Modulators of atp-binding transporters

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

 

Cross-reference to related applications

The present application claims priority to patent application U.S. serial No. 12/635927, filed December 11, 2009. The content of this application are incorporated in this application by reference in its entirety.

Field of the invention

The present invention relates to modulators of ATP-Binding Cassette ("ABC") transporters or fragments, including transmembrane regulator conductance cystic fibrosis ("CFTR"), compositions and methods in which they are used. The present invention also relates to methods of treating ABC Transporter mediated diseases using such modulators.

Background of the invention

ABC transporters are a family of membrane transport proteins that regulate the transport of many different 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) for their specific activity. It was discovered that some of these transporters are politicalscene-resistant proteins (e.g., MDR1-P glycoprotein, or poliglecaprone-resistant protein MRP1), defending malignant RA�new cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on the identity of their sequences and functions.

ABC transporters regulate various important physiological role in the body and provide protection against environmentally harmful compounds. Therefore, they represent an important potential target for drugs for the treatment of diseases associated with defects of the conveyor, preventing transport of the drug from the target cell and interference in other diseases where modulation of the activity of the ABC Transporter may be useful.

One member of the family of ABC transporters, usually associated with a disease, is a cAMP/ATP-mediated anion channel, CFTR. CFTR is expressed in various cell types, including absorptive and secretory epithelial cells, where it regulates the flow of anions through the membrane, and the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of transport of electrolytes in the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein comprising a tandem repeat of transmembrane domains, each containing six transmembrane DV�inih helices and a nucleotide binding domain. These two transmembrane domain are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular traffic.

The gene encoding CFTR has been identified and sequenced (See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). A defect in this gene causes mutations in CFTR that lead to cystic fibrosis ("CF"), naibolee common fatal genetic disease in humans. Cystic fibrosis affects approximately one out of every 2,500 infants in the United States. From the U.S. General population, 10 million people have one copy of the defective gene without any visible effects of the disease. In contrast, subjects with two copies of the CF associated 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 anion secretion causing an imbalance in the transport of ions and fluids. The resulting decrease in anion transport contributes to increased accumulation of mucus in the lungs with accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory for�of Alemania, CF patients typically suffer from gastrointestinal problems and insufficient pancreatic function that, if left untreated, leads to death. Moreover, most men with cystic fibrosis are infertile, and fertility is reduced in women with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, subjects with one copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea - possibly explaining the relatively high prevalence of CF gene in the population.

The sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). Currently identified more than 1000 disease causing mutations in the CF gene (http://www.genet.sickkids.on.ca/cftr/). The most common mutation is deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and it is usually pointed to as ΔF508-CFTR. This mutation occurs in approximately 70% of cystic fibrosis cases, and it is associated with severe disease.

The deletion of residue 508 in ΔF508-CFTR prevents the proper laying of the nascent protein. This leads to the inability of the mutant protein goes� from the ER and move to the plasma membrane. As a result, the number of channels present in the membrane, far from the one observed in cells expressing wild-type CFTR. In addition to disrupted traffic, this mutation leads to a defect in the Gating mechanism of the channel. All together, the reduced number of channels in the membrane and the defect gate mechanism, lead to reduced anion transport across the epithelium, leading to impaired transport of ions and fluids. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). However, studies have shown that reduced the number of ΔF508-CFTR in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to ΔF508-CFTR, R117H-CFTR and G551D-CFTR, other disease-causing mutations in CFTR that result in disturbed website traffic, synthesis, and/or the Gating mechanism of the channel could be adjusted either by activation or down-regulation for change of anion secretion and modify 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, chloride and bicarbonate) represents one element in an important mechanism of transport of ions and water across the epithelium. Other elements include the epithelial Na+channel, ENaC, Na+/2C1-/K+co-Transporter, Na+-K+-Infusny� pump and the basolateral membrane K +channels, which are responsible for the absorption of chlorine in the cell.

These elements work together to achieve directed transport through the epithelium via their selective expression and localization in the cell. Absorption of chlorine occurs as a result of the coordinated activity of ENaC and CFTR present on the apical membrane, and Na+-K+-ATPase pump and Cl ion channels expressed on the basolateral cell surface. Secondary active transport of chlorine from the luminal side leads to the intracellular accumulation of chlorine, which can then passively leave the cell via Cl-channels, resulting in a vectorial transport. The location of Na+/2C1-/7K+co-Transporter, Na+-K+-ATPase pump and the basolateral membrane K+channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chlorine via CFTR on the luminal side. Because water is probably never itself is not actively transported, its flow through the epithelium depends on a very small transepithelial osmotic gradients generated by the bulk flow of sodium and chlorine.

Assume that the defective bicarbonate transport due to mutations in CFTR cause some defects in secretory functions. See, for example, “Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis,” Paul M. Quinton, Lancet 2008; 32: 415-417.

Mutations in CFTR are associated with mild CFTR dysfunction, also evident in patients with conditions in which some manifestations of the disease are common with CF, but do not reach the diagnostic criteria for CF. They include congenital bilateral absence of VAS deferens, idiopathic chronic pancreatitis, chronic bronchitis and chronic rhinosinusitis. Other diseases in which is reputed to be the mutant CFTR is a risk factor, together with modified genes or environmental factors include primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis and asthma.

It has also been demonstrated that cigarette smoke, hypoxia, and environmental factors that induce the transfer of the hypoxic signal, disrupt CFTR function and may contribute to some forms of respiratory diseases, such as chronic bronchitis. Diseases that may occur because of impaired CFTR function, but do not reach the diagnostic criteria of CF, defined as CFTR-related diseases.

