in several Portions KNO3(253 g, 2.5 mol) for 90 minutes the Reaction mixture was stirred at 0°C for 2 hours and poured into ice water (20 l). The obtained precipitate was separated by filtration and thoroughly washed with water, dried and paracrystal byvaut of diethyl ether, receiving methyl(2-tert-butyl-4-bromo-5-nitrophenyl)carbonate (332 g, yield 60% for stage 3).

C-14-a; 2-tert-Butyl-4-bromo-5-NITROPHENOL

To a solution of methyl(2-tert-butyl-4-bromo-5-nitrophenyl)carbonate (121,5 g, 0,366 mol) in methanol (1000 ml) portions add potassium hydroxide (30,75 g, 0,549 mol). After complete addition, the mixture is stirred at room temperature for 3 hours and acidified with 1N. HCl solution to pH=7. The methanol is removed and water is added. The mixture is extracted with ethyl acetate and the organic layer is separated, dried over Na2SO4and concentrate, receiving 2-tert-butyl-4-bromo-5-NITROPHENOL (-14-) (100 g, yield 99%).

1-tert-Butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene

To a mixture of 2-tert-butyl-4-bromo-5-NITROPHENOL (-14-) (1.1 g, 4 mmol) and Cs2CO3(1.56 g, 4.8 mmol) in DMF (8 ml) add benzylbromide (500 μl, 4.2 mmol). The mixture is stirred at room temperature for 4 hours, diluted with H2Oh and twice extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After removal of solvent the residue is purified column chromatography (0-5% EtOAc-hexane)to give 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (1,37 g, yield 94%).

1H-NMR (400 MHz, CDCl3): δ a 7.62 (s, 1H), 7,53 (s, 1H), 7,43 (m, 5H), with 5.22 (s, 2H), of 1.42 (s, 9H).

1-tert-Butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nor is Robinson

A mixture of 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (913 mg, 2.5 mmol), KF (291 mg, 5 mmol), KBr (595 mg, 5 mmol), CuI (570 mg, 3 mmol), methylchlorothiazide (1.6 ml, 15 mmol) and DMF (5 ml) is stirred at a temperature of 125°C in a sealed tube overnight, cooled to room temperature, diluted with water and three times extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over anhydrous MgSO4. After removal of solvent the residue is purified column chromatography (0-5% EtOAc-hexane)to give 1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (591 mg, yield 67%).

1H-NMR (400 MHz, CDCl3): δ 7,66 (s, 1H), 7,37 (m, 5H), 7,19 (s, 1H), total of 5.21 (s, 2H), 1,32 (s, 9H).

C-14; 5-Amino-2-tert-butyl-4-cryptomaterial

To boiling under reflux to a solution of 1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (353 mg, 1.0 mmol) and ammonium formate (350 mg, 5.4 mmol) in EtOH (10 ml) is added 10%Pd/C (245 mg). The mixture is then refluxed for 2 hours, cooled to room temperature and filtered through celite. After removal of solvent the residue is purified column chromatography, obtaining 5-amino-2-tert-butyl-4-triptoreline (C-14) (120 mg, yield 52%).

1H-NMR (400 MHz, CDCl3): δ 7,21 (s, 1H), equal to 6.05 (s, 1H), 1,28 (s, 9H).

HPLC: retention time of 3.46 min, 10-99% CH3 CN, the analysis time of 5 minutes

ESI-MS: 234,1 m/z (MH+).

Example 10

The General scheme

a) ArB(OH)2, K2CO3Pd(PPh3)4H2O, DMF or ArB(OH)2, (dppf)PdCl2, K2CO3, EtOH; (b) H2, Raney Nickel, MeOH or HCO2NH4Pd/C, EtOH or SnCl2·2H2O.

A specific example

2-tert-Butyl-4-(2-ethoxyphenyl)-5-NITROPHENOL

To a solution of 2-tert-butyl-4-bromo-5-NITROPHENOL (-14-) (by 8.22 g, 30 mmol) in DMF (90 ml) is added 2-ethoxyphenylurea acid (5,48 g, 33 mmol), potassium carbonate (4,56 g, 33 mmol), water (10 ml) and Pd(PPh3)4(1.73 g, 1.5 mmol). The mixture is heated at 90°C for 3 hours in nitrogen atmosphere. The solvent is removed under reduced pressure. The residue is distributed between water and ethyl acetate. The combined organic layers washed with water and saturated salt solution, dried and purified column chromatography (petroleum ether-ethyl acetate=10:1)to give 2-tert-butyl-4-(2-ethoxyphenyl)-5-NITROPHENOL (9,2 g, yield 92%).

1H-NMR (DMSO-d6) δ 10,38 (s, 1H), was 7.36 (s, 1H), 7,28 (m, 2H), was 7.08 (s, 1H), 6,99 (t, 1H, J=7,35 Hz), 6,92 (d, 1H, J=8.1 Hz), of 3.84 (q, 2H, J=6.6 Hz), of 1.35 (s, 9H), of 1.09 (t, 3H, J=6.6 Hz).

ESI-MS: 314,3 m/z (MH+).

S-15; 2-tert-Butyl-4-(2-ethoxyphenyl)-5-aminophenol

To a solution of 2-tert-butyl-4-(2-ethoxyphenyl)-5-NITR the phenol (3.0 g, 9.5 mmol) in methanol (30 ml) was added Raney Nickel (300 mg). The mixture is stirred in hydrogen atmosphere (1 ATM.) at room temperature for 2 hours. The catalyst is filtered off and the filtrate concentrated. The residue is purified column chromatography (petroleum ether-ethyl acetate=6:1)to give 2-tert-butyl-4-(2-ethoxyphenyl)-5-aminophenol (S-15) (2.35 g, yield 92%).

1H-NMR (DMSO-d6) δ 8,89 (s, 1H), 7,19 (t, 1H, J=4, 2 Hz), 7,10 (d, 1H, J=1.8 Hz), was 7.08 (d, 1H, J=1.8 Hz), 6,94 (t, 1H, J=3.6 Hz), to 6.67 (s, 1H), 6,16 (s, 1H), 4,25 (s, 1H), 4,00 (q, 2H, J=6.9 Hz), 1.26 in (s, 9H), 1,21 (t, 3H, J=6.9 Hz).

ESI-MS: 286,0 m/z (MH+).

Other examples

S-16; 2-tert-Butyl-4-(3-ethoxyphenyl)-5-aminophenol

2-tert-Butyl-4-(3-ethoxyphenyl)-5-aminophenol (S-16) synthesized following the General scheme above, on the basis of 2-tert-butyl-4-bromo-5-NITROPHENOL (-14-and 3-ethoxyphenylacetic acid.

HPLC: retention time 2,77 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 286,1 m/z (MH+).

C-17; 2-tert-Butyl-4-(3-ethoxycarbonylphenyl)-5-aminophenol

2-tert-Butyl-4-(3-ethoxycarbonylphenyl)-5-aminophenol (C-17) synthesized following the General scheme above, on the basis of 2-tert-butyl-4-bromo-5-NITROPHENOL (-14-) and 3-(methoxycarbonyl)phenylboronic acid.

HPLC: retention time 2,70 min, 10-99% CH3/sub> CN, the analysis time of 5 minutes

ESI-MS: 300,5 m/z (MH+).

Example 11

1-tert-Butyl-2-methoxy-5-bromo-4-nitrobenzene

To a mixture of 2-tert-butyl-4-bromo-5-NITROPHENOL (-14-) (1.5 g, 5.5 mmol) and Cs2CO3(2.2 g, 6.6 mmol) in DMF (6 ml) add methyliodide (5150 μl, 8.3 mmol). The mixture is stirred at room temperature for 4 hours, diluted with H2Oh and twice extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After removal of solvent the residue is washed with hexane, obtaining 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (1.1 g, yield 69%).

1H-NMR (400 MHz, CDCl3): δ 7,58 (s, 1H), 7,44 (s, 1H), 3,92 (s, 3H), of 1.39 (s, 9H).

1-tert-Butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene

A mixture of 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (867 mg, 3.0 mmol), KF (348 mg, 6 mmol), KBr (714 mg, 6 mmol), CuI (684 mg, 3.6 mmol), methylchlorothiazide (2.2 ml, or 21.0 mmol) in DMF (5 ml) is stirred at a temperature of 125°C in a sealed tube overnight, cooled to room temperature, diluted with water and three times extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over anhydrous MgSO4. After removal of solvent the residue is purified column chromatography (0-5% EtOAc-hexane)to give 1-tert-butyl-2-methoxy-5-(Tr is permitil)-4-nitrobenzene (512 mg, yield 61%).

1H-NMR (400 MHz, CDCl3): δ 7,60 (s, 1H), 7,29 (s, 1H), 3,90 (s, 3H), of 1.33 (s, 9H).

S-18; 1-tert-Butyl-2-methoxy-5-(trifluoromethyl)-4-aminobenzoyl

To boiling under reflux to a solution of 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene (473 mg, 1.7 mmol) and ammonium formate (473 mg, 7,3 mmol) in EtOH (10 ml) is added 10%Pd/C (200 mg). The mixture is refluxed for 1 hour, cooled and filtered through celite. The solvent is removed by evaporation, getting 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-aminobenzoyl (S-18) (403 mg, yield 95%).

1H-NMR (400 MHz, CDCl3): δ 7,19 (s, 1H), 6,14 (s, 1H), was 4.02 (USS, 2H), 3,74 (s, 3H), 1,24 (s, 9H).

Example 12

S-27; 2-tert-Butyl-4-bromo-5-aminophenol

To a solution of 2-tert-butyl-4-bromo-5-NITROPHENOL (-14-) (12 g, while 43.8 mmol) in Meon (90 ml) was added Ni (2.4 g). The reaction mixture is stirred in hydrogen atmosphere (1 ATM.) within 4 hours. The mixture is filtered and the filtrate concentrated. The crude product is recrystallized from ethyl acetate and petroleum ether, receiving 2-tert-butyl-4-bromo-5-aminophenol (S-27) (7.2 g, yield 70%).

1H-NMR (DMSO-d6): δ 9.15, with (s, 1H), 6,91 (s, 1H), 6,24 (s, 1H), 4,90 (USS, 2H), 1,22 (s, 9H).

ESI-MS: 244,0 m/z (MH+).

Example 13

S-24; 2,4-di-tert-Butyl-6-(N-methylamino)phenol

A mixture of 2,4-di-tert-butyl-6-aminophenol (S-9) (5,08 g, 23 mmol), NaBH3CN (to 4.41 g, 70 mmol) and paraformaldehyde (2.1 g, 70 mmol) in methanol (50 ml) stirred at the boil under reflux for 3 hours. After removal of solvent the residue is purified column chromatography (petroleum ether-EtOAc=30:1)to give 2,4-di-tert-butyl-6-(N-methylamino)phenol (S-24) (800 mg, yield 15%).

1H-NMR (DMSO-d6): δ 8,67 (s, 1H), 6,84 (s, 1H), of 5.99 (s, 1H), 4,36 (sq,J=4,8 Hz, 1H), 2,65 (l,J=4,8 Hz, 3H), of 1.23 (s, 18H).

ESI-MS: 236,2 m/z (MH+).

Example 14

2-Methyl-2-phenylpropane-1-ol

To a solution of 2-methyl-2-phenylpropionic acid (82 g, 0.5 mol) in THF (200 ml) added dropwise brandibelle (2M, 100 ml) at a temperature of 0-5°C. the Mixture is stirred at this temperature for 30 min and then refluxed for 1 hour. After cooling, add methanol (150 ml) and water (50 ml). The mixture is extracted with EtOAc (3 times 100 ml) and the combined organic layers washed with water and saturated salt solution, dried over Na2SO4and concentrated, obtaining 2-methyl-2-phenylpropane-1-ol in the form of oil (70 g, yield 77%).

2-[(2-Methoxyethoxy)-1,1-dimethylethyl]benzene

To a suspension of NaH (29 g, 0.75 mol) in THF (200 ml) added dropwise a solution of 2-methyl-2-animproved-1-ol (75 g, 0.5 mol) in THF (50 ml) at 0°C. the Mixture is stirred at 20°C for 30 min and then added dropwise a solution of 1-bromo-2-methoxyethane (104 g, 0.75 mol) in THF (100 ml) at 0°C. the Mixture is stirred at a temperature of 20°C. overnight, poured into water (200 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers washed with water and saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography (silica gel, petroleum ether)to give 2-[(2-methoxyethoxy)-1,1-dimethylethyl]benzene in the form of oil (28 g, yield 27%).

1-[2-(2-Methoxyethoxy)-1,1-dimethylethyl]-4-nitrobenzene

To a solution of 2-[(2-methoxyethoxy)-1,1-dimethylethyl]benzene (52 g, 0.25 mol) in CHCl3(200 ml) add KNO3(50.5 g, 0.5 mol) and TMSCl (54 g, 0.5 mol). The mixture is stirred at 20°C for 30 min and then add AlCl3(95 g, 0.7 mol). The reaction mixture is stirred at 20°C for 1 hour and poured into ice water. The organic layer is separated and the aqueous layer was extracted with CHCl3(3 times 50 ml). The combined organic layers washed with water and saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography (silica gel, petroleum ether)to give 1-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-4-nitrobenzene (6 g, exit 10).

4-[2-(2-Methoxyethoxy)-1,1-dimethylethyl]phenylamine

A suspension of 1-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-4-nitrobenzene (8,1 g, 32 mmol) and Raney Nickel (1 g) in Meon (50 ml) is stirred in hydrogen atmosphere (1 ATM.) at room temperature for 1 hour. The catalyst is filtered off and the filtrate is concentrated, obtaining 4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenylamine (5.5 g, yield 77%).

4-[2-(2-Methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenylamino

To a solution of 4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenylamine (5.8 g, 26 mmol) in H2SO4(20 ml) is added KNO3(2,63 g, 26 mmol) at 0°C. After complete addition, the mixture is stirred at this temperature for 20 min and then poured into ice water. The mixture is extracted with EtOAc (3 times 50 ml). The combined organic layers washed with water and saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography (petroleum ether-EtOAc=100:1)to give 4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenylamino (5 g, 71%yield).

N-{4-[2-(2-Methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenyl}ndimethylacetamide

To a suspension of NaHCO3(10 g, 0.1 mol) in dichloromethane (50 ml) is added 4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenylamino (5 g, 30 mmol) and acetylchloride (3 ml, 20 mmol) at a temperature of 0-5°C. the Mixture is stirred overnight at a temperature of 15°C and the ATEM poured into water (200 ml). The organic layer is separated and the aqueous layer was extracted with dichloromethane (2 times 50 ml). The combined organic layers washed with water and saturated salt solution, dried over Na2SO4and concentrate to dryness, obtaining N-{4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenyl}ndimethylacetamide (5.0 g, yield 87%).

N-{3-Amino-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}ndimethylacetamide

A mixture of N-{4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenyl}ndimethylacetamide (5 g, 16 mmol) and Raney Nickel (1 g) in Meon (50 ml) is stirred in hydrogen atmosphere (1 ATM.) at room temperature for 1 hour. The catalyst is filtered off and the filtrate concentrated. The residue is purified column chromatography (petroleum ether-EtOAc=100:1)to give N-{3-amino-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}ndimethylacetamide (1.6 g, yield 35%).

N-{3-Hydroxy-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}ndimethylacetamide

To a solution of N-{3-amino-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}ndimethylacetamide (1.6 g, 5.7 mmol) in H2SO4(15%, 6 ml) is added NaNO2at a temperature of 0-5°C. the Mixture is stirred at this temperature for 20 min and then poured into ice water. The mixture is extracted with EtOAc (3 times 30 ml). The combined organic layers washed with water and saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography (petroleum ether-EtOA=100:1), receiving N-{3-hydroxy-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}ndimethylacetamide (0.7 g, yield 38%).

S-25; 2-(1-(2-Methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol

A mixture of N-{3-hydroxy-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}ndimethylacetamide (1 g, 3.5 mmol) and HCl (5 ml) is refluxed for 1 hour. The mixture is alkalinized solution of Na2CO3to pH=9 and then extracted with EtOAc (3 x 20 ml). The combined organic layers washed with water and saturated salt solution, dried over Na2SO4and concentrate to dryness. The residue is purified column chromatography (petroleum ether-EtOAc=100:1)to give 2-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol (S-25) (61 mg, yield 6%).

1H-NMR (CDCl3) δ 9,11 (users, 1H), of 6.96-6,98 (d, J=8 Hz, 1H), 6,26-6,27 (d, J=4 Hz, 1H), 6,17-to 6.19 (m, 1H), 3,68 at 3.69 (m, 2H), 3,56-3,59 (m, 4H), 3,39 (s, 3H), of 1.37 (s, 6H).

ESI-MS: 239,9 m/z (MH+).

Example 15

4,6-di-tert-Butyl-3-nitrocyclohexane-3,5-diene-1,2-dione

To a solution of 3,5-di-tert-butylcyclohexyl-3,5-diene-1,2-dione (4,20 g of 19.1 mmol) in acetic acid (115 ml) is added slowly HNO3(15 ml). The mixture is heated at 60°C for 40 min before pouring in N2About (50 ml). The mixture is left to stand at room temperature for 2 hours, then placed for 1 hour in an ice bath. Solid with eraut and washed with water, getting 4,6-di-tert-butyl-3-nitrocyclohexane-3,5-diene-1,2-dione (1.2 g, yield 24%).

1H-NMR (400 MHz, DMSO-d6): δ 6.89 in (s, 1H), 1.27mm (s, 9H), 1,24 (s, 9H).

4,6-di-tert-Butyl-3-nitrobenzene-1,2-diol

In a separating funnel, make a mixture of THF/N2About (1:1, 400 ml), 4,6-di-tert-butyl-3-nitrocyclohexane-3,5-diene-1,2-dione (4.59 g, 17.3 mmol) and Na2S2O4(3 g, 17.3 mmol). Separating funnel sealed and shaken for 2 min. the Mixture was diluted with EtOAc (20 ml). The layers are separated and the organic layer was washed with saturated salt solution, dried over MgSO4and concentrate, receiving 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (3.4 g, yield 74%), which is used without further purification.

1H-NMR (400 MHz, DMSO-d6): δ 9,24 (s, 1H), 8,76 (s, 1H), 6.87 in (s, 1H), of 1.35 (s, 9H), 1,25 (s, 9H).

S-26; 4,6-di-tert-Butyl-3-aminobenzo-1,2-diol

To a solution of 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (1.92 g, 7.2 mmol) in EtOH (70 ml) is added 5% of the mass. palladium-on-coal (200 mg). The mixture is stirred in hydrogen atmosphere (1 ATM.) within 2 hours. In the reaction mixture re-add 5% of the mass. palladium-on-coal (200 mg) and stirred under hydrogen atmosphere (1 ATM.) over the next 2 hours. The mixture is filtered through celite, the filtrate concentrated and purified column chromatography (10-40% ethyl acetate-hexane)to give 4,6-di-tert-butyl-3-aminobenzo-1,2-diol (S-26) (560 mg, yield 33%).

H-NMR (400 MHz, CDCl3): δ 7,28 (s, 1H), of 1.42 (s, 9H), to 1.38 (s, 9H).

Anilines

Example 1

The General scheme

A specific example

D-1; 4-Chlorobenzene-1,3-diamine

A mixture of 1-chloro-2,4-dinitrobenzene (100 mg, 0.5 mmol) and SnCl2·2H2O (1.12 g, 5 mmol) in ethanol (2.5 ml) was stirred at room temperature overnight. Add water and then the mixture is alkalinized to pH=7-8 with saturated solution of NaHCO3. The solution is extracted with ethyl acetate. The combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated, obtaining 4-chlorobenzene-1,3-diamine (D-1) (79 mg, quantitative yield).

HPLC: retention time min 0,38, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 143,1 m/z (MH+).

Other examples

D-2; 4,6-Dichlorobenzene-1,3-diamine

4,6-Dichlorobenzene-1,3-diamine (D-2) synthesized following the General scheme above, on the basis of 1,5-dichloro-2,4-dinitrobenzene. Yield (95%).

HPLC: retention time of 1.88 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 177,1 m/z (MH+).

D-3; 4-Methoxybenzoyl-1,3-diamine

4-Methoxybenzoyl-1,3-diamine (D-3) synthesized following the General scheme above, is stepping down from 1-methoxy-2,4-dinitrobenzene. Output (quantitative).

HPLC: retention time min 0,31, 10-99% CH3CN, the analysis time of 5 minutes

D-4; 4-Cryptomaterial-1,3-diamine

4-Cryptomaterial-1,3-diamine (D-4) synthesized following the General scheme above, on the basis of 2,4-dinitro-1-cryptomaterial. Output (89%).

HPLC: retention time of 0.91 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 193.3 M. m/z (MH+).

D-5; 4-Propoxyphenol-1,3-diamine

4-Propoxyphenol-1,3-diamine (D-5) synthesized following the General scheme above starting from 5-nitro-2-propoxyphenyl. Output (79%).

HPLC: retention time of 0.54 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 167,5 m/z (MH+).

Example 2

The General scheme

a) HNO3H2SO4; (b) SnCl2·2H2O, EtOH or H2Pd/C, MeOH.

A specific example

2,4-Dinitropropanol

The solution propylbenzene (10 g, 83 mmol) in concentrated H2SO4(50 ml) cooled to 0°C for 30 min and added in several portions a solution of H2SO4(50 ml) and fuming HNO3(25 ml), previously cooled to 0°C within 15 minutes Later, the mixture is stirred at a temperature of 0°C within 30 min and then allowed to warm to room temperature. The mixture is then poured into a mixture of ice (200 g) with water (100 ml) and extracted with diethyl ether (2 times 100 ml). The combined extracts washed with N2O (100 ml) and saturated salt solution (100 ml), dried over MgSO4, filtered and concentrated, obtaining 2,4-dinitropropanol (15.6 g, yield 89%).

1H-NMR (CDCl3, 300 MHz) δ 8,73 (d, J=2.2 Hz, 1H), scored 8.38 (DD, J=8,3, J=2,2, 1H), 7,6 (d, J=8.5 Hz, 1H), 2,96 (DD, 2H), 1,73 (m, 2H), 1.06 a (t, J=7.4 Hz, 3H).

D-6; 4-Propylbenzoyl-1,3-diamine

To a solution of 2,4-dinitropropanol (2,02 g, 9.6 mmol) in ethanol (100 ml) add SnCl2(9,9 g, 52 mmol), and then concentrated HCl (10 ml). The mixture is refluxed for 2 hours, poured into ice water (100 ml) and neutralized with solid sodium bicarbonate. Then the solution is alkalinized 10%NaOH solution to pH~10, extracted with diethyl ether (2 times 100 ml). The combined organic layers washed with saturated salt solution (100 ml), dried over MgSO4, filtered and concentrated, obtaining 4-propylbenzoyl-1,3-diamine (D-6) (1.2 g, yield 83%). No further purification for use in the next stage; however, the product is not stable over a long period of time.

1H-NMR (CDCl3, 300 MHz) δ PC 6.82 (d, J=7.9 Hz, 1H), 6,11 (DD, J=7,5, J=2.2 Hz, 1H), the 6.06 (d, J=2.2 Hz, 1H), 3,49 (users, 4H, NH2), of 2.38 (t, J=7.4 Hz, 2H), 1,58 (m, 2H), and 0.98 (t, J=7.2 Hz, 3H).

ESI-MS: 151,5 m/z (MH +).

Other examples

D-7; 4-Ethylbenzene-1,3-diamine

4-Ethylbenzene-1,3-diamine (D-7) synthesized following the General scheme above, on the basis of ethylbenzene. Total yield (76%).

D-8; 4-Isopropylbenzene-1,3-diamine

4-Isopropylbenzene-1,3-diamine (D-8) synthesized following the General scheme above, on the basis of cumene. Total yield (78%).

D-9; 4-tert-Butylbenzoyl-1,3-diamine

4-tert-Butylbenzoyl-1,3-diamine (D-9) synthesized following the General scheme above, on the basis of tert-butylbenzene. Total yield (48%).

1H-NMR (400 MHz, CDCl3): δ 7,01 (d, J=8,3 Hz, 1H), 6,10 (DD, J=2,4, 8,3 Hz, 1H), 6,01 (d, J=2.4 Hz, 1H), 3,59 (user., 4H), to 1.37 (s, 9H);

13C-NMR (100 MHz, CDCl3): δ 145,5, 145,3, 127,6, 124,9, 105,9, 104,5, 33,6, 30,1.

ESI-MS: 164,9 m/z (MH+).

Example 3

The General scheme

a) KNO3H2SO4; (b) (i) HNO3H2SO4; (ii) Na2S, S, H2O; c) Boc2O, NaOH, THF; d) H2Pd/C, MeOH.

A specific example

4-tert-Butyl-3-nitrophenylamino

To a mixture of 4-tert-butylbenzylamine (10.0 g, 67,01 mmol), dissolved in H2SO4(98%, 60 ml)is added slowly KNO3(8.1 g, 80,41 mmol) at te is the temperature of 0°C. After complete addition, the reaction mixture is left to warm to room temperature and stirred over night. The mixture was then poured into ice water and alkalinized with saturated solution of NaHCO3to pH=8. The mixture is repeatedly extracted with CH2Cl2. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography (petroleum ether-EtOAc=10:1)to give 4-tert-butyl-3-nitrophenylamino (10 g, yield 77%).

tert-Butyl ester (4-tert-butyl-3-nitrophenyl)carbamino acid

A mixture of 4-tert-butyl-3-nitrophenylamino (4.0 g, to 20.6 mmol) and Vos2On (4.72 in g, 21.6 mmol) in NaOH solution (2n., 20 ml) and THF (20 ml) was stirred at room temperature overnight. THF is removed under reduced pressure. The residue is dissolved in water and extracted with CH2Cl2. The organic layer was washed with NaHCO3and saturated salt solution, dried over Na2SO4and concentrate, receiving tert-butyl ester (4-tert-butyl-3-nitrophenyl)carbamino acid (4.5 g, yield 74%).

D-10; tert-Butyl methyl ether (3-amino-4-tert-butylphenyl)carbamino acid

A suspension of tert-butyl methyl ether (4-tert-butyl-3-nitrophenyl)carbamino acid (3.0 g, 10,19 mol) and 10%Pd/C (1 g) in Meon (40 ml) is stirred in hydrogen atmosphere (1 ATM. at room temperature over night. After filtration the filtrate is concentrated and the residue purified column chromatography (petroleum ether-EtOAc=5:1)to give tert-butyl methyl ether (3-amino-4-tert-butylphenyl)carbamino acid (D-10) as a brown oil (2.5 g, yield 93%).

1H-NMR (CDCl3) δ 7,10 (d, J=8,4 Hz, 1H), 6,92 (s, 1H), 6,50-6,53 (m, 1H), 6,36 (s, 1H), 3,62 (users, 2H), 1,50 (s, 9H), to 1.38 (s, 9H).

ESI-MS: 528,9 m/z (2M+H+).

Other examples

D-11; tert-Butyl methyl ether (3-amino-4-isopropylphenyl)carbamino acid

tert-Butyl methyl ether (3-amino-4-isopropylphenyl)carbamino acid (D-11) synthesized following the General scheme above, on the basis of cumene. Total yield (56%).

D-12; tert-Butyl methyl ether (3-amino-4-ethylphenyl)carbamino acid

tert-Butyl methyl ether (3-amino-4-ethylphenyl)carbamino acid (D-12) synthesized following the General scheme above, on the basis of ethylbenzene. Total yield (64%).

1H-NMR (CD3OD, 300 MHz) δ 6.87 in (d, J=8.0 Hz, 1H), 6.87 in (d, J=8.0 Hz, 1H), for 6.81 (d, J=2,2 1H), 6,63 (DD, J=8,1 J=2,2 1H), 2,47 (kV, J=7,4 Hz, 2H).

ESI-MS: 237,1 m/z (MH+).

D-13; tert-Butyl methyl ether (3-amino-4-propylphenyl)carbamino acid

tert-Butyl methyl ether (3-amino-4-propylphenyl)carbamino acid (D-13) synthesize, SL is blowing the overall scheme of things above, on the basis of propylbenzene. Total yield (48%).

Example 4

Benzyl ester of (3-amino-4-tert-butylphenyl)carbamino acid

A solution of 4-tert-butylbenzoyl-1,3-diamine (D-9) (657 mg, 4 mmol) and pyridine (of 0.39 ml, 4.8 mmol) in a mixture of CH2Cl2/Meon (12/1,8 ml) cooled to 0°C and added dropwise a solution of benzylbromide (0.51 ml, 3.6 mmol) in CH2Cl2(8 ml) for 10 minutes the Mixture is stirred at 0°C for 15 min, then warmed to room temperature. After 1 hour, the mixture was washed with 1M citric acid solution (2 x 20 ml), saturated aqueous sodium bicarbonate (20 ml), dried (Na2SO4), filtered and concentrated in vacuo, obtaining the crude benzyl ether (3-amino-4-tert-butylphenyl)carbamino acid in the form of a brown viscous resin (0.97 g), which is used without further purification.

1H-NMR (400 MHz, CDCl3) δ 7,41-to 7.32 (m, 6H,), 7,12 (d, J=8.5 Hz, 1H) 6.89 in (users, 1H), to 6.57 (DD, J=2,3, 8.5 Hz, 1H), 5,17 (s, 2H), 3,85 (users, 2H), to 1.38 (s, 9H).

13C-NMR (100 MHz, CDCl3, mixture of rotamers) δ 153,3 (OSiR.), 145,3, 136,56, 136,18, 129,2, 128,73, 128,59, 128,29, 128,25, 127,14, 108,63 (OSiR.), 107,61 (OSiR.), 66,86, 33,9, 29,7.

ESI-MS: 299,1 m/z (MH+).

Benzyl ether (4-tert-butyl-3-formylamino)carbamino acid

A solution of benzyl ether (3-amino-4-tert-bout fenil)carbamino acid (0.97 g, 3.25 mmol) and pyridine (0,43 ml of 5.25 mmol) in CH2Cl2(7.5 ml) is cooled to 0°C and within 2 minutes added dropwise a solution of mixed formic-acetic anhydride (3.5 mmol, obtained by mixing formic acid (158 μl, 4.2 mmol, 1.3 EQ.) and acetic anhydride (0,32 ml, 3.5 mmol, 1.1 equiv.) undiluted and aged for 1 hour) in CH2Cl2(2.5 ml). After complete addition, the mixture is left to warm to room temperature, after which the sediment is deposited, and the resulting suspension is stirred over night. The mixture was washed with 1M citric acid solution (2 x 20 ml), saturated aqueous sodium bicarbonate (20 ml), dried (Na2SO4) and filtered. From the murky mixture is deposited a thin layer of solids on top of the dryer, and HPLC analysis shows that this is required of formamide. The filtrate is concentrated to approximately 5 ml and diluted with hexane (15 ml) for further deposition of formamide. The desiccant (Na2SO4) suspended in methanol (50 ml), filtered and the filtrate combined with the substance recrystallized from a mixture of CH2Cl2/hexane. The resulting mixture was concentrated, obtaining benzyl ester (4-tert-butyl-3-formylamino)carbamino acid in the form of not-quite-white solid (650 mg, yield 50% in stage 2).1H and13/sup> C-NMR (CD3OD) show that the product is in the form of a mixture of rotamers.

1H-NMR (400 MHz, CD3OD, mixture of rotamers) δ of 8.27 (s, 1H), 8,17 (s, 1H,-b), 7,42-7,26 (m, 8H), to 5.17 (s, 1H), 5,15 (s, 1H,-b), a 4.86 (s, 2H), of 1.37 (s, 9H-a)of 1.36 (s, 9H-b)

13C-NMR (100 MHz, CD3OD, mixture of rotamers) δ 163,9, 163,5, 155,8, 141,40, 141,32, 139,37, 138,88, 138,22, 138,14, 136,4, 135,3, 129,68, 129,65, 129,31, 129,24, 129,19, 129,13, 128,94, 128,50, 121,4 (OSiR.), 118,7 (OSiR.), 67,80, 67,67, 35,78, 35,52, 31,65, 31,34.

ESI-MS: 327,5 m/z (MH+).

N-(5-Amino-2-tert-butylphenyl)formamid

In a flask with a capacity of 100 ml is administered benzyl ester (4-tert-butyl-3-formylamino)carbamino acid (650 mg, 1,99 mmol), methanol (30 ml) and 10%Pd/C (50 mg) and stirred under hydrogen atmosphere (1 ATM.) for 20 hours. Add CH2Cl2(5 ml) to quench the catalyst, the mixture was then filtered through celite and concentrated, obtaining N-(5-amino-2-tert-butylphenyl)formaldehyde in the form of not-quite-white solid (366 mg, yield 96%). Rocamarina mixture according to the1H and13C-NMR (DMSO-d6).

1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 9,24 (d, J=10.4 Hz, 1H), 9.15, with (s, 1H), 8,23 (d, J=1.5 Hz, 1H), of 8.06 (d, J=10.4 Hz, 1H), 7,06 (d, J=8.5 Hz, 1H), 7,02 (d, J=8.5 Hz, 1H), 6,51 (d, J=2.5 Hz, 1H), 6,46 (DD, J=2.5 and 8.5 Hz, 1H), 6,39 (DD, J=2.5 and 8.5 Hz, 1H), 6,29 (d, J=2.5 Hz, 1H), of 5.05 (s, 2H), is 4.93 (s, 2H), 1.27mm (s, N).

13C-NMR (100 MHz, DMSO-d6, mixture of rotamers) δ 164,0, 160,4, 147,37, 146,74, 135,38, 135,72, 132,48, 131,59, 127,31, 126,69, 115,15, 115,01, 112,43, 112,00, 33,92, 33,57, 31,33, 30,92.

ESI-MS: 193,1 m/z (MH +).

D-14; 4-tert-Butyl-N3-methylbenzo-1,3-diamine

In a flask with a capacity of 100 ml injected N-(5-amino-2-tert-butylphenyl)formamid (340 mg, 1.77 mmol) and purge with nitrogen. Add THF (10 ml) and the solution cooled to 0°C. for 2 minutes, add a solution of sociallyengaged in THF (4.4 ml, 1M solution). Then, the mixture is left to warm to room temperature. After boiling under reflux for 15 hours a yellow suspension is cooled to a temperature of 0°C, quenched with water (170 ml), 15%aqueous NaOH solution (170 ml) and water (510 ml), are added sequentially and stirred at room temperature for 30 minutes the Mixture is filtered through celite and the filter cake washed with methanol (50 ml). The combined filtrates concentrated in vacuo, obtaining a gray-brown solid, which was partitioned between chloroform (75 ml) and water (50 ml). The organic layer was separated, washed with water (50 ml), dried (Na2SO4), filtered and concentrated, obtaining 4-tert-butyl-N3-methylbenzo-1,3-diamine (D-14) as a brown oil that solidifies upon standing (313 mg, yield 98%).

1H-NMR (400 MHz, CDCl3) δ 7,01 (d, J=8,1 Hz, 1H), equal to 6.05 (DD, J=2,4, 8,1 Hz, 1H), 6,03 (d, J=2.4 Hz, 1H), 3,91 (users, 1H), 3,52 (users, 2H), 2,86 (s, 3H), of 1.36 (s, 9H).

