Modulators of atp-binding cassette transporters

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula A-I, where G1 stands for hydrogen atom or R'; G2 stands for halogen atom, CN, CF3, isopropyl or phenyl, where said isopropyl or phenyl is optionally substituted with up to three substituents, independently selected from WRW; G3 stands for isopropyl or (C3-C10)cycloaliphatic ring, where said G3 is optionally substituted with up to three substituents, independently selected from WRW; W stands for bond or (C1-C6)alkylidene chain, where up to two methylene groups of W residue are optionally and independently substituted for -CO2- or -O-; RW stands for R'; and R' is independently selected from hydrogen atom or (C1-C8)alkyl group. Invention also relates to method of obtaining compound of formula FF (stands for bromine atom, fluorine atom or tret-butyl; G3 stands for tret-butyl) by hydrogenation of respective nitrocompound in presence of palladium catalyst and to methods of obtaining C-9 and 433 compounds, which include stage of hydrogenation of respective nitrocompound in presence of palladium catalyst as intermediate stage.

EFFECT: formula A-I compounds, which are intermediate for synthesis of modulators of ATP-binding cassette ("ABC") transporters.

35 cl, 4 tbl, 80 ex

 

Cross-reference to related applications

Under section 35 U. S. C. § 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 contents of each of the foregoing applications is incorporated herein by reference.

The technical field to which the invention relates

The present invention relates to modulators of transporters of the ATP-binding cassette ("ABC") or fragments thereof, including mucoviscidosis transmembrane regulator conductance ("FTR"), compositions containing them and methods for their preparation. The present invention also relates to methods of treating diseases mediated by the ABC-Transporter, with the use of such modulators.

Background of the invention

ABC Transp�rtery 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 cellular adenosine triphosphate (ATP) due to their specific activities. Some of these transporters are disclosed as protein resistance to many drugs (like glycoprotein MDR1-P or squirrel resistance to numerous drugs, MRP1), defending malignant cancer cells against chemotherapeutic agents. Currently identified 48 ABC transporters and on the basis of their sequence identity and function they are divided into 7 families.

ABC Transporters regulate many important physiological functions in the body and provide protection against the harmful compounds present in the environment. As a result, they represent important potential targets for therapeutics 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-�of ransporter, usually associated with disease, is a camp/ATP-mediated transmembrane protein that performs the function of anion channel, CFTR. CFTR is expressed in many cell types, including absorbent and secretory epithelial cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including the tissue of the airway and tissue of the digestive tract. CFTR is composed of approximately 1480 amino acids that encode a protein, replenishing tandem repeat of 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 cellular transport.

Encoding the CFTR gene was 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)). A defect in this gene causes mutations in CFTR cause cystic fibrosis ("CF"), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one out of every 2,500 children in the United States. Of the total US population up �about 10 million inhabitants contain one copy of the defective gene without obvious pathological effects. In contrast, individuals with two copies of the associated with the CF gene suffer from debilitating and fatal effects of CF, including chronic lung disease.

In patients with cystic fibrosis mutations in CFTR endogenously 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 the accompanying microbial infections that ultimately cause death of patients with CF. In addition to respiratory disease, patients with CF typically suffer from gastrointestinal problems and pancreatic insufficiency, a consequence of which, if left untreated, is death. Moreover, most men with cystic fibrosis infertile and women with cystic fibrosis decreases fertility. In contrast to the severe effects of two copies of the associated with the CF gene, individuals with one copy of the CF associated gene exhibit increased resistance to cholera and to dehydration arising from diarrhea, which may explain the relatively high frequency of the CF gene in the population.

By sequencing the CFTR gene of CF chromosomes revealed a variety of 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 deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and it is usually referred to as ΔF508-CFTR. This mutation occurs in approximately 70% of cases of cystic fibrosis and is associated with serious diseases.

The deletion of residue 508 in ΔF508-CFTR prevents the formed protein from the correct folding. This leads to the inability of the mutant protein to exit the ER and directed transport in the plasma membrane. As a result, the number of channels present in the membrane, becomes much smaller than that observed in cells expressing CFTR wild type". In addition to worsened the directed transportation of 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 ions through the epithelium, leading to defective transport of ions and fluids (Quinton P. M., FASEB J., 4:2709-2727 (1990)). However, studies have shown that reduced the number of ΔF508-CFTR in the membrane are functional, although to a lesser extent than CFTR "di�wow type" (Dalemans et al., Nature Lond., 354:526-528 (1991); Dennung et al., supra; Pasyk Foskett, J. Cell. Biochem., 270:12347-12350 (1995)). In addition to ΔF508-CFTR, other disease caused by mutations in CFTR that result in defective directional transport, defective synthesis and/or the opening of a defective membrane channel can be adjusted in the direction of boost or attenuation due to changes in the secretion of anions and reducing the progression and/or severity of the disease.

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

These elements act together to achieve directed transport through the epithelium due to their selective expression and localization in the cell. Adsorption of chloride is due to the coordinated activity of ENaC and CFTR present at the apical membrane, and Na+-K+-ATPase pump and Cl--channels expressed on the basolateral cell surface. Secondary active transport of chloride from the luminal region leads to intracellular accumulation x�orida, which can then passively leave through the Cl-channels, leading to transport of infection. The system of Na+/2Cl-/K+-cotransporter, Na+-K+-ATPase pump and the basolateral membrane K+-channels on the basolateral surface and CFTR in the luminal region coordinate the secretion of chloride through CFTR in the luminal region. Since the water is, probably, she never actively transported, its flow through the epithelium depends on very small transepithelial osmotic gradients generated by the influx 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 diseases and other diseases associated with protein folding mediated CFTR. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), a disease of dry eye and sjögren's syndrome. COPD is characterized by respiratory failure, which is progressive and not fully reversible. Respiratory disorder caused by hypersecretion of mucus, emphysema and bronchiolitis. Activators of mutant CFTR or CFTR wild type" provide for possible treatment of mucus hypersecretion and impaired clearance of ciliated epithelium, which is common in COPD. Concrete�, increasing the secretion of anions through CFTR may facilitate the transport of fluid to the surface of the respiratory tract for the hydration of mucus and optimize the viscosity priciliano fluid. This should lead to increased clearance of ciliated epithelium and weakening of the symptoms associated with COPD. Disease dry eye is characterized by a decrease in the allocation of the lacrimal fluid and atypical of the tear film lipid, protein and mucinosa profiles. There are many causes of the disease dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies and diseases such as cystic fibrosis and Sjogren's syndrome. Increasing the secretion of anions at the expense of CFTR will enhance the transport of fluid from the corneal endothelial cells and the secretory glands around the eye to increase corneal hydration. This should help to reduce the symptoms associated with the disease dry eye. Sjogren's syndrome is an autoimmune disease in which the immune system affects vlagopoulos glands throughout the body including eyes, mouth, skin, tissue of the respiratory tract, liver, vagina, and intestine. Symptoms include disease dry eye, disease of the mouth and vagina, and lungs. Disease targetbase with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis/dermatomyositis. Suppose that the transport of the defective protein causes the disease, treatment options are limited. Modulators of CFTR activity can hydrational different organs affected by disease, and help reduce the associated with the disease symptoms.

As discussed above, it is believed that the deletion of residue 508 in ΔF508-CFTR prevents the protein formed from proper folding, resulting in the inability of this mutant protein to exit the ER and directed transport in the plasma membrane. As a result, in the plasma membrane there are an insufficient number of Mature protein and significantly reduced 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 for a large number of other isolated and inherited diseases. There are two ways, according to which may affect the function of ER-mechanism: or at the expense of loss of communication with ER export of the proteins leading to degradation, or by the ER accumulation of these defective, with abnormal folding of proteins [Aridor M. et al., Nature Med.,5(7), 745-751 (1999); Shastry, B. S. et al., Neurochem. International,43, 1-7 (2003); Rutishauer J. et al., Swiss Wkly Me, 132, 211-222 (2002); Morello, J. P. et al., TIPS,21, 466-469 (2000); Bross P., 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 of ΔF508-CFTR as discussed above), hereditary emphysema (due to A1-antitrypsin; 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 hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysaccharidosis (due to lysosomal enzyme processing), Sandhoff disease/Tay-Sachs (due to β-hexosaminidase), 's disease crigler/Najjar type II (due to UDP-glucuronyl-seatransport), polyendocrinopathy/hyperinsulemia, diabetes mellitus (due to insulin receptor), macrosomia of Larona (caused by hormone receptor growth), lack of 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 A1-antitrypsin; PiZ-�variant b), congenital hyperthyroidism, osteopathies (due to procollagen type I, II, IV), hereditary hypofibrinogenemia (due to fibrinogen), adrenocorticotropic hormone deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neurophysiology DI (due to vasopressin hormone/V2-receptor), nephrogenic DI (due to aquaporins (II), the syndrome of Charcot-Marie-Tooth syndrome (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, pick's disease; some neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonic dystrophy, as well as the spongiform enteropathy, such as hereditary disease Creutzfeldt-Jakob disease (caused by a defect in the processing of prion protein), Fabry disease (due to lysosomal α-galactosidase A) and the syndrome of Straussler-Sheinker (caused by a defect of processing Prp).

In addition to the high level of regulation of CFTR activity, decreased secretion of anions by CFTR modulators may be useful for the treatment �ecretary diarrhoea in which case the epithelial transport of water danger increases as a result of the activated amplifying the secretion of means of transport of chlorides. The mechanism involves the increase of camp and stimulation of CFTR.

Although there are numerous causes of diarrhea, the major consequences of diarrhoeal diseases, resulting from excessive chloride transport are common to all types of diarrhea include dehydration, acidosis, impaired growth and death.

Acute and chronic diarrhea represent a significant health problem in many areas of the world. Diarrhea is a significant factor in malnutrition and the leading cause of death (5,000,000 deaths / year) in the case of children aged less than five years.

Secretory diarrheas are also a dangerous condition in patients with the acquired immunodeficiency syndrome (AIDS) and chronic inflammatory intestinal disease (IBD). 16 million travelers to developing countries from industrialized States find diarrhea, and the severity and incidence of diarrhea vary depending on the country and area of travel.

Diarrhea in farm animals and Pets such as cows, pigs and horses, sheep, goats, cats and dogs, is the leading cause of death of these animals. Diarrhea can occur olubugo significant changes such as weaning or physical action, as well as in response to a variety of bacterial or viral infections and generally occurs in the first five hours of life of the animal.

The most common of causing diarrhoea bacteria is enterotoxigenic E. coli (ETEC) having polesny the K99 antigen. The usual viral causes of diarrhea are rotavirus and coronavirus. Other infectious agents are, among others, Cryptosporidium, giardia lamblia and Salmonella spp.

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

Therefore there is a need for modulators of the activity of the ABC-Transporter and compositions containing them, which can be used to modulate activity of the ABC-Transporter in the plasma membrane of a mammal.

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

There is use if�need for methods of modulating the activity of the ABC-Transporter in ex vivo the plasma membrane of a mammal.

There is a need for modulators of CFTR activity that 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 the plasma membrane of a mammal.

Brief description of the invention

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

or their pharmaceutically acceptable salts, where R1, R2, R3, R4, R5, R6, R7and Ar1generally and in classes and subclasses described below.

These compounds and pharmaceutically acceptable compositions are useful for treating or reducing the severity of several 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 hypercholesterolemia, x�lumichrome type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysaccharidosis, Sandhoff disease/Tay-Sachs, a disease crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes mellitus, macrosomia of Larona, lack of teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Tooth syndrome, a disease of 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, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonic dystrophy, as well as spongiform encephalopathies, such as congenital disease Creutzfeldt-Jakob disease, Fabry disease, syndrome Straussler-Sheinker, D, disease, dry eye and Sjogren's syndrome.

Detailed description of the invention

I. General description of compounds of the invention

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

or their pharmaceutically acceptable salts, where:

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

W is a bond or optionally substituted (C1-C6)alkylidene chain, where up to two methylene groups of the residue W is optionally and independently replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR', -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -CNR'-, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -SO2-, -NR'-, -SO2NR'-, -NR'SO2or NR'SO2NR'-;

RWindependently means R', halogen, NO2, CN, CF3or OCF3;

m is 0-5;

each of R1, R2, R3, R4and R5independently 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 not�avisio replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR', -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -CNR'-, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -SO2-, -NR'-, -SO2NR'-, -NR'SO2or NR'SO2NR'-;

RXindependently means R', a halogen atom, NO2, CN, 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 hydrogen atom or optionally substituted groups selected from (C1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatom, 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 radicals 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 hetero, independently selected from nitrogen atoms, oxygen or sulfur.

According� some other implementation options, provides compounds of formula (I):

or their pharmaceutically acceptable salts, where:

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

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

RWindependently means R', a halogen atom, NO2, CN, CF3or OCF3;

m is 0-5;

each of R1, R2, R3, R4and R5independently 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 not necessarily and independently replaced with n� -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR', -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -CNR'-, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -SO2-, -NR'-, -SO2NR'-, -NR'SO2or NR'SO2NR'-;

RXindependently means R', a halogen atom, NO2, CN, CF3or OCF3;

R6means a hydrogen atom, CF3, -OR', -SR', or optionally substituted (C1-C8aliphatic group;

R7means hydrogen atom or (C1-C6aliphatic group, optionally substituted-S-RX;

R' is independently selected from hydrogen atom or optionally substituted groups selected from (C1-C8aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatom, 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 radicals 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 hetero, independently selected from nitrogen atoms, oxygen Il� sulfur;

provided that:

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

(ii) when R1, R2, R3, R5, R6and R7denote hydrogen and R4means a methoxy group, then Ar1is not 2-fluorophenyl or 3-fluorophenyl;

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

(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, denote a methylenedioxy group, then Ar1is not 4-chlorophenyl, bromperidol, 4-nitrophenyl, 4-carbomethoxyamino, 6-ethoxybenzothiazole-2-yl, 6-carbomethoxyamino-2-yl, 6-halogenmethyl-2-yl, 6-nitrobenzothiazole-2-yl or 6-titanomagnetite-2-silt;

(vi) when R1, R4, R5, R6and R7mean hydrogen, R2and R3taken together, denote a methylenedioxy group, then Ar1is not 4-substituted phenyl, where the abovementioned Deputy is-SO2NHRXX, RXXmeans 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 R7denote hydrogen and R4mean CF3, Omagh, chlorine atom, SCF3or CF3then Ar1is not 5-methyl-1,2-oxazol-3-yl, thiazol-2-yl, 4-fluorophenyl, pyrimidine-2-yl, 1-methyl-1,2-(1H)-pyrazol-5-yl, pyridin-2-yl, phenyl, N-methylimidazole-2-yl, imidazol-2-yl, 5-methylimidazole-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 pyrimidine-2-yl, 4,6-dimethylpyrimidin-2-yl, 4-methoxy-6-methyl-1,3,5-triazine-2-and�Ohm, 5-bromopyridin-2-yl, pyridin-2-yl or 3,5-dichloropyridine-2-silt;

x) when R1, R2, R3, R4, R5and R7each means a hydrogen atom, R6means hydroxyl, then Ar1is 2,6-dichloro-4-aminosulfonyl;

(xi) when R2or R3means optionally substituted N-piperazin, N-piperidyl or N-morpholinyl, then Ar1not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl or indazole;

(xii) when R2means optionally substituted with cyclohexylamino, then Ar1is not optionally substituted 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 Ar1is not 4,5-dihydro-1,3-thiazol-2-IOM, Tizol-2-yl, or [3,5-bis(trifluoromethyl)-1H-pyrazol-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-fluorophenyl, 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 not 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 R2not an atom of chlorine;

(e) when R1, R2, R4, R5, R6and R7each means a hydrogen atom, then R3not an atom of chlorine;

xvii) when R1, R3, R4, R5, R6and R7each means a hydrogen atom and R2mean CF3or OCF3then Ar1this is not [3,5-bis(trifluoromethyl)-1H-pyrazol-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 with-och2CH2by phenyl, -och2CH2-(2-triftormetilfullerenov), -och2CH2-(6,7-dimethoxy-1,2,3,4-tetrahydro�isoquinoline-2-yl), or substituted 1H-pyrazol-3-yl;

and

xix) excluded the following two connections:

2. Connections and definitions

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

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

The term "CFTR" as used in this description, means mucoviscidosis regulator transmembrane conductance or the mutation which is able to regulatory activity, including, but not limited to, ΔF508-CFTR and G551D-CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/ against CFTR-mutation).

The term "modulating" as used in this description, means increase or decrease due to the measurable amount.

For the purposes of the present invention, the chemical elements are identified in accordance with�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 herein by reference.

As described in this description, the compounds according to the invention can be optionally substituted by one or more substituents as illustrated above in General or in the form of a specific example 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 of the 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 a specified group, the Deputy may be either the same, or in any other position. Combinations of substituents, the performance of the�nye according to the present invention, preferable are those which lead to the formation of stable or chemically possible connection. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions that allowed for their production, 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 that is not substantially altered when kept at a temperature of 40°C or below, in the absence of moisture or other chemically reactive conditions, at least during the 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 which 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 single binding site 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 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-C8)-hydrocarbon or bicyclic or tricyclic (C8-C14) is the hydrocarbon that is completely saturated or which contains one or more elements of unsaturation, but which is not aromatic, that has a single binding site with the rest of the molecule, where any individual ring in the above bicyclic ring system is a 3-7-membered. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkinyl� groups and their "hybrids", such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicycloalkyl (e.g., position), bridging bicycloalkyl, such as norbornyl or [2,2,2]bicycloalkyl, or bridging tricyclohexyl such as adamantyl.

The term "heteroaromatics", as used herein, means aliphatic groups wherein one or two carbon atoms, independently, substituted by one or more oxygen atoms, sulfur, nitrogen, phosphorus or silicon. Heteroaromatics residues may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocyclic", "heterocyclyl", "heterocyclizations" or "heterocyclic" groups.

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 implementation of heterocycl", "heterocyclyl", "geterotsiklicheskikh" or "heterocyclic" includes from three to fourteen ring members, where one or more ring members� represent a heteroatom, independently selected from oxygen atoms, 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; quaternion form of any basic nitrogen or a substitutable nitrogen of the 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 linked to the principal carbon chain through an oxygen atom ("alkoxy") or sulfur atom ("thioalkyl").

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

The term "aryl" used either individually or as part of a larger remnant, as in "aralkyl", "arakaki or "Ari�oxyalkyl", 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 3-to 7-membered. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems, as explained in the 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 3-to 7-membered. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Aryl (including aralkyl, Alcoxy, aryloxyalkyl and the like) or heteroaryl (including heteroalkyl and heteroaromatics, and the like) may contain one or several deputies. Suitable unsaturated substituents at the carbon atom of the aryl �Lee heteroaryl select from a halogen atom; -Ro; -ORo; -SRo; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph) optionally substituted with Ro; -O(Ph) optionally substituted with Ro; -(CH2)1-2(Ph) optionally substituted with Ro; -CH=CH(Ph) optionally substituted with 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 existing independent of Rochoose from a hydrogen atom, an optionally substituted C1-6aliphatic groups, unsubstituted 5-6-membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or-CH2(Ph), or, notwithstanding the definition above, two independent existing Rowithin the same Deputy or different substituents, taken together with the atom(atoms), with which(whom) is associated with each group Roform a 3-8-membered cycloalkyl, heterocyclyl, aryl or hetero�sterile ring having 0-3 heteroatom, independently selected from nitrogen atoms, oxygen or sulfur. Optional substituents in the aliphatic group of Rochoose from the NH2NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, HE, (C1-4aliphatic group), NO2, CN, CO2H, CO2(C1-4aliphatic group), O(halo-C1-4aliphatic group) or halo(C1-4aliphatic group), where each of the above With a1-4aliphatic 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 atom 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 hydrogen atom or optionally substituted C1-6aliphatic group. Optional substituents in the case of the aliphatic group of R* are selected from NH2NH(C1-4aliphatic groups�), N(C1-4aliphatic group)2, halogen atom, C1-4aliphatic group, HE, (C1-4aliphatic group), NO2, CN, CO2H, CO2(C1-4aliphatic group), O(halo-C1-4aliphatic group) or halo(C1-4aliphatic group), where each of the above With a1-4aliphatic groups of R*is unsubstituted.

Optional substituents at the nitrogen atom non-aromatic heterocyclic ring is 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, an 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 heteroatom independently selected from oxygen atoms, nitrogen or sulfur, or, notwithstanding the definition above, two independent existing R+in the same Deputy or different substituents, taken together with the atom (atoms), to�which(whom) is associated with each group R +form a 3-8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatom, independently selected from nitrogen atoms, oxygen or sulfur. Optional substituents in the aliphatic group or the phenyl ring of R+choose from the NH2NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen atom, C1-4aliphatic group, HE, (C1-4aliphatic group), NO2, CN, CO2H, CO2(C1-4aliphatic group), O(halo-C1-4aliphatic group) or halo-C1-4aliphatic group, where each of the above With a1-4aliphatic groups of R+is unsubstituted.

The term "alkylidene chain" refers to linear or branched carbon chain that may be fully saturated or comprises one or more elements of unsaturation and has two places 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 joined in one and the same carbon atom of the ring to the rest of the molecule.

As detailed above, in some embodiments, two independent existing Ro(or +or any other variable, also defined herein), taken together with the atom (atoms), with whom(which) relates each variable, form a 3-8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatom, independently selected from nitrogen atoms, oxygen or sulfur. Concrete rings that are formed when two independent United existing Ro(or R+or any other variable, also defined in this description), together with the atom(atoms), with whom(which) relates each variable, include, but are not limited to, the following: a) two independent existing Ro(or R+or any other variable, also defined in this description) which are connected to the same atom and are 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-yl, piperazine-1-yl or morpholine-4-ilen group; and b) two independent existing Ro(or R+or any other variable, also defined in this description) which are connected to different atoms and are taken together with both of these atoms, form a ring, for example where a phenyl group is 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:. Should be taken into account that may be obtained from a variety of other rings, when two independent existing Ro(or R+or any other variable, also defined in this description) are combined together with the atom(atoms), with which (whom) each variable is associated, 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 of any ring of the bicyclic ring system:

Unless otherwise noted, also imply that the structures presented in this description, include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z)- and (E) isomers of the double bond and conformational (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�come in the scope of this invention. Unless otherwise stated, all tautomeric forms of 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, compounds of formula (I) can exist as tautomers:

Additionally, unless otherwise indicated, also imply that presented in this description of the structure include compounds that differ only in 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 sensors in biological tests.

3. Description of examples of connections

In some embodiments of the present invention Ar1choose from:

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

And1and A2together represent an 8-14-membered aromatic, bicyclic or tricyclic aryl ring, where each number�CH contains of 0-4 heteroatom, independently selected from nitrogen atoms, oxygen or sulfur.

In some embodiments, A1means optionally substituted 6-membered aromatic ring having 0-4 heteroatom of where the above-mentioned heteroatom means nitrogen. In some embodiments, A1means 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, A1means optionally substituted 5-membered aromatic ring having 0-3 heteroatom, where the above-mentioned heteroatom means nitrogen, oxygen or sulfur. In some embodiments, A1means optionally substituted 5-membered aromatic ring having 1-2 nitrogen atom. In one embodiment, the implementation of A1means optionally substituted 5-membered aromatic ring, other than thiazolyl.

In some embodiments, A2means optionally substituted 6-membered aromatic ring having 0-4 heteroatom of where the above-mentioned heteroatom means nitrogen. In some embodiments, A2means optionally substituted phenyl. Or And 2means optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl.

In some embodiments, A2means optionally substituted 5-membered aromatic ring having 0-3 heteroatom, where the above-mentioned heteroatom means nitrogen, oxygen or sulfur. In some embodiments, A2means optionally substituted 5-membered aromatic ring having 1-2 nitrogen atom. In some embodiments, A2means optionally substituted pyrrolyl.

In some embodiments, A2means optionally substituted 5 to 7-membered, saturated or unsaturated heterocyclic ring having 1-3 heteroatom independently selected from nitrogen atoms, sulfur or oxygen. Examples of such rings include piperidyl, piperazin, morpholinyl, thiomorpholine, pyrrolidine, tetrahydrofuranyl, etc.

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

In some embodiments, ring A2choose from:

where's the ring And2condensed with a ring And a1on two adjacent atoms of a ring.

In other embodiments, W is a bond or means optionally substituted C1-6alkylidene chain, where one or two methylene groups are optionally and independently replaced with O, NR', S, SO or SO2or COO, CO, SO2NR', NR'SO2, C(O)NR', NR'C(O), OC(O), OC(O)NR', and RWmeans R' or halogen. In other embodiments, each of WRWindependently means-C1-C3alkyl, C1-C3perhalogenated,- (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, m is 0 or m is 1, or m is 2. In some embodiments, m is 3. In other embodiments, m is equal to 4.

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

In some embodiments, R6means a hydrogen atom or R6means optionally substituted C1-8aliphatic group. In some embodiments, R6means optionally substituted C1-4aliphatic group. In certain other embodiments, R6means -(O-C1-4aliphatic group) or -(S-C1-4aliphatic group). Preferably, R6means-OMe or-S. In some other embodiments, R6mean CF3.

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

In another embodiment, the implementation according to the present invention, R1, R2, R3, R4and R5simultaneously mean hydrogen. In another embodiment, the implementation according to the present invention, R1, R2, R3, R4 , R5and R6simultaneously mean hydrogen.

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

In some embodiments, X is a bond or optionally substituted C1-6alkylidene chain, where one or two non-adjacent methylene groups are optionally and independently replaced with O, NR', S, SO2or COO, CO, and RXmeans R' or halogen. In other embodiments, each of RXindependently means-C1-3alkyl,- (C1-3alkyl), -CF3, -OCF3, -SCF3, -F, -Cl, -Br, IT, -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, R7means a hydrogen atom. In another embodiment, a separate implementation of R7means linear or razvetvlenno� 1-4aliphatic group.

In some embodiments, RWselected from the group consisting of a halogen atom, a cyanide groups, CF3, CHF2, OCHF2, Me,

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

O-fluorophenyl, O-dipthera, O-methoxyphenyl, O-tolil,

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

N(Et)2, C(O)CH3, C(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)bromide

4-methyl-2,4-dihydropyrazol-3-one-2-yl, benzimidazol-2-Il

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-dimethylphenyl), 5-methylphenyl, -SO2-N-piperidyl,

2-tolila, 3-tolila, 4-tolila, O-butyl, NHCO2C(Me)3That 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-dimethylphenyl, 3,4-dimethylphenyl, 4-hydroxymethylene,

4-dimethylaminophenyl, 2-triptoreline,

3-trifluoromethyl�Anila, 4-triptoreline, 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-dimethoxyphenyl, 2,5-dimethoxyphenyl,

2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl,

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

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

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

5-isopropyl-2-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl,

4-fluorophenyl, 3-cyanophenyl, 3-chlorphenyl, 4-chlorphenyl,

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

3,4-dipthera, 3.5-dipthera, 3-chloro-4-fluorophenyl,

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-methysulfonylmethane,

4-methysulfonylmethane,

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-piperazinyl, -NHCO2Et,

-NHCO2Me, N-pyrrolidinyl, -NHS2(CH2)2 N-piperidine,

-NHS2(CH2)2N-morpholine, -NHS2(CH2)2N(Me)2, COCH2N(Me)COCH2NHMe,

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

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

C(Me)2CO2Et, -CHOHMe, CH2CO2Et, -C(Me)2CH2NHCO2C(Me)3, O(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)2CH2NHC2(CH2)3CH3C(Me)2CH2NHC2(CH2)2OMe, C(OH)(CF3)2,

-C(Me)2CH2NHC2CH2-tetrahydrofuran-3-yl, C(Me)2CH2O(CH2)2OMe or

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

In one embodiment, the implementation of the R' means of Alamogordo.

In one embodiment, the implementation of R' is C1-C8aliphatic group, optionally substituted with up to 3 substituents selected from a halogen atom, CN, CF3, CHF2, OCF3or OCHF2where the two methylene groups of the above With1-With8the aliphatic group is optionally replaced by-CO-,

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

-N(C1-C4alkyl)SOP(Cl-C4alkyl)-, -OVOP(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, the implementation of the R' means a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatom, independently selected from nitrogen atoms, oxygen or sulfur, wherein R' is optionally substituted up to 3 substituents selected from a halogen atom, CN, CF3, CHF2, OCF3, OCHF2or C1-C6alkyl, where the two methylene groups of the above With1-C6alkyl optionally replaced by-CO-, -CNH(C1-C4alkyl)-, -CO2-, -OCO-,

-N(C1-C4alkyl)CO2-, -O-, -N(C1-C4alkyl)SOP(Cl-C4and�CML)-,

The OVOP(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, the implementation of the R' is an 8-12-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from nitrogen atoms, oxygen or sulfur, wherein R' is optionally substituted up to 3 substituents, selected from halogen, CN, CF3, CHF2, OCF3, OCHF2or C1-C6alkyl, where the two methylene groups of the above With1-C6alkyl optionally replaced by-CO-, -CNH(C1-C4alkyl)-, -CO2-, -OCO-,

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

The OVOP(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, the implementation of the two 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 bi�clichesque ring, having of 0-4 heteroatom independently selected from nitrogen atoms, oxygen or sulfur, wherein R' is optionally substituted up to 3 substituents selected from a halogen atom, CN, CF3, CHF2, OCF3, OCHF2or C1-C6alkyl, where the two methylene groups of the above With1-C6alkyl optionally replaced by-CO-, -CNH(C1-C4alkyl)-, -CO2-, -OCO-,

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

The OVOP(C1-C4alkyl)-, -N(C1-C4alkyl)CO-, -S-, -N(C1-C4alkyl)-,

-SO2N(C1-C4alkyl)-, N(C1-C4alkyl)SO2- or

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

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

According to another embodiment of the, present invention relates to compounds of the formulaIIIAthe formulaIIIBthe formulaIIICthe formulaIIIDor 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 implementation of joint� formula IIIAthe formulaIIIBthe formulaIIICthe formulaIIIDor of the formulaIIIEhave y vstrechaemosti Deputy X-RX, where y is 0-4; and y is 1; or y is equal to 2.

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

In some embodiments, the formulaIIIAX1, X2, X3, X4and X5taken together, denote optionally substituted ring selected from:

In some embodiments, the formulaIIIBthe formulaIIICthe formulaIIIDor of the formulaIIIEX1, X2, X3, X4, X5and X6taken together with the ring And2signify optionally substituted ring selected from:

In some embodiments, 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-fluorophenyl, O-dipthera, O-methoxyphenyl, O-tolil, O-benzyl, SMe, SCF3, SCHF2, SEt, CH2CN, NH2, NHMe, N(Me)2, NHEt, N(Et)2, C(O)CH3, C(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, benzimidazol-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, X and RXtaken together mean Me, Et, halogen, CN, CF3HE, OMe, OEt, SO2N(Me)(fluorophenyl), SO2-(4-demerol-1-yl) or SO2-N-pyrrolidinyl.

According to another embodiment of the, present invention relates to compounds of the formulaIVAthe formulaIVBor of the formulaIVC:

In one embodiment, the compounds of the formulaIVAthe formulaIVBand the formulaIVC have vstrechaemosti Deputy X-R X, where y is 0-4; and y is 1; or y is equal to 2.

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

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

In one embodiment of 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 heteroatom, selected from the atoms O, S or N. Examples of rings include piperidinyl, 4,4-dimethylpiperidine, etc.

In one embodiment of 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 heteroatom, selected from the atoms O, S or N.

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

According to one embodiment of the formulaIVA, provides the compound of the formulaVA-1:

where each of WRW2and WRW4independently chosen from a hydrogen atom, CN, CF3, halogen, linear or branched C1-C6of alkyl, 3-12-membered cycloaliphatic group, phenyl, C5-With10heteroaryl or C3-C7heterocyclic group, where the above-mentioned 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'C(O)OR', -NR'C(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R'); and

WRW5selected from the group consisting of a hydrogen atom, -OH, NH2, CN, CHF2, NHR', N(R')2, -NHC(O)R', -NHC(O)OR', NHSO2R', -OR', CH2OH, CH2N(R')2, C(O)OR', SO2NHR', SO2 N(R')2or CH2NHC(O)OR'; or WRW4and WRW5taken together, form a 5-7-membered ring containing 0-3 heteroatom selected from the atoms N, O and S, where the aforementioned ring is optionally substituted with up to three substituents WRW.

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

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

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

each of 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 abovementioned WRW2and WRW4independently and optionally substituted with up to three substituents selected from the group consisting of-OR', -CF3, -OCF3, -SCF3atom of halogen, -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'C(O)OR', -NR'C(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R'); and

WRW5selected from the group �ostoja from a hydrogen atom, -OH, NH2, CN, NHR', N(R')2, -NHC(O)R', -NHC(O)OR', NHSO2R', -OR', CH2OH, C(O)OR', SO2NHR' or CH2NHC(O)O-(R').

In one embodiment of 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'C(O)OR', -NR'C(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R');

WRW4means linear or branched C1-C6alkyl; and

WRW5mean IT.

In one embodiment, the implementation of each of WRW2and WRW4independently selected from CF3or halogen atom. In one embodiment, the implementation of each of WRW2and WRW4independently chosen from a hydrogen atom, an optionally substituted linear or branched C1-C6of alkyl. In some embodiments, each of WRW2and WRW4independently selected from optionally substituted n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-(ethoxycarbonyl)ethyl, 1,1-dimethyl-3-(tert-butoxycarbonylamino�)propyl or n-pentile.

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

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

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

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

In one embodiment, the implementation of WRW5selected from the group consisting of a hydrogen atom, CHF2NH2, CN, NHR', N(R')2, CH 2N(R')2, -NHC(O)R', -NHC(O)OR', -OR', C(O)OR' or SO2NHR'; or WRW5means-OR', for example, HE.

In some embodiments, WRW5selected from the group consisting of a hydrogen atom, NH2, CN, CHF2NH(C1-C6alkyl), N(C1-C6alkyl)2, -NHC(O)(Cl-C6alkyl), -CH2NHC(O)O(Cl-C6alkyl), -NHC(O)O(Cl-C6alkyl), -OH, -O(C1-C6alkyl), C(O)O(Cl-C6alkyl), CH2O(Cl-C6alkyl) or SO2NH2. In another embodiment of the WRW5selected from the group consisting of-OH, OMe, NH2, -NHMe, -N(Me)2, -CH2NH2, CH2OH, 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 of the compound of the formulaVA-1has one, preferably several, or more preferably all of the following features:

(i) WRW2means hydrogen;

(ii) WRW4means linear or branched C1-C6alkyl or aliphatic monocyclic or bicyclic group; and

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

CN, CHF2NH2NH(C1-C6alkyl), N(C1-C6alkyl)2,

-NHC(O)(Cl-C6alkyl), -NHC(O)O(Cl-C6alkyl),

-CH2C(O)O(Cl-C 6alkyl), -OH, -O(C1-C6alkyl), C(O)O(Cl-C6alkyl)

or SO2NH2.

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

(i) WRW2means a halogen atom, Cl-C6alkyl, CF3, CN or phenyl, optionally substituted up to 3 substituents selected from Cl-C4alkyl,- (Cl-C4alkyl) or halogen atom;

(ii) WRW4mean CF3, a halogen atom, Cl-C6alkyl or C6-C10cycloaliphatic group; and

iii) WRW5IT means that NH2NH(Cl-C6alkyl) or N(Cl-C6alkyl).

In one embodiment, the implementation of X-RXis in position 6 rhinolining ring. In some embodiments, X-RXtaken together, imply the Cl-C6alkyl,- (Cl-C6alkyl) or a halogen atom.

In one embodiment, the implementation of X-RXis in position 5 rhinolining ring. In some embodiments, X-RXtaken together, imply-IT.

In another embodiment of the present invention relates to compounds of the formulaVA-1where WRW4and WRW5taken together, form a 5-7-membered ring containing 0-3 heteroatom selected from an atom�in N, O or S, where the aforementioned ring is optionally substituted with up to three WRW-deputies.

In some embodiments, WRW4and WRW5taken together, form an optionally substituted 5 to 7-membered, saturated, unsaturated or aromatic ring containing 0 heteroatoms. In other embodiments, 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, 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, WRW4and WRW5taken together, form an optionally substituted 5 to 7-membered ring containing 1 oxygen atom as a heteroatom.

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

where:

Y means-CH2, C(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 the formulaVA-2have y vstrechaemosti Deputy X-RX, where y is 0-4. In one embodiment implemented�y I equal to 0; or y is 1; or y is equal to 2.

In one embodiment, the implementation of Y means C(O). In another embodiment of the Y means C(O)Oh; or Y means S(O)2or ; Y means-CH2.

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

In one embodiment, the implementation of W is a bond.

In another embodiment, the implementation of RWmean Cl-C6aliphatic group, a halogen atom, CF3or phenyl, optionally substituted Cl-C6an alkyl, a halogen atom, a cyano group or CF3where up to two methylene groups of the above Cl-C6aliphatic group or a Cl-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl. Examples of embodiments of WRWinclude methyl, ethyl, propyl, tert-butyl or 2-ethoxyphenyl.

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

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

where:

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

In one embodiment, the implementation of n is 0-2.

In another embodiment, the implementation of m is 0-2. In one embodiment, the implementation of m is 0. In one embodiment, the implementation of m is 1; or m is 2.

In one embodiment, the implementation of QRQtaken together, denote a halogen atom, CF3, OCF3, CN, Cl-C6aliphatic group,-Cl-C6aliphatic group, O-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-C6alkyl, O-(Cl-C6of alkyl, halogen, cyanide groups, HE or CF3where up to two methylene groups of the above Cl-C6aliphatic group or a Cl-C6�of Lila optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, SOR', SO2R', -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl.

Examples QRQinclude methyl, isopropyl, sec-butyl, gidroximetil, 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 of 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 the formulaVA-4have vstrechaemosti Deputy X-RX, where y is 0-4. In one embodiment, the implementation of y is 0; or y is 1; or y is equal to 2.

In one embodiment, the implementation of RWmean Cl-C12aliphatic group, 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, cyanide groups, the carbonyl group, HE or CF3where up to two methylene groups of the above Cl-C6aliphatic group or a Cl-C6Alki�and optionally replaced with-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl.

Examples RWinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, vinyl, cyanomethyl, gidroximetil, hydroxyethyl, hydroxybutyl, cyclohexyl, adamantyl or-C(CH3)2-NHC(O)O-T, where T is C1-C4alkyl, methoxyethyl or tetrahydrofuranyl.

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

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

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

In another embodiment, the implementation of m is 1 or 2, and RWmeans a halogen atom, CF3, CN, Cl-C6aliphatics�a second group, O-(Cl-C6aliphatic group or phenyl, where the abovementioned aliphatic group and phenyl optionally substituted with up to three substituents selected from Cl-C6alkyl, O-(Cl-C6of alkyl, halogen, cyanide groups, HE or CF3where up to two methylene groups of the above Cl-C6aliphatic group or a Cl-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl.