In addition to cystic fibrosis, modulation of CFTR activity may be useful for other diseases not directly related to mutations in CFTR, such as secretory diseases and other associated with the laying of protein diseases mediated by CFTR. CFTR regulates the flow� of chloride and bicarbonate across the epithelium of many cells to control the movement of fluids solubilization of the protein, the viscosity of the mucus and enzyme activity. Defects in CFTR can cause blockage of the respiratory tract or the ducts in many organs, including the liver and pancreas. Potentiating funds are compounds that increase associated with the Gating mechanism of the activity of CFTR present in the cell membrane. Any disease, which includes thickening of mucus, impaired regulation of fluid, impaired mucous clearance or blockage of the ducts that lead to inflammation and tissue destruction, may be a candidate for potentiating funds.

These include, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, induced by Smoking, COPD, chronic bronchitis, rhinosinusitis, constipation, dry eye disease, and Sjogren syndrome, gastroesophageal reflux, bile stone disease, rectal prolapse, and inflammatory bowel disease. COPD is characterized by airflow limitation that is progressive and not fully reversible. Airflow limitation is due to hypersecretion of mucus, emphysema and bronchiolitis. Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired clearance resnitchatogo epithelium, which is common in COPD. In particular, increased�e anion secretion across CFTR may facilitate the transport of the liquid surface in the respiratory tract fluid for hydration of mucus and optimization of viscosity priciliano fluid. This can lead to increased clearance resnitchatogo epithelium and reduction of symptoms associated with COPD. In addition, by preventing the development of infection and inflammation result in improved clearance of the Airways CFTR modulators can prevent or slow down parenchymal destruction of the respiratory tract, which is characteristic of emphysema, and to reduce or reverse the increase in the number and size of cells secreting mucus, which is the cause of hypersecretion of mucus in the respiratory diseases. The dry eye disease is characterized by reduced tear production and abnormal profiles of the tear lipid film, protein and mucin. There are many causes of dry eye disease, 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 anion secretion across CFTR may increase the transport of fluid from the corneal endothelial cells and the secretory glands around the eye, increasing the hydration of the cornea. This helps to alleviate symptoms associated with dry eye disease. Sjogren's syndrome is an autoimmune disease in which the immune system attacks producing moisture glands throughout the body including eyes, mouth, skin�, respiratory tissue, liver, vagina and intestines. Symptoms include, dry eyes, mouth, and vagina, as well as lung disease. This disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis and polymyositis/dermatomyositis. Believe that a violation of protein traffic causes the disease, treatment options are restricted. Modulators of CFTR activity can hydrational various organs affected by the disease, and can help alleviate the associated symptoms. In subjects with cystic fibrosis are repeated episodes of intestinal obstruction and more cases of rectal prolapse, bile stone disease, gastroesophageal reflux, gastrointestinal tumors, and inflammatory bowel disease, indicating that CFTR function may play an important role in the prevention of such diseases.

As discussed above, it is considered that the deletion of residue 508 in ΔF508-CFTR prevents the proper laying of the nascent protein, which leads to the inability of the mutant protein to exit the ER and move to the plasma membrane. As a result, the plasma membrane contains an insufficient number of Mature protein, and transport of chlorine in epithelial tissues is significantly reduced. Indeed, it was shown that this cellular pheno�Yong defective ER processing of the CFTR poweredcom ER mechanism lies at the basis not only for CF disease, but also a wide range of other individual and hereditary diseases. Two ways, resulting in poor performance ER mechanism, involve either the loss of communication with the ER export of the proteins leading to degradation, or the ER accumulation of these defective/irregular stacking of proteins [Aridor M, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B. S., et al., Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et al., TIPS, 21, pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198 (1999)]. Diseases associated with the first class improper function ER include cystic fibrosis (due to improper stacking of ΔF508-CFTR as discussed above), hereditary emphysema (due to a1-antitrypsin; not Piz variants), hereditary hemochromatosis, disturbances of coagulation-fibrinolysis, such as protein C deficiency, hereditary angioedema type 1, lipid processing, such as familial hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia, disease lysosomal accumulation, such as I-cell disease/pseudo-Hurler, Hurler (because lizosomnah processing enzymes), disease Sandhof/Tay-Sachs (due to β-hexosaminidase) syndrome, crigler-Najjar type II (due to UDP-glucuronyl-sialyl-transferase), polyendocrinopathy/hyperinsulinemia, diabetes mellitus (due to insulin receptor), dwarfism of Larona (due to receptor growth hormone) deficits mil�of peroxidase, primary hypoparathyroidism (because preproparathyroid hormone), melanoma (due to tyrosinase). Diseases associated with the latter class of improper function of the ER include Glycans CDG type 1, hereditary emphysema (due to A1-Antitrypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to type I, II, IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen), deficiency ACT (because α1-antichymotrypsin), diabetes insipidus (DI), neurophysiology DI (due to vasopressin/V2-receptor), nephrogenic DI (due to aquaporins (II), syndrome Charcot-Marie-Tooth syndrome (due to peripheral myelin protein 22), the disease Perlizaeus-Merzbacher, neurodegenerative diseases such as Alzheimer's disease (because of βAPP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, pick's disease, some polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary disease of Creutzfeldt-Jakob disease (due to a defect in the processing of prion protein), Fabry disease (due to lysosomal α-galactosidase A), the syndrome of Straussler-Sheinker (because of a defect processing Prp), infertility, pancreat�t, pancreatic insufficiency, osteoporosis, osteopenia, Gorham's syndrome, chloride channelopathies, congenital myotonia (form Thomson and Becker), a syndrome of Barter type III, dent disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal disease accumulation, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with situs situs inversus (also known as syndrome Kartagener), PCD without situs situs inversus and ciliary aplasia, and liver disease.