13C-NMR (100 MHz, CDCl3): δ 148,4, 145,7, 127,0, 124,3, 103,6, 98,9, 33,5, 31,15, 30,31

ESI-MS: 179,1 m/z (MH+).

Example 5

The General scheme

A specific example

2,4-Dinitropropanol

The solution propylbenzene (10 g, 83 mmol) in concentrated H2SO4(50 ml) cooled to 0°C for 30 min and added in several portions a solution of concentrated H2SO4(50 ml) and fuming HNO3(25 ml), previously cooled to 0°C, for 15 minutes the Mixture is stirred at 0°C for an additional 30 minutes and then allowed to warm to room temperature. The mixture is then poured into a mixture of ice (200 g) with water (100 ml) and extracted with diethyl ether (2 times 100 ml). The combined extracts washed with N2O (100 ml) and saturated salt solution (100 ml), dried over MgSO4, filtered and concentrated, obtaining 2,4-dinitropropanol (15.6 g, yield 89%).

1H-NMR (CDCl3, 300 MHz) δ 8,73 (d, J=2.2 Hz, 1H), scored 8.38 (DD, J=8,3, 2.2 Hz, 1H), 7,6 (d, J=8.5 Hz, 1H), 2,96 (m, 2H), 1,73 (m, 2H), 1.06 a (t, J=7.4 Hz, 3H).

4-Propyl-3-nitroaniline

A suspension of 2,4-dinitropropanol (2 g, 9.5 mmol) in N2O (100 ml) is refluxed and vigorously stirred. Added dropwise within 45 minutes translucent orange-red solution of polysulfide (300 ml, 10 equiv.) pre-recip the config by heating managerat of sodium sulfide (10.0 g), powder sulfur (2,60 g) and H2O (400 ml). Red-brown solution was refluxed for 1.5 hours. The mixture is cooled to a temperature of 0°C and then extracted with diethyl ether (2 x 200 ml). The combined organic extracts dried over MgSO4, filtered and concentrated under reduced pressure, obtaining 4-propyl-3-nitroaniline (1.6 g, yield 93%), which is used without further purification.

tert-Butyl methyl ether (3-nitro-4-propylphenyl)carbamino acid

4-Propyl-3-nitroaniline (1,69 g, 9.4 mmol) was dissolved in pyridine (30 ml) under stirring. Add the BOC-anhydride (2,05 g, 9.4 mmol). The mixture is stirred and refluxed for 1 hour, then the solvent is removed in vacuum. The oil obtained is again dissolved in CH2Cl2(300 ml) and washed with water (300 ml) and saturated salt solution (300 ml), dried over Na2SO4filter and concentrate. Crude oil, which contains both monocularly and bis-acylated microproduct, purified column chromatography (0-10% CH2Cl2-MeOH)to give tert-butyl methyl ether (3-nitro-4-propylphenyl)carbamino acid (2.3 g, yield 87%).

tert-Butyl methyl ether(3-nitro-4-propylphenyl)carbamino acid

To a solution of tert-butyl methyl ether (3-nitro-4-propylphenyl)carbamino acid (200 mg, 0.71 mmol) in the IPA (5 ml) is added Ag 2O (1.0 g, 6.0 mmol), then methyliodide (0,20 ml, 3.2 mmol). The resulting suspension is stirred at room temperature for 18 hours and filtered through a layer of celite. The filter cake was washed with CH2Cl2(10 ml). The filtrate was concentrated in vacuo. The crude oil is purified column chromatography (0-10% CH2Cl2-MeOH)to give tert-butyl methyl ether(3-nitro-4-propylphenyl)carbamino acid as a yellow oil (110 mg, yield 52%).

1H-NMR (CDCl3, 300 MHz) δ for 7.78 (d, J=2.2 Hz, 1H), 7,42 (DD, J=8,2, 2.2 Hz, 1H), 7,26 (d, J=8,2 Hz, 1H), 3.27 to (s, 3H), of 2.81 (t, J=7.7 Hz, 2H), of 1.66 (m, 2H), 1.61 of (s, 9H), of 0.97 (t, J=7.4 Hz, 3H).

D-15; tert-Butyl methyl ether (3-amino-4-propylphenyl)methylcarbamate acid

To a solution of tert-butyl methyl ether(3-nitro-4-propylphenyl)carbamino acid (110 mg, of 0.37 mmol) in EtOAc (10 ml) is added 10%Pd/C (100 mg). The resulting suspension is stirred at room temperature in an atmosphere of H2(1 ATM.) within 2 days. The course of the reaction is controlled by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was filtered through a layer of celite. The filtrate was concentrated in vacuo, obtaining tert-butyl methyl ether (3-amino-4-propylphenyl)methylcarbamate acid (D-15) as a colourless crystalline compound (80 mg, yield 81%).

ESI-MS: 265,3 m/z (MH+).

Other examples

D-16; tert-Butyl methyl ether (3-amino-4-ethylphenyl)methylcarbamate acid

tert-Butyl methyl ether (3-amino-4-ethylphenyl)methylcarbamate acid (D-16) synthesized following the General scheme above, on the basis of ethylbenzene. Total yield (57%).

D-17; tert-Butyl methyl ether (3-amino-4-isopropylphenyl)methylcarbamate acid

tert-Butyl methyl ether (3-amino-4-isopropylphenyl)methylcarbamate acid (D-17) synthesized following the General scheme above, on the basis of cumene. Total yield (38%).

Example 6

2'-Ethoxy-2,4-dinitrobiphenyl

In the pressure vessel, enter 2-ethoxyphenylurea acid (0.66 g, 4.0 mmol), KF (0,77 g, 13 mmol), Pd2(dba)3(16 mg, 0.02 mmol) and 2,4-dinitrophenol (0,99 g, 4.0 mmol) in THF (5 ml). The vessel is rinsed with argon for 1 min, then add three-tert-butylphosphine (0.15 ml, 0.48 mmol, 10%solution in hexano). The reaction vessel is rinsed with argon for an additional 1 min, sealed and heated at 80°C during the night. After cooling to room temperature the solution is filtered through a layer of celite. The filter cake was washed with CH2Cl2(10 ml) and the combined organic extracts are concentrated under reduced pressure, poluchenierazreshenija product, 2'-ethoxy-2,4-dinitrobiphenyl (0.95 g, yield 82%). Further purification is not carried out.

1H-NMR (300 MHz, CDCl3) δ is 8.75 (s, 1H), 8,43 (d, J=8.7 Hz, 1H), 7,60 (d, J=8,4 Hz, 1H), 7,40 (t, J=7.8 Hz, 1H), 7,31 (d, J=7.5 Hz, 1H), was 7.08 (t, J=7.5 Hz, 1H), to 6.88 (d, J=8,4 Hz, 1H), 3,44 (kV, 7=6.6 Hz, 2H), 1,24 (t, J=6,6 Hz, 3H).

HPLC: retention time of 3.14 min, 10-100% CH3CN, gradient 5 minutes

2'-Ethoxy-2-nitrobiphenyl-4-ylamine

Clear orange-red solution of polysulfide (120 ml, 7.5 equiv.) previously obtained by heating the monohydrate of sodium sulfide (10 g), sulfur (1.04 g) and water (160 ml), added dropwise at a temperature of 90°C for 45 min to a suspension of 2'-ethoxy-2,4-dinitrobiphenyl (1.2 g, 4.0 mmol) in water (40 ml). Red-brown solution was refluxed for 1.5 hours. The mixture is cooled to room temperature and add solid NaCl (5 g). The solution is extracted with CH2Cl2(3 times 50 ml) and the combined organic extracts are concentrated, obtaining 2'-ethoxy-2-nitrobiphenyl-4-ylamine (0,98 g, yield 95%), which is used in the next stage without further purification.

1H-NMR (300 MHz, CDCl3) δ 7,26 (m, 2H), 7,17 (d, J=2.7 Hz, 1H), 7,11 (d, J=7.8 Hz, 1H), 7,00 (t, J=6,9 Hz, 1H), 6,83 (m, 2H), 3,91 (kV, J=6,9 Hz, 2H), 1,23 (t, J=7.2 Hz, 3H).

HPLC: retention time of 2.81 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 259,1 m/z (MH+).

tert-Butyl ether (2'-ethoxy-2-nitrobiphenyl-4-yl)carbamino acid

A mixture of 2'-ethoxy-2-nitrobiphenyl-4-ylamine (0,98 g, 4.0 mmol) and Vos2Of (2.6 g, 12 mmol) is heated jet air dryer. After spending the initial substances, according to TLC, the crude mixture was purified flash chromatography (silica gel, CH2Cl2)to give tert-butyl ether (2'-ethoxy-2-nitrobiphenyl-4-yl)carbamino acid (1.5 g, yield 83%).

1H-NMR (300 MHz, CDCl3) δ to 7.99 (s, 1H), 7,55 (d, J=8,4 Hz, 1H), 7,25 (m, 3H), of 6.99 (t, J=7.5 Hz, 1H), PC 6.82 (m, 2H), 3,88 (kV, J=6,9 Hz, 2H), 1,50 (s, 9H), of 1.18 (t, J=6.9 Hz, 3H).

HPLC: retention time 3,30 min, 10-100% CH3CN, gradient 5 minutes

D-18; tert-Butyl ether (2'-ethoxy-2-aminobiphenyl-4-yl)carbamino acid

To a solution of NiCl2·6H2O (0.26 g, 1.1 mmol) in EtOH (5 ml) is added NaBH4(40 mg, 1.1 mmol) at a temperature of -10°C. There is a gas and forms a black precipitate. After stirring for 5 minutes and add a solution of tert-butyl methyl ether (2'-ethoxy-2-nitrobiphenyl-4-yl)carbamino Islami (0.50 g, 1.1 mmol) in EtOH (2 ml). Then add additional NaBH4(80 mg, 60 mmol) in 3 portions over 20 minutes the Reaction mixture was stirred at 0°C for 20 min, then add the NH4OH (4 ml, 25%aqueous solution). The resulting solution was stirred for 20 minutes. The crude mixture is filtered through a small layer of silica gel. A silica gel layer was washed with 5%RAS is a thief Meon in CH 2Cl2(10 ml) and the combined organic extracts are concentrated under reduced pressure, obtaining tert-butyl ether (2'-ethoxy-2-aminobiphenyl-4-yl)carbamino acid (D-18) (0.36 g, quantitative yield), which is used without further purification.

HPLC: retention time 2,41 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 329,3 m/z (MH+).

Example 7

D-19; N-(3-Amino-5-triptoreline)methanesulfonamide

A solution of 5-cryptomaterial-1,3-diamine (250 mg, of 1.42 mmol) in pyridine (0,52 ml) and CH2Cl2(6.5 ml) cooled to 0°C. Slowly add methanesulfonanilide (171 mg, 1,49 mmol) with such speed, that the solution temperature remained below 10°C. the Mixture is stirred at a temperature of ~8°C and then, after 30 minutes, allowed to warm to room temperature. After stirring at room temperature for 4 hours the reaction is nearly completed, according to GHMC analysis. The reaction mixture was quenched with saturated aqueous NH4Cl (10 ml), extracted with CH2Cl2(4 x 10 ml), dried over Na2SO4, filtered and concentrated, obtaining N-(3-amino-5-triptoreline)-methanesulfonamide (D-19in the form of a reddish semi-solid substances (0.35 g, yield 97%), which is used without further purification.

1NMR (CDCl 3, 300 MHz): δ 6,76 (m, 1H), 6,70 (m, 1H), 6,66(s, 1H), to 3.02 (s, 3H).

ESI-MS: 255,3 m/z (MH+).

Cyclic amines

Example 1

7-Nitro-1,2,3,4-tetrahydroquinolin

To a mixture of 1,2,3,4-tetrahydroquinoline (20,0 g, 0.15 mol), dissolved in H2SO4(98%, 150 ml)is added slowly KNO3(18.2 g, 0.18 mol) at 0°C. the Reaction mixture was left to warm to room temperature and stirred over night. The mixture is then poured into ice water and alkalinized with saturated solution of NaHCO3to pH=8. After extraction of CH2Cl2the combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography (petroleum ether-EtOAc, 10:1)to give 7-nitro-1,2,3,4-tetrahydroquinolin (6.6 g, yield 25%).

tert-Butyl ester of 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid

A mixture of 7-nitro-1,2,3,4-tetrahydroquinoline (4.0 g, 5,61 mmol), BOC2(1.29 g, of 5.89 mmol) and DMAP (0.4 g) in CH2Cl2stirred at room temperature overnight. After dilution with water the mixture is extracted with CH2Cl2. The combined organic layers washed with NaHCO3and saturated salt solution, dried over Na2SO4and concentrate, receiving tert-Putilov the th ether 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid, which is used in the next stage without further purification.

DC-1; tert-Butyl 7-amino-3,4-dihydroquinoline-1(2H)-carboxylate

A suspension of the crude tert-butyl methyl ether 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid (4.5 g, 16.2 mol) and 10%Pd/C (0.45 g) in the Meon (40 ml) stirred in an atmosphere of H2(1 ATM.) at room temperature over night. After filtration the filtrate is concentrated and the residue purified column chromatography (petroleum ether-EtOAc, 5:1)to give tert-butyl 7-amino-3,4-dihydroquinoline-1(2H)-carboxylate (DC-1) as a brown solid (1.2 g, yield 22% over 2 stages).

1H-NMR (CDCl3) δ to 7.15 (d, J=2 Hz, 1H), at 6.84 (d, J=8 Hz, 1H), 6,36-6,38 (m, 1H), 3,65-3,68 (m, 2H), 3,10 (users, 2H), 2,66 (t, J=6.4 Hz, 2H), 1,84-1,90 (m, 2H), of 1.52 (s, 9H).

ESI-MS: 496,8 m/z (2M+H+).

Example 2

3-(2-Hydroxyethyl)-1,3-dihydroindol-2-he

Stir the mixture oxyindole (5.7 g, 43 mmol) and Raney Nickel (10 g) in ethane-1,2-diole (100 ml) is heated in the autoclave. After completion of the reaction the mixture is filtered and the excess diol is removed in vacuum. The residual oil is triturated in hexane, obtaining 3-(2-hydroxyethyl)-1,3-dihydroindol-2-it is in the form of a colorless crystalline solid (4.6 g, yield 70%).

1,2-Dihydro-3-Spiro-1'-cyclopropyl-1H-indole-2-he

It is aStore 3-(2-hydroxyethyl)-1,3-dihydroindol-2-she (4.6 g, 26 mmol) and triethylamine (10 ml) in CH2Cl2(100 ml) was added dropwise MsCl (3.4 g, 30 mmol) at -20°C. Then the mixture is left to warm to room temperature and stirred over night. The mixture is filtered and the filtrate concentrated in vacuo. The residue is purified column chromatography, obtaining the crude 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole-2-it is in the form of a yellow solid (2.5 g), which are used directly in the next stage.

1,2-Dihydro-3-Spiro-1'-cyclopropyl-1H-indol

To a solution of 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole-2-she (2.5 g, crude) in THF (50 ml) was added in several portions LiAlH4(2 g, 52 mmol). After boiling the mixture under reflux it poured on crushed ice, alkalinized with an aqueous solution of ammonia to pH=8 and extracted with EtOAc. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate, receiving crude 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole as a yellow solid (about 2 g), which are used directly in the next stage.

6-Nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indol

To a cooled solution (temperature : from -5°C to -10about(C) NaNO3(1.3 g, of 15.3 mmol) in H2SO4(98%, 30 ml) was added dropwise 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (2 g, neocidin the first) for 20 minutes After complete addition, the reaction mixture is stirred for 40 min and poured on crushed ice (20 g). The cooled mixture was then alkalinized NH4OH and extracted with EtOAc. The organic layer was washed with saturated salt solution, dried over Na2SO4and concentrate under reduced pressure, obtaining 6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole in the form of a dark gray solid (1.3 g).

1-Acetyl-6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indol

NaHCO3(5 g) is suspended in a solution of 6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (1.3 g, crude) in CH2Cl2(50 ml). During vigorous stirring added dropwise acetylchloride (720 mg). The mixture is stirred for 1 hour and filtered. The filtrate was concentrated in vacuo. The residue is purified column flash chromatography on silica gel, receiving 1-acetyl-6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (0.9 g, yield 15% for 4 steps).

DC-2; 1-Acetyl-6-amino-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indol

A mixture of 1-acetyl-6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (383 mg, 2 mmol) and Pd/C (10%, 100 mg) in EtOH (50 ml) was stirred at room temperature in an atmosphere of H2(1 ATM.) within 1.5 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with a mixture of HCl/MeOH, getting 1-azet is l-6-amino-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole ( DC-2) (300 mg, yield 90%) as hydrochloride.

Example 3

Phenylamide 3-methylbut-2-ene acid

A mixture of 3-methylbut-2-ene acid (100 g, 1 mol) and SOCl2(119 g, 1 mol) is refluxed for 3 hours. The excess SOCl2removed under reduced pressure. Add CH2Cl2(200 ml), then aniline (93 g, 1.0 mol) in Et3N (101 g, 1 mol) at 0°C. the Mixture is stirred at room temperature for 1 hour and quenched with a solution of HCl (5%, 150 ml). The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers washed with water (2 times 100 ml) and saturated salt solution (100 ml), dried over Na2SO4and concentrate, getting phenylamide 3-methylbut-2-ene acid (120 g, yield 80%).

4,4-Dimethyl-3,4-dihydro-1H-quinoline-2-he

AlCl3(500 g, 3.8 mol) is carefully added to the suspension phenylamide 3-methylbut-2-ene acid (105 g, 0.6 mol) in benzene (1000 ml). The reaction mixture is stirred at a temperature of 80°C. overnight and poured into ice water. The organic layer is separated and the aqueous layer was extracted with ethyl acetate (3 times 250 ml). The combined organic layers washed with water (2 times 200 ml) and saturated salt solution (200 ml), dried over Na2SO4concentration is irout, getting 4,4-dimethyl-3,4-dihydro-1H-quinoline-2-he (90 g, yield 86%).

4,4-Dimethyl-1,2,3,4-tetrahydroquinolin

A solution of 4,4-dimethyl-3,4-dihydro-1H-quinoline-2-it (35 g, 0.2 mol) in THF (100 ml) was added dropwise to a suspension of LiAlH4(18 g, 0.47 mol) in THF (200 ml) at 0°C. After complete addition, the mixture is stirred at room temperature for 30 min and then slowly heated to the boiling temperature under reflux for 1 hour. The mixture is then cooled to a temperature of 0°C. Carefully add water (18 ml) and NaOH solution (10%, 100 ml)to quench the reaction. The solid is filtered off and the filtrate is concentrated and receiving 4,4-dimethyl-1,2,3,4-tetrahydroquinolin.

4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydroquinolin

To a mixture of 4,4-dimethyl-1,2,3,4-tetrahydroquinoline (33 g, 0.2 mol) in H2SO4(120 ml) is added slowly KNO3(20.7 g, 0.2 mol) at 0°C. After complete addition, the mixture is stirred at room temperature for 2 hours, carefully poured into ice water and alkalinized Na2CO3to pH=8. The mixture is extracted with ethyl acetate (3 x 200 ml). The combined extracts washed with water and saturated salt solution, dried over Na2SO4and concentrate, receiving 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroquinolin (21 g, yield 50%).

tert-Butyl ether 4,4-dimethyl-7-nitro-3,4-dig the DRO-2H-quinoline-1-carboxylic acid

A mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline (25 g, 0.12 mol) and Boc2O (55 g, 0.25 mol) is stirred at a temperature of 80°C for 2 days. The mixture is purified by chromatography on silica gel, receiving tert-butyl ether 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid (8 g, yield 22%).

DC-3;tert-Butyl 7-amino-3,4-dihydro-4,4-dimethylindoline-1(2H)-carboxylate

A mixture of tert-butyl methyl ether of 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid (8,3 g, 0.03 mol) and Pd/C (0.5 g) in methanol (100 ml) is stirred in hydrogen atmosphere (1 ATM.) at room temperature over night. The catalyst is filtered off and the filtrate concentrated. The residue is washed with petroleum ether, receiving tert-butyl 7-amino-3,4-dihydro-4,4-dimethylindoline-1(2H)-carboxylate (DC-3) (7.2 g, yield 95%).

1H-NMR (CDCl3) δ 7,11? 7.04 baby mortality (m, 2H), 6,45-6,38 (m, 1H), 3,71-to 3.67 (m, 2H), 3,50 of 3.28 (m, 2H), 1,71-to 1.67 (m, 2H)and 1.51 (s, 9H), 1,24 (s, 6H).

Example 4

1-Chloro-4-methylpentan-3-one

Ethylene is bubbled through a solution of Isobutyraldehyde (50 g, 0.5 mol) and AlCl3(68,8 g, 0.52 mol) in anhydrous CH2Cl2(700 ml) at 5°C. After 4 hours, the absorption of ethylene was stopped and the mixture is stirred at room temperature overnight. The mixture is then poured into cold dilute HCl solution and extracted with CH2Cl2. Together the major organic phases are washed with saturated salt solution, dried over Na2SO4, filtered and concentrated, obtaining the crude 1-chloro-4-methylpentan-3-one, which is used directly in the next stage without further purification.

4-Methyl-1-(phenylamino)pentane-3-one

A suspension of the crude 1-chloro-4-methylpentan-3-one (about 60 g), aniline (69,8 g, 0.75 mol) and NaHCO3(210 g, 2.5 mol) in CH3CN (1000 ml) is refluxed overnight. After cooling, the insoluble salt is filtered off and the filtrate concentrated. The residue was diluted with CH2Cl2, washed with 10%HCl solution (100 ml) and saturated salt solution, dried over Na2SO4, filtered and concentrated, obtaining the crude 4-methyl-1-(phenylamino)pentane-3-one.

4-Methyl-1-(phenylamino)pentane-3-ol

At a temperature of -10°C. NaBH4(56.7 g, 1.5 mol) is slowly added to a mixture of crude 4-methyl-1-(phenylamino)pentane-3-one (about 80 g) in the Meon (500 ml). After complete addition, the reaction mixture is left to warm to room temperature and stirred for 20 minutes the Solvent is removed and the residue redistribute between water and CH2Cl2. The organic phase is separated, washed with saturated salt solution, dried over Na2SO4filter and concentrate. The obtained resin was triturated in diethyl ether, receiving 4-methyl-1-(phenylamino)pentane-3-ol in the form of logo solid (22 g, yield 23%).

5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin

A mixture of 4-methyl-1-(phenylamino)pentane-3-ol (22 g, 0.11 mol) in 98%H2SO4(250 ml) is stirred at 50°C for 30 minutes, the Reaction mixture was poured into ice water, alkalinized with a saturated solution of NaOH to pH=8 and extracted with CH2Cl2. The combined organic phases are washed with saturated salt solution, dried over Na2SO4filter and concentrate. The residue is purified column chromatography (petroleum ether)to give 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin in the form of a brown oil (1.5 g, yield 8%).

5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin

At 0°C, KNO3(0,76 g, rate of 7.54 mmol) added in several portions to a solution of 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.1 g, 6,28 mmol) in H2SO4(15 ml). After stirring for 15 min at this temperature, the mixture was poured into ice water, alkalinized with saturated solution of NaHCO3to pH=8 and extracted with EtOAc. The organic layer was washed with saturated salt solution, dried over Na2SO4and concentrate, receiving crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin (1.2 g), which is used directly in the next stage without further purification.

1-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)alanon

p> Acetylchloride (of 0.77 ml, 11 mmol) are added to a suspension of the crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.2 g, the 5.45 mmol) and NaHCO3(1,37 g, 16.3 mmol) in CH2Cl2(20 ml). The mixture is refluxed for 1 hour. After cooling, the mixture was poured into water and extracted with CH2Cl2. The organic layer was washed with saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography, obtaining 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)alanon (of 1.05 g, yield 64% over two stages).

DC-4; 1-(8-Amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo[b]azepin-1-yl)alanon

A suspension of 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone (1,05 g, 40 mmol) and 10%Pd/C (0.2 g) in Meon (20 ml) stirred in an atmosphere of H2(1 ATM.) at room temperature for 4 hours. After filtration, the filtrate concentrated, obtaining 1-(8-amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo[b]azepin-1-yl)Etalon in the form of a white solid substance (DC-4) (880 mg, yield 94%).

1H-NMR (CDCl3) δ 7,06 (d, J=8.0 Hz, 1H), 6,59 (DD, J=8,4, 2.4 Hz, 1H), 6,50 (users, 1H), 4,18-of 4.05 (m, 1H), 3.46 in-to 3.36 (m, 1H), of 2.23 (s, 3H), 1,92-of 1.85 (m, 1H), 1,61-is 1.51 (m, 3H), 1,21 (s, 3H), 0,73 (t, J=7.2 Hz, 3H).

ESI-MS: 233,0 m/z (MH+).

Example 5

1'-Benzyl-Spiro[1H-inden-1,4'-piperidine]-3(2H)-he

A mixture of 1,1-dimethylethyl the new ester of 2,3-dihydro-3-oxaspiro[1H-inden-1,4'-piperidine]-1'-carboxylic acid (9,50 g, 31,50 mmol) in a saturated solution of HCl in MeOH (50 ml) is stirred at a temperature of 25°C during the night. The solvent is removed under reduced pressure, getting not quite white solid (7.50 g). To a solution of the solid in anhydrous CH3CN (30 ml) is added anhydrous K2CO3(a 7.85 g, 56,80 mmol). The suspension is stirred for 5 min and added dropwise to benzylbromide (5,93 g, 34,65 mmol) at room temperature. The mixture is stirred for 2 hours, poured on crushed ice and extracted with CH2Cl2. The combined organic layers dried over Na2SO4and concentrated in vacuo, obtaining the crude 1'-benseler[1H-inden-1,4'-piperidine]-3(2H)-he (to 7.93 g, yield 87%), which is used without further purification.

The reaction of 1'-benseler[1H-inden-1,4'-piperidine]-3(2H)-it

To a solution of 1'-benseler[1H-inden-1,4'-piperidine]-3(2H)-she (of 7.93 g, 27,25 mmol) in EtOH (50 ml) is added hydroxylamine hydrochloride (3,79 g, 54,50 mmol) and anhydrous sodium acetate (as 4.02 g, 49,01 mmol) in one portion. The mixture is refluxed for 1 hour and then cooled to room temperature. The solvent is removed under reduced pressure and add 200 ml of water. The mixture is extracted with CH2Cl2. The combined organic layers dried over Na2SO4and concentrate, getting oxime 1'-benseler[1H-inden-1,4'-piperidine]-3(2H)it (EUR 7.57 g, yield 91%), which is used without further purification.

1,2,3,4-Tetrahydroquinolin-4-Spiro-4'-(N'-benzylpiperidine)

To a solution of oxime 1'-benseler[1H-inden-1,4'-piperidine]-3(2H)-it (EUR 7.57 g, 24,74 mmol) in anhydrous CH2Cl2(150 ml) was added dropwise DIBAL-H (135,7 ml, 1M solution in toluene) at 0°C. the Mixture is stirred at 0°C for 3 hours, diluted with CH2Cl2(100 ml) and quenched with NaF (20,78 g, 495 mmol) and water (6.7 g, 372 mmol). The resulting suspension is vigorously stirred at 0°C for 30 minutes After filtration the residue was washed with CH2Cl2. The combined filtrates concentrated in vacuo, getting not quite brown oil, which was purified column chromatography on silica gel (CH2Cl2-MeOH, 30:1)to give 1,2,3,4-tetrahydroquinolin-4-Spiro-4'-(N'-benzylpiperidine) (2,72 g, yield 38%).

1,2,3,4-Tetrahydroquinolin-4-Spiro-4'-piperidine

A suspension of 1,2,3,4-tetrahydroquinolin-4-Spiro-4'-(N'-benzylpiperidine) (300 mg, of 1.03 mmol) and Pd(OH)2/C (30 mg) in the Meon (3 ml) is stirred in an atmosphere of H2(55 psi) at a temperature of 50°C during the night. After cooling, the catalyst is filtered off and washed with Meon. The combined filtrates are concentrated under reduced pressure, getting 1,2,3,4-tetrahydroquinolin-4-Spiro-4'-piperidine as a white solid (176 mg, yield 85%), which is sportsouth without further purification.

tert-Butyl ether 7'-nitrospira[piperidine-4,4'(1 N)-quinoline]-2',3'-dihydrocarvone acid

KNO3(69,97 mg, 0.69 mmol) is added in several portions to a suspension of 1,2,3,4-tetrahydroquinolin-4-Spiro-4'-piperidine (133 mg, 0.66 mmol) in 98%H2SO4(2 ml) at 0°C. After complete addition, the reaction mixture is left to warm to room temperature and then stirred for 2 hours. The mixture is then poured on crushed ice and alkalinized 10%NaOH solution to pH~8. Added dropwise Boc2O (172 mg, of 0.79 mmol) and the mixture is stirred at room temperature for 1 hour. The mixture is then extracted with EtOAc and the combined organic layers dried over Na2SO4, filtered and concentrated, obtaining the crude tert-butyl ether 7'-nitrospira[piperidine-4,4'(1 N)-quinoline]-2',3'-dihydrocarvone acid (230 mg), which is used in the next stage without further purification.

tert-Butyl ether 7'-nitrospira[piperidine-4,4'(1 N)-1-acetylcholin]-2',3'-dihydrocarvone acid

Acetylchloride (260 mg, 3,30 mmol) are added dropwise to a suspension of tert-butyl methyl ether 7'-nitrospira[piperidine-4,4'(1 N)-quinoline]-2',3'-dihydrocarvone acid (230 mg) and NaHCO3(1,11 g, 13,17 mmol) in MeCN (5 ml) at room temperature. The reaction mixture is refluxed for 4 hours. After ohlazhdeniye filtered and the filtrate concentrated. The residue is purified column chromatography (petroleum ether-EtOAc, 10:1)to give tert-butyl ether 7'-nitrospira[piperidine-4,4'(1 N)-1-acetylcholin]-2',3'-dihydrocarvone acid (150 mg, yield 58% over 2 stages).

DC-5; tert-Butyl ether 7'-aminosterol[piperidine-4,4'(1 N)-1-acetylcholin]- 2',3'-dihydrocarvone acid

A suspension of tert-butyl methyl ether 7'-nitrospira[piperidine-4,4'(1 N)-1-acetylcholin]-2',3'-dihydrocarvone acid (150 mg, 0,39 mmol) and Raney Nickel (15 mg) in Meon (2 ml) is stirred in an atmosphere of H2(1 ATM.) at a temperature of 25°C during the night. The catalyst was removed by filtration and washed with Meon. The combined filtrates are dried over Na2SO4, filtered and concentrated, obtaining tert-butyl ether 7'-aminosterol[piperidine-4,4'(1 N)-1-acetylcholin]-2',3'-dihydrocarvone acid (DC-5) (133 mg, yield 96%).

Example 6

2-(2,4-Dinitrophenyl)acetic acid

Et3N (1.5 g, 15 mmol) and mercaptohexanol acid (1 g, 11 mmol) are added to a solution of 1-chloro-2,4-dinitrobenzene (of 2.26 g, 10 mmol) in 1,4-dioxane (50 ml) at room temperature. After stirring at room temperature for 5 hours add H2O (100 ml). The resulting suspension is extracted with ethyl acetate (3 times 100 ml). An ethyl acetate extract is washed with water and saturated salt solution, su is at over Na 2SO4and concentrate, receiving 2-(2,4-dinitrophenyl)acetic acid (2.3 g, yield 74%), which is used without further purification.

DC-7; 6-Amino-2H-benzo[b][1,4]thiazin-3(4H)-he

A solution of 2-(2,4-dinitrophenyl)acetic acid (2.3 g, 9 mmol) and chloride dihydrate tin-(II) (22,6 g, 0.1 mol) in ethanol (30 ml) is refluxed overnight. After removal of the solvent under reduced pressure the residual suspension was diluted with water (100 ml) and alkalinized 10%solution of Na2CO3to pH=8. The resulting suspension is extracted with ethyl acetate (3 times 100 ml). An ethyl acetate extract is washed with water and saturated salt solution, dried over Na2SO4and concentrate. The residue was washed with CH2Cl2getting 6-amino-2H-benzo[b][1,4]thiazin-3(4H)-he (DC-7) as a yellow powdery substance (1 g, yield 52%).

1H-NMR (DMSO-d6): δ 10,24 (s, 1H), to 6.88 (d, 1H,J=6Hz), to 6.19-6,21 (m, 2H), further 5.15 (s, 2H), or 3.28 (s, 2H).

ESI-MS: 181,1 m/z (MH+).

Example 7

N-(2-Bromo-5-nitrophenyl)ndimethylacetamide

Acetic anhydride (1.4 ml, of 13.8 mmol) is added dropwise to a stirred solution of 2-bromo-5-nitroaniline (3 g, of 13.8 mmol) in glacial acetic acid (30 ml) at 25°C. the Reaction mixture was stirred at room temperature overnight and then poured input. The precipitate was separated by filtration, washed with water and dried in vacuum, obtaining N-(2-bromo-5-nitrophenyl)ndimethylacetamide as not quite white solid (3.6 g, yield 90%).

N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)ndimethylacetamide

At a temperature of 25°With a solution of 3-bromo-2-methylpropene (3.4 g, at 55.6 mmol) in anhydrous DMF (30 ml) was added dropwise to a solution of N-(2-bromo-5-nitrophenyl)ndimethylacetamide (3.6 g, a 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 ml). The reaction mixture is stirred at a temperature of 25°C during the night. The reaction mixture was then filtered and the filtrate treated with a saturated solution of Na2CO3. The organic layer is separated and the aqueous layer was extracted with EtOAc. The combined organic extracts washed with water and saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo, obtaining N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)ndimethylacetamide as a Golden solid (3.1 g, yield 85%).

ESI-MS: 313 m/z (MH+).

1-(3,3-Dimethyl-6-nitroindoline-1-yl)alanon

A solution of N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)ndimethylacetamide (3.1 g, 10.2 mmol), hydrate tetraethylammonium (2.4 g, 149 mmol), sodium formate (1.08 g, 18 mmol), sodium acetate (2.76 g, 34,2 mmol) and palladium acetate (0.32 g, 13,2 mmol) in anhydrous DMF (50 ml) was stirred at 80°C for 15 hours under nitrogen atmosphere. After the OHL is being introduced, the mixture is filtered through celite. Celite was washed with EtOAc and the combined filtrates washed with a saturated solution of NaHCO3. The separated organic layer is washed with water and saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure, obtaining 1-(3,3-dimethyl-6-nitroindoline-1-yl)Etalon in the form of a brown solid (2.1 g, yield 88%).