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

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

where:

the ring b means a 5-7-membered monocyclic or bicyclic, heterocyclic or heteroaryl ring, optionally substituted with 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 implementation soy�of inane formula VA-6have y vstrechaemosti Deputy X-RX, where y is 0-4. In one embodiment, the implementation of y is 0; or y is 1; or y is equal to 2.

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

In one embodiment, the implementation of n is 0-2; or n is 0; or n is 1.

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

In another embodiment of the ring means In a 5-6 membered monocyclic, heteroaryl ring having up to 2 heteroatoms selected from the atoms O, S or N, optionally substituted with up to n vstrechaemosti, Deputy-Q-RQ. Such rings include benzimidazol-2-yl, 5-methylfuran-2-yl, 2,5-dimethylpyrrole-1-yl, pyridin-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-Tiantian-2-yl, 3-chloro-5-triptorelin-2-yl.

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

where:

Odie� of Q 1and Q3mean N(WRW) and the other of Q1and Q3selected from O, S or N(WRW);

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

m is 0-3; and

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

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

In one embodiment, the implementation of Q3mean N(WRW); examples WRWinclude a hydrogen atom, C1-C6aliphatic group, C(Oh)1-C6aliphatic group, or C(O)OS1-C6aliphatic group.

In another embodiment, the implementation of Q3mean N(WRW), Q2means C(O) CH2, CH2-CH2and Q1means O.

In another embodiment of 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 form With3-C6cycloalkyl or heterocyclic ring having up to two heteroatoms, SEL�data of O atoms, S or NR', where the aforementioned ring is optionally substituted with 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 the formulaV-b-2have y vstrechaemosti Deputy X-RX, where y is 0-4. In one embodiment, the implementation of y is 0; or y is 1; or y is equal to 2.

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

In another embodiment, the implementation of each of RW3means a hydrogen atom, C1-C4alkyl; or both RW3taken together, form C3-C6cycloaliphatic group or 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 rings include cyclopropyl, cyclopentyl, optionally substituted piperidyl, etc.

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

where:

Q4is a bond, C(O), C(O)or S(O)2/sub> ;

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

In one embodiment, the implementation of Q4means With(About); or Q4means C(O)O. In another embodiment, the implementation of RW1mean C1-C6alkyl. Examples RW1include methyl, ethyl or tert-butyl.

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

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

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

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

where:

ring And2means phenyl or 5-6-membered heteroaryl ring, where ring A2and fused with him the phenyl ring, together have up 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 the formulaV-b-5have y vstrechaemosti Deputy X-RX, where y is 0-4. In one embodiment, the implementation of y is 0; or y is 1; or y is equal to 2.

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

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

where the aforementioned ring is optionally substituted as described above.

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

In one embodiment, the implementation of the ring And2means phenyl.

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

Examples of W in the formulaV-b-5include a bond, C(O), C(O)Oh or C1-C6alkylen.

Examples RWin the formulaV-b-5include a cyano group, a halogen atom, C1-C6aliphatic group, C3-C6cycloaliphatic group, an aryl, a 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-C6alkyl,-C1-C6of alkyl, halogen, cyanide groups, HE or CF3where up to two methylene groups of the above With1-C6aliphatic group or a C1-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl.

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

where:

G4means a hydrogen atom, atom �of alogena, CN, CF3, CHF2, CH2F, optionally substituted C1-C6the aliphatic group, aryl-C1-C6alkyl or phenyl, where G4optionally substituted up to 4 substituents WRW; where up to two methylene groups of the above With1-C6aliphatic group or a C1-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-.

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

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

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

In one embodiment, the implementation of the G4means a hydrogen atom. Or G5means a hydrogen atom.

In another embodiment, the implementation of the G4means a hydrogen atom, and G5mean C1-C6aliphatic group, where the abovementioned aliphatic group optionally substituted C1-C6an alkyl, a halogen atom, a cyano group or CF3where up to two metileno�x groups With the above 1-C6aliphatic group or a C1-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl.

In another embodiment, the implementation of the G4means a hydrogen atom, and G5means a cyano group, 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, the implementation of the G5means a hydrogen atom, and G4means a halogen atom, C1-C6aliphatic group or phenyl, where the abovementioned aliphatic group or phenyl optionally substituted C1-C6an alkyl, a halogen atom, a cyano group or CF3where up to two methylene groups of the above With1-C6aliphatic group or a C1-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl.

In another embodiment, the implementation of the G5means a hydrogen atom, and G4means a halogen atom, CF3ethoxycarbonyl, tert-butyl,2-methoxyphenyl, 2-ethoxyphenyl, (4-C(O)NH(CH2)2-NMe2)phenyl, 2-methoxy-4-chlorophenyl, pyridin-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminoethyl, ethyl, tert-butyl or piperidine-1-ylcarbonyl.

In another embodiment, the implementation of the G4and G5both are hydrogen, and the nitrogen atom of the above-mentioned indole ring substituted C1-C6aliphatic group, C(O)(C1-C6aliphatic group) or benzyl, where the abovementioned aliphatic group, or benzyl optionally substituted C1-C6an alkyl, a halogen atom, a cyano group or CF3where up to two methylene groups of the above With1-C6aliphatic group or a C1-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, -NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl.

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

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

or their pharmaceutically acceptable salts,

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

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

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

/tr> tr> N-(2-ethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamidetd align="center"> 460
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
5 N-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
6N-[3-(gidroximetil)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
7N-(4-benzoylamino-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
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-
carboxamide
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
164-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]indole]-
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-Carbo�Samid
25N-[2-(3-acetylaminophenol)phenyl]-4-oxo-1H-quinoline-3-carboxamide
264-oxo-N-[2-(1-piperidyl)phenyl]-1H-quinoline-3-carboxamide
27N-[1-[2-[methyl(2-methylaminomethyl)amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
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 ether [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-diethylprop)-2-fluoro-5-hydroxyphenyl]-4-hydroxyquinoline-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-carboxamide
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
44 N-(2-methylbenzothiazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
45N-(2-cyano-3-fluorophenyl)-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-fluorophenyl)-4-oxo-1H-quinoline-3-carboxamide
49N-[2-(2,6-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
504-oxo-N-(2,4,6-trimethylphenyl)-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
54 4-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-diokso-3-piperidyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
58N-[3-amino-4-(triptoreline)phenyl]-4-oxo-1H-quinoline-3-carboxamide
59N-[2-(5-isopropyl-2-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
60tert-butyl ether [4-isopropyl-3-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
61N-(2,3-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
624-oxo-N-[3-(triptoreline)phenyl]-1H-quinoline-3-carboxamide
63N-[2-(2,4-differenl)phenyl]-4-ox�-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 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 of 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-methylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
80N-(2-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
814-oxo-N-(3-propionylcarnitine)-1H-quinoline-3-carboxamide
82N-(4-diethylamino-2-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide
83N-[2-(3-cyanophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
84 N-(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-methylphenyl)-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
94 N-(5-amino-2-methylphenyl)-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]oxazine Serie-6-yl)-4-oxoindole-3-carboxamide
106N-(2-cyano-4,5-dimethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
107tert-butyl ether 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-carboxamide
113N-(3-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carbox�MFA
114tert-butyl ether [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 [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid
120N-(2-methoxy-5-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide
121N-(3,4-dichlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
122N-(3,4-dimethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
123N-[2-(furyl)phenyl]-4-oxo-1H-quinoline-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 ether [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
133 N-[3-chloro-5-[2-(1-piperidyl)ethylsulfanyl]phenyl]-4-oxo-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-fluorophenyl)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 [2-methyl-5-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]aminoarabinose acid
1424-oxo-N-(2-Deut-butylphenyl)-1H-quinoline-3-�carboxamid
143N-(2-fluoro-5-hydroxy-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
144N-(3-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
145ethyl ester 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
152 4-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-hydroxyquinoline-3-carboxamide
154N-[3,5-bis(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
1554-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 ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]his 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-methylphenyl)-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
172173N-(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-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide
1814-oxo-N-[2-(p-tolyl)phenyl]-1H-quinoline-3-carboxamide
182 N-[2-(4-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
183tert-butyl ether 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-carboxamide
188ethyl ester 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-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
1914-oxo-N-(5-chinolin)-1H-quinoline-3-carboxamide
192 N-(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-fluorophenyl)-4-oxo-1H-quinoline-3-carboxamide
199N-[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-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide
202N-[2-(5-chloro-2-methoxide�l)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-adamantyl)-5-hydroxy-2-methylphenyl]-4-oxo-1H-quinoline-3-carboxamide
209N-[4-(gidroximetil)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-DIH�droperidol-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-benzimidazol-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
2194-oxo-N-pyrazine-2-yl-1H-quinoline-3-carboxamide
220N-(2,3-dihydroxy-4,6-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
221methyl ester [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-propylphenyl]aminoarabinose acid
222N-(3-chloro-2-cyanophenyl)-4-oxo-1H-quinoline-3-carb�camid
223N-[2-(4-methylsulfinylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
2244-oxo-N-[4-[2-[(2,2,2-triptorelin)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-benzimidazol-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 3-[4-hydroxy-2-[(4-oxo-1H-quinoline-3-yl)carbylamine]-5-tert-butylphenyl]benzoic acid
232 N-(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-amino-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-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
2474-oxo-N-[2-(2-phenoxyphenyl)phenyl]-1H-quinoline-3-carboxamide
248N-(3-acetylamino-4-methylphenyl)-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-[(oxo-1H-quinolin-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-benzotriazole-5-yl)-4-oxo-1H-quinoline-3-carboxamide
257N-(4-fluoro-3-methylphenyl)-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-dimethylphenyl)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
264N-(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 of [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)-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]his aminoarabinose acid
2744-oxo-6-pyrrolidin-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-fluorophenyl)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
281 N-(2,4-dimethylphenyl)-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-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide
290N-[2-(3-isopropylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
291 N-(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-carboxamide
297N-[2-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
298ethyl [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
301 N-[4-(4-methyl-4H-1,2,4-triazole-3-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
302N-[2-[4-(gidroximetil)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 ether [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)phenyl]-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
311 N-[2-(5-methyl-2-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
312N-[2-(2,4-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
313N-[2-(2-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
314N-(2-ethyl-6-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide
315N-(2,6-dimethylphenyl)-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-piperidyl)ethylsulfanyl]-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-benzoylpiperazine-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
322N-(2-ethyl-6-sec-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
323methyl ether [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-carboxamide
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-carbamoyl-5-methylphenyl)-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-(3-methylsulfonylamino-4-propylphenyl)-4-oxo-1H-quinol�h-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
350 N-(1-naphthyl)-4-oxo-1H-quinoline-3-carboxamide
351N-(5-ethyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
352tert-butyl ether 2-[6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indol-3-yl]his 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-Oxon-quinoline-3-carboxamide
360N-[4-(deformedarse)phenyl]-4-oxo-1H-quinoline-3-carboxamide
361N-[2-(2,5-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
362N-(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-(triftormetilfullerenov)phenyl]-1H-quinoline-3-carboxamide
372N-[2-(4-methyl-1-piperidyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
373N-indane-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
380
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
384N-[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
390391N-[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-adamantyl)-2-fluoro-5-hydroxyphenyl]-4-hydroxyquinoline-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-dimethylphenyl)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-hydroxyquinoline-3-carboxamide
404N-[5-(2,6-dimethoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
405N-(4-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide
4066-[(4-fluorophenyl)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-carboxy�ID
4104-oxo-N-[2-(4-phenoxyphenyl)phenyl]-1H-quinoline-3-carboxamide
4117-chloro-4-oxo-N-phenyl-1H-quinoline-3-carboxamide
412ethyl ester 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-7-carboxylic acid
4134-oxo-N-(2-phenoxyphenyl)-1H-quinoline-3-carboxamide
414N-(3H-benzimidazol-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-yl)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-acetaminophen�l)-4-oxo-1H-quinoline-3-carboxamide
420ethyl ester of 2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propane 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
426N-(4-chloro-5-hydroxy-2-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide
427tert-butyl ether 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
429 N-[3-amino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
430N-(2-isopropyl-6-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide
431N-(3-Dapsone base)-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-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide
435N-[2-(2-pertenece)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide
436N-[2-(3,4-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
437N-benzo[1,3]dioxol-5-yl-4-oxo-1H-quinoline-3-carboxamide
438N-[5-(deformity)-2,4-di-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide
439 N-(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-quinoxaline-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 N-(m-tolyl)-4-oxo-1H-quinoline-3-carboxamide
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-adamantyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide
4564-oxo-N-[3-(triftormetilfullerenov)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
butyl ether [2-methyl-2-[4-[(4-oxo-1H-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 ether [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 ether [3-[(4-oxo-1H-quinoline-3-yl)carbylamine]-4-propylphenyl]aminoarabinose acid
472ethyl ester of [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
479 N-(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 [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]his aminoarabinose acid
483N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)phenyl]-4-hydroxyquinoline-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 of the present invention relates to compounds useful as intermediates for the synthesis of compounds of the formulaI. In one embodiment, the implementation of such compounds correspond to the formulaA-I:

or salts thereof;

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')3�whether B(OR') 2;

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

G3means isopropyl or C3-C10cycloaliphatic ring, where the aforementioned G3optionally substituted up to 3 substituents independently selected from WRWwhere W and RWhave the meanings as described above for formula I and its embodiments;

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

In one embodiment of the present invention relates to compounds of formula A-I, provided that when G2and G3every means tert-butyl group, then 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 up to 3 substituents, independently selected from R'; and

G3means isopropyl or C3-C10cycloaliphatic ring, where the aforementioned G3optionally substituted up to 3 �zamestitelyami, independently selected from R';

In another embodiment, the implementation of:

G1means a hydrogen atom;

G2means a halogen atom, preferably a fluorine atom; and

G3mean C3-C10cycloaliphatic ring, where the aforementioned G3optionally substituted up to 3 substituents, independently selected from methyl, ethyl, propyl or butyl.

In another embodiment, the implementation of:

G1means a hydrogen atom;

G2means CN, a halogen atom or CF3; or

G3means isopropyl or C3-C10cycloaliphatic ring, where the aforementioned G3optionally substituted up to 3 substituents, independently selected from R'.

In another embodiment, the implementation of:

G1means a hydrogen atom;

G2means phenyl, optionally substituted up to 3 substituents, independently selected from-O-C1-C4alkyl, CF3, halogen atom or CN; and

G3means isopropyl or C3-C10cycloaliphatic ring, where the aforementioned G3optionally substituted up to 3 substituents, independently selected from R'.

Examples G3include optionally substituted cyclopentyl, cyclohexyl, cycloheptyl or adamantyl. Or G3means branched C3-C8the aliphatic chain. PR�measures G 3include isopropyl, tert-butyl, 3,3-diethylprop-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 of the present invention relates to the compound of the formulaA-II:

or salts thereof, where:

G4means a hydrogen atom, a halogen atom, CN, CF3, CHF2, CH2F, optionally substituted C1-C6aliphatic group, aralkyl or phenyl ring, optionally substituted with up to 4 substituents WRW;

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

provided that both, G4and G5, are not simultaneously hydrogen;

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

In one embodiment, the implementation of the G4means a hydrogen atom. Or G5means a hydrogen atom.

In another embodiment, the implementation of the G4means a hydrogen atom, and G5mean C1-C6aliphatic group, where the abovementioned aliphatic group optionally substituted C1-C6by alkyl, halogen, cyano or CF3 where up to two methylene groups of the above With1-C6aliphatic group or a C1-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-C4alkyl.

In another embodiment, the implementation of the G4means a hydrogen atom, and G5means a cyano group, 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, the implementation of the G5means a hydrogen atom, and G4means a halogen atom, C1-C6aliphatic group or phenyl, where the abovementioned aliphatic group or phenyl optionally substituted (replaced) With1-C6an alkyl, a halogen atom, a cyano group or CF3where up to two methylene groups of the above With1-C6aliphatic group or a C1-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-With4alkyl.

In another embodiment, the implementation of the G5means a hydrogen atom, and G4 means a halogen atom, ethoxycarbonyl, tert-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C(O)NH(CH2)2-NMe2, 2-methoxy-4-chlorophenyl, pyridin-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminoethyl, ethyl, tert-butyl or piperidine-1-ylcarbonyl.

Associated with the formula A-II variant of the implementation of the nitrogen atom of the above-mentioned indole ring substituted C1-C6aliphatic group, C(O)(C1-C6aliphatic group) or benzyl, where the abovementioned aliphatic group, or benzyl optionally substituted (replaced) With1-C6an alkyl, a halogen atom, a cyano group or CF3where up to two methylene groups of the above With1-With6aliphatic group or a C1-C6alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the implementation of the above R' is C1-With4alkyl.

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

4. General scheme of synthesis

Compounds according to the present invention is easily obtained using methods known in this field. Illustrated below are examples of ways to�osobov obtain the compounds according to the present invention.

The scheme below illustrates the synthesis of acids - precursors of the compounds according to the present invention.

Synthesis of acid-precursors ofP-IV-A, P-IV-BorP-IV-C

a) (CO2Et)2CH2; (b) (CO2Et)2CH=CH(OEt); (c) CF3CO2H, PPh3CCl4Et3N; (d) MeI; (e) PPA or diphenyl ether; (f) NaOH.

Synthesis of acid-precursors ofP-IV-A, P-IV-BorP-IV-C

a) AcONH4; (b) EtOCHC(CO2Et)2, 130AboutC; C) Ph2O, ∆T; d) I2Hcl , EtOH; (e) NaOH.

Synthesis of acid-precursors ofP-IV-A, P-IV-BorP-IV-C

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

Synthesis of amine precursorP-III-A:

a) (CH3)2SO4; (b) K3Fe(CN)6, NaOH, H2O; c) HNO3, H2SO4; (d) RCOCH3, MeOH, NH3; e) H2the Raney-Nickel.

Synthesis of amine precursorP-IV-A:

a) HNO3, Or; b) Na2S2O4, THF/H2About; C) H2, Pd/C.

Synthesis of amine precursorP-V-A-1:

a) KNO3, H2SO 4; (b) NaNO2, H2SO4-H2O; c) NH4CO2H, Pd-C; (d) R X; e) NH4CO2H, Pd-C.

Synthesis of amine precursorP-V-A-1:

a) SO2Cl2, R2=Cl; b) R2H, R2=alkyl; C) NBS, R1=Br; (d) ClCO2R, TEA; e) HNO3, H2SO4; f) base; (g) ArB(OH)2, R1=Br; h) [H]; i) R X, R1=Br; j) ClCF2CO2Me; k) [H]; l) [H].

Synthesis of amine precursorP-V-A-1:

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

Synthesis of amine precursorP-V-A-1:

a) HNO3, H2SO4; 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)2, Pd(PPh3; (C) [H]; d) BH3; (e) (BOC)2O; f) [H]; (g) (H2SO4, H2O; 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 precursorP-V-A-1:

(a) CHCl2OMe; b) KNO3, H2SO4;) Desiccator; (d) Fe.

Synthesis of amine precursorP-V-A-3:

Ar=aryl or heteroaryl

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

Synthesis of amine precursorP-V-B-1:

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

Synthesis of amine precursorP-V-B-1:

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

PG=protective group.

Synthesis of amine precursorP-V-B-1:

a) HSCH2CO2H; b) [H].

Synthesis of amine precursorP-V-b-2:

(a) AlCl3; b) [H]; c) (i) R1R2CHCCH2CH2Cl; (ii) NaBH4; (d) NH2OH; e) DIBAL-H; f) nitration; g) protection; h) [H];

PG=protective group.

Synthesis of amine precursorP-V-b-3:

a) nitration; b) protection; C) [H].

PG=protective group.

Synthesis of amine precursorP-V-b-5:

(a) when X=Cl, Br, I: RX, K2CO3, DMF or CH3CN; when X=OH: RX, TFFH, DIEA, THF; (b) H2, Pd-C, EtOH or SnCl2·2H2Oh, EtOH or SnCl2·2H2Oh, DIEA, EtOH.

Synthesis of amine precursorP-V-b-5:

a) RCOCl, Et3N, CH2Cl2; (b) n-BuLi, THF; (C) NaBH4, AcOH; d) KNO3, H2SO4; (e) DDQ, 1,4-dioxane; (f) NaNO2, HCl, SnCl2·2H2Oh, H2O; g) MeCOR, EtOH; (h) PPA; (i) LiAlH4, THF or H2, Raney Nickel, EtOH or MeOH.

Synthesis of amine precursorP-V-b-5:

(a) NaNO2, HCl, SnCl2·2H2Oh, H2O; (b) RCH2COR, AcOH, EtOH; (c) H3PO4, toluene; (d) H2, Pd-C, EtOH.

Synthesis of amine precursorR-V-b-5:

(a) NaNO2, HCl, SnCl2·2H2Oh, H2O; (b) RCH2SLEEP, AcOH, EtOH; (c) H3PO4, toluene; (d) H2, Pd-C, EtOH.

Synthesis of amine precursorR-V-b-5:

(a) RX (X=Br, I), triflic zinc, TBAI, DIEA, toluene; (b) H2, Raney Nickel, EtOH or H2, Pd-C, EtOH or SnCl2·2H2Oh, 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 precursorR-V-b-5:

(a) HNO3, H2SO4; (b) Me2NCH(OMe)2, DMF; (c) H2, Raney Nickel, EtOH.

Synthesis of amine precursorR-V-b-5:

a)when PG=SO2Ph: PhSO2Cl, Et3N, DMAP, CH2Cl2; when PG=Ac: AcCl, NaHCO3, CH2Cl2; (b) when R=RCO: (RCO)2 O, AlCl3, CH2Cl2; when R=Br: Br2, AcOH; c) HBr or HCl; (d) KNO3, H2SO4; (e) MnO2, CH2Cl2or DDQ, 1,4-dioxane; f) H2, Raney Nickel, EtOH.

Synthesis of amine precursorR-V-b-5:

(a) NBS, DMF; (b) KNO3, H2SO4; (c) HC=CSiMe3, Pd(PPh3)2Cl2, CuI, Et3N, toluene, H2O; d) CuI, DMF; e) H2, Raney Nickel, MeOH.

Synthesis of amine precursorR-V-A-3orR-V-A-6:

Ar=aryl or heteroaryl;

a) ArB(OH)2, Pd(PPh3)4, K2CO3, H2O, THF or ArB(OH)2, Pd2(dba)3, P(tBu)3, KF, THF.

Synthesis of amine precursorR-V-A-4:

R=CN, CO2Et; a) MeI, NaOtBu, DMF; (b) HCO2K, Pd-C, EtOH or HCO2NH4, Pd-C, EtOH.

Synthesis of amine precursorR-V-A-4:

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

Synthesis of amine precursorR-V-b-4:

(a) H2, Pd-C, MeOH.

Synthesis of amine precursorR-V-b-4:

(a) NaBH4, MeOH; (b) H2, Pd-C, MeOH; (c) NH2OH, pyridine; (d) H2, Pd-C, MeOH; e) Vos2O, Et3N, MeOH.

The synthesis of compounds of the formulaI

(a) Ar1R7NH, binder, base, solvent. Examples of conditions used: 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, DMFA.

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, DMFA.

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

(a) SnCl2·2H2Oh, EtOH; (b) PG=BOC: TFUC, CH2Cl2; (c) CH2O, NaBH3CN, CH2Cl2, MeOH; (d) RXCl, DIEA, THF or RXCl, NMM, 1,4-dioxane or RXCl, CH2Cl2, DMF; e) R ' R”NH, LiClO4, CH2Cl2, iPrOH.

The synthesis of compounds of the formulaV-b-2

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

The synthesis of compounds of the formulaV-A-2

a) when PG=BOC: TFUC, CH2Cl2.

a) when PG=BOC: TFUC, CH2Cl2; (b) ROCOCl, Et3N, DMF.

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

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

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

5. Use, ready-dosed form and introduction

Pharmaceutically acceptable compositions

As discussed above, the present invention relates to compounds that are useful as modulators of ABC transporters and thus are 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 hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysaccharidosis, Sandhoff disease/Tay-Sachs, disease crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes, m�croomia of Larona, the deficit teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroidism, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Tooth syndrome, a disease of 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, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonic dystrophy, as well as spongiform encephalopathies, such as congenital disease Creutzfeldt-Jakob disease (caused by a defect in the processing of prion protein), Fabry disease, syndrome Straussler-Sheinker, D, disease, dry eye or Sjogren syndrome.

Accordingly, according to another aspect of the present invention provides pharmaceutically acceptable compositions, where these compositions contain any of the compounds as described herein, and optionally pharmaceutically acceptable carrier, adjuvant or excipient. According to some variants of implementation, these compositions additionally� 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 a prodrug includes, but is not limited to, pharmaceutically acceptable salts, 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, the connection, in any other manner described herein, or a metabolite or residue.

As used in this description, the term "pharmaceutically acceptable salt" refers to those salts which are, within the medical health assessment, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and consistent with the acceptable ratio of 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, the connection according to the present�Adamu to the 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), incorporated herein by reference. Pharmaceutically acceptable salts of the compounds according to the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic additive salts of acids are salts formed by amino groups 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, benzolsulfonat, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, aconsultant, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonic, lactobionic�, lactate, laurate, lauryl sulfate, 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 alkali metal salts, 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 such quaternization. Examples of salts of alkaline or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations, Quaternary ammonium and amine formed using counterions such as halide ion, hydroxyl ion, a carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

As described above, the pharmaceutically acceptable composition according to the present invention optionally contain pharmaceutically acceptable� media adjuvant or excipient, which, as used herein, includes any and all solvents, diluents, or other liquid filler, auxiliary for dispersing or suspending means, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, depending on specific desired dosing form. 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 where any normal the carrier medium is incompatible with the compounds according to the invention, such as causing undesirable biological effect or otherwise interacting in a harmful 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, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protaminsulphate, intrigejosa, kalogeropoulos, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, blackpooler with plastic and polyoxypropylene blocks, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as nutricosmetics, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipient, 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 ethyloleate and ethyl laurate; agar; buferiruemoi agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; apyrogenic 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 also in the composition may be present to�acitelli, agents, contributing to the release, coating agents, sweeteners, flavouring and flavouring agents, preservatives and antioxidants, in accordance with the manufacturer's rating.

The use of compounds and pharmaceutically acceptable compositions

According to still another aspect, the present invention relates to a method for treating conditions, diseases and disorders involving the activity of the ABC-Transporter, for example, CFTR. According to some variants of implementation, the present invention relates to a method for treating conditions, diseases or disorders involving a deficiency in the activity of the ABC-Transporter, comprising administering a composition containing a compound of formula (I), to a subject, preferably to 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 hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia; lysosomal diseases of accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysaccharidosis, Sandhoff disease/Tay-�Aqsa, disease crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes mellitus, macrosomia of Larona, lack of teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroidism, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Tooth syndrome, a disease of 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 myotonic dystrophy, as well as spongiform encephalopathies, such as congenital disease Creutzfeldt-Jakob disease (caused by a defect in the processing of prion protein), Fabry disease, syndrome Straussler-Sheinker, D, disease, dry eye or Sjogren's syndrome comprising the stage of introduction of the above to a mammal an effective amount of a composition containing a compound according to the present invention.

According to an alternative preferred embodiment of the present invention apply� to a method for the treatment of cystic fibrosis, including the stage of introduction of the above to a mammal an effective amount of a composition containing a compound according to the present invention.

According to the present invention, "effective amount" of a compound or farmatsevticheskii acceptable composition is an amount effective for treating or reducing 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 hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysaccharidosis, Sandhoff disease/Tay-Sachs, a disease crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes mellitus, macrosomia of Larona, lack of teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroidism, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Tooth syndrome, a disease of Pelizaeus-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, bole�June Parkinson, side amyotrophies sclerosis, progressive supranuclear, the disease Peak; heavy polylaminate neurological disorders, such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonic dystrophy, as well as spongiform encephalopathies, such as congenital disease Creutzfeldt-Jakob disease (caused by a defect in the processing of prion protein), Fabry disease, syndrome Straussler-Sheinker, D, disease, dry eye or Sjogren syndrome.

The compounds and compositions in accordance with the method according to the present invention, can be administered using any amount and any route of administration, effective in treating or easing 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 hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia; disease lysosomal accumulation, such as disease I-cellular inclusions/pseudocontrol gurler, mucopolysaccharidosis, Sandhoff disease/Tay-Sachs, disease crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes, microso�of Oia Larona, the deficit teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroidism, osteopathies, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Tooth syndrome, a disease of 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, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral of pallidoluysian and myotonic dystrophy, as well as spongiform encephalopathies, such as congenital disease Creutzfeldt-Jakob disease (caused by a defect in the processing of prion protein), Fabry disease, syndrome Straussler-Sheinker, D, disease, dry eye or Sjogren syndrome.

In accordance with one variant of implementation, the compounds and compositions according to the present invention are useful to treat or ameliorate the severity of cystic fibrosis in patients who manifested residual CFTR activity in the apical membrane of respiratory and nerespectarea epithelium. The presence of residual CFTR activity in epithelial surface�t can be easily determined, using known in the field methods, for example, standard electrophysiological, biochemical or histochemical methods. Using such 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 surface cell density. Using such methods, residual CFTR activity can be readily 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 variant of implementation, the compounds and compositions according to the present invention are useful to treat or ameliorate the severity of cystic fibrosis in patients who have been induced or increased residual CFTR activity using pharmacological methods or gene therapy. Such methods increase the amount of CFTR on the cell surface, inducing, thus, missing still the CFTR activity in a patient or increasing the existing level of residual CFTR activity in a patient.

In accordance with one variant of implementation, the compounds and compositions according to this image�meniu useful to treat or ameliorate the severity of cystic fibrosis in patients with certain genotypes, that exhibit residual CFTR activity, as, e.g., class III mutations (impaired regulation or the opening of a membrane channel), mutation class IV (altered conductance), or class V mutations (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 of patients who exhibit residual CFTR activity include patients homozygous for one of these classes or heterozygous with any other class of mutations, including mutations of class I, class II mutations, or a mutation for which there is no classification.

In accordance with one variant of implementation, the 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 amount needed varies from subject to subject, depending�Ty of kind, age and General condition of the subject, the severity of the infection, the particular agent, the route 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 in this description, refers to a physically discrete unit of the corresponding agent subjected to the treatment of the patient. However, it should be clear that the total daily dose of the compounds and compositions according to the present invention should be defined by a regular doctor within a medical health assessment. The specific effective dose for any particular patient or organism depends on a number of factors, including the offense that needs to be treated, and the severity of this violation, the activity specifically, the compounds used 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 used with a specific connection, and the like factors well known in medicine. The term "patient" as used�ized in this description, means an animal, preferably a mammal, and, highly preferably, human.

Pharmaceutically acceptable compositions according to the present invention can introduce people and other animals orally, rectally, parenterally, intracisternally, vnutrivaginalno, intraperitoneally, topically (as powders, ointments or drops), buccal, in the form of oral or nasal spray, or the like, depending on the severity of the infection to be treated. According to some variants of implementation, the compounds according to the invention can be administered orally or parenterally at dose level of 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 a day, to achieve the desired therapeutic effect.

Liquid dose 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 metered-dose forms may contain inert diluents commonly used in this field, such as, for example, water or other solvents, solubilizers agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, e�ylcarbonyl, 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), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitane esters of fatty acids, and mixtures thereof. Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifiers and suspendresume agents, sweeteners, flavorings and fragrances.

Injectable preparations, for example sterile injectable aqueous or oily suspension, can be obtained according to known art, using suitable dispersing agents or wetting agents and suspendida agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic, 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 a solvent or suspendida environment. D�I this purpose can be used any tasteless non-volatile oil, including synthetic mono - or diglycerides. In addition, in preparations for injection using 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.

For the purpose of prolonging the effect of the compounds according to the present invention, it is often desirable to slow the absorption of the 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 speed of absorption of the compound then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral form is entered the connection will be terminated by dissolution or suspendirovanie compounds in the oil filler. Injectable form of depo get by creating matrices for microencapsulation of compounds from biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of connection to kalimero and nature specifically used polymer, you can control the rate of release of connection. Examples of other biodegradable polymers include poly(complex orthoevra) and poly(anhydrides). Injectable depot compositions are also obtained by incorporating the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal injection are preferably suppositories which can be obtained by mixing the compounds according to the present invention with suitable non-irritation by excipients or carriers such as cocoa butter, polyethylene glycol 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 connection.

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, �polivinilpirrolidon, sucrose and the Arabian gum, (C) humectants, such as glycerol, d) dezintegriruetsja agents, such as agar-agar, calcium carbonate, potato or tapiokovogo 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 agents, 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 mixtures thereof. 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 in the form of tablets, dragees, capsules, pills and granules can be obtained with applied coatings and shells such as enteric shell or other coatings well known in the field of pharmaceuticals. They may not necessarily contain opalescent components and may also be�ü composition such that only release the active ingredient (the active ingredients) or preferably in a particular part of the gastrointestinal tract, optionally, in a delayed manner. Examples of commissioned compositions 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 can also be in microencapsulated form with one or more excipients, as described above. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be obtained with applied coatings and shells such as enteric membranes, coatings controlled release and other coatings well known in the field of pharmaceuticals. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such metered-dose forms may also include, as is the case in normal practice, additional substances other than inert diluents, for example lubricants for tab�of tiravanija and other excipients for tableting, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms can also include buferiruemoi agents. They may not necessarily contain opalescent components and can also be of such composition that only release the active ingredient (the active ingredients) or preferably in a particular part of the gastrointestinal tract, optionally, in a delayed manner. Examples of commissioned compositions which can be used include polymeric substances and waxes.

Dosed forms for local or transdermal injection of the compounds according to the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, metered-dose 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. Ocular composition, ear drops and eye drops are also considered within the scope of the present invention. Additionally, according to the present invention assumes the use of transdermal patches, which have the added advantage of the implementation of the controlled delivery of compounds into the body. Such metered-dose form is produced by races�or met through the distribution of compounds in a suitable environment. Can also be used as a booster to increase the flow of compounds 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 treating or alleviating the severity of the diseases, conditions or disorders where hyperactivity or inactively ABC-transporters involved in the disease, condition or violation. When hyperactivity or inactively ABC Transporter implicated in a particular disease, condition or disorder, the disease, condition or violation can also be named as "mediated by the ABC-Transporter the disease, condition or violation." Accordingly, according to another aspect, the present invention relates to a method for treating or alleviating the severity of the diseases, conditions or disorders where hyperactivity or inactively ABC-Transporter involved in the painful condition.

The activity of the compounds used according to the present invention as modulators of ABC Transporter may be determined in accordance with STRs�Obama, usually 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 therapy, i.e., the compounds and pharmaceutically acceptable compositions can be administered 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 the case of combined modes is chosen based on the compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect. You should also take into account that in the case of therapies used to achieve the desired effect for the same disorder (for example, proposed in the invention, the compound can be administered concurrently with another agent used to treat the same disorders) 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, are known as "appropriate for the disease or condition�, undergoes the treatment."

According to one variant of implementation, the additional agent selected from a mucolytic agent, a bronchodilator agent, antibiotic, anti-infective agent, an anti-inflammatory agent, 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 number that should be generally introduced into the composition containing therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent disclosed in the present compositions is from about 50% to 100%, based on the amount normally present in a composition containing such an agent as the only therapeutically active agent.

Compounds according to the present invention or containing pharmaceutically acceptable compositions can also be introduced into compositions for coating 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 impl�tiramola funds comprising a compound according to the present invention, as described above, and according to classes and subclasses, as specified herein, and a carrier suitable for coating the above implantable device. According to still another aspect, the present invention relates to implantable device to which the coating when using the composition containing the compound according to the present invention, as described above, and according to classes and subclasses, as specified herein, and a carrier suitable for coating the above implantable device. Suitable coatings and the regular receipt of the implantable device with the coating described in U.S. patents 6099562, 5886026 and 5304121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethylsiloxane, polycaprolactone, polyethylene glycol, polyacrylic acid, copolymer of ethylene and vinyl acetate, and mixtures thereof. The coating can optionally be additionally protected with a suitable, applied on top of coating of Versiliana, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics of the composition.

Another aspect of the invention relates to moderateintensity ABC Transporter in a biological sample or a patient (e.g., in vitro or in vivo) method, which comprises administering to a patient or contacting the above-mentioned biological sample of a compound of formula (I) or 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, tear fluid or other body fluids or extracts of them.

Modulation of activity of the ABC-Transporter, for example, CFTR, in a biological sample suitable for a variety of purposes that are known to the person skilled in the art. 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 modulating the activity of anion channel in vitro or in vivo, provides the stage of contacting the above-mentioned channel with a compound of formula (I). According to a preferred implementation options, the anion channel is a chloride channel or a bicarbonate channel. According to other preferred variants of implementation, anionic channel is chloridi� channel.

According to an alternative embodiment of the, present invention relates to a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting cells with the above compound of 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 is CFTR.

According to another preferred embodiment of the activity of the ABC-Transporter is determined by measuring the transmembrane voltage potential. To measure the voltage potential across the membrane in a biological sample can be used any known in the field 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 a measuring apparatus for determining changes in fluorescence�orescence, such as 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 a fluorescent phospholipid, CC2-DMPE, which is associated with outer "leaf" cytoplasmic membrane and acts as a FRET donor. Changes of transmembrane potential (Vm) cause a redistribution of the negatively charged DiSBAC2(3) in the cytoplasmic membrane and therefore changes the amount of energy transferred from CC2-DMPE. Changes in fluorescence emission can be monitored using the device VIPRTMII, which is an integrated liquid handling system and fluorescent detector designed to conduct based on the cell screening using 96 - or 384-well titration microplates.

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 compound of formula (I) or any of its above-mentioned variants of implementation; and (ii) tools�tion 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 comprises 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 a compound of formula (I). In preferred embodiments, the kit is used to determine the density of CFTR.

In order to better understand the invention described in this description, the following examples are given. Assuming that these examples are given for illustrative purposes only and is not to be construed as limiting in any way the invention.

EXAMPLES

Example 1

The General scheme of obtaining the acid components:

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

A specific example

Diethyl ether 2-phenylaminopyrimidine acid

A mixture of aniline (up to 25.6 g, 0.28 mol) and diethyl-2-(ethoxymethylene)malonate (62,4 g, 0.29 mole) 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 which is used in next step without further purification.

1H NMR (d-DMSO) δ 11,00 (d, 1H), 8,54 (d, J=13,6 Hz, 1H), of 7.36-7,39 (m, 2H), 7,13-7,17 (m, 3H), 4,17-of 4.33 (m, 4H), of 1.18-of 1.40 (m, 6H).