Other diseases associated with a mutation in the CFTR include male infertility caused by congenital bilateral absence of VAS deferens (CBAVD), mild pulmonary form of the disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA). Cm. “CFTR-opathies: disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations,” Peader G. Noone and Michael R. Knowles, Respir. Res. 2001, 2: 328-332 (included in this application by reference).

In addition to positive regulation of CFTR activity, reducing anion secretion by CFTR modulators may be useful for the treatment of secretory diarrheas, in which epithelial water transport increases significantly as a result of enhancing the secretion of means that activate chloride transport. This mechanism involves the increase of cAMP and stimulation of CFTR.

Although there are numerous causes of diarrhea, the major consequences of diarrhea, which results�tat excessive chloride transport are common to all, and include dehydration, acidosis, growth retardation, and death. Acute and chronic diarrhea represent a serious health problem in many regions of the world. Diarrhoea is a major factor in eating disorders and a major cause of mortality (5,000,000 deaths/year) in children aged under 5 years.

Secretory diarrheas are also a dangerous condition in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). 16 million travelers visiting developing countries from industrialized countries every year develop diarrhea, with the severity and incidence of diarrhea varies depending on the visited country or region.

Diarrhea in livestock and domestic animals such as cows, pigs and horses, sheep, goats, cats and dogs, also known as dysentery, is the leading cause of death in these animals. Diarrhea can occur as a result of any significant changes, such as cessation of breastfeeding or physical movement, as well as in response to various bacterial or viral infections and generally occurs within the first few hours of life of the animal.

Bacteria most frequently causing diarrhea, is enterotoxigenic E. coli (ETEC) containing the K99 pilus antigen. The main viruses that cause diarrhea are rotavirus and coronavirus. Other infectious agents include, among others, cryptosporidium, giardia lamblia and salmonella.

The symptoms of rotavirus infection include water excretion of feces, dehydration and weakness. Coronavirus causes a more severe disease in newborn animals and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus, or a combination of viral and bacterial microorganisms simultaneously. This has significantly increased the severity of the disease.

Accordingly, there is a need for modulators of the activity of the ABC Transporter and compositions on their basis, which can be used to modulate the activity of the ABC Transporter in the cell membrane of a mammal.

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

There is a need for methods of modulating the activity of the ABC Transporter in ex vivo cell membrane of a mammal.

There is a need for modulators of CFTR activity that can be used to modulate aktivnosti CFTR in the cell membrane of a mammal.

There is also a need for strong and selective CFTR-sweaty�jirousek means, including wild type and mutant forms of human CFTR. These mutant CFTR forms include, but are not limited to, ΔF508del, G551D, R117H, 2789+5G>A.

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

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

Brief description of the invention

It was found that the compounds of the present invention and containing pharmaceutically acceptable compositions are useful as modulators of the activity of the ABC Transporter. These compounds have the General formula I:

or pharmaceutically acceptable salt of such a compound, where R1, R2, R3, R4, R5, R6, R7and Ar1described generally and in classes and subclasses below.

These compounds and pharmaceutically acceptable compositions are useful for treating or reducing the severity of various diseases, disorders or conditions including, but not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, disturbances of coagulation-fibrinolysis, such as protein C deficiency, hereditary angioedema type 1, lipid processing, such as familial hypercholesterolemia, x�lumichrome type 1, abetalipoproteinemia, disease lysosomal accumulation, such as I-cell disease/Pseudo-Hurler, Hurler's disease Sandhof/Tay-Sachs syndrome, crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, dwarfism of Larona, lack of teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, deficiency ACT, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Tooth syndrome, a disease Perlizaeus-Merzbacher, neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, pick's disease, some polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary disease of Creutzfeldt-Jakob disease, Fabry disease, syndrome Straussler-Sheinker, COPD, disease, dry eye and Sjogren's syndrome.

Detailed description of the invention

I. General description of compounds of the present invention:

The present invention relates to compounds of formula I, useful�m as modulators of the activity of ABC Transporter:

or pharmaceutically acceptable salt of such a compound, where:

Ar1is a 5-6 membered aromatic monocyclic ring containing 0-4 hetero, independently selected from nitrogen, oxygen or sulfur, where the specified ring optionally is 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, oxygen or sulfur, where Ar1contains m, the number of substituents, each independently selected from WRW;

W is a bond or is an optionally substituted C1-C6alkylidene chain, where up to two methylene units in W are optionally and independently replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR', -NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-;

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

m has a value of 0-5;

each of R1, R2, R3, R4and R5independently represents-X-RX;

X represents a bond or is an optionally substituted C1-C6alkylidene chain, where up d� two methylene units in X are optionally and independently replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR', -NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-;

RXindependently represents R', halogen, NO2, CN, CF3or OCF3;

R6represents hydrogen, CF3, -OR', -SR' or optionally substituted C1-6aliphatic group;

R7represents hydrogen or C1-6aliphatic group, optionally substituted by a group-X-RX;

R' is independently selected from hydrogen or optionally substituted groups selected from C1-C8aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring containing 0-3 heteroatom, independently selected from nitrogen, oxygen, or sulfur, or an 8-12-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two present R' taken together with the atom(atoms) to which they relate, with the formation of optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring containing 0-4 hetero, independently selected from nitrogen, oxygen or sulfur.