DC-8; 1-(6-Amino-3,3-dimethyl-2,3-dihydroindol-1-yl)alanon

10%Pd/C (0.2 g) are added to a suspension of 1-(3,3-dimethyl-6-nitroindoline-1-yl)ethanone (2.1 g, 9 mmol) in Meon (20 ml). The reaction mixture was stirred in an atmosphere of H2(40 psi) at room temperature over night. Pd/C was filtered and the filtrate was concentrated in vacuo, obtaining the crude product, which was purified column chromatography, obtaining 1-(6-amino-3,3-dimethyl-2,3-dihydroindol-1-yl)alanon (DC-8) (1.3 g, yield 61%).

Example 8

2,3,4,5-Tetrahydro-1H-benzo[b]azepin

DIBAL (90 ml, 90 mmol) is added dropwise to a solution of 4-dihydro-2H-naphthalene-1-he-oxime (3 g, 18 mmol) in dichloromethane (50 ml) at 0°C. the Mixture is stirred at this temperature for 2 hours. The reaction mixture was quenched with dichloromethane (30 ml), then treated with NaF (2 g, 0.36 mol) and H2O (5 ml, 0.27 mol). Vigorous stirring of the obtained suspension is continued at 0°C for 30 min After filtration the Finance filtrate concentrated. The residue is purified column flash chromatography, getting 2,3,4,5-tetrahydro-1H-benzo[b]azepin in the form of a colorless oil (1.9 g, yield 70%).

8-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin

At a temperature of -10°C 2,3,4,5-tetrahydro-1H-benzo[b]azepin (1.9 g, 13 mmol) are added dropwise to a solution of KNO3(3 g, 30 mmol) in H2SO4(50 ml). The mixture is stirred for 40 minutes, poured on crushed ice, alkalinized with an aqueous solution of ammonia up to pH 13 and extracted with EtOAc. The combined organic phases are washed with saturated salt solution, dried over Na2SO4and concentrate, receiving 8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin as a black solid (1.3 g, 51%yield), which was used without further purification.

1-(8-Nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)alanon

Acetylchloride (1 g, 13 mmol) are added dropwise to a mixture of 8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.3 g, 6.8 mmol) and NaHCO3(1 g, 12 mmol) in CH2Cl2(50 ml). After stirring for 1 hour the mixture is filtered and the filtrate concentrated. The residue is dissolved in CH2Cl2, washed with saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography, obtaining 1-(8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)Etalon in the form of a yellow solid (1.3 g, yield 80%).

DC-9;1-(8-Amino-2,3,4,5-t is tragidramas[b]azepin-1-yl)alanon

A mixture of 1-(8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone (1.3 g, 5.4 mmol) and Pd/C (10%, 100 mg) in EtOH (200 ml) stirred in an atmosphere of H2(1 ATM.) at room temperature for 1.5 hours. The mixture is filtered through a layer of celite and the filtrate is concentrated, obtaining 1-(8-amino-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)alanon (DC-9) as a white solid (1 g, yield 90%).

1H-NMR (CDCl3) δ 7,01 (d, J=6.0 Hz, 1H), 6,56 (DD, J=6,0, 1.8 Hz, 1H), 6,50 (d, J=1.8 Hz, 1H), 4,66-br4.61 (m, 1H), 3,50 (users, 2H), 2,64 is 2.55 (m, 3H), 1,94 is 1.91 (m, 5H), 1.77 in-1,72 (m, 1H), 1,32-of 1.30 (m, 1H).

ESI-MS: to 204.1 m/z (MH+).

Example 9

6-Nitro-4H-benzo[1,4]oxazin-3-one

At a temperature of 0°C, chlorocatechol (8,75 ml, 0.11 mol) is added dropwise to a mixture of 4-nitro-2-aminophenol (to 15.4 g, 0.1 mol), benzyltrimethylammonium (18.6 g, 0.1 mol) and NaHCO3(42 g, 0.5 mol) in chloroform (350 ml) within 30 min After complete addition, the reaction mixture was stirred at 0°C for 1 hour, then at a temperature of 50°C during the night. The solvent is removed under reduced pressure and the residue is treated with water (50 ml). The solid is separated by filtration, washed with water and recrystallized from ethanol, getting 6-nitro-4H-benzo[1,4]oxazin-3-one as pale yellow solid (8 g, yield 41%).

6-Nitro-3,4-dihydro-2H-benzo[1,4]oxazin

The Solution BHsub> 3·Me2S in THF (2 M, of 7.75 ml of 15.5 mmol) are added dropwise to a suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (0.6 g, 3.1 mmol) in THF (10 ml). The mixture is stirred at room temperature overnight. The reaction mixture was quenched Meon (5 ml) at 0°C and then add water (20 ml). The mixture is extracted with Et2O and the combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate, getting 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazin as a red solid (0.5 g, yield 89%), which is used without further purification.

4-Acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazin

With vigorous stirring and at room temperature, added dropwise acetylchloride (1,02 g, 13 mmol) to a mixture of 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.8 g, 10 mmol) and NaHCO3(7,14 g, 85 mmol) in CH2Cl2(50 ml). After complete addition, the reaction mixture is stirred for 1 hour at this temperature. The mixture is filtered and the filtrate concentrated in vacuo. The residue is treated with a mixture of Et2O:hexane (1:2, 50 ml) under stirring for 30 min and then filtered, obtaining 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazin in the form of a pale yellow solid (2 g, yield 90%).

DC-10; 4-Acetyl-6-amino-3,4-dihydro-2H-benzo[1,4]oxazin

A mixture of 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxa is in (1.5 g, of 67.6 mmol) and Pd/C (10%, 100 mg) in EtOH (30 ml) stirred in an atmosphere of H2(1 ATM.) throughout the night. The catalyst is filtered off and the filtrate concentrated. The residue is treated with HCl/MeOH, receiving 4-acetyl-6-amino-3,4-dihydro-2H-benzo[1,4]oxazin (DC-10in the form of not-quite-white solid (1.1 g, yield 85%).

1H-NMR (DMSO-d6) δ 10,12 (users, 2H), 8,08 (users, 1H), 6.90 to-7,03 (m, 2H), 4,24 (t, J=4,8 Hz, 2H), 3,83 (t, J=4,8 Hz, 2H), of 2.23 (s, 3H).

ESI-MS: USD 192.1 m/z (MH+).

Example 10

Hydrochloride 1,2,3,4-Tetrahydro-7-nitroisoquinoline

1,2,3,4-Tetrahydroisoquinoline (6.3 ml, 50.0 mmol) are added dropwise to a stirred, cooled with ice, to a solution of concentrated H2SO4(25 ml). Portions add KNO3(5.6 g, 55,0 mmol), keeping the temperature below 5°C. the Mixture is stirred at room temperature overnight, carefully poured into ice solution of concentrated NH4OH and then three times extracted with CHCl3. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate. The obtained dark brown oil is added to EtOH, cooled in an ice bath and treated with concentrated HCl. The yellow precipitate was separated by filtration and recrystallized from methanol, getting hydrochloride 1,2,3,4-tetrahydro-7-nitroethanol is in the form of a yellow solid (2.5 g, yield 23%).

1H-NMR (400 MHz, DMSO-d6) δ 9,86 (s, 2H), by 8.22 (d, J=1.6 Hz, 1H), 8,11 (DD, J=8,5, 2.2 Hz, 1H), 7,53 (d, J=8,5 Hz,lH), to 4.38 (s, 2H), 3,38 (s, 2H), 3,17-3,14 (m, 2H).

HPLC: retention time of 0.51 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 179,0 m/z (MH+).

tert-Butyl-3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate

A mixture of 1,2,3,4-tetrahydro-7-nitroisoquinoline (2.5 g, 11.6 mmol), 1,4-dioxane (24 ml), H2O (12 ml) and 1N. NaOH solution (12 ml) cooled in an ice bath and add Boc2O (2.8 g, 12.8 mmol). The mixture is stirred at room temperature for 2.5 hours, alkalinized 5%solution of KHSO4to pH=2-3 and then extracted with EtOAc. The organic layer is dried over MgSO4and concentrate, receiving tert-butyl-3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, quantitative yield), which is used without further purification.

1H-NMR (400 MHz, DMSO-d6) δ 8,13 (d, J=2.3 Hz, 1H), 8,03 (DD, J=8,4, 2.5 Hz, 1H), 7,45 (d, J=8.5 Hz, 1H), 4,63 (s, 2H), 3,60 is 3.57 (m, 2H), 2,90 (t, J=5,9 Hz, 2H), of 1.44 (s, 9H).

HPLC: retention time 3,51 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 279,2 m/z (MH+).

DC-6; tert-Butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate

Pd(OH)2(330,0 mg) is added to a stirred solution of tert-butyl-3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, 12,0 mmol) in Meon (56 ml) under nitrogen atmosphere. The reaction mixture was stirred at atmospherewith (1 ATM.) at room temperature for 72 hours. The solid is removed by filtration through celite. The filtrate is concentrated and purified column chromatography (15-35% EtOAc-hexane)to give tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (DC-6) as a pink oil (2.0 g, yield 69%).

1H-NMR (400 MHz, DMSO-d6) δ 6,79 (d, J=8,1 Hz, 1H), 6,40 (DD, J=8,1, 2.3 Hz, 1H), of 6.31 (s, 1H), 4,88 (s, 2H), 4,33 (s, 2H), 3,48 (t, J=5,9 Hz, 2H), 2,58 (t, J=5,9 Hz, 2H), of 1.42 (s, 9H).

HPLC: retention time of 2.13 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 249,0 m/z (MH+).

Other amines

Example 1

4-Bromo-3-nitrobenzonitrile

To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in concentrated H2SO4(10 ml) added dropwise at a temperature of 0°C. nitric acid (6 ml). The reaction mixture was stirred at 0°C for 30 min and then at room temperature for 2.5 hours. The resulting solution was poured into ice water. The white precipitate was separated by filtration and washed with water until until the wash water is neutral. The solid is recrystallized twice from a mixture of ethanol/water (1:1, 20 ml)to give 4-bromo-3-nitrobenzonitrile in the form of a white crystalline substance (2.8 g, yield 56%).

1H-NMR (300 MHz, DMSO-d6): δ 8,54 (s, 1H), of 8.06 (d, J=8,4 Hz, 1H), to 7.99 (d, J=8,4 Hz, 1H).

13C-NMR (75 MHz, DMSO-d 6): δ 150,4, 137,4, 136,6, 129,6, 119,6, 117,0, 112,6.

HPLC: retention time 1,96 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 227,1 m/z (MH+).

2'-Ethoxy-2-nitrobiphenyl-4-carbonitril

In a round bottom flask with a capacity of 50 ml of making 4-bromo-3-nitrobenzonitrile (1.0 g, 4.4 mmol), 2-ethoxyphenylurea acid (731 mg, 4.4 mmol), Pd2(dba)3(18 mg, to 0.022 mmol) and potassium fluoride (786 mg, 13.5 mmol). The reaction vessel vacuum and filled with argon. Add anhydrous THF (300 ml), then P(t-Bu)3(of 0.11 ml, 10% wt. in hexane). The reaction mixture was stirred at room temperature for 30 min and then heated at a temperature of 80°C for 16 hours. After cooling to room temperature the mixture is filtered through a layer of celite and concentrate. 2'-Ethoxy-2-nitrobiphenyl-4-carbonitril isolated in the form of a yellow solid (1.12 g, yield 95%).

1H-NMR (300 MHz, DMSO-d6) δ 8,51 (s, 1H), to 8.20 (d, J=8,1 Hz, 1H), 7,68 (d, J=8,4 Hz, 1H), 7,41 (t, J=and 8.4 Hz, 1H), 7,37 (d, J=7.5 Hz, 1H), was 7.08 (t, J=7.5 Hz, 1H), 7,03 (l, J=8,1 Hz, 1H), 3,91 (kV, J=7.2 Hz, 2H), 1,12 (t, J=7.2 Hz, 3H).

13C-NMR (75 MHz, DMSO-d6): δ 154,9, 149,7, 137,3, 137,2, 134,4, 131,5, 130,4, 128,4, 125,4, 121,8, 117,6, 112,3, 111,9, 64,1, 14,7.

HPLC: retention time 2,43 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 269,3 m/z (MH+).

4-Aminomethyl-2'-ethoxymethyl-2-ylamine

To a solution of 2'-ethoxy-2-nitrobiphenyl-4-carbonitrile (500 mg, of 1.86 mmol) in the THF (80 ml) add a solution BH 3·THF (5.6 ml, 10% wt. in THF, 5.6 mmol) at 0°C for 30 minutes the Reaction mixture was stirred at 0°C for 3 hours and then at room temperature for 15 hours. The reaction mixture is cooled to a temperature of 0°C and add the mixture of H2O/THF (3 ml). After shaking at room temperature for 6 hours, volatiles are removed under reduced pressure. The residue is dissolved in EtOAc (100 ml) and extracted with 1N. HCl solution (2 times 100 ml). The aqueous phase is alkalinized 1H. NaOH solution to pH=1 and extracted with EtOAc (3 times 50 ml). The combined organic layers washed with water (50 ml), dried over Na2SO4, filtered and evaporated. After drying in vacuum allocate 4-aminomethyl-2'-ethoxymethyl-2-ylamine as a brown oil (370 mg, yield 82%).

1H-NMR (300 MHz, DMSO-d6) δ 7,28 (dt, J=7,2 Hz, J=1.8 Hz, 1H), to 7.09 (DD, J=7,2 Hz, J=1.8 Hz, 1H), 7,05 (d, J=7.5 Hz, 1H), of 6.96 (dt, J=7,2 Hz, J=0.9 Hz, 1H), 6,83 (d, J=7.5 Hz, 1H), 6,66 (d, J=1.2 Hz, 1H), to 6.57 (DD, J=7.5 Hz, J=1.5 Hz, 1H), 4,29 (s, 2H), was 4.02 (q, J=6.9 Hz, 2H), 3,60 (s, 2H), 1,21 (t, J=6.9 Hz, 3H).

HPLC: retention time of 1.54 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 243,3 m/z (MH+).

E-1; tert-Butyl ether (2-amino-2'-ethoxymethyl-4-ylmethyl)carbamino acid

A solution of Boc2O (123 mg, of 0.565 mmol) in 1,4-dioxane (10 ml) added dropwise within 30 min to a solution of 4-aminomethyl-2'-ethoxymethyl-2-ylamine (24 mg, 1.13 mmol) in 1,4-dioxane (10 ml). The reaction mixture was stirred at room temperature for 16 hours. Volatiles are removed on a rotary evaporator. The residue is purified flash chromatography (silica gel, EtOAc-CH2Cl2, 1:4)to give tert-butyl ether (2-amino-2'-ethoxymethyl-4-ylmethyl)carbamino acid (E-1) as a pale yellow oil (119 mg, yield 31%).

1H-NMR (300 MHz, DMSO-d6) δ 7,27 (m, 2H), 7,07 (DD, J=7,2 Hz, J=1.8 Hz, 1H), 7,03 (d, J=7.8 Hz, 1H), 6,95 (dt, J=7,2 Hz, J=0.9 Hz, 1H), for 6.81 (d, J=7.5 Hz, 1H), 6,55 (s, 1H), 6,45 (DD, J=7.8 Hz, J=1.5 Hz, 1H), 4,47 (s, 2H), 4,00 (kV, J=7.2 Hz, 2H), to 1.38 (s, 9H), of 1.20 (t, J=7.2 Hz, 3H).

HPLC: retention time of 2.34 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 343,1 m/z (MH+).

Example 2

2-Bromo-1-tert-butyl-4-nitrobenzene

To a solution of 1-tert-butyl-4-nitrobenzene (of 8.95 g, 50 mmol) and silver sulfate (10 g, 32 mmol) in 50 ml of 90%sulfuric acid are added dropwise bromine (of 7.95 g, 50 mmol). Continue to stir at room temperature overnight, then the mixture is poured into dilute Hydrosulphite solution of sodium and extracted three times with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After filtration, the filtrate concentrated, receiving 2-bromo-1-tert-butyl-4-nitrobenzene (12.7 g, yield 98%), which is used without further purification.

1NAMR (400 MHz, CDCl3): δ of 8.47 (d, J=2.5 Hz, 1H), 8,11 (DD, J=8,8, 2.5 Hz, 1H), 7,63 (d, J=8,8 Hz, 1H), 1.57 in (s, 9H).

HPLC: retention time of 4.05 min, 10-100% CH3CN, gradient 5 minutes

2-tert-Butyl-5-nitrobenzonitrile

To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (2,13 g, 8.2 mmol) and Zn(CN)2(770 mg, 6,56 mmol) in DMF (10 ml) is added Pd(PPh3)4(474 mg, 0.41 mmol) under nitrogen atmosphere. The mixture is heated in a tightly closed vessel at a temperature of 205°C for 5 hours. After cooling to room temperature the mixture is diluted with water and twice extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After removal of solvent the residue is purified column chromatography (0-10% EtOAc-hexane)to give 2-tert-butyl-5-nitrobenzonitrile (1,33 g, yield 80%).

1H-NMR (400 MHz, CDCl3): δ 8,55 (d, J=2.3 Hz, 1H), at 8.36 (DD, J=8,8, 2.2 Hz, 1H), 7,73 (d, J=8,9 Hz, 1H), 1,60 (s, 9H).

HPLC: retention time of 3.42 min, 10-100% CH3CN, gradient 5 minutes

E-2; 2-tert-Butyl-5-aminobenzonitrile

To boiling under reflux to a solution of 2-tert-butyl-5-nitrobenzonitrile (816 mg, 4.0 mmol) in EtOH (20 ml) is added ammonium formate (816 mg, 12.6 mmol), followed by 10%Pd/C (570 mg). Then the reaction mixture is refluxed for 90 min, cooled to room temperature and filtered through celite. The filtrate is concentrated and receiving 2-tert-b is Tyl-5-aminobenzonitrile ( E-2) (630 mg, yield 91%), which is used without further purification.

HPLC: retention time of 2.66 min, 10-99% CH3CN, gradient 5 minutes

ESI-MS: 175,2 m/z (MH+).

Example 3

(2-tert-Butyl-5-nitrophenyl)methanamine

To a solution of 2-tert-butyl-5-nitrobenzonitrile (612 mg, 3.0 mmol) in THF (10 ml) add a solution BH3·THF (12 ml, 1M solution in THF, to 12.0 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 70°C overnight and cooled to 0°C. Add methanol (2 ml), then 1N. HCl (2 ml). After boiling under reflux for 30 min the solution was diluted with water and extracted with EtOAc. The aqueous layer was alkalinized 1H. NaOH solution and twice extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After removal of solvent the residue is purified column chromatography (0-10% MeOH-CH2Cl2), receiving (2-tert-butyl-5-nitrophenyl)methanamine (268 mg, yield 43%).

1H-NMR (400 MHz, DMSO-d6) δ 8,54 (d, J=2.7 Hz, 1H), to 7.99 (DD, J=8,8, 2.8 Hz, 1H), 7,58 (d, J=8,8 Hz, 1H), a 4.03 (s, 2H), 2,00 (t, J=2.1 Hz, 2H), 1,40 (s, 9H).

HPLC: retention time of 2.05 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 209,3 m/z (MH+).

tert-Butyl-2-tert-butyl-5-nitrobenzylidene

A solution of (2-tert-butyl-5-nitrophenyl)methanamine (208 mg, 1 mmol) and Boc2 O (229 mg, 1.05 mmol) in THF (5 ml) is refluxed for 30 minutes After cooling to room temperature the solution was diluted with water and extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After filtration the filtrate is concentrated and receiving tert-butyl-2-tert-butyl-5-nitrobenzylamine (240 mg, yield 78%), which is used without further purification.

1H-NMR (400 MHz, DMSO-d6) δ compared to 8.26 (d, J=2.3 Hz, 1H), 8,09 (DD, J=8,8, 2.5 Hz, 1H), 7,79 (t, J=5,9 Hz, 1H), 7,68 (d, J=8,8 Hz, 1H), to 4.52 (d, J=6.0 Hz, 2H), to 1.48 (s, 18H).

HPLC: retention time and 3.72 min, 10-100% CH3CN, gradient 5 minutes

E-4; tert-Butyl-2-tert-butyl-5-aminobenzylidene

To a solution of tert-butyl-2-tert-butyl-5-nitrobenzylamine (20 mg, 0,065 mmol) in a mixture of 5% Asón-Meon (1 ml) is added 10%Pd/C (14 mg) in a nitrogen atmosphere. The mixture is stirred in hydrogen atmosphere (1 ATM.) at room temperature for 1 hour. The catalyst was removed by filtration through celite and the filtrate is concentrated and receiving tert-butyl-2-tert-butyl-5-aminobenzoylglutamate (E-4), which is used without further purification.

1H-NMR (400 MHz, CDCl3) δ to 7.09 (d, J=8.5 Hz, 1H), 6,62 (d, J=2.6 Hz, 1H), 6,47 (DD, J=8,5, and 2.6 Hz, 1H), br4.61 (users, 1H), and 4.40 (d, J=5,1 Hz, 2H), 4,15 (users, 2H), 1.39 in (s, 9H), of 1.29 (s, 9H).

HPLC: retention time 2,47 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 279,3 m/z (H +).

Example 4

2-tert-Butyl-5-nitrobenzoic acid

A solution of 2-tert-butyl-5-nitrobenzonitrile (204 mg, 1 mmol) in 5 ml of 75%H2SO4subjected to microwave treatment at 200°C for 30 minutes the Reaction mixture is poured on ice, extracted with EtOAc, washed with saturated salt solution and dried over MgSO4. After filtration, the filtrate concentrated, receiving 2-tert-butyl-5-nitrobenzoic acid (200 mg, yield 90%), which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ at 8.36 (d, J=2.6 Hz, 1H), 8,24 (DD, J=8,9, and 2.6 Hz, 1H), 7,72 (d, J=8,9 Hz, 1H)and 1.51 (s, 9H).

HPLC: retention time of 2.97 min, 10-100% CH3CN, gradient 5 minutes

Methyl-2-tert-butyl-5-nitrobenzoate

To a mixture of 2-tert-butyl-5-nitrobenzoic acid (120 mg, of 0.53 mmol) and K2CO3(147 mg, 1.1 mmol) in DMF (5.0 ml) add CH3I (40 μl, 0.64 mmol). The reaction mixture was stirred at room temperature for 10 min, diluted with water and extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After filtration the filtrate is concentrated and receiving methyl-2-tert-butyl-5-nitrobenzoate, which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ to 8.20 (d, J=2.6 Hz, 1H), 8,17 (t, J=1.8 Hz, 1H), 7,66 (d, J=8.6 Hz, 1H), 4,11 (s, 3H), USD 1.43 (s, 9H).

E-6 ; Methyl-2-tert-butyl-5-aminobenzoate

To boiling under reflux to a solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38 mmol) in EtOH (2.0 ml) add potassium formate (400 mg, 4.76 mmol) in water (1 ml), then 20 mg of 10%Pd/C. Then the reaction mixture was refluxed for 40 min, cooled to room temperature and filtered through celite. The filtrate is concentrated and receiving methyl-2-tert-butyl-5-aminobenzoate (E-6) (76 mg, yield 95%), which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ of 7.24 (d, J=8.6 Hz, 1H), to 6.67 (DD, J=8,6, 2.7 Hz, 1H), 6,60 (d, J=2.7 Hz, 1H), 3,86 (s, 3H), of 1.34 (s, 9H).

HPLC: retention time 2,19 min, 10-99% CH3CN, gradient 5 minutes

ESI-MS: 208,2 m/z (MH+).

Example 5

2-tert-Butyl-5-nitrobenzene-1-sulphonylchloride

A suspension of 2-tert-butyl-5-nitrobenzylamine (0,971 g, 5 mmol) in concentrated HCl (5 ml) cooled to a temperature of 5-10°C and added dropwise a solution of NaNO2(0,433 g, 6.3 mmol) in H2O (0,83 ml). Continue to stir for 0.5 hours, the mixture is then filtered under vacuum. The filtrate is added simultaneously with a solution of Na2SO3(1,57 g, 12.4 mmol) in H2O (2.7 ml) to a stirred solution of CuSO4(0,190 g, from 0.76 mmol) and Na2SO3(1,57 g, 12.4 mmol) in HCl (11.7 ml) and H2O (2.7 ml) at a temperature of 3-5°C. Continue to stir during the course the e 0.5 hour and the precipitate is filtered off, washed with water and dried, obtaining 2-tert-butyl-5-nitrobenzene-1-sulphonylchloride (0,235 g, yield 17%).

1H-NMR (400 MHz, DMSO-d6): δ 9,13 (d, J=2.5 Hz, 1H), at 8.36 (DD, J=8,9 and 2.5 Hz, 1H), 7,88 (d, J=8,9 Hz, 1H), equal to 1.59 (s, 9H).

2-tert-Butyl-5-nitrobenzene-1-sulfonamide

To a solution of 2-tert-butyl-5-nitrobenzene-1-sulphonylchloride (100 mg, 0.36 mmol) in diethyl ether (2 ml) is added aqueous NH4OH (128 μl, 3.6 mmol) at 0°C. the Mixture is stirred at room temperature overnight, diluted with water and extracted with diethyl ether. The combined extracts in diethyl ether, washed with saturated salt solution and dried over Na2SO4. After removal of solvent the residue is purified column chromatography (0-50% EtOAc-hexane)to give 2-tert-butyl-5-nitrobenzene-1-sulfonamide (of 31.6 mg, yield 34%).

E-7; 2-tert-Butyl-5-aminobenzoyl-1-sulfonamide

A solution of 2-tert-butyl-5-nitrobenzene-1-sulfonamida (32 mg, 0.12 mmol) and SnCl2·2H2O (138 mg, 0.61 mmol) in EtOH (1.5 ml) is heated in a microwave oven at 100°C for 30 minutes the Mixture is diluted with EtOAc and water, alkalinized with saturated solution of NaHCO3and filtered through celite. The organic layer is separated from the water and dried over Na2SO4. The solvent is removed by evaporation, receiving 2-tert-butyl-5-aminobenzoyl-1-sulfonamide (E-7) (28 mg, yield 100%)which is used is comfort without further purification.

HPLC: retention time of 1.99 min, 10-99% CH3CN, gradient 5 minutes

ESI-MS: 229,3 m/z (MH+).

Example 6

E-8; (2-tert-Butyl-5-AMINOPHENYL)methanol

To a solution of methyl 2-tert-butyl-5-aminobenzoate (159 mg, to 0.72 mmol) in THF (5 ml) added dropwise LiAlH4(1,4 ml, 1M solution in THF, 1.4 mmol) at 0°C. the Reaction mixture is refluxed for 2 hours, diluted with H2O and extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. After filtration, the filtrate concentrated, receiving (2-tert-butyl-5-AMINOPHENYL)methanol (E-8) (25 mg, yield 20%), which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ 7,17 (d, J=8.5 Hz, 1H), 6.87 in (d, J=2.6 Hz, 1H), 6,56 (DD, J=8,4, 2.7 Hz, 1H), a 4.83 (s, 2H), of 1.36 (s, 9H).

Example 7

1-Methylprednisonelipitor

The methyl sulfate (30 ml, 39,8 g, 0,315 mol) are added dropwise to dry pyridine (25,0 g, 0,316 mol). The mixture is stirred at room temperature for 10 min, then at 100°C for 2 hours. The mixture is cooled to room temperature, obtaining the crude 1-methylpyridine-monomethylether (64,7 g, quantitative yield), which is used without further purification.

u> 1-Methyl-2-pyridone

A solution of 1-methylprednisonepurchase (50 g, 0,243 mol) in water (54 ml) is cooled to 0°C. Prepare separate solutions of potassium ferricyanide (160 g, 0,486 mol) in water (320 ml) and sodium hydroxide (40 g, 1000 mol) in water (67 ml) and added dropwise from two separating funnels to a well stirred solution of 1-methylprednisonepurchase, with such speed that the temperature of the reaction mixture did not exceed 10°C. the Rate of addition of the two solutions is adjusted to enter the entire solution of sodium hydroxide in the reaction mixture when added only half of a solution of potassium ferricyanide. After complete addition, the reaction mixture is left to warm to room temperature and stirred over night. Add anhydrous sodium carbonate (to 91.6 g) and the mixture is stirred for 10 minutes the Organic layer was separated and the aqueous layer was extracted with CH2Cl2(3 times 100 ml). The combined organic layers are dried and concentrated, obtaining 1-methyl-2-pyridone (25,0 g, yield 94%), which is used without further purification.

1-Methyl-3,5-dinitro-2-pyridone

1-Methyl-2-pyridone (25,0 g, 0,229 mol) is added to sulfuric acid (500 ml) at 0°C. After stirring for 5 min added dropwise nitric acid (200 ml) at 0°C. After complete addition, reacciona the temperature is slowly increased to 100°C and then support it for 5 hours. The reaction mixture is poured on ice, alkalinized with potassium carbonate solution to pH=8 and extracted with CH2Cl2(3 times 100 ml). The combined organic layers dried over Na2SO4and concentrate, getting 1-methyl-3,5-dinitro-2-pyridone (12.5 g, yield 28%), which is used without further purification.

2-Isopropyl-5-nitropyridine

To a solution of 1-methyl-3,5-dinitro-2-pyridone (8.0 g, 40 mmol) in methyl alcohol (20 ml) added dropwise 3-methyl-2-butanone (5,1 ml, 48 mmol), then a solution of ammonia in methyl alcohol (10.0 g, 17%, 100 mmol). The reaction mixture is heated at 70°C for 2.5 hours at atmospheric pressure. The solvent is removed in vacuo, the residual oil dissolved in CH2Cl2and then filtered. The filtrate is dried over Na2SO4and concentrate, receiving 2-isopropyl-5-nitropyridine (1.88 g, yield 28%).

F-9; 2-Isopropyl-5-aminopyridine

2-Isopropyl-5-nitropyridine (1,30 g, 7.82 mmol) is dissolved in methyl alcohol (20 ml) and added Raney Nickel (0.25 g). The mixture is stirred in hydrogen atmosphere (1 ATM.) at room temperature for 2 hours. The catalyst is filtered off and the filtrate was concentrated in vacuo, obtaining 2-isopropyl-5-aminopyridine (F-9) (0.55 g, yield 52%).

1H-NMR (CDCl3): δ with 8.05 (s, 1H), 6,93-of 6.99 (m, 2H), 3,47 (USS, 2H), 2,92-to 3.02 (m, 1H), 1,24-of 1.26 (m, 6H).

ESI-MS: 137,2 m/z (MH+

Example 8

Diethyl ether 2,4-di-tert-butylphenyl ether phosphoric acid

To a suspension of NaH (60%in mineral oil, of 6.99 g, 174,7 mmol) in THF (350 ml) was added dropwise a solution of 2,4-di-tert-butylphenol (35 g, 169,6 mmol) in THF (150 ml) at 0°C. the Mixture is stirred at 0°C for 15 min and then added dropwise diethyl ether phosphorochloridate acid (to 30.15 g, 174,7 mmol) at 0°C. After complete addition, the mixture is stirred at this temperature for 15 minutes, the Reaction mixture was quenched a saturated solution of NH4Cl (300 ml). The organic layer is separated and the aqueous phase extracted with Et2O (2 x 350 ml). The combined organic layers washed with saturated salt solution, dried over anhydrous Na2SO4and concentrated in vacuo, obtaining the crude diethyl ether 2,4-di-tert-butylphenyl ester of phosphoric acid as a yellow oil (51 g, contaminated with some amount of mineral oil), which is used directly in the next stage.

1,3-di-tert-Butylbenzoyl

NH3(liquid, 250 ml) add a solution of diethyl ether 2,4-di-tert-butylphenyl ether phosphoric acid (51 g, crude, obtained in the previous phase, approximately 0.2 mol) in Et2O (anhydrous,150 ml) at -78°C in an atmosphere of nitrogen. To the solution add small pieces of metallic lithium to the until will not retain the blue color of the solution. The reaction mixture was stirred at -78°C for 15 min and then quenched with saturated solution of NH4Cl until then, until the mixture becomes colorless. Liquid NH3is evaporated and the residue is dissolved in water, extracted with Et2O (2 x 300 ml). The combined organic phases are dried over Na2SO4and concentrate, receiving crude 1,3-di-tert-butylbenzoyl in the form of a yellow oil (30,4 g, yield 94% for stage 2, contaminated with a small amount of mineral oil which is used directly in the next stage.

2,4-di-tert-Butylbenzaldehyde and 3,5-di-tert-butylbenzaldehyde

To a stirred solution of 1,3-di-tert-butylbenzene (30 g, 157,6 mmol) in anhydrous CH2Cl2(700 ml) was added TiCl4(37,5 g, 197 mmol) at 0°C, then added dropwise MeOCHCl2(27,3 g, 236,4 mmol). The reaction mixture was left to warm to room temperature and stirred for 1 hour. The mixture is then poured into ice water and extracted with CH2Cl2. The combined organic phases are washed with NaHCO3and saturated salt solution, dried over Na2SO4and concentrate. The residue is purified column chromatography (petroleum ether)to give a mixture of 2,4-di-tert-BU is albenzaalbenza and 3,5-di-tert-butylbenzaldehyde (21 g, yield 61%).

2,4-di-tert-Butyl-5-nitrobenzaldehyde and 3,5-di-tert-butyl-2-nitrobenzaldehyde

To a mixture of 2,4-di-tert-butylbenzaldehyde and 3,5-di-tert-butylbenzaldehyde in H2SO4(250 ml) was added in several portions KNO3(of 7.64 g of 75.6 mmol) at 0°C. the Reaction mixture is stirred at this temperature for 20 min and then poured on crushed ice. The mixture is alkalinized with NaOH solution to pH=8 and extracted with Et2O (3 x 10 ml). The combined organic layers washed with water and saturated salt solution and concentrated. The residue is purified column chromatography (petroleum ether)to give a mixture of 2,4-di-tert-butyl-5-nitrobenzaldehyde and 3,5-di-tert-butyl-2-nitrobenzaldehyde (2:1 according to NMR) as a yellow solid (14,7 g, yield 82%). After further purification column chromatography (petroleum ether) include 2,4-di-tert-butyl-5-nitrobenzaldehyde (2.5 g, contains 10% of 3,5-di-tert-butyl-2-nitrobenzaldehyde).

1,5-di-tert-Butyl-2-deformity-4-nitrobenzene and 1,5-di-tert-butyl-3-deformity-2-nitrobenzene

2,4-di-tert-Butyl-5-nitrobenzaldehyde (2.4 g, 9,11 mmol, contains 10% of 3,5-di-tert-butyl-2-nitrobenzaldehyde) in transparent desiccator-the solution is stirred at room temperature for 5 hours. The reaction mixture was poured into a cooled saturated solution of NaHCO3and extracted dichloro is an. The combined organic layers dried over Na2SO4concentrate and purify column chromatography (petroleum ether)to give 1,5-di-tert-butyl-2-deformity-4-nitrobenzene (1.5 g) and a mixture of 1,5-di-tert-butyl-2-deformity-4-nitrobenzene and 1,5-di-tert-butyl-3-deformity-2-nitrobenzene (0.75 g, contains 28% of 1,5-di-tert-butyl-3-deformity-2-nitrobenzene).