Ethyl 4-hydroxyquinoline-3-carboxylic acid

In a three-neck flask 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 was heated at a temperature of about 70°C and stirred for 4 hours. The mixture is cooled to room temperature and filtered. The residue was treated with an aqueous solution of Na2CO3, filtered, washed with water and dried. Ethyl 4-hydroxyquinoline-3-carboxylic acid was obtained as a pale brown solid (15.2 g, yield 70%). The crude product was used for next step without further purification.

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

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

1H NMR (d-DMSO) δ ones was 15.34 (s, 1H), be 13.42 (s, 1H), 8,89 (s, 1H), 8,28 (d, J=8,0 Hz, 1H), of 7.88 (m, 1H), 7,81 (d, J=8.4 Hz, 1H), 7,60 (m, 1H).

A specific example

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

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

1H-NMR (DMSO-d6): δ 15,2 (ush.s, 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) was stirred in hydrogen atmosphere (1 ATM) for 4 hours at room temperature. The Raney-Nickel was 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, 2.64 mmol) and diethyl-2-(ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at the�erature 100°C for 2 hours. After cooling, the reaction mixture was recrystallized from methanol (10 ml) to obtain the diethyl ester of 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, 24.2 mmol) was slowly added to polyphosphoric acid (30 g) at a temperature of 120°C. the Mixture was stirred at this temperature for 30 minutes and then cooled to room temperature. Add absolute ethanol (30 ml) and the resulting mixture was brought to reflux for 30 minutes. The mixture was made basic with aqueous sodium bicarbonate solution at a temperature of 25°C and extracted with EtOAc (4x 100 ml). The organic layers were 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, yield 30%).

Ethyl 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) was stirred in hydrogen atmosphere (2.5 ATM) over night. The catalyst was removed by filtration and the reaction mixture was conc�Ute under reduced pressure. The resulting oil was dissolved in CH2Cl2(100 ml) and washed with aqueous sodium bicarbonate solution and water. The organic layer was 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 5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1 g, 7.1 mmol) in 10% NaOH (50 ml) was heated to reflux overnight and then cooled to room temperature. The mixture was extracted with diethyl ether. The aqueous phase is separated and acidified with concentrated Hcl solution to pH=1-2. The resulting precipitate is separated by filtration, yielding 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), to 8.71 (s, 1H), 7,71 (t, J=8,1 Hz, 1H), 7,18 (d, J=8.4 Hz, 1H), about 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 mole) in Et2O at room temperature was added, dropwise, during 30 min, ethylmalonate (24 g, 0.15 mole). Then �about drops add phenylisothiocyanate (20,3 g, 0,15 mol) with stirring for 30 minutes. The mixture is boiled to reflux for 1 hour and then stirred overnight at room temperature. The solid is separated, washed with anhydrous diethyl ether (200 ml) and dried under vacuum to give diethyl ester sodium salt 2-(mercaptopropionate)of malonic acid in the form of a pale yellow powder (46 g, yield 97%).

Diethyl ether 2-(methylsulfonylmethan)malonic acid

Within 30 minutes was added dropwise methyliodide (17,7 g, 125 mmol) to a solution of diethyl ether sodium salt of 2-(mercaptopropionate)malonic acid (33 g, 104 mmol) in DMF (100 ml), cooled in an ice bath. The mixture was 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, yielding diethyl ether 2-(methylsulfonylmethan)of malonic acid in the form of a pale yellow solid (27 g, yield 84%).

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

A mixture of diethyl ether 2-(methylsulfonylmethan)malonic acid (27 g, 87 mmol) in 1,2-dichlorobenzene (100 ml) was heated to reflux for 1.5 hours. The solvent was removed under reduced davleniya oily residue was treated with hexane, getting 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) was heated to reflux in NaOH solution (10%, 100 ml) for 1.5 hours. After cooling, the mixture was acidified with concentrated Hcl to pH=4. The obtained solid substance was separated by filtration, washed with water (100 ml) and MeOH (100 ml) to give 2-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-16) as a white solid (6 g, yield 85%).

1H-NMR (CDCl3) δ 16,4 (user.s, 1H), 11.1 V (user.s, 1H), to 8.19 (d, J=8 Hz, 1H), with 8.05 (d, J=8 Hz, 1H), 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~200AboutC; d) 10% NaOH.

2,2,2-Cryptor-N-phenylacetonitrile

A mixture of Ph3P (138,0 g, 526 mmol), Et3N (of 21.3 g, 211 mmol), CCl4(170 ml) and TFOC (20 g, 175 mmol) was 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 with reverse holodilnikov for 3 hours. The solvent was removed under vacuum and add hexane. Precipitation (Ph3RO and Ph3P) is filtered off and washed with hexane. The filtrate was distilled under reduced pressure, getting 2,2,2-Cryptor-N-phenylacetonitrile (19 g), which is used for next step 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) was added diethylmalonate (18.5 g, 116 mmol) at 0°C. the Mixture was stirred for 30 minutes at this temperature and added 2,2,2-Cryptor-N-phenylacetonitrile (19 g, 92 mmol) at 0°C. the Reaction mixture is allowed to warm to room temperature and stirred over night. The mixture was diluted with CH2CL2, washed with saturated sodium bicarbonate solution and saturated brine. The combined organic layers dried over Na2SO4, filtered and concentrated, yielding diethyl ether 2-(2,2,2-Cryptor-1-phenyliminomethyl)malonic acid, which was used directly in next step without further purification.

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

Diethyl ether 2-(2,2,2-Cryptor-1-phenyliminomethyl)malonic acid is heated at a temperature of 210°C for 1 hour with continuous stirring. �rity purify separated by column chromatography (petroleum ether), getting ethyl ester 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 NaOH solution brought to reflux for 2 hours. After cooling, dichloro methane is added, the aqueous phase is separated and acidified with concentrated Hcl to pH=4. The resulting precipitate is separated by filtration, washed with water and Et2O, yielding 4-hydroxy-2-trifloromethyl-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-of 7.83 (t, J=14,4 Hz, 1H), 7,50-7,53 (t, J=15 Hz, 1H).

ESI-MS: RUB 257.0 m/z (MH+).

Example 5

(a) CH3C(O)ONH4, toluene; (b) EtOCHC(CO2Et)2, 130AboutC; c) Ph2O; d) I2Hcl , EtOH; (e) NaOH.

3-Aminocyclopent-2-Aenon

A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and ONH4(38.5 g, 0.5 mol) in toluene is boiled to reflux for 5 hours when using a Dean stark. The obtained oily layer is separated and concentrated under reduced pressure, obtaining 3-aminocyclopent-2-Aenon (49,9 g, yield 90%) which was used directly in next step without further purification.

u> 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, 31.2 mmol) was stirred at 130°C for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified column chromatography (silica gel, ethyl acetate) to obtain the diethyl ester of 2-[(3-oxocyclohexa-1 enylamine)methylene]malonic acid (7.5 g, yield 90%).

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

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

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

To a solution of the ethyl ester of 4,5-diokso-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (1.6 g, 6.8 mmol) in ethanol (100 ml) was added iodine (4.8 g, 19 mmol). The mixture is brought to reflux for 19 hours and then concentrated under reduced pressure. The obtained solid substance was washed with ethyl�cetecom, 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 (20 ml) was heated to reflux over night. After cooling, the mixture was extracted with diethyl ether. The aqueous phase is separated and acidified with concentrated Hcl to pH=1-2. The resulting precipitate is separated by filtration, receiving 5-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-3) (540 mg, yield 87%).

1H-NMR (DMSO-d6) δ 13,7 (user., 1H), 13.5 in (user., 1H), and 12.6 (s, 1H), of 8.82 (s, 1H), 7,68 (t, J=8,1 Hz, 1H), 7,18 (d, J=8.4 Hz, 1H), about 6,82 (d, J=8.4 Hz, 1H).

ESI-MS: is 205.9 m/z (MH+).

Example 6

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

2,4-Dichloraniline

A suspension of quinoline-2,4-diol (15 g, 92,6 mmol) in POCl3brought to reflux for 2 hours. After cooling, the solvent was removed under reduced pressure, yielding 2,4-dichloraniline, which is used without further purification.

2,4-Dimethoxyaniline

To a suspension of 2,4-dichloraniline in MeOH (100 ml) was added sodium methoxide (50 g). The mixture is boiled to reflux for a period�s 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure, yielding 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 (11.5 g, to 60.8 mmol) in anhydrous THF was added dropwise n-BuLi (2.5 M solution in hexane, 48.6 ml, 122 mmol) at 0°C. After stirring for 1.5 hours at 0°C the mixture was added to a solution of ethylchloride 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) was heated to reflux in NaOH solution (10%, 100 ml) for 1 hour. After cooling, the mixture was acidified with concentrated Hcl to pH=4. Received odocoileus 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 8,01-8,04 (d, J=12 Hz, 1H), 7,66-7,76 (m, 2H), of 7.42-7,47 (t, J=22 Hz, 2H), of 4.09 (s, 3H), 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-fluorophenyl)methylsulfanyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
A-76-(4-demerol-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-di�hydrochinon-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-aminoindole

Example 1

The General scheme:

(a) RX (X=Cl, Br, I), K2CO3, DMF or CH3CN; (b) H2, Pd/C, EtOH or SnCl2·2H2O, EtOH.

A specific example

1-Methyl-6-nitro-1H-indole

To a solution of 6-nitroindole (4,05 g, 25 mmol) in DMF (50 ml) was added K2CO3(8,63 g of 62.5 mmol) and Me (is 5.33 g, 37.5 mmol). After stirring at room temperature over night the mixture was poured into water and extracted with ethyl acetate. The combined organic layers dried over Na2SO4and concentrated under vacuum to give 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, a 24.4 mmol) and 10% Pd/C (0,43 g) in EtOH (50 ml) was stirred in hydrogen atmosphere (1 ATM) at room temperature over night. After filtration the filtrate is concentrated and acidified with a solution of Hcl-MeOH (4 mol/l), receiving hydrochloride 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

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

1-Benzyl-1H-indol-6-ylamine (B-2) was synthesized following the General scheme above, on the basis of 6-nitroindole and bromide. Overall yield (~40%). HPLC: retention time 2,19 min, 10-99% CH3CN, the analysis time of 5 min.

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

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

1-(6-Aminoindan-1-yl)alanon (B-3) was synthesized following the General scheme presented in�more based on 6-of nitroindole and acetyl chloride. Overall yield (~40%). HPLC: retention time 0.54 min, 10-99% CH3CN, the analysis time of 5 min.

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 mole) in CH2CL2(300 ml) was added, dropwise, isobutylparaben (27,3 g, 0.2 mmol) at -20°C in argon atmosphere. After stirring for 0.5 hours was added, dropwise hydrochloride of the ethyl ester methylaminoethanol acid (30.5 g, 129 mmol) at -20°C. the Mixture is allowed 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 Na2SO4, filtered and concentrated. Balance purify separated by column chromatography (petroleum ether/EtOAc=1:1), obtaining the 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 {[2-(tert-butoxycarbonylmethylene)acetyl]methylamino}acetic acid (12.3 g, to 42.7 mmol) and LiOH (8.9 g, 214 mmol) in N2 About (20 ml) and THF (100 ml) was stirred over night. Volatile solvent was removed under vacuum and the residue was extracted with diethyl ether (2 times 100 ml). The aqueous phase was acidified to pH=3 with dilute Hcl solution and then extracted with CH2CL2(2 × 300 ml). The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrated under vacuum to give {[2-(tert-butoxycarbonylmethylene)acetyl]methylamino}acetic acid as a colorless oil (10 g, yield 90%).

1H-NMR (CDCl3): δ 7,17 (ush.s, 1H), 4,14-of 4.04 (m, 4H), 3,04-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)-2-oxoethyl]carbamoyl}methyl)carbamino acid

To a mixture of {[2-(tert-butoxycarbonylmethylene)acetyl]methylamino}acetic acid (13,8 g, 53 mmol) and TFFH (21.0 g, of 79.5 mmol) in anhydrous THF (125 ml) was added DIEA (with 27.7 ml, 159 mmol) at room temperature in a nitrogen atmosphere. The solution was stirred at room temperature for 20 min. was Added a solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 ml) and the reaction mixture was heated at 60°C for 18 hours. The solvent is evaporated and the crude mixture reallocate between EtOAc and water. The organic layer is separated, washed with water (3 times), dried over Na2SO4and concentrate it. Then add di�tilby ether and EtOAc. The obtained solid substance was separated by filtration, washed with diethyl ether and air dried, yielding tert-butyl ether methyl({methyl[2-(6-nitroindole-1-yl)-2-oxoethyl]carbamoyl}methyl)carbamino acid (6.42 g, yield 30%).

1H-NMR (400 MHz, DMSO-d6) δ to 1.37 (m, 9H), 2,78 (m, 3H), 2,95 (d, J=1.5 Hz, 1H), 3,12 (d, J=2,1 Hz, 2H), 4,01 (d, J=13,8 Hz, 0,6 H), 4,18 (d, J=12.0 Hz, 1,4 H), to 4.92 (d, J=3,4 Hz, 1,4 H), 5.08 mm (d, J=11,4 Hz, 0,6 H), 7,03 (m, 1H), 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 min.

ESI-MS: 405,5 m/z (MH+).

B-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-nitroindole-1-yl)-2-oxoethyl]carbamoyl}methyl)carbamino acid (12.4 g, 30,6 mmol), SnCl2·2H2O (34.5 g, 153,2 mmol) and DIEA (to 74.8 ml, 429 mmol) in ethanol (112 ml) is heated at a temperature of 70°C for 3 hours. Add water and EtOAc and the mixture was 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 (B-26) (11,4 g, quantitative yield).

HPLC: retention time of 2.11 min, 10-99% CH3CN, the analysis time of 5 min.

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

2-Substituted 6-aminoindole

p> Example 1

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

3-Nitrophenylamino (27.6 g, 0.2 mol) was dissolved in a mixture of H2About (40 ml) and 37% Hcl solution (40 ml). Added a solution of NaNO2(13,8 g, 0.2 mol) in N2About (60 ml) at 0°C, then SnCl2·H2O (was 135.5 g, 0.6 mol) in 37% Hcl solution (100 ml) at this temperature. After stirring at 0°C for 0.5 hour, the solid is isolated by filtration and washed with water to give the 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 mole) and ethyl ester of 2-oxopropanoic acid (22,3 g, to 0.19 mol) was dissolved in ethanol (300 ml). The mixture was 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 was used directly in the next step.

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 previous stage was dissolved in toluene (300 ml). Add the PPA (30 g). The mixture is boiled with reverse�m fridge over night and then cooled to room temperature. The solvent was removed, yielding 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) was dropwise added 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 brought to reflux overnight and then cooled to a temperature of 0°C. To the mixture is added N2About at 7.8 ml) and 10% NaOH (7.8 ml) at 0°C. the Insoluble solid was removed by filtration. The filtrate is dried over Na2SO4, filtered and concentrated 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 7.57 the (ush.C; 1H), 7,27 (d, J=8,8 Hz, 1H), 6,62 (s, 1H), is 6.51-a 6.53 (m, 1H), 6,07 (s, 1H), 3,59-of 3.25 (ush.s, 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 (In--b ) (0.5 g, 2,13 mmol) in 10% NaOH (20 ml) was heated to reflux overnight and then cooled to room temperature. The mixture was extracted with diethyl ether. The aqueous phase is separated and acidified with Hcl to pH=1-2. The obtained solid is isolated by filtration, yielding 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 amide and 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) was heated to reflux for 2 hours. The benzene and excess SOCl2removed under reduced pressure. The residue was dissolved in CH2CL2(250 ml). Added dropwise NH4OH (21,76 g 0,32 mol) at 0°C. the Mixture was stirred at room temperature for 1 hour. The obtained solid is isolated by filtration, obtaining the crude amide compound 6-nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H-indole-2-carboxylic acid (9 g, yield 68%) which was used directly in the next step.

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

Amide compound 6-nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H-indole-2-carboxylic acid (5 g, 24 mmol) Sol�critics in CH 2CL2(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 separated. The aqueous layer was extracted with EtOAc (3 times 100 ml). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue is purified column chromatography, yielding 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, 13.4 mmol) and Raney Nickel (500 mg) in EtOH (50 ml) was stirred at room temperature in hydrogen atmosphere (1 ATM) for 1 hour. The Raney-Nickel was filtered off. The filtrate was evaporated under reduced pressure and was purified column chromatography, obtaining 6-amino-1H-indole-2-carbonitrile (B-5) (1 g, yield 49%).

1H-NMR (DMSO-d6): δ of 12.75 (ush.s, 1H), 7,82 (d, J=8 Hz, 1H), EUR 7.57 (s, 1H), of 7.42 (s, 1H), 7,15 (d,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 mole) in CH2CL2add 2,2-dime�ylpropionic (25,3 g, 0,21 mol) at a temperature of 10°C. the Mixture was stirred over night at room temperature, washed with an aqueous solution of Hcl (5%, 80 ml), saturated solution of NaHCO3and saturated brine, dried over Na2SO4and concentrated under vacuum to give 2,2-dimethyl-N-o-tripropionin (35.0 g, yield 92%).

2-tert-Butyl-1H-indole

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 15°C. the Mixture is stirred overnight at a temperature of 15°C, cooled in a bath of ice water and treated with a saturated solution of NH4Cl. The organic layer separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4, 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-indole

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

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

To a solution of compound 2-tert-butyl-2,3-dihydro-1H-indole and 2-tert-butyl-1H-indole (9.7 g) in H2SO4(98%, 80 ml) was slowly added KNO3(5.6 g, up 55.7 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 1 hour, carefully poured on crushed ice, made basic with Na2CO3up to 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-tert-Butyl-6-nitro-1H-indole

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 to reflux for 2.5 hours the mixture was 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 MeOH (10 ml) was added Raney Nickel (0.2 g). The mixture was stirred at room temperature in hydrogen atmosphere (1 ATM) for 3 hours.The resulting mixture was filtered and the filtrate concentrated. The residue was washed with petroleum ether, yielding 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), of 6.46 (s, 1H), of 6.25 (DD, J=1,8, 8,1 Hz, 1H), 5,79 (d, J=1,8 Hz, 1H), 4,52 (s, 2H), 1,24 (s, 9H).

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

3-Substituted 6-aminoindole

Example 1

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

The sodium hydroxide solution (10%, 15 ml) was slowly added 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 room temperature the mixture was poured into ice water and the resulting precipitate is isolated by filtration, washed with water and air dried, yielding N-(3-nitrophenyl)-N'-proprietarytrading, which was used directly in the next step.

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

A mixture of N-(3-nitrophenyl)-N'-proprietarytrading dissolved in 85% H3RO4(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 resulting oil was basified with 10% NaOH to pH=8. The aqueous layer was extracted with EtOAc (3 times 100 ml). The combined org�organic layers are dried, filtered, and concentrated under reduced pressure, yielding a mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (1.5 g, yield 86% for two steps) which was used directly in the next step.

B-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) was stirred overnight under a hydrogen atmosphere (1 ATM) at room temperature. Pd/C was filtered off and the filtrate is concentrated under reduced pressure. Balance purify separated by column chromatography, yielding 3-methyl-1H-indol-6-ylamine (B-7) (0.6 g, yield 24%).

1H-NMR (CDCl3): δ RUB 7.59 (ush.s, 1H), 7,34 (d, J=8,0 Hz, 1H), was 6.77 (s, 1H), only 6.64 (s, 1H), to 6.57 (m, 1H), 3,57 (ush.s, 2H), 2,28 (s, 3H).

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

Example 2

6-Nitro-1H-indole-3-carbonitril

To a solution of 6-nitroindole (with 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 allowed to warm to room temperature and stirred for 2 hours. The mixture was poured into ice water, basified with a saturated solution NaHCO3to pH=7-8, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4/sub> and concentrate, receiving 6-nitro-1H-indole-3-carbonitrile (4.6 g, yield 82%).

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

A suspension of 6-nitro-1H-indole-3-carbonitrile (4.6 g, of 24.6 mmol) and 10% Pd/C (0.46 g) in EtOH (50 ml) was 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-indole-3-carbonitrile (In-8) (1 g, yield 99%) as a pink powder.

1H-NMR (DMSO-d6): δ 11,51 (s, 1H), 7,84 (d,J=2.4 Hz, 1H), 7,22 (d,J=8.4 Hz, 1H), 6,62 (s, 1H), 6,56 (d,J=8.4 Hz, 1H), 5,0 (s, 2H).

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

Example 3

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

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

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

To a mixture of DMF (35 ml) and Me (74,6 g, 0.53 mole) in water (35 ml) and THF (400 ml) �dobavlaut dimethyl(6-nitro-1H-indole-3-ylmethyl)amine (23 g, 0,105 mol). Then the reaction mixture is boiled to reflux for 10 min, was added potassium cyanide (54,6 g, is 0.84 mol) and the mixture continue to boil to reflux over night. The mixture is then cooled to room temperature and filtered. The filtrate was washed with saturated brine (3 x 300 ml), dried over Na2SO4, filtered and concentrated. The residue is purified column chromatography, obtaining (6-nitro-1H-indol-3-yl)acetonitrile (-9-) (7.5 g, yield 36%).

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

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

1H-NMR (DMSO-d6): δ 10,4 (ush.s, 1H), 7,18 (d, J=8.4 Hz, 1H), 6,94 (s, 1H), of 6.52 (s, 1H), to 6.42 (DD, J=8,4, a 1.8 Hz, 1H), 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 (B-9) (8.6 g, 42.8 mmol) in anhydrous THF (200 ml) was added 2M solution of a complex of borane-dimethyl sulfide in THF (214 ml, 0.43 mol) at 0°C. the Mixture is boiled with reverse refrigerator�com over night in a nitrogen atmosphere. The mixture is then cooled to room temperature and add a solution of (BOC)2About (14 g, of 64.2 mmol) and Et3N (89,0 ml, 0.64 mole) in THF. The reaction mixture is left to stir overnight and then poured into ice water. The organic layer separated and the aqueous phase extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with water and saturated brine, dried over Na2SO4, filtered and concentrated 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%).

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

A mixture of tert-butyl methyl ether [2-(6-nitro-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) for 5 hours. The Raney-Nickel was 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 (B-10) (3 g, yield 67;).

1H-NMR (DMSO-d6) δ 10,1 (user.s, 1H), 7,11 (d, J=8.4 Hz, 1H), was 6.77-6,73 (m, 2H), of 6.46 (d, J=1.5 Hz, 1H), 6.32 per (DD, J=8,4, and 2.1 Hz, 1H), 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+).

When�EP 5

The General scheme

(a) RX (X=Br, I), triflic zinc, TBAI, DIEA, toluene; (b) H2, Raney Nickel, EtOH or SnCl2·2H2Oh, EtOH.

A specific example

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

To a mixture of 6-nitroindole (1 g, 6, 2 mmol), triflate zinc (of 2.06 g, 5.7 mmol) and TWO (1.7 g, 5,16 mmol) in anhydrous toluene (11 ml) was added DIEA (1.47 g, to 11.4 mmol) at room temperature in a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes at a temperature of 120°C, then added tert-butylbromide (0,707 g, 5,16 mmol). The resulting mixture was stirred for 45 minutes 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) to obtain 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=to 8.7 Hz, 1H), 7,25 (s, 1H), 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, and 13.7 mmol) and Raney-Nickel (0.5 g) in ethanol was stirred at room temperature in hydrogen atmosphere (1 ATM) for 3 hours. The catalyst was filtered off and the filtrate concentrated to dryness. Balance purify separated by column chromatography on silica gel (petroleum ether/EtOA=4:1), getting 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 (d, J=1.2 Hz, 1H), 6,66 (s, 1H), to 6.57 (DD, J=0,8, or 8.6 Hz, 1H), 3,60 (ush.s, 2H), of 1.42 (s, 9H).

Other examples

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

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

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

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

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

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

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

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

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

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

HPLC: retention time of 2.32 min, 10-99% CH3CN, the analysis time of 5 min.

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

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

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

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

ESI-MS: of 201.5 m/z (MH+).

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

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

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

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

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

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

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

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

4-Substituted 6-aminoindole

2-Methyl-3,5-dinitrobenzoic acid

To the mixture NGO3(95%, 80 ml) and N2SO4(98%, 80 ml) was slowly added 2-methylbenzoic acid (50 g, of 0.37 mol) at 0°C. After complete addition the reaction mixture was stirred for 1.5 �aces, maintaining the temperature below 30°C, poured into ice water and stirred for 15 min the resulting precipitate is separated by filtration and washed with water to give 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) was heated to reflux for 4 hours and then concentrated to dryness. Add CH2CL2(50 ml) and EtOH (80 ml). The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with EtOAc (3 times 100 ml). The combined extracts washed with saturated solution of Na2CO3(80 ml), water (2 times 100 ml) and saturated brine (100 ml), dried over Na2SO4and concentrate to dryness, obtaining the ethyl ester of 2-methyl-3,5-dinitrobenzoic acid (50 g, yield 88%).

Ethyl ether 2-(2-dimethylaminophenyl)-3,5-dinitrobenzoic acid

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

In-18; Ethyl ester of 6-am�but-1H-indole-4-carboxylic acid

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

1H-NMR (DMSO-d6) δ 10,76 (user.s, 1H), 7,11-7,14 (m, 2H), 6,81-about 6,82 (m, 1H), 6,67-6,68 (m, 1H), 4,94 (user.s, 2H), 4,32-of 4.25 (q, J=7,2 Hz, 2H), 1,35-of 1.31 (t, J=7,2, 3H).

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

5-Substituted 6-aminoindole

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-methylbenzol with 27.5 g, 25 mmol) at such a speed that the temperature did not exceed 35°C. the Mixture is left to stir for 30 min at room temperature and poured into ice water (500 �l). The resulting precipitate (a mixture of desired product and 1-fluoro-3-methyl-2,4-dinitrobenzene, approximately 7:3) was separated by filtration and purified by recrystallization from 50 ml of diisopropyl ether, yielding 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) was heated at 100°C for 4 hours. The solution was cooled and poured into water. Red precipitate is separated by filtration, sufficiently washed with water and dried, yielding [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]dimethylamine (8 g, of 31.4 mmol) and Raney Nickel (8 g) in EtOH (80 ml) was stirred in hydrogen atmosphere (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 obtain 5-fluoro-1H-indol-6-ylamine (B-20) in the form of a brown solid (1 g, yield 16%).

1H-NMR (DMSO-d6): δ 10,56 (ush.s, 1H), 7,07 (d, J=12 Hz, 1H), 7,02 (m, 1H), 6,71 (d, J=8 Hz, 1H), 6,17 (s, 1H), of 3.91 (ush.s, 2H).

ESI-MS: 150,1 m/z (MH+).

Other examples

B-21; 5-Chloro-1H-Indo�-6-ylamine

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

1H-NMR (CDCl3): δ of 7.85 (ush.s, 1H), 7,52 (s, 1H), 7,03 (s, 1H), of 6.79 (s, 1H), system 6.34 (s, 1H), of 3.91 (ush.s, 2H).

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

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

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

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

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

Example 2

1-Benzolsulfonat-2,3-dihydro-1H-indole

To a mixture of DMAP (1.5 g), benzolsulfonat (24 g, 136 mmol) and 2,3-dihydro-1H-indole (14.7 g, 124 mmol) in CH2CL2(200 ml) was added, dropwise, Et3N (19 g, 186 mmol) in water bath with ice. After completion of the addition the mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4and concentrated to dryness under reduced pressure, obtaining 1-benzolsulfonat-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) was added acetic anhydride (54 ml). A mixture of peremeci�up within 15 min. Dropwise added a solution of 1-benzolsulfonat-2,3-dihydro-1H-indole (46,9 g, 0.18 mole) in CH2CL2(1070 ml). The mixture is stirred for 5 hours and quenched by the slow addition of crushed ice. The organic layer separated and the aqueous layer was extracted with CH2CL2. The combined organic layers washed with a saturated aqueous solution of NaHCO3and saturated brine, dried over Na2SO4and concentrated under vacuum to give 1-(1-benzazolyl-2,3-dihydro-1H-indol-5-yl)alanon (42,6 g, yield 79%).

1-Benzolsulfonat-5-ethyl-2,3-dihydro-1H-indole

To stir magnetic stirrer TFUK (1600 ml) for 1 hour at 0°C was added sodium borohydride (64 g, 1,69 mol). To this mixture was dropwise added a solution of 1-(1-benzazolyl-2,3-dihydro-1H-indol-5-yl)ethanone (40 g, 0.13 mole) in TFOC (700 ml) for 1 hour. The mixture is stirred over night at 25°C, diluted with H2About (1600 ml) and basified with pellets of sodium hydroxide at 0°C. the Organic layer separated and the aqueous layer was extracted with CH2CL2. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrated under reduced pressure. Balance purify separated by column chromatography on silica gel, receiving 1-benzolsulfonat-5-ethyl-2,3-dihydro-1H-indole (16,2 g, yield 43%)

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

A mixture of 1-benzolsulfonat-5-ethyl-2,3-dihydro-1H-indole (15 g, 0.05 mol) in NVG (48%, 162 ml) was heated to reflux for 6 hours. The mixture was made basic with a saturated solution of NaOH to pH=9 and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated under reduced pressure. Balance purify separated by 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-indole

To a solution of 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 17 mmol) in N2SO4(98%, 20 ml) was slowly added 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, carefully poured over ice, basified with NaOH solution to pH=9 and extracted with ethyl acetate. The combined extracts washed with saturated salt solution, dried over Na2SO4and concentrated to dryness. Balance purify separated by 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-indole

To a solution of 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 9.9 mmol) in CH2CL2(30 ml) was added MnO2(4 g, 46 mmol). The mixture was stirred at room temperature for 8 hours. Solid otfil�throwaway and the filtrate is concentrated to dryness, getting 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 was filtered off and the filtrate concentrated to dryness. Balance purify separated by column chromatography on silica gel, receiving 5-ethyl-1H-indol-6-ylamine (B-23) (760 mg, yield 48%).

1H-NMR (CDCl3) δ 7,90 (user.s, 1H), 7,41 (s, 1H), 7,00 (s, 1H), 6,78 (s, 2H), 6,39 (s, 1H), 3,39 (user.s, 2H), 2,63 (kV, J=7,2 Hz, 2H), of 1.29 (t, J=6,9 Hz, 3H).

ESI-MS: 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) was added dropwise NBS (531 g, 3 mol) in DMF (500 ml) at room temperature. After completion of the addition the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, saturated brine, dried over Na2SO4and concentrate it. The crude product is directly used in next step without further purification.

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

2-Bromo-4-tert-butylbenzylamine (162 g, 0.71 mole) was added, dropwise, to N2SO4(410 ml) at room temperature to obtain a clear solution. Received transp�th solution is then cooled to a temperature in the range from -5°C to -10°C. Dropwise added a solution of KNO3(82.5 g., of 0.82 mol) in N2SO4(410 ml), maintaining the temperature between -5 to -10°C. After complete addition the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with 5% aqueous solution of Na2CO3and saturated brine, dried over Na2SO4and concentrate it. Balance purify separated by column chromatography (EtOAc/petroleum ether=1/10) to give 2-bromo-4-tert-butyl-5-nitroaniline as a yellow solid (152 g, yield 78%).

4-tert-Butyl-5-nitro-2-trimethylsilylmethylamine

To a mixture of 2-bromo-4-tert-butyl-5-nitrophenylamino (27,3 g, 100 mmol) in toluene (200 ml) and water (100 ml) in a nitrogen atmosphere is added Et3N (of 27.9 ml, 200 mmol), Pd(PPh3)2Cl2(2.11 g, 3 mmol), CuI (950 mg, 0.5 mmol) and trimethylsilylacetamide (of 21.2 ml, 150 mmol). The reaction mixture is heated at a temperature of 70°C in a tightly closed flask 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% aqueous solution of NH4OH and water, dried over Na2SO4and concentrate it. The crude product is purified column chromatography (0-10% EtOAc/petroleum ether) to give 4-tert-butyl-5-nitro-2-trimethylsilylmethylamine as a viscous �brown liquid (25 g, the yield 81%).

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

To a solution of 4-tert-butyl-5-nitro-2-trimethylsilylmethylamine (25 g, 86 mmol) in DMF (100 ml) in a nitrogen atmosphere is added CuI (8.2 g, 43 mmol). The mixture was heated at 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 was washed with water, dried over Na2SO4and concentrate it. 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%).

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

The Raney-Nickel (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (14.7 g, 67 mmol) in methanol (100 ml). The mixture was stirred in hydrogen atmosphere (1 ATM) at 30°C for 3 hours. The catalyst was filtered off. The filtrate is dried over Na2SO4and concentrate it. The crude viscous dark brown oil is purified column chromatography (10-20% EtOAc/petroleum ether) to give 5-tert-butyl-1H-indol-6-ylamine (B-24) as a gray solid (11 g, yield 87%).

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

Example 4

5-Methyl-2,4-dinitrobenzene to�slots

To a mixture of HNO3(95%, 80 ml) and H2SO4(98%, 80 ml) was slowly added 3-methylbenzoic acid (50 g, of 0.37 mol) at 0°C. After complete addition the mixture was stirred for 1.5 hours, maintaining the temperature below 30°C. the Mixture was poured into ice water and stirred for 15 min. the Precipitate was separated by filtration and washed with water, yielding 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 obtained mixture in EtOH (150 ml) was added dropwise SOCl2(53.5 g, 0.45 mole). The mixture is brought to reflux for 2 hours and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 ml) and extracted with 10% aqueous solution of Na2CO3(120 ml). 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. The organic layer was washed with saturated brine (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 5-(2-dimethylaminophenyl)-2,4-dinitrobenzoic acid

A mixture of ethyl ester 5-methyl-2,4-dinitrobenzoic acid (39 g, 0.15 mole) and dimethoxyphenylethylamine (32 g, 0.27 mol) in DMF (200 ml) was heated temperature100°C for 5 hours. The mixture was poured into ice water. The precipitate was separated by filtration and washed with water to give ethyl 5-(2-dimethylaminophenyl)-2,4-dinitrobenzoic acid (15 g, yield 28%).

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

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

1H-NMR (DMSO-d6) δ is 10.68 (s, 1H), 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-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 mol) in CH2CL2(600 ml), cooled in a bath of ice water, added dropwise acetyl chloride (of 78.5 g, 1.0 mol). The mixture was 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)alanon� (58,0 g, 0,36 mol) in acetic acid (3000 ml) was added Br2(87.0 g, of 0.54 mol) at a temperature of 10°C. the Mixture was 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 was used directly in the next step.

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

A mixture of crude 1-(5-bromo-2,3-dihydroindol-1-yl)ethanone (100 g, 0.34 mol) in Hcl (20%, 1200 ml) was heated to reflux for 6 hours. The mixture was made basic with a 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 concentrated under reduced pressure. Balance purify separated by 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-indole

To a solution of 5-bromo-2,3-dihydro-1H-indole (45 g, 0,227 mol) in N2SO4(98%, 200 ml) was slowly added 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, carefully poured over ice, basified with a solution of Na2CO3to pH=8 and extracted with ethyl acetate. The combined organic extracts washed with saturated salt solution, dried over Na2SO4and concentrated to dryness. Balance purify separated by column chromatography on silica gel, receiving 5-bromo-6-nitro-2,3-dihydro-1H-indole (42 g, yield 76%).

5-Bromo-6-nitro-1H-indole

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 mole). The mixture was stirred at 80°C for 2 hours. The solid is filtered off and the filtrate concentrated to dryness. Balance purify separated by 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, 31,1 mmol) and Raney Nickel (1 g) in ethanol was stirred in hydrogen atmosphere (1 ATM) at room temperature for 2 hours. The catalyst was filtered off and the filtrate concentrated to dryness. Balance purify separated by column chromatography on silica gel, receiving 5-bromo-1H-indol-6-ylamine (In-27) (2 g, yield 30%).

1H-NMR (DMSO-d6): δ of 10.6 (s, 1H), 7,49 (s, 1H), of 6.79-7,02 (m, 1H), of 6.79 (s, 1H), 6,14-USD 6.16 (m, 1H), to 4.81 (s, 2H).

7-Substituted 6-aminoindole

3-Methyl-2,6-dinitrobenzoic acid

To a mixture of HNO3(95%, 80 ml) and H2SO4(98%, 80 ml) was slowly added 3-methylbenzoic acid (50 g, of 0.37 mol) at 0°C. After complete addition the mixture was stirred for 1.5 hours, maintaining the temperature below 30°C. the Mixture you�ivut in ice water and stirred for 15 min. The precipitate was separated by filtration and washed with water, yielding 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 obtained mixture in EtOH (150 ml) was added dropwise SOCl2(53.5 g, 0.45 mole). The mixture is brought to reflux for 2 hours and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 ml) and extracted with 10% aqueous solution of Na2CO3(120 ml). 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 resulting precipitate is separated by filtration, washed with water and air dried, yielding 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 mole) and SOCl2(80 ml) was heated to reflux for 4 hours. The excess SOCl2removed under reduced pressure and the residue was added dropwise to a solution of EtOH (100 ml) and Et3N (50 ml). The mixture was stirred at 20°C for 1 hour and concentrated to dryness. The residue was dissolved in EtOAc (100 ml), washed with a solution of Na2CO3(10%, 2 times 40 ml), water (2 × 50 ml) and saturated brine (50 ml), dried over Na2SO4and concentrated, obtaining the ethyl ester of 3-methyl-2,6-dinitrobenzene�th acid (20 g, yield 53%).

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

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

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

A mixture of ethyl ester of 3-(2-dimethylaminophenyl)-2,6-dinitrobenzoic acid (30 g, 0,097 mol) and Raney Nickel (10 g) in EtOH (1000 ml) was stirred in hydrogen atmosphere (50 psi) for 2 hours. The catalyst was filtered off and the filtrate concentrated to dryness. Balance purify separated by column chromatography on silica gel, obtaining the ethyl ester of 6-amino-1H-indole-7-carboxylic acid (B-19) as an off-white solid (3.2 g, yield 16%).

1H-NMR (DMSO-d6) δ to 10.38 (s, 1H), 7,44-7,41 (d, J=to 8.7 Hz, 1H), 6,98 (t, 1H), 6,65 (s, 2H), 6,50-of 6.46 (m, 1H), 6,27-of 6.26 (m, 1H), 4,43-4,36 (kV, J=7,2 Hz, 2H), of 1.35 (t, J=7,2 Hz, 3H).

Phenols

Example 1

2-tert-Butyl-5-nitroaniline

To a chilled solution of sulfuric acid (90%, 50 ml) added dropwise 2-tert-butylbenzylamine (4.5 g, 30 mmol) at 0°C. Portionwise addition�make potassium nitrate (4.5 g, 45 mmol) at 0°C. the Reaction mixture was stirred at 0-5°C for 5 min, poured into ice water and then extracted with EtOAc three times. 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-H2About, receiving 2-tert-butyl-5-nitroaniline (3.7 g, yield 64%).