In some others�many variants of embodiment are provided compounds of the formula I:

or pharmaceutically acceptable salt of such a compound, where:

Ar1is a 5-6 membered aromatic monocyclic ring containing 0-4 hetero, independently selected from nitrogen, oxygen or sulfur, where the specified ring optionally is 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, oxygen or sulfur, where Ar1contains m, the number of substituents, each independently selected from WRW;

W is a bond or is an optionally substituted C1-C6alkylidene chain, where up to two methylene units in W are optionally and independently replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR', -NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -SO2NR'-, NR'SO2-, -NR'SO2NR'-;

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

m has a value of 0-5;

each of R1, R2, R3, R4and R5independently represents-X-RX;

X represents a bond or is an optionally substituted C1-C6alkylidene chain, where up to DV�x methylene chain in X is optionally and independently replaced by-CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR', -NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-;

RXindependently represents R', halogen, NO2, CN, CF3or OCF3;

R6represents hydrogen, CF3, -OR', -SR' or optionally substituted C1-C8aliphatic group;

R7represents hydrogen or C1-C6aliphatic group, optionally substituted by a group-X-RX;

R' is independently selected from hydrogen or optionally substituted group selected from C1-C8aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring containing 0-3 heteroatom, independently selected from nitrogen, oxygen, or sulfur, or an 8-12-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two present R' taken together with the atom(atoms) to which they relate, with the formation of optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring containing 0-4 hetero, independently selected from nitrogen, oxygen, or sulfur;

<> provided that:

(i) when R1, R2, R3, R4, R5, R6and R7represent hydrogen, then Ar1cannot represent a phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, phenyl 3,5-dicarboxylic acid, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro-4-methylphenyl, phenyl 3-carboxylic acid, 2-fluorophenyl, 3-fluorophenyl, 3-triptoreline, 3-ethoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 3,4-dimethylphenyl, 2-ethylphenyl or 4-ethoxycarbonylphenyl;

(ii) when R1, R2, R3, R5, R6andR7represent hydrogen and R4represents methoxy, then Ar1cannot be a 2-fluorophenyl or 3-fluorophenyl;

(iii) when R1, R3, R4, R5, R6andR7represent hydrogen, R2represents a 1,2,3,4-tetrahydroisoquinoline-1-yl-sulfonyl, then Ar1can't be a 3-triptoreline;

(iv) when R1, R2, R3, R4, R5andR7represent hydrogen, R6is methyl, then Ar1can not be a phenyl;

(v) when R1, R4, R5, R6andR7represent Soboh� hydrogen, R2and R3taken together, are methylenedioxy, then Ar1cannot be 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-carboethoxy, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl, 6-halo-benzothiazol-2-yl, 6-nitro-benzothiazol-2-yl or 6-thiocyano-benzothiazol-2-yl.

(vi) when R1, R4, R5, R6andR7represent hydrogen, R2and R3taken together, are methylenedioxy, then Ar1can't be a 4-substituted phenyl, where the Deputy is a-SO2NHRxxwhere Rxxrepresents 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl;

(vii) when R1, R2, R3, R4, R5, R6and R7represent hydrogen, then Ar1can't be a 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 R7represent hydrogen, and R4is a CF3, OMe, chloro, SCF3or OCF3then Ar1not a 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-methyl-imidazol-2-yl, imidazol-2-yl, 5-methyl-imidazol-2-yl, 1,3-oxazol-2-yl or 1,3,5-(1H)-triazole-2-yl;

ix) R 1, R2, R3, R4, R5, R6and R7each represents hydrogen, then Ar1cannot be pyrimidine-2-yl, 4,6-dimethyl-pyrimidine-2-yl, 4-methoxy-6-methyl-1,3,5-triazine-2-yl; 5-bromo-pyridin-2-yl, pyridin-2-yl or 3,5-dichloro-pyridin-2-yl;

x) when R1, R2, R3, R4, R5and R7each represents hydrogen, R6represents hydroxy, then Ar1can not represent a 2,6-dichloro-4-aminosulfonyl-phenyl;

(xi) when R2or R3is an optionally substituted n-piperazin, n-piperidyl or N-morpholinyl, then Ar1cannot be an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl or indazole;

(xii) when R2represents an optionally substituted, cyclohexylamino, then Ar1may not represent optionally substituted phenyl, pyridyl or thiadiazolyl;

xiii) Ar1cannot be an optionally substituted tetrazolyl;

(xiv) when R2, R4, R5, R6and R7each represents hydrogen, and R1and R3both are CF3, chlorine, methyl or methoxy, then Ar1not a 4,5-dihydro-1,3-thiazol-2-yl, ties�l-2-yl, or [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl;

xv) when R1, R4, R5, R6and R7each represents hydrogen, and Ar1represents a thiazol-2-yl, then neither R2no R3cannot be isopropyl, chlorine or CF3;

xvi) when Ar1is a 4-methoxyphenyl, 4-triptoreline, 2-fluorophenyl, phenyl or 3-chlorophenyl, then:

(a) when R1, R2, R4, R5, R6and R7each represents hydrogen, then R3may not represent methoxy; or

(b) when R1, R3, R4, R5, R6and R7each represents hydrogen, thenR2cannot be chlorine; or

c) when R1, R2, R3, R5, R6and R7each represents hydrogen, thenR4may not represent methoxy; or

(d) when R1, R3, R4, R6and R7each represents hydrogen, and R5represents ethyl, then R2cannot be chlorine;

e) when R1, R2, R4, R5, R6and R7each represents hydrogen, thenR3cannot be chlorine;

xvi) when R1, R3, R4, R5, R6and R7each represents hydrogen, and R2is CF 3or OCF3then Ar1cannot be [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl;

xvii) when R1, R2, R4, R5, R6and R7each represents hydrogen, and R3represents hydrogen or CF3then Ar1cannot be a phenyl substituted with-OCH2CH2Ph, -OCH2CH2(2-trifluoromethyl-phenyl), -OCH2CH2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl), or substituted 1H-pyrazol-3-yl; and

xviii) the following two compounds are excluded:

2. Compounds and definitions:

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

The term "ABC-Transporter" as used in this application, means ABC-Transporter protein or a fragment thereof containing at least one binding domain, where the specified protein or a fragment thereof is present in vivo or in vitro. The term "binding domain", as used in this application, means a domain on the ABC-Transporter, which can communicate with the modulator. See, e.g., Hwang, T. C. et al., J. Gen. Physiol. (1998): 111(3), 77-90.