E-10; 1,5-di-tert-Butyl-2-deformity-4-aminobenzoyl

To a suspension of iron powder (5.1 g, to 91.1 mmol) in 50%acetic acid (25 ml) was added 1,5-di-tert-butyl-2-deformity-4-nitrobenzene (1.3 g, 4,56 mmol). The reaction mixture is heated at a temperature of 115°C for 15 minutes, the Solid is filtered off, washed with acetic acid and CH2Cl2. The combined filtrate is concentrated and treated with a solution of HCl in MeOH. The precipitate was separated by filtration, washed with Meon and dried, obtaining hydrochloride 1,5-di-tert-butyl-2-deformity-4-aminobenzene (E-10) as a white solid (1.20 g, yield 90%).

1H-NMR (DMSO-d6): δ 7,35-of 7.70 (t, J=53,7 Hz, 1H), 7,56 (s, 1H), 7,41 (s, 1H), 1,33-of 1.36 (d, J=8,1 Hz, 1H).

ESI-MS: 256,3 m/z (MH+).

Example 9

The General scheme

APd(PPh3)4, K2CO3H2O, THF;BPd2(dba)3, P(tBu)3, KF, THF.

Method And

In vitro 2 drachmas, 2-bromaniline (100 mg ,58 mmol) and the appropriate arylboronic acid (0.82 mmol) dissolved in THF (1 ml). Type H2O (500 ml), then K2CO3(200 mg, 1.0 mmol) and Pd(PPh3)4(100 mg, 0.1 mmol). The tube rinsed with argon and sealed. Then the tube is heated at a temperature of 75°C for 18 hours. The crude sample was diluted with EtOAc and filtered through a layer of silica gel. The organic layers are concentrated by Savant Speed-vacuum. The crude amine is used without further purification.

Method In

In the tube 2 drachmas enter the appropriate arylboronic acid (0,58 mmol), then KF (110 mg, 1.9 mmol). Solids suspended in THF (2 ml) and then add 2 bromaniline (70 μl, of 0.58 mmol). The tube rinsed with argon for 1 min Add P(tBu)3(100 µl, 10%solution in hexano), then Pd2(dba)3(900 μl, 0,M solution in THF). The tube is again rinsed with argon and sealed. The tube is shaken on an orbital shaker at room temperature for 30 min and heated in the heating module at a temperature of 80°C for 16 hours. Then the test tube is cooled to a temperature of 20°C and the suspension is passed through a layer of celite. This layer washed with EtOAc (5 ml). The organic layers are combined and concentrated in vacuo, obtaining the crude amine, which is used without further purification.

The table below includes amines, obtained according to the General with the Birmingham, above.

3'-ethoxymethyl-2-ylamine
ProductNameWay
F-14'-methylbiphenyl-2-ylamineA
F-23'-methylbiphenyl-2-ylamineA
F-32'-methylbiphenyl-2-ylamineA
F-42',3'-dimethylbiphenyl-2-ylamineA
F-5(2'-aminobiphenyl-4-yl)methanolA
F-6N*4'*,N*4'*-dimethylbiphenyl-2,4'-diamineB
F-72'-triptorelin-2-ylamineB
F-8(2'-aminobiphenyl-4-yl)acetonitrileA
F-94'-isobutylidene-2-ylamine A
F-103'-triptorelin-2-ylamineB
F-112-pyridine-4-elfenliedB
F-122-(1H-indol-5-yl)phenylamineB
F-133',4'-dimethylbiphenyl-2-ylamineA
F-144'-isopropylphenyl-2-ylamineA
F-153'-isopropylidene-2-ylamineA
F-164'-triptorelin-2-ylamineB
F-174'-methoxybiphenyl-2-ylamineB
F-183'-methoxybiphenyl-2-ylamineB
F-192-benzo[1,3]dioxol-5-elfenliedB
F-20B
F-214'-ethoxymethyl-2-ylamineB
F-222'-ethoxymethyl-2-ylamineB
F-234'-methylsulfinylphenyl-2-ylamineB
F-243',4'-dimethoxybiphenyl-2-ylamineB
F-252',6'-dimethoxybiphenyl-2-ylamineB
F-262',5'-dimethoxybiphenyl-2-ylamineB
F-272',4'-dimethoxybiphenyl-2-ylamineB
F-285'-Chloro-2'-methoxybiphenyl-2-ylamineB
F-294'-cryptomaterial-2-ylamineB
F-303'-cryptomaterial-2-silt the B
F-314'-phenoxybiphenyl-2-ylamineB
F-322'-fluoro-3'-methoxybiphenyl-2-ylamineB

F-332'-phenoxybiphenyl-2-ylamineB
F-342-(2,4-dimethoxypyrimidine-5-yl)phenylamineB
F-355'-isopropyl-2'-methoxybiphenyl-2-ylamineB
F-362'-cryptomaterial-2-ylamineB
F-374'-forbiden-2-ylamineB
F-383'-forbiden-2-ylamineB
F-392'-forbiden-2-ylamineB
F-402'-aminomethan the l-3-carbonitril B
F-414'-fluoro-3'-methylbiphenyl-2-ylamineB
F-424'-chlorobiphenyl-2-ylamineB
F-433'-chlorobiphenyl-2-ylamineB
F-443',5'-diferuloyl-2-ylamineB
F-452',3'-diferuloyl-2-ylamineB
F-463',4'-diferuloyl-2-ylamineB
F-472',4'-diferuloyl-2-ylamineB
F-482',5'-diferuloyl-2-ylamineB
F-493'-chloro-4'-forbiden-2-ylamineB
F-503',5'-dichlorobiphenyl-2-ylamineB
F-512',5'-dichlorobiphenyl-2-ylamineB
F-522',3'-dichlorobiphenyl-2-ylamineB
F-533',4'-dichlorobiphenyl-2-ylamineB
F-54methyl ester of 2'-aminobiphenyl-4-carboxylic acidB
F-55methyl ester of 2'-aminobiphenyl-3-carboxylic acidB
F-562'-methylsulfinylphenyl-2-ylamineB
F-57N-(2'-aminobiphenyl-3-yl)ndimethylacetamideB
F-584'-methysulfonylmethane-2-ylamineB
F-592',4'-dichlorobiphenyl-2-ylamineB
F-604'-methysulfonylmethane-2-ylamineB
F-61isopropyl ester of 2'-aminobiphenyl-2-carboxylic acidB
F-622-furan-2-elfenliedB
F-631-[5-(2-AMINOPHENYL)thiophene-2-yl]alanonB
F-642-benzo[b]thiophene-2-elfenliedB
F-652-benzo[b]thiophene-3-elfenliedB
F-662-furan-3-elfenliedB
F-672-(4-methylthiophene-2-yl)phenylamineB
F-685-(2-AMINOPHENYL)thiophene-2-carbonitrileB

Example 10

Ethyl-2-(4-nitrophenyl)-2-methylpropanoate

tert-Piperonyl sodium (466 mg, is 4.85 mmol) are added to DMF (20 ml) at 0°C. the Cloudy solution is again cooled to a temperature of 5°C. Add ethyl-4-nitrophenylacetate (1.0 g, 4,78 mmol). Hemp is RNA, the suspension is cooled to a temperature of 5°C and add methyliodide (0,688 ml, is 4.85 mmol) for 40 minutes, the Mixture is stirred at 5-10°C for 20 min and then re-add tert-piperonyl sodium (466 mg, is 4.85 mmol) and methyliodide (0,699 ml, is 4.85 mmol). The mixture is stirred at 5-10°C for 20 min and the third time add tert-piperonyl sodium (47 mg, 0.48 mmol), then methyliodide (0,057 ml, 0.9 mmol). Add ethyl acetate (100 ml) and HCl (0.1 n., 50 ml). The organic layer is separated, washed with saturated salt solution and dried over Na2SO4. After filtration the filtrate is concentrated and receiving ethyl-2-(4-nitrophenyl)-2-methylpropanoate (900 mg, yield 80%), which is used without further purification.

G-1; Ethyl-2-(4-AMINOPHENYL)-2-methylpropanoate

A solution of ethyl-2-(4-nitrophenyl)-2-methylpropanoate (900 mg, 3.8 mmol) in EtOH (10 ml) is treated with 10%Pd/C (80 mg) and heated to a temperature of 45°C. Add a solution of potassium formate (4,10 g, 48.8 mmol) in H2O (11 ml) for 15 min. the Reaction mixture was stirred at 65°C for 2 hours and then treated with 300 mg of Pd/C. the Reaction mixture is stirred for 1.5 hours and then filtered through celite. The volume of solvent is reduced to approximately 50% under reduced pressure and extracted with EtOAc. The organic layers dried over Na2SO4and the solvent is removed under reduced pressure, obtaining ethyl-2-(4-AMINOPHENYL)-2-methylpropanoate (G-1) (670 m is, yield 85%).

1H-NMR (400 MHz, CDCl3): δ 7,14 (d, J=8.5 Hz, 2H), 6,65 (d, J=8.6 Hz, 2H), 4,10 (sq, J=7,1 Hz, 2H), 1,53 (s, 6H), of 1.18 (t, J=7,1 Hz, 3H).

Example 11

G-2; 2-(4-AMINOPHENYL)-2-methylpropan-1-ol

A solution of ethyl-2-(4-AMINOPHENYL)-2-methylpropanoate (30 mg, 0,145 mmol) in THF (1 ml) is treated with LiAlH4(1M solution in THF, 0,226 ml, 0,226 mmol) at 0°C and stirred for 15 minutes, the Reaction mixture was treated with 0,1N. NaOH solution, extracted with EtOAc and the organic layers dried over Na2SO4. The solvent is removed under reduced pressure, obtaining 2-(4-AMINOPHENYL)-2-methylpropan-1-ol (G-2), which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ 7,17 (d, J=8.5 Hz, 2H), to 6.67 (d, J=8.5 Hz, 2H), 3,53 (s, 2H), 1.28 (in, 6H).

Example 12

2-Methyl-2-(4-nitrophenyl)propanenitrile

A suspension of tert-butoxide sodium (662 mg, 6,47 mmol) in DMF (20 ml) at 0°With handle 4-nitrophenylacetonitrile (1000 mg, 6,18 mmol) and stirred for 10 minutes added dropwise methyliodide (400 μl, 6,47 mmol) for 15 minutes the Solution is stirred at a temperature of 0-10°C for 15 min and then at room temperature over the next 15 minutes To the resulting purple solution was added tert-piperonyl sodium (662 mg, 6,47 mmol) and the solution stirred for 15 mi the. Added dropwise methyliodide (400 μl, 6,47 mmol) for 15 min and the solution stirred overnight. Add tert-piperonyl sodium (192 mg, 1.94 mmol) and the reaction mixture was stirred at 0°C for 10 minutes Add methyliodide (186 μl, 2,98 mmol) and the reaction mixture is stirred for 1 hour. The reaction mixture was then partitioned between 1N. HCl solution (50 ml) and EtOAc (75 ml). The organic layer was washed with 1N. HCl solution and saturated salt solution, dried over Na2SO4and concentrated, obtaining 2-methyl-2-(4-nitrophenyl)propanenitrile in the form of a green solid waxy substance (1.25 g, yield 99%).

1H-NMR (400 MHz, CDCl3): δ 8,24 (d, J=8,9 Hz, 2H), 7,66 (d, J=8,9 Hz, 2H), 1.77 in (s, 6H).

2-Methyl-2-(4-nitrophenyl)propan-1-amine

To a cooled solution of 2-methyl-2-(4-nitrophenyl)propanenitrile (670 mg, 3.5 mmol) in THF (15 ml) added dropwise BH3(1M solution in THF, 14 ml, 14 mmol) at 0°C. the Mixture is heated to room temperature and heated at 70°C for 2 hours. Add 1H. HCl (2 ml), then NaOH, up until the pH reaches a value >7. The mixture is extracted with diethyl ether and the extract in diethyl ether concentrate, receiving 2-methyl-2-(4-nitrophenyl)propan-1-amine (610 mg, yield 90%)which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ to 8.20 (d, J=9.0 Hz, 2H), and 7.4 (d, J=9.0 Hz, 2H), 2,89 (s, 2H), 1,38 (s, 6H).

tert-Butyl-2-methyl-2-(4-nitrophenyl)propellernet

To a cooled solution of 2-methyl-2-(4-nitrophenyl)propan-1-amine (600 mg, 3.1 mmol) and 1H. the NaOH solution (3 ml, 3 mmol) in 1,4-dioxane (6 ml) and water (3 ml) was added Boc2O (742 mg, 3.4 mmol) at 0°C. the Reaction mixture was left to warm to room temperature and stirred over night. The reaction mixture was acidified with 5%solution of KHSO4and then extracted with ethyl acetate. The organic layer is dried over MgSO4and concentrate, receiving tert-butyl-2-methyl-2-(4-nitrophenyl)propylgallate (725 mg, yield 80%), which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ 8,11 (d, J=8,9 Hz, 2H), 7,46 (d, J=8,8 Hz, 2H), 3,63 (s, 2H), 1,31-of 1.29 (m, 15H).

G-3; tert-Butyl-2-methyl-2-(4-AMINOPHENYL)propellernet

To boiling under reflux to a solution of tert-butyl-2-methyl-2-(4-nitrophenyl)propylgallate (725 mg, 2.5 mmol) and ammonium formate (700 mg, 10.9 mmol) in EtOH (25 ml) add 5% of the mass. Pd/C (400 mg). The mixture is refluxed for 1 hour, cooled and filtered through celite. The filtrate is concentrated and receiving tert-butyl-2-methyl-2-(4-AMINOPHENYL)propylgallate (G-3) (550 mg, yield 83%), which is used without further purification.

1H-NMR (400 MHz, DMSO-d6) δ of 6.99 (d, J=8.5 Hz, 2H), of 6.49 (d, J=8.6 Hz, 2H), around 4.85 (s, 2H), 3,01 (d, J=6.3 Hz, 2H), 136 (C, 9H).

HPLC: retention time 2,02 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 265,2 m/z (MH+).

Example 13

7-Nitro-1,2,3,4-tetrahydronaphthalen-1-ol

7-Nitro-3,4-dihydro-2H-naphthalene-1-he (200 mg, 1.05 mmol) dissolved in methanol (5 ml) and added in several portions NaBH4(78 mg, 2.05 mmol). The reaction mixture was stirred at room temperature for 20 min, then concentrated and purified column chromatography (10-50% ethyl acetate-hexane)to give 7-nitro-1,2,3,4-tetrahydronaphthalen-1-ol (163 mg, yield 80%).

1H-NMR (400 MHz, CD3CN) δ 8,30 (d, J=2.3 Hz, 1H), 8,02 (DD, J=8,5, 2.5 Hz, 1H), 7,33 (d, J=8.5 Hz, 1H), amounts to 4.76 (t, J=5.5 Hz, 1H), 2,96 is 2.80 (m, 2H), 2,10-1,99 (m, 2H), 1,86-to 1.77 (m, 2H).

HPLC: retention time 2,32 min, 10-99% CH3CN, the analysis time of 5 minutes

N-1; 7-Amino-1,2,3,4-tetrahydronaphthalen-1-ol

7-Nitro-1,2,3,4-tetrahydronaphthalen-1-ol (142 mg, 0.73 mmol) dissolved in methanol (10 ml) and the flask is rinsed with N2(gaseous). Add 10%Pd/C (10 mg) and the reaction mixture is stirred in hydrogen atmosphere (1 ATM.) at room temperature over night. The reaction mixture is filtered and the filtrate is concentrated and receiving 7-amino-1,2,3,4-tetrahydronaphthalen-1-ol (N-1) (113 mg, yield 95%).

HPLC: retention time of 0.58 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 164,5 m/z (MH+).

Example 14

The reaction of 7-nitro-3,4-dihydro-2H-naphthalene-1-it

To a solution of 7-nitro-3,4-dihydro-2H-naphthalene-1-she (500 mg, 2,62 mmol) in pyridine (2 ml) add a solution of hydroxylamine (1 ml, ~50%solution in water). The reaction mixture was stirred at room temperature for 1 hour, then concentrated and purified column chromatography (10-50% ethyl acetate-hexane), receiving the oxime 7-nitro-3,4-dihydro-2H-naphthalene-1-it (471 mg, yield 88%).

HPLC: retention time to 2.67 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 207,1 m/z (MH+).

1,2,3,4-tetrahydronaphthalene-1,7-diamine

The reaction of 7-nitro-3,4-dihydro-2H-naphthalene-1-it (274 mg, of 1.33 mmol) was dissolved in methanol (10 ml) and the flask is rinsed with N2(gaseous). Add 10%Pd/C (50 mg) and the reaction mixture is stirred in hydrogen atmosphere (1 ATM.) at room temperature over night. The reaction mixture is filtered and the filtrate is concentrated and receiving 1,2,3,4-tetrahydronaphthalene-1,7-diamine (207 mg, yield 96%).

1H-NMR (400 MHz, DMSO-d6) δ 6,61-to 6.57 (m, 2H), 6,28 (DD, J=8,0, 2.4 Hz, 1H), to 4.62 (s, 2H), to 3.58 (m, 1H), 2,48 is 2.44 (m, 2H), 1,78 is 1.70 (m, 2H), 1,53 to 1.37 (m, 2H).

N-2; tert-Butyl ether (7-amino-1,2,3,4-tetrahydronaphthalen-1-yl)carbamino acid

To a solution of 1,2,3,4-tetrahydronaphthalene-1,7-diamine (154 mg, 0.95 mmol) and triethylamine (139 μl, 1.0 mmol) in methanol (2 ml), cooled to 0°C, add di-tert-Buti is dicarbonate (207 mg, 0.95 mmol). The reaction mixture was stirred at 0°C and then concentrated and purified column chromatography (5-50% methanol-dichloromethane)to give tert-butyl ester (7-amino-1,2,3,4-tetrahydronaphthalen-1-yl)carbamino acid (N-2) (327 mg, quantitative yield).

HPLC: retention time of 1.95 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 263,1 m/z (MH+).

Example 15

N-(2-Bromobenzyl)-2,2,2-triptorelin

To a solution of 2-bromobenzylamine (1.3 ml, about 10.8 mmol) in methanol (5 ml) add ethyltryptamine (1,54 ml, 21.6 mmol) and triethylamine (1.4 ml, about 10.8 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo, obtaining N-(2-bromobenzyl)-2,2,2-triptorelin (3,15 g, quantitative yield).

HPLC: retention time of 2.86 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 283,9 m/z (MH+).

I-1; N-(4'-Aminobiphenyl-2-ylmethyl)-2,2,2-triptorelin

A mixture of N-(2-bromobenzyl)-2,2,2-trifurcated (282 mg, 1.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (284 mg, 1.3 mmol), Pd(OAc)2(20 mg, 0.09 mmol) and PS-PPh3(40 mg, 3 mmol/g, 0.12 mmol) dissolved in DMF (5 ml) and added 4M solution of K2CO3(0.5 ml). The reaction mixture is heated at a temperature of 80°C during the night. The mixture is filter the Ute, concentrated and purified column chromatography (0-50% ethyl acetate-hexane)to give N-(4'-aminobiphenyl-2-ylmethyl)-2,2,2-triptorelin (I-1) (143 mg, yield 49%).

HPLC: retention time 1,90 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 295,5 m/z (MH+).

Commercially available amines

AminName
J-12-methoxy-5-methylbenzenamine
J-22,6-diisopropylbenzene

J-3pyridine-2-amine
J-44-pentylbenzene
J-5isoquinoline-3-amine
J-6aniline
J-74-phenoxybenzamine
J-82-(2,3-dimethylphenoxy)pyridine-3-amine
J-94-ethynylbenzoate
J-102-second-is universally
J-112-amino-4,5-dimethoxybenzonitrile
J-122-tert-butylbenzylamine
J-131-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)alanon
J-144-(4-methyl-4H-1,2,4-triazole-3-yl)benzolamide
J-152'-aminomethylphenol-4-ylamine
J-161H-indazol-6-ylamine
J-172-(2-methoxyphenoxy)-5-(trifluoromethyl)benzolamide
J-182-tert-butylbenzylamine
J-192,4,6-trimethylbenzene
J-205,6-dimethyl-1H-benzo[d]imidazol-2-amine
J-212,3-dihydro-1H-inden-4-amine
J-222-sec-butyl-6-ethylbenzylamine
J-23the quinoline-5-amine
J-244-(benzyloxy is)benzolamide
J-252'-methoxybiphenyl-2-ylamine
J-26benzo[c][1,2,5]thiadiazole-4-amine
J-273-benzylpencillin
J-284-isopropylbenzylamine
J-292-(phenylsulfonyl)benzolamide
J-302-methoxybenzylamine
J-314-amino-3-ethylbenzonitrile
J-324-methylpyridin-2-amine
J-334-chlorobenzenamine
J-342-(benzyloxy)benzolamide
J-352-amino-6-chlorobenzonitrile
J-363-methylpyridin-2-amine
J-374-aminobenzonitrile
J-383-chloro-2,6-diethylbenzene
J-393-phenoxybenzamine
J-402-benzylpencillin
J-412-(2-pertenece)pyridine-3-amine
J-425-chloropyridin-2-amine
J-432-(trifluoromethyl)benzolamide
J-44(4-(2-AMINOPHENYL)piperazine-1-yl)(phenyl)metano
J-451H-benzo[d][1,2,3]triazole-5-amine
J-462-(1H-indol-2-yl)benzolamide
J-474-methylbiphenyl-3-ylamine
J-48pyridine-3-amine
J-493,4-dimethoxybenzoate
J-503H-benzo[d]imidazol-5-amine
J-513-aminobenzonitrile
J-526-chloropyridin-3-amine

J-53o-toluidine
J-541H-indol-5-amine
J-55[1,2,4]triazolo[1,5-a]pyridin-8-amine
J-562-methoxypyridine-3-amine
J-572-butoxybenzoate
J-582,6-dimethylbenzenamine
J-592-(methylthio)benzolamide
J-602-(5-methylfuran-2-yl)benzolamide
J-613-(4-AMINOPHENYL)-3-ethylpiperidine-2,6-dione
J-622,4-dimethylbenzenamine
J-635-herperidin-2-amine
J-644-cyclohexylbenzene
J-654-aminobenzenesulfonamide
J-662-ethylbenzylamine
J-674-fluoro-3-methylbenzenamine
J-682,6-dimethoxypyridine-3-the min
J-694-tert-butylbenzylamine
J-704-second-butylbenzylamine
J-715,6,7,8-tetrahydronaphthalen-2-amine
J-723-(pyrrolidin-1-sulfonyl)phenylamine
J-734-adamantane-1-elfenlied
J-743-amino-5,6,7,8-tetrahydronaphthalen-2-ol
J-75benzo[d][1,3]dioxol-5-amine
J-765-chloro-2-phenoxybenzamine
J-77N1-cosevent-1,2-diamine
J-783,4-dimethylbenzylamine
J-792-(triptoreline)benzolamide
J-801H-indole-7-amine
J-813-methoxybenzylamine
J-82the quinoline-8-amine
J-83 2-(2,4-divergence)pyridine-3-amine
J-842-(4-AMINOPHENYL)acetonitrile
J-852,6-dichlorbenzene
J-862,3-dihydrobenzofuran-5-amine
J-87p-toluidine
J-882-methylinosine-8-amine
J-892-tert-butylbenzylamine
J-903-chlorobenzenamine
J-914-tert-butyl-2-chlorobenzenamine
J-922-aminobenzenesulfonamide
J-931-(2-AMINOPHENYL)alanon
J-94m-toluidine
J-952-(3-chloro-5-(trifluoromethyl)pyridine-2-yloxy)benzolamide
J-962-amino-6-methylbenzonitrile
J-972-(prop-1-EN-2-yl)benzolamide
J-984-amino-N-pyridin-2-albenzaalbenza
J-992-ethoxybenzoate
J-100naphthalene-1-amine
J-101biphenyl-2-ylamine
J-1022-(trifluoromethyl)-4-isopropylbenzylamine

td align="center"> J-112
J-1032,6-diethylbenzene
J-1045-(trifluoromethyl)pyridin-2-amine
J-1052-aminobenzamide
J-1063-(triptoreline)benzolamide
J-1073,5-bis(trifluoromethyl)benzolamide
J-1084-vinylbenzoate
J-1094-(trifluoromethyl)benzolamide
J-1102-morpholinopropan
J-1115-amino-1H-benzo[d]imidazol-2(3H)-he
the quinoline-2-amine
J-1133-methyl-1H-indol-4-amine
J-114pyrazin-2-amine
J-1151-(3-AMINOPHENYL)alanon
J-1162-ethyl-6-isopropylbenzylamine
J-1172-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)benzolamide
J-118N-(4-amino-2,5-dioxyphenyl)benzamid
J-1195,6,7,8-tetrahydronaphthalen-1-amine
J-1202-(1H-benzo[d]imidazol-2-yl)benzolamide
J-1211,1-dioxo-1H-1λ*6*-benzo[b]thiophene-6-ylamine
J-1222.5-diethoxybenzene
J-1232-isopropyl-6-methylbenzenamine
J-124tert-butyl 5-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate
J-1252-(2-AMINOPHENYL)ethanol
J-126(4-AMINOPHENYL)methanol
J-1275-methylpyridin-2-amine
J-1282-(pyrrolidin-1-yl)benzolamide
J-1294-propylbenzoate
J-1303,4-dichlorbenzene
J-1312-phenoxybenzamine
J-132biphenyl-2-ylamine
J-1332-chlorobenzenamine
J-1342-amino-4-methylbenzonitrile
J-135(2-AMINOPHENYL)(phenyl)metano
J-136aniline
J-1373-(triptoreline)benzolamide
J-1382-(2,5-dimethyl-1H-pyrrol-1-yl)benzolamide
J-1394-(morpholine-4-sulfonyl)phenylamine
J-140 2 methylbenzo[d]thiazol-5-amine
J-1412-amino-3,5-dichlorobenzonitrile
J-1422-fluoro-4-methylbenzenamine
J-1436-ethylpyridine-2-amine
J-1442-(1H-pyrrol-1-yl)benzolamide
J-1452-methyl-1H-indol-5-amine
J-146the quinoline-6-amine
J-1471H-benzo[d]imidazol-2-amine
J-1482-o-tolerant[d]oxazol-5-amine
J-1495-vinylpyridin-2-amine
J-150biphenyl-2-ylamine
J-1514-(deformedarse)benzolamide

J-1525-tert-butyl-2-methoxybenzylamine
J-1532-(2-tert-butylphenoxy)benzolamide
J-154 3-aminobenzamide
J-1554-morpholinomethyl
J-1566 aminobenzo[d]oxazol-2(3H)-he
J-1572-phenyl-3H-benzo[d]imidazol-5-amine
J-1582.5-dichloropyridine-3-amine
J-1592.5-dimethylbenzenamine
J-1604-(phenylthio)benzolamide
J-1619H-fluoren-1-amine
J-1622-(4-AMINOPHENYL)-1,1,1,3,3,3-hexaferrite-2-ol
J-1634-bromo-2-ethylbenzylamine
J-1644-methoxybenzylamine
J-1653-(piperidine-1-sulfonyl)phenylamine
J-166cinoxacin-6-amine
J-1676-(trifluoromethyl)pyridine-3-amine
J-1683-(trifluoromethyl)-2-methylbenzoate the
J-169(2-AMINOPHENYL)(phenyl)methanol
J-170aniline
J-1716-methoxypyridine-3-amine
J-1724-butylbenzylamine
J-1733-(morpholine-4-sulfonyl)phenylamine
J-1742,3-dimethylbenzylamine
J-175aniline
J-176biphenyl-2-ylamine
J-1772-(2,4-dichlorphenoxy)benzolamide
J-178pyridine-4-amine
J-1792-(4-methoxyphenoxy)-5-(trifluoromethyl)benzolamide
J-1806-methylpyridin-2-amine
J-1815-chloro-2-ferbenstein
J-1821H-indol-4-amine
J-1836-morpholino ridin-3-amine
J-184aniline
J-1851H-indazol-5-amine
J-1862-[(cyclohexylethylamine)methyl]phenylamine
J-1872 phenylbenzo[d]oxazol-5-amine
J-188naphthalene-2-amine
J-1892-aminobenzonitrile
J-190N1,N1-diethyl-3-methylbenzo-1,4-diamine
J-191aniline
J-1922-butylbenzylamine
J-1931-(4-AMINOPHENYL)ethanol
J-1942-amino-4-methylbenzamide
J-195the quinoline-3-amine
J-1962-(piperidine-1-yl)benzolamide
J-1973-aminobenzenesulfonamide
J-1982-ethyl-6-methylben is alamin
J-199biphenyl-4-ylamine
J-2002-(o-tolyloxy)benzolamide
J-2015-amino-3-methylbenzo[d]oxazol-2(3H)-he

J-2024-ethylbenzylamine
J-2032-isopropylbenzylamine
J-2043-(trifluoromethyl)benzolamide
J-2052-amino-6-perbenzoate
J-2062-(2-AMINOPHENYL)acetonitrile
J-2072-(4-pertenece)pyridine-3-amine
J-208aniline
J-2092-(4-methylpiperidin-1-yl)benzolamide
J-2104-ferbenstein
J-2112-propylbenzene
J-2124-(triptoreline)benzenes, the
J-2133-aminophenol
J-2142,2-debtorrent[d][1,3]dioxol-5-amine
J-2152,2,3,3-titrator-2,3-dihydrobenzo[b][1,4]dioxin-6-amine
J-216N-(3-AMINOPHENYL)ndimethylacetamide
J-2171-(3-AMINOPHENYL)-3-methyl-1H-pyrazole-5(4H)-he
J-2185-(trifluoromethyl)benzene-1,3-diamine
J-2195-tert-butyl-2-methoxybenzoyl-1,3-diamine
J-220N-(3-amino-4-ethoxyphenyl)ndimethylacetamide
J-221N-(3-AMINOPHENYL)methanesulfonamide
J-222N-(3-AMINOPHENYL)propionate
J-223N1,N1-xylene-1,3-diamine
J-224N-(3-amino-4-methoxyphenyl)ndimethylacetamide
J-225benzene-1,3-diamine
J-226 4-methylbenzo-1,3-diamine
J-2271H-indol-6-amine
J-2286,7,8,9-tetrahydro-5H-carbazole-2-amine
J-2291H-indol-6-amine
J-2301H-indol-6-amine
J-2311H-indol-6-amine
J-2321H-indol-6-amine
J-2331H-indol-6-amine
J-2341H-indol-6-amine
J-2351H-indol-6-amine
J-2361H-indol-6-amine
J-2371H-indol-6-amine
J-2381H-indol-6-amine
J-2391-(6-amino-2,3-dihydroindol-1-yl)alanon
J-2405-chlorobenzene-1,3-diamine

Amides (compounds of formula (I)

The General scheme

a) Ar1 R7NH, binder, base, solvent. The examples used conditions: HATU, DIEA, DMF; BOP, DIEA, DMF; HBTU, Et3N, CH2Cl2; PFP-TFUC, pyridine.

A specific example

215; 4-Oxo-N-phenyl-1H-quinoline-3-carboxamide

To a solution of 4-hydroxyquinolin-3-carboxylic acid (A-1) (19 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (34,9 μl, 0.2 mmol) in DMF (1 ml) was added aniline (18,2 μl, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The resulting solution is filtered and purified HPLC (10-99% CH3CN/H2O)to give 4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, yield 45%).

1H-NMR (400 MHz, DMSO-d6) δ 12,97 (s, 1H), 12,50 (s, 1H) 8,89 (s, 1H), 8.34 per (DD, J=8,1, 1.1 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H) 7,75 (m, 3H) at 7.55 (t, J=8,1 Hz, 1H), 7,37 (t, J=7.9 Hz, 2H), 7,10 (t, J=6,8 Hz, 1H).

HPLC: retention time to 3.02 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 265,1 m/z (MH+).

The table below presents a list of other examples of substances synthesized according to the General scheme above.