1H-NMR (400 MHz, CDCl3): δ 7,56 (DD, J=to 8.7, 2.4 Hz, 1H), of 7.48 (d, J=2.4 Hz, 1H), of 7.36 (d, J=to 8.7 Hz, 1H), 4,17 (s, 2H), 1,46 (s, 9H).

HPLC: retention time 3,27 min, 10-99% CH3CN, the analysis time of 5 min.

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

C-1-a; 2-tert-Butyl-5-NITROPHENOL

To a mixture of 2-tert-butyl-5-nitroaniline (1,94 g, 10 mmol) in 40 ml of a 15% N2SO4dropwise added a solution of NaNO2(763 mg, 11.0 mmol) in water (3 ml) at 0°C. the resulting mixture was stirred at 0-5°C for 5 min. an Excess of NaNO2neutralized with urea, then add 5 ml of a mixture of H2SO4-N2About (mass./wt.=1:2) and the mixture is boiled to reflux for 5 min. Then add three aliquots of 5 ml of a mixture of H2SO4-N2About (mass./wt.=1:2) while boiling to reflux. The reaction mixture was cooled to room temperature and twice extracted with EtOAc. The combined organic layers washed with saturated� brine, and dried over MgSO 4. After removal of solvent, the residue is purified column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-5-NITROPHENOL (C-1) (1.2 g, yield 62%).

1H-NMR (400 MHz, CDCl3): δ 7,76 (DD, J=8,6, and 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 min.

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

To boiling to reflux a solution of 2-tert-butyl-5-NITROPHENOL (C-1) (196 mg, 1.0 mmol) in EtOH (10 ml) was added ammonium formate (200 mg, 3.1 mmol), then 140 mg of 10% Pd/C. the reaction mixture was brought to reflux 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 (C-1) (144 mg, yield 87%).

1H-NMR (400 MHz, DMSO-d6): δ 8,76 (s, 1H), 6,74 (d, J=8,3 Hz, 1H), 6,04 (d, J=2,3 Hz, 1H), 5,93 (DD, J=8,2, 2,3 Hz, 1H), 4,67 (s, 2H), 1.26 in (s, 9H).

HPLC: retention time 2,26 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: to 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) (100 mg, 0.52 mmol) and K2CO3(86 mg, 0,62 mmol) in DMF (2 ml) was added 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, yielding 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, yield 76%) which was used without further purification.

1H-NMR (400 MHz, CDCl3): δ of 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 to reflux a solution of 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 0.4 mmol) in EtOH (2 ml) was added potassium formate (300 mg, 3.6 mmol) in water (1 ml), then 10% Pd/C (15 mg). Then the reaction mixture is boiled to reflux for 60 min, cooled to room temperature and filtered through celite. The filtrate is concentrated to dryness, yielding 4-tert-butyl-3-methoxyaniline (C-2) (52 mg, yield 72%) which was used without further purification.

HPLC: retention time 2,29 min, 10-99% CH3CN, the analysis time of 5 min.

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

Other examples

C-3; 3-(2-Ethoxyethoxy)-4-tert-butylbenzo�Amin

3-(2-Ethoxyethoxy)-4-tert-butylbenzylamine (C-3) was synthesized following the General scheme above, on the basis of 2-tert-butyl-5-NITROPHENOL (C-1) 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 (t, J=5,2 Hz, 2H), 3,76 (t, J=5,2 Hz, 2H), 3,53 (kV, J=7,0 Hz, 2H), of 1.27 (s, 9H), of 1.16 (t, J=7,0 Hz, 3H).

HPLC: retention time 2,55 min, 10-99% CH3CN, the analysis time of 5 min.

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) was synthesized following the General scheme above, on the basis of 2-tert-butyl-5-NITROPHENOL (C-1) and 2-bromoethanol.

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

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

Example 3

N-(3-Hydroxyphenyl)acetamide and 3-formelementname acetic acid ester

To a vigorously 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 mole) for 30 min at 0°C. After complete addition the reaction mixture was brought to reflux overnight and then cooled to room temperature. An excess of NaHCO3removed by filtration. Filter�t was 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 concentrated under reduced pressure, yielding a mixture of N-(3-hydroxyphenyl)acetamide and 3-formelementname ether acetic acid (35 g, 4:1, according to NMR analysis). The mixture was used directly in the next step.

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

A suspension mixture of N-(3-hydroxyphenyl)acetamide and 3-formelementname ether acetic acid (18,12 g, 0.12 mole), 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 mole) in benzene (250 ml) was heated to reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer separated. The aqueous phase was extracted with EtOAc (3 x 300 ml). The combined organic layers washed with saturated salt solution, dried over anhydrous Na2SO4and concentrate it. Balance purify separated by column chromatography, yielding N-[3-(3-methylbut-3-enyloxy)phenyl]acetamide (11 g, yield 52%).

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

A mixture of N-[3-(3-methylbut-3-enyloxy)phenyl]acetamide (2.5 g, to 11.4 mmol) and AlCl3(4,52 g, to 34.3 mmol) in torbenson (50 ml) was heated to reflux over night. After cooling, the reaction mixture was poured into water. The organic layer separated and the aqueous layer �xtraceroute EtOAc (3 times 40 ml). The combined organic layers washed with saturated salt solution, dried over anhydrous Na2SO4and concentrated in vacuo. Balance purify separated by column chromatography, yielding N-(4,4-DIMETHYLPROPANE-7-yl)acetamide (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)acetamide (1.35 g, 6.2 mmol) in 20% Hcl solution (30 ml) was heated to reflux for 3 hours and then cooled to room temperature. The reaction mixture was made basic with 10% aqueous NaOH to pH=8 and extracted with EtOAc (3 times 30 ml). The combined organic layers washed with saturated salt solution, dried over anhydrous Na2SO4and concentrated, yielding 3,4-dihydro-4,4-dimethyl-2H-chromen-7-amine (C-5) (1 g, yield 92%).

1H-NMR (DMSO-d6) δ of 6.87 (d, J=8.4 Hz, 1H), 6,07 (DD, J=8,4, 2.4 Hz, 1H), 5,87 (d, J=2.4 Hz, 1H), 4.75 in (s, 2H), 3,99 (t, J=5.4 Hz, 2H), 1,64 (t, J=5.1 Hz, 2H), of 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) HNO3, H2SO4or KNO3, H2SO4or HNO3, AcOH; d) piperidine, CH2Cl2; (e) HCO2NH4, Pd/C, EtOH or SnCl2·2H2Oh, EtOH or H2, Pd/C, MeOH.

A specific example/p>

2-tert-Butyl-4-forfinal

4-Terfenol (5 g, 45 mmol) and tert-butanol (5,9 ml, 63 mmol) was dissolved in CH2CL2(80 ml) and treated with concentrated sulfuric acid (98%, 3 ml). The mixture was stirred at room temperature over night. The organic layer was washed with water, neutralized with NaHCO3, dried over MgSO4and concentrate it. Balance purify separated by 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 9,32 (s, 1H), 6,89 (DD, J=11,1, at 3.1 Hz, 1H), 6,84-of 6.79 (m, 1H), 6,74 (DD, J=8,7, with 5.3 Hz, 1H), of 1.33 (s, 9H).

2-tert-Butyl-4-performancebut

To a solution of 2-tert-butyl-4-terfenol (2,63 g, a 15.7 mmol) and Net3(3,13 ml of 22.5 mmol) in dioxane (45 ml) was added methylchloroform (1,27 ml, 16.5 mmol). The mixture was stirred at room temperature for 1 hour. The precipitate is removed by filtration. The filtrate is then diluted with water and extracted with diethyl ether. Extract in diethyl ether was washed with water and dried over MgSO4. After removal of solvent, the residue is purified column chromatography, obtaining 2-tert-butyl-4-performancebut (2.08 g, yield 59%).

1H-NMR (400 MHz, DMSO-d6): δ of 7.24 (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-) and 2-tert-butyl-4-for-nitrophenylarsonic ( C-6-)

To a solution of 2-tert-butyl-4-performancebut (1,81 g, 8 mmol) in N2SO4(98%, 1 ml) was slowly added a cooled mixture of N2SO4(1 ml) and HNO3(1 ml) at 0°C. the Mixture was stirred for 2 hours until it warms up to room temperature, poured over ice and extracted with diethyl ether. Extract in diethyl ether washed with saturated brine, dried over MgSO4and concentrate it. Balance purify separated by column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-4-fluoro-5-nitrophenylarsonic (C-7-) (1.2 g, yield 55%) and 2-tert-butyl-4-fluoro-6-nitrophenylarsonic (C-6-) (270 mg, yield 12%).

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

1H-NMR (400 MHz, DMSO-d6): δ 8,24 (d, J=7,1 Hz, 1H), 7,55 (d, J=13,4 Hz, 1H), 3,90 (s, 3H), 1,32 (s, 9H).

2-tert-Butyl-4-fluoro-6-nitrophenylarsonic (C-6-):

1H-NMR (400 MHz, DMSO-d6): δ and 8.04 (DD, J=to 7.6 and 3.1 Hz, 1H), 7,69 (DD, J=10,1, at 3.1 Hz, 1H), of 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-nitrophenylarsonic (C-7-) (1,08 g, 4 mmol) in CH2Cl2(40 ml) was added piperidine (3.94 in ml, 10 mmol). The mixture was stirred at room temperature for 1 hour and extracted with 1N. NaOH (3 times). The aqueous layer was acidified with 1N. a solution of Hcl and extracted with diethyl e�Il. Extract in diethyl ether washed with saturated salt solution, dried (MgSO4) and concentrated, yielding 2-tert-butyl-4-fluoro-5-NITROPHENOL (530 mg, yield 62%).

1H-NMR (400 MHz, DMSO-d6): δ 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-forfinal

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

1H-NMR (400 MHz, DMSO-d6): δ 8,83 (ush.s, 1H), 6,66(d, J=13,7 Hz, 1H), from 6.22 (d, J=8,5 Hz, 1H), 4,74 (ush.s, 2H), 1.26 in (s, 9H).

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

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) was synthesized following the General scheme above, on the basis of 4-chlorophenol and tert-butanol. Overall yield (6%).

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

ESI-MS: of 200.2 m/z (MH+).

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

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

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

ESI-MS: 224,2 m/z (MH+).

C-19; 5-Amino-2-(3-ethylpent-3-yl)-4-forfinal

5-Amino-2-(3-ethylpent-3-yl)-4-terfenol (C-19) was synthesized following the General scheme above, on the basis of 4-terfenol and 3-ethyl-3-pentothal. Total output (1%).

C-20; 2-Adamantyl-5-amino-4-forfinal

2-Adamantyl-5-amino-4-terfenol (C-20) was 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-methylcyclohexyl)phenol (S-21) was 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) was 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-forfinal

5-Amino-2-(3-ethyl-2,2-dimethyle�tan-3-yl)-4-terfenol ( S-23) was synthesized following the General scheme above, on the basis of 4-terfenol and 3-ethyl-2,2-dimethylpentan-3-ol.

Example 5

C-6; 2-tert-Butyl-4-fluoro-6-aminopenicillanic

To boiling to reflux a solution of 2-tert-butyl-4-fluoro-6-nitrophenylacetate (250 mg, 0,92 mmol) and ammonium formate (250 mg, 4 mmol) in EtOH (10 ml) was added 5% Pd/C (170 mg). The mixture is then brought to reflux for 1 hour, cooled and filtered through celite. The solvent was removed by evaporation and the residue is purified column chromatography (0-15% EtOAc-hexane) to give 2-tert-butyl-4-fluoro-6-aminopenicillanic (C-6) (60 mg, yield 27%).

HPLC: retention time 3,35 min, 10-99% CH3CN, the analysis time of 5 min.

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) was added, dropwise, to a solution of 2,4-di-tert-butylphenol (a 103.2 g, 500 mmol), Et3N (139 ml, 1000 mmol) and DMAP (3,05 g, 25 mmol) in dichloromethane (400 ml), cooled in a bath of ice water at 0°C. the Mixture is allowed to warm to room temperature while stirring overnight, then filtered over silica gel (approximately 1 l), using �rity 10% ethyl acetate-hexane (~4 l) as eluent. The combined filtrates 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 7,35 (d, J=2.4 Hz, 1H), 7,29 (DD, J=Of 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 the cooled mixture of sulfuric acid (2 ml) and nitric acid (2 ml). The addition is carried out slowly so that the reaction temperature did not exceed 50°C. the Reaction mixture is left to stir for 2 hours until it warms up to room temperature. The reaction mixture was then poured into water with ice and extracted with diethyl ether. The diethyl ether layer was dried (MgSO4), concentrate and purify separated by column chromatography (0-10% ethyl acetate-hexane), yielding 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-nitrophenylamino ether of carbonic acid in the form of a pale yellow solid (4,28 g), motoroils directly in the next step.

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 MeOH (65 ml) and added KOH (2.0 g, 36 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then acidified (pH=2-3) by addition of concentrated Hcl and partitioned between water and diethyl ether. The diethyl ether layer was dried (MgSO4), concentrate and purify separated by column chromatography (0-5% ethyl acetate-hexane), yielding 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:

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), 1,30 (C, 9H).

2,4-di-tert-Butyl-6-NITROPHENOL:

1H-NMR (400 MHz, CDCl3): δ 11,48 (s, 1H), 7,98 (d, J=2.5 Hz, 1H), 7,66 (d, J=2.4 Hz, 1H), of 1.47 (s, 9H), of 1.34 (s, 9H).

S-9; 5-Amino-2,4-di-tert-butylphenol

To boiling to reflux a solution of 2,4-di-tert-butyl-5-NITROPHENOL (of 1.86 g, 7.4 mmol) and ammonium formate (1,86 g) in ethanol (75 ml) was added 5 wt%. palladium-on-charcoal (Pd/C) (900 mg). The reaction mixture was stirred while boiling to reflux for 2 hours, cooled to room temperature and filtered through C�lit. Celite was washed with methanol and the combined filtrates concentrated, yielding 5-amino-2,4-di-tert-butylphenol in the form of a grey solid (1.66 g, quantitative yield).

1H-NMR (400 MHz, DMSO-d6): δ 8,64 (s, 1H, HE), at 6.84 (s, 1H), 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 min.

ESI-MS: 222,4 m/z (MH+).

C-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) was heated in a microwave at 100°C for 30 min. the Mixture was diluted with EtOAc and water, made basic with a saturated solution of NaHCO3and filtered through celite. The organic layer separated and dried over Na2SO4. The solvent was removed by evaporation, yielding 6-amino-2,4-di-tert-butylphenol (C-8), which is used without further purification.

HPLC: retention time of 2.74 min, 10-99% CH3CN, the analysis time of 5 min.

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 mole) and SO2Cl2(37,5 g, 0.28 mole) in CH2Cl2added MeOH (9.0 g, 0.28 mol) at 0°C. After complete addition the mixture is stirred over night at room temperature and then added water (20 ml). The resulting solution was extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Balance purify separated by column chromatography (petroleum ether/EtOAc=50:1) to give 4-tert-butyl-2-chlorophenol (47,0 g, yield 95%).

4-tert-Butyl-2-khlorfenilalanina

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 is allowed to warm to room temperature and then stirred for 30 min. the Reaction mixture was washed with H2Oh, the organic layer dried over Na2SO4and concentrated, obtaining 4-tert-butyl-2-khlorfenilalanina (56.6 g, yield 92%) which was used directly in the next step.

4-tert-Butyl-2-chloro-5-nitrophenylarsonic

4-tert-Butyl-2-khlorfenilalanina (36,0 g, 0.15 mole) was dissolved in concentrated H2SO4(100 ml) at 0°C. Portions add KNO3(Of 0.53 g, 5.2 mmol) over 25 min. the Reaction mixture was stirred for 1.5 hours and poured over ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers washed with aqueous solution of NaHCO3, dried over Na2SO4and concentrated under vacuum to give 4-tre�-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) was added to 4-tert-butyl-2-chloro-5-nitrophenylarsonic (40,0 g, 139 mmol) in MeOH (100 ml). After 30 min, the reaction mixture was acidified with 1N. a solution of Hcl and extracted with dichloromethane. The combined organic layers were 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 MeOH (50 ml) was added Ni (1.2 g). The reaction mixture is shaken in hydrogen atmosphere (1 ATM) for 4 hours. The reaction mixture was filtered and the filtrate concentrated. Balance purify separated by 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 9,33 (s, 1H), 6,80 (s, 1H), from 6.22 (s, 1H), 4,76 (s, 1H), 1,23 (s, 9H).

ESI-MS: 200,1 m/z (MH+).

Example 8

2-Adamantyl-4-methylphenylethylamine

Ethylchloride (of 0.64 ml, 6.7 mmol) was added, dropwise, to a solution of 2-adamantyl-4-METHYLPHENOL (1,09 g, 4.5 mmol), Et3N (1.25 ml, 9 mmol) and DMAP (catalytic amount) in d�the chloromethane (8 ml), cooled on a water bath with ice, at 0°C. the Mixture is allowed to warm to room temperature while stirring overnight, then filtered and the filtrate concentrated. Balance purify separated by column chromatography (10-20% ethyl acetate-hexane), getting 2-adamantyl-4-methylphenylethylamine in the form of a yellow oil (1,32 g, yield 94%).

2-Adamantyl-4-methyl-5-nitrophenylarsonic

To a chilled solution of 2-adamantyl-4-methylphenylethylamine (1,32 g, 4.2 mmol) in N2SO4(98%, 10 ml) was added in small portions KNO3(510 mg, 5.0 mmol) at 0°C. the Mixture was stirred for 3 hours until it warms up to room temperature, poured over ice and then extracted with dichloromethane. The combined organic layers were washed with a solution of NaHCO3and saturated brine, dried over MgSO4and concentrated to dryness. Balance purify separated by column chromatography (0-10% EtOAc-hexane) to obtain 2-adamantyl-4-methyl-5-nitrophenylarsonic (378 mg, yield 25%).

2-Adamantyl-4-methyl-5-NITROPHENOL

To a solution of 2-adamantyl-4-methyl-5-nitrophenylacetate (378 mg, 1.05 mmol) in CH2CL2(5 ml) was 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), getting 2-adamantyl-4-methyl-5-NITROPHENOL (231 mg, yield 77%).

C-12; 2-Adamantyl-4-methyl-5-aminophenol

To a solution of 2-adamantyl-4-methyl-5-NITROPHENOL (231 mg, 1.6 mmol) in EtOH (2 ml) was added 5 wt%. palladium-on-coal (10 mg). The mixture was stirred in hydrogen atmosphere (1 ATM) overnight and then filtered through celite. The filtrate is evaporated to dryness, yielding 2-adamantyl-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 min.

ESI-MS: 258,3 m/z (MH+).

Example 9

2-tert-Butyl-4-Bromphenol

To a solution of 2-tert-butylphenol (250 g, 1.67 mol) in CH3CN (1500 ml) was added NBS (300 g, 1.67 mol) at room temperature. After completion of the addition the mixture was stirred at room temperature overnight and then the solvent was removed. Add petroleum ether (1000 ml) and the obtained white precipitate was filtered off. The filtrate was 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 restropo drops add methylchloroform (155 ml) at 0°C. After completion of the addition the mixture was stirred at 0°C for 2 hours, quenched with saturated aqueous ammonium chloride and diluted with water. The organic layer separated and washed with water and saturated brine, dried over Na2SO4and concentrated, obtaining the 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) was dissolved in concentrated H2SO4(1000 ml) at 0°C. Portions add KNO3(253 g, 2.5 mol) for 90 min. the Reaction mixture was stirred at 0°C for 2 hours and poured into ice water (20 l). The resulting precipitate is separated by filtration and thoroughly washed with water, dried and recrystallized from diethyl ether, yielding 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 per g, 0,549 mol). After completion of the addition the mixture was stirred at room temperature for 3 hours and acidified with 1N. a solution of Hcl to pH=7. The methanol was removed and water was added. The mixture extramuralization and the organic layer separated, dried over Na2SO4and concentrate, receiving 2-tert-butyl-4-bromo-5-NITROPHENOL (C-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 (C-14-) (1.1 g, 4 mmol) and Cs2CO3(1,56 g, 4.8 mmol) in DMF (8 ml) was added the bromide (500 μl, 4.2 mmol). The mixture was 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 obtain 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (1.37 g, yield 94%).

1H-NMR (400 MHz, CDCl3): δ 7.62 mm (s, 1H), 7,53 (s, 1H), 7,43 (m, 5H), 5,22 (s, 2H), of 1.42 (s, 9H).

1-tert-Butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene

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), methylchloroform (1.6 ml, 15 mmol) and DMF (5 ml) was stirred at 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 by chronochromie (0-5% EtOAc-hexane), getting 1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (591 mg, yield 67%).

1H-NMR (400 MHz, CDCl3): δ 7,66 (s, 1H), value of 7, 37 (m, 5H), of 7.19 (s, 1H), to 5.21 (s, 2H), 1,32 (s, 9H).

C-14; 5-Amino-2-tert-butyl-4-triptoreline

To boiling to reflux 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) was added 10% Pd/C (245 mg). The mixture is then brought to reflux 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-cryptomaterial (C-14) (120 mg, yield 52%).

1H-NMR (400 MHz, CDCl3): δ 7,21 (s, 1H), to 6.05 (s, 1H), of 1.28 (s, 9H).

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

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

Example 10

The General scheme

a) ArB(OH)2, K2CO3, Pd(PPh3)4, H2O, DMF or ArB(OH)2, (dppf)PdCl2, K2CO3Hcl , EtOH; (b) H2, Raney Nickel, MeOH or HCO2NH4, Pd/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 (C-14-) (8,22 g, 30 mmol) in DMF (90 ml) d�billaut 2-ethoxypropionate 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 was heated at 90°C for 3 hours in a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue is partitioned between water and ethyl acetate. The combined organic layers were washed with water and saturated brine, 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 to 10.38 (s, 1H), of 7.36 (s, 1H), 7,28 (m, 2H), was 7.08 (s, 1H), 6,99 (t, 1H, J=7,35 Hz), at 6.92 (d, 1H, J=8,1 Hz), 3,84 (kV, 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-NITROPHENOL (3.0 g, 9.5 mmol) in methanol (30 ml) was added Raney Nickel (300 mg). The mixture was stirred in hydrogen atmosphere (1 ATM) at room temperature for 2 hours. The catalyst was filtered off and the filtrate concentrated. Balance purify separated by column chromatography (petroleum ether / ethyl acetate=6:1), receiving 2-tert-butyl-4-(2-ethoxyphenyl)-5-aminophenol (S-15) (2,35 g, yield 92%).

1H-NMR (DMSO-d6) δ 8,89 (s, 1H), of 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 (kV, 2H, J=6,9 Hz), 1.26 in (s, 9H), To 1.21 (t, 3H, J=6,9 Hz).

ESI-MS: 286,0 m/z (MH+).

Other �the company

S-16; 2-tert-Butyl-4-(3-ethoxyphenyl)-5-aminophenol

2-tert-Butyl-4-(3-ethoxyphenyl)-5-aminophenol (S-16) was synthesized following the General scheme above, on the basis of 2-tert-butyl-4-bromo-5-NITROPHENOL (C-14-3. ethoxypropionate acid.

HPLC: retention time of 2.77 min, 10-99% CH3CN, the analysis time of 5 min.

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) was synthesized following the General scheme above, on the basis of 2-tert-butyl-4-bromo-5-NITROPHENOL (C-14-) and 3-(methoxycarbonyl)phenylboronic acid.

HPLC: retention time 2.70 m min, 10-99% CH3CN, the analysis time of 5 min.

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 (C-14-) (1.5 g, 5.5 mmol) and Cs2CO3(2.2 g, 6,6 mmol) in DMF (6 ml) was added methyliodide (5150 μl of 8.3 mmol). The mixture was 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 the solvent the residue was washed with hexane�, getting 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), methylchloroform (2.2 ml, 21,0 mmol) in DMF (5 ml) was stirred at 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 obtain 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-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 to reflux 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) was added 10% Pd/C (200 mg). The mixture is boiled to reflux for 1 hour, cooled and filtered through celite. The solvent was removed by evaporation, yielding 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-aminobenzoyl (C-18/b> ) (403 mg, yield 95%).

1H-NMR (400 MHz, CDCl3): δ of 7.19 (s, 1H), 6,14 (s, 1H), was 4.02 (ush.s, 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 (C-14-) (12 g, with 43.8 mmol) in MeOH (90 ml) was added Ni (2.4 g). The reaction mixture was stirred in hydrogen atmosphere (1 ATM) for 4 hours. The mixture was filtered and the filtrate concentrated. The crude product was recrystallized from ethyl acetate and petroleum ether, yielding 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), for 6.24 (s, 1H), 4,90 (ush.s, 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) was stirred while boiling to reflux for 3 hours. After removal of solvent, the residue is purified column chromatography (petroleum ether-EtOAc=30:1), yielding 2,4-di-tert-butyl-6-(N-methylamino)phenol (S-24) (800 mg, yield 15%).

1H-NMR (DMSO-d6): δ 8,67 (s, 1H), at 6.84 (s, 1H), of 5.99 (s, 1H), 4,36 (sq,J=4,8 Hz, 1H), 2,65 (d,J=4,8 Hz, 3H), 1,23 (s, 18H).

ESI-MS: 236,2 m/z (MH+).

Example 14

2-Methyl-2-phenylpropan-1-ol

To a solution of 2-methyl-2-fenilpropionovoy acid (82 g, 0.5 mol) in THF (200 ml) was added, dropwise, porandamaterjalid (2M, 100 ml) at a temperature of 0-5°C. the Mixture was stirred at this temperature for 30 min and then brought to reflux for 1 hour. After cooling, add methanol (150 ml) and water (50 ml). The mixture was extracted with EtOAc (3 times 100 ml) and the combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated, obtaining 2-methyl-2-phenylpropan-1-ol as an 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) was added, dropwise, a solution of 2-methyl-2-phenylpropan-1-ol (75 g, 0.5 mol) in THF (50 ml) at 0°C. the Mixture was stirred at 20°C for 30 min and then added dropwise a solution of 1-bromo-2-ethoxyethane (104 g, 0.75 mol) in THF (100 ml) at 0°C. the Mixture was stirred at 20°C overnight, poured into water (200 ml) and extracted with EtOAc (3 times 100 ml). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrate it. Balance purify separated by column chromatography (silica gel, petroleum ether) to give 2-[(2-methoxyethoxy)-1,1-dim�teletel]benzene as an 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 l3(200 ml) was added KNO3(50.5 g, 0.5 mol) and TMSCl (54 g, 0.5 mol). The mixture was stirred at 20°C for 30 min and then added AlCl3(95 g, 0.7 mole). The reaction mixture was stirred at 20°C for 1 hour and poured into ice water. The organic layer separated and the aqueous layer was extracted with l3(3 times 50 ml). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrate it. Balance purify separated by column chromatography (silica gel, petroleum ether) to give 1-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-4-nitrobenzene (6 g, yield 10%).

4-[2-(2-Methoxyethoxy)-1,1-dimethylethyl]Veniamin

A suspension of 1-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-4-nitrobenzene (8.1 g, 32 mmol) and Raney Nickel (1 g) in MeOH (50 ml) was stirred in hydrogen atmosphere (1 ATM) at room temperature for 1 hour. The catalyst was 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 N2SO4(20 ml) was added KNO3(2,63 g, 26 mmol) �ri a temperature of 0°C. After completion of the addition the mixture was stirred at this temperature for 20 min and then poured into ice water. The mixture was extracted with EtOAc (3 times 50 ml). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrate it. Balance purify separated by column chromatography (petroleum ether-EtOAc=100:1) to give 4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenylamino (5 g, yield 71%).

N-{4-[2-(2-Methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenyl}acetamide

To a suspension of NaHCO3(10 g, 0.1 mol) in dichloromethane (50 ml) was added 4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenylamino (5 g, 30 mmol) and acetyl chloride (3 ml, 20 mmol) at a temperature of 0-5°C. the Mixture was stirred over night at 15°C and then poured into water (200 ml). The organic layer separated and the aqueous layer was extracted with dichloromethane (2 times 50 ml). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrate to dryness, obtaining N-{4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenyl}acetamide (5.0 g, yield 87%).

N-{3-Amino-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}acetamide

A mixture of N-{4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]-3-nitrophenyl}acetamide (5 g, 16 mmol) and Raney Nickel (1 g) in MeOH (50 ml) was stirred in hydrogen atmosphere (1 ATM) at room temperature for 1 �Asa. The catalyst was filtered off and the filtrate concentrated. Balance purify separated by column chromatography (petroleum ether-EtOAc=100:1) to give N-{3-amino-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}acetamide (1.6 g, yield 35%).

N-{3-Hydroxy-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}acetamide

To a solution of N-{3-amino-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}acetamide (1.6 g, 5.7 mmol) in N2SO4(15%, 6 ml) was added NaNO2at a temperature of 0-5°C. the Mixture was stirred at this temperature for 20 min and then poured into ice water. The mixture was extracted with EtOAc (3 times 30 ml). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrate it. Balance purify separated by column chromatography (petroleum ether-EtOAc=100:1) to give N-{3-hydroxy-4-[2-(2-methoxyethoxy)-1,1-dimethylethyl]phenyl}acetamide (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}acetamide (1 g, 3.5 mmol) and Hcl (5 ml) was heated to reflux for 1 hour. The mixture was made basic with a solution of Na2CO3to pH=9 and then extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated to dryness. The residue is purified column� chromatography (petroleum ether-EtOAc=100:1), getting 2-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol (S-25) (61 mg, yield 6%).

1H-NMR (CDCl3) δ 9,11 (user.s, 1H), of 6.96-6,98 (d, J=8 Hz, 1H), of 6.26-6,27 (d, J=4 Hz, 1H), 6,17-6,19 (m, 1H), 3,68-of 3.69 (m, 2H), 3,56-3,59 (m, 4H), 3,39 (s, 3H), of 1.37 (s, 6H).

ESI-MS: to 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, 19,1 mmol) in acetic acid (115 ml) was slowly added HNO3(15 ml). The mixture was heated at 60°C for 40 min before pouring in the H2About (50 ml). The mixture is left to stand at room temperature for 2 hours, then placed for 1 hour in an ice bath. The solid is collected and washed with water to give 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 (s, 1H), of 1.27 (s, 9H), 1,24 (s, 9H).

4,6-di-tert-Butyl-3-nitrobenzene-1,2-diol

To make a separatory funnel 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). The funnel is stoppered and shaken for 2 min. the Mixture was diluted with EtOAc (20 ml). The layers were separated and the organic layer washed with saturated brine, dried over MgSO4and concentrated, yielding 4,6-di-tert-b�teel-3-nitrobenzene-1,2-diol (3.4 g, yield 74%) which was used without further purification.

1H-NMR (400 MHz, DMSO-d6): δ 9,24 (s, 1H), 8,76 (s, 1H), 6,87 (s, 1H), of 1.35 (s, 9H), 1,25 (s, 9H).

C-26; 4,6-di-tert-Butyl-3-aminobenzene-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) was added 5 wt%. palladium-on-charcoal (200 mg). The mixture was stirred in hydrogen atmosphere (1 ATM) for 2 hours. In the reaction mixture is added 5% by weight. palladium-on-charcoal (200 mg) and stirred in hydrogen atmosphere (1 ATM) for 2 hours. The mixture was filtered through celite, the filtrate concentrated and purified column chromatography (10-40% ethyl acetate-hexane) to give 4,6-di-tert-butyl-3-aminobenzene-1,2-diol (C-26) (560 mg, yield 33%).

1H-NMR (400 MHz, CDCl3): δ 7,28 (s, 1H), of 1.42 (s, 9H), to 1.38 (s, 9H).

Aniline

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 over night. Water was added and the mixture is then basified to pH=7-8 with saturated solution of NaHCO3. The solution was extracted with ethyl acetate. The combined organic layers washed with saturated salt solution, dried on� Na 2SO4, filtered and concentrated, obtaining 4-chlorobenzene-1,3-diamine (D-1) (79 mg, quantitative yield).

HPLC: retention time of 0.38 min, 10-99% CH3CN, the analysis time of 5 min.

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) was 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 min.

ESI-MS: 177,1 m/z (MH+).

D-3; 4-Methoxybenzoyl-1,3-diamine

4-Methoxybenzoyl-1,3-diamine (D-3) was synthesized following the General scheme above, on the basis of 1-methoxy-2,4-dinitrobenzene. Output (quantitative).

HPLC: retention time 0,31 min, 10-99% CH3CN, the analysis time of 5 min.

D-4; 4-Cryptomaterial-1,3-diamine

4-Cryptomaterial-1,3-diamine (D-4) was 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 min.

ESI-MS: 193,3 m/z (MH+).

D-5; 4-Propoxybenzene-1,3-diamine

4-Propoxybenzene-1,3-diamine (D-5) was synthesized, with�edua the overall scheme of things above, on the basis of 5-nitro-2-propoxyphenyl. Output (79%).

HPLC: retention time 0.54 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 167,5 m/z (MH+).

Example 2

The General scheme

(a) HNO3, H2SO4; (b) SnCl2·2H2Oh, EtOH or H2, Pd/C, MeOH.

A specific example

2,4-Dinitropropanol

A solution of propylbenzene (10 g, 83 mmol) in concentrated H2SO4(50 ml) was cooled to 0°C for 30 min and the portions was added a solution of N2SO4(50 ml) and fuming HNO3(25 ml), previously cooled to 0°C for 15 min. Then the mixture was stirred at 0°C for 30 min and then allowed to warm to room temperature. The mixture was poured into a mixture of ice (200 g) with water (100 ml) and extracted with diethyl ether (2 times 100 ml). The combined extracts were washed with H2O (100 ml) and saturated brine (100 ml), dried over MgSO4, filtered and concentrated, yielding 2,4-dinitropropanol (15.6 g, yield 89%).

1H-NMR (CDCl3, 300 MHz) δ 8,73 (d, J=2,2 Hz, 1H), to 8.38 (DD, J=8,3, J=2,2, 1H), and 7.6 (d, J=8,5 Hz, 1H), 2,96 (DD, 2H), 1,73 (m, 2H), of 1.06 (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) is added�t SnCl 2(9,9 g, 52 mmol), then concentrated HCl (10 ml). The mixture is brought to reflux for 2 hours, poured into ice water (100 ml) and neutralized with solid sodium bicarbonate. The solution was then made basic with 10% NaOH 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 need to be further purified for use in the next stage; however, the product is not stable over a long period of time.

1H-NMR (CDCl3, 300 MHz) δ about 6,82 (d, J=7.9 Hz, 1H), 6,11 (DD, J=7,5, J=2,2 Hz, 1H), of 6.06 (d, J=2,2 Hz, 1H), 3,49 (user.s, 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) was synthesized following the General scheme above, on the basis of ethylbenzene. Overall yield (76%).

D-8; 4-Isopropylbenzene-1,3-diamine

4-Isopropylbenzene-1,3-diamine (D-8) was synthesized following the General scheme above, on the basis of isopropylbenzene. Overall yield (78%).

D-9; 4-tert-Butylbenzoyl-1,3-d�Amin

4-tert-Butylbenzoyl-1,3-diamine (D-9) was synthesized following the General scheme above, on the basis of tert-butylbenzene. Overall 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) and 3.59 (user., 4H), of 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) KNO3, H2SO4; (b) (i) HNO3, H2SO4; (ii) Na2S, S, H2O; c) Vos2O, NaOH, THF; (d) H2, Pd/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 N2SO4(98%, 60 ml), slowly add KNO3(8.1 g, 80,41 mmol) at 0°C. After complete addition the reaction mixture is allowed to warm to room temperature and stirred over night. The mixture was then poured into ice water and made basic with a saturated solution of NaHCO3to pH=8. The mixture was several times extracted with CH2CL2. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate it. Balance purify separated by column chromatography (petroleum ether-EtOAc=10:1) to give 4-tert-butyl-3-nitrophenylamino (10 g, yield 77%).

<> tert-Butyl ether (4-tert-butyl-3-nitrophenyl)carbamino acid

A mixture of 4-tert-butyl-3-nitrophenylamino (4.0 g, 20.6 mmol) and BOC2About (4.72 in g, 21.6 mmol) in NaOH (2n., 20 ml) and THF (20 ml) was stirred at room temperature over night. THF was removed under reduced pressure. The residue was dissolved in water and extracted with CH2CL2. The organic layer was washed with NaHCO3and saturated brine, dried over Na2SO4and concentrate, receiving tert-butyl ether (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 MeOH (40 ml) was 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 obtain tert-butyl methyl ether (3-amino-4-tert-butylphenyl)carbamino acid (D-10) in the form of a brown oil (2.5 g, yield 93%).

1H-NMR (CDCl3) δ 7,10 (d, J=8.4 Hz, 1H), at 6.92 (s, 1H), 6,50-a 6.53 (m, 1H), 6,36 (s, 1H), 3,62 (user.s, 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-Amin�-4-isopropylphenyl)carbamino acid

tert-Butyl methyl ether (3-amino-4-isopropylphenyl)carbamino acid (D-11) was synthesized following the General scheme above, on the basis of isopropylbenzene. Overall 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) was synthesized following the General scheme above, on the basis of ethylbenzene. Overall yield (64%).

1H-NMR (CD3OD 300 MHz) δ of 6.87 (d, J=8,0 Hz, 1H), of 6.87 (d, J=8,0 Hz, 1H), is 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) was synthesized following the General scheme above, on the basis of propylbenzene. Overall yield (48%).

Example 4

Benzyl ether (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/MeOH (12/1,8 ml) was cooled to 0°C and dropwise added a solution of benzylchloride (of 0.51 ml, 3.6 mmol) in CH2CL2(8 ml) for 10 min. the Mixture was stirred at 0°C in the Techa�s 15 min, then heated to room temperature. After 1 hour, the mixture was washed with 1M citric acid solution (2 × 20 ml), saturated aqueous sodium bicarbonate solution (20 ml), dried (Na2SO4), filtered and concentrated in vacuum to give crude benzyl ether (3-amino-4-tert-butylphenyl)carbamino acid in the form of a brown viscous resin (0,97 g), used without further purification.

1H-NMR (400 MHz, CDCl3) δ 7,41-7,32 (m, 6H,), 7,12 (d, J=8,5 Hz, 1H) 6,89 (user.s, 1H), to 6.57 (DD, J=2,3, 8,5 Hz, 1H), 5,17 (s, 2H), 3,85 (user.s, 2H), 1,38 (s, 9H).