The term "CFTR" as used in this application, means the regulator transmembrane conductance cystic fibrosis or its mutation, capable of regulator activity, including, but not limited to, ΔF508 CFTR and G551D CFTR (see, for example, http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).

The term "modulating", as used in this application, means an increase or decrease of the quantity that can be measured.

For the purposes of the present invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, General principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the full contents of which are incorporated in this application by reference.

As described in the present application, the compounds of the present invention can optionally be substituted by one or more substituents, such as are illustrated generically above, or presented on the example of particular classes, subclasses and species of the present invention. It should be clear that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Generally, the term "substituted", regardless of whether a hundred�t before him, the word "optional" 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 at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one Deputy, selected from a specified group, such substituents may be the same or different from each other in each position. Combinations of substituents envisioned by the present invention preferably are those which lead to the formation of stable or chemically feasible compounds. The term "stable", as used in this application, refers to compounds that are essentially not altered by being subjected to the conditions that make possible the reception, detection and, preferably, their separation, purification, and use for one or more appointments as disclosed in this application. In some embodiments, embodiments, a stable compound or chemically feasible compound is a such that essentially does not change when held at a temperature of 40ºC or below, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term "aliphati�die" or "aliphatic group", as used in this application, means a linear (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or which contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or which contains one or more units of unsaturation, but which is not aromatic (also referred to in this application as "carbocycle", "cycloaliphatic" or "cycloalkyl"), which has one attachment point to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, embodiments aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In the following embodiments embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in some embodiments, embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments of the incarnation "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-8the hydrocarbon or bicyclic or tricyclic C8-14the hydrocarbon, co�which is completely saturated or which contains one or more units of unsaturation, but which is not aromatic, that has a single point of connection to the rest of the molecule, where any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkyline groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., position) associated bridging the communication bicycloalkyl, such as norbornyl or [2,2,2]bicyclo-octyl, or linked by bridging communication tricyclic group such as adamantyl.

The term "heteroaromatics", as used in this application, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more atoms selected from oxygen, sulfur, nitrogen, phosphorus or silicon. Heteroaromatics groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl", "geterotsiklicheskie" or "heterocyclic" groups.

The term "heterocycle", "heterocyclyl", "geterotsiklicheskikh" or "heterocyclic", as he �is therefore particularly suitable in the present application, means non-aromatic, monocyclic, bicyclic or tricyclic ring system in which one or more ring members is an independently selected heteroatom. In some embodiments of the incarnation "heterocycle", "heterocyclyl", "heterocyclizations" or "heterocyclic" group contains from three to fourteen ring members, where one or more ring members are a heteroatom independently selected from the group comprising oxygen, sulfur, nitrogen or phosphorus, and each ring in the system contains 3 to 7 ring members.

The term "heteroatom" means one or more atoms selected from 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 a heterocyclic ring, 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 in this application, means that the group contains one or more units of unsaturation.

The term "alkoxy" or "thioalkyl" as used in this application, refers to an alkyl group, as defined above, attached to the principal carbon chain through an oxygen atom ("alkoxy") or sulfur (thioalkyl").

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

The term "aryl" used alone or as part of a larger group, as in "aralkyl", "arakaki" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring system containing from five to fourteen ring members, where at least one ring in the system is aromatic, and where each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems defined in the present application is below.

The term "heteroaryl", used alone or as part of a larger group, as in "heteroalkyl" or "heteroaromatics", refers to monocyclic, bicyclic and tricyclic ring systems containing from five to fourteen ring members, where at least one ring in the system is aromatic, at least one �also in the system contains one or more heteroatoms, and where each ring in the system contains 3 to 7 ring members. 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) group may contain one or several deputies. Suitable substituents on the unsaturated carbon atom aryl or heteroaryl group selected from halogen; -RO; -ORO; -SRO; 1,2-methylene-dioxo; 1,2-Ethylenedioxy; phenyl (Ph) optionally substituted by a group RO; -O(Ph) optionally substituted by a group RO; -(CH2)1-2(Ph), optionally substituted by a group RO; -CH=CH(Ph) optionally substituted by a group 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)2; or -(CH2)0-2NC(O)R Owhere in each independent case, ROselected from hydrogen, 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 members present in the group ROon the same Deputy or different substituents, taken together with the atom(s) associated with each ROgroup, form a 3-8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring containing 0-3 heteroatom, independently selected from the group comprising nitrogen, oxygen or sulfur. Optional substituents in the aliphatic group of ROselected from NH2NH(C1-4aliphatic group), N(C1-4aliphatic group)2of halogen, (C1-4aliphatic group, OH, O(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 C1-4aliphatic groups of ROis unsubstituted.

Aliphatic or heteroaromatics group or non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic� or heteroaromatics group or non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon 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 the group including hydrogen or optionally substituted C1-6aliphatic group. Optional substituents in the aliphatic group of R* are selected from NH2NH(C1-4aliphatic group), N(C1-4aliphatic group)2of halogen, (C1-4aliphatic group, OH, 0(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 C1-4aliphatic groups of R* is unsubstituted.

Optional substituents on the nitrogen non-aromatic heterocyclic ring are selected from-R+, -N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2or-NR+SO2R+; where R+represents hydrogen, 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 Goethe�acyclically ring, containing one to four heteroatoms, independently selected from the group comprising oxygen, nitrogen or sulfur, or, notwithstanding the definition above, two independent members present in the group R+on the same Deputy or different substituents, taken together with the atom(s) associated with each R+group, form a 3-8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring containing 0-3 heteroatom, independently selected from the group comprising nitrogen, oxygen or sulfur. Optional substituents in the aliphatic group or the phenyl ring of R+selected from NH2NH(C1-4aliphatic group), N(C1-4aliphatic group)2of halogen, (C1-4aliphatic group, OH, O(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 C1-4aliphatic groups of R+is unsubstituted.