The compound of the formula IAcidAmin
2A-1C-2
3A-1J-17
4A-1J-110
5A-1G-2
6A-1E-8
7A-1J-118
8A-1D-7
9A-1J-197
11A-1F-7
12A-1F-6
13A-1E-2
15A-1J-56
16A-1J-211
18A-1J-161
19A-1J-112
20 A-1J-200
21A-1J-98
23A-1C-15
24A-1J-72
25A-1F-57
26A-1J-196
29A-21J-208
31A-1J-87
32A-1B-21
33A-1J-227
34A-1C-19
36A-1J-203
37A-1J-80
38A-1J-46
39A-17 D-10
40A-1J-125
42A-1J-95
43A-1C-16
44A-1J-140
45A-1J-205
47A-1J-102
48A-1J-181
49A-1F-25
50A-1J-19
51A-7B-24
52A-1F-2
53A-1J-178
54A-1J-26
55A-1J-219
56A-1J-74
57A-1J-61
58A-1D-4
59A-1F-35

102
60A-1D-11
61A-1J-174
62A-1J-106
63A-1F-47
64A-1J-111
66A-1J-214
67A-10J-236
68A-1F-55
69A-1D-8
70 A-1F-11
71A-1F-61
72A-1J-66
73A-1J-157
74A-1J-104
75A-1J-195
76A-1F-46
77A-1B-20
78A-1J-92
79A-1F-41
80A-1J-30
81A-1J-222
82A-1J-190
83A-1F-40
84A-1 J-32
85A-1F-53
86A-1J-15
87A-1J-39
88A-1G-3
89A-1J-134
90A-1J-18
91A-1J-38
92A-1C-13
93A-1F-68
95A-1J-189
96A-1B-9
97A-1F-34
99A-1J-4
100A-1J-182
A-1J-117
103A-2C-9
104A-1B-4
106A-1J-11
107A-1DC-6
108A-1DC-3
109A-1DC-4
110A-1J-84
111A-1J-43
112A-11J-235
113A-1B-7
114A-1D-18

115A-1F-62
116A-3 J-229
118A-1F-12
120A-1J-1
121A-1J-130
122A-1J-49
123A-1F-66
124A-2B-24
125A-1J-143
126A-1C-25
128A-22J-176
130A-14J-233
131A-1J-240
132A-1J-220
134A-1F-58
135A-1
136A-1C-8
137A-6C-9
138A-1F-44
139A-1F-59
140A-1J-64
142A-1J-10
143A-1C-7
144A-1J-213
145A-1B-18
146A-1J-55
147A-1J-207
150A-1J-162
151A-1F-67
152A-1J-156
153A-1C-23
154A-1J-107
155A-1J-3
156A-1F-36
160A-1D-6
161A-1C-3
162A-1J-171
164A-1J-204
165A-1J-65
166A-1F-54
167A-1J-226
168A-1J-48
169A-1B-1
170A-1J-42
171A-1F-52
172A-1F-64
173A-1J-180
174A-1F-63
175A-1DC-2
176A-1J-212

177A-1J-57
178A-1J-153
179A-1J-154
180A-1J-198
181A-1F-1
182A-1F-37
183A-1DC-1
184A-15 J-231
185A-1J-173
186A-1B-15
187A-1B-3
188A-1B-25
189A-1J-24
190A-1F-49
191A-1J-23
192A-1J-36
193A-1J-68
194A-1J-37
195A-1J-127
197A-1J-167
198A-1J-210
199A-1F
200A-1H-1
201A-1J-96
202A-1F-28
203A-1B-2
204A-1C-5
205A-1J-179
206A-1J-8
207A-1B-17
208A-1C-12
209A-1J-126
210A-17J-101
211A-1J-152
212A-1J-217
213A-1F-51
214A-1J-221
215A-1J-136
216A-1J-147
217A-1J-185
218A-2C-13
219A-1J-114
220A-1C-26
222A-1J-35
223A-1F-23
224A-11-1
226A-1J-129
227A-1J-120
228A-1J-169
229A-1J-59

230A-1J-145
231A-1C-17
233A-1J-239
234A-1B-22
235A-1E-9
236A-1J-109
240A-1J-34
241A-1J-82
242A-1D-2
244A-1J-228
245A-1J-177
246A-1J-78
247A-1F-33
250 A-1J-224
252A-1J-135
253A-1F-30
254A-2B-20
255A-8C-9
256A-1J-45
257A-1J-67
259A-1B-14
261A-1F-13
262A-1DC-7
263A-1J-163
264A-1J-122
265A-1J-40
266A-1C-14
267A-1/td> J-7
268A-1E-7
270A-1B-5
271A-1D-9
273A-1H-2
274A-8B-24
276A-1J-139
277A-1F-38
278A-1F-10
279A-1F-56
280A-1J-146
281A-1J-62
283A-1F-18
284A-1J-16
285A-1 F-45
286A-1J-119
287A-3C-13
288A-1C-6
289A-1J-142
290A-1F-15
291A-1C-10
292A-1J-76

J-85
293A-1J-144
294A-1J-54
295A-1J-128
296A-17J-12
297A-1J-138
301A-1J-14
302 A-1F-5
303A-1J-13
304A-1E-1
305A-1F-17
306A-1F-20
307A-1F-43
308A-1J-206
309A-1J-5
310A-1J-70
311A-1J-60
312A-1F-27
313A-1F-39
314A-1J-116
315A-1J-58
317A-1
319A-2C-7
320A-1B-6
321A-1J-44
322A-1J-22
324A-1J-172
325A-1J-103
326A-1F-60
328A-1J-115
329A-1J-148
330A-1J-133
331A-1J-105
332A-1J-9
333A-1F-8
334A-1DC-5/td>
335A-1J-194
336A-1J-192
337A-1C-24
338A-1J-113
339A-1B-8
344A-1F-22
345A-2J-234
346A-12J-6
348A-1F-21
349A-1J-29
350A-1J-100
351A-1B-23
352A-1B-10
353A-1D-10
354A-1J-186
355A-1J-25

J-33
357A-1B-13
358A-24J-232
360A-1J-151
361A-1F-26
362A-1J-91
363A-1F-32
364A-1J-88
365A-1J-93
366A-1F-16
367A-1F-50
368A-1D-5
369 A-1J-141
370A-1J-90
371A-1J-79
372A-1J-209
373A-1J-21
374A-16J-238
375A-1J-71
376A-1J-187
377A-5J-237
378A-1D-3
380A-1J-99
381A-1B-24
383A-1B-12
384A-1F-48
385A1 J-83
387A-1J-168
388A-1F-29
389A-1J-27
391A-1F-9
392A-1J-52
394A-22J-170
395A-1C-20
397A-1J-199
398A-1J-77
400A-1J-183
401A-1F-4
402A-1J-149
403A-1C-22
405A-1
406A-6B-24
407A-3C-7
408A-1J-81
410A-1F-31
411A-13J-191
412A-1B-19
413A-1J-131
414A-1J-50
417A-1F-65
418A-1J-223

J-193
419A-1J-216
420A-1G-1
421A-1C-18
422 A-1J-20
423A-1B-16
424A-1F-42
425A-1J-28
426A-1C-11
427A-1J-124
428A-1C-1
429A-1J-218
430A-1J-123
431A-1J-225
432A-1F-14
433A-1C-9
434A-1J-159
435A-1J-41
436A-1/td> F-24
437A-1J-75
438A-1E-10
439A-1J-164
440A-1J-215
441A-1D-19
442A-1J-165
443A-1J-166
444A-1E-6
445A-1J-97
446A-1J-121
447A-1J-51
448A-1J-69
449A-1J-94
450A-1
451A-1J-31
452A-1J-108
453A-1D-1
454A-1J-47
455A-1J-73
456A-1J-137
457A-1J-155
458A-1C-4
459A-1J-53
461A-1J-150
463A-1J-202
464A-3C-9
465A-1E-4
466A-1J-2
467A-1J-86
468A-20J-184
469A-12J-132
470A-1J-160

473A-21J-89
474A-1J-201
475A-1J-158
477A-1J-63
478A-1B-11
479A-4J-230
480A-23J-175
481A-1J-188
483A-1C-21
484 A-1D-14
B-26-IA-1B-26
B-27-IA-1B-27
C-27-IA-1C-27
D-12-IA-1D-12
D-13-IA-1D-13
D-15-IA-1D-15
D-16-IA-1D-16
D-17-IA-1D-17
DC-10-IA-1DC-10
DC-8-IA-1DC-8
DC-9-IA-1DC-9

Indoles

Example 1

The General scheme

A specific example

188-I; 6-[(4-Oxo-1H-quinoline-3-yl)carbylamine]-1H-indol-5-Carbo the OIC acid

A mixture of ethyl ester of 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-5-carboxylic acid (188) (450 mg, 1.2 mmol) and 1H. NaOH solution (5 ml) in THF (10 ml) is heated at a temperature of 85°C during the night. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was acidified with 1N. HCl solution to pH=5 and the precipitate is filtered off, washed with water and dried in the air, getting 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-5-carboxylic acid (188-I) (386 mg, yield 93%).

1H-NMR (400 MHz, DMSO-d6) δ 12,92-was 12.75 (m, 2H), 11,33 (s, 1H), 8,84 (s, 1H), 8,71 (s, 1H), 8.30 to (DD, J=8,1, 0.9 Hz, 1H), they were 8.22 (s, 1H), 7,80-7,72 (m, 2H), 7,49 (t, J=8.0 Hz, 1H), 7,41 (t, J=2.7 Hz, 1H), 6,51 (m,H).

HPLC: retention time 2,95 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 376,2 m/z (MH+).

343; N-[5-(Isobutylamino)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide

To a solution of 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-5-carboxylic acid (188-I) (26 mg, 0.08 mmol), HATU (38 mg, 0.1 mmol) and DIEA (35 μl, 0.2 mmol) in DMF (1 ml) add isobutylamine (7 mg, 0.1 mmol) and the reaction mixture stirred at 65°C over night. The resulting solution is filtered and purified HPLC (10-99% CH3CN/H2O)to give the product, N-[5-(isobutylamino)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (343) (20 mg, yield 66%).

1H-NMR (400 MHz, DMSO-d6) δ 12,66 (d, J=7,4 Hz, 1H), 12,42 (s, 1H), 11,21 (s, 1H), 8,81 (d, J=6,6 Hz, 1H), 847 (s, 1H), at 8.36 (t, J=5.6 Hz, 1H), 8,30 (d, J=8,4 Hz, 1H), 7,79 (t, J=7.9 Hz, 1H), 7,72-7,71 (m, 2H), 7,51 (t, J=7.2 Hz, 1H), 7,38 (m, 1H), 6.48 in (m, 1H), 3,10 (t, J=6.2 Hz, 2H), of 1.88 (m, 1H), 0,92 (d, J=6,7 Hz, 6H).

HPLC: retention time 2,73 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 403,3 m/z (MH+).

Another example

148; 4-Oxo-N-[5-(1-piperidinylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide

4-Oxo-N-[5-(1-piperidinylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide (148) synthesized following the General scheme above, linking acid (188-I) with piperidine. Total yield (12%).

HPLC: retention time and 2.79 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 415,5 m/z (MH+).

Example 2

The General scheme

A specific example

158; 4-Oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide

A mixture of N-(5-bromo-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide (In-27-I) (38 mg, 0.1 mol), phenylboronic acid (18 mg, 0.15 mmol), (dppf)PdCl2(catalytic amount) and K2CO3(100 μl, 2M solution) in DMF (1 ml) is heated in a microwave oven at 180°C for 10 min, the Reaction mixture was filtered and purified HPLC (10-99% CH3CN/H2O)to give the product, 4-oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide (158) (5 mg, yield 13%).

HPLC: EMA retention of 3.05 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 380,2 m/z (MH+).

The table below presents a list of other examples of substances synthesized according to the above General scheme.

The compound of the formula IBaronova acid
2372-methoxyphenylalanine acid
3272-ethoxyphenylurea acid
4042,6-dimethoxyaniline acid
15-chloro-2-methoxyphenylalanine acid
3424-isopropylaniline acid
3474-(2-dimethylaminoethanol)phenylboronic acid
653-pyridineboronic acid

Example 3

27; N-[1-[2-[Methyl(2-methylaminomethyl)amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide

To a solution of tert-butyl methyl ether methyl{[methyl(2-oxo-2-{6-[(4-oxo-1,4-dihydrodiol the n-3-carbonyl)amino]indol-1-yl}ethyl)carbarnoyl]methyl}carbamino acid ( In-26-I) (2.0 g, 3.7 mmol)dissolved in a mixture of CH2Cl2(50 ml) and methanol (15 ml)add a solution of HCl (60 ml, 1,25M solution in methanol). The reaction mixture was stirred at room temperature for 64 hours. The precipitated product is separated by filtration, washed with diethyl ether and dried in high vacuum, obtaining the hydrochloride of N-[1-[2-[methyl(2-methylaminomethyl)amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (27in the form of a grayish-white solid (1.25 g, yield 70%).

1H-NMR (400 MHz, DMSO-d6) δ 13,20 (d, J=6,7 Hz, 1H), 12,68 (s, 1H), 8,96 cent to 8.85 (m, 1H), 8,35 (d, J=7.9 Hz, 1H), to $ 7.91-to 7.77 (m, 3H), of 7.64-rate of 7.54 (m, 3H), PC 6.82 (m, 1H), of 5.05 (s, 0,7H), 4,96 (s, 1,3H), 4,25 (t, J=5.6 Hz, 1,3H), 4,00 (t, J=5.7 Hz, 0,7H), 3,14 (s, 2H), to 3.02 (s, 1H), 2,62 (t, J=5,2 Hz, 2H), 2,54 (t, J=5.4 Hz, 1H).

HPLC: retention time of 2.36 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 446,5 m/z (MH+).

Phenols

Example 1

The General scheme

A specific example

275; 4-Benzyloxy-N-(3-hydroxy-4-tert-butylphenyl)quinoline-3-carboxamide

To a mixture of N-(3-hydroxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (428) (6,7 mg, 0.02 mmol) and Cs2CO3(13 mg, 0.04 mmol) in DMF (0.2 ml) is added BnBr (10 μl, 0.08 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture is filtered and iseut, using HPLC, receiving 4-benzyloxy-N-(3-hydroxy-4-tert-butylphenyl)quinoline-3-carboxamide (275).

lH-NMR (400 MHz, DMSO-d6) δ 12,23 (s, 1H), for 9.47 (s, 1H), 9,20 (s, 1H), 8,43 (d, J=7.9 Hz, 1H), 7,79 (t, J=2.0 Hz, 2H), 7,56 (m, 1H), 7,38-7,26 (m, 6H), 7,11 (d, J=8,4 Hz, 1H), 6,99 (DD, J=8,4, 2,1 Hz,1H), to 5.85 (s, 2H), of 1.35 (s, 9H).

HPLC: retention time 3,93 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 427,1 m/z (MH+).

Another example

415; N-(3-Hydroxy-4-tert-butylphenyl)-4-methoxyquinoline-3-

carboxamid

N-(3-Hydroxy-4-tert-butylphenyl)-4-methoxyquinoline-3-carboxamide (415) synthesized following the General scheme above, subjecting the interaction of N-(3-hydroxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (428with methyliodide.

1H-NMR (400 MHz, DMSO-d6) δ of 12.26 (s, 1H), 9,46 (s, 1H), 8,99 (s, 1H), 8,42 (t, J=4,2 Hz, 1H), 7.95 is-7,88 (m, 2H), to 7.61-of 7.69 (m, 1H), 7,38 (d, J=2.1 Hz, 1H), 7,10 (d, J=8,4 Hz, 1H), of 6.96 (DD, J=8,4, and 2.1 Hz, 1H), 4,08 (s, 3H), 1,35 (s, 9H).

HPLC: retention time of 3.46 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 351,5 m/z (MH+).

Example 2

where

NMP=2-nitro-2-methyl-1-propanol

476; N-(4-tert-Butyl-2-cyano-5-hydroxyphenyl)-1,4-dihydro-4-oxoindole-3-carboxamide

To a suspension of N-(4-tert-butyl-2-bromo-5-hydroxyphenyl)-1,4-dihydro-4-oxoindole-3-carboxamide (-27-I) (84 mg, 0.2 mmol), Zn(CN)sub> 2(14 mg, 0.12 mmol) in NMP (1 ml) is added under nitrogen atmosphere Pd(PPh3)4(16 mg, 0.014 mmol). The mixture is heated in a microwave oven at 200°C for 1 hour, filtered and purified using preparative HPLC, obtaining N-(4-tert-butyl-2-cyano-5-hydroxyphenyl)-1,4-dihydro-4-oxoindole-3-carboxamide (476).

1H-NMR (400 MHz, DMSO-d6) δ 13,00 (d, J=6,4 Hz, 1H), 12,91 (s, 1H), 8,89 (d, J=6,8 Hz, 1H), 8.34 per (d, J=8,2 Hz, 1H), 8,16 (s, 1H), 7,85 to 7.75 (m, 2H), 7,56-rate of 7.54 (m, 1H), 7,44 (s, 1H), 1,35 (s, N).

HPLC: retention time of 3.42 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 362,1 m/z (MH+).

Anilines

Example 1

The General scheme

A specific example

260; N-(5-Amino-2-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide

A mixture of tert-butyl methyl ether [3-[(4-oxo-1H-quinoline-3-yl)carbylamine]-4-tert-butylphenyl]aminoarabinose acid (353) (33 mg, 0.08 mmol), TFUK (1 ml) and CH2Cl2(1 ml) was stirred at room temperature overnight. The solution is concentrated and the residue dissolved in DMSO (1 ml) and purified HPLC (10-99% CH3CN/H2O)to give the product, N-(5-amino-2-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (260) (15 mg, yield 56%).

1H-NMR (400 MHz, DMSO-d6) ∆ 13,23 (d, J=6,6 Hz, 1H), 12,20 (s, 1H), 10,22 (users, 2H), 8,88 (d, J=6,8 Hz, 1H) to 8.34 (d, J=7.8 Hz, 1H), 7,86-7,80 (m, 3H) 7,56-7,52 (m, 2H), 7,15 (DD, J=8,5, 2.4 Hz, 1H), of 1.46 (s, 9H).

HPLC: retention time of 2.33 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 336,3 m/z (MH+).

The table below presents a list of other examples of substances synthesized according to the above General scheme.

The original intermediate productProduct
60101
D-12-I282
D-13-I41
114393
D-16-I157
D-15-I356
D-17-I399

Example 2

The General scheme

A specific example

485; N-(3-Dimethylamino-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide

To a suspension of N-(3-amino-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (271) (600 mg, 1.8 mmol) in CH2Cl2(15 ml) and methanol (5 ml) is added acetic acid (250 ml) and formaldehyde (268 μl, 3.6 mmol, 37% of the mass. in the ie). After 10 min, one portion add cyanoborohydride sodium (407 mg, 6.5 mmol). Additional formaldehyde (135 μl, 1.8 mmol, 37% of the mass. in water) is added over 1.5 hours and 4.2 hours. After 4.7 hours, the mixture is diluted with diethyl ether (40 ml), washed with water (25 ml) and saturated salt solution (25 ml), dried (Na2SO4), filtered and concentrated. The obtained red-brown foam purified preparative HPLC, obtaining N-(3-dimethylamino-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (485) (108 mg, yield 17%).

lH-NMR (300 MHz, SDS3) δ 13,13 (users, 1H), 12,78 (s, 1H), 8,91 (users, 1H), 8,42 (users, 1H), of 8.37 (d, J=8,1 Hz, 1H), 7,72-7,58 (m, 2H), 7,47-7,31 (m, 3H), 3,34 (s, 6H), of 1.46 (s, 9H).

HPLC: retention time of 2.15 min, 10-100% CH3CN, the analysis time of 5 minutes

ESI-MS: 364,3 m/z (MH+).

The table below presents a list of other examples of substances synthesized according to the above General scheme.

The original intermediate productProduct
69117
160462
282409
4198

Example 3

Odashima

A specific example

94;N-(5-Amino-2-were)-4-oxo-1H-quinoline-3-carboxamide

To a solution of 4-hydroxyquinolin-3-carboxylic acid (A-1) (50 mg, 0.26 mmol), HBTU (99 mg, 0.26 mmol) and DIEA (138 μl, of 0.79 mmol) in THF (2.6 ml) is added 2-methyl-5-nitrovanillin (40 mg, 0.26 mmol). The mixture is heated at a temperature of 150°C in a microwave oven for 20 min and the resulting solution concentrated. The residue is dissolved in EtOH (2 ml) and add SnCl2·2H2O (293 mg, 1.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture is alkalinized solution of NaHCO3to pH=7-8 and extracted with ethyl acetate. The combined organic layers washed with saturated salt solution, dried over Na2SO4filter and concentrate. The residue is dissolved in DMSO and purified HPLC (10-99% CH3CN/H2O)to give the product, N-(5-amino-2-were)-4-oxo-1H-quinoline-3-carboxamide (94) (6 mg, yield 8%).

HPLC: retention time of 2.06 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 294,2 m/z (MH+).

Another example

17; N-(5-Amino-2-propoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide

N-(5-Amino-2-propoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide (17) receive, following the General scheme, bringing the military above, on the basis of 4-hydroxyquinolin-3-carboxylic acid (A-1) and 5-nitro-2-propoxyphenyl. Output (9%).

HPLC: retention time 3,74 min, 10-99% CH3CN, the analysis time is 5 minutes

ESI-MS: 338,3 m/z (MH+).

Example 4

The General scheme

X=CO, CO2, SO2: a) R2XC1, DIEA, THF or R2XC1, NMM, 1,4-dioxane or R2XC1, Et3N, CH2Cl2, DMF.

A specific example

248; N-(3-Acetylamino-4-were)-4-oxo-1H-quinoline-3-carboxamide

To a solution of N-(3-amino-4-were)-4-oxo-1H-quinoline-3-carboxamide (167) (33 mg, 0.11 mmol) and DIEA (49 μl, 0.28 mmol) in THF (1 ml) add acetylchloride (16 μl, 0.22 mmol). The reaction mixture was stirred at room temperature for 30 minutes IHMS analysis shows that diallylamine happened. Add a solution of piperidine (81 μl, 0.82 mmol) in CH2Cl2(2 ml) and then the reaction mixture was stirred for 30 min, after which by IHMS-analysis detected only the desired product. The reaction solution is concentrated and the residue is dissolved in DMSO and purified HPLC (10-99% CH3CN/H2O)to give the product, N-(3-acetylamino-4-were)-4-oxo-1H-quinoline-3-carboxamide (248) (4 mg, yield 11%).

1H-NMR (400 MHz, DMSO-d6) δ 12,95 (d, J=6,6Hz, 1H), 12,42 (s, 1H), of 9.30 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), with 8.33 (DD, J=8,1, 1.3 Hz,1H), the 7.85-7,81 (m, 2H), 7,76 (d, J=7.8 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,49 (DD, J=8,2, 2.2 Hz, 1H), 7,18 (d, J=8,3 Hz, 1H), 2,18 (s, 3H), of 2.08 (s, 3H).

HPLC: retention time of 2.46 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 336,3 m/z (MH+).

The table below presents a list of other examples of substances synthesized according to the above General scheme.

On the basis ofXR2Product
260COMe316
260COneopentyl196
429COMe379
41COMe232
101COMe243
8COMe149
271 CO2Et127
271CO2Me14
167CO2Et141
69CO2Me30
160CO2Me221
160CO2Et382
69CO2Et225
282CO2Me249
282CO2Et472
41CO2Me471
101CO2 Me239
101CO2Et269
8CO2Me129
8CO2Et298
160SO2Me340

Example 5

The General scheme

A specific example

4-Oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonate)phenyl]-1,4-dihydroquinoline-3-carboxamide

To a suspension of N-[3-amino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide (429) (500 mg, 1.4 mmol) in 1,4-dioxane (4 ml) was added NMM (0.4 ml, 3.6 mmol). Add β-Kharatishvili (0.16 ml and 1.51 mmol) in argon atmosphere. The mixture is stirred at room temperature for 6.5 hours, after which thin layer chromatography (mixture of CH2Cl2-EtOAc, 8:2) shows the new spot with a very similar Rfthe original substance. Add another 0.5 EQ. NMM and the mixture is stirred at room temperature overnight. IHMS-anal is C the crude mixture shows conversion to the desired product > 85%. The mixture is concentrated, treated with 1M HCl solution (5 ml) and extracted with EtOAc (3 x 10 ml) and CH2Cl2(3 times 10 ml). The combined organic extracts dried over Na2SO4, filtered and concentrated, obtaining 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonate)phenyl]-1,4-dihydroquinoline-3-carboxamide as an orange foam (0,495 g, yield 79%), which is used in the next stage without further purification.

1H-NMR (d6-acetone, 300 MHz) δ of 8.92 (s, 1H), to 8.41 is 8.38 (m, 1H), 7,94 (m, 2H), 7,78 (users, 2H), 7,53-7,47 (m, 1H), 7,30 (s, 1H), 6.87 in-6,79 (DD, J=9.9 Hz, 1H), 6,28 (d, J=16.5 Hz, 1H), 6,09 (d, J=9.9 Hz, 1H).

ESI-MS: 436,4 m/z (MH+).

318; 4-Oxo-N-[3-[2-(1-piperidyl)ethylsulfonyl]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide

A mixture of 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonate)phenyl]-1,4-dihydroquinoline-3-carboxamide (50 mg, 0.11 mmol), piperidine (18 μl, 1.6 EQ.) and LiClO4(20 mg, 1.7 EQ.) suspended in a solution of CH2Cl2:isopropanol (1:1, 1.5 ml). The mixture is refluxed at a temperature of 75°C for 18 hours. After this time, IHMS analysis shows conversion to the desired product is >95%. The crude mixture was purified HPLC with reversed phase, receiving 4-oxo-N-[3-[2-(1-piperidyl)ethylsulfonyl]-5-(trifluoromethyl)-phenyl]-1H-quinoline-3-carboxamide (318) as a yellowish solid (15 mg, yield 25%).

1H S is (d 6-acetone, 300 MHz) δ 8,92 (users, 1H), and 8.4 (d, J=8,1 Hz, 1H), 8,05 (users, 1H), 7,94 (users, 1H), 7,78 (users, 2H), 7,53-7,51 (m, 1H), was 7.36 (users, 1H), 3,97 (t, J=7.2 Hz, 2H), 3,66 (t, J=8 Hz, 2H), 3,31-3,24 (m, 6H), 1,36-1,31 (m, 4H).

ESI-MS: 489,1 m/z (MH+).

The table below presents a list of other examples of substances synthesized according to the above General scheme.

The original intermediate productAminProduct
429morpholine272
429dimethylamine359
131piperidine133
131morpholine46

Example 6

The General scheme

A specific example

258; N-Indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide

A mixture of N-(1-acetylindole-6-yl)-4-oxo-1H-quinoline-3-carboxamide (233) (43 mg, 0.12 mmol), 1H. NaOH solution (0.5 ml) and ethanol (0.5 ml) is refluxed for 48 hours. The solution is the end of tryout and the residue is dissolved in DMSO (1 ml) and purified HPLC (10-99% CH 3CN/H2O)to give the product, N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide (258) (10 mg, yield 20%).

HPLC: retention time of 2.05 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 306,3 m/z (MH+).

The table below presents a list of other examples of substances synthesized according to the above General scheme.

On the basis ofProductConditionsSolvent
DC-8-I386NaOHEtOH
DC-9-I10HC1EtOH
17522HC1EtOH
10935HC1EtOH
334238NaOHEtOH
DC-10-I105NaOHTHF

Example 2

The General scheme

A specific example

299; 4-Oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide

A mixture of tert-butyl methyl ether 7-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1,2,3,4-tetrahydroquinolin-1-carboxylic acid (183) (23 mg, 0.05 mmol), TFUK (1 ml) and CH2Cl2(1 ml) was stirred at room temperature overnight. The solution is concentrated and the residue dissolved in DMSO (1 ml) and purified HPLC (10-99% CH3CN/H2O)to give the product, 4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide (299) (7 mg, yield 32%).

HPLC: retention time of 2.18 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 320,3 m/z (MH+).

Another example

300; N-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide

N-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (300) synthesized following the General scheme above from tert-butyl ether 4,4-dimethyl-7-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1,2,3,4-tetrahydroquinolin-1-carboxylic acid (108). Output (33%).

lH-NMR (400 MHz, DMSO-d6), δ 13,23 (d, J=6,6 Hz, 1H), 12,59 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), with 8.33 (d, J=7.7 Hz, 1H), 7,86-7,79 (m, 3H), 7,58-7,42 (m, 3H), 3,38 (m, 2H), of 1.88 (m, 2H), of 1.30 (s, 6H).

HPLC: retention time of 2.40 is in, 10-99% CH3CN, the analysis time is 5 minutes

ESI-MS: 348,2 m/z (MH+).

Other examples

Example 1

The General scheme

A specific example

163; (4-Aminomethyl-2'-ethoxymethyl-2-yl)amide of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

tert-Butyl ether {2'-ethoxy-2-[(4-oxo-1,4-dihydroquinoline-3-carbonyl)amino]biphenyl-4-ylmethyl}carbamino acid (304) (40 mg, 0,078 mmol) is stirred in a mixture of CH2Cl2/TFOC (3:1, 20 ml) at room temperature for 1 hour. Volatiles are removed on a rotary evaporator. The crude product is purified preparative HPLC, obtaining (4-aminomethyl-2'-ethoxymethyl-2-yl)amide of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (163) as a yellow-brown solid (14 mg, yield 43%).

1H-NMR (300 MHz, DMSO-d6) δ 12,87 (d, J=6.3 Hz, 1H), 11,83 (s, 1H), 8,76 (d, J=6.3 Hz, 1H), 8,40 (s, 1H), compared to 8.26 (users, 2H), 8,01 (DD, J=8,4 Hz, J=1.5 Hz, 1H), of 7.75 (dt, J=8,1 Hz, J=1.2 Hz, 1H), to 7.67 (d, J=7.8 Hz, 1H), 7,47-7,37 (m, 2H,), from 7.24 (s, 2H), 7,15 (DD, J=7.5 Hz, J=1.8 Hz, 1H), 7,10 (d, J=8,1 Hz, 1H), 7,02 (dt, J=7.5 Hz, J=0.9 Hz, 1H), 4.09 to (m, 2H), Android 4.04 (q, J=6.9 Hz, 2H), 1,09 (t, J=6.9 Hz, 3H).

HPLC: retention time 1,71 min, 10-100% CH3CN, gradient 5 minutes

ESI-MS: 414,1 m/z (MH+).

Another example

390; N-[3-(Aminomethyl)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-to Roxane

N-[3-(Aminomethyl)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide (390) synthesized following the General scheme above from tert-butyl ether [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-tert-butylphenyl]methylaminomethyl acid (465).

HPLC: retention time of 2.44 min, 10-99% CH3CN, gradient 5 minutes

ESI-MS: 350,3 m/z (M+H+).

Example 2

The General scheme

A specific example

3-(2-(4-(1-Amino-2-methylpropan-2-yl)phenyl)acetyl)quinoline-4(1H)-he

tert-Butyl ether (2-methyl-2-{4-[2-oxo-2-(4-oxo-1,4-dihydroquinoline-3-yl)ethyl]phenyl}propyl)carbamino acid (88) (0.50 g, 1.15 mmol), TFUK (5 ml) and CH2Cl2(5 ml) are combined and stirred at room temperature overnight. Then the reaction mixture is neutralized 1H. NaOH solution. The precipitate was separated by filtration, receiving the product, 3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)acetyl)quinoline-4(1H)-he, in the form of a brown solid (651 mg, yield 91%).

HPLC: retention time of 2.26 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 336,5 m/z (M+H+).

323; Methyl ester of [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid

Methylchloroform (0,012 g, 0,150 mmol) are added to a solution of 3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)aceti is)quinoline-4(1H)-she (0.025 g, of 0.075 mmol), tea (0,150 mmol, 0,021 ml) and DMF (1 ml) and stirred at room temperature for 1 hour. Then added piperidine (0,074 ml, 0,750 mmol) and the reaction mixture is stirred for 30 minutes, the Reaction mixture was filtered and purified preparative HPLC (10-99% CH3CN/H2O)to give the product, methyl ester [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid (323).

1H-NMR (400 MHz, DMSO-d6) δ 12,94 (users, 1H), to 12.44 (s, 1H), 8,89 (s, 1H), with 8.33 (DD, J=8,2, 1.1 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), to 7.67 (d, J=8,8 Hz, 2H), 7,54 (t, J=8,1 Hz, 1H), 7,35 (d, J=8.7 Hz, 2H), 7,02 (t,J=6.3 Hz, 1H), 3,50 (s, 3H), 3,17 (d, J=6.2 Hz, 2H), 1,23 (s, 6H).

HPLC: retention time of 2.93 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 394,0 m/z (MH+).

The table below presents a list of other examples of substances synthesized according to the above General scheme.

ProductCharformat
119ethylchloride
416propylchloride
460butylchloroformate
251and butylchloroformate
341neopatrimonial
282-methoxyethylamine
396(tetrahydrofuran-3-yl)methylchloroform

Example 3

The General scheme

A specific example

273-I; N-(1-Aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide

To a solution of tert-butyl methyl ether [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]aminoarabinose acid (273) (250 mg, 0.6 mmol) in dichloromethane (2 ml) add TFOC (2 ml). The reaction mixture was stirred at room temperature for 30 minutes To the reaction mixture add dichloromethane (10 ml) and the solution washed with saturated solution of NaHCO3(5 ml). Thus, the precipitate begins to form in the organic layer, the combined organic layers are concentrated, obtaining N-(1-aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (273-I) (185 mg, yield 93%).

HPLC: retention time of 1.94 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 334,5 m/z (MH+).

159; Methyl ether [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]aminoarabinose acid

To a solution of N-(1-aminotetralin-7-is)-4-oxo-1H-quinoline-3-carboxamide ( 273-I) (65 mg, 0.20 mmol) and DIEA (52 μl, 0.29 mmol) in methanol (1 ml) add methylchloroform (22 μl, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 hour. IHMS analysis of the reaction mixture shows peaks corresponding to the products both mono-and bis-addition. Added piperidine (2 ml) and the reaction mixture was stirred overnight, after which detected only the product of a mono-connection. The resulting solution is filtered and purified HPLC (10-99% CH3CN/H2O)to give the product, methyl ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]aminoarabinose acid (159) (27 mg, yield 35%).

HPLC: retention time of 2.68 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: 392,3 m/z (MH+).

Another example

482; Ethyl ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]aminoarabinose acid

Ethyl ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]aminoarabinose acid (482) synthesized following the General scheme above, of the amine (273-Iand ethylchloride. Total yield (18%).

HPLC: retention time 2,84 min, 10-99% CH3CN, the analysis time of 5 minutes

ESI-MS: is 406.5 m/z (MH+).

In the table, below, presents the characteristic data of the compounds according to the present invention obtained in the above examples.