13C-NMR (100 MHz, CDCl3the 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-butylphenyl)carbamino acid (or = 0.97 g, 3.25 mmol) and pyridine (0,43 ml of 5.25 mmol) in CH2CL2(7.5 ml) was cooled to 0°C and within 2 minutes, dropwise added 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 EQ.), undiluted and aged for 1 hour) in CH2CL2(2.5 ml). After completion of the addition the mixture is allowed to warm to room temperature, after �it in her precipitate, and the resulting suspension was stirred over night. The mixture was washed with 1M citric acid solution (2 × 20 ml), saturated aqueous sodium bicarbonate solution (20 ml), dried (Na2SO4) and filtered. From the muddy mixture is deposited a thin layer of solids on top of the dryer, and HPLC-analysis shows that it is a required formamide. The filtrate was concentrated to a volume of approximately 5 ml and diluted with hexane (15 ml) for further deposition of formamide. Dehumidifier (Na2SO4) suspended in methanol (50 ml), filtered off and the filtrate was combined with the substance, recrystallized from a mixture of CH2CL2/hexane. The resulting mixture was concentrated, yielding the benzyl ether (4-tert-butyl-3-formylamino)carbamino acid as an off-white solid (650 mg, yield 50% over 2 stages).1H and13C-NMR (CD3OD) show that the product is in the form of a mixture of rotamers.

1H-NMR (400 MHz, CD3OD, mixture of rotamers) δ 8,27 (s, 1H), 8,17 (s, 1H-(b), of 7.42-7,26 (m, 8H), 5,17 (s, 1H), 5,15 (1H-b), with 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)formamide

In a flask of 100 ml enter�t 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 in 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 as an off-white solid (366 mg, yield 96%). Rocamarina compound according1H and13C-NMR (DMSO-d6).

1H-NMR (400 MHz, DMSO-d6the 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), 8,06 (d, J=10.4 Hz, 1H), 7,06 (d, J=8,5 Hz, 1H), 7,02 (d, J=8,5 Hz, 1H), is 6.51 (d, J=2.5 Hz, 1H), of 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), to 5.05 (s, 2H), is 4.93 (s, 2H), of 1.27 (s, 9H).

13C-NMR (100 MHz, DMSO-d6the 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: of 193.1 m/z (MH+).

D-14; 4-tert-Butyl-N3-methylbenzo-1,3-diamine

In a flask of 100 ml administered N-(5-amino-2-tert-butylphenyl)formamide (340 mg, 1,77 mmol) and purged with nitrogen. Add THF (10 ml) and the solution was cooled to a temperature of 0°C. for 2 minutes was added a solution of hydride in THF (4.4 ml, 1M solution). Then the mixture is allowed to warm to room temperature. After boiling to reflux for 15 hours a yellow suspension is cooled to a temperature of 0°C, quenched with water (170 μl), 15% aqueous NaOH (170 ml) and water�St (510 µl), are added sequentially, and stirred at room temperature for 30 min. the Mixture was filtered through celite and the filter cake washed with methanol (50 ml). The combined filtrates concentrated under vacuum to give a gray-brown solid, which was partitioned between chloroform (75 ml) and water (50 ml). The organic layer is separated, washed with water (50 ml), dried (Na2SO4), filtered and concentrated, obtaining 4-tert-butyl-N3-methylbenzo-1,3-diamine (D-14) in the form of a brown oil which solidifies on standing (313 mg, yield 98%).

1H-NMR (400 MHz, CDCl3) δ 7,01 (d, J=8,1 Hz, 1H), to 6.05 (DD, J=2,4, 8,1 Hz, 1H), 6,03 (d, J=2.4 Hz, 1H), of 3.91 (user.s, 1H), 3,52 (user.s, 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

A solution of propylbenzene (10 g, 83 mmol) in concentrated H2SO4(50 ml) was cooled to 0°C for 30 min and the portions was added a solution of concentrated H2SO4(50 ml) and fuming HNO3(25 ml), previously cooled to 0°C for 15 min. the Mixture was stirred at 0°C in flowing�e additional 30 minutes and then allowed to warm to room temperature. The mixture was poured into a mixture of ice (200 g) with water (100 ml) and extracted with diethyl ether (2 times 100 ml). The combined extracts were washed with H2O (100 ml) and saturated brine (100 ml), dried over MgSO4, filtered and concentrated, yielding 2,4-dinitropropanol (15.6 g, yield 89%).

1H-NMR (CDCl3, 300 MHz) δ 8,73 (d, J=2,2 Hz, 1H), to 8.38 (DD, J=8,3, 2,2 Hz, 1H), and 7.6 (d, J=8,5 Hz, 1H), 2,96 (m, 2H), 1,73 (m, 2H), of 1.06 (t, J=7,4 Hz, 3H).

4-Propyl-3-nitroaniline

A suspension of 2,4-dinitropropanol (2 g, 9.5 mmol) in N2About (100 ml) was heated to reflux and vigorously stirred. Added dropwise within 45 minutes transparent orange-red solution of polysulfide (300 ml, 10 EQ.), prior to heating of managerat of sodium sulfide (10.0 g), sulfur powder (2,60 g) and H2About (400 ml). The red-brown solution is brought to reflux for 1.5 hours. The mixture is cooled to a temperature of 0°C and then extracted with diethyl ether (2 × 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 was 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) with stirring. Add the BOC-ang�grid (2.05 g, 9,4 mmol). The mixture was stirred and brought to reflux for 1 hour, then the solvent was removed in vacuum. The resulting oil was redissolved in CH2Cl2(300 ml) and washed with water (300 ml) and saturated brine (300 ml), dried over Na2SO4, filtered and concentrated. Crude oil, which contains as monocularly and bis-acylated microproduct purify separated by column chromatography (0-10% CH2Cl2-MeOH) to obtain 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 DMF (5 ml) was added Ag2O (1.0 g, 6.0 mmol), then methyliodide (0.20 ml, 3.2 mmol). The resulting suspension was 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. Crude oil is purified column chromatography (0-10% CH2Cl2-MeOH) to obtain tert-butyl methyl ether(3-nitro-4-propylphenyl)carbamino acid as a yellow oil (110 mg, yield 52%).

1H-NMR (CDCl3, 300 MHz) δ 7,78 (d, J=2,2 Hz, 1H), of 7.42 (DD, J=8,2 and 2.2 Hz, 1H), 7,26 (d, J=8,2 Hz, 1H), 3,27 (s, 3H), of 2.81 (t, J=7,7 Hz, 2H), of 1.66 (m, 2H), to 1.61 (s, 9H), 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) was added 10% Pd/C (100 mg). The resulting suspension was stirred at room temperature in the atmosphere of H2(1 ATM) for 2 days. The reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was filtered through a layer of celite. The filtrate was concentrated under vacuum to give tert-butyl methyl ether (3-amino-4-propylphenyl)methylcarbamate acid (D-15) as colorless 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) was synthesized following the General scheme above, on the basis of ethylbenzene. Overall 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) was synthesized following the General scheme above, on the basis of isopropylbenzene. General o�d (38%).

Example 6

2'-Ethoxy-2,4-dinitrobiphenyl

In the pressure vessel, enter 2-ethoxypropionate 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 was purged with argon for 1 min, then add three-tert-butylphosphine (0.15 ml, 0.48 mmol, 10% solution in hexano). The reaction vessel was purged with argon for an additional 1 min, sealed and heated at 80°With during the night. After cooling to room temperature the solution was filtered through a layer of celite. The filter cake was washed with CH2Cl2(10 ml) and the combined organic extracts concentrated under reduced pressure, obtaining the crude product, 2'-ethoxy-2,4-dinitrobiphenyl (0.95 g, yield 82%). Further purification is not carried out.

1H-NMR (300 MHz, CDCl3) δ of 8.75 (s, 1H), 8,43 (d, J=to 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 (q, 7=6,6 Hz, 2H), 1,24 (t, J=6,6 Hz, 3H).

HPLC: retention time 3,14 min, 10-100% CH3CN, gradient 5 min.

2'-Ethoxy-2-nitrobiphenyl-4-ylamine

Transparent orange-red solution of polysulfide (120 ml, 7.5 EQ.), preformed by heating the monohydrate of sodium sulfide (10 g), sulfur (1.04 g) and water (160 ml), was added, dropwise, at the rate�the atur 90°C for 45 min to a suspension of 2'-ethoxy-2,4-dinitrobiphenyl (1.2 g, 4.0 mmol) in water (40 ml). The red-brown solution is brought to reflux for 1.5 hours. The mixture is cooled to room temperature and add solid NaCl (5 g). The solution was 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 for next step 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), of 3.91 (q, 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 min.

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 BOC2Oh (2.6 g, 12 mmol) was heated jet air dryer. After consumption of the starting materials, according to TLC, the crude mixture was purified flash chromatography (silica gel, CH2Cl2) to obtain tert-butyl ether (2'-ethoxy-2-nitrobiphenyl-4-yl)carbamino acid (1.5 g, yield 83%).

1H-NMR (300 MHz, CDCl3) δ is 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), about 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 min.

D-18; tert-Butyl ether (2'-ethoxy-2-aminobiphenyl-4-yl)�karbaminovoi acid

To a solution of NiCl2·6H2Oh (0.26 g, 1.1 mmol) in EtOH (5 ml) was added NaBH4(40 mg, 1.1 mmol) at a temperature of -10°C. nabludaetsa gas evolution and a black precipitate is formed. After stirring for 5 min was added a solution of tert-butyl methyl ether (2'-ethoxy-2-nitrobiphenyl-4-yl)carbamino acid (0.50 g, 1.1 mmol) in EtOH (2 ml). Then add additional NaBH4(80 mg, 60 mmol) in 3 portions over 20 min. the Reaction mixture was stirred at 0°C for 20 min, then add NH4OH (4 ml, 25% aqueous solution). The resulting solution was stirred for 20 minutes. The crude mixture was filtered through a small layer of silica gel. The silica layer was washed with 5% solution of MeOH in CH2Cl2(10 ml) and the combined organic extracts concentrated under reduced pressure, obtaining tert-butyl ether (2'-ethoxy-2-aminobiphenyl-4-yl)carbamino acid (D-18) (0.36 g, quantitative yield) which was used without further purification.

HPLC: retention time 2,41 min, 10-100% CH3CN, gradient 5 min.

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) was cooled to 0°C. Slowly add�control methanesulfonanilide (171 mg, 1,49 mmol) at such a rate that the solution temperature remained below 10°C. the Mixture was 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 almost complete, according to GHMC-analysis. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (10 ml), extracted with CH2Cl2(4 x 10 ml), dried over Na2SO4, filtered and concentrated, obtaining N-(3-amino-5-triptoreline)-methanesulfonamide (D-19) as a reddish semi-solid substances (0.35 g, yield 97%) which was used without further purification.

1H-NMR (CDCl3, 300 MHz): δ 6,76 (m, 1H), 6,70 (m, 1H), 6,66(s, 1H), 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 mole) dissolved in H2SO4(98%, 150 ml), slowly add KNO3With 18.2 g, 0.18 mol) at 0°C. the Reaction mixture is allowed to warm to room temperature and stirred over night. Then the mixture was poured into ice water and made basic with a saturated solution of NaHCO3to pH=8. After extraction CH2Cl2the combined organic�ski layers washed with saturated salt solution, dried over Na2SO4and concentrate it. Balance purify separated by 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), BOC2Oh (1.29 g, of 5.89 mmol) and DMAP (0.4 g) in CH2CL2was stirred at room temperature over night. After dilution with water the mixture was extracted with CH2CL2. The combined organic layers washed with NaHCO3and saturated brine, dried over Na2SO4and concentrate, receiving tert-butyl ester of 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid, which was used for next step without further purification.

DC-1; tert-Butyl-7-amino-3,4-dihydroquinoline-1(2H)-carboxylate

A suspension of crude tert-butyl ester of 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid (4.5 g, 16.2 per mol) and 10% Pd/C (0.45 g) in MeOH (40 ml) was stirred in the 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) in the form of a brown solid (1.2 g, yield 22% over 2 stages).

1H-NMR CDCl 3) δ 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 (user.s, 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

A stirred mixture of oxindole (5.7 g, 43 mmol) and Raney Nickel (10 g) in ethane-1,2-diol (100 ml) was heated in an autoclave. After completion of the reaction the mixture was filtered and the excess diol was removed under vacuum. The residual oil is triturated in hexane, yielding 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-indol-2-he

To a solution of 3-(2-hydroxyethyl)-1,3-dihydroindol-2-one (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 allowed to warm to room temperature and stirred over night. The mixture was filtered and the filtrate concentrated in vacuo. Balance purify separated by column chromatography, yielding the crude 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indol-2-it is in the form of a yellow solid (2.5 g) which was used directly in the next step.

1,2-Dihydro-3-Spiro-1'-cyclopropyl-1H-indole

To a solution of 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indol-2-one (2.5 g, n�cleaned) in THF (50 ml) portions add LiAlH 4(2 g, 52 mmol). After boiling the mixture to reflux it was poured onto crushed ice, made basic with aqueous ammonia solution to pH=8 and extracted with EtOAc. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrated, obtaining the crude 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole as a yellow solid (about 2 g) which was used directly in the next step.

6-Nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole

To a chilled solution (temperature from -5°C to -10aboutC) 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, crude) for 20 min. After complete addition the reaction mixture was stirred for the next 40 min and was poured onto crushed ice (20 g). The cooled mixture was then made basic with NH4OH and extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated under reduced pressure, yielding 6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole as a dark gray solid (1.3 g).

1-Acetyl-6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole

NaHCO3(5 g) was suspended in a solution of 6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (1.3 g, crude) in CH2CL2(50 ml). In� vigorous stirring added dropwise acetyl chloride (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, yielding 1-acetyl-6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (0.9 g, yield 15% over 4 steps).

DC-2; 1-Acetyl-6-amino-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole

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 the atmosphere of H2(1 ATM) for 1.5 hours. The catalyst was filtered off and the filtrate is concentrated under reduced pressure. The residue was treated with a mixture of HCl/MeOH, getting 1-acetyl-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-envoy acid

A mixture of 3-methylbut-2-envoy acid (100 g, 1 mol) and SOCl2(119 g, 1 mol) was heated to reflux 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 was stirred at room temperature for 1 hour and quenched with a solution of HCl (5%, 150 ml). The aqueous layer is separated and extracted with CH2Cl2. About�United organic layers are washed with water (2 times 100 ml) and saturated brine (100 ml), dried over Na2SO4and concentrate, receiving phenylamide 3-methylbut-2-envoy acid (120 g, yield 80%).

4,4-Dimethyl-3,4-dihydro-1H-quinoline-2-he

AlCl3(500 g, 3.8 mol) is added cautiously to a suspension of phenylamide 3-methylbut-2-envoy acid (105 g, 0.6 mol) in benzene (1000 ml). The reaction mixture was stirred at 80°C overnight and poured into ice water. The organic layer separated and the aqueous layer was extracted with ethyl acetate (3 times 250 ml). The combined organic layers washed with water (2 × 200 ml) and saturated brine (200 ml), dried over Na2SO4and concentrated, yielding 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-quinolin-2-one (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 was stirred at room temperature for 30 min and then slowly heated to boiling temperature to reflux for 1 hour. The mixture is then cooled to a temperature of 0°C. Carefully add water (18 ml) and NaOH (10%, 100 ml) to extinguish the reaction. The solid is filtered off and the filtrate is concentrated, yielding 4,4-dimethyl-1,2,3,4-tetrahydroquinolin.

4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydrothieno�n

To a mixture of 4,4-dimethyl-1,2,3,4-tetrahydroquinoline (33 g, 0.2 mol) in H2SO4(120 ml) was slowly added KNO3(20.7 g, 0.2 mol) at 0°C. After complete addition the mixture was stirred at room temperature for 2 hours, carefully poured into ice water and made basic with Na2CO3to pH=8. The mixture was extracted with ethyl acetate (3 x 200 ml). The combined extracts are washed with water and saturated brine, dried over Na2SO4and concentrated, yielding 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroquinolin (21 g, yield 50%).

tert-Butyl ether 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid

A mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline (25 g, 0.12 mole) and BOC2O (55 g, 0.25 mol) was stirred at 80°C for 2 days. The mixture was 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 ether 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) was stirred in hydrogen atmosphere (1 ATM) at room temperature over night. The catalyst was filtered off and the filtrate concentrated. The residue was washed with petroleum ether, �aluca 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-to 7.04 (m, 2H), 6,45-6,38 (m, 1H), 3,71-to 3.67 (m, 2H), 3,50-or 3.28 (m, 2H), 1,71-to 1.67 (m, 2H), 1,51 (s, 9H), 1,24 (s, 6H).

Example 4

1-Chloro-4-methylpentan-3-one

Ethylene is bubbled through a solution of isobutyramide (50 g, 0.5 mol) and AlCl3(Of 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 was stirred at room temperature over night. The mixture was poured into cold diluted HCl solution and extracted with CH2Cl2. The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered and concentrated, obtaining the crude 1-chloro-4-methylpentan-3-one, which was used directly in next step without further purification.

4-Methyl-1-(phenylamino)pentane-3-one

A suspension of crude 1-chloro-4-methylpentan-3-she (about 60 g), aniline (69,8 g, 0.75 mol) and NaHCO3(210 g, 2.5 mol) in CH3CN (1000 ml) was heated to reflux over night. After cooling, the insoluble salt was filtered and the filtrate concentrated. The residue was diluted with CH2Cl2, washed with 10% HCl solution (100 ml) and saturated brine, 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) was gradually added to a mixture of crude 4-methyl-1-(phenylamino)pentane-3-she (about 80 g) in MeOH (500 ml). After completion of the addition the reaction mixture is allowed to warm to room temperature and stirred for 20 min. the Solvent was removed and the residue reallocate between water and CH2Cl2. The organic phase was separated, washed with saturated brine, dried over Na2SO4, filtered and concentrated. The resulting resin was triturated in diethyl ether, receiving 4-methyl-1-(phenylamino)pentane-3-ol as a white 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) was stirred at 50°C for 30 min. the Reaction mixture was poured into ice water, basified with saturated NaOH solution to pH=8 and extracted with CH2Cl2. The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered and concentrated. Balance purify separated by 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

When �temperature 0°C, KNO3(0,76 g, 7,54 mmol) portionwise added 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, basified with a saturated solution NaHCO3to pH=8 and extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated, obtaining the crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.2 g) which was used directly in next step without further purification.

1-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)alanon

Acetyl chloride (of 0.77 ml, 11 mmol) was added to a suspension of crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.2 g, of 5.45 mmol) and NaHCO3(1.37 g, 16.3 mmol) in CH2Cl2(20 ml). The mixture is boiled to reflux for 1 hour. After cooling, the mixture was poured into water and extracted with CH2Cl2. The organic layer was washed with saturated brine, dried over Na2SO4and concentrate it. The residue is purified column chromatography, obtaining 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)alanon (1.05 g, yield 64% over two steps).

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-Tetra�drobenzo[b]azepin-1-yl)ethanone (1.05 g, 40 mmol) and 10% Pd/C (0.2 g) in MeOH (20 ml) was stirred in the atmosphere of H2(1 ATM) at room temperature for 4 hours. After filtration the filtrate is concentrated, obtaining 1-(8-amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo[b]azepin-1-yl)Etalon in the form of white solids (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 (user.s, 1H), 4,18-of 4.05 (m, 1H), 3.46 in-3,36 (m, 1H), 2,23 (s, 3H), 1,92-of 1.85 (m, 1H), 1,61-is 1.51 (m, 3H), 1,21 (s, 3H), of 0.73 (t, J=7,2 Hz, 3H).

ESI-MS: 233,0 m/z (MH+).

Example 5

1'-Benzyl-Spiro[1H-indene-1,4'-piperidine]-3(2H)-he

A mixture of 1,1-dimethylethylene ether 2,3-dihydro-3-oxaspiro[1H-indene-1,4'-piperidine]-1'-carboxylic acid (9,50 g, 31,50 mmol) in a saturated HCl solution in MeOH (50 ml) was stirred at 25°C during the night. The solvent was removed under reduced pressure, getting not quite white solid (7,50 g). To a solution of the solid in anhydrous CH3CN (30 ml) was added anhydrous K2CO3(7.85 g, 56,80 mmol). The suspension was stirred for 5 min and added dropwise to the bromide (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[1�-indene-1,4'-piperidine]-3(2H)-he (7,93 g, yield 87%) which was used without further purification.

Oxime 1'-benseler[1H-indene-1,4'-piperidine]-3(2H)-she

To a solution of 1'-benseler[1H-indene-1,4'-piperidine]-3(2H)-she (7,93 g, 27,25 mmol) in EtOH (50 ml) was added hydroxylamine hydrochloride (3,79 g, 54,50 mmol) and anhydrous sodium acetate (4,02 g, 49,01 mmol) in one portion. The mixture is boiled to reflux for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and 200 ml of water. The mixture was extracted with CH2Cl2. The combined organic layers dried over Na2SO4and concentrated, yielding the oxime 1'-benseler[1H-indene-1,4'-piperidine]-3(2H)-she (EUR 7.57 g, yield 91%) which was used without further purification.

1,2,3,4-Tetrahydroquinolin-4-Spiro-4'-(N'-benzylpiperidine)

To a solution of oxime 1'-benseler[1H-indene-1,4'-piperidine]-3(2H)-she (EUR 7.57 g, 24,74 mmol) in anhydrous CH2Cl2(150 ml) was added dropwise DIBAL-H (of 135.7 ml, 1M solution in toluene) at 0°C. the Mixture was stirred at 0°C for 3 hours, diluted with CH2Cl2(100 ml) and quenched NaF (20,78 g, 495 mmol) and water (6.7 g, 372 mmol). The resulting suspension is vigorously stirred at 0°C for 30 min. After filtration the residue was washed with CH2Cl2. The combined filtrates concentrated in vacuo, receiving not quite brown�e oil, which purify separated by 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 MeOH (3 ml) was stirred in the atmosphere of H2(55 psi) at 50°With during the night. After cooling, the catalyst was filtered off and washed with MeOH. The combined filtrates concentrated under reduced pressure, yielding 1,2,3,4-tetrahydroquinolin-4-Spiro-4'-piperidine as a white solid (176 mg, yield 85%) which was used 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) in portions was added 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 allowed to warm to room temperature and then stirred for 2 hours. The mixture was then poured on crushed ice and made basic with 10% NaOH to pH~8. Added dropwise Vos2O (172 mg, 0.79, which mmol) and the mixture was stirred at room temperature for 1 hour. Then the mixture was extracted with EtOAc and join�United organic layers are dried over Na 2SO4, filtered and concentrated, obtaining the crude tert-butyl ether 7'-nitrospira[piperidine-4,4'(1 N)-quinoline]-2',3'-dihydrocarvone acid (230 mg), which was used for next step without further purification.

tert-Butyl ether 7'-nitrospira[piperidine-4,4'(1 N)-1-acetylcholin]-2',3'-dihydrocarvone acid

Acetyl chloride (260 mg, 3,30 mmol) was 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 brought to reflux for 4 hours. After cooling, the suspension was filtered and the filtrate concentrated. Balance purify separated by column chromatography (petroleum ether-EtOAc, 10:1) to obtain 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 MeOH (2 ml) was stirred in the atmosphere of H2(1 ATM) at 25°C during the night. The catalyst was removed by filtration and washed with MeOH. Are United by� the filtrates dried over Na 2SO4, 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 mercaptoacetic acid (1 g, 11 mmol) was added to a solution of 1-chloro-2,4-dinitrobenzene (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 was extracted with ethyl acetate (3 times 100 ml). Ethylacetate extract was washed with water and saturated brine, dried over Na2SO4and concentrated, obtaining 2-(2,4-dinitrophenyl)acetic acid (2.3 g, yield 74%), 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) was heated to reflux over night. After removal of the solvent under reduced pressure the residual suspension was diluted with water (100 ml) and made basic with 10% aqueous solution of Na2CO3to pH=8. The resulting suspension was extracted with ethyl acetate (3 times 100 ml). Ethylacetate extract was washed with water and saturated RA�a tvory salt, dried over Na2SO4and concentrate it. The residue was washed with CH2Cl2getting 6-amino-2H-benzo[b][1,4]thiazin-3(4H)-he (DC-7) as a yellow powder (1 g, yield 52%).

1H-NMR (DMSO-d6): δ 10,24 (s, 1H), to 6.88 (d, 1H,J=6Hz), 6,19-6,21 (m, 2H), further 5.15 (s, 2H), or 3.28 (s, 2H).

ESI-MS: to 181.1 m/z (MH+).

Example 7

N-(2-Bromo-5-nitrophenyl)acetamide

Acetic anhydride (1.4 ml, of 13.8 mmol) was 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 into water. The precipitate was separated by filtration, washed with water and dried under vacuum to give N-(2-bromo-5-nitrophenyl)acetamide as an off-white solid (3.6 g, yield 90%).

N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide

The temperature is 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)acetamide (3.6 g, a 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 ml). The reaction mixture was stirred at 25°C during the night. The reaction mixture was then filtered and the filtrate treated with saturated solution of Na2CO3. The organic layer separated and the aqueous �Loy extracted with EtOAc. The combined organic extracts are washed with water and saturated brine, dried over MgSO4, filtered and concentrated under vacuum to give N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide in the form of 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)acetamide (3.1 g, 10.2 mmol), hydrate of 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 in a nitrogen atmosphere. After cooling, the mixture was filtered through celite. Celite was washed with EtOAc and the combined filtrates washed with saturated solution of NaHCO3. The separated organic layer was washed with water and saturated brine, 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) was added to a suspension of 1-(3,3-dimethyl-6-nitroindoline-1-yl)ethanone (2.1 g, 9 mmol) in MeOH (20 ml). The reaction mixture was stirred in the atmosphere of H2(40 psi) at room temperature over night. Pd/C was filtered� and the filtrate was concentrated in vacuo, getting the crude product which is 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) was added, dropwise, to a solution of 4-dihydro-2H-naphthalene-1-it-oxime (3 g, 18 mmol) in dichloromethane (50 ml) at 0°C. the Mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with dichloromethane (30 ml), then treated with NaF (2 g, 0.36 mole) and H2O (5 ml, 0.27 mole). Vigorous stirring of the obtained suspension is continued at 0°C for 30 min. After filtration the filtrate is concentrated. The residue is purified column flash chromatography, receiving 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]azepine (1.9 g, 13 mmol) was added, dropwise, to a solution of KNO3(3 g, 30 mmol) in H2SO4(50 ml). The mixture was stirred for 40 min, poured over crushed ice, made basic with aqueous ammonia solution to pH=13 and extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over Na2SO4and concentrate, receiving 8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin black �solid substance (1.3 g, yield 51%) which was used without further purification.

1-(8-Nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)alanon

Acetyl chloride (1 g, 13 mmol) was 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 was filtered and the filtrate concentrated. The residue was dissolved in CH2Cl2, washed with saturated brine, dried over Na2SO4and concentrate it. The residue is purified column chromatography, obtaining 1-(8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)Etalon as a yellow solid (1.3 g, yield 80%).

DC-9;1-(8-Amino-2,3,4,5-tetrahydrobenzo[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) was stirred in the atmosphere of H2(1 ATM) at room temperature for 1.5 hours. The mixture was 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, of 1.8 Hz, 1H), 6,50 (d, J=1,8 Hz, 1H), 4,66-USD 4.61 (m, 1H), 3,50 (user.s, 2H), 2,64-by 2.55 (m, 3H), 1,94 is 1.91 a (m, 5H), 1,77-1,72 (m, 1H), 1,32-of 1.30 (m, 1H).

ESI-MS: 204,1 m/z (MH+).

Example 9

6-Nitro-4H-benzo[1,4]oxazine Serie-3-�n

At 0°C, chlorocatechol (of 8.75 ml, 0.11 mole) was added, dropwise, to a mixture of 4-nitro-2-aminophenol (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 50°With during the night. The solvent was removed under reduced pressure and the residue treated with water (50 ml). The solid is separated by filtration, washed with water and recrystallized from ethanol, yielding 6-nitro-4H-benzo[1,4]oxazine Serie-3-one as pale yellow solid (8 g, yield 41%).

6-Nitro-3,4-dihydro-2H-benzo[1,4]oxazine Serie

A solution of BH3·Me2S in THF (2 M, the 7.75 ml, 15.5 mmol) was added, dropwise, to a suspension of 6-nitro-4H-benzo[1,4]oxazine Serie-3-she (0.6 g, 3.1 mmol) in THF (10 ml). The mixture was stirred at room temperature over night. The reaction mixture was quenched with MeOH (5 ml) at 0°C and then added water (20 ml). The mixture was extracted with Et2O and the combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate, receiving 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine Serie a red solid (0.5 g, yield 89%) which was used without further purification.

4-Acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine Serie

When e�ergional stirring and at room temperature, added dropwise acetyl chloride (1.02 g, 13 mmol) to a mixture of 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine Serie (1.8 g, 10 mmol) and NaHCO3(Of 7.14 g, 85 mmol) in CH2Cl2(50 ml). After completion of the addition the reaction mixture was stirred for 1 hour at this temperature. The mixture was filtered and the filtrate concentrated in vacuo. The residue was treated with a mixture of Et2O:hexane (1:2, 50 ml) with stirring for 30 min and then filtered, yielding 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine Serie 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]oxazine Serie

A mixture of 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine Serie (1.5 g, of 67.6 mmol) and Pd/C (10%, 100 mg) in EtOH (30 ml) was stirred in the atmosphere of H2(1 ATM) over night. The catalyst was filtered off and the filtrate concentrated. The residue was treated with HCl/MeOH, yielding 4-acetyl-6-amino-3,4-dihydro-2H-benzo[1,4]oxazine Serie (DC-10) as an off-white solid (1.1 g, yield 85%).

1H-NMR (DMSO-d6) δ 10,12 (user.s, 2H), 8,08 (user.s, 1H), 6,90-7,03 (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: 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) was added, dropwise, to a stirred, cooled with ice, the solution concentrate�Anna H 2SO4(25 ml). Portions add KNO3(5.6 g, 55,0 mmol), maintaining the temperature below 5°C. the Mixture was stirred at room temperature over night, carefully poured into chilled with ice, a solution of concentrated NH4OH and then three times extracted with CHCl3. The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate it. The obtained dark brown oil was added to EtOH, cooled in an ice bath and treated with concentrated HCl. The yellow precipitate is separated by filtration and recrystallized from methanol, yielding the hydrochloride 1,2,3,4-tetrahydro-7-nitroisoquinoline as a yellow solid (2.5 g, yield 23%).

1H-NMR (400 MHz, DMSO-d6) δ was 9.86 (s, 2H), 8,22 (d, J=1.6 Hz, 1H), 8,11 (DD, J=8,5, and 2.2 Hz, 1H), 7,53 (d, J=8,5 Hz,lH), of 4.38 (s, 2H), 3,38 (s, 2H), 3,17-3,14 (m, 2H).

HPLC: retention time 0,51 min, 10-99% CH3CN, the analysis time of 5 min.

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) was cooled in an ice bath and add Vos2O (2.8 g, 12.8 mmol). The mixture was stirred at room temperature for 2.5 hours, made basic with 5% solution of KHSO4to pH=2-3 and then extracted with EtOAc. The organic layer drying� over MgSO 4and concentrate, receiving tert-butyl-3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, quantitative yield) which was 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 min.

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) was added to a stirred solution of tert-butyl-3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, 12,0 mmol) in MeOH (56 ml) in a nitrogen atmosphere. The reaction mixture was stirred in hydrogen atmosphere (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), while receiving 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 of 6.79 (d, J=8,1 Hz, 1H), 6,40 (DD, J=8,1, 2,3 Hz, 1H), of 6.31 (s, 1H), of 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 2,13 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 249,0 m/z (MH+).

Other amines

Example 1

4-B�ω-3-nitrobenzonitrile

To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in concentrated H2SO4(10 ml) was added, dropwise at 0°With 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. A white precipitate is separated by filtration and washed with water until until the washing water becomes neutral. The solid is recrystallized twice from a mixture of ethanol/water (1:1, 20 ml) to obtain 4-bromo-3-nitrobenzonitrile in the form of a white crystalline material (2.8 g, yield 56%).

1H-NMR (300 MHz, DMSO-d6): δ 8,54 (s, 1H), 8,06 (d, J=8.4 Hz, 1H), 7,99 (d, J=8.4 Hz, 1H).

13C-NMR (75 MHz, DMSO-d6): δ 150,4, 137,4, 136,6, 129,6, 119,6, 117,0, 112,6.

HPLC: retention time of 1.96 min, 10-100% CH3CN, gradient 5 min.

ESI-MS: 227,1 m/z (MH+).

2'-Ethoxy-2-nitrobiphenyl-4-carbonitrile

In a round bottom flask with a capacity of 50 ml, contributed 4-bromo-3-nitrobenzonitrile (1.0 g, 4.4 mmol), 2-ethoxyquinoline acid (731 mg, 4.4 mmol), Pd2(dba)3(18 mg, 0,022 mmol) and potassium fluoride (786 mg, 13.5 mmol). The reaction vessel is evacuated and filled with argon. Added anhydrous THF (300 ml), then P(t-Bu)3(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 resulting mixture was filtered through a layer of celite and concentrate. 2'-Ethoxy-2-nitrobiphenyl-4-carbonitrile isolated as a yellow solid (1.12 g, yield 95%).

1H-NMR (300 MHz, DMSO-d6) δ 8,51 (s, 1H), 8,20 (l, J=8,1 Hz, 1H), 7,68 (d, J=8.4 Hz, 1H), 7,41 (t, J=8.4 Hz, 1H), value of 7, 37 (d, J=7.5 Hz, 1H), was 7.08 (t, J=7.5 Hz, 1H), 7,03 (d, J=8,1 Hz, 1H), of 3.91 (q, J=7,2 Hz, 2H), of 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 per min, 10-100% CH3CN, gradient 5 min.

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, 1.86 mmol) in THF (80 ml) was added a solution of BH3·THF (5.6 ml, 10% wt. in THF, 5.6 mmol) at 0°C for 30 min. 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 was added a mixture of H2O/THF (3 ml). After shaking at room temperature for 6 hours, volatiles are removed under reduced pressure. The residue was dissolved in EtOAc (100 ml) and extracted with 1N. HCl solution (2 × 100 ml). The aqueous phase was made basic with 1N. NaOH to pH=1 and extracted with EtOAc (3 times 50 ml). The combined organic layers industrial�up with water (50 ml), dried over Na2SO4, filtered and evaporated. After drying in vacuo providing 4-aminomethyl-2'-ethoxymethyl-2-ylamine in the form of a brown oil (370 mg, yield 82%).

1H-NMR (300 MHz, DMSO-d6) δ to 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 min.

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, 0,565 mmol) in 1,4-dioxane (10 ml) is added over 30 min to a solution of 4-aminomethyl-2'-ethoxymethyl-2-ylamine (274 mg, and 1.13 mmol) in 1,4-dioxane (10 ml). The reaction mixture was stirred at room temperature for 16 hours. Volatiles removed on a rotary evaporator. The residue is purified flash chromatography (silica gel, EtOAc-CH2Cl2, 1:4) to obtain tert-butyl ether (2-amino-2'-ethoxymethyl-4-ylmethyl)carbamino acid (E-1) in the form of 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), is 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), 1,38 (s, 9H), of 1.20 (t, J=7,2 Hz, 3H).

HPLC: retention time 2,34 min, 0-100% CH 3CN, gradient 5 min.

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 (8,95 g, 50 mmol) and silver sulfate (10 g, 32 mmol) in 50 ml of 90% sulfuric acid was added dropwise bromine (7.95 g, 50 mmol). Continue to stir at room temperature overnight, then the mixture was poured into a dilute solution of sodium hydrosulfite and extracted with EtOAc three times. The combined organic layers washed with saturated salt solution and dried over MgSO4. After filtration the filtrate is concentrated, obtaining 2-bromo-1-tert-butyl-4-nitrobenzene (12.7 g, yield 98%) which was used without further purification.

1H-NMR (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), of 1.57 (s, 9H).

HPLC: retention time of 4.05 min, 10-100% CH3CN, gradient 5 min.

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) was added Pd(PPh3)4(474 mg, 0.41 mmol) in a nitrogen atmosphere. The mixture was heated in a tightly closed vessel at a temperature of 205°C for 5 hours. After cooling to room temperature the mixture was diluted with water and twice extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried n�d MgSO 4. 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), to 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 3,42 min, 10-100% CH3CN, gradient 5 min.

E-2; 2-tert-Butyl-5-aminobenzonitrile

To boiling to reflux a solution of 2-tert-butyl-5-nitrobenzonitrile (816 mg, 4.0 mmol) in EtOH (20 ml) was added ammonium formate (816 mg, 12.6 mmol) followed by 10% Pd/C (570 mg). Then the reaction mixture is boiled to reflux for 90 min, cooled to room temperature and filtered through celite. The filtrate is concentrated, yielding 2-tert-butyl-5-aminobenzonitrile (E-2) (630 mg, yield 91%) which was used without further purification.

HPLC: retention time of 2.66 min, 10-99% CH3CN, gradient 5 min.

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) was added a solution of BH3·THF (12 ml, 1M solution in THF, 12.0 mmol) in a nitrogen atmosphere. The reaction mixture was stirred at 70°C overnight and cooled to a temperature of 0°C. Add methanol (2 ml), then 1N. HCl solution (2 ml). After boiling with obra�tion fridge for 30 min the solution was diluted with water and extracted with EtOAc. The aqueous layer was made basic with 1N. NaOH 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), 7,99 (DD, J=8,8, 2,8 Hz, 1H), 7,58 (d, J=8,8 Hz, 1H), 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 min.

ESI-MS: of 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 BOC2O (229 mg, 1.05 mmol) in THF (5 ml) was heated to reflux for 30 min. 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, obtaining tert-butyl-2-tert-butyl-5-nitrobenzylamine (240 mg, yield 78%) which was 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), 4,52 (d, J=6,0 Hz, 2H), to 1.48 (s, 18H).

HPLC: retention time 3,72 min, 10-100% CH3CN, gradient 5 min.

E-4; tert-Butyl-2-tert-butyl-5-AMI�benzylcarbamoyl

To a solution of tert-butyl-2-tert-butyl-5-nitrobenzaldehyde (20 mg, 0,065 mmol) in a mixture of 5% Acoh-MeOH (1 ml) was added 10% Pd/C (14 mg) in a nitrogen atmosphere. The mixture was stirred in hydrogen atmosphere (1 ATM) at room temperature for 1 hour. The catalyst was removed by filtration through celite and the filtrate was concentrated, 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, 2,6 Hz, 1H), 4.61 record (user.s, 1H), 4,40 (d, J=5.1 Hz, 2H), 4,15 (user.s, 2H), of 1.39 (s, 9H), of 1.29 (s, 9H).

HPLC: retention time 2,47 min, 10-100% CH3CN, gradient 5 min.

ESI-MS: 279,3 m/z (MH+).

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 min. the Reaction mixture was poured on ice, extracted with EtOAc, washed with saturated brine, and dried over MgSO4. After filtration the filtrate is concentrated, yielding 2-tert-butyl-5-nitrobenzoic acid (200 mg, yield 90%) which was used without further purification.