The term "alkylidene chain" refers to a straight or branched carbon chain that may be fully saturated or may contain one or more units of unsaturation and has two points of connection to the rest of the molecule. The term "spirocyclohexane" refers to Kar�aziklicescoe ring, which may be fully saturated or may contain one or more units of unsaturation and has two points of connection are from the same ring carbon atom to the rest of the molecule.

As explained above, in some embodiments embodiment, two independently present Ro(or R+or any other variable similarly defined in the present application), taken together with the atom(atoms) to which each variable is associated with the formation of a 3-8-membered cycloalkyl, heterocyclic, aryl or heteroaryl ring containing 0-3 heteroatom, independently selected from nitrogen, oxygen, or sulfur. Examples of rings that are formed when two independently present Ro(or R+or any other variable similarly defined in the present application) are taken together with the atom(atoms) to which each variable is bound include, but are not limited to, the following: (a) two independently present Ro(or R+or any other variable similarly defined in the present application) which are connected to the same atom and are taken together by this atom to form a ring, for example, N(Ro)2where both are present Rotaken together with the nitrogen atom to form a piperidine-1-yl, piperazine-1-ilen� or morpholine-4-ilen group; and (b) two independently present Ro(or R+or any other variable similarly defined in the present application) which are connected to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two present OROthese two present Rotaken together with the oxygen atoms to which they relate, with the formation of a condensed 6-membered oxygen-containing ring:It should be clear that a variety of other rings can be formed when two independently present Ro(or R+or any other variable similarly defined in the present application) are taken together with the atom(atoms) to which each variable is bound and that the examples given above are not intended to limit.

Deputy representing the relationship, for example, bicyclic ring system, as shown below, means that the Deputy can be attached to any ring atom that may be substituted in either ring of the bicyclic ring system:

Unless otherwise specified, it is assumed that the patterns presented in this application also include all isomeric (e.g., enantiomeric, d�stereometria and geometric (or conformational)) forms of the structures; for example, the R and S configurations for each asymmetric center, (Z) and (E) isomers on double bond and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the compounds of the present invention included in the scope of the present invention. Unless otherwise stated, all tautomeric forms of compounds of the present invention included in the scope of the present invention. For example, when R5in the compounds of formula I represents hydrogen, compounds of formula I may exist as tautomers:

In addition, unless otherwise indicated, the patterns presented in this application, also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having presented the structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon carbon13C or14C, included in the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

3. Description of illustrative compounds:

In some embodiments, embodiments of the present invention, Ar1selected from:

where ring A1is a 5-6-membered monocyclic aromatic ring containing 0-4 hetero, independently selected from nitrogen, oxygen, or sulfur; or

A1and A2together represent an 8-14 aromatic, bicyclic or tricyclic aryl ring, where each ring contains 0-4 of heteroatom independently selected from nitrogen, oxygen or sulfur.

In some embodiments of the incarnation, A1represents an optionally substituted 6-membered aromatic ring containing 0-4 heteroatom of where the specified heteroatom is a nitrogen. In some embodiments of the incarnation, A1represents optionally substituted phenyl. Or A1represents optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl. Or A1represents an optionally substituted pyrazinyl or triazinyl. Or A1represents optionally substituted pyridyl.

In some embodiments of the incarnation, A1represents an optionally substituted 5-membered aromatic ring containing 0-3 heteroatom, where said heteroatom is a nitrogen, oxygen or sulfur. In some embodiments of the incarnation, A1represents an optionally substituted 5-membered aromatic ring containing 1-2 of nitrogen atom. � one embodiment, A1represents an optionally substituted 5-membered aromatic ring that is different from thiazolyl.

In some embodiments of the incarnation, A2represents an optionally substituted 6-membered aromatic ring containing 0-4 heteroatom of where the specified heteroatom is a nitrogen. In some embodiments of the incarnation, A2represents optionally substituted phenyl. Or A2represents optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl.

In some embodiments of the incarnation, A2represents an optionally substituted 5-membered aromatic ring containing 0-3 heteroatom, where said heteroatom is a nitrogen, oxygen or sulfur. In some embodiments of the incarnation, A2represents an optionally substituted 5-membered aromatic ring containing 1-2 of nitrogen atom. In some embodiments of the incarnation, A2represents an optionally substituted pyrrolyl.

In some embodiments of the incarnation, A2is an optionally substituted 5-7-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of such rings include piperidyl, piperazin, morpholinyl, thiomorpholine, pyrrolidine, t�traditionnel, etc.

In some embodiments of the incarnation, A2is an optionally substituted 5-10-membered saturated or unsaturated carbocyclic ring. In one embodiment, A2is an optionally substituted 5-10-membered saturated carbocyclic ring. Examples of such rings include cyclohexyl, cyclopentyl, etc.

In some embodiments, embodiments, ring A2selected from:

where ring A2condensed with ring A1via two adjacent ring atom.

In other embodiments, embodiments, W is a bond or is an optionally substituted C1-6alkylidene chain, where one or two methylene link optionally and independently replaced by Deputy O, NR', S, SO or SO2or COO, CO, SO2NR', NR'SO2, C(O)NR', NR'C(O), OC(O), OC(O)NR', and RWrepresents R' or halogen. In the following embodiments of the incarnation, everyone at the WRWindependently represents-C1-C3alkyl, C1-C3perhalogenated, -O(C1-C3alkyl), -CF3, -OCF3, -SCF3, -F, -Cl, -Br, or-COOR', -COR', -O(CH2)2N(R')(R'), -O(CH2)N(R')(R'), -CON(R')(R'), -(CH2)2OR', -(CH2)OR', optionally substituted monocyclic Il� bicyclic aromatic 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 embodiment, m is 0. Or m has a value of 1. Or m has the value 2. In some embodiments embodiment, m has a value of 3. In other embodiments embodiment, m has the value 4.