3,33
Table 2
Conn.No.LC-MS M+1LC-RT minConn.No.LC-MS M+1LC-RT minConn.No.LC-MS M+1LC-RT min
1444,33,1923the rate of 457.5of 3.5645308,13,18
2350,1the 3.824398,33,1346490,11,89
3455,33,7525397,12,3847375,3
4350,32,8126348,1of 2.5148is 317.13,06
5337,3was 2.7627446,22,3349400,12,88
6351,4328438,42,950307,3is 3.08
7472,33,629to 307.13,3251521,53,79
8to 307.11,2130379,12,6252 354,13,02
9344,12,4331278,93,0353266,11,99
10334,22,232338,2354323,32,97
11408,12,9133the volume reached 303.92,8355366,32,6
12383,12,6334397,14,1956335,43,18
13346,33,4835362,22,53 57403,12,86
14394,3of 3.0736307,33,2558364,33,02
15296,32,6837the volume reached 303.92,9859412,13,31
16307,33,3838380,33,3360422,23,53
17338,33,7439480,53,8261293,13,05
18352,93,6240309,1 2,4662349,13,4
19316,32,7141321,11,8863376,12,89
20371,33,5342460,03,7164321,12,31
21421,12,6643the rate of 457.53,665381,51,85
22332,2of 2.2144336,12,9566345,13,32
67332,33,17109 404,53,17151360,03
68398,12,85110the volume reached 303.92,75152it was 322.32,31
69322,52,37111333,13153425,1to 4.52
70341,12,15112348,5of 3.07154401,3of 3.77
71426,12,6113318,33,02155266,12,11
72293,1with 3.27 114499,23,74156424,13,12
73380,92,4115330,1to 2.67157321,02,13
74334,13,32116320,23,18158380,23,05
75316,32,43117349,11,32159392,32,68
76376,12,97118379,12,61160321,1of 1.34
77322,5 2,93119408,4of 3.07161409,23,82
78344,12,38120309,12,93162296,32,61
79372,1of 3.07121333,13,69163413,11,71
80295,32,78122325,12,66164333,13,33
81336,32,73123330,12,64165344,12,41
82 350,32,11124378,33,4166398,12,83
83365,1Z76125294,3of 2.21167294,32,12
84280,32,11126411,13,06168265,91,96
85408,03,25127408,53,221693182,98
86370,32,08128369,13,53170300,3is 3.08
87357,13,5129365,11,74171408,0is 3.08
88436,33,37130440,23,57172396,03,14
89the volume reached 303.93,1131313,02,4173280,32,14
90321,13,43132RUB 365.92,73174388,02,58
91355,23,47133488,11,97175374,2 2,85
92295,23,84134402,12,25176349,13,38

93371,02,75135384,12,94177sauce 337,13,5
94294,2to 2.06136393,14,33178413,34
95290,12,78137580,54,1179308,52,33
96343,02,75 138376,12,98180307,3is 3.08
97402,12,59139408,03,17181354,12,97
98349,11,96140346,14182358,12,89
99334,13,13141366,32,89183420,33,47
100the volume reached 303.92,63142321,3to 3.58184372,32,66
101322,5 2,35143355,23,45185414,12,96
102443,13,97144281,32,49186372,33,59
103411,23,85145376,22,98187346,32,9
104318,02,94146306,3of 2.51188376,22,95
105322,22,4147376.3 onwith 3.27189370,93,38
106 350,32,86148415,52,79190392,03,09
107420,23,37149349,11,45191316,32,1
108USD 448,2of 3.77150430,03,29192280,32,13
193326,33,02235308,42,12277358,12,89
194290,12,98236333,13,35278408,13,09
195280,32,14237410,32,96279386,12,88
196434,53,38238489,42,78280316,3to 2.06
197334,13,15239379,02,62281293,13,22
198283,13240370,9the 3.65282to 307.11,22
199354,12,96241316,32,61283370,1 3
200335,52,49242348,3is 3.08284305,3to 2.57
201the volume reached 303.9is 3.08243363,02,44285376,12,88
202404,03,19244358,13,48286319,13,35
203394,33,42245425,13,69287411,24,15
204349,33,32246292,93,2288 413,3the 3.8
205455,53,74247432,13,23289297,33,25
206386,13,5248336,32,46290382,13,19
207390,32,71249365,02,54291371,03,57
208429,73,89250352,32,53292to € 391.13,69
209294,12,39251436,23,38 293330,33,05
210385,23,72252368,93,17294the volume reached 303.9to 2.67
211to 351.33,53253424,13,25295334,3of 2.26
212360,92,45254340,1is 3.08296365,33,6
213408,03,3255526,53,89297358,33,26
214358,12,7256306,1 2,4298379,11,91
215265,3of 3.07257297,33,28299320,32,18
216305,32,27258306,32,05300348,22,4
217305,32,41259360,3of 3.46301346,3of 2.26
218413,23,98260336,32,33302370,12,28
219266,92,48261 368,1is 3.08303362,2of 2.51
220409,03,35262352,32,7304513,23,66
221379,12,68263372,93,69305370,12,98
222324,3with 3.27264353,13,42306384,13,11
223386,13,14265354,93,4307374,03,05
224466,3is 3.08 266405,34,05308304,12,71
225393,12,75267357,13,43309316,32,83
226306,13,6268400,36,01310320,1to 3.73
227381,12,24269393,02,75311344,93,43

228371,12,84270329,33,02312 400,12,86
229311,12,93271336,52,75313358,12,8
230318,12,81272524,11,87314335,13,52
231471,33,41273434,53,17315293,12,9
232363,1to 2.57274493,5of 3.46316378,52,84
233348,52,75275427,13,93 317333,22,91
234372,33,2276414,32,81318522,11,8
319373,33,59361400,12,91403423,1of 4.45
320360,13,5362355,5of 3.46404440,32,87
321453,53,12363388,12,92405299,33,16
322349,33,7364330,3406547,33,74
323394,02,93365to 307.12,6407371,3the 3.8
324320,13,81366408,13,09408295,32,9
325321,33,22367408,03,14409335,11,82
326418,02,5368338,22,33410432,13,41
327424,23,2369 358,13,29411299,13,17
328to 307.1was 2.76370299,13,03412376,22,93
329396,33,72371365,0with 3.27413357,13,37
330299,33,02372362,12,66414305,32,11
331308,32,25373305,33,38415351,53,44
332288,02,5 374350,33,01416422,43,23
333379,12,61375319,33,4417396,0to 2.67
334531,33,26376382,33,48418308,32,23
335it was 322.32,41377340,2is 3.08419it was 322.32,48
336321,53,52378310,32,07420379,13,2
337of 407.5 3,37379389,02,53421,419,23,82
338318,32,73380309,33,02422333,12,48
339329,02,75381360,23,18423376.3 on3,02
340399,12,6382393,12,84424374,03,06
341450,4of 3.56383332,33,2425306,13,53
342 422,33,41384376,12,87426371,32,95
343403,32,73385393,93,32427420,33,3
344384,1of 3.07386334,32,3428337,23,32
345322,22,96387347,13,22429348,32,98
346333,13,38388424,13,3430321,33,22
347of 494.51,97389355,3the 3.65431280,32,09
348384,13,12390350,32,44432382,13,22
349405,32,85391396,13,43433393,23,71
350315,13,23392300,32,86434293,13,12
351332,33,18393RUB 399.42,12435376.3 on 3,22
352447,53,17394293,13,17436400,12,88
353436,33,53395433,54,21437309,32,82
354390,32,36396464,42,97438427,5a 3.87
355370,93,37397341,33,45439295,32,8
356335,01,81398434,33,1440 395,33,61
357346,3is 3.08399335,01,75441425,0to 2.67
358338,23,15400to 351.32,11442412,33,35
359482,11,74401368,13,09443317,32,45
360331,3of 3.07402342,12,96444to 379.23,42
445to 305.5is 3.08459279,32,9 473363,3of 3.64
446353,12,85460436,23,38474336,32,8

447290,12,88461341,33,23475334 33,23
448321,33,5462349,11,9476362,13,42
449279,13,22463292,13,35477283,92,8
450 308,11,97464409,44,03478360,33,44
451318,13,28465450,5the 3.65479334,32,59
452290,13,32466349,335480323,53,22
453314,12,75467307,32,98481315,33 25
454355,1to 3.58468279,12,98482is 406.52,84
455398,13,6469409,13,69483409 54,35
456365,1the 3.65470373,3of 3.64484349,12,16
457350,3of 2.26471379,02,73485363,12,15
458381,23,19472379,0to 2.67

These NMR individual compounds are shown below in table 2-A.

Table 2-a
Connection # These NMR
21H-NMR (300 MHz, CDCl3) δ of 12.53 (s, 1H), 11,44 (users, J=6.0 Hz, 1H), 9,04 (d, J=6,7 Hz, 1H), 8,43 (d, J=7.8 Hz, 1H), 7,51 (t, J=7,3 Hz, 1H), 7,43 (t, J=7.5 Hz, 1H), 7,33-7,21 (m, 3H), 7,10 (d, J=8,2 Hz, 1H), 3,79 (s, 3H), 1,36 (, 9H)
5H-NMR (400 MHz, DMSO-d6) δ 12,94 (users, 1H), 12,41 (s, 1H), 8,88 (s, 1H), 8.34 per (DD, J=8,1 Hz, 1H), 7,82 (DDD, J=8, 8, 1 Hz, 1H), of 7.75 (d, J=8 Hz, 1H), to 7.64 (DD, J=7.2 Hz, 2H), 7,54 (DDD, J=8, 8, 1 Hz, 1H), 7,35 (DD, J=7,2 Hz, 2H), of 4.66 (t, J=5 Hz, 1H), 3,41 (d, J=5 Hz, 2H), 1,23 (C, 6N)
81H-NMR (CD3OD, 300 MHz) δ 8,86 (s, 1H), 8,42 (d, J=8.5 Hz, 1H), 7,94 (s, 1H), 7,81 (t, J=8,3 Hz, 1H), to 7.67 (d, J=8,3 Hz, 1H), 7,54-7,47 (m, 1H), 7,38 (d, J=8.5 Hz, 1H), 2,71 (kV, J=7.7 Hz, 2H), of 1.30 (t, J=7.4 Hz, 3H)
10H-NMR (400 MHz, DMSO-d6) δ 13,02 (d, J=6,4 Hz, 1H), 12,58 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), with 8.33 (DD, J=8.1 Hz, 1.2 Hz, 1H), 7,89-to 7.77 (m, 3H), 7,56 (t, J=8,1 Hz, 1H), 7,39 (d, J=7.8 Hz, 1H), 7,26 (d, J=8,4 Hz, 1H), 3,23 (m, 2H), of 2.81 (m, 2H), was 1.94 (m, 2H), 1,65 (m, 2H)
13H-NMR (400 MHz, DMSO-d6) δ of 13.05 (users, 1H), 12,68 (s, 1H), 8,89 (s, 1H), 8,35 (t, J=2.5 Hz, 1H), 8,32 (d, J=1.1 Hz, 1H), 7,85-7,76 (m, 3H), 7,58-rate of 7.54 (m, 2H), 1,47 (s, 9H)
14H-NMR (400 MHz, DMSO-d6) δ 1.32 to (C, N), to 3.64 (s, 3H), of 7.36 (d, J=8,4 Hz, 1H), 7,55 (m, 3H), 7,76 (d, J=8.0 Hz, 1H), 7,83 (m, 1H), with 8.33 (d, J=7,0 Hz, 1H), 8,69 (s, 1H), 8,87 (d, J=6,7 Hz, 1H), 12,45 (s, 1H), 12,97 (s, 1H)

27H-NMR (400 MHz, DMSO-d6) δ 13,20 (d, J=6,7 Hz, 1H), 12,68 (s, 1H), 8,96 cent to 8.85 (m, 4H), 8,35 (d, J=7.9 Hz, 1H), to $ 7.91-to 7.77 (m, 3H), of 7.64-rate of 7.54 (m, 3H), PC 6.82 (m, 1H), of 5.05 (s, 0,7H), 4,96 (s, 1,3H), 4,25 (t, J=5.6 Hz, 1,3H), 4,00 (t, J=5.7 Hz, 0,7H), 3,14 (s, 2H), to 3.02 (s, 1H), 2,62 (t, J=5,2 Hz, 2H), 2,54 (t, J=5.4 Hz, 1H)
29H-NMR (400 MHz, CDCl3) δ is 9.09 (s, 1H), to 8.62 (DD, J=8,1, 1.5 Hz, 1H), 7,83-7,79 (m, 3H), EUR 7.57 (d, J=7.2 Hz, 1H), 7,38 (t, J =7,6 Hz, 2H), 7,14 (t, J=7.4 Hz, 2H), of 5.05 (m, 1H), 1.69 in (d, J =6.6 Hz, 6H)
32H-NMR (400 MHz, DMSO-d6) δ 12,93 (d, J=6,6 Hz, 1H), 12,74 (s, 1H), 11,27 (s, 1H), 8,91 (d, J=6,7 Hz, 1H), 8,76 (s, 1H), of 8.37 (d, J=8,1 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), to 7.77 (d, J=7,6 Hz, 1H), of 7.70 (s, 1H), 7,54 (t, J=8,1 Hz, 1H), 7,38 (m, 1H), 6,40 (m, 1H)
33H-NMR (400 MHz, DMSO-d6) δ 12,92 (s, 1H), 12,47 (s, 1H), 11,08 (s, 1H), of 8.90 (s, 1H), 8,35 (DD, J=8,1, 1.1 Hz, 1H), 8,20 (t, J=0.8 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,50 (d, J=8,4 Hz, 1H), 7,30 (t, J=2.7 Hz, 1H), 7,06 (DD, J=8,4, 1.8 Hz, 1H), 6,39 (m, 1H)
35H-NMR (400 MHz, DMSO-d6) δ 13,01 (d, J=6,7 Hz, 1H), 12,37 (s, 1H), 8,86 (d, J =6,8 Hz, 1H), with 8.33 (DD, J=8,1, 1.3 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,76 (d, J=8,2 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), was 7.36 (s, 1H), 7,19 (d, J=8,4 Hz, 1H), was 7.08 (d, J=8,2 Hz, 1H), 3,29 (m, 2H), of 1.85 (m, 1H), 1,73-of 1.53 (m, 3H), 1,21 (s, 3H), 0,76 (t, J=7.4 Hz, 3H)
43H-NMR (400 MHz, DMSO-d6) δ 12,77 (s, H), 11,94 (s, 1H), of 9.56 (s, 1H), 8,81 (s, 1H), 8,11 (DD, J=8,2, 1.1 Hz, 1H), 7,89 (s, 1H), 7,79 to 7.75 (m, 1H), of 7.70 (d, J=7.7 Hz, 1H), 7,49 was 7.45 (m, 1H), 7,31 (t, J=8,1 Hz, 1H), 7,00 (s, 1H), 6,93-6,87 (m, 3H), 4,07 (kV, J=7,0 Hz, 2H), to 1.38 (s, 9H), of 1.28 (t, J=7.0 Hz, 3H)
47H-NMR (400 MHz, DMSO-d6) δ 1,24 (d, J=6.9 Hz, 6H), to 3.00 (m, 1H), 7,55 (m, 3H), 7,76 (d, J=7.7 Hz, 1H), 7,83 (m, 1H), compared to 8.26 (d, J=8,2 Hz, 1H), with 8.33 (d, J=9,2 Hz, 1H), 8,89 (s, 1H), 12,65 (s, 1H), 12,95 (s, 1H)
56H-NMR (400 MHz, DMSO-d6) δ 12,81 (d, J=6,7 Hz, 1H), 12,27 (s, 1H), 9,62 (s, 1H), 8,82 (d, J=6,7 Hz, 1H), 8,32 (DD, J=8,2, 1.3 Hz, 1H), 8,07 (s, 1H), 7,80 (t, J=8,4 Hz, 1H), 7,73 (d, J=7.8 Hz, 1H), 7,52 (t, J=8,1 Hz, 1H), 6,58 (, 1H), 2,62 (m, 4H), 1,71 (m, 4H)
58H-NMR (400 MHz, DMSO-d6) δ 12,95 (d, J=6,6 Hz, 1H), KZT 12.39 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), with 8.33 (d, J=7,3 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), of 7.75 (d, J=7.8 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), 7,29 (d, J=2.5 Hz, 1H), 7,07 (DD, J=8,7, 1.3 Hz, 1H), 6,91 (DD, J=8,8, 2.5 Hz, 1H), 5,44 (users, 2H)

64H-NMR (400 MHz, DMSO-d6) δ 12,92 (s, 1H), 12,41 (s, 1H), 10,63 (s, 1H), 10,54 (s, 1H), 8,86 (s, 1H), with 8.33 (d, J=8,1 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), 7,69 (s, 1H), 7,54 (t, J=8,1 Hz, 1H),? 7.04 baby mortality (d, J=8,3 Hz, 1H), make 6.90 (d, J=8,3 Hz, 1H)
69H-NMR (400 MHz, DMSO-d6) δ 13,06 (d, J=6,5 Hz, 1H), 12,51 (s, 1H), 8,88 (d, J=6,6 Hz, 1H), with 8.33 (DD, J=8,1, 1.0 Hz, 1H), 7,85-7,74 (m, 3H), 7,55 (t, J=8,1 Hz, 1H), 7,38 (DD, J=8,4, 1.9 Hz, H), to 7.32 (d, J=8.5 Hz, 1H), 3,03 (septet, J=6.8 Hz, 1H), 1,20 (d, J=6,7 Hz, 6H)
761H-NMR (CDCl3, 300 MHz) δ 8,84 (d, J=6,6 Hz, 1H), 8,31 (d, J=6.2 Hz, 1H), 8,01 (d, J=7.9 Hz, 1H), 7,44-7,13 (m, 8H), is 6.78 (d, J=7.5 Hz, 1H),
77H-NMR (400 MHz, DMSO-d6) δ 6,40 (m, 1H), was 7.36 (t, J=2.7 Hz, 1H), 7,43 (d, J=11.8 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,80 (m, 2H), at 8.36 (d, J=9,2 Hz, 1H), 8,65 (d, J=6,8 Hz, 1H), 8,91 (s, 1H), 11,19 (s, 1H), 12,72 (s, 1H), 12,95 (, 1H)
88H-NMR (400 MHz, DMSO-d6) δ 12,96 (d, J=6,6 Hz, 1H), 12,42 (s, 1H), 8,89 (d, J=6,7 Hz, 1H), with 8.33 (DD, J=8,1, 1.2 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.8 Hz, 1H), 7,66 (d, J=8.7 Hz, 2H), 7,54 (t, J=8,1 Hz, 1H), 7,34 (d, J=8,7 Hz, 2H), 6,67 (t, J=6.3 Hz, 1H), 3,12 (d, J=6.3 Hz, 2H), of 1.35 (s, 9H), 1,22 (s, 6H)
901H-NMR (400 MHz, DMSO-d6) δ 11,98 (s, 1H), 8,89 (s, 1H), 8.34 per (DD, J=8,2, 1.1 Hz, 1H), 7,84 to 7.75 (m, 2H), to 7.59 (DD, J=7,8, 1.5 Hz, 1H), 7,55-7,51 (m, 1H), 7,42 (DD, J=7,9, 1.5 Hz, 1H), 7,26-7,21 (m, 1H), 7,19-7,14 (m, 1H), USD 1.43 (s, 9H)
96H NMR (400 MHz, DMSO-d6) δ to 12.58 (s, 1H), 11.11 (with, 1H), 8,89 (s, 1H), 8,35 (DD, J=8,1, 1.1 Hz, 1H), they were 8.22 (d, J=1.5 Hz, 1H), 7,83-7,74 (m, 2H), 7,56-7,51 (m, 2H), 7,30 (d, J=2.3 Hz, 1H), 7,13 (DD, J=8,5, 1.8 Hz, 1H), a 4.03 (d, J=0,5 Hz, 2H)
103H-NMR (400 MHz, DMSO-d6) δ of 1.37 (s, 9H), to 1.38 (s, 9H), was 7.08 (s, 1H), 7,17 (s, 1H), 7,74 (m, 1H), 7,86 (m, 1H), 7,98 (DD, J=9,2, 2,9 Hz, 1H), 8,90 (d, J=6,7 Hz, 1H), of 9.21 (s, 1), 11,71 (s, 1H), 13,02 (d, J=6,7 Hz, 1H)
1041H-NMR (400 MHz, DMSO-d6) δ 12,93 (d, J=6,6 Hz, 1H), 12,41 (s, 1H), 10,88 (s, 1H), 8,88 (d, J=6,7 Hz, 1H), at 8.36-8.34 per (m, 1H), with 8.05 (d, J=0.8 Hz, 1H), 7,84 to 7.75 (m, 2H), 7,56-7,52 (m, 1H), 7,35 (d, J=8,3 Hz, 1H), 7,01 (DD, J=8,4, 1,9 Hz, 1H), 6,07-6,07 (m, 1H), is 2.37 (s, 3H)

107H-NMR (400 MHz, DMSO-d6) δ to 12.52 (s, 1H), 8,87 (s, 1H), with 8.33 (DD, J=8,2, 1.1 Hz, 1H), 7,81 (t, J=8,3 Hz, 1H), of 7.75 (d, J=7.7 Hz, 1H), EUR 7.57-7,51 (m, 3H), 7,15 (d, J=8,3 Hz, 1H), 4,51 (s, 2H), of 3.56 (t, J=5.7 Hz, 2H), 2,75 (t, J=5.5 Hz, 2H), of 1.44 (s, 9H)
109H-NMR (400 MHz, DMSO-d6) δ 12,97 (users, 1H), 12,45 (s, 1H), 8,89 (s, 1H), with 8.33 (DD, J=8,2, 1.1 Hz, 1H), 7,88 (s, 1H), 7,82 (t, J=8,4 Hz, 1H), of 7.75 (d, J=7.7 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), 7,43 (m, 1H), 7,31 (d, J=8.5 Hz, 1H), 4,01 (m, 1H), 3,41 (m, 1H), of 2.21 (s, 3H), of 1.85 (m, 1H), 1,68-is 1.51 (m, 3H), of 1.23 (s, 3H), of 0.71 (t, J=7.4 Hz, 3H)
1131H-NMR (400 MHz, DMSO-d6) δ 12,92 (d, J=6,6 Hz, 1H), 12,46 (s, 1H), of 10.72 (d, J=1.5 Hz, 1H), 8,89 (d, J=6,7 Hz, 1H), 8,35 (DD, J=8,1, 1.2 Hz, 1H), 8,13 (d, J=1.5 Hz, 1H), 7,84 to 7.75 (m, 2H), 7,56-7,52 (m, 1H), 7,44 (d, J=8,4 Hz, 1H), 7,07? 7.04 baby mortality (m, 2H), 2,25 (d, J=0.9 Hz, 3H)
1141H-NMR (300 MHz, DMSO-d6) δ 12,65 (d, J=6,9 Hz, 1H), 11,60 (s, 1H), was 9.33 (s, 1H), 8,71 (d, J=6,6 Hz, 1H), at 8.36 (d, J=1.8 Hz, 1H), 8,03 d, J=7.8 Hz, 1H), 7,66 (t, J=7.2 Hz, 1H), 7,60 (d, J=8,1 Hz, 1H), 7,38 (t, J=7.8 Hz, 1H), 7.29 trend (t, J=7.5 Hz, 1H), 7,12 (m,2H), 6,97 (m, 3H), of 3.97 (m, 2H), 1,45 (s, 9H), of 1.06 (t, J=6.6 Hz, 3H),
126H-NMR (400 MHz, DMSO-d6) δ 12,94 (s, 1H), of 12.33 (s, 1H), 9,49 (s, 1H), 8,88 (s, 1H), 8,35 (DD, J=8,7, 0.5 Hz, 1H), 7,86-of 7.82 (m, 1H), to 7.77 (d, J=7.8 Hz, 7,58-rate of 7.54 (m, 1H), 7,40 (d, J=2.2 Hz, 1H), 7,11 (d, J=8.5 Hz, 1H), 6,98 (DD, J=an 8.4 and 2.2 Hz, 1H), to 3.67 (s, 2H), 3,51-3,47 (m, 2H), 3,44-to 3.41 (m, 2H), on 3.36 (s, 3H), of 1.33 (s, 6H)
127H-NMR (400 MHz, DMSO-d6) δ of 1.23 (t, J=7.0 Hz, 3H), of 1.32 (s, 9H), 4,10 (kV, J=7,0 Hz, 2H), was 7.36 (d, J=8.5 Hz, 1H), 7,54 (m, 3H), 7,76 (d, J=7.9 Hz, 1H), 7,82 (m, 1H) 8,33 (d, J=9,2 Hz, 1H), 8,64 (s, 1H), 8,87 (s, 1H), 12,45 (s, 1H), 12,99 (s, 1H)
1291H-NMR (CD3OD, 300 MHz) δ 8,83 (s, 1H), to 8.41 (d, J=8,1 Hz, 1H), 7,80 (m, 2H), 7,65 (d, J=8,1 Hz, 1H), 7,55 (m, 2H), 7,22 (d, J=8,1 Hz, 1H), 3,76 (s, 3H, OMe), 2,62 (kV, J=7.5 Hz, 2H), 1,21 (t, J=7.5 Hz, 3H)
1311H-NMR (300 MHz, DMSO-d6) δ 12,37 (s, 1H), 8,81 (s, 1H), 8,30 (d, J=8,1 Hz, 1H), to 7.77 (m, 2H), 7,52 (t, J=7.2 Hz, 1H), to 7.09 (s, 1H), 6,74 (s, 1H), 6,32 (s, 1H), vs. 5.47 (s, 2H)
1351H-NMR (CDCl3, 300 MHz) δ 8,86 (d, J=6,6 Hz, 1H), 8,32 (d, J=6.2 Hz, 1H), 8,07 (d, J=7.9 Hz, 1H), 7,47-7,24 (m, 6H), 6,95-6,83 (m, 3H), 5,95 (s, 2H),

136H-NMR (400 MHz, DMSO-d6) δ of 1.29 (s, 9H), of 1.41 (s, 9H), to 7.09 (d, J=2.4 Hz, 1H), 7,47 (d, J=2.3 Hz, 1H), EUR 7.57 (t, J=8,1 Hz, 1H), to 7.77 (d, J=7.8 Hz, 1H), 7,85 (t, J=8,4 Hz, 1H), at 8.36 (d, J=9.5 Hz, 1H), 8,93 (d, J=6,8 Hz, 1H), 9,26 (s, 1H), 12,66 (s, 1H), 13,04 (d, J=6,6 Hz, 1H)
141H-NMR (400 MHz, DMSO-d6) δ 12,96 (d, J=6,6 Hz, 1H), 12,42 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), with 8.33 (DD, J=8,1, 1.2 Hz, 1H), 7,85 to 7.75 (m, 3H), 7,55 (t, J=8,1 Hz, 1H), 7,46 (DD, J=8,2, 2.2 Hz, 1H), 7,16 (d, J=8.5 Hz, 1H), 4,14 (kV, J=the 7.1 Hz, 2H), 2,18 (s, 3H), of 1.27 (t, J=7,1 Hz, 3H)
143H-NMR (400 MHz, DMSO-d6) δ 12,96 (d, J=6,8 Hz, 1H), 12,56 (s, 1H), 9,44 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), 8.34 per (DD, J=8,2, 1.3 Hz, 1H), 8,08 (d, J=7,4 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), of 7.00 (d, J=13.3 Hz, 1H), of 1.34 (s, 9H)
1501H-NMR (DMSO-d6, 300 MHz) δ 8,86 (d, J=6,9 Hz, 1H), 8,63 (s, 1H), 8,30 (d, J=8,1 Hz, 1H), 7,86 (d, J=8.7 Hz, 2H), 7,82-7,71 (m, 2H), to 7.64 (d, J=8,4 Hz, 2H), 7,52 (TD, J=1.2 Hz, 1H),
1571H-NMR (CD3OD, 300 MHz) δ 8,91 (s, 1H), to 8.57 (s, 1H), 8,45 (d, J=8,3 Hz, 1H), 7,83 (t, J=7.2 Hz, 1H), 7,69 (d, J=9.0 Hz, 1H), EUR 7.57 (t, J=7.9 Hz, 1H), 7,46 (d, J=8.5 Hz, 1H), 7,16 (d, J=6.0 Hz, 1H), is 3.08 (s, 3H, NMe), 2,94 (kV, J=7,4 Hz, 2H), 1,36 (t, J=7.4 Hz, 3H),
161H-NMR (400 MHz, DMSO-d6) δ 12,96 (s, 1H), 12,41 (s, 1H), 8,88 (s, 1H), with 8.33 (DD, J=8,2, 1.2 Hz, 1H), 7,84-7,80 (m, 1H), of 7.75 (d, J=7.9 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,44 (s, 1H), 7,19 (s, 2H), 4,13 (t, J=4.6 Hz, 2H), 3,79 (t, J=4,6 Hz, 2H), 3,54 (kV, J=7,0 Hz, 2H), of 1.36 (s, 9H)and 1.15 (t, J=7.0 Hz, 3H)
1631H-YAM who (300 MHz, DMSO-d6) δ 12,87 (d, J=6.3 Hz, 1H), 11,83 (s, 1H), 8,76 (d, J=6.3 Hz, 1H), 8,40 (s, 1H), compared to 8.26 (users, 2H), 8,08 (DD, J=8,4 Hz, J=1.5 Hz, 1H), to 7.75 (m, 1H), to 7.67 (d, J=7.8 Hz, 1H), 7,47-7,37 (m, 2H), 7,24 (d, J=0.9 Hz, 1H), 7,15 (DD, J=7.5 Hz, J=1.8 Hz, 1H), 7,10 (d, J=8,1 Hz, 1H), 7,02 (dt, J=7.5 Hz, J=0.9 Hz, 1H), 4,07 (m, 4H), 1,094 (t, J=6.9 Hz, 3H),
167H-NMR (400 MHz, DMSO-d6) δ 2,03 (s, 3H), 4,91 (s, 2H), to 6.95 (m, 3H), 7,53 (m, 1H), of 7.75 (d, J=8,2 Hz, 1H), 7,81 (m, 1H), with 8.33 (d, J=8.0 Hz, 1H), 8,84 (s, 1H), 12,20 (s, 1H), 12,90 (s, 1H)

1691H-NMR (400 MHz, DMSO-d6) δ 12,94 (d, J=5.3 Hz, 1H), 12,51 (s, 1H), 8,89 (d, J=6.3 Hz, 1H), at 8.36 (DD, J=8,1, 1.1 Hz, 1H), of 8.06 (t, J=0.7 Hz, 1H), 7,85 to 7.75 (m, 2H), EUR 7.57-7,51 (m, 2H), 7,28 (d, J=3.1 Hz, 1H), 7,24 (DD, J=8,4, 1.8 Hz, 1H), to 6.39 (DD, J=3.1 and 0.8 Hz, 1H), of 3.78 (s, 3H)
1781H-NMR (400 MHz, DMSO-d6) δ 12,86 (s, 1H), 8,89 (d, J=6,8 Hz, 1H), 8,65 (DD, J=8,1, 1,6 Hz, 1H), 8,19 (DD, J=8,2, 1.3 Hz, 1H), 7,80-7,71 (m, 2H), of 7.48-7,44 (m, 2H), 7.24 to 7,20 (m, 1H), 7,16-to 7.09 (m, 2H),? 7.04 baby mortality-7,00 (m, 1H), 6,80 (DD, J=to 8.0, 1.3 Hz, 1H), 6,69 (DD, J=8,1, 1.4 Hz, 1H), 1,45(s, 9H)
1831H-NMR (400 MHz, DMSO-d6) δ 12,42 (s, 1H), 8,88 (s, 1H), with 8.33 (DD, J=8,2, 1.1 Hz, 1H), of 8.06 (d, J=2.1 Hz, 1H), 7,84 to 7.75 (m, 2H), 7,56-7,52 (m, 1H), 7,38 (DD, J=8,2, 2.1 Hz, 1H), was 7.08 (d, J=8,3 Hz, 1H), 3,66-3,63 (m, 2H), 2,70 (t, J=6,5 Hz, 2H), 1,86 and 1.80 (m, 2H)and 1.51 (s, 9H)
1861H-NMR (400 MHz, DMSO-d 6) δ 12,93 (s, 1H), 12,47 (s, 1H), of 10.72 (s, 1H), 8,89 (s, 1H), 8,35 (DD, J=8,2, 1.1 Hz, 1H), 8,13 (d, J=1.6 Hz, 1H), 7,82 (t, J=8,2 Hz, 1H), 7,76 (d, J=7.8 Hz, 1H), 7,54 (t, J=7.5 Hz, 1H), 7,50 (d, J=8,4 Hz, 1H), 7,05-7,02 (m, 2H), 3,19 (quintet, J=8,2 Hz, 1H), 2,08 (m, 2H), 1,82 is 1.60 (m, 6H)
1871H-NMR (400 MHz, DMSO-d6) δ 12,63 (s, 1H), 8,91 (s, 1H), 8,87-8,87 (m, 1H), at 8.36 (DD, J=8,2, 1.2 Hz, 1H), 7,85 to 7.75 (m, 3H), of 7.64-7,53 (m, 3H), of 6.71 (DD, J=3,7, 0.5 Hz, 1H), to 2.67 (s, 3H)
188H-NMR (400 MHz, DMSO-d6) δ 12,84 (s, 1H), of 12.73 (d, J=6,6 Hz, 1H), is 11.39 (s, 1H), cent to 8.85 (d, J=6,7 Hz, 1H), 8,61 (s, 1H), with 8.33 (d, J=6,8 Hz, 1H), 8,23 (s, 1H), 7,80 (t, J=8,4 Hz, 1H), 7,73 (d, J=7.8 Hz, 1H), 7,52 (t, J=8,1 Hz, 1H), the 7.43 (m, 1H), 6,54 (m, 1H), to 4.38 (q, J=7,1 Hz, 2H), 1,36 (t, J=7,1 Hz, 3H)
204H-NMR (400 MHz, DMSO-d6) δ 12,97 (s, 1H), 12,37 (s, 1H), 8,87 (d, J=1.2 Hz, 1H), 8,32 (d, J=8,2 Hz, 1H), 7,82 (DD, J=8,2, 7,0 Hz, 1H), of 7.75 (d, J=8,3 Hz, 1H), 7,54 (t, J=7.5 Hz, 1H), 7,32-7,28 (m, 2H), 7,05 (d, J=8,4 Hz, 1H), 4.16 the (t, J=4.9 Hz, 2H), 1,78 (t, J=4.9 Hz, 2H), 1,29 (s, 6H),
207H-NMR (400 MHz, DMSO-d6) δ 12,92 (users, 1H), 12,50 (s, 1H), 10,95 (s, 1H), 8,89 (s, 1H), 8,35 (DD, J=8,2, 1.1 Hz, 1H), 8,17 (d, J=1.5 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,46 (d, J=8,4 Hz, 1H), 7,21 (d, J=2.3 Hz, 1H), 7,06 (DD, J=8,5, 1.8 Hz, 1H), 4.09 to (kV, J=7,1 Hz, 2H), and 3.72 (s, 2H), 1,20 (t, J=7,1 Hz, 3H)

215H-NMR (400 MHz, DMSO-d 6) δ 12,97 (s, 1H), 12,50 (s, 1H), 8,89 (s, 1H), 8.34 per (DD, J=8,1, 1.1 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), to 7.75 (m, 3H), 7,55 (t, J=8,1 Hz, 1H), 7,37 (t, J=7.9 Hz, 2H), 7,10 (t, J=6,8 Hz, 1H)
220H-NMR (400 MHz,DMSO-d6) δ 12,99(d, J=6,6 Hz, 1H), 12,07 (s, 1H), 8,93 (d, J=6,8 Hz, 1H), 8,35 (d, J=7,1 Hz, 1H), of 8.27 (s, 1H), 8,12 (s, 1H), 7,85-to 7.77 (m, 2H), 7,54 (TD, J=7,5, 1.2 Hz, 1H), for 6.81 (s, 1H), 1,37 (d, J=3,9 Hz, 9H), of 1.32 (d, J=17,1 Hz, 9H)
2251H-NMR (CD3OD, 300 MHz) δ 8,79 (s, 1H), of 8.37 (d, J=7.9 Hz, 1H), to 7.75 (m, 2H), to 7.61 (d, J=8,3 Hz, 1H), 7.5 (m, 2H), 7,29 (d, J=8,3 Hz, 1H), 4,21 (kV, J=7,2, 2H), 3,17 (m, 1H), 1,32 (t, J=7.2 Hz, 3H), 1,24 (d, J=6,9 Hz, 6H),
2321H-NMR (CD3OD, 300 MHz) δ 8,87 (s, 1H), 8,45 (d, J=8,25, 1H), 8,27 (m, 1H), 7,83 (t, J=6,88, 1H), to 7.67 (d, J=8,25, 1H), 7,54 (t, J=7,15, 1H), 7,39 (d, J=6,05, 1H), 7,18 (d, J=8,5, 1H), 2,77 (t, J=6.87 in, 2H), 2,03 (s, 3H), 1,7 (kV, 2H), was 1.04 (t, J=7,42, 3H)
2331H-NMR (400 MHz,DMSO-d6) was 12.75 δ (d, J=13,6 Hz, 1H), 8,87 (s, 1H), 8,32-of 8.28 (m, 2H), 7,76-of 7.70 (m, 2H), 7,60 (d, J=7.8 Hz, 1H), 7,49 was 7.45 (m, 1H), 7,18 (d, J=8,4 Hz, 1H), 4,11 (t, J=8,3 Hz, 2H), 3,10 (t, J=7.7 Hz, 2H), 2,18(s, 3H)
2341H-NMR (400 MHz,DMSO-d6) δ 12,49 (s, 1H), 11,50 (s, 1H), of 8.90 (s, 1H), at 8.36-8.34 per (m, 2H), of 7.97 (s, 1H), 7,85-7,81 (m, 1H), to 7.77 to 7.75 (m, 1H), 7,56 is 7.50 (m, 2H), 6,59 return of 6.58 (m, 1H)
2351H-NMR (400 MHz,DM is About -d6) δ to 13.09 (d, J=6,5 Hz, 1H), was 12.75 (s, 1H), 9,04 (s, 1H), of 8.92 (d, J=6,8 Hz, 1H), 8,42 (d, J=7,1 Hz, 1H), 8.34 per (d, J=6,9 Hz, 1H), 7,85 (t, J=8,4 Hz, 1H), 7,78 (d, J=7.7 Hz, 1H), 7,63-7,56 (m, 2H), 3.15 in (m, 1H), 1,29 (d, J=6.9 Hz, 6H)
2381H-NMR (400 MHz,DMSO-d6) δ 12,93 (d, J=6,4 Hz, 1H), 12,29 (s, 1H), cent to 8.85 (d, J=6,7 Hz, 1H), 8,32 (d, J=8,1 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), of 7.75 (d, J=7.9 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), 7,17 (m, 2H), 6,94 (m, 1H), 3,79 (m, 2H,), 3,21-2,96 (m, 4H), 1.91 a to 1.76 (m, 4H), of 1.52 (m, 2H), USD 1.43 (s, 9H)
242H-NMR (400 MHz,DMSO-d6) δ 12,95 (d, J=6,6 Hz, 1H), 12,65 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), 8.34 per (DD, J=8,1, 1.1 Hz, 1H), 8,17 (s, 1H), 7,83 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.8 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), 7,37 (s, 1H), ceiling of 5.60 (, 2H)