1H-NMR (400 MHz, CDCl3): δ to 8.36 (d, J=2,6 Hz, 1H), 8,24 (DD, J=the 8.9 and 2.6 Hz, 1H), 7,72 (d, J=8,9 Hz, 1H), 1,51 (s, 9H).

HPLC: retention time of 2.97 min, 10-100% CH3N a 5 min gradient

Methyl-2-tert-butyl-5-nitrobenzoate

To a mixture of 2-tert-butyl-5-nitrobenzoic acid (120 mg, 0.53 mmol) and K2CO3(147 mg, 1.1 mmol) in DMF (5.0 ml) was added 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, obtaining methyl-2-tert-butyl-5-nitrobenzoate, which is used without further purification.

1H-NMR (400 MHz, CDCl3): δ 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), 1,43 (s, 9H).

E-6; Methyl-2-tert-butyl-5-aminobenzoate

To boiling to reflux a solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38 mmol) in EtOH (2.0 ml) was added potassium formate (400 mg, 4.76 mmol) in water (1 ml), then 20 mg of 10% Pd/C. the reaction mixture was brought to reflux for 40 min, cooled to room temperature and filtered through celite. The filtrate is concentrated, obtaining methyl-2-tert-butyl-5-aminobenzoate (E-6) (76 mg, yield 95%) which was used without further purification.

1H-NMR (400 MHz, CDCl3): δ 7,24 (d, J=8,6 Hz, 1H), to 6.67 (DD, J=8,6, and 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 min.

ESI-MS: 28,2 m/z (MH +).

Example 5

2-tert-Butyl-5-nitrobenzene-1-sulphonylchloride

A suspension of 2-tert-butyl-5-nitrobenzamide (0,971 g, 5 mmol) in concentrated HCl (5 ml) was 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, then the mixture was filtered under vacuum. The filtrate is added simultaneously with a solution of Na2SO3(Of 1.57 g, 12.4 mmol) in H2O (2.7 ml) to a stirred solution of CuSO4(0,190 g, 0,76 mmol) and Na2SO3(Of 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 for 0.5 hours and the resulting precipitate was filtered off, washed with water and dried, yielding 2-tert-butyl-5-nitrobenzene-1-sulphonylchloride (0,235 g, yield 17%).

1H-NMR (400 MHz, DMSO-d6): δ of 9.13 (d, J=2.5 Hz, 1H), to 8.36 (DD, J=the 8.9, 2.5 Hz, 1H), of 7.88 (d, J=8,9 Hz, 1H), 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) was added aqueous NH4OH (128 μl, 3.6 mmol) at 0°C. the Mixture was stirred at room temperature overnight, diluted with water and extracted with diethyl ether. The pooled extracts in diethyl ether, washed with saturated brine, and dried over Na2SO4. �after removal of the solvent the residue is purified column chromatography (0-50% EtOAc-hexane), receiving 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-sulfonamide (32 mg, 0.12 mmol) and SnCl2·2H2Oh (138 mg, 0.61 mmol) in EtOH (1.5 ml) was heated in a microwave at 100°C for 30 min. the Mixture was diluted with EtOAc and water, made basic with a saturated solution of NaHCO3and filtered through celite. The organic layer is separated from water and dried over Na2SO4. The solvent was removed by evaporation, yielding 2-tert-butyl-5-aminobenzoyl-1-sulfonamide (E-7) (28 mg, yield 100%) which was used without further purification.

HPLC: retention time of 1.99 min, 10-99% CH3CN, gradient 5 min.

ESI-MS: 229,3 m/z (MH+).

Example 6

E-8; (2-tert-Butyl-5-Dapsone base)methanol

To a solution of methyl 2-tert-butyl-5-aminobenzoate (159 mg, 0,72 mmol) in THF (5 ml) was added, dropwise LiAlH4(1.4 ml, 1M solution in THF, 1.4 mmol) at 0°C. the Reaction mixture is brought to reflux 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 is concentrated, yielding (2-tert-butyl-5-Dapsone base)methanol (E-8) (25 mg, yield 20%), which is used�t without further purification.

1H-NMR (400 MHz, CDCl3): δ 7,17 (d, J=8,5 Hz, 1H), of 6.87 (d, J=2,6 Hz, 1H), 6,56 (DD, J=8,4, and 2.7 Hz, 1H), a 4.83 (s, 2H), of 1.36 (s, 9H).

Example 7

1-Methylprednisonelipitor

Metilsulfate (30 ml of 39.8 g, 0,315 mol) was added dropwise to anhydrous pyridine (25.0 g, 0,316 mol). The mixture was stirred at room temperature for 10 min, then at 100°C for 2 hours. The mixture is cooled to room temperature, yielding crude 1-methylpyridine-monomethylether (64,7 g, quantitative yield) which was used without further purification.

1-Methyl-2-pyridon

A solution of 1-methylprednisonepurchase (50 g, 0,243 mol) in water (54 ml) was cooled to a temperature of 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 separatory funnels to the 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 controlled so that to enter all of the sodium hydroxide solution in the reaction mixture when added, only half of a solution of potassium ferricyanide. After completion of the addition the reaction mixture is allowed to warm to room tempera�URS and stirred over night. Add anhydrous sodium carbonate (91,6 g) and the mixture was stirred for 10 min, the Organic layer separated and the aqueous layer was extracted with CH2Cl2(3 times 100 ml). The combined organic layers dried and concentrated, obtaining 1-methyl-2-pyridon (25,0 g, yield 94%) which was used without further purification.

1-Methyl-3,5-dinitro-2-pyridon

1-Methyl-2-pyridon (25,0 g, 0,229 mol) was 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 the reaction temperature is slowly increased to 100°C and then maintained for 5 hours. The reaction mixture was poured on ice, basified with a solution of potassium carbonate to pH=8 and extracted with CH2Cl2(3 times 100 ml). The combined organic layers dried over Na2SO4and concentrated, obtaining 1-methyl-3,5-dinitro-2-pyridon (12.5 g, yield 28%) which was 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 methanol (20 ml) was added, dropwise, 3-methyl-2-butanone (5,1 ml, 48 mmol), then a solution of ammonia in methanol (10.0 g, 17%, 100 mmol). The reaction mixture is heated at a temperature of 70°C for 2.5 hours at atmospheric pressure. The solvent was removed under vacuum, OS�sharpening oil was dissolved in CH 2Cl2and then filtered. The filtrate is dried over Na2SO4and concentrated, yielding 2-isopropyl-5-nitropyridine (1.88 g, yield 28%).

E-9; 2-Isopropyl-5-aminopyridin

2-Isopropyl-5-nitropyridine (1,30 g, of 7.82 mmol) was dissolved in methanol (20 ml) and added Raney Nickel (0.25 g). The mixture was stirred in hydrogen atmosphere (1 ATM) at room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo, yielding 2-isopropyl-5-aminopyridine (E-9) (0.55 g, yield 52%).

1H-NMR (CDCl3): δ with 8.05 (s, 1H), 6,93-of 6.99 (m, 2H), 3,47 (ush.s, 2H), 2,92-3,02 (m, 1H), 1,24-1,26 (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, EUR 169.6 mmol) in THF (150 ml) at 0°C. the Mixture was stirred at 0°C for 15 min and then added dropwise diethyl ether phosphorochloridate acid (of 30.15 g, 174,7 mmol) at 0°C. After complete addition the mixture was stirred at this temperature for 15 min. the Reaction mixture was quenched with a saturated solution of NH4Cl (300 ml). The organic layer separated and the aqueous phase extracted with Et 2O (2 × 350 ml). The combined organic layers washed with saturated salt solution, dried over anhydrous Na2SO4and concentrated in vacuum to give crude diethyl ether 2,4-di-tert-butylanisole of phosphoric acid ester as a yellow oil (51 g, contaminated with some mineral oil), which was used directly in the next step.

1,3-di-tert-Butylbenzoyl

NH3(liquid, 250 ml) was added a solution of diethyl ether 2,4-di-tert-butylanisole of phosphoric acid ester (51 g, crude, obtained on the previous step, about 0.2 mol) in Et2O (anhydrous, 150 ml) at a temperature of -78°C in a nitrogen atmosphere. To the solution was added small pieces of lithium metal until then, will continue until the blue color of the solution. The reaction mixture was stirred at -78°C for 15 min and then quenched with a saturated solution of NH4Cl up until the mixture becomes colorless. Liquid NH3evaporated and the residue dissolved in water, extracted with Et2O (2 × 300 ml). The combined organic phases dried over Na2SO4and concentrated, obtaining the 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 was 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(A 37.5 g, 197 mmol) at 0°C, then added dropwise MeOCHCl2(27,3 g, 236,4 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 1 hour. The mixture was poured into ice water and extracted with CH2Cl2. The combined organic phases were washed with NaHCO3and saturated brine, dried over Na2SO4and concentrate it. Balance purify separated by column chromatography (petroleum ether), yielding a mixture of 2,4-di-tert-butylbenzaldehyde 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) portions add KNO3(Of 7.64 g, to 75.6 mmol) at 0°C. the Reaction mixture was stirred at this temperature for 20 min and then poured on crushed ice. The mixture was made basic with NaOH to pH=8 and extracted with Et2O (3 times 10 ml). The combined organic layers were washed with water and saturated brine, and concentrated. Balance purify separated by column chromatography (petroleum ether),�will of 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) was isolated 2,4-di-tert-butyl-5-nitrobenzaldehyde (2.5 g, containing 10% 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, of 9.11 mmol, contains 10% 3,5-di-tert-butyl-2-nitrobenzaldehyde) in transparent desiccator the solution was stirred at room temperature for 5 hours. The reaction mixture was poured into a cooled saturated solution of NaHCO3and extracted with dichloromethane. The combined organic layers dried over Na2SO4, concentrate and purify separated by 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, 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 min the Solid was filtered, washed with acetic acid and CH2Cl2. The combined filtrate to�will centerour and treated with a solution of HCl in MeOH. The precipitate was separated by filtration, washed with MeOH and dried, yielding the hydrochloride is 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

A) Pd(PPh3)4, K2CO3, H2O, THF;B) Pd2(dba)3, P(tBu)3, KF, THF.

Method And

In the vial 2 dram, 2-bromoaniline (100 mg, of 0.58 mmol) and the appropriate arylboronic acid (0,82 mmol) was dissolved in THF (1 ml). Add H2O (500 μl), then K2CO3(200 mg, 1.0 mmol) and Pd(PPh3)4(100 mg, 0.1 mmol). The tube was purged with argon and sealed. Then the tube is heated at a temperature of 75°C for 18 hours. Untreated sample is diluted with EtOAc and filtered through a layer of silica gel. The organic layers are concentrated by Savant Speed-vacuum. The crude amine was used without further purification.

Method In

In vial 2 dram, introduce appropriate arylboronic acid (0,58 mmol), then KF (110 mg, 1.9 mmol). Solids suspended in THF (2 ml) and then added 2-bromoaniline (70 μl, of 0.58 mmol). The tube was purged with argon for 1 min. Add P(tBu)3(100 μl, 10% �actor in hexano), then Pd2(dba)3(900 μl of 0.005 M solution in THF). The tube was again purged 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 tube is cooled to a temperature of 20°C and the suspension was passed through a layer of celite. This layer was washed with EtOAc (5 ml). Organic layers combined and concentrated under vacuum to give the crude amine, which was used without further purification.

The table below includes amines obtained according to the General scheme presented above.

ProductNameMethod
F-14'-methylbiphenyl-2-ylamineA
F-23'-methylbiphenyl-2-ylamineA
F-32'-methylbiphenyl-2-ylamineA
F-42',3'-dimethylbiphenyl-2-ylamineA
b> 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'-isobutylphenyl-2-ylamineA
F-103'-cryptomaterial-2-ylamineB
F-112-pyridin-4-elfenliedB
F-122-(1H-indol-5-yl)phenylamineB
F-133',4'-dimethylbiphenyl-2-ylamineA
F-144'-isopropylphenyl-2-ylamineA
F-153'-isopropy� - biphenyl-2-ylamine A
F-164'-triptorelin-2-ylamineB
F-174'-methoxybiphenyl-2-ylamineB
F-183'-methoxybiphenyl-2-ylamineB
F-192-benzo[1,3]dioxol-5-elfenliedB
F-203'-ethoxymethyl-2-ylamineB
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-ylamineB
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-36 2'-cryptomaterial-2-ylamineB
F-374'-forbiden-2-ylamineB
F-383'-forbiden-2-ylamineB
F-392'-forbiden-2-ylamineB
F-402'-aminobiphenyl-3-carbonitrilB
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-ylamine B
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> B
F-57N-(2'-aminobiphenyl-3-yl)acetamideB
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-Dapsone base)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-Dapsone base)thiophene-2-carbonitrileB

Example 10

Ethyl-2-(4-nitrophenyl)-2-methylpropanoate

tert-Butoxide sodium (466 mg, is 4.85 mmol) was added to a DMF (20 ml) at 0°C. the Cloudy solution was re-cooled to a temperature of 5°C. Add ethyl-4-nitrophenylacetate (1.0 g, 4,78 mmol). The purple slurry was cooled to a temperature of 5°C and add methyliodide (0,688 ml, is 4.85 mmol) for 40 min. the Mixture was stirred at 5-10°C for 20 min and then re-add tert-butoxide sodium (466 mg, is 4.85 mmol) and methyliodide (read 0.699 ml, is 4.85 mmol). The mixture was stirred at 5-10°C for 20 min and the third time add tert-butoxide 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 brine, and dried over Na2SO4. After filtration the filtrate is concentrated, getting ethyl-2-(4-nitrophenyl)-2-methylpropanoate (900 mg, yield 80%) which was used without further purification.

G-1; Ethyl-2-(4-Dapsone base)-2-methylpropanoate

Dissolve� ethyl-2-(4-nitrophenyl)-2-methylpropanoate (900 mg, The 3.8 mmol) in EtOH (10 ml) was treated with 10% Pd/C (80 mg) and heated to a temperature of 45°C. was Added a solution of potassium formate (4.10 g, and 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 was 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. Organic layers dried over Na2SO4and the solvent removed under reduced pressure, obtaining the ethyl-2-(4-Dapsone base)-2-methylpropanoate (G-1) (670 mg, yield 85%).

1H-NMR (400 MHz, CDCl3): δ 7,14 (d, J=8,5 Hz, 2H), of 6.65 (d, J=8,6 Hz, 2H), 4,10 (kV, J=7,1 Hz, 2H), 1,53 (s, 6H), of 1.18 (t, J=7,1 Hz, 3H).

Example 11

G-2; 2-(4-Dapsone base)-2-methylpropan-1-ol

A solution of ethyl-2-(4-Dapsone base)-2-methylpropanoate (30 mg, 0,145 mmol) in THF (1 ml) was treated with LiAlH4(1M solution in THF, 0,226 ml, 0,226 mmol) at 0°C and stirred for 15 min. the Reaction mixture was treated with 0,1 n NaOH, extracted with EtOAc and the organic layers dried over Na2SO4. The solvent was removed under reduced pressure, obtaining 2-(4-Dapsone base)-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), of 1.28 (s, 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°treated With 4-nitrophenylacetonitrile (1000 mg, 6.18 of mmol) and stirred for 10 min. dropwise add methyliodide (400 μl, 6,47 mmol) within 15 min. the Solution was stirred at a temperature of 0-10°C for 15 min and then at room temperature for 15 min. To the resulting purple solution was added tert-butoxide sodium (662 mg, 6,47 mmol) and the solution was stirred for 15 min added dropwise methyliodide (400 μl, 6,47 mmol) for 15 min and the solution was stirred over night. Add tert-butoxide 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 was 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 brine, dried over Na2SO4and concentrated, obtaining 2-methyl-2-(4-nitrophenyl)propanenitrile as a green waxy solid 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), of 1.77 (s, 6H).

2-Methyl-2-(4-nitrophenyl)propane-1-amine

To a chilled solution of 2-methyl-2-(4-nitrophenyl)propanenitrile (670 mg, 3.5 mmol) in THF (15 ml) was added dropwise BH3(1M solution in THF, 14 ml, 14 mmol) at 0°C. the Mixture was heated to room temperature and heated at a temperature of 70°C for 2 hours. Add 1H. HCl solution (2 ml), then NaOH, until then, until the pH reaches a value >7. The mixture was extracted with diethyl ether and the extract in diethyl ether was concentrated, obtaining 2-methyl-2-(4-nitrophenyl)propane-1-amine (610 mg, yield 90%) which was used without further purification.

1H-NMR (400 MHz, CDCl3): δ 8,20 (d, J=9,0 Hz, 2H), 7,54 (d, J=9,0 Hz, 2H), 2,89 (s, 2H), 1,38 (s, 6H).

tert-Butyl-2-methyl-2-(4-nitrophenyl)propellernet

To a chilled solution of 2-methyl-2-(4-nitrophenyl)propane-1-amine (600 mg, 3.1 mmol) and 1H. 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 is allowed 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 was used without further purification.

1H-NMR (400 MHz, CDCl3): δ 8,11 (d, J=8,9 Hz, 2H), of 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-Dapsone base)propellernet

To boiling to reflux 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) was added 5 wt%. Pd/C (400 mg). The mixture is boiled to reflux for 1 hour, cooled and filtered through celite. The filtrate was concentrated, receiving tert-butyl-2-methyl-2-(4-Dapsone base)propylgallate (G-3) (550 mg, yield 83%) which was 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), is 4.85 (s, 2H), 3,01 (d, J=6.3 Hz, 2H), of 1.36 (s, 9H).

HPLC: retention time 2,02 min, 10-99% CH3CN, the analysis time of 5 min.

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) was dissolved in methanol (5 ml) and portions add NaBH4(78 mg, 2,05 mmol). The reaction mixture was stirred at room temperature for 20 min, then concentrate and purify separated by column chromatography (10-50% ethyl acetate-hexane) to obtain 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), to 7.33 (d, J=8,5 Hz, 1H), 4,76 (t, J=5,5 Hz, 1H), 2,96-2,80 (m, 2H), 2,10-of 1.99 (m, 2H), 1,86-to 1.77 (m, 2H).

HPLC: retention time of 2.32 min, 10-99% CH3CN, BP�mja analysis 5 min.

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) was dissolved in methanol (10 ml) and the flask was purged with N2(gaseous). Add 10% Pd/C (10 mg) and the reaction mixture was stirred in hydrogen atmosphere (1 ATM) at room temperature over night. The reaction mixture was filtered and the filtrate is concentrated, yielding 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 min.

ESI-MS: 164,5 m/z (MH+).

Example 14

The oxime 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) was added 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), yielding the oxime 7-nitro-3,4-dihydro-2H-naphthalene-1-one (471 mg, yield 88%).

HPLC: retention time of 2.67 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 207,1 m/z (MH+).

1,2,3,4-tetrahydronaphthalene-1,7-diamine

The oxime 7-nitro-3,4-dihydro-2H-naphthalene-1-one (274 mg, of 1.33 mmol) was dissolved in methanol (10 ml) and the flask was purged with N2(gaseous). Add 10% Pd/C (50 mg) and the reaction mixture per�mesilat in hydrogen atmosphere (1 ATM) at room temperature over night. The reaction mixture was filtered and the filtrate is concentrated, yielding 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), 4,62 (s, 2H), 3,58 (m, 1H), 2,48-of 2.44 (m, 2H), 1,78-1,70 (m, 2H), 1,53-of 1.37 (m, 2H).

H-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, was added di-tert-BUTYLCARBAMATE (207 mg, 0.95 mmol). The reaction mixture was stirred at 0°C and then concentrate and purify separated by column chromatography (5-50% methanol-dichloro methane) to obtain tert-butyl ether (7-amino-1,2,3,4-tetrahydronaphthalen-1-yl)carbamino acid (H-2) (327 mg, quantitative yield).

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

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, 10.8 mmol) in methanol (5 ml) was added ethyltryptamine (1,54 ml, 21.6 mmol) and triethylamine (1.4 ml, 10.8 mmol) in a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under vacuum to give N-(2-bromobenzyl)-2,2,2-trifurcated (3,15 �, quantitative output).

HPLC: retention time 2,86 min, 10-99% CH3CN, the analysis time of 5 min.

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) was dissolved in DMF (5 ml) and added 4M solution of K2CO3(0.5 ml). The reaction mixture was heated at 80°With during the night. The mixture was filtered, concentrated and purified column chromatography (0-50% ethyl acetate-hexane), receiving N-(4'-aminobiphenyl-2-ylmethyl)-2,2,2-trifurcated (I-1) (143 mg, yield 49%).

HPLC: retention time of 1.90 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 295,5 m/z (MH+).

Commercially available amines

AminName
J-12-methoxy-5-methylbenzenamine
J-22,6-diisopropylbenzene
J-3pyridin-2-amine
J-44-pentylbenzene
J-5isoquinoline-3-amine
J-6aniline
J-74-phenoxybenzamine
J-82-(2,3-dimethylphenoxy)pyridin-3-amine
J-94-ethynylbenzoate
J-102-sec-butylbenzoate
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)benzoylamine
J-152'-aminomethylphenol-4-ylamine
J-161H-indazol-6-ylamine
J-172-(2-methoxyphenoxy)-5-(trifluoromethyl)benzolamide
J-182-tert-butylbenzylamine
J-19 2,4,6-trimethylbenzene
J-205,6-dimethyl-1H-benzo[d]imidazol-2-amine
J-212,3-dihydro-1H-indene-4-amine
J-222-sec-butyl-6-ethylbenzylamine
J-23quinoline-5-amine
J-244-(benzyloxy)benzoylamine
J-252'-methoxybiphenyl-2-ylamine
J-26benzo[c][1,2,5]thiadiazole-4-amine
J-273-benzylbenzoate
J-284-isopropylbenzylamine
J-292-(phenylsulfonyl)benzoylamine
J-302-methoxybenzylamine
J-314-amino-3-ethylbenzonitrile
J-324-methylpyridine-2-amine
J-334-chlorobenzenamine
J-342-(benzyloxy)benzoylamine
J-352-amino-6-chlorobenzonitrile
J-363-methylpyridine-2-amine
J-374-aminobenzonitrile
J-383-chloro-2,6-diethylbenzene
J-393-phenoxybenzamine
J-402-benzylbenzoate
J-412-(2-pertenece)pyridin-3-amine
J-425-chloropyridin-2-amine
J-432-(trifluoromethyl)benzolamide
J-44(4-(2-Dapsone base)piperazine-1-yl)(phenyl)methanon
J-451H-benzo[d][1,2,3]triazole-5-amine
J-462-(1H-indol-2-yl)benzoylamine
J-474-methylbiphenyl-3-ylamine
J-48PIR�DIN-3-amine
J-493,4-dimethoxybenzoate
J-503H-benzo[d]imidazole-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-butoxybenzene
J-582,6-dimethylbenzenamine
J-592-(methylthio)benzoylamine
J-602-(5-methylfuran-2-yl)benzoylamine
J-613-(4-Dapsone base)-3-ethylpiperidine-2,6-dione
J-622,4-dimethylbenzenamine
J-635-PIF�pyridin-2-amine
J-644-cyclohexylbenzene
J-654-aminobenzenesulfonamide
J-662-ethylbenzylamine
J-674-fluoro-3-methylbenzenamine
J-682,6-dimethoxypyridine-3-amine
J-694-tert-butylbenzylamine
J-704-sec-butylbenzoate
J-715,6,7,8-tetrahydronaphthalen-2-amine
J-723-(pyrrolidin-1-sulfonyl)phenylamine
J-734-adamantan-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-torbenson-1,2-diamine
3,4-dimethylbenzenamine
J-792-(triptoreline)benzoylamine
J-801H-indole-7-amine
J-813-methoxybenzylamine
J-82the quinoline-8-amine
J-832-(2,4-divergence)pyridin-3-amine
J-842-(4-Dapsone base)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-Dapsone base)alanon
J-94m-toluidine
J-952-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)benzoylamine
J-962-amino-6-methylbenzonitrile
J-972-(prop-1-EN-2-yl)benzoylamine
J-984-amino-N-pyridine-2-albenzaalbenza
J-992-ethoxybenzoate
J-100naphthalene-1-amine
J-101the biphenyl-2-ylamine
J-1022-(trifluoromethyl)-4-isopropylbenzylamine
J-1032,6-diethylbenzene
J-1045-(trifluoromethyl)pyridin-2-amine
J-1052-aminobenzamide,
J-1063-(triptoreline)benzoylamine
J-107 3,5-bis(trifluoromethyl)benzolamide
J-1084-vinylbenzoate
J-1094-(trifluoromethyl)benzolamide
J-1102-morpholinopropan
J-1115-amino-1H-benzo[d]imidazol-2(3H)-he
J-112the quinolin-2-amine
J-1133-methyl-1H-indol-4-amine
J-114the pyrazine-2-amine
J-1151-(3-Dapsone base)alanon
J-1162-ethyl-6-isopropylbenzylamine
J-1172-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)benzoylamine
J-118N-(4-amino-2,5-dioxyphenyl)benzamide
J-1195,6,7,8-tetrahydronaphthalen-1-amine
J-1202-(1H-benzo[d]imidazol-2-yl)benzoylamine
J-1211,1-d�oxo-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-Dapsone base)ethanol
J-126(4-Dapsone base)methanol
J-1275-methylpyridine-2-amine
J-1282-(pyrrolidin-1-yl)benzoylamine
J-1294-propylbenzoate
J-1303,4-dichlorbenzene
J-1312-phenoxybenzamine
J-132the biphenyl-2-ylamine
J-1332-chlorobenzenamine
J-1342-amino-4-methylbenzonitrile
J-135(2-Dapsone base)(phenyl)methanon
J-136 aniline
J-1373-(triptoreline)benzoylamine
J-1382-(2,5-dimethyl-1H-pyrrol-1-yl)benzoylamine
J-1394-(morpholine-4-sulfonyl)phenylamine
J-1402 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)benzoylamine
J-1452-methyl-1H-indol-5-amine
J-146quinoline-6-amine
J-1471H-benzo[d]imidazol-2-amine
J-1482-o-tolerant[d]oxazol-5-amine
J-1495-vinylpyridin-2-amine
J-150the biphenyl-2-yl�min
J-1514-(deformedarse)benzoylamine
J-1525-tert-butyl-2-methoxybenzylamine
J-1532-(2-tert-butylphenoxy)benzoylamine
J-1543-aminobenzamide,
J-1554-morpholinomethyl
J-1566 aminobenzo[d]oxazol-2(3H)-he
J-1572-phenyl-3H-benzo[d]imidazole-5-amine
J-1582,5-dichloropyridine-3-amine
J-1592,5-dimethylbenzenamine
J-1604-(phenylthio)benzoylamine
J-1619H-fluoren-1-amine
J-1622-(4-Dapsone base)-1,1,1,3,3,3-hexaferrite-2-ol
J-1634-bromo-2-ethylbenzylamine
J-1644-methoxybenzylamine
J-1653-(piperidine-1-sulfonyl)phenylamine
J-166quinoxaline-6-amine
J-1676-(trifluoromethyl)pyridin-3-amine
J-1683-(trifluoromethyl)-2-methylbenzenamine
J-169(2-Dapsone base)(phenyl)methanol
J-170aniline
J-1716-methoxypyridine-3-amine
J-1724-butylbenzylamine
J-1733-(morpholine-4-sulfonyl)phenylamine
J-1742,3-dimethylbenzenamine
J-175aniline
J-176the biphenyl-2-ylamine
J-1772-(2,4-dichlorophenoxy)benzoylamine
J-178pyridin-4-amine
J-1792-(4-methoxyphenoxy)-5-(triptime�l)benzoylamine
J-1806-methylpyridine-2-amine
J-1815-chloro-2-forbindelsen
J-1821H-indol-4-amine
J-1836-morpholinopropan-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-Dapsone base)ethanol
J-1942-amino-4-methylbenzamide
J-195the quinoline-3-amine
J-1962-(piperidine-1-yl)benzoylamine
J-1973-aminobenzenesulfonamide
J-1982-ethyl-6-methylbenzenamine
J-199biphenyl-4-ylamine
J-2002-(o-tolyloxy)benzoylamine
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-Dapsone base)acetonitrile
J-2072-(4-pertenece)pyridin-3-amine
J-208aniline
J-209J-2104-forbindelsen
J-2112-propylbenzene
J-2124-(triptoreline)benzoylamine
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-Dapsone base)acetamide
J-2171-(3-Dapsone base)-3-methyl-1H-pyrazol-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)acetamide
J-221N-(3-Dapsone base)methanesulfonamide
J-222N-(3-Dapsone base)propionamide
N1,N1-xylene-1,3-diamine
J-224N-(3-amino-4-methoxyphenyl)acetamide
J-225benzene-1,3-diamine
J-2264-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-indole-6-�min
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) Ar1R7NH, binder, base, solvent. Examples of conditions used: HATU, DIEA, DMF; BOP, DIEA, DMF; HBTU, Et3N, CH2Cl2; PFP-TFUK, pyridine.

A specific example

215; 4-Oxo-N-phenyl-1H-quinoline-3-carboxamide

To a solution of 4-hydroxyquinoline-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 was filtered and purified by 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), of 8.34 (DD, J=8,1, 1,1 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H) the 7.75 (m, 3H) 7,55 (t, J=8,1 Hz, 1H), value of 7, 37 (t, J=7.9 Hz, 2H), 7,10 (t, J=6,8 Hz, 1H).

HPLC: retention time 3,02 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 265,1 m/z (MH+).

The table below presents the list of other examples of substances synthesized according to the General scheme, p�evidenoe above.

D-18 A-1 D-10 423 A-1
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
20A-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
36 A-1J-203
37A-1J-80
38A-1J-46
39A-17D-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-1 F-2
53A-1J-178
54A-1J-26
55A-1J-219
56A-1J-74
57A-1J-61
58A-1D-4
59A-1F-35
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
70A-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
A-1J-190
83A-1F-40
84A-1J-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
97 A-1F-34
99A-1J-4
100A-1J-182
102A-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-1
115A-1F-62
116A-3J-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-1F-19
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
183/td> A-1DC-1
184A-15J-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
198J-210
199A-1F-3
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-1 J-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-1 J-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-3
250A-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-1J-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-1F-45
286A-1J-119
287A-3C-13
288A-1C-6
289A-1J-142
290A-1F-15
291A-1C-10
292A-1J-76
293A-1J-144
294A-1J-54
295A-1J-128
296A-17J-12
297A-1J-138
301A-1J-14
32 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
317 A-1J-85
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-1 DC-5
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-1
354A-1J-186
355A-1J-25
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
369A-1J-11
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
385A-1J-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-1J-33
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
419A-1J-216
420A-1G-1
421A-1C-18
422A-1J-20
A-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-1F-24
437/td> A-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-1J-193
451J-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-1 J-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
484A-1D-14
B-26-I-1 B-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-indole-5-carboxylic acid

A mixture of ethyl ester of 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-5-carbon�th acid ( 188) (450 mg, 1.2 mmol) and 1N. NaOH solution (5 ml) in THF (10 ml) was heated at 85°C for 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 air dried, yielding 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) of 12.92 δ-12,75 (m, 2H), 11,33 (s, 1H), is 8.84 (s, 1H), of 8.71 (s, 1H), 8,30 (DD, J=8,1, 0.9 Hz, 1H), 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), is 6.51 (m,H).

HPLC: retention time of 2.95 min, 10-99% CH3CN, the analysis time of 5 min.

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) was added to isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65°C overnight. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O), yielding 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), of 8.47 (s, 1H), to 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 (m, 1H), 3,10 t, J=6.2 Hz, 2H), of 1.88 (m, 1H), of 0.92 (d, J=6,7 Hz, 6H).

HPLC: retention time 2,73 min, 10-99% CH3CN, the analysis time of 5 min.

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) was synthesized following the General scheme above, linking acid (188-I) with piperidine. Total output (12%).

HPLC: retention time 2,79 min, 10-99% CH3CN, the analysis time of 5 min.

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) was heated in a microwave oven at 180°C for 10 min. the Reaction mixture was filtered and purified by 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: retention time of 3.05 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: USD 380.2 m/z (MH+).

In �Alice, below, a list of other examples of substances synthesized according to the General scheme above.

The compound of the formula IBaronova acid
2372-methoxyphenylalanine acid
3272-ethoxypropionate 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 ether methyl{[methyl(2-oxo-2-{6-[(4-oxo-1,4-dihydroquinoline-3-carbonyl)amino]indol-1-yl}ethyl)carbamoyl]methyl}carbamino acid (�-26-I ) (2.0 g, 3.7 mmol) dissolved in a mixture of CH2Cl2(50 ml) and methanol (15 ml), was added a solution of HCl (60 ml, 1.25 M 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 to give the hydrochloride of N-[1-[2-[methyl(2-methylaminomethyl)amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (27) in 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-of 8.85 (m, 1H), 8,35 (d, J=7.9 Hz, 1H), 7,91-to 7.77 (m, 3H), of 7.64-7,54 (m, 3H), about 6,82 (m, 1H), to 5.05 (s, 0,7 H), 4,96 (s, 1,3 H), 4,25 (t, J=5,6 Hz, 1,3 H), of 4.00 (t, J=5,7 Hz, 0,7 H), 3,14 (s, 2H), 3,02 (s, 1H), 2,62 (t, J=5,2 Hz, 2H), 2,54 (t, J=5.4 Hz, 1H).

HPLC: retention time 2,36 min, 10-99% CH3CN, the analysis time of 5 min.

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) was added BnBr (10 ul, 0.08 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and purified�, using HPLC, yielding 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 min.

ESI-MS: 427,1 m/z (MH+).

Another example

415; N-(3-Hydroxy-4-tert-butylphenyl)-4-methoxyquinoline-3-

carboxamide

N-(3-Hydroxy-4-tert-butylphenyl)-4-methoxyquinoline-3-carboxamide (415) was synthesized following the General scheme above, exposing 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), of 9.46 (s, 1H), 8,99 (s, 1H), to 8.42 (t, J=4,2 Hz, 1H), 7,95-of 7.88 (m, 2H), 7,61-7,69 (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), Of 1.35 (s, 9H).

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

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 (C-27-I) (84 mg, 0.2 mmol), Zn(C) 2(14 mg, 0.12 mmol) in NMP (1 ml) was added in a nitrogen atmosphere, Pd(PPh3)4(16 mg, 0,014 mmol). The mixture was heated in a microwave oven at 200°C for 1 hour, filtered and purified using preparative HPLC, yielding 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), of 8.34 (d, J=8,2 Hz, 1H), 8,16 (s, 1H), a 7.85-of 7.75 (m, 2H), 7,56-7,54 (m, 1H), 7,44 (s, 1H), of 1.35 (s, 9H).

HPLC: retention time 3,42 min, 10-100% CH3CN, gradient 5 min.

ESI-MS: to 362.1 m/z (MH+).

Aniline

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), TFOC (1 ml) and CH2Cl2(1 ml) was stirred at room temperature over night. The solution was concentrated and the residue dissolved in DMSO (1 ml) and purified by HPLC (10-99% CH3CN/H2O), yielding 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 (user.s, 2H), 8,88 (d, J=6,8 Hz, 1H) of 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), 1,46 (s, 9H).

HPLC: retention time of 2.33 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 336,3 m/z (MH+).

The table below presents the list of other examples of substances synthesized according to the General scheme above.

Source the 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) was added acetic acid (250 μl) and formaldehyde (268 μl, 3.6 mmol, 37% wt. in�de.). After 10 min, one portion add cyanoborohydride sodium (407 mg, 6.5 mmol). Additional formaldehyde (135 μl, 1.8 mmol, 37% wt. in water) was added after 1.5 hours and 4.2 hours. After 4.7 hours, the mixture was diluted with diethyl ether (40 ml), washed with water (25 ml) and saturated brine (25 ml), dried (Na2SO4), filtered and concentrated. The obtained red-brown foam was purified preparative HPLC, receiving N-(3-dimethylamino-4-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (485) (108 mg, yield 17%).

lH-NMR (300 MHz, SDS3) ∆ 13,13 (user.s, 1H), of 12.78 (s, 1H), 8,91 (user.s, 1H), to 8.42 (user.s, 1H), 8,37 (d, J=8,1 Hz, 1H), 7,72-7,58 (m, 2H), 7,47-7,31 (m, 3H), 3,34 (s, 6H), 1,46 (s, 9H).

HPLC: retention time of 2.15 min, 10-100% CH3CN, the analysis time of 5 min.

ESI-MS: 364,3 m/z (MH+).

The table below presents the list of other examples of substances synthesized according to the General scheme above.

Source the intermediate productProduct
69117
160462
282409
4198

Example 3

Odashima

A specific example

94; N-(5-Amino-2-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide

To a solution of 4-hydroxyquinoline-3-carboxylic acid (A-1) (50 mg, 0,26 mmol), HBTU (99 mg, 0,26 mmol) and DIEA (138 µl, 0.79, which mmol) in THF (2.6 ml) was added 2-methyl-5-nitrophenylamino (40 mg, 0,26 mmol). The mixture was heated at 150°C in microwave oven for 20 min and the resulting solution concentrated. The residue was dissolved in EtOH (2 ml) and add Snl2·2H2Oh (293 mg, 1.3 mmol). The reaction mixture was stirred at room temperature over night. The reaction mixture was made basic with a solution of NaHCO3to pH=7-8, and extracted with ethyl acetate. The combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99% CH3CN/H2O), yielding the product, N-(5-amino-2-methylphenyl)-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 min.

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) is prepared by following the General scheme, when�Eden above, on the basis of 4-hydroxyquinoline-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, DMFA.

A specific example

248; N-(3-Acetylamino-4-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide

To a solution of N-(3-amino-4-methylphenyl)-4-oxo-1H-quinoline-3-carboxamide (167) (33 mg, 0.11 mmol) and DIEA (49 μl, 0.28 mmol) in THF (1 ml) was added acetyl chloride (16 μl, 0.22 mmol). The reaction mixture was stirred at room temperature for 30 min. GHMS analysis shows that Vallirana happened. Added 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 was concentrated and the residue dissolved in DMSO and purified by HPLC (10-99% CH3CN/H2O), yielding the product, N-(3-acetylamino-4-methylphenyl)-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), 9,30 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), of 8.33 (DD, J=8,1, of 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 and 2.2 Hz, 1H), 7,18 (d, J=8,3 Hz, 1H), 2,18 (s, 3H), 2,08 (s, 3H).

HPLC: retention time of 2.46 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 336,3 m/z (MH+).

The table below presents the list of other examples of substances synthesized according to the General scheme above.

On the basis ofXR2Product
260WITHMe316
260WITHneopentyl196
429WITHMe379
41WITHMe232
101WITHMe243
8WITHMe149
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 of 1.51 mmol) in argon atmosphere. The mixture was 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 initial substance. Add another 0.5 EQ. NMM and the mixture was stirred at room temperature over night. IHMS-anal�h the crude mixture shows conversion to the desired product > 85%. The mixture is concentrated and treated with a 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 for next step without further purification.