In one embodiment, R5is a X-RX. In some embodiments embodiment, R5represents hydrogen. Or R5is an optionally substituted C1-8aliphatic group. In some embodiments embodiment, R5is an optionally substituted C1-4aliphatic group. Or R5represents benzyl.

In some embodiments embodiment, R6represents hydrogen. Or R6is an optionally substituted C1-8aliphatic group. In some embodiments embodiment, R6is an optionally substituted C1-4aliphatic group. In some other embodiments embodiment, R6represents -(O-C1-4aliphatic group) or -(S-C1-4aliphatic group). Preferably, R6represents-OMe or-SMe. In some other embodiments embodiment, R6is a CF3.

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

In another embodiment of the present invention, R1, R2, R3, R4and R5simultaneously represent hydrogen. In another embodiment of the present invention, R1, R2, R3, R4, R5and R6simultaneously represent hydrogen.

In another embodiment of the present invention, R2is a X-RXwhere X represents-SO2NR'- and RXrepresents R'; i.e., R2is a-SO2N(R')2. In one embodiment, two R' taken together form an optionally substituted 5-7-membered ring with 0-3 additional heteroatoms selected from nitrogen, oxygen or sulfur. Or R1, R3, R4, R5and R6simultaneously represent hydrogen and R2is a SO2N(R')2.

In some embodiments embodiment, X represents a bond or is an optionally substituted C1-6alkylidene chain, where one or two nonadjacent methylene link optionally and independently replaced by O, NR', S, SO2 or COO, CO, and RXrepresents R' or halogen. In the following embodiments of the incarnation, everyone XRXindependently represents-C1-3alkyl, -O(C1-3alkyl), -CF3, -OCF3, -SCF3, -F, -Cl, -Br, OH, -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 embodiment, R7represents hydrogen. In some other embodiments embodiment, R7represents C1-4linear or branched aliphatic group.

In some embodiments embodiment, RWselected from halogen, 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-(amino-pyridyl), SO2NH2, SO2Ph, SO2NHPh, SO2-N-morpholino, SO2-N-pyrrolidyl, n-pyrrolyl, N-morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4-Methyl-2,4-dihydro-pyrazol-3-one-2-yl, benzimidazol-2-yl, furan-2-yl, 4-methyl-4H-[1,2,4]triazole-3-yl, 3-(4'-chlorophenyl)-[1,2,4]oxidiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph, NHSO2Me, 2-indolyl, 5-indolyl, -CH2 CH2OH, -OCF3O-(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)3O-(2-tert-butyl)phenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-hydroxymethylene, 4-dimethylaminophenyl, 2-triptoreline, 3-triptoreline, 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-phenyl, 4-trifloromethyl, 2-phenoxyphenyl, 4-phenoxyphenyl, 2-fluoro-3-methoxy-phenyl, 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-fluoro-phenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl�and, 3-isopropoxycarbonyl, 3-acetamidophenyl, 4-fluoro-3-methylphenyl, 4-methanesulfonyl-phenyl, 4-methanesulfonyl-phenyl, 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, -NHSO2(CH2)2n-piperidine, -NHSO2(CH2)2N-morpholine, -NHSO2(CH2)2N(Me)2, COCH2N(Me)COCH2NHMe, -CO2Et, O-propyl, -CH2CH2NHCO2C(Me)3,hydroxy, 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-1-cyclooctyl, 1-methyl-1-cycloheptyl, C(Et)2C(Me)3, C(Et)3, CONHCH2CH(Me)22-aminomethyl-phenyl, 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)2CH2 NHCO2(CH2)3CH3C(Me)2CH2NHCO2(CH2)2OMe, C(OH)(CF3)2, -C(Me)2CH2NHCO2CH2-tetrahydrofuran-3-yl, C(Me)2CH2O(CH2)2OMe or 3-ethyl-2,6-dioxopiperidin-3-yl.

In one embodiment, R' represents hydrogen.

In one embodiment, R' is a C1-C8aliphatic group, optionally having up to 3 substituents selected from halogen, CN, CF3, CHF2, OCF3or OCHF2where up to two methylene units in the specified C1-C8aliphatic group optionally substituted with-CO-, -CONH(C1-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO2-, -O-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2- or-N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.

In one embodiment, R' is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring containing 0-3 heteroatom, independently selected from nitrogen, oxygen, or sulfur, wherein R' optionally has up to 3 substituents selected from halogen, CN, CF3, CHF2, OCF3, OCHF2or C1-C6 alkyl, where up to two methylene units in the specified C1-C6, the alkyl optionally substituted by-CO-, -CONH(C1-C4 alkyl)-, -CO2-, -OC-, -N(C1-C4 alkyl)CO2-, -O-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2- or-N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.

In one embodiment, R' is an 8-12-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R' optionally has up to 3 substituents selected from halogen, CN, CF3, CHF2, OCF3, OCHF2or C1-C6 alkyl, where up to two methylene units in the specified C1-C6, the alkyl optionally replaced by-CO-, -CONH(C1-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO2-, -O-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2- or-N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.

In one embodiment, the present two R' taken together with the atom(atoms) to which they relate, with the formation of optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring containing 0-4 hetero, independently selected from nitrogen, oxygen, or sulfur, wherein R' optionally has up to 3 substituents selected from halogen, CN, CF3, CHF2, OCF3, OCHF2or C1-C6 alkyl�, where up to two methylene units in the specified C1-C6, the alkyl optionally substituted by-CO-, -CONH(C1-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO2-, -O-, -N(C1-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO2N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO2- or-N(C1-C4 alkyl)SO2N(C1-C4 alkyl)-.