2431H-NMR (CD3OD, 300 MHz) δ 8,87 (s, 1H), 8,45 (d, J=8,25, 1H), 8,27 (m, 1H), 7,83 (t, J=6,88, 1H), to 7.67 (d, J=8,25, 1H), 7,54 (t, J=7,15, 1H), 7,39 (d, J=6,05, 1H), 7,18 (d, J=8,5, 1H), 2,77 (t, J=6.87 in, 2H), 2,03 (s, 3H), 1,7 (kV, 2H), was 1.04 (t, J=7,42, 3H) NMR shows the presence of regioisomer
244H-NMR (400 MHz,DMSO-d6) δ 12,89 (s, 1H), 12,42 (s, 1H), 10,63 (s, 1H), 8,88 (d, J=6,7 Hz, 1H), 8,35 (d, J=8,2 Hz, 1H), 8,03 (d, J=1.6 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), 7,29 (d, J=8,3 Hz, 1H), 7,02 (DD, J=8,4, 1.8 Hz, 1H), 2,69 (t, J=5.3 Hz, 2H), 2,61 (t, J=5.0 Hz, 2H), equal to 1.82 (m, 4H)
248H-NMR (400 M is t; DMSO-d6) δ 12,95 (d, J=6,6 Hz, 1H), 12,42 (s, 1H), of 9.30 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), with 8.33 (DD, J=8,1, 1.3 Hz, 1H), 7,85-7,81 (m, 2H), 7,76 (d, J=7.8 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,49 (DD, J=8,2, 2.2 Hz, 1H), to 7.18 (d, J=8,3 Hz, 1H), 2,18 (s, 3H), of 2.08 (s, 3H)
259H-NMR (400 MHz,DMSO-d6) δ 0,86 (t, J=7.4 Hz, 3H), of 1.29 (d, J=6.9 Hz, 3H), 1,67 (m, 2H), 2,88 (m, 1H), 7,03 (m, 2H), 7,53 (m, 2H), 7,80 (m, 2H), 8,13 (s, 1H), 8,35 (d, J=8,2 Hz, 1H), 8,89 (s, 1H), 10,75 (s, 1H), 12,45 (s, 1H), 12,84 (s, 1H)
260H-NMR (400 MHz, DMSO-d6) ∆ 13,23 (d, J=6,6 Hz, 1H), 12,20 (s, 1H), 10,22 (users, 2H), 8,88 (d, J=6,8 Hz, 1H), 8.34 per (d, J=7.8 Hz, 1H), 7,86-7,80 (m, 3H), 7,56-7,52 (m, 2H), 7,15 (DD, J=8,5, 2.4 Hz, 1H), of 1.46 (s, 9H)
2611H-NMR (DMSO-d6, 300 MHz) δ 11,99 (s, 1H, NH), 8,76 (s, J=6,6 Hz, 1H), compared to 8.26 (d, J=6.2 Hz, 1H), of 8.09 (d, J=7.9 Hz, 1H), 7,72-7,63 (m, 2H), 7,44-to 7.09 (m, 7H), to 2.46 (s, 3H), of 2.25 (s, 3H),
2621H-NMR (400 MHz, DMSO-d6) δ 13,00 (s, 1H), of 12.53 (s, 1H), to 10.62 (s, 1H), 8,88 (s, 1H), with 8.33 (DD, J=8,2, 1.2 Hz, 1H), 7,85 to 7.75 (m, 2H), EUR 7.57-to 7.50 (m, 2H), 7,34-7,28 (m, 2H), 3.46 in (s, 2H)
266H-NMR (400 MHz, DMSO-d6) δ 12,94 (d, J=6,6 Hz, 1H), 12,57 (s, 1H), 10,37 (s, 1H), 8,88 (d, J=6,8 Hz, 1H), 8.34 per-8,32 (m, 1H), to 7.99 (s, 1H), 7,85-7,81 (m, 1H), 7,76 (d, J=7.8 Hz, 1H), 7,56-7,52 (m, 1H), 7,38 (s, 1H), of 1.37 (s, 9H)
268H-NMR (400 MHz, DMSO-d6) δ 13,02 (s, 1H), br12.62 (s, 1H), 8,91 (s, 1H), 8.34 per DD, J=8,1, 1.1 Hz, 1H), they were 8.22 (d, J=2.4 Hz, 1H), 8,14 (DD, J=8,8, 2.4 Hz, 1H), to 7.84 (t, J=8,3 Hz, 1H), to 7.77 (d, J=7.8 Hz, 1H), 7,65-rate of 7.54 (m, 4H), of 1.52 (s, 9H)

271H-NMR (400 MHz, DMSO-d6) δ to 1.38 (s, 9H), to 4.01 (s, 2H), 7,35 (s, 2H), 7,55 (m, 1H), 7,65 (s, 1H), 7,79 (d, J=8,2 Hz, 1H), 7,83 (m, 1H), with 8.33 (d, J=7,6 Hz, 1H), 8,86 (d, J=6,8 Hz, 1H), 12,49 (s, 1H), 13,13 (s, 1H)
2721H-NMR (Acetone-d6, 300 MHz) δ of 8.92 (d, J=6,6 Hz, 1H), 8,39 (d, J=7.8 Hz, 1H), 7,94 (s, 1H), 7,79 (s, 1H), to 7.77 (s, 2H), 7,53 (m, 1H), was 7.36 (s, 1H), 3,94-3,88 (m, 5H), 3,64-3,59 (m, 3H), 3,30 (m, 4H),
274H-NMR (400 MHz, DMSO-d6) δ 13,21 (d, J=6,6 Hz, 1H), 11,66 (s, 1H), 10,95 (s, 1H), 9,00 (d, J=6,5 Hz, 1H), 8,65 (d, J=2.1 Hz, 1H), 8,18 (DD, J=8,7, 2.2 Hz, 1H), of 7.97 (d, J=8,8 Hz, 1H), EUR 7.57 (m, 2H), 7,31 (t, J=2.7 Hz, 1H), 6,40 (t, J=2.0 Hz, 1H), 3,19 (m, 4H), to 1.67 (m, 4H), of 1.46 (s, 9H)
275H-NMR (400 MHz, DMSO-d6) δ 12,23 (s, 1H), for 9.47 (s, 1H), 9,20 (s, 1H), 8,43 (d, J=7.9 Hz, 1H), 7,79 (t, J=2.0 Hz, 2H), 7,56 (m, 1H), 7,38-7,26 (m, 6H), 7,11 (d, J=8,4 Hz, 1H), 6,99 (DD, J=8,4, and 2.1 Hz, 1H), to 5.85 (s, 2H), 1,35 (s, 9H)
2821H-NMR (CD3OD, 300 MHz) δ of 8.90 (s, 1H), 8,51 (s, 1H), 8,44 (d, J=7.9 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,69 (d, J=8.5 Hz, 1H), 7,56 (t, J=7.7 Hz, 2H), 7,42 (d, J=7.9 Hz, 1H), 7,07 (d, J=5.8 Hz, 1H), 2,93 (kV, J=7,4 Hz, 2H), 1,36 (t, J=7.5 Hz, 3H),
2831H-NMR CDCl 3, 300 MHz) δ 8,82 (d, J=6,6 Hz, 1H), 8,29 (d, J=6.2 Hz, 1H), of 8.06 (d, J=7.9 Hz, 1H), 7,43-7,24 (m, 6H), 7,02 (m, 2H), 6.87 in-for 6.81 (DD, 2H), 3,76 (s, 3H),
287H-NMR (400 MHz, DMSO-d6) δ 13,51 (s, 1H), 13,28 (d, J=6,6 Hz, 1H), 11,72 (d, J=2.2 Hz, 1H), 9,42 (s, 1H), 8,87 (d, J=6,9 Hz, 1H), 8,04 (d, J=7,4 Hz, 1H), to 7.67 (t, J=8,2 Hz, 1H), 7,17 (DD, J=8,3, 0.8 Hz, 1H), 7,01 (d, J=13,7 Hz, 1H), for 6.81 (DD, J=8,1, 0.8 Hz, 1H), 2,10 (m, 2H), 1,63 is 1.34 (m, 8H), 1.26 in (s, 3H)
288H-NMR (400 MHz, DMSO-d6) δ 13,16 (s, 1H), is 12.85 (s, 1H), 8,98 (s, 1H), 8,43 (DD, J=8,1, 1.1 Hz, 1H), 8.34 per (DD, J=10,3, 3.1 Hz, 1H), to 7.93 (t, J=8,4 Hz, 1H), 7,86 (d, J=7.7 Hz, 1H), 7,66 (t, J=8,1 Hz, 1H), 7,03 (DD, J=10,7, and 3.2 Hz, 1H), 4,06 (s, 3H), of 1.42 (s, 9H)
295H-NMR (400 MHz, DMSO-d6) δ to 1.98 (m, 4H), 3.15 in (m, 4H),? 7.04 baby mortality (m, 2H), 7,17 (d, J=7.8 Hz, 1H), 7,52 (m, 1H), 7,74 (d, J=7.8 Hz, 1H), 7,81 (m, 1H), 8,19 (DD, J=7,9, and 1.4 Hz, 1H), with 8.33 (d, J=8,1 Hz, 1H), 8,88 (d, J=6,7 Hz, 1H), 12,19 (s, 1H), 12,87 (s, 1H)

299H-NMR (400 MHz, DMSO-d6) δ 12,93-12,88 (m, 1H), 12,18 (s, 1H), 8,83 (d, J=6,8 Hz, 1H), scored 8.38-8,31 (m, 1H), 7,85-to 7.67 (m, 2H), EUR 7.57-7,51 (m, 1H), 6,94 (s, 1H), for 6.81-6,74 (m, 2H), 3,19-and 3.16 (m, 2H), 2,68-2,61 (m, 2H), 1,80-to 1.79 (m, 2H)
300H-NMR (400 MHz, DMSO-d6) ∆ 13,23 (d, J=6,6 Hz, 1H), 12,59 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), with 8.33 (d, J=7.7 Hz, 1H), 7,86-7,79 (m, 3H), 7,58-7,42 (m, 3H), 3,38 (m, 2H), of 1.88 (m, 2H), of 1.30 (s, 6H)
303 1H-NMR (400 MHz, DMSO-d6) δ 12,96 (d, J=6,5 Hz, 1H), 12,47 (s, 0,4H), 12,43 (s, 0,6H), 8,87 (DD, J=6,7, and 2.3 Hz, 1H), with 8.33 (d, J=8,1 Hz, 1H), 7,82 (t, J=8,2 Hz, 1H), of 7.75 (d, J=8,3 Hz, 1H), 7,62-7,52 (m, 3H), 7,17 (d, J=8,3 Hz, 1H), 4,66 (s, 0,8H), 4,60 (s, 1,2H), 3,66 (t, J=5,9 Hz, 2H), and 2.83 (t, J=5.8 Hz, 1,2H), 2,72 (t, J=5,9 Hz, 0,8H), is 2.09 (m, 3H)
3041H-NMR (300 MHz, DMSO-d6) δ 11,70 (s, 1H), total of 8.74 (s, 1H), 8,15 (s, 1H), 8,07 (m, 1H), 7,72 (m, 1H), 7,63 (d, J=8,4 Hz, 1H), 7,45-7,31 (m, 3H), 7,15-to 6.95 (m, 5H), 4,17 (d, J=6.0 Hz, 2H), was 4.02 (q, J=6.9 Hz, 2H), 1,40 (s, 9H), 1,09 (t, J=6.9 Hz, 3H),
3071H-NMR (CDCl3, 300 MHz) δ 8,81 (d, J=6,6 Hz, 1H), 8,30 (d, J=6.2 Hz, 1H), 8,02 (d, J=7.9 Hz, 1H), 7,44-7,26 (m, 9H), 6,79 (d, J=7.5 Hz, 1H)
3181H-NMR (Acetone-d6, 300 MHz) δ 8,92 (users, 1H), 8,40 (d, J=8,1 Hz, 1H), 8,05 (users, 1H), 7,94 (users, 1H), 7,78 (users, 2H), 7,52 (m, 1H), was 7.36 (users, 1H), 3,97 (t, J=7.2 Hz, 2H), 3,66 (t, J=8 Hz, 2H), 3,31-3,24 (m, 6H), 1,36 to 1.31 (m, 4H)
3201H NMR (400 MHz, DMSO-d6) δ 12,90 (s, 1H), to 12.44 (s, 1H), 10,86 (s, 1H), of 8.90 (s, 1H), 8,35 (DD, J=8,2, 1.0 Hz, 1H), 8,12 (t, J=0.8 Hz, 1H), 7,84 to 7.75 (m, 2H), 7,56-7,52 (m, 1H), 7,37 (d, J=8,3 Hz, 1H), 6,99 (DD, J=8,4, 1.9 Hz, 1H), between 6.08 and 6,07 (m, 1H), of 1.35 (s, 9H)
321H-NMR (400 MHz, DMSO-d6) δ of 2.93 (m, 4H), and 3.72 (m, 4H), 7,10 (m, 2H), 7,27 (d, J=7.8 Hz, 1H), 7,51 (m, 6H), 7,74 (d, J=8,2 Hz, 1H), 7,81 (m, 1H), 8,40 (d, J=8,1 Hz, 1H), 8,58 (d, J=8.0 Hz, 1H), 8,88 (d, J=6,7 Hz, 1H), 12,69 (Prov., 1H), 12,86 (s, 1H)
323H-NMR (400 MHz, DMSO-d6) δ 12,94 (users, 1H), to 12.44 (s, 1H), 8,89 (s, 1H), with 8.33 (DD, J=8,2, 1.1 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), to 7.67 (d, J=8,8 Hz, 2H), 7,54 (t, J=8,1 Hz, 1H), 7,35 (d, J=8.7 Hz, 2H), 7,02 (t, J=6.3 Hz, 1H), 3,50 (s, 3H), 3,17 (d, J=6.2 Hz, 2H), 1,23 (s, 6H)

334H-NMR (400 MHz, DMSO-d6) δ 13,02 (users, 1H), 12,46 (s, 1H), 8,89 (s, 1H), with 8.33 (DD, J=8,2, 1.1 Hz, 1H), 7,89 (s, 1H), 7,82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.8 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,44 (m, 1H), 7,37 (d, J=8.6 Hz, 1H), 3,85 (m, 2H), and 3.72 (t, J=6.0 Hz, 2H), 3,18-3,14 (m, 2H), of 2.23 (s, 3H), of 1.93 (t, J=5.7 Hz, 2H), 1,79 (m, 2H), 1,53 (m, 2H), USD 1.43 (s, 9H)
337H-NMR (400 MHz, DMSO-d6) δ 12,19 (s, 1H), 9,35 (s, 1H), they were 8.22 (DD, J=8,1, 1.1 Hz, 1H), 8,08 (s, 1H), 7,74-of 7.70 (m, 1H), 7,65 (d, J=7.8 Hz, 1H), 7,44-7,40 (m, 1H), 7.23 percent (s, 1H), and 3.31 (s, 3H), of 1.37 (s, 9H), of 1.36 (s, 9H)
3511H-NMR (400 MHz, DMSO-d6) δ 12,92 (s, 1H), 12,34 (s, 1H), 10,96 (s, 1H), 8,91 (s, 1H), 8,48 (s, 1H), of 8.37 (d, J=8,1 Hz, 1H), 7,84-7,76 (m, 2H), 7,53 (t, J=7,4 Hz, 1H), 7,39 (s, 1H), 7,26 (t, J=2,6 Hz, 1H), 6,34 (s, 1H), 2,89-2,84 (m, 2H), 1,29 (t, J=7.4 Hz, 3H)
3531H-NMR (400 MHz, DMSO-d6) δ 11,90 (s, 1H), of 9.30 (s, 1H), 8,88 (s, 1H), 8.34 per (DD, J=8,2, 1.1 Hz, 1H), 7,84-7,71 (m, 3H), 7,55 is 7.50 (m, 1H), 7,28-7,26 (m, 1H), 7,20-7,17 (m, 1H), 1,47 (s, 9H), to 1.38 (s, 9H)
356357H-NMR (400 MHz, DMSO-d6) δ 12,91 (d, J=6,6 Hz, 1H), 12,45 (s, 1H), of 10.73 (d, J=1.9 Hz, 1H), 8,89 (d, J=6,7 Hz, 1H), 8,35 (DD, J=8,1, 1.3 Hz, 1H), 8,13 (d, J=1.6 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), 7,76 (d, J=7,7Hz, 1H), EUR 7.57-7,51 (m, 2H), 7,06-7,02 (m, 2H), 3,12 (septet, J=6.6 Hz, 1H), 1,31 (d, J=6.9 Hz, 6H)
3631H-NMR (CDCl3, 300 MHz) δ 8,86 (d, J=6,6 Hz, 1H), 8,24 (d, J=6.2 Hz, 1H), 8,14 (d, J=7.9 Hz, 1H), 7,43-7,16 (m, 5H), 7,02-6,92 (m, 2H), 6,83 (d, J=7.9 Hz, 2H), a 3.87 (s, 3H)
3681H-NMR (400 MHz, DMSO-d6) δ 12,97 (d, J=6,6 Hz, 1H), 12,36 (s, 1H), 8,86 (d, J=6,7 Hz, 1H), with 8.33 (DD, J=8,1, 1.0 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.8 Hz, 1H), 7.62mm (s, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,25 (DD, J=8,7, 2,2 Hz, 1H), 7,01 (d, J=8,8 Hz, 1H), 3,98 (t, J=6.5 Hz, 2H), 1,78 (sextet, J=6,9 Hz, 2H), of 1.02 (t, J=7.4 Hz, 3H)
375H-NMR (400 MHz, DMSO-d6) δ 12,93 (d, J=6.2 Hz, 1H), 12,35 (s, 1H), 8,86 (d, J=6,7 Hz, 1H), with 8.33 (d, J=6,9 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), of 7.75 (d, J=7.8 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), 7,47-the 7.43 (m, 2H),? 7.04 baby mortality (d, J=8,2 Hz, 1H), a 2.71 (m, 4H), of 1.75 (m, 4H)

378H-NMR (400 MHz, DMSO-d6) δ 12,98 (d, J=6,6 Hz, 1), KZT 12.39 (s, 1H), 8,86 (d, J=6,7 Hz, 1H), with 8.33 (DD, J=8,1, 1.2 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), to 7.77 (d, J=7.7 Hz, 1H), 7,69 (s, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,31 (DD, J=8,8, 2.4 Hz, 1H), 7,06 (d, J=8,8 Hz, 1H), 3,85 (s, 3H)
3791H-NMR (300 MHz, DMSO-d6) δ 12,79 (s, 1H), 10.30 a.m. (s, 1H), cent to 8.85 (s, 1H), 8,32 (d, J=7.8 Hz, 1H), of 8.06 (s, 1H), to 7.93 (s, 1H), 7,81 (t, J=7.8 Hz, 1H), 7,74 (d, J=6,9 Hz, 1H), 7,73 (s, 1H), 7,53 (t, J=6,9 Hz, 1H), 2,09 (s, 3H)
381H-NMR (400 MHz, DMSO-d6) δ 12,78 (users, 1H), 11,82 (s, 1H), 10,86 (s, 1H), 8,83 (s, 1H), 8,28 (DD, J=8,1, 1.0 Hz, 1H), of 7.75 (t, J=8,3 Hz, 1H), 7,69 (d, J=7.7 Hz, 1H), 7,49-the 7.43 (m, 3H), of 7.23 (m, 1H), 6,32 (m, 1H), of 1.39 (s, 9H)
3821H-NMR (CD3OD, 300 MHz) δ 8,83 (s, 1H), 8,40 (d, J=7,4 Hz, 1H), 7,81-7,25 (m, 2H), 7,65 (d, J=8,3 Hz, 1H), 7,51 (d, J=8,2, 1H), 7,24 (d, J=8,3, 1H), 2,58 (t, J=7.7 Hz, 2H), 2,17 (s, 3H), 1,60 (m, 2H), 0,97 (t, J=the 7.4 Hz, 3H),
383H-NMR (400 MHz, DMSO-d6) δ of 1.27 (t, J=7.5 Hz, 3H), 2,70 (kV, J=7.7 Hz, 2H), 7,05 (m, 2H), 7,47 (d, J=8,4 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), 8,13 (s, 1H), 8,35 (d, J=6,9 Hz, 1H), 8,89 (d, J=6,7 Hz, 1H), of 10.73 (s, 1H), 12,46 (s, 1H), 12,91 (s, 1H)
386H-NMR (400 MHz, DMSO-d6) δ of 13.18 (d, J=6,8 Hz, 1H), 12,72 (s, 1H), 8,88 (d, J=6,8 Hz, 1H), 8.34 per (d, J=8,1 Hz, 1H), of 8.09 (s, 1H), 7,86-7,79 (m, 2H), 7,58 is 7.50 (m, 2H), 7,43 (d, J=8,2 Hz, 1H), 3,51 (s, 2H), 1,36 (s, 6H)
3931H-NMR (300 MG IS, MeOH) δ 8,78 (s, 1H), 8,45 (d, J=2.1 Hz, 1H), 8,16 (d, J=8,1 Hz, 1H), 7,71 (t, J=6,9 Hz, 1H), 7,56 (d, J=8.7 Hz, 1H), 7,39 (m, 3H), 7,18 (m, 2H), 7,06 (m, 2H), was 4.02 (m, 2H), 1,13 (t, J=6,9 Hz, 3H)
3991H-NMR (CD3OD, 300 MHz) δ 8,91 (s, 1H), 8,51 (s, 1H), 8,42 (d, J=8,3 Hz, 1H), to 7.84 (t, J=7.2 Hz, 1H), to 7.67 (d, J=9.0 Hz, 1H), 7,56 (t, J=7.9 Hz, 1H), 7,46 (d, J=8.5 Hz, 1H), 7,24 (d, J=6.0 Hz, 1H), 3,48 (m, 1H), 3,09 (s, 3H, NMe), of 1.39 (d, J=6.8 Hz, 6H)
412H-NMR (400 MHz, DMSO-d6) δ 12,81-12,79 (m, 2H), 10,96 (s, 1H), 8,87 (d, J=6,7 Hz, 1H), 8,35 (d, J=8,1 Hz, 1H), to 7.99 (d, J=8.6 Hz, 1H), 7,83-7,73 (m, 3H), 7,53 (t, J=8,1 Hz, 1H), was 7.36 (m, 1H), of 6.52 (m, 1H), 4,51 (kV, J=7,1 Hz, 2H), to 1.37 (t, J=7,1 Hz, 3H)

415H-NMR (400 MHz, DMSO-d6) δ of 12.26 (s, 1H), 9,46 (s, 1H), 8,99 (s, 1H), 8,43-to 8.41 (m, 1H), 7,94-7,88 (m, 2H), 7,65-to 7.61 (m, 1H), 7,38 (d, J=2.1 Hz, 1H), 7,10 (d, J=8,4 Hz, 1H), of 6.96 (DD, 1H), 4,08 (s, 3H), of 1.35 (s, 9H)
420H-NMR (400 MHz, DMSO-d6) δ 12,91 (users, 1H), 12,51 (s, 1H), 8,89 (s, 1H), with 8.33 (DD, J=8, 1 Hz, 2H), 7,82 (DDD, J=8, 8, 1 Hz, 1H), of 7.75 (DD, J=8, 1 Hz, 1H), of 7.70 (d, J=9 Hz, 2H), 7,54 (DDD, J=8, 8, 1 Hz, 1H), 4.09 to (kV, J=7 Hz, 2H)and 1.51 (s, 6H), of 1.13 (t, J=7 Hz, 3H)
423H-NMR (400 MHz, DMSO-d6) δ 12,91 (users, 1H), 12,48 (s, 1H), 10,81 (d, J=1.8 Hz, 1H), 8,89 (s, 1H), 8,35 (DD, J=8,2, 1.1 Hz, 1H), 8,14 (d, J=1.6 Hz, 1H), 7,82 (t, J=7,6 Hz, 1H), 7,76 (d, J=7.8 Hz, 1H), 7,56-of 7.48 (m, 2H), 7,11 (d, J=the 2.2 Hz, 1H), 7,05 (DD, J=8,5, 18 Hz, 1H), 3,62 (t, J=7,3 Hz, 2H), 3,48 (kV, J=7,0 Hz, 2H), only 2.91 (t, J=7,3 Hz, 2H), 1.14 in (t, J=7.0 Hz, 3H)
4251H-NMR (DMSO-d6, 300 MHz) δ 8,84 (s, 1H), 8,29 (d, J=8,1 Hz, 1H), 7,78-of 7.70 (m, 2H), to 7.61 (d, J=8,4 Hz, 2H), 7,50 (t, J=7.8 Hz, 1H), 7,20 (d, J=8.7 Hz, 2H), 2,85 (Gex., J=6,9 Hz, 1H), 1,19 (d, J=6.9 Hz, 6H),
427H-NMR (400 MHz, DMSO-d6) δ 1,45 (s, 9H), 2,84 (t, J=5,9 Hz, 2H), 3,69 (m, 2H), 4,54 (s, 1H), 6,94 (d, J=7.5 Hz, 1H), 7,22 (t, J=7.9 Hz, 1H), 7,55 (m, 1H), to 7.77 (d, J=7.7 Hz, 1H), 7,83 (m, 1H), 8,24 (d, J=8.0 Hz, 1H), of 8.37 (d, J=9,2 Hz, 1H), 8,91 (s, 1H), 12,36 (s, 1H), 12,99 (s, 1H)
4281H-NMR (300 MHz, CD3OD) δ 12,30 (s, 1H), 8,83 (s, 1H), scored 8.38 (d, J=7,4 Hz, 1H), 7,78 (see. dt, J=1,1, 7,1 Hz, 1H), to 7.64 (d, J=8,3 Hz, 1H), 7,53 (see. t, J=7.5 Hz, 1H), 7,21 (userd, J=0.9 Hz, 1H), 7,15 (d, J=8,4 Hz, 1H), 6,98 (DD, J=2.1 a, and 8.4 Hz, 1H), to 1.38 (s, 9H)
429H-NMR (400 MHz, DMSO-d6) δ 13,13 (d, J=6,8 Hz, 1H), 12,63 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), with 8.33 (d, J=7,0 Hz, 1H), to 7.84 (t, J=8,3 Hz, 1H), 7,78 (d, J=7,6 Hz, 1H), 7,56 (t, J=8,1 Hz, 1H), 7,51 (s, 1H), 7,30 (s, 1H), 6,77 (s, 1H)
433H-NMR (400 MHz, DMSO-d6) δ 12,87 (users, 1H), 11,82 (s, 1H), 9,20 (s, 1H), 8,87 (s, 1H), with 8.33 (DD, J=8,2, 1.1 Hz, 1H), 7,81 (t, J=8,3 Hz, 1H), of 7.75 (d, J=7.7 Hz, 1H), 7,52 (t, J=8,1 Hz, 1H), 7,17 (s, 1H), 7,10 (s, 1H), to 1.38 (s, 9H), of 1.36 (s, 9H)
438H-NMR (400 MHz, DMSO-d6) δ 12,97 (d, J=6,6 Hz, 1H), 12,08 (s,1H), of 8.90 (d, J=6,8 Hz, 1H), 8,35-to 8.34 (m, 1H), 8,03 (s, 1H), 7,85-7,81 (m, 1H), to 7.77-7,71 (m, 1H), 7,58-7,44 (m, 2H), of 1.46 (s, 9H), of 1.42 (s, 9H)

4411H-NMR (Acetone-d6, 300 MHz) δ 11,90 (users, 1H), 8,93 (users, 1H), 8,42 (d, J=8,1 Hz, 1H), 8,08 (s, 1H), 7,92 (s, 1H), 7,79 (m, 2H), EUR 7.57 (m, 1H), was 7.36 (s, 1H), 3,13 (s, 3H)
444H-NMR (400 MHz, DMSO-d6) δ 12,56 (s, 1H), 12,17 (userd, J=6 Hz, 1H), 8,89 (d, J=6 Hz, 1H), 8,42 (DD, J=9, 2 Hz, 1H), to 7.77 (d, J=2 Hz, 1H), 7,68 (DD,J=9, 2 Hz, 1H), 7,60 (DDD, J=9, 9, 2 Hz, 1H), 7,46-7,40 (m, 3H), 3,47 (s, 3H), of 1.35 (s, 9H)
448H-NMR (400 MHz, DMSO-d6) δ 12,96 (users, 1H), 12,42 (s, 1H), 8,88 (s, 1H), with 8.33 (DD, J=8,2, 1.1 Hz, 1H), 7,82 (t, J=8,3 Hz, 1H), of 7.75 (d, J=7.7 Hz, 1H), 7,66 (d, J=8.7 Hz, 2H), 7,54 (t, J=8,1 Hz, 1H), 7,39 (d, J=8.7 Hz, 2H), 1,29 (, 9H)
453H-NMR (400 MHz, DMSO-d6) δ 12,95 (d, J=6,5 Hz, 1H), 12,38 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), with 8.33 (d, J=8,1 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), 7,76 (d, J=7.8 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), 7,28 (d, J=2.4 Hz, 1H), 7,15 (d, J=8,6 Hz, 1H), 6,94 (DD, J=8,6, and 2.4 Hz, 1H)
458H-NMR (400 MHz, DMSO-d6) δ 12,97 (d, J=7,1 Hz, 1H), KZT 12.39 (s, 1H), 8,88 (d, J=6,8 Hz, 1H), with 8.33 (d, J=7.9 Hz, 1H), 7,83 (t, J=7,6 Hz, 1H), of 7.75 (d, J=8,2 Hz, 1H), 7,55 (t, J=7,6 Hz, 1H), 7,47 (s, 1H), 7,17 (s, 2H), Android 4.04 (t, J=5.0 Hz, 2H), 3,82 (t, J=5.0 Hz, 2H), of 1.36 (s, 9H)
461 1H-NMR (DMSO-d6, 300 MHz) δ of $ 11.97 (s, 1H), and 8.7 (s, 1H), 8,30 (d, J=7.7 Hz, 1H), 8,07 (d, J=7.7 Hz, 1H), 7,726-7,699 (m, 2H), 7,446 -7,357 (m, 6H), 7,236-7,178 (m, 2H);13C-NMR (DMSO-d6, 75 MHz) δ 176,3, 163,7, 144,6, 139,6, 138,9, 136,3, 134,0, 133,4, 131,0, 129,8, 129,2, 128,4, 128,1, 126,4, 126,0, 125,6, 124,7, 123,6, 119,6, 111,2
4631H-NMR (DMSO-d6, 300 MHz) δ 8,83 (s, 1H), 8,29 (d, J=7.8 Hz, 1H), 7,78-of 7.70 (m, 2H), to 7.61 (d, J=7.8 Hz, 2H), 7,51 (t, 1H), 7,17 (d, J=8.1 Hz, 2H), 2.57 m (kV, J=7.5 Hz, 2H), 1,17 (t, J=7.5 Hz, 1H), to 0.92 (t, J=7.8 Hz, 3H),
4641H-NMR (400 MHz, DMSO-d6) δ of 1.37 (s, 9H), to 1.38 (s, 9H), to 6.80 (DD, J=8,1, 0.9 Hz, 1H), 7,15 (m, 3H), 7,66 (t, J=8,2 Hz, 1H), 8,87 (d, J=6,9 Hz, 1H), 9,24 (s, 1H), 11,07 (s, 1H), 13,23 (d, J=6,5 Hz, 1H), 13,65 (s, 1H)
465H-NMR (400 MHz, DMSO-d6) δ 12,94 (d, J=6.0 Hz, 1H), 12,40 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), with 8.33 (d, J=8,2 Hz, 1H), 7,84 to 7.75 (m, 3H), EUR 7.57-the 7.43 (m, 2H), 7,31 (d, J=8.6 Hz, 1H), and 4.40 (d, J=5.8 Hz, 2H), of 1.44 (s, 9H), to 1.38 (s, 9H)

4711H-NMR (CD3OD, 300 MHz) δ 8,87 (s, 1H), 8,44 (d, J=8,25, 1H), 8,18 (m, 1H), 7,79 (t, J=6,88, 1H), to 7.67 (d, J=8,25, 1H), 7,54 (t, J=7,15, 1H), 7.23 percent (d, J=6,05, 1H), 7,16 (d, J=8,5, 1H), of 3.73 (s, 3H), of 2.75 (t, J=6.87 in, 2H), 1,7 (kV, 2H), of 1.03 (t, J=7,42, 3H)
4761H-NMR (400 MHz, DMSO-d6) δ 13,00 (d, J=6,4 Hz, 1H), 12,91 (s, 1H), of 10.72 (s, 1H), 8,89 (d, J=6,8 Hz, 1H), 8.34 per (d, J=8,2 Hz, 1H), 8,16 (s, 1H), 7,8 to 7.75 (m, 2H), 7,56-rate of 7.54 (m, 1H), 7,44 (s, 1H), of 1.35 (s, 9H)
4781H-NMR (400 MHz, DMSO-d6) δ of 1.40 (s, 9H), 6,98 (d, J=2.4 Hz, 1H),? 7.04 baby mortality (DD, J=8,6, 1.9 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,66 (d, J=8.6 Hz, 1H), 7,76 (d, J=7.7 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), 8,13 (d, J=1.7 Hz, 1H), 8,35 (d, J=8,1 Hz, 1H), 8,89 (d, J=6,7 Hz, 1H), a 10.74 (s, 1H), to 12.44 (s, 1H), 12,91 (s, 1H)
4841H-NMR (300 MHz, DMSO-d6) δ 12,90 (d, J=6.3 Hz, 1H), 12,21 (s, 1H), cent to 8.85 (d, J=6,8 Hz, 1H), 8,31 (d, J=8.0 Hz, 1H), 7,79 (see.dt, J=12, 8.0 Hz, 1H), 7,72 (d, J=8,3 Hz, 1H), 7,52 (DD, J=6,9, 8,1 Hz, 1H), 7,05 (d, J=8,3 Hz, 1H), 6,94 (with obvious direct doublet, 1H), 1H), 6.90 to (d explicit direct doublet, J=8,4 Hz, 1H), 2,81 (s, 3H), of 1.34 (s, 9H)
4851H-NMR (300 MHz, CDCl3) δ 13,13 (users, 1H), 12,78 (s, 1H), 8,91 (users, 1H), 8,42 (users, 1H), of 8.37 (d, J=8,1 Hz, 1H), 7,72-7,58 (m, 2H), 7,47-7,31 (m, 3H), 3,34 (s, 6H), of 1.46 (s, 9H)

C) Tests for the detection and identification of corrective ΔF508-CFTR connection properties

I) Optical methods for determining the transmembrane potential to test for modulation of ΔF508-CFTR connection properties

Optical test against the transmembrane potential using potentialcustomers ERET sensors described by Gonzalez and Tsien (see J.E. Gonzalez and R.Y. Tsien “Voltage sensing by fluorescence resonance energy transfer in single celles”, Biophys. J.,69(4), 1272-1280 (1995); and J.E. Gonzalez and R.Y. Tsien “Improved indicators of cell membrane potntial that use fluorescence energy transfer”, Chem. Biol.,4(4), 269-277 (1997)), in combination with the measuring apparatus for determining changes in fluorescence, such as the Voltage/Ion Probe Reader (VIPR) (see J.E. Gonzalez. K. Oades, et al., “Cell-based assays and instrumentation for screening ion-channel targets”, Drug Discov. Today,4(9), 431-439 (1999)).