1H-NMR (d6-acetone, 300 MHz) δ 8,92 (s, 1H), to 8.41 is 8.38 (m, 1H), 7,94 (m, 2H), 7,78 (user.s, 2H), 7,53-7,47 (m, 1H), 7,30 (s, 1H), 6,87-of 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)ethylsulfanyl]-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 was brought to reflux at a temperature of 75°C for 18 hours. After this time, GHMC-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)ethylsulfanyl]-5-(trifluoromethyl)-phenyl]-1H-quinoline-3-carboxamide (318) as yellowish solid (15 mg, yield 25%).

1H YAM� (d 6-acetone, 300 MHz) δ 8,92 (user.s, 1H), and 8.4 (d, J=8,1 Hz, 1H), 8,05 (user.s, 1H), 7,94 (user.s, 1H), 7,78 (user.s, 2H), 7,53-7,51 (m, 1H), of 7.36 (user.s, 1H), 3,97 (t, J=7,2 Hz, 2H), 3,66 (t, J=8 Hz, 2H), 3,31-3,24 (m, 6H), 1,36-of 1.31 (m, 4H).

ESI-MS: 489,1 m/z (MH+).

The table below presents the list of other examples of substances synthesized according to the General scheme above.

Source the intermediate productAminProduct
429the morpholine272
429dimethylamine359
131the piperidine133
131the morpholine46

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), 1N. solution Paon (0.5 ml) and ethanol (0.5 ml) was heated to reflux for 48 hours. The Koh solution�antiroot and the residue dissolved in DMSO (1 ml) and purified by HPLC (10-99% CH 3CN/H2O), yielding 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 min.

ESI-MS: 306,3 m/z (MH+).

The table below presents the list of other examples of substances synthesized according to the General scheme above.

On the basis ofProductConditionsSolvent
DC-8-I386NaOHEtOH
DC-9-I10HC1EtOH
17522HC1EtOH
10935HC1EtOH
334238NaOHEtOH
DC-10-I105NaOHTHF

Example 2/u>

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), TFOC (1 ml) and CH2Cl2(1 ml) was stirred at room temperature over night. The solution was concentrated and the residue dissolved in DMSO (1 ml) and purified by 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 min.

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) was synthesized following the General scheme above, on the basis of 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), ∆ 13,23 (d, J=6,6 Hz, 1H), of 12.59 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), of 8.33 (d, J=7,7 Hz, 1H), 7,86-7,79 (m, 3H), 7,58-of 7.42 (m, 3H), 3,38 (m, 2H), of 1.88 (m, 2H), 1,30 (C, 6H).

HPLC: retention time of 2.40 �Jn, 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) was stirred in a mixture of CH2Cl2/TFOC (3:1, 20 ml) at room temperature for 1 hour. Volatiles 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), of 8.26 (user.s, 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), 7,67 (d, J=7,8 Hz, 1H), 7,47-value of 7, 37 (m, 2H), 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), of 4.09 (m, 2H), of 4.04 (q, J=6,9 Hz, 2H), of 1.09 (t, J=6,9 Hz, 3H).

HPLC: retention time 1,71 min, 10-100% CH3CN, gradient 5 min.

ESI-MS: 414,1 m/z (MH+).

Another example

390; N-[3-(Aminomethyl)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-�carboxamid

N-[3-(Aminomethyl)-4-tert-butylphenyl]-4-oxo-1H-quinoline-3-carboxamide (390) was synthesized following the General scheme above, on the basis of tert-butyl ether [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-tert-butylphenyl]methylaminoethanol acid (465).

HPLC: retention time of 2.44 min, 10-99% CH3CN, gradient 5 min.

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)quinolin-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 over night. Then the reaction mixture was neutralized with 1N. NaOH. The precipitate was separated by filtration, receiving the product, 3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H)-he, in the form of a brown solid (651 mg, yield 91%).

HPLC: retention time 2,26 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 336,5 m/z (M+H+).

323; Methyl ester [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]propyl]aminoarabinose acid

Methylchloroform (0.012 g, 0,150 mmol) was added to a solution of 3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)ACO�yl)quinoline-4(1H)-she (0.025 g, Of 0.075 mmol), tea (0,150 mmol, of 0.021 ml) and DMF (1 ml) and stirred at room temperature for 1 hour. Then added piperidine (to 0.074 ml, and 0.750 mmol) and the reaction mixture was stirred for 30 min. the Reaction mixture was filtered and purified preparative HPLC (10-99% CH3CN/H2O) to give the product, methyl ether [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 (user.s, 1H), 12,44 (s, 1H), 8,89 (s, 1H), of 8.33 (DD, J=8,2, 1,1 Hz, 1H), of 7.82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7,7 Hz, 1H), 7,67 (d, J=8,8 Hz, 2H), 7,54 (t, J=8,1 Hz, 1H), 7,35 (d, J=to 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 min.

ESI-MS: 394,0 m/z (MH+).

The table below presents the list of other examples of substances synthesized according to the General scheme above.

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 ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]his aminoarabinose acid (273) (250 mg, 0.6 mmol) in dichloromethane (2 ml) was added TFOC (2 ml). The reaction mixture was stirred at room temperature for 30 min. To the reaction mixture add dichloro methane (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 1,94 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 334,5 m/z (MH+).

159; Methyl ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]his aminoarabinose acid

To a solution of N-(1-aminotetralin-7-�l)-4-oxo-1H-quinoline-3-carboxamide ( 273-I) (65 mg, 0.20 mmol) and DIEA (52 μl, 0.29 mmol) in methanol (1 ml) was added 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 of mono-and bis-addition. Added piperidine (2 ml) and the reaction mixture was stirred overnight, after which the product is detected only mono-accession. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O) to give the product, methyl ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]his aminoarabinose acid (159) (27 mg, yield 35%).

HPLC: retention time of 2.68 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 392,3 m/z (MH+).

Another example

482; Ethyl [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]his aminoarabinose acid

Ethyl [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]his aminoarabinose acid (482) was synthesized following the General scheme above, from amine (273-Iand ethylchloride. Overall yield (18%).

HPLC: retention time of 2.84 min, 10-99% CH3CN, the analysis time of 5 min.

ESI-MS: 406,5 m/z (MH+).

The table below presents the characteristic data of compounds according to the present invented�Yu, obtained in accordance with the above examples.

td align="center"> 47 138
Table 2
Conn. No.LC-MS M+1LC-RT minConn. No.LC-MS M+1LC-RT minConn. No.LC-MS M+1LC-RT min
1444,33,1923To 457.53,5645308,13,18
2Is 350.13,824398,33,1346490,11,89
3455,3Of 3.7525397,12,38375,33,33
4350,3With 2.8126348,12,5148317,13,06
5337,32,7627446,22,3349400,12,88
6351,4328438,42,950307,33,08
7472,33,629307,13,3251521,53,79
8307,11,2130379,1 2,6252354,13,02
9344,12,4331278,93,0353266,11,99
10334,22,232338,2354323,32,97
11408,12,9133303,92,8355366,32,6
12383,12,6334397,14,1956335,43,18
13346,33,4835 362,22,5357403,12,86
14394,3Of 3.0736307,33,2558364,33,02
15296,32,6837303,92,9859412,13,31
16307,33,3838380,33,3360422,23,53
17338,33,7439480,53,8261293,13,05
18352,93,62 40309,12,4662349,13,4
19316,32,7141321,11,8863376,12,89
20371,33,5342460,03,7164321,12,31
21421,12,6643To 457.53,665381,51,85
22332,22,2144336,12,9566345,13,32
67332,3 3,17109404,53,17151360,03
68398,12,85110303,92,75152To 322.32,31
69322,52,37111333,13153425,14,52
70341,12,15112348,5Of 3.07154401,33,77
71426,12,6113318,33,02155266,12,11
72 293,13,27114499,23,74156424,13,12
73380,92,4115330,12,67157321,02,13
74334,13,32116320,23,18158USD 380.23,05
75316,32,43117349,11,32159392,32,68
76376,12,97118379,12,61160321,1To 1.34
322,52,93119To 408.4Of 3.07161409,23,82
78344,12,38120309,12,93162296,32,61
79372,1Of 3.07121333,1Of 3.69163413,11,71
80295,32,78122325,12,66164333,13,33
81336,32,73123330,12,64165344,182350,32,11124378,33,4166398,12,83
83365,1Z76125294,32,21167294,32,12
84280,32,11126411,13,06168265,91,96
85408,03,25127408,53,221693182,98
86370,32,08128369,13,53170 To 300.33,08
87357,13,5129365,11,74171408,03,08
88436,3Of 3.37130440,23,57172396,03,14
89303,93,1131313,02,4173280,32,14
90321,13,43132365,92,73174388,0Of 2.58
91Of 355.23,47133488,11,97 175374,22,85
92295,23,84134402,12,25176349,13,38
93371,02,75135To 384.1To 2.94177337,13,5
94294,22,06136393,14,33178413,34
95290,12,78137580,54,1179308,52,33
96343,02,75376,12,98180307,33,08
97402,12,59139408,03,17181354,12,97
98349,11,96140346,14182358,12,89
99334,13,13141366,32,89183420,33,47
100303,92,63142321,33,58184372,32,66
101322,5 Of 2.35143Of 355.23,45185414,12,96
102443,1At 3.97144281,32,49186372,33,59
103411,23,85145376,22,98187346,32,9
104318,0To 2.94146306,32,51188376,22,95
105Over 322.22,4147376,33,27189370,93,38
106 350,32,86148415,52,79190392,03,09
107420,2Of 3.37149349,11,45191316,32,1
108USD 448,23,77150430,03,29192280,32,13
193326,33,02235308,42,12277358,12,89
194290,12,98236333,13,35278408,13,09
195280,32,14237410,32,96279386,12,88
196434,53,38238489,42,78280316,32,06
197334,13,15239379,02,62281293,13,22
198283,13240370,93,65282307,11,22
199354,12,96241316,32,61283370,1 3
200335,52,49242348,33,08284305,32,57
201303,93,08243363,02,44285376,12,88
202404,03,19244358,13,48286319,13,35
203394,33,42245425,1Of 3.69287411,24,15
204349,33,32246292,93,2288 413,33,8
205455,53,74247432,13,23289297,33,25
206386,13,5248336,32,46290382,13,19
207390,32,71249365,02,54291371,03,57
208429,73,89250352,32,53292391,1Of 3.69
209294,12,39251436,23,38 293330,33,05
210385,23,72252368,93,17294303,92,67
211351,33,53253424,13,25295334,3At 2.26
212360,92,45254340,13,08296365,33,6
213408,03,3255526,53,89297358,33,26
214358,12,7256306,1 2,4298379,1Of 1.91
215265,3Of 3.07257297,3Or 3.28299320,32,18
216305,32,27258306,32,05300348,22,4
217305,32,41259360,33,46301346,3At 2.26
218413,2Of 3.98260336,32,33302370,12,28
219266,92,48261 368,13,08303362,22,51
220409,03,35262352,32,7304513,23,66
221379,12,68263372,9Of 3.69305370,12,98
222324,33,27264353,13,42306To 384.13,11
223386,13,14265354,93,4307374,03,05
224466,33,08 266405,34,05308304,12,71
225393,12,75267357,13,43309316,32,83
226306,13,6268400,36,01310To 320.13,73
227Of 381.12,24269393,02,75311344,93,43
228371,12,84270329,33,02312400,12,86
229311,12,93271336,52,75313358,12,8
230318,1With 2.81272524,11,87314335,13,52
231471,33,41273434,53,17315293,12,9
232363,12,57274RUR 493.53,46316378,52,84
233348,52,75275427,13,93317 333,22,91
234372,33,2276414,3With 2.81318522,11,8
319373,33,59361400,12,91403423,14,45
320360,13,5362355,53,46404440,32,87
321453,53,12363388,12,92405299,33,16
322349,33,7364330,32,68 406547,33,74
323394,02,93365307,12,6407371,33,8
324To 320.13,81366408,13,09408295,32,9
325321,33,22367408,03,14409335,1Of 1.82
326418,02,5368338,22,33410432,13,41
327USD 424.23,2369358,1 3,29411299,13,17
328307,12,76370299,13,03412376,22,93
329396,33,72371365,03,27413357,1Of 3.37
330299,33,02372To 362.12,66414305,32,11
331308,32,25373305,33,38415351,53,44
332288,02,5374 350,33,01416422,43,23
333379,12,61375319,33,4417396,02,67
334531,33,26376382,33,48418308,32,23
335To 322.32,41377340,23,08419To 322.32,48
336321,53,52378310,32,07420379,13,2
337Of 407.5Of 3.37 379389,02,53421,419,23,82
338318,32,73380309,33,02422333,12,48
339329,02,75381To 360.23,18423376,33,02
340399,12,6382393,12,84424374,03,06
341450,43,56383332,33,2425306,13,53
342422,3 3,41384376,12,87426371,32,95
343403,32,73385393,93,32427420,33,3
344To 384.1Of 3.07386334,32,3428337,23,32
345Over 322.22,96387347,13,22429348,32,98
346333,13,38388424,13,3430321,33,22
3471,97389355,33,65431280,32,09
348To 384.13,12390350,32,44432382,13,22
349405,32,85391396,13,43433393,23,71
350315,13,23392To 300.32,86434293,13,12
351332,33,18393399,42,12435376,33,22
352447,53,17394293,13,17436400,12,88
353436,33,53395433,54,21437309,32,82
354390,32,36396464,42,97438427,5Of 3.87
355370,9Of 3.37397341,33,45439295,32,8
356335,01,81398434,33,1440395,3 3,61
357346,33,08399335,01,75441425,02,67
358338,23,15400351,32,11442412,33,35
359482,11,74401368,13,09443317,32,45
360331,3Of 3.07402342,12,96444379,23,42
445To 305.53,08459279,32,9473 363,3Of 3.64
446353,12,85460436,23,38474336,32,8
447290,12,88461341,33,23475334 33,23
448321,33,5462349,11,9476To 362.13,42
449279,13,22463292,13,35477283,92,8
450308,11,97464 RUB 409.44,03478360,33,44
451318,1Or 3.28465450,53,65479334,32,59
452290,13,32466349,335480323,53,22
453314,12,75467307,32,98481315,33 25
454355,13,58468279,12,98482406,52,84
455398,1 3,6469409,1Of 3.69483409 54,35
456365,13,65470373,3Of 3.64484349,12,16
457350,3At 2.26471379,02,73485363,12,15
458381,23,19472379,02,67

NMR data of individual compounds are presented below in table 2-A.

/tr> /tr>
Table 2-A
Compound No.NMR data
21H-NMR (300 MHz, Dl ) δ of 12.53 (s, 1H), 11,44 (user.C, 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), to 7.33-7,21 (m, 3H), 7,10 (d, J=8,2 Hz, 1H), 3,79 (s, 3H), of 1.36 (s, 9H)
5H-NMR (400 MHz, DMSO-d6) δ 12,94 (user.s, 1H), 12,41 (s, 1H), 8,88 (s, 1H), of 8.34 (DD, J=8,1 Hz, 1H), of 7.82 (DDD, J=8, 8, 1 Hz, 1H), of 7.75 (d, J=8 Hz, 1H), of 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 (s, 6H)
81H-NMR (CD3OD, 300 MHz) δ 8,86 (s, 1H), to 8.42 (d, J=8,5 Hz, 1H), 7,94 (s, 1H), 7,81 (t, J=8,3 Hz, 1H), 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), 1,30 (t, J=7,4 Hz, 3H)
10H-NMR (400 MHz, DMSO-d6) δ 13,02 (d, J=6,4 Hz, 1H), is 12.58 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), of 8.33 (DD, J=8,1 Hz, 1.2 Hz, 1H), to 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), 1,94 (m, 2H), 1,65 (m, 2H)
13H-NMR (400 MHz, DMSO-d6) δ 13,05 (user.s, 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), a 7.85-7,76 (m, 3H), 7,58-7,54 (m, 2H), 1,47 (s, 9H)
14H-NMR (400 MHz, DMSO-d6) δ 1,32 (s, 9H), of 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), of 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
29H-NMR (400 MHz, Dl3) δ a 9.09 (s, 1H), 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), to 5.05 (m, 1H), 1,69 (d, J =6,6 Hz, 6H)
32H-NMR (400 MHz, DMSO-d6) δ 12,93 (d, J=6,6 Hz, 1H), by 12.74 (s, 1H), 11,27 (s, 1H), 8,91 (d, J=6,7 Hz, 1H), 8,76 (s, 1H), 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 of 12.92 (s, 1H), 12,47 (s, 1H), of 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, a 1.8 Hz, 1H), 6,39 (m, 1H)
35H-NMR (400 MHz, DMSO-d6) δ 13,01 (d, J=6,7 Hz, 1H), of 12.37 (s, 1H), 8,86 (d, J =6,8 Hz, 1H), of 8.33 (DD, J=8,1, 1.3 Hz, 1H), of 7.82 (t, J=8,3 Hz, 1H), 7,76 (d, J=8,2 Hz, 1H), 7,54 (t, J=8,1 Hz, 1H), of 7.36 (s, 1H), of 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), of 0.76 (t, J=7,4 Hz, 3H)
43H-NMR (400 MHz, DMSO-d6) δ 12,77 (s, 1H), 11,94 (s, 1H), of 9.56 (s, 1H), 8,81 (s, 1H), 8,11 (DD, J=8,2, 1,1 Hz, 1H), to 7.89 (s, 1H), 7,79-the 7.75 (m, 1H), of 7.70 (d, J=7,7 Hz, 1H), 7,49-7,45 (m, H), 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), 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), 3,00 (m, 1H), 7,55 (m, 3H), 7,76 (d, J=7,7 Hz, 1H), 7,83 (m, 1H), of 8.26 (d, J=8,2 Hz, 1H), of 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), of 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), To 6.58 (s, 1H), 2,62 (m, 4H), 1,71 (m, 4H)
58H-NMR (400 MHz, DMSO-d6) δ 12,95 (d, J=6,6 Hz, 1H), 12,39 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), of 8.33 (d, J=7,3 Hz, 1H), of 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=to 8.7, 1.3 Hz, 1H), 6,91 (DD, J=8,8, 2.5 Hz, 1H), 5,44 (user.s, 2H)
64H-NMR (400 MHz, DMSO-d6) δ of 12.92 (s, 1H), 12,41 (s, 1H), 10,63 (s, 1H), 10,54 (s, 1H), 8,86 (s, 1H), of 8.33 (d, J=8,1 Hz, 1H), of 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), to 7.04 (d, J=8,3 Hz, 1H), 6,90 (d, J=8,3 Hz, 1H)
69H-NMR (400 MHz, DMSO-d6) δ 13,06 (d, J=6,5 Hz, 1H), for 12.51 (s, 1H), 8,88 (d, J=6,6 Hz, 1H), of 8.33 (DD, J=8,1, 1.0 Hz, 1H), a 7.85-7,74 (m, 3H), 7,55 (t, J=8,1 Hz, 1H), 7,38 (DD, J=8,4, and 1.9 Hz, 1H), 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 (Dl3, 30 MHz) δ is 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), 6,78 (d, J=7.5 Hz, 1H),
77H-NMR (400 MHz, DMSO-d6) δ 6,40 (m, 1H), of 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), to 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 (s, 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), of 8.33 (DD, J=8,1, of 1.2 Hz, 1H), of 7.82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7,8 Hz, 1H), 7,66 (d, J=to 8.7 Hz, 2H), 7,54 (t, J=8,1 Hz, 1H), 7,34 (d, J=to 8.7 Hz, 2H), to 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), of 8.34 (DD, J=8,2, 1,1 Hz, 1H), 7,84-the 7.75 (m, 2H), members, 7.59 (DD, J=7,8, 1.5 Hz, 1H), 7,55-7,51 (m, 1H), of 7.42 (DD, J=7,9, 1.5 Hz, 1H), 7,26-7,21 (m, 1H), of 7.19-7,14 (m, 1H), 1,43 (s, 9H)
96H NMR (400 MHz, DMSO-d6) δ is 12.58 (s, 1H), to 11.11 (s, 1H), 8,89 (s, 1H), 8,35 (DD, J=8,1, 1,1 Hz, 1H), 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, of 1.8 Hz, 1H), 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), 9,21 (s, 1H), 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), 1088 (s, 1H), 8,88 (d, J=6,7 Hz, 1H), 8,36-of 8.34 (m, 1H), with 8.05 (d, J=0.8 Hz, 1H), 7,84-the 7.75 (m, 2H), 7,56-7,52 (m, 1H), 7,35 (d, J=8,3 Hz, 1H), 7,01 (DD, J=8,4, and 1.9 Hz, 1H), 6,07-6,07 (m, 1H), is 2.37 (s, 3H)
107H-NMR (400 MHz, DMSO-d6) δ 12,52 (s, 1H), 8,87 (s, 1H), of 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), 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 (user.s, 1H), 12,45 (s, 1H), 8,89 (s, 1H), of 8.33 (DD, J=8,2, 1,1 Hz, 1H), of 7.88 (s, 1H), of 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), 1,23 (s, 3H), of 0.71 (t, J=7,4 Hz, 3H)
1131H-NMR (400 MHz, DMSO-d6) of 12.92 δ (d, J=6,6 Hz, 1H), of 12.46 (s, 1H), 10,72 (d, J=1.5 Hz, 1H), 8,89 (d, J=6,7 Hz, 1H), 8,35 (DD, J=8,1, of 1.2 Hz, 1H), 8,13 (d, J=1.5 Hz, 1H), 7,84-the 7.75 (m, 2H), 7,56-7,52 (m, 1H), 7,44 (d, J=8.4 Hz, 1H), 7,07-to 7.04 (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), 9,33 (s, 1H), of 8.71 (d, J=6,6 Hz, 1H), to 8.36 (d, J=1,8 Hz, 1H), 8,03 l, 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 (t, J=7.5 Hz, 1H), 7,12 (m, 2H), 6,97 (m, 3H), 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), 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=78 Hz, 7,58-7,54 (m, 1H), 7,40 (d, J=2,2 Hz, 1H), 7,11 (d, J=8,5 Hz, 1H), 6,98 (DD, J=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), 3,36 (s, 3H), of 1.33 (s, 6H)
127H-NMR (400 MHz, DMSO-d6) δ is 1.23 (t, J=7,0 Hz, 3H), 1,32 (s, 9H), 4,10 (kV, J=7,0 Hz, 2H), of 7.36 (d, J=8,5 Hz, 1H), 7,54 (m, 3H), 7,76 (d, J=7.9 Hz, 1H), 7,82 (m, 1H) of 8.33 (d, J=9,2 Hz, 1H), 8,64 (s, 1H), 8,87 (s, 1H), 12,45 (C, 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 of 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 per (s, 1H), 5,47 (s, 2H)
1351H-NMR (Dl3, 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-of 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), a 7.85 (t, J=8.4 Hz, 1H), to 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), of 8.33 (DD, J=8,1, of 1.2 Hz, 1H), a 7.85-of 7.75 (m, 3H), 7,55 (t, J=8,1 Hz, 1H), of 7.46 (DD, J=8,2, 2, Hz, 1H), made 7.16 interest (d, J=8,5 Hz, 1H), 4,14 (kV, J=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), of 8.34 (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), 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=to 8.7 Hz, 2H), 7,82-7,71 (m, 2H), of 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 (l, J=9,0 Hz, 1H), EUR 7.57 (t, J=7.9 Hz, 1H), of 7.46 (d, J=8,5 Hz, 1H), made 7.16 interest (d, J=6,0 Hz, 1H), is 3.08 (s, 3H, PME), To 2.94 (q, J=7,4 Hz, 2H), of 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), of 8.33 (DD, J=8,2, of 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), of 7.19 (s, 2H), 4,13 (t, J=4,6 Hz, 2H), 3,79 (m, J=4,6 Hz, 2H), 3,54 (kV, J=7,0 Hz, 2H), of 1.36 (s, 9H), of 1.15 (t, J=7,0 Hz, 3H)
1631H-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), of 8.26 (user.s, 2H), 8,08 (DD, J=8.4 Hz, J=1.5 Hz, 1H), of 7.75 (m, 1H), 7,67 (d, J=7,8 Hz, 1H), 7,47-value of 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), 6,95 (m, 3H), 7,53 (m, 1H), of 7.75 (d, J=8,2 Hz, 1H), 7,81 (m, 1H), of 8.33 (d, J=8,0 Hz, 1H), is 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), for 12.51 (s, 1H), 8,89 (d, J=6.3 Hz, 1H), to 8.36 (DD, J=8,1, 1,1 Hz, 1H), 8,06 (t, J=0.7 Hz, 1H), a 7.85-of 7.75 (m, 2H), EUR 7.57-7,51 (m, 2H), 7,28 (d, J=3.1 Hz, 1H), from 7.24 (DD, J=8,4, 1,8 Hz, 1H), 6,39 (DD, J=3,1, 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), to 8.19 (DD, J=8,2, 1.3 Hz, 1H), 7,80-7,71 (m, 2H), of 7.48-7,44 (m, 2H), 7,24-7,20 (m, 1H), made 7.16 interest-to 7.09 (m, 2H), 7,04-7,00 (m, 1H), 6,80 (DD, J=8,0, a 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), of 8.33 (DD, J=8,2, 1,1 Hz, 1H), 8,06 (d, J=2.1 Hz, 1H), 7,84-the 7.75 (m, 2H), 7,56-7,52 (m, 1H), 7,38 (DD, J=8,2, and 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-of 1.80 (m, 2H), 1,51 (s, 9H)
1861H-NMR (400 MHz, DMSO-d6) δ 12,93 (s, 1H), 12,47 (s, 1H), 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), of 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-to 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), to 8.36 (d�, J=8,2, of 1.2 Hz, 1H), a 7.85-of 7.75 (m, 3H), of 7.64-7,53 (m, 3H), 6,71 (DD, J=3,7, 0.5 Hz, 1H), 2,67 (s, 3H)
188H-NMR (400 MHz, DMSO-d6) δ 12.84 per (s, 1H), of 12.73 (d, J=6,6 Hz, 1H), is 11.39 (s, 1H), of 8.85 (d, J=6,7 Hz, 1H), 8,61 (s, 1H), of 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), 7,43 (m, 1H), 6,54 (m, 1H), 4.38 gigabytes (kV, J=7,1 Hz, 2H), of 1.36 (t, J=7,1 Hz, 3H)
204H-NMR (400 MHz, DMSO-d6) δ 12,97 (s, 1H), of 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 (t, J=4,9 Hz, 2H), 1,78 (t, J=4,9 Hz, 2H), 1,29 (s, 6H),
207H-NMR (400 MHz, DMSO-d6) of 12.92 δ (user.s, 1H), 12,50 (s, 1H), of 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), of 7.82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7,7 Hz, 1H), 7,55 (t, J=8,1 Hz, 1H), of 7.46 (d, J=8.4 Hz, 1H), 7,21 (d, J=2,3 Hz, 1H), 7,06 (DD, J=8,5, of 1.8 Hz, 1H), of 4.09 (q, J=7,1 Hz, 2H), and 3.72 (s, 2H), 1,20 (t, J=7,1 Hz, 3H)
215H-NMR (400 MHz, DMSO-d6) δ 12,97 (s, 1H), 12,50 (s, 1H), 8,89 (s, 1H), of 8.34 (DD, J=8,1, 1,1 Hz, 1H), 7,83 (t, J=8,3 Hz, 1H), of 7.75 (m, 3H), 7,55 (t, J=8,1 Hz, 1H), value of 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), 8,27 (s, 1H), 8,12 (s, 1H), a 7.85-to 7.77 (m, 2H), 7,54 (TD, J=to 7.5, 1.2 Hz, 1H), is 6.81 (s, 1H), of 1.37 (d, J=3,9 Hz, 9H), 1,32 (d, J=17,1 Hz, 9H)
1H-NMR (CD3OD, 300 MHz) δ 8,79 (s, 1H), 8,37 (d, J=7.9 Hz, 1H), of 7.75 (m, 2H), 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=of 8.25, 1H), 8,27 (m, 1H), 7,83 (t, J=to 6.88, 1H), 7,67 (d, J=of 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, 2H), 2,03 (s, 3H), 1,7 (kV, 2H), was 1.04 (t, J=of 7.42, 3H)
2331H-NMR (400 MHz, DMSO-d6) of 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), 7,49-7,45 (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), 8,36-of 8.34 (m, 2H), 7,97 (s, 1H), a 7.85-7,81 (m, 1H), to 7.77-of 7.75 (m, 1H), 7,56-of 7.50 (m, 2H), 6,59-to 6.58 (m, 1H)
2351H-NMR (400 MHz, DMSO-d6) throughout 13.09 δ (d, J=6,5 Hz, 1H), of 12.75 (s, 1H), 9,04 (s, 1H), 8,92 (d, J=6,8 Hz, 1H), to 8.42 (d, J=7,1 Hz, 1H), of 8.34 (d, J=6,9 Hz, 1H), a 7.85 (t, J=8.4 Hz, 1H), 7,78 (d, J=7,7 Hz, 1H), 7,63-7,56 (m, 2H), 3,15 (m, 1H), of 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), of 8.85 (d, J=6,7 Hz, 1H), 8,32 (d, J=8,1 Hz, 1H), of 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-of 1.76 (m, 4H), of 1.52 (m, 2H), 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), of 8.34 (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), value of 7, 37 (s, 1H), Of 5.60 (s, 2H)
2431H-NMR (CD3OD, 300 MHz) δ 8,87 (s, 1H), 8,45 (d, J=of 8.25, 1H), 8,27 (m, 1H), 7,83 (t, J=to 6.88, 1H), 7,67 (d, J=of 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, 2H), 2,03 (s, 3H), 1,7 (kV, 2H), was 1.04 (t, J=of 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), of 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, a 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 MHz, DMSO-d6) δ 12,95 (d, J=6,6 Hz, 1H), 12,42 (s, 1H), 9,30 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), of 8.33 (DD, J=8,1, 1.3 Hz, 1H), a 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 and 2.2 Hz, 1H), 7,18 (d, J=8,3 Hz, 1H), 2,18 (s, 3H), 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 per (s, 1H)
260H-NMR (400 MHz, DMSO-d6) ∆ 13,23 (d, J=6,6 �C, 1H), 12,20 (s, 1H), 10,22 (user.s, 2H), 8,88 (d, J=6,8 Hz, 1H), of 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), 1,46 (s, 9H)
2611H-NMR (DMSO-d6, 300 MHz) δ is 11.99 (s, 1H, NH), 8,76 (s, J=6,6 Hz, 1H), of 8.26 (d, J=6,2 Hz, 1H), 8,09 (d, J=7.9 Hz, 1H), 7,72-7,63 (m, 2H), 7,44-to 7.09 (m, 7H), 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), 10,62 (s, 1H), 8,88 (s, 1H), of 8.33 (DD, J=8,2, of 1.2 Hz, 1H), a 7.85-of 7.75 (m, 2H), EUR 7.57-7,50 (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), of 8.34-8,32 (m, 1H), 7,99 (s, 1H), a 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), 12,62 (s, 1H), 8,91 (s, 1H), of 8.34 (DD, J=8,1, 1,1 Hz, 1H), 8,22 (d, J=2.4 Hz, 1H), 8,14 (DD, J=8,8, 2.4 Hz, 1H), 7,84 (t, J=8,3 Hz, 1H), to 7.77 (d, J=7,8 Hz, 1H), 7,65-7,54 (m, 4H), of 1.52 (s, 9H)
271H-NMR (400 MHz, DMSO-d6) δ 1,38 (s, 9H), 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), of 8.33 (d, J=7,6 Hz, 1H), 8,86 (d, J=6,8 Hz, 1H), 12,49 (s, 1H), 13,13 (1H)
2721H-NMR (Acetone-d6, 300 MHz) δ 8,92 (d, J=6,6 Hz, 1H), of 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), of 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), of 10.95 (s, 1H), of 9.00 (d, J=6,5 Hz, 1H), 8,65 (d, J=2.1 Hz, 1H), 8,18 (DD, J=to 8.7, 2.2 Hz, 1H), 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), 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), of 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), of 7.82 (t, J=8,3 Hz, 1H), 7,69 (d, J=8,5 Hz, 1H), 7,56 (t, J=7,7 Hz, 2H), of 7.42 (d, J=7.9 Hz, 1H), 7,07 (d, J=5.8 Hz, 1H), 2,93 (kV, J=7,4 Hz, 2H), of 1.36 (t, J=7.5 Hz, 3H),
2831H-NMR (Dl3, 300 MHz) δ of 8.82 (d, J=6,6 Hz, 1H), 8,29 (d, J=6,2 Hz, 1H), 8,06 (d, J=7.9 Hz, 1H), 7,43-of 7.24 (m, 6H), 7,02 (m, 2H), 6,87-is 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), of 9.42 (s, 1H), 8,87 (d, J=6,9 Hz, 1H), 8,04 (d, J=7,4 Hz, 1H), 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), is 6.81 (DD, J=8,1, 0.8 Hz, 1H), 2,10 (m, 2H), 1,63-of 1.34 (m, 8H), 1.26 in (s, 3H)
288H-NMR (400 MHz, DMSO-d6) δ 13,16 (s, 1H), of 12.85 (s, 1H), 8,98 (s, 1H), 8,43 (DD, J=8,1, 1,1 Hz, 1H), of 8.34 (DD, J=10,3, at 3.1 Hz, 1H), 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, 3,2 Hz, 1H), 4,06 (s, 3H), of 1.42 (s, 9H)
295H-NMR (400 MHz, DMSO-d6) δ 1.98 m (m, 4H), 3,15 (m, 4H), to 7.04 (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), to 8.19 (DD, J=7,9, 1,4 Hz, 1H), of 8.33 (d, J=8,1 Hz, 1H), 8,88 (d, J=6,7 Hz, 1H), 12,19 (s, 1H), to 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), to 8.38-8,31 (m, 1H), a 7.85-7,67 (m, 2H), EUR 7.57-7,51 (m, 1H), 6,94 (s, 1H), 6,81-6,74 (m, 2H), 3,19-3,16 (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), of 12.59 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), of 8.33 (d, J=7,7 Hz, 1H), 7,86-7,79 (m, 3H), 7,58-of 7.42 (m, 3H), 3,38 (m, 2H), of 1.88 (m, 2H), 1,30 (C, 6H)
3031H-NMR (400 MHz, DMSO-d6) δ 12,96 (d, J=6,5 Hz, 1H), 12,47 (s, 0,4 H), of 12.43 (s, 0,6 H), 8,87 (DD, J=6,7, and 2.3 Hz, 1H), of 8.33 (d, J=8,1 Hz, 1H), of 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), Of 4.66 (s, 0,8 H), 4,60 (s, 1,2 H), 3,66 (t, J=5,9 Hz, 2H), 2,83 (t, J=5.8 Hz, 1,2 H), of 2.72 (t, J=5,9 Hz, 0,8 H), 2,09 (m, 3H)
3041H-NMR (300 MHz, DMSO-d6) δ 11,70 (s, 1H), is 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), Of 1.09 (t, J=6,9 Hz, 3H),
3071H-NMR (Dl3, 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), of 6.79 (d, J=7.5 Hz, 1H)
3181H-NMR (Acetone-d6, 300 MHz) δ 8,92 (user.s, 1H), 8,40 (d, J=8,1 Hz, 1H), 8,05 (user.s, 1H), 7,94 (user.s, 1H), 7,78 (user.s, 2H), 7,52 (m, 1H), of 7.36 (user.s, 1H), 3,97 (t, J=7,2 Hz, 2H), 3,66 (t, J=8 Hz, 2H), 3,31-3,24 (m, 6H), 1,36-of 1.31 (m, 4H)
3201H NMR (400 MHz, DMSO-d6) δ 12,90 (s, 1H), 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-the 7.75 (m, 2H), 7,56-7,52 (m, 1H), value of 7, 37 (d, J=8,3 Hz, 1H), 6,99 (DD, J=8,4, and 1.9 Hz, 1H), 6,08-6,07 (m, 1H), of 1.35 (s, 9H)
321H-NMR (400 MHz, DMSO-d6) δ 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 (s, 1H), 12,86 (s, 1H)
323H-NMR (400 MHz, DMSO-d6) δ 12,94 (user.s, 1H), 12,44 (s, 1H), 8,89 (s, 1H), of 8.33 (DD, J=8,2, 1,1 Hz, 1H), of 7.82 (t, J=8,3 Hz, 1H), 7,76 (d, J=7,7 Hz, 1H), 7,67 (d, J=8,8 Hz, 2H), 7,54 (t, J=8,1 Hz, 1H), 7,35 (d, J=to 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 (user.s, 1H), of 12.46 (s, 1H), 8,89 (s, 1H), of 8.33 (DD, J=8,2, 1,1 Hz, 1H), to 7.89 (s, 1H), of 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), value of 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), 1,43 (s, 9H)
337H-NMR (400 MHz, DMSO-d6) δ 12,19 (s, 1H), 9,35 (s, 1H), 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 of 12.92 (s, 1H), 12,34 (s, 1H), at 10.96 (s, 1H), 8,91 (s, 1H), 8.48 to (s, 1H), 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), system 6.34 (s, 1H), 2,89-2,84 (m, 2H), of 1.29 (t, J=7,4 Hz, 3H)
3531H-NMR (400 MHz, DMSO-d6) δ 11,90 (s, 1H), 9,30 (s, 1H), 8,88 (s, 1H), of 8.34 (DD, J=8,2, 1,1 Hz, 1H), 7,84-7,71 (m, 3H), 7,55-of 7.50 (m, 1H), 7,28-7,26 (m, 1H), 7,20-7,17 (m, 1H), of 1.47 (s, 9H), to 1.38 (s, 9H)
3561H-NMR (CD3OD, 300 MHz) δ 8,89 (s, 1H), 8,59 (s, 1H), 8,45 (d, J=8,3 Hz, 1H), 7,83 (t, J=7,2 Hz, 1H), 7,69 (l, J=9,0 Hz, 1H), EUR 7.57 (t, J=7.9 Hz, 1H), of 7.42 (d, J=8,5 Hz, 1H), 7,17 (d, J=6,0 Hz, 1H), 3,09 (s, 3H, PME)Or 2.91 (t, J=7,4 Hz, 2H), 1,76 (m, 2H), of 1.09 (t, J=7,4 Hz, 3H)
357H-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 (Dl3, 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-made 7.16 interest (m, 5H), 7,02-at 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), of 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), 7.62 mm (s, 1H), 7,55 (t, J=8,1 Hz, 1H), 7,25 (DD, J=8,7, The 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), 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), of 8.33 (d, J=6,9 Hz, 1H), of 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), to 7.04 (d, J=8,2 Hz, 1H), 2,71 (m, 4H), of 1.75 (m, 4H)
378H-NMR (400 MHz, DMSO-d6) δ 12,98 (d, J=6,6 Hz, 1H), 12,39 (s, 1H), 8,86 (d, J=6,7 Hz, 1H), of 8.33 (DD, J=8,1, of 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), of 8.85 (s, 1H), 8,32 (d, J=7,8 Hz, 1H), 8,06 (s, 1H), 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 (user.s, 1H), 11,82 (s, 1H), 10,86 (s, 1H), 8,83 (s, 1H), of 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), 7.23 percent (m, 1H), 6.32 per (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=7,4 Hz, 3H),
383H-NMR (400 MHz, DMSO-d6) δ 1.27 mm (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), of 12.46 (s, 1H), 12,91 (s, 1H)
386H-NMR (400 MHz, DMSO-d6) δ 13,18 (d, J=6,8 Hz, 1H), 12,72 (s, 1H), 8,88 (d, J=6,8 Hz, 1H), of 8.34 (d, J=8,1 Hz, 1H), 8,09 (s, 1H), 7,86-7,79 (m, 2H), 7,58-of 7.50 (m, 2H), 7,43 (d, J=8,2 Hz, 1H), 3,51 (s, 2H), 1,36 (s, 6H)
3931H-NMR (300 MHz, 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=to 8.7 Hz, 1H), 7,39 (m, 3H), 7,18 (m, 2H), 7,06 (m, 2H), was 4.02 (m, 2H), of 1.13 (t, J=6,9 Hz, 3H)
3991H-NMR (CD3OD, 300 MHz) δ 8,91 (s, 1H), 8,51 (s, 1H), to 8.42 (d, J=8,3 Hz, 1H), 7,84 (t, J=7,2 Hz, 1H), 7,67 (d, J=9,0 Hz, 1H), 7,56 (t, J=7.9 Hz, 1H), of 7.46 (d, J=8,5 Hz, 1H), 7,24 (d, J=6,0 Hz, 1H), 3,48 (m, 1H), Of 3.09 (s, 3H, PME), of 1.39 (d, J=6,8 Hz, 6H)
412H-NMR (400 MHz, DMSO-d6) δ 12,81-12,79 (m, 2H), at 10.96 (s, 1H), 8,87 (d, J=6,7 Hz, 1H), 8,35 (d, J=8,1 Hz, 1H), 7,99 (d, J=8,6 Hz, 1H), 7,83-7,73 (m, 3H), 7,53 (t, J=8,1 Hz, 1H), of 7.36 (m, 1H), of 6.52 (m, 1H), 4,51 (kV, J=7,1 Hz, 2H), And 1.37 (t, J=7,1 Hz, 3H)
415H-NMR (400 MHz, DMSO-d6) δ of 12.26 (s, 1H), of 9.46 (s, 1H), 8,99 (s, 1H), 8,43-to 8.41 (�, 1H), 7,94-of 7.88 (m, 2H), 7,65-7,61 (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 (user.s, 1H), for 12.51 (s, 1H), 8,89 (s, 1H), of 8.33 (DD, J=8, 1 Hz, 2H), of 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), of 4.09 (q, J=7 Hz, 2H), 1,51 (s, 6H), of 1.13 (t, J=7 Hz, 3H)
423H-NMR (400 MHz, DMSO-d6) δ 12,91 (user.s, 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), of 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=2,2 Hz, 1H), 7,05 (DD, J=8,5, of 1.8 Hz, 1H), 3,62 (t, J=7,3 Hz, 2H), 3,48 (kV, J=7,0 Hz, 2H), of 2.91 (t, J=7,3 Hz, 2H), 1.14 in (t, J=7,0 Hz, 3H)
4251H-NMR (DMSO-d6, 300 MHz) δ is 8.84 (s, 1H), 8,29 (d, J=8,1 Hz, 1H), 7,78-of 7.70 (m, 2H), 7,61 (d, J=8.4 Hz, 2H), 7,50 (t, J=7,8 Hz, 1H), 7,20 (d, J=to 8.7 Hz, 2H), 2,85 (hex., 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), of 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), 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), to 8.38 (d, J=7,4 Hz, 1H), 7,78 (see. dt, J=1,1, 7,1 Hz, 1H), of 7.64 (d, J=8,3 Hz, 1H), 7,53 (see. t, J=7.5 Hz, 1H), 7,21 (user.d, J=0.9 Hz, 1H), 7,15 (d, J=8.4 Hz, 1H), 6,98 (DD, J=2,1, 8.4 G�, 1H), 1,38 (s, 9H)
429H-NMR (400 MHz, DMSO-d6) ∆ 13,13 (d, J=6,8 Hz, 1H), 12,63 (s, 1H), 8,86 (d, J=6,8 Hz, 1H), of 8.33 (d, J=7,0 Hz, 1H), 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), was 6.77 (s, 1H)
433H-NMR (400 MHz, DMSO-d6) δ 12,87 (user.s, 1H), 11,82 (s, 1H), 9,20 (s, 1H), 8,87 (s, 1H), of 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), 1,38 (s, 9H), Of 1.36 (s, 9H)
438H-NMR (400 MHz, DMSO-d6) δ 12,97 (d, J=6,6 Hz, 1H), to 12.08 (s, 1H), 8,90 (d, J=6,8 Hz, 1H), 8,35-of 8.34 (m, 1H), 8,03 (s, 1H), a 7.85-7,81 (m, 1H), to 7.77-7,71 (m, 1H), 7,58-7,44 (m, 2H), 1,46 (s, 9H), of 1.42 (s, 9H)
4411H-NMR (Acetone-d6, 300 MHz) δ 11,90 (user.s, 1H), 8,93 (user.s, 1H), to 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), of 7.36 (s, 1H), 3,13 (s, 3H)
444H-NMR (400 MHz, DMSO-d6) δ 12,56 (s, 1H), 12,17 (user.d, J=6 Hz, 1H), 8,89 (d, J=6 Hz, 1H), to 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), of 7.46-7,40 (m, 3H), 3,47 (s, 3H), of 1.35 (s, 9H)
448H-NMR (400 MHz, DMSO-d6) δ 12,96 (user.s, 1H), 12,42 (s, 1H), 8,88 (s, 1H), of 8.33 (DD, J=8,2, 1,1 Hz, 1H), of 7.82 (t, J=8,3 Hz, 1H), of 7.75 (d, J=7,7 Hz, 1H), 7,66 (d, J=to 8.7 Hz, 2H), 7,54 (t, J=8,1 Hz, 1H), 7,39 (d, J=to 8.7 Hz, 2H), 1,29 (s, 9H)
H-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), of 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, 2.4 Hz, 1H)
458H-NMR (400 MHz, DMSO-d6) δ 12,97 (d, J=7,1 Hz, 1H), 12,39 (s, 1H), 8,88 (d, J=6,8 Hz, 1H), of 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), of 4.04 (t, J=5.0 Hz, 2H), 3,82 (t, J=5.0 Hz, 2H), of 1.36 (s, 9H)
4611H-NMR (DMSO-d6, 300 MHz) δ 11,97 (s, 1H), to 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), 7,61 (d, J=7,8 Hz, 2H), 7,51 (t, 1H), 7,17 (d, J=8,1 Hz, 2H), 2,57 (kV, J=7.5 Hz, 2H), of 1.17 (t, J=7.5 Hz, 1H), 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), 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), of 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), of 8.33 (d, J=8,2 Hz, 1H), 7,84-the 7.75 (m, 3H), EUR 7.57-743 (m, 2H), 7,31 (d, J=8,6 Hz, 1H), 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=of 8.25, 1H), 8,18 (m, 1H), 7,79 (t, J=to 6.88, 1H), 7,67 (d, J=of 8.25, 1H), 7,54 (t, J=7,15, 1H), 7.23 percent (d, J=6,05, 1H), made 7.16 interest (d, J=8,5, 1H), 3,73 (s, 3H), 2,75 (t, J=6,87, 2H), 1,7 (kV, 2H), of 1.03 (t, J=of 7.42, 3H)
4761H-NMR (400 MHz, DMSO-d6) δ 13,00 (d, J=6,4 Hz, 1H), 12,91 (s, 1H), 10,72 (s, 1H), 8,89 (d, J=6,8 Hz, 1H), of 8.34 (d, J=8,2 Hz, 1H), 8,16 (s, 1H), a 7.85-of 7.75 (m, 2H), 7,56-7,54 (m, 1H), 7,44 (s, 1H), of 1.35 (s, 9H)
4781H-NMR (400 MHz, DMSO-d6) δ 1,40 (s, 9H), 6,98 (d, J=2.4 Hz, 1H), to 7.04 (DD, J=8,6, and 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=the 1.7 Hz, 1H), 8,35 (d, J=8,1 Hz, 1H), 8,89 (d, J=6,7 Hz, 1H), 10,74 (s, 1H), 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), of 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 (d explicit direct doublet, J=8.4 Hz, 1H), 2,81 (s, 3H), of 1.34 (s, 9H)
4851H-NMR (300 MHz, Dl3) ∆ 13,13 (user.s, 1H), of 12.78 (s, 1H), 8,91 (user.s, 1H), to 8.42 (user.s, 1H), 8,37 (d, J=8,1 Hz, 1H), 7,72-7,58 (m, 2H), 7,47-7,31 (m, 3H), 3,34 (s, 6H), 1,46 (s, 9H)

B) Tests in the detection and ODA�division corrective ΔF508-CFTR connection properties

(I) Optical methods for determining the transmembrane potential to test for modulation of ΔF508-CFTR connection properties

Optical test of 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 potential that use fluorescence energy transfer”, Chem. Biol.,4(4), 269-277 (1997)), in combination with a measuring apparatus for determining changes in fluorescence, such as 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 the fluorescent phospholipid, CC2-DMPE, which is associated with outer "leaf" cytoplasmic membrane and acts as a FRET donor. Changes of transmembrane potential (Vm) cause a redistribution of the negatively charged DiSBAC2(3) in the cytoplasmic membrane and therefore changes the amount of energy transferred from CC2-DMPE. Changes in fluorescent emission control, using a device VIPRTMII, which is an int�integrated liquid handling system and a fluorescence detector, designed for conduction-based cell screening using 96 - or 384-well titration microplates.

Identification of correction compounds

To identify small molecules that correct the defect transport associated with ΔF508-CFTR, developed the test with only the addition of homozygous teruya cells (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 "temperature correction" ΔF508-CFTR. Cells were then washed 3 times with a solution of ringer-Krebs and loaded potentialcustomers dyes. To activate ΔF508-CFTR, to each well along with not containing Cl-the medium was added with 10 μm Forskolin and the CFTR-amplifier, genistein (20 μm). The outflow of Cl-that promoted the addition of not containing Cl-environment in response to activation of ΔF508-CFTR and attainable transmembrane depolarization optionally controlled using based on FRET potentialcustomers dyes.

Identification of compounds amplifiers

To identify enhancers ΔF508-CFTR, developed the test with dual point�th add homozygous tiirough cells. During the first add to each well was added containing Cl-environment with the test compound or without him. After 22 seconds, to activate ΔF508-CFTR was introduced a second additive containing Cl-environment, including 2-10 μm Forskolin. The extracellular concentration of Cl-after both additions was 28 mm, which was promotional outflow of Cl-in response to the activation of ΔF508-CFTR, and attainable transmembrane depolarization was determined optically using based on FRET potentialcustomers dyes.

Solutions

The Eyewash solution No. 1 (in mm):
NaCl 160, KCl 4.5 And CaCl22, MgCl21, HEPES 10, pH=7,4, mounted with NaOH;
The Eyewash solution, containing no chlorides:
chloride salt in the solution for washing No. 1 replaced gluconate salts;
CC2-DMPE:
prepared as a 10 mm stock solution in dimethyl sulfoxide (DMSO) and stored at -20aboutWith;
DiSBAC2(3):
prepared as a 10 mm stock solution and stored at -20°C.

Cell culture

For optical measurements of transmembrane potential used murine NIH3T3 fibroblasts stably expressing ΔF508-CFTR. Cells were maintained at 37°C in an atmosphere With 5% CO2and 90% humidity in modified according to the method of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25 mm HEPES, in flasks for culturing cells with an area of 175 cm2. For all optical tests, the cells were sown in the amount of 30,000 per well covered in Matrigel 384 well plates and cultured for 2 hours at 37°C before culturing at a temperature of 27°C for 24 hours to test the gain. For corrective tests, cells were cultured at a temperature of 27°C or 37°C with compounds or without them for 16-24 hours.

B) Electrophysiological tests to determine the modulating ΔF508-CFTR connection properties

1. Test in Ussing-chamber

Experiments in Ussing-chamber was performed with the use of polarized epithelial cells expressing ΔF508-CFTR to further characterize modulators of ΔF508-CFTR identified in optical tests. FRTΔF508-CFTR-Epithelial cell�Ki, 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 locking system potential (Voltage-clamp System; Departmen of Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, Canada). Transepithelial resistance was determined by application of the pulse is 2 mV. In these conditions, the FRT - epithelium showed a resistance of 4 Kω/cm2or more. The solutions were maintained at a temperature of 27°C and using them barbotirovany the air. Electrode potential bias and the resistance of the liquid was adjusted using the insert without cells. Under these conditions, the current reflects the flow of Cl-through ΔF508-CFTR expressed in the apical membrane. ISCin the numerical value achieved by using the interface MRA XIE and AcqKnowledge software (ν3.2.6; BIOPAC Systems, Santa Barbara, Canada).

Identification of corrective connections

According to a specific Protocol, used a concentration gradient of Cl-from basolateral to apical membranes. To achieve this gradient, used a conventional ringer's solution in the case of the basolateral membrane, whereas apical NaCl was replaced with equimolar amounts of sodium gluconate (by setting pH to 7.4 with NaOH), yielding a large concentration gradient of Cl-through the epithelium. �CE experiments were carried out using intact monolayers. To fully activate ΔF508-CFTR, was used by Forskolin (10 μm) and the PDE inhibitor, IBMX (100 μm), followed by the addition of the amplifier CFTR genistein (50 μm).

As observed in other cell types, incubation at low temperatures of FRT cells stably expressing ΔF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with 10 μm of the test compounds for 24 hours at 37°C and then washed 3 times prior to registration. Mediated camp and genistein ISCin treated compound cells was normalized to that obtained at 27°C and 37°C controls and expressed in the form of activity in percent. Pre-incubation of cells with the correction compound 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 concentration gradient of Cl-from basolateral to apical membranes. To achieve this gradient, used a conventional ringer's solution in the case of the basolateral membrane and added nystatin (360 μg/ml), whereas apical NaCl was replaced with equimolar amounts of sodium gluconate (by setting pH to 7.4 with NaOH), �aluca 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 alleged efficiency amplifiers ΔF508-CFTR was compared with the efficiency 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 solution pH of 7.4, mounted with NaOH.
The apical solution (in mm):
same as basolateral solution with replacement of NaCl with sodium gluconate (135).

Cell culture

For experiments in Ussing-chamber against alleged modulators of ΔF508-CFTR identified under optical tests the authors used a rat epithelial cells Fischer (FRT cells) expressing ΔF508-CFTR (FRTΔF508-CFTR). Cells were cultured on cell culture inserts Costar Snapwell and were cultured for five days at a temperature of 37°C and � the presence of 5% CO 2in a modified method Kuna environment DIN, supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 µm/ml streptomycin. Prior to use for characterizing the reinforcing activity of the compounds, the cells were incubated at a temperature of 27°C for 16-48 hours before correction for ΔF508-CFTR. To determine the activity of correction compounds, the cells were incubated at a temperature of 27°C or 37°C with coupling or without him in the next 24 hours.

2. Registration of whole cells

Macroscopic current of ΔF508-CFTR (IΔF508) subjected to correction by the temperature and the test compounds of NIH3T3 cells stably expressing ΔF508-CFTR were monitored using the perforated "patch", the registration of a whole cell. Briefly, the patch clamp-registration of IΔF508carried out at room temperature using a patch clamp amplifier Axopatch 200D (Axon Instruments Inc., Foster City, Canada). All registrations were carried out at the selected frequency of 10 kHz 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 isolation resistance > 20 Gohm and series resistance < 15 Mω. The generation of the pulse, obtaining �data and analysis carried out, using a personal computer equipped with interface Digidata 1320 A/D with Clampex 8 (Axon Instruments Inc.). The solution contained <250 ál of salt and continuously subjected to perfusion at a rate of 2 ml/min when using a perfusion system in gravity mode.

Identification of corrective connections

To determine the activity of correction compounds for increasing the density of functional ΔF508-CFTR in the plasma membrane, the authors used the methods described above perforated "patch"-registration for the measurement of the current density after treatment within 24 hours of corrective connections. To fully activate ΔF508-CFTR, to the cells was added 10 μm of Forskolin and 20 μm genistein. In the conditions 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 correction compounds on CFTR current density, the cells were incubated with 10 μm of the 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 (% active�STI). Prior to registration, the cells were washed 3 times extracellular environment to register to remove any remaining test compound. The pre-incubation with 10 mm of correction compounds significantly increases dependent on camp and genistein current compared with that obtained at a temperature of 37°C controls.

Identification of compounds amplifiers

The ability of the amplifiers ΔF508-CFTR to increase the macroscopic ΔF508-CFTR Cl--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 in IΔF508with similar efficacy and effectiveness observed in the case of optical tests. In all studied cells, the potential for reversion before and during the application of the amplifier was around -30 mV, which is a calculated 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 brought up to 7.35 with CsOH).
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 fibroblasts NI3T3 stably expressing ΔF508-CFTR, used for registration of whole cells. Cells were maintained at 37°C in an atmosphere With 5% CO2and 90% humidity in modified according to the method of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25 mm HEPES, in flasks for culturing cells with an area of 175 cm2. For registration of whole cells, 2500-5000 cells were seeded on coated with poly-L-lysine cover glasses and 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 correctors.

3. Registration of one channel

Activity one channel corrected by the temperature ΔF508-CFTR stably expressed in NIH3T3 cells, and the activity of the compounds amplifiers was determined using excisional from the wrong side of a membrane "patch". Briefly, the registration of fixing the potential activity of one channel were performed at room temperature using a patch clamp-�silical Axopatch 200B (Axon Instruments Inc.). All registrations were carried out at the chosen frequency of 10 kHz and when you use a lowpass filter on 400 Hz. "Patch"-pipettes were made from 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 adding 1 mm Mg-ATP, and 75 nm of the 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 with gravitational regime. The inflow was placed next to the "patch", reaching full replacement solution for 1-2 seconds. To preserve the activity of ΔF508-CFTR in a time of rapid perfusion, Eyewash solution was added nonspecific fosfatazy inhibitor F-(10 mm NaF). In these conditions of registration the activity of the channel is maintained constant throughout the duration of the "patch"-registration (up to 60 minutes). Currents caused by the movement of positive charge from intracellular to extracellular solution solution (anions move in the opposite direction), 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 od�vremennykh discoveries have defined the number of active channels during the experiment. To determine the amplitude of the current of one channel, the data recorded after 120 seconds the activity of ΔF508-CFTR, was filtered offline at 100 Hz and then used to construct the histograms of the amplitudes of all pixels that are aligned on multicausal functions using the software Bio-Patch Analysis (Bio-Logic Comp. France). Full microscopic current and open probability (Pabout) was determined after 120 seconds channel activity. Paboutwas determined using the software Bio-Patch, or from the ratio Rabout=I/i(N), where I=low current, i=the amplitude of the current of one channel, and N=number of active channels in the patch".

Solutions

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 from the membrane patch clamp-registrations used murine NIH3T3 fibroblasts. Cells were held at pace�the atur 37°C in an atmosphere With 5% CO 2and 90% humidity in modified according to the method of Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal calf serum, 1 X NEAA, β-ME, 1 X pen/strep, and 25 mm HEPES, in flasks for culturing cells with an area of 175 cm2. For enrolments of one channel, 2500-5000 cells were seeded on coated with poly-L-lysine cover glasses and cultured for 24-48 hours at a temperature of 27°C before use.

Compounds according to the invention are useful as modulators of transporters of the ATP-binding cassette. The following table 3 presents / EC50 and relative efficacy of certain embodiments in table 1.

The following table 3 presents the following values:

/ EC50: “+++”means < 10 um; “++” means between 10 μm to 25 μm; “+” means between 25 µm to 60 µm.

% Efficiency: “+” means < 25%; “++” means between 25% and 100%; “+++” means > 100%.

43
Table 3
Conn. No./ EC50 (μm)% ActivityConn. No./ EC50 (μm)% Activity Conn. No./ EC50 (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++++++++++
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+++++144+++++
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+++++174+++++
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+++++272++++
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+++++
+++++396++++441+++++
353+++++397+++++442++
354+++++398++++443++
355+++++399+++++444+++++
356+++++400++445++++++
+++++401+++++446++
358+++++402++++447++++
359++++403+++++448+++++
360+++++404+++++449+++++
450++++462+++++474++
+++++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. The compound corresponding to the formula A-I:

where:
G1means a hydrogen atom or R';
G2means a halogen atom, CN, CF3, isopropyl or phenyl, where the abovementioned isopropyl or phenyl optionally substituted with up to three substituents independently selected from WRW;
G3means isopropyl or (C3-C10)cycloaliphatic ring, where the aforementioned G3optionally substituted with up to three substituents independently selected from WRW;
W is a bond or (C1-C6)alkylidene chain, where up to two methylene groups of the residue W is optionally and independently replaced by-CO2- or-O-;
RWmeans R'; and
R' is independently selected from hydrogen atom or (C1-C8)alkyl group.

2. The compound according to claim 1, where:
G1means a hydrogen atom;
G2means a halogen atom or isopropyl, where the above isopropyl optionally substituted with up to three substituents, independently selected from R'; and
G3means isopropyl or (C3-C103optionally substituted with up to three substituents, independently selected from R'.

3. The compound according to claim 2, where:
G1means a hydrogen atom; G2means a halogen atom; and
G3means (C3-C10)cycloaliphatic ring, where the aforementioned G3optionally substituted with up to three substituents, independently selected from methyl, ethyl, propyl or butyl.

4. The compound according to claim 1, where:
G1means a hydrogen atom;
G2means CN, a halogen atom or CF3; and
G3means isopropyl or (C3-C10)cycloaliphatic ring, where the aforementioned G3optionally substituted with up to three substituents, independently selected from R'.

5. The compound according to claim 1, where:
G1means a hydrogen atom;
G2means phenyl, optionally substituted with up to three substituents, independently selected from-O-(C1-C4)alkyl; and
G3means isopropyl or (C3-C10)cycloaliphatic ring, where the aforementioned G3optionally substituted with up to three substituents, independently selected from R',

6. The compound according to claim 1, where G3choose from cyclopentyl, cyclohexyl, cycloheptyl or adamantyl.

7. The compound according to claim 1, where G3means branched (C3-C8)aliphatic�forge a chain.

8. The compound according to claim 1, where the compound is a C-9:

9. A method for producing a compound of formula FF:

comprising hydrogenation of a compound of formula EE:

in the presence of a palladium catalyst,
where,
G2means a bromine atom, a fluorine atom or tert-butyl; and
G3means tert-butyl;

10. A method according to claim 9, where the hydrogenation is carried out in the presence of ammonium formate.

11. A method according to claim 9 or 10, wherein the hydrogenation is carried out in the presence of a solvent.

12. A method according to claim 11, where the solvent is ethanol.

13. A method according to claim 11 or 12, where the solvent at the boiling point.

14. A method according to claim 9, further comprising nitration of a compound of formula CC:

by reacting the compound of formula CC with a mixture of nitric acid and sulfuric acid to obtain the compound of formula DD:

hydrolization of a compound of formula DD base to produce a compound of the formula:

15. A method according to claim 14, where the ratio of sulfuric acid to nitric acid in the mixture used at the stage of nitration, is about 2:1.

16. A method according to claim 14 or 15, where hydrolization carried out using methanol and KOH.

17. �p on p. 14 or 15, further comprising the interaction of a compound of formula AA

with methylchloroform in the presence of base to produce a compound of formula CC:

18. A method according to claim 17, where the interaction is carried out in the presence of 4-dimethylaminopyridine (DMAP).

19. A method according to claim 17 or 18, where the interaction is carried out in the presence of a solvent.

20. A method according to claim 19, where the solvent is dichloro methane.

21. A method according to claim 9, where G2and G3both are tert-butyl.

22. A method of producing compound C-9:

which includes stages:
the interaction of 2,4-di-tert-butylphenol with methylchloroform with obtaining 2,4-di-tert-butylphenylmethyl:

the interaction of 2,4-di-tert-butylphenylmethyl with a mixture of nitric acid and sulfuric acid to give 2,4-di-tert-butyl-5-nitrophenylarsonic:

the interaction of 2,4-di-tert-butyl-5-nitrophenylarsonic with a mixture of methanol and KOH to obtain 2,4-di-tert-butyl-5-NITROPHENOL:

hydrogenation of 2,4-di-tert-butyl-5-NITROPHENOL in the presence of ammonium formate using palladium on coal as a palladium catalyst, and ethanol as a solvent.

23. FPIC�according to claim b 22, where the ratio of sulfuric acid to nitric acid in the mixture is about 2:1.

24. The method of obtaining compounds 433:

including interaction of the compounds C-9

with connection A-1

in the presence of a coupling agent, base and solvent.

25. A method according to claim 24, further comprising a method of obtaining compound (C-9:

which includes stages:
the interaction of 2,4-di-tert-butylphenol with methylchloroform with obtaining 2,4-di-tert-butylphenylmethyl:

the interaction of 2,4-di-tert-butylphenylmethyl with a mixture of nitric acid and sulfuric acid to give 2,4-di-tert-butyl-5-nitrophenylarsonic:

the interaction of 2,4-di-tert-butyl-5-nitrophenylarsonic with a mixture of methanol and KOH to obtain 2,4-di-tert-butyl-5-NITROPHENOL:

hydrogenation of 2,4-di-tert-butyl-5-NITROPHENOL in the presence of ammonium formate and palladium on coal as a palladium catalyst and ethanol as solvent.

26. A method according to claim 25, where the ratio of sulfuric acid to nitric acid in the mixture is about 2:1.

27. A method according to claim 24, further comprising a method of obtaining a compound A-1

which includes stages:
the interaction of aniline with diethyl-2-(ethoxymethylene)malonate at a temperature of 140-150°C to produce a compound MM

the interaction of the MM connection with polyphosphoric acid in the presence of phosphorylchloride at a temperature of about 70°C to produce a compound NN

the interaction of the NN connection with NaOH for about 2 hours before treatment of the HCl solution.

28. A method according to claim 27, where the interaction is carried out without dilution.

29. A method according to any one of claims. 24-28, where the binding agent is selected from the group consisting of HATU, BOP, HBTU and PFP-TFUK.

30. A method according to any one of claims. 24-28, where the base is selected from the group consisting of DIEA, Et3N and pyridine.

31. A method according to any one of claims. 24-28, where the solvent is selected from the group consisting of DMF, CH2Cl2and pyridine.

32. A method according to any one of claims. 24-28, where the binding agent, base and solvent are HATU, DIEA and DMF, respectively.

33. A method according to any one of claims. 24-28, where the binding agent, base and solvent are BOP, DIEA and DMF, respectively.

34. A method according to any one of claims. 24-28, where the binding agent, base and solvent are HBTU, Et3N and CH2Cl2respectively.

35. A method according to any one of claims. 24-28, where the binding agent, base and solvent are PFP-TFUK and pyridi�, where pyridine is used as base and solvent.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of synthesis of compounds with biological activity, namely to method of obtaining compound 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane. Essence of method consists in interaction of 3,6-dioxaoctane-1,8-diamine with N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine in medium ethanol-chloroform (1:2 volume) in presence of catalyst SmCl3·6H2O with molar ratio 3,6-dioxaoctane-1,8-diamine:N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:SmCl3·6H2O=1:2:(0.03-0.07) at temperature (~20°C) and atmospheric pressure for 2.5-3.5 h. Invention also relates to application of 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane as agent with fungicidal activity for fighting fungal diseases of agricultural crops.

EFFECT: improved method of obtaining 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane, possessing fungicidal activity against Botrytis cinerea.

2 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides of general formula: , where R=5-methyl-1,3-thiazol-2-yl, or 4-ethoxycarbonylmethyl-1,3-thiazol-2-yl, or 6-methylpyridin-2-yl, or 5-chloropyridin-2-yl, or pyrimidin-2-yl. Novel N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide derivatives which exhibit analgesic activity are obtained.

EFFECT: high activity of derivatives.

2 tbl, 7 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic compound, representing cyclo-bis[(1Z)-1-imino -2-methyl-1H-inden-3-yl-1,2,4-thiadiazole-3,5-diamine]

EFFECT: compound as acid dye for silk, wool and polyamide 6.

3 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), possessing an activity with respect to cytokines, versions of based on them pharmaceutical compositions and their application. Formula (I) compounds can be applied for treatment or prevention asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gouty arthritis. In general formula (I) L is selected from the group, consisting of -C(O)-, -CH2-, Ar1 represents a mono-, di- or trisubstituted phenyl ring, where substituents are independently selected from the group, consisting of a halogen and -C1-4alkyl; Ar2 represents an optionally substituted thiadiazolyl ring, where the substituent represents -C1-4alkyl, -C3-5cycloalkyl, -methylcyclopropyl, phenyl or a 5- or 6-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring with 9 or 10 atoms, with the said heteroaromatic ring containing 1, 2 or 3 heteroatoms, selected from the group, consisting of S, O and N, where the said phenyl or heteroaromatic ring is optionally mono- or disubstituted with substituents, independently selected from the group, consisting of a halogen, -C1-6alkyl, optionally substituted with 1-4 fluorine atoms, -O-C1-6alkyl, -CF3 and oxo.

EFFECT: increased efficiency of the application of the compounds.

16 cl, 1 tbl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, namely, deals with compounds of formula , suitable for reduction of regulation of biological activity of melanocortin-5 receptor (MC5R). Such diseases and/or conditions include, but are not limited by, acne, seborrhoea, seborrheic dermatitis, cancer and inflammatory diseases.

EFFECT: compounds of claimed invention can be applied for treatment of diseases and/or conditions, in which reducing regulation of MC5R is favourable.

3 cl, 109 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-(1,2,5-oxadiazol-3-yl)benzamides of formula , in which R stands for an alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, cyano, nitro, methylsulphenyl, acetylamino, methoxycarbonyl, methylcarbonyl, piperidinylcarbonyl, halogen, amino, or heteroaryl, selected from the group, including 1,2,3-triazolyl, 1,2,4-triazolyl, benzisoxazolyl, thiophenyl, pyridinyl and benzimidazol-2-yl, or heterocyclyl, selected from the group, including piperidinyl, respectively selected with s residues, selected from the group, including methyl, ethyl, methoxy and halogen; X and Z independently on each other respectively stand for nitro, halogen, cyano, alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, OR1, S(O)nR2, alkyl-OR1 with 1-6 carbon atoms in alkyl, or heteroaryl, selected from the group, including 1,2,4-triazolyl; Y stands for nitro, halogen, OR1, S(O)nR2, NR1COR1, O-alkylheterocyclyl with 1-6 carbon atoms in the alkyl, and where heterocyclyl is selected from 1,4-dioxan-2-yl, O-alkyl heteroaryl with 1-6 carbon atoms in the alkyl, and where the heteroaryl is selected from pyrazolyl, alkyl-OR1 with 1-6 carbon atoms in the alkyl, alkyl-NR1SO2R2 with 1-6 carbon atoms in the alkyl, NR1R2, tetrahydrofuranyloxymethyl, tetrahydrofuranylmethoxymethyl, O(CH2)-3,5-dimethyl-1,2-oxazol-4-yl, O(CH2)2-O(3,5-dimethoxypyrimidin-2-yl, O(CH2)-5-pyrrolidin-2-one, O(CH2)-5-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one, or heteroaryl, selected from the group, including 1,2,3-triazolyl and pyrazolyl, or heterocyclyl, selected from the group, including 4,5-dihydro-1,2-oxazol-3-yl and tetrahydropyrimidi-2(1H)-on-1-yl, respectively substituted with s residues, selected from the group, including methyl, methoxy and cyanomethyl; R1stands for hydrogen, alkyl with 1-6 carbon atoms, alkinyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, cycloalkylalkyl with 2-6 carbon atoms in the cycloalkyl and 1-6 carbon atoms in the alkyl, phenyl or phenylalkyl with 1-6 carbon atoms in the alkyl, with six last residues being substituted with s residues, selected from the group, including a halogen, OR3 and CON(R3)2; R2 stands for alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or phenyl with 1-6 carbon atoms alkyl, with the five last residues being substituted with s residues, selected from the group, including a halogen, OR3, OCOR3, CO2R3, COSR3 and CON(R3)2; R3 stands for hydrogen or alkyl with 1-6 carbon atoms; n stands for 0, 1 or 2; s stands for 0, 1, 2 or 3. The invention also relates to the application of N-(1,2,5-oxadiazol-3-yl)benzamides of formula (I), as a herbicidal preparation and for fighting undesirable plants.

EFFECT: N-(1,2,5-oxadiazol-3-yl)benzamides, possessing herbicidal activity.

9 cl, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to azetidine-substituted isoxazoline derivatives of formula (1), where A represents phenyl, naphtyl or heteroaryl, where said heteroaryl represents 5-6-membered aromatic monocyclic ring and contains 1 N heteroatom; each of R1a, R1b and R1c independently represents hydrogen, halogen, cyano, nitro or C1-C6halogenalkyl; R2 represents halogen, cyano or nitro; R3 represents hydrogen, halogen, hydroxyl, cyano, N3 or -NHR4; R4 represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5 or -C(NR7)R5; R5 represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, representing 5-6-membered aromatic monocyclic ring, containing from 1 to 3 heteroatoms, each of which is independently selected from N, O and S, or C0-C6alkylheterocycle, where said heterocycle represents 4-membered monocyclic ring, containing 1 heteroatom, selected from N, O and S; R6 represents C1-C6halogenalkyl; R7 represents cyano; Ra represents hydrogen, C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl; Rb represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; Rc represents C1-C6alkyl, C1-C6halogenalkyl, C1-C6halogenalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl or C0-C3alkylphenyl, each of which is possibly substituted with at least one substituent, selected from cyano or halogen, each of groups C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl ad R5 can be possibly and independently substituted with at least one substituent, selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenalkoxy, C1-C6halogenalkyl, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rc and -C(O)NRaRb; and where grouping C0-C6alkylheteroaryl or C1-C6alkylheterocycle as R5 can be possibly additionally substituted with at least one substituent, selected from halogen, oxo, hydroxyl, C1-C6alkyl and -SH; n represents integer number 0 or 1, and p represents integer number 0, 1 or 2 and its stereoisomers. Invention also relates to pharmaceutical or veterinary composition, possessing parasiticidal activity, containing therapeutic amount of formula (I) derivative and pharmaceutically or veterinarily acceptable excipient, diluents or carrier.

EFFECT: azetidine-substituted isoxazoline derivatives of formula (1), intended for manufacturing means for treatment or control of parasitic infection or invasion in animal.

20 cl, 5 tbl, 225 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining (S)-2-methoxy-3-{4[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl}propionic acid of formula (I) or its salts, in which formula (II) compound or its salt is hydrated in the presence of an iridium-including catalyst, in which the catalyst includes iridium and formula (III) compound, in which R1 stands for hydrogen, isopropyl, phenyl or benzyl and in which R2 stands for phenyl, 3,5-dimethylphenyl or 3,5-di-tert-butylphenyl. The invention also relates to the application of a complex of the catalyst, containing iridium and the formula (III) compound for obtaining the formula (I) compound.

EFFECT: obtaining the formula (I) compound with a high degree of conversion and enantiomeric purity.

6 cl, 4 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula I, or their racemic mixture, or their individual optic isomers, or pharmaceutically acceptable salts possessing the properties of TGR bile acid receptor agonist. The invention also refers to methods for preparing the compounds. In general formula I , X represents amino group R'R"N, wherein the substitutes R' and R" can be optionally identical, or represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl; substituted C1-C6alkyl, wherein the substitute is specified in phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy, phenyloxy, C3-C6cycloalkyl, 5-6-merous heteroaryl with 1 nitrogen atom; aryl specified in phenyl optionally substituted by fluorine, C1-C3alkyl, C1-C3 alkoxy; 5-6-merous heteroaryl with nitrogen atom as heteroatom; C2-C4alkenyl, acyl specified in C1-C6alkylcarbonyl or C3-C6cycloalkylcarbonyl; or substituted oxygroup, which represents hydroxy group, wherein hydrogen is substituted by C1-C6alkyl optionally substituted by hydroxy, di(C1-C3alkyl)amino, phenyl, which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C2-C4alkenyl; and 5-6-merous heterocyclyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom; R1a and R1b represents hydrogen, C1-C3alkyl, or R1a and R1b together form methylene chain -(CH2)n-, wherein n=2-5; R1c and R1d represents hydrogen, C1-C3alkyl; R2 represents acyl group specified in C1-C6alkylcarbonyl, wherein alkyl can be substituted by phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C3-C6cycloalkylcarbonyl; phenylcarbonyl, which can be substituted by halogen, C1-C3alkyl, C1-C3alkoxygroup, oxygroup, C1-C3alkylene dioxygroup; 5-6-merous heteroarylcarbonyl with nitrogen atom, or oxygen atom, or sulphur atom as heteroatom, optionally substituted by carboxy, halogen or C1-C3alkoxycarbonyl, substituted aminocarbonyl group, wherein the substitute can be specified in C1-C6alkyl optionally substituted by C1-C3alkoxycarbonyl, halogen, 5-6-merous heteroaryl together with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom; C3-C6cycloalkyl; phenyl optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkoxycarbonyl, C1-C3alkylenedioxygroup; 5-6-merous heteroarym with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom optionally substituted by carboxy, C1-C3alkoxycarbonyl; aminocarbonyl group substituted by C1-C3alkyl; sulphonyl group specified in alkylsuphonyl optionally substituted by hydroxyl group, cyano group, phenyl, which is optionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group; henylsulphonyl oprtionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group, cyano group, C1-C3alkylene dioxygroup, or 5-6-merous heteroarylsulphonyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy group; R3 represents hydrogen.

EFFECT: compounds can be used for preparing the pharmaceutical composition applicable in treating or preventing metabolic diseases, such as diabetes, obesity, diabetic obesity, metabolic syndrome, hypercholesterolemia, dislipidemia.

14 cl, 17 dwg, 8 tbl, 16 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, namely, deals with compounds of formula , suitable for reduction of regulation of biological activity of melanocortin-5 receptor (MC5R). Such diseases and/or conditions include, but are not limited by, acne, seborrhoea, seborrheic dermatitis, cancer and inflammatory diseases.

EFFECT: compounds of claimed invention can be applied for treatment of diseases and/or conditions, in which reducing regulation of MC5R is favourable.

3 cl, 109 ex, 7 tbl

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