These potentialcustomers tests based on the change in resonant with fluorescence energy transfer (FRET) between membranectomy, potentialcustomers dye, DiSBAC2(3) and fluorescent phospholipid, CC2-DMPE, which is connected with an external "leaf" of the cytoplasmic membrane and acts as a FRET donor. Changes in transmembrane potential (Vmto cause a redistribution of the negatively charged DiSBAC2(3) in the cytoplasmic membrane and accordingly the amount of energy transmitted from the CC2-DMPE. Changes in fluorescence emission control using the device VIPRTMII, which is an integrated liquid manipulator and fluorescent detector is designed to conduct-based cell screening using 96 - or 384-well titration microplate.

Identification of corrective compounds

To identify small molecules that correct the defect transportation associated with ΔF508-CFTR, developed the test with only the addition of homozygous teruya the entrances (HTS). Cells were incubated in not containing serum medium for 16 hours at 37°C in the presence or in the absence (negative control) test connection. As a positive control, cells seeded in 384-well plates, incubated for 16 hours at a temperature of 27°C for temperature correction of ΔF508-CFTR. The cells were then washed 3 times with a solution of ringer-Krebs and loaded potentialcustomers dyes. To activate ΔF508-CFTR, in each well along with not containing Cl-medium was added to 10 μm of Forskolin and CFTR-amplifier, genistein (20 μm). The outflow of Cl-, promoted by adding not containing Cl-environment, in response to the activation of ΔF508-CFTR and attainable transmembrane depolarization optional controlled using based on FRET potentialcustomers dyes.

Identification of compounds-amplifiers

To identify amplifiers ΔF508-CFTR, developed the test with double addition of homozygous teruya cells. The first time you add to each well was added not containing Cl-environment with the test compound or without him. After 22 seconds, to activate ΔF508-CFTR was introduced a second additive containing no Cl-environment, including 2-10 μm of Forskolin. The extracellular concentration of Cl-after both additions was 28 mm, to the which was promotional outflow Cl -in response to the activation of ΔF508-CFTR, and attainable transmembrane depolarization was determined optically using based on FRET potentialcustomers dyes.

Solutions

The rinse solution No. 1 (in mm):
NaCl 160, KCl 4.5 Is, CaCl22, MgCl21, HEPES 10, pH=7,4 installed with NaOH;
The rinse solution that does not contain chlorides:

chloride salt in the rinse solution No. 1 replaced gluconate salts;
CC2-DMPE:
were prepared as a 10 mm initial solution in dimethyl sulfoxide (DMSO) and kept at -20aboutC;
DiSBAC2(3):
were prepared as a 10 mm initial solution and kept at -20°C.

Cell culture

For optical measurements of transmembrane potential used murine NIH3T3 fibroblasts stably expressing ΔF508-CFTR. Cells remove ivali at 37°C in an atmosphere with 5% CO 2and a humidity of 90% modified by way of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 × NEAA, β-ME, 1 × pen/strep, and 25 mm HEPES, flasks for cell culture area 175 cm2. For all optical tests, the cells were sown in the amount of 30,000 per well in covered with Matrigel 384-well plates and were cultured for 2 hours at 37°C before cultivation at 27°C for 24 hours for the dough to rise. For adjustment of the tests, the cells were cultured at 27°C or 37°C with compounds or without them for a period of 16-24 hours.

C) Electrophysiological tests to determine the modulating ΔF508-CFTR connection properties

1. Test in Ussing-chamber

Experiments in Ussing chamber was carried out using polarized epithelial cells expressing ΔF508-CFTR to further characterize modulators ΔF508-CFTR identified in optical tests. FRTΔF508-CFTR-Epithelial cells cultured on cell culture inserts Costar Snapweil, were placed in an Ussing chamber (Physiologic Instruments, Inc., San Diego, Canada) and the monolayers were continuously subjected to a short circuit, using a system of fixed potential (Voltage-clamp System; Departmen of Bioengineering, University of Iowa, IA, and Physiologic Instruments, Inc., San Diego, Canada). Transepithelial resistance was determined PU is eaten application of the pulse is 2 mV. Under these conditions, FRT - epithelium showed 4 Kω/cm2or more. The solution was kept at a temperature of 27°C and through them was barbotirovany the air. Electrode bias potential and the resistance of the liquid was adjusted using the insert without cells. Under these conditions, the current represents the flow of Cl-due to ΔF508-CFTR expressed in the apical membrane. ISCin the numeric value is achieved by using the interface MRA-CE and software AcqKnowledge (ν3.2.6; BIOPAC Systems, Santa Barbara, Canada).

Identification of corrective connections

According to a specific Protocol, used a gradient concentration of Cl-from basolateral to the apical membrane. To achieve this gradient, used normal ringer's solution in the case basolateral membrane, whereas apical NaCl was replaced with equimolar amounts of sodium gluconate (setting the pH to 7.4 with NaOH), receiving a large concentration gradient of Cl-through the epithelium. All experiments were performed using intact monolayers. To fully activate ΔF508-CFTR, used Forskolin (10 μm) and the PDE inhibitor, IBMX (100 μm), followed by the addition amplifier CFTR, genistein (50 μm).

As was found in other cell types, incubation at low temperatures FRT cells stably expressing ΔF508-CFTR by increasing the em density functional CFTR in the plasma membrane. To determine the activity of correction compounds, cells were incubated with 10 μm of test compounds for 24 hours at 37°C and then washed 3 times prior to registration. Mediated camp and genistein ISCin the treated compound cells was normalized to that obtained at 27°C and 37°C controls and were expressed as activity in percent. Pre-incubation of cells with corrective connection significantly increased mediated camp and genistein ISCcompared with those obtained at 37°C controls.

Identification of compounds-amplifiers

According to a specific Protocol, used a gradient concentration of Cl-from basolateral to the apical membrane. To achieve this gradient, used normal ringer's solution in the case basolateral membrane and added nystatin (360 μg/ml), whereas apical NaCl was replaced with equimolar amounts of sodium gluconate (setting the pH to 7.4 with NaOH), receiving a large concentration gradient of Cl-through the epithelium. All experiments were carried out after 30 minutes after administration of nystatin. Forskolin (10 μm) and all test compounds were added on both sides of the cell culture inserts. The efficiency of the alleged amplifiers ΔF508-CFTR was compared with the effectiveness of the known amplifier, genestein.

Solutions

Basolateral solution (in mm):
NaCl (135), CaCl2(1,2), MgCl2(1,2), K2HPO4(2,4), KH2PO4(0,6), N-hydroxyethylpiperazine-N'-2-econsultation (HEPES) (10) and dextrose (10). the pH of the solution to 7.4 installed using NaOH.
The apical solution (in mm):
same as basolateral solution, with the replacement of NaCl with sodium gluconate (135).

Cell culture

For experiments in Ussing-chamber in relation to the alleged modulators ΔF508-CFTR, identified according to the optical tests authors used a rat epithelial cells Fisher (FRT cells)expressing ΔF508-CFTR (FRTΔF508-CFTR). Cells were cultured on cell culture inserts Costar Snapwell and were cultured for five days at 37°C and in the presence of 5% CO2in a modified method Kuna environment Gama, supplemented with 5% fetal calf serum, 100 U/ml penicillin and 100 μm/ml streptomycin. To use for characterization of enhancing the activity of the compounds, the cells were incubated at 27°C for 16-48 hours before the correction on what I ΔF508-CFTR. To determine the activity of correction compounds, the cells were incubated at 27°C or 37°C With connection or without within 24 hours.

2. Registration of whole cells

Macroscopic current ΔF508-CFTR (IΔF508) subjected to the correction due to the temperature and the test connection NIH3T3 cells stably expressing ΔF508-CFTR was controlled using perforated "patch", the registration of the whole cell. Briefly, the patch-clamp-check-IΔF508was carried out at room temperature using the patch-clamp amplifier Axopatch 200D (Axon Instruments Inc., Foster City, Canada). All registration is conducted at the chosen frequency of 10 kHz and using a low pass filter at 1 kHz. Pipettes had a resistance of 5-6 Mω when filled with intracellular solution. In these conditions of registration, the calculated potential reversion to Cl-(ECl) at room temperature was -28 mV. All registrations had shut the resistance of >20 D and the serial resistance of <15 Mω. The pulse generation, data acquisition and analysis were carried out using a personal computer with interface Digidata 1320 A/D together with Clampex 8 (Axon Instruments Inc.). The solution contained <250 ál of salt and continuously subjected to perfusion with a speed of 2 ml/min using perfusion in gravity mode.

Identification corre is exporting connections

To determine the activity of correction compounds for increasing the density functional ΔF508-CFTR in the plasma membrane, the authors used the above methods perforated "patch"-registration for the measurement of current density after processing within 24 hours of corrective compounds. To fully activate ΔF508-CFTR, the cells were added to 10 microns of Forskolin and 20 μm genistein. In terms of registration, according to the invention, the current density after incubation for 24 hours at a temperature of 27°C was higher than the density observed after incubation for 24 hours at 37°C. These results are consistent with the known effects of low-temperature incubation on the density of ΔF508-CFTR in the plasma membrane. To determine the effects of corrective connections on the current density of CFTR, cells were incubated with 10 μm of test compounds for 24 hours at 37°C and the current density was compared with that obtained at temperatures of 27°C and 37°C controls (% activity). Prior to registration, the cells were washed 3 times extracellular environment to register in order to remove any remaining test compounds. The incubation with 10 mm of corrective compounds significantly increases dependent on camp and genistein current compared with that obtained when temperature is 37°C controls.

Identification of compounds-amplifiers

The ability of the amplifiers ΔF508-CFTR to increase the macroscopic ΔF508-CFTR Cl--the current (IΔF508) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using the methods perforated "patch"-registration. Amplifiers identified in optical tests, caused a dose-dependent increase of IΔF508with similar efficacy and effectiveness observed in the case of optical tests. In all investigated cells, a potential reversion to and during the application of the amplifier was about -30 mV, which represents the estimated ECl(-28 mV).

Solutions

Intracellular solution (in mm):
the cesium aspartate (90), CsCl (50), MgCl2(1), HEPES (10), and 240 μg/ml amphotericin-B (pH, increased to 7.35 with CsOH).
The extracellular solution (in mm):
N-methyl-D-glucamine (NMDG)-Cl (150), MgCl2(2), CaCl2(2), HEPES (10) (pH brought up to 7.35 with HCl).

Cell culture

Murine NIH3T3 fibroblasts stably expressing ΔF508-CFTR was used for registration of whole cells. Cells : rival at 37°C in an atmosphere with 5% CO 2and a humidity of 90% modified by way of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 × NEAA, β-ME, 1 × pen/strep, and 25 mm HEPES, flasks for cell culture area 175 cm2. For registration of whole cells, 2500-5000 cells were sown on covered with poly-L-lysine glass cover and were cultured for 24-48 hours at a temperature of 27°C before use to test the activity of the amplifiers; and incubated with corrective connection or without it at a temperature of 37°C to determine the activity of the correctors.

3. Registration of one channel

Activity one channel corrected by temperature ΔF508-CFTR stably expressed in NIH3T3 cells, and the activity of the compounds of the amplifiers was determined using excisional on the reverse side of the membrane "patch". Briefly, the registration of fixed potential activity of one channel was carried out at room temperature using the patch-clamp amplifier Axopatch 200B (Axon Instruments Inc.). All registration is conducted at the chosen frequency of 10 kHz and using a lowpass filter at 400 Hz. "Patch-pipettes were made of glass Corning Kovar Sealing No. 7052 (World Precision Instruments, Inc., Sarasota, Finland) and they had a resistance of 5-8 Mω when filled with the extracellular solution. ΔF508-CFTR was activated after excision by EXT the effect of 1 mm Mg-ATP and 75 nm of camp-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI). After stabilization of the activity of the channel "patch" was subjected to perfusion, using the system to microperfusion gravity regime. The inflow was placed next to the "patch", reaching full replacement solution for 1-2 seconds. To preserve the activity of ΔF508-CFTR during rapid perfusion, the rinse solution was added nonspecific fosfatazy inhibitor F-(10 mm NaF). In these conditions, check the activity feed was maintained constant throughout the duration of the "patch"-registration (up to 60 minutes). Currents caused by movement of a positive charge from the intracellular solution to the extracellular solution (displacements of the anions in the opposite direction), was positive currents. The pipette potential (Vp) maintained at 80 mV.

Channel activity was analyzed on the basis of membrane "patches", containing ≤2 active channels. The maximum number of simultaneous discoveries to determine the number of active channels during the experiment. To determine the amplitude of the current of one channel, data recorded after 120 seconds of activity of ΔF508-CFTR, were filtered offline at 100 Hz and then used to build the histograms of the amplitude at all points, which leveled by multicausal functions using programme the e provision of Bio-Patch Analysis (Bio-Logic Comp. France). Full microscopic current and the probability of opening (Pabout) was determined after 120 seconds for channel activity. Paboutwas determined using the software Bio-Patch, or the ratio Rabout=I/i(N), where I=weak current, i=current amplitude of one channel and N=number of active channels in the patch".

Solutions

The extracellular solution (in mm):
NMDG (150), aspartic acid (150), CaCl2(5), MgCl2(2) and HEPES (10) (pH brought up to 7.35 with TRIS-base).
Intracellular solution (in mm):
NMDG-Cl (150), MgCl2(2), EGTA (5), TES (10) and TRIS-base (14) (pH brought up to 7.35 with HCl).

Cell culture

For excision of the membrane patch-clamp-registrations used murine NIH3T3 fibroblasts. Cells kept at 37°C in an atmosphere with 5% CO2and a humidity of 90% modified by way of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 × NEAA, β-ME, 1 × pen/strep, and 25 mm HEPES, flasks for cell culture area 175 cm2. For registrations one channel, 2500-5000 cells were sown on covered the Oli-L-lysine glass cover and were cultured for 24-48 hours at a temperature of 27°C before use.

Compounds according to the invention are useful as modulators of Transporter ATP-binding cassettes. The following table 3 presents ES and the relative effectiveness of some embodiments of table 1.

The following table 3 presents the following values:

AS: “+++”means <10 μm; “++” means from 10 μm to 25 μm; “+” means from 25 μm to 60 μm.

% Efficiency: “+” means <25%; “++” means from 25% to 100%; “+++” indicates >100%.

Table 3
Conn. No.AS (µm)% ActivityConn. No.AS (µm)% ActivityConn. No.AS (µm)% Activity
1+++++17+++++34+++++
2+++++18+++++35+++++
3+++++19+++36+++++
4+++++20+++++37+++++
5++++21++38+++++
6++++++22++++39++++
7 ++23+++++40++
8+++++24++41+++++
9++25++++42+++++
10+++++26+++++43+++++
11+++++28++++44++++
12 +++++29++++46++++
13+++++30+++++47+++++
14+++++31+++++48+++++

15++++32+++++49+++++
16+++++33+++++ 50+++++
51+++++95++++140+++++
52+++++96+++++141++++
53++97+++++142+++++
54++98+++++143+++++
55++99++++++++++
56+++++100++145+++++
57+++++101++146++
58+++++102++++147+++++
59++++++103++++++148+++++
60+++++104+++++ 149++++
61+++++105++++150+++++
62+++++106++151+++++
63+++++107++++152++
64++108+++++153+++++
65+++++109++++ 154++
66++++110++155++
67+++++111+++++156+++++
68+++++112+++++157+++++
69+++++113+++++158+++++
70++++114+++++ 159++++
71+++++115+++++160+++++
72+++++116+++++161+++++
73++117+++++162++
74++118+++++163++++
75++119+++++ 164+++++
76+++++120++++165++
77+++++122++166+++++
78++123+++++167++++
79+++++124++++++168++
80+++++125++++ 169++++
81++126+++++170++
82+++++127+++++171+++++
83+++++128++172+++++
84++129++++173++
85+++++130++++++++++
86++++131+++++175++++
87+++++132++176+++++
88+++++133++++177++++++
89++134+++++178+++++
90+++++135++++++ 179++
91+++++136+++++180+++++
92+++++137+++++181+++++
93+++++138+++++182+++++
94+++++139+++++183+++++
184++228+++++++++
185++229+++++273++++++
186+++++230++++274+++++
187+++++231+++++275++++
188+++++232++++276++++

189+++++ 233+++277++++++
190+++++234+++++278+++++
191++235+++++279+++++
192++236+++++280++
193++++237+++++281+++++
194+ +238+++++282+++++
195++239+++++283++++++
196+++++240+++++284++++
197++241++++285+++++
198+++++242+++++286++++++
199+++ ++243++++287+++++
200++++244+++++288+++++
201+++245+++++289+++++
202+++++246+++++290+++++
203+++++247+++++291+++++
204+++ ++248++++292+++++
205+++++249++++293+++++
206+++++250++294++++
207+++++251+++++295+++++
208+++++252++++296++++
209++ ++253+++++297+++++
210++++254+++++298+++++
211+++++255+++++299+++++
212++256++300+++++
213+++++257+++++301++
214++ ++258+++++302++++
215+++++259+++++303++++
216++260+++++304+++++
217++++261+++++305++++++
218+++++262+++++306++++++
219+ +263+++++307+++++
220+++++264++++308++++
221+++++265+++++309++
222++++266+++++310+++++
223+++++267+++++311+++++
224+++ ++268++++312+++++
225+++++269+++++313+++++
226+++++270+++++314+++++
227++271+++++315+++++
316++++361++++++405+++++
317+++ ++362+++++406+++++
318++++363++++++407+++++
319+++++364+++++408+++++
320+++++365++++409+++++
321+++++366+++++410++++++
322+++ ++367+++++411+++++
323+++++368+++++412+++++
324+++++369+++413+++++
325+++++370+++++414++
326++++371+++++415+++++
327+++ ++372+++++416+++++

328++373+++++417+++++
329++++374++418++++
330+++++375+++++419++
331++376++420 +++++
332+++++377++++421+++++
333+++++378++++423+++++
334++++379++++424+++++
335++380+++++425+++++
336+++++381+++++426 +++++
337+++++382+++++427+++++
338++++383+++++428+++++
339+++++384+++++429+++++
340+++++385+++++430+++++
341+++++386+++++431 ++++
342+++++387+++++432+++++
343++++388+++++433+++++
344+++++389+++++434+++++
345+++++390++435+++++
346+++++391+++++436 +++++
347++++392++437++
348+++++393+++++438+++++
350+++++394++439+++++
351+++++395+++++440+++++
352+++++396++++441 +++++
353+++++397+++++442++
354+++++398++++443++
355+++++399+++++444+++++
356+++++400++445++++++
357+++++401+++++446 ++
358+++++402++++447++++
359++++403+++++448+++++
360+++++404+++++449+++++
450++++462+++++474++
451+++++463+++++476++
452+++++464+++++477++
453+++++465+++++478+++++
454++466+++++479+++++
455+++++467++480++
456+++++468++481 +++++
457++469+++++482++++
458+++++470+++++483+++++
459+++++471+++++484+++++
460+++++472+++++485+++++
461+++++473++++

1. A method of treating or attenuating the severity of the disease in a patient, where the disease selected from cystic fibrosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), a disease of "dry eyes", including the introduction of a specified patient an effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide, having the chemical structure:

2. The method according to claim 1, where the disease is cystic fibrosis.

3. The method according to claim 1, where the disease is COPD.

4. The method according to claim 2, where the patient has the mutation class III mutation class IV or mutation of class V of cystic fibrosis transmembrane conductance regulator (CFTR).

5. The method according to claim 4, where the patient has the mutation class III of cystic fibrosis transmembrane conductance regulator.

6. The method according to claim 4, where the patient has a mutation of cystic fibrosis transmembrane conductance regulator, which is a mutation violated the regulation, mutation discovery of membrane channel mutation altered conductivity or mutation reduced synthesis.

7. The method according to claim 6, where this mutation is a mutation of the opening of the membrane channel.

8. The method according to claim 2, where the patient has cystic fibrosis regulator transmembrane the conductivity with the G551D mutation.

9. The method of claim 8, where the patient is homozygous for the G551D mutation.

10. The method of claim 8, where the patient is heterozygous for G551D mutation.

11. The method according to claim 2, where the patient possesses a cystic fibrosis transmembrane regulator conductivity with ΔF508 mutation.

12. The method according to claim 11, where the patient is homozygous for the ΔF508 mutation.

13. The method according to claim 11, where the patient is heterozygous for ΔF508 mutation.

14. A method of treating or attenuating the severity of cystic fibrosis in a patient who manifests residual CFTR activity, including the stage of introduction of the indicated patient a pharmaceutical composition comprising N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.

15. A method of treating or attenuating the severity of cystic fibrosis in a patient who manifests residual CFTR activity, where this residual CFTR activity is induced or enhanced with the use of pharmacological methods, including the stage of introduction of the indicated patient a pharmaceutical composition comprising N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.

16. A method of treating or attenuating the severity of cystic fibrosis in a patient who manifests residual CFTR activity, where this residual CFTR activity increases with the use of pharmacological method, where the specified pharmacologists who definition method has the effect of increasing the number of CFTR, located on the cell surface, including the stage of introduction of the indicated patient a pharmaceutical composition comprising N-(5-hydroxy-2, 4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazine derivatives represented by general formula (I): 0, where R1 is a hydrogen atom; C1-C6 alkyl; COR5; SO2R5; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10; m assumes values from 1 to 6; n assumes values from 2 to 6; R2 is phenyl; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenylpyridine or a benzene ring condensed with a saturated or unsaturated monocyclic heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, other than indole, R3 is methyl or ethyl; R4 and R′4 are identical or different and denote a hydrogen atom; a halogen atom; C1-C6 alkyl; NR7R8; SO2Me; as well as stereoisomers, salts and solvates thereof, for therapeutic use and which are capable of inhibiting 11β-HSD1 on an enzymatic and cellular level.

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining N-(1,5,3-dithiazonan-3-yl)amides of general formula (1): where R=p-C5H4N (a), (CH3)3CO (b), m-C5H4N (c), which consists in the following: hydrazides of general formula RC(O)NHNH2 (R=mentioned above) undergo interaction with 1,4-butanedithiol, preliminarily mixed at 20°C with water formaldehyde solution, in presence of catalyst crystallohydrate of copper chloride CuCl2·2H2O with molar ration 1,4-butanedithiol: CH2O : RC(O)NHNH2 : CuCl2·2H2O = 10:20:10:(0.3-0.7) at 75-85°C and atmospheric pressure for 44-52 h.

EFFECT: elaborated is method of obtaining novel compounds, which can be applied as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-[methylenebis(1,4-phenylene)]-, 3,3'-[oxybis(1,4-phenylene)]- and 3,3'-(3,3'-dimethoxybiphenyl-4, 4'-diyl)-bis-1,5,3-dithiazepinanes of general formula (1): R=4-C6H4-CH2-C6H4-4/, 4-C6H4-O-C6H4-4/, 4-H3COC6H3-C6H3OCH3-4/ which consists in the following: arylamines [diaminodiphenylmethane, diaminodiphenyloxide, dimethoxybenzidine] undergo interaction with N-tert-butyl-1,5,3-dithiazepinane in presence of catalyst Sm(NO3)3·6H2O in argon atmosphere with molar ratio arylamine:N-tert-butyl-1,5,3-dithiazeoinane: Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) at temperature ~20°C in system of solvents ethanol-chloroform for 2.5-3.5 h.

EFFECT: increased efficiency of applying compound as antibacterial, antifungal and antiviral agents, biologically active complexants, selective sorbents and extractants of precious metals, special reagents for suppressing bacterial vital activity in different technical media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 3,3'-[oxa(thia)alkane-α,ω-diyl]-bis-1,5,3-dithiazepinanes of general formula (1) R=CH2CH2OCH2CH2, (CH2CH2O)2CH2CH2, (CH2CH2S)2 , which consists in the following: oxa(thia)alkane-α,ω-diamine (3-oxapentane-1,5-diamine, 3,6-dioxaoctane-1,8-diamine, 3,4-dithiahexane-1,6-diamine) undergoes interaction with 1-oxa-3,6-dithiacycloheptane in ethanol-chloroform system of solvents in argon medium in presence of catalyst SmCl3·6H2O with molar ratio oxa(thia)alkane-α,ω-diamine: 1-oxa-3,6-dithiacycloheptane: SmCl3·6H2O = 10 : 20 : (0.3-0.7) at room (~20°C) temperature for 2.5-3.5 h.

EFFECT: elaborated is method of obtaining novel compounds which can be applied as selective sorbents and extractants of precious metals, preparations for protection of leather, fur, fabrics against biodamage, biologically active substances with respect to various microorganisms and sulfate-reducing bacteria.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely, to method of obtaining N-(1,5,3-dithiazonan-3-yl)amides of general formula (1) where R=p-C5H4N (a), (CH3)3CO (b), m-C5H4N (c), which consists in the fact, that N1,N1,N8,N8-tetramethyl-2.7-dithiaoctane-1.8-diamine is subjected to interaction with hydrazide of general formula RC(O)NHNH2 [R=upper said] in presence of catalyst samarium nitrate crystalhydrate Sm(NO3)3·6H2O, at molar ratio N1,N1,N8,N8-tetramethyl-2.7-dithiaoctane-1.8-diamine: RC(O)NHNH2 : Sm(NO3)3·6H2O = 10 : 10 : (0.3-0.7) at temperature 75-85°C and atmospheric pressure in mixture of solvents ethyl alcohol-chloroform for 20-28 h.

EFFECT: method of obtaining novel compounds, which can be applied as biologically active compounds, selective sorbents and extractants of noble and precious metals, is developed.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula or , where Ar1 represents phenyl group, optionally substituted with one or several identical or non-identical halogen atoms; R1 represents hydrogen atom; R4, R5, R6a, R6b represent hydrogen atoms; Y, Z independently represent linear C1-4 alkylene group, optionally substituted with one linear C1-4 alkyl group; Ar2 stands for condensed with benzene 5-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, substituted with one linear C1-4 alkyl group, or derivative of 5- or 6-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, condensed with heteroaromatic 6-memebered ring, containing one or two nitrogen atoms, substituted with one linear C1-4 alkyl group, linear C1-4 alkoxygroup or group -NR7R8, where R7 and R8 independently stand for hydrogen atom, linear or branched C1-4 alkyl group, or R7 and R8 together with nitrogen atom form group of general formula , where R2, R3 represent linear C1-4 alkyl groups, A stands for group -CHR12, oxygen atom or group -NR9, where R12 and R9 stand for hydrogen atom or linear C1-4 alkyl group, m has value 1 or 2, n has value 1 or 2, o has value 0 or 1, p has value 0 or 1, Q stands for group -O-, group -N--H or group -N--CO-R10, where R10 stands for linear C1-4 alkyl group or -NH-R11 group, where R11 represents linear C1-4 alkyl group; and to their salts. Invention also relates to methods of obtaining therein and to based on them pharmaceutical composition, possessing antagonistic activity with respect to receptor CCR3.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions, which can be applied in medicine for obtaining medication, intended for treating asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory intestinal diseases, ulcerous colitis, Crohn's disease, allergic conjunctivitis, multiple sclerosis or HIV-infection and AIDS-associated diseases.

14 cl, 3 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to compounds of the general formula I , and its pharmaceutically acceptable salts, where R1, R2 and R3 represent hydrogen, D, E, G, J and L represent CH; n equals to an integer number 1 or 2; W represents oxygen; R4 represents C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, where the said C1-6alkyl is possibly substituted with one substituent, independently selected from a group, consisting of hydrogen, C1-4alkyl, C3-6cycloalkyl and C3-6cycloalkenyl; Y represents carbonyl; R5 represents C1-6alkyl, C1-6alkoxy or C3-4heteroaryl, which represents a heterocyclic aromatic ring, containing 1-2 heteroatoms, selected from nitrogen and oxygen. The invention also relates to a pharmaceutical composition based on a formula I compound, application of the formula I compound and a method of prevention, treatment of alleviation of a disease, associated with abnormal angiogenesis.

EFFECT: obtained are novel compounds useful in treatment of diseases associated with unregulated angiogenesis, such as cancer, as well as skin and eye diseases.

13 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using an oxadiazolyl compound of the formula I

,

wherein R1 and R2 mean hydrogen; X means a methylene group; Y represents an oxygen atom; n represents an integer of 0, 1, 2 or 3, and m represents an integer of 0 or 1; R3 means a group of N-oxide pyridine according to the formula B which is attached as shown by an unmarked bond: ,

wherein R4, R5, R6 and R7 are the same or different and mean hydrogen, lower alkyl, halogen, haloalkyl, trifluoromethyl; the term "alkyl" means carbon chains, unbranched or branched, containing one to six carbon atoms; the term "halogen" means fluorine, chlorine, bromine or iodine; or its pharmacologically acceptable salt for preparing a drug for preventing or treating diseases related to the central and peripheral nervous system, wherein the above drug is administered according to a dosage regimen characterised by a dosage rate within approximately twice a day to approximately once every two days.

EFFECT: optimising the dosage regimen.

84 cl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2-amino-5,5-difluoro-5,6-dihydro-4H-[1,3]oxazin-4-yl)-phenyl]-amide derivatives of formula I, having BACE1 and/or BACE2 inhibiting activity, pharmaceutical compositions based thereon and use thereof as therapeutically active substances. In general formula

,

R1 is selected from a group consisting of i) a 5-6-member heteroaryl containing 1-2 heteroatoms selected from nitrogen and oxygen, and ii) 5-6-member heteroaryl containing 1-2 heteroatoms selected from nitrogen and oxygen, substituted with 1-4 substitutes, individually selected from amide, cyano, cycloalkyl, cycloalkyl-lower alkynyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkoxy, halogen atom, lower haloalkoxy, lower haloalkyl, lower alkyl and nitro; iii) lower alkyl; iv) lower alkyl substituted with 1-5 substitutes individually selected from a halogena tom and hydroxy; v) lower alkenyl substituted with furanyl; vi) cycloalkyl substituted with 1-4 substitutes individually selected from a halogen atom, lower haloalkyl; R2 is selected from a group consisting of i) hydrogen atom, ii) halogen atom, R3 is a lower alkyl; R4 is selected from a group consisting of i) a hydrogen atom, and ii) lower alkyl; R5 is selected from a group consisting of i) a hydrogen atom, and ii) lower alkyl; n equals 0, 1 or 2.

EFFECT: active compounds in the present invention are useful in therapeutic and/or preventive treatment, for example, of Alzheimer's disease and type 2 diabetes.

29 cl, 10 tbl, 83 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of compounds of formula I, where R1 represents hydrogen atom, C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl, substituted with halogen atom, C1-7-alkoxy, substituted with halogen atom, halogen atom, cyano, nitro, hydroxy, C(O)O-C1-7-alkyl, S(O)2-C1-7-alkyl, C(O)OCH2-phenyl, OCH2-phenyl, tetrazol-1-yl, phenyl, possibly substituted with halogen atom, or represents phenyloxy, possibly substituted with halogen atom, or represents benzyl, possibly substituted with halogen atom, or represents benzyloxy, possibly substituted with halogen atom; in case, when n>1, R1 substituents can be similar or different; X represents -O-(CH2)2-, -O-CHR"-CH2-, -O-CH2-CHR', -O-CR"2-CH2-, -(CH2)2-CHR'-, -CHR'-(CH2)2-, -CR"2-(CH2)2-, -CH2-CHR'-CH2-, -CH2-CR"2-CH2-, -CHR"-O-CH2-, -CR"2-O-CH2-, -CF2(CH2)2-, -CR"2-CH2-, -SiR"2-(CH2)2-, -S-(CH2)2-, -S(O)2-(CH2)2-, -(CH2)4-, -CH2-O-(CH2)2-, formula (a) or (b), where m has value 0, 1, 2 or 3; R' represents C1-7-alkyl, C1-7-alkoxy or C1-7-alkyl, substituted with halogen atom; R" represents C1-7-alkyl or C1-7-alkyl, substituted with halogen atom; R2 represents hydrogen atom or C1-7-alkyl; Y represents phenyl, naphthyl, C3-6-cycloalkyl or pyridin-2- or 3-yl, pyrimidin-2-yl or quinolin-6 or 7-yl; n has value 1, 2 or 3; or pharmaceutically acceptable salt of acid attachment in manufacturing medication for treatment anxiety disorders, bipolar disorder, stress-induced disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson disease, neurodegenerative disorders, Alzheimer's disease, epilepsy and migraine. Invention also relates to compounds of formula I, where R1 represents hydrogen atom, C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl, substituted with halogen atom, C1-7-alkoxy, substituted with halogen atom, halogen atom, cyano, nitro, hydroxy, C(O)O-C1-7-alkyl, S(O)2-C1-7-alkyl, C(O)OCH2-phenyl, OCH2phenyl, tetrazol-1-yl, phenyl, possibly substituted with halogen atom, or represents phenyloxy, possibly substituted with halogen atom, or represents benzyl, possibly substituted with halogen atom, or represents benzyloxy, possibly substituted with halogen atom; in case when n>1, R1 substituents can be similar or different; X represents -(CH2)2-CHR', -CHR'-(CH2)2-, -CR"2-(CH2)2-, -CH2-CHR'-CH2-, -CH2-CR"2-CH2-, -CF2(CH2)2-, formula (a), where m has value 0, 1, 2 or 3; R' represents C1-7-alkyl, C1-7-alkoxy or C1-7-alkyl, substituted with halogen atom; R" represents C1-7-alkyl or C1-7-alkyl, substituted with halogen atom; R2 represents hydrogen atom or C1-7-alkyl; Y represents phenyl, naphthyl, C3-6-cycloalkyl or pyridin-2- or 3-yl, pyrimidin-2-yl or chinolin-6 or 7-yl; n has value 1, 2 or 3; or pharmaceutically acceptable salt of acid attachment. Also claimed are methods of obtaining formula (I) compounds.

EFFECT: 4,5-dihydro-oxazol-2-ylamine derivatives for treatment of diseases, associated with biological function of receptors, associated with trace amines.

22 cl, 1 tbl, 176 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

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