In accordance with one variant of embodiment, the present invention provides compounds of the formulaIIAor of the formulaIIB:

In accordance with another embodiment, the present invention provides compounds of the formulaIIIAthe formulaIIIBthe formulaIIICthe formulaIIIDor of the formulaIIIE:

where each of X1, X2, X3, X4and X5independently selected from CH or N; and

X6represents O, S or NR'.

In one embodiment, the compounds of the formulaIIIAthe formulaIIIBthe formulaIIICthe formulaIIIDor of the formulaIIIEhave y number of present deputies X-RXwhere y has a value of 0-4. Or y has a value of 1. Or y has a value of 2.

In some embodiments, embodiments of the formulaIIIA, X1, X2, X3, X4and X5taken together with WRWandm, represent optionally substituted phenyl.

In some embodiments, embodiments of the formulaIIIA, X1, X2 , X3, X4and X5taken together, represent an optionally substituted ring selected from:

In some embodiments, embodiments of the formulaIIIBthe formulaIIICthe formulaIIIDor of the formulaIIIE, X1, X2, X3, X4, X5or X6taken together with ring A2represent an optionally substituted ring selected from:

In some embodiments of the incarnation,RWselected from halogen, 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-(amino-pyridyl), SO2NH2, SO2Ph, SO2NHPh, SO2-N-morpholino, SO2-N-pyrrolidyl, n-pyrrolyl, N-morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4-Methyl-2,4-dihydro-pyrazol-3-one-2-yl, benzimidazol-2-yl, furan-2-yl, 4-meth�l-4H-[1,2,4]triazole-3-yl, 3-(4'-chlorophenyl)-[1,2,4]oxidiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph or NHSO2Me.

In some embodiments embodiment, X and RXtaken together, represents Me, Et, halogen, CN, CF3, OH, OMe, OEt, SO2N(Me)(fluorophenyl), SO2-(4-methyl-piperidine-1-yl or SO2-N-pyrrolidinyl.

In accordance with another embodiment, the present invention provides compounds of the formulaIVAthe formulaIVBor of the formulaIVC:

In one embodiment, compounds of the formulaIVAthe formulaIVBand the formulaIVChave y number of present deputies X-RXwhere y has a value of 0-4. Or y has a value of 1. Or y has a value of 2.

In one embodiment, the present invention provides compounds of the formulaIVAthe formulaIVBand the formulaIVCwhere X represents a bond and RXrepresents hydrogen.

In one embodiment, the present invention provides compounds of formula formulaIVBand the formulaIVCwhere the ring A2represents an optionally substituted saturated, unsaturated or aromatic seven membered ring with 0-3 heteroatoms selected from O, S or N. Examples of rings include azepane, 5,5-dimethyl of azepane, etc.

In one embodiment, the present invention provides�AET compounds of the formula IVBandIVCwhere the ring A2represents an optionally substituted saturated, unsaturated or aromatic six-membered ring with 0-3 heteroatoms selected from O, S or N. Examples of rings include piperidinyl, 4,4-dimethylpiperidine, etc.

In one embodiment, the present invention provides compounds of the formulaIVBandIVCwhere the ring A2represents an optionally substituted saturated, unsaturated or aromatic five-membered ring with 0-3 heteroatoms selected from O, S or N.

In one embodiment, the present invention provides compounds of the formulaIVBandIVCwhere the ring A2represents an optionally substituted five-membered ring with one nitrogen atom, for example, pyrrolyl or pyrrolidinyl.

In accordance with one embodiment of the formulaIVAthat is ensured by the following compound of the formulaVA-1:

where each of WRW2and WRW4independently selected from hydrogen, CN, CF3, halogen, C1-C6 linear or branched alkyl, 3-12-membered cycloaliphatic group, phenyl, C5-C10 of heteroaryl or C3-C7 heterocyclic group, where the specified heteroaryl or heterocyclic group contains up to 3 heteroatoms selected from O, S or N, where the specified WRW2and WRW4netavis�mo and optionally has up to three substituents, selected from-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 phenoxy, -N(R')(R'), -NR'C(O)OR', -NR'C(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R'); and

WRW5selected from hydrogen, -OH, NH2, CN, CHF2, NHR', N(R')2, -NHC(O)R', -NHC(O)OR', NHSO2R', -OR', CH2OH, CH2N(R')2, C(O)OR', SO2NHR', SO2N(R')2or CH2NHC(O)OR'. Or WRW4and WRW5taken together, form a 5-7-membered ring containing 0-3 heteroatom selected from N, O or S, where the specified ring optionally has up to three WRWdeputies.

In one embodiment, the compounds of the formulaVA-1have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y is set to 0.

In one embodiment, the present invention provides compounds of the formulaVA-1where X represents a bond and RXrepresents hydrogen.

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

each of WRW2and WRW4independently selected from hydrogen, CN, CF3, halogen, C1-C6 linear or branched alkyl, 3-12-membered cycloaliphatic group, or phenyl,where the specified WR W2and WRW4independently and optionally has up to three substituents selected from-OR', -CF3, -OCF3, -SCF3, 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'), -NC(O)OR', -NC(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R'); and

WRW5selected from hydrogen, -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, the present invention provides compounds of the formulaVA-1where:

WRW2represents a phenyl ring, optionally containing up to three substituents selected from-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 phenoxy, -N(R')(R'), -NR'C(O)OR', -NR'C(O)R', -(CH2)2N(R')(R') or -(CH2)N(R')(R');

WRW4represents a C1-C6 linear or branched alkyl; and

WRW5represents OH.

In one embodiment, each of WRW2and WRW4independently selected from CF3or halogen. In one embodiment, each of WRW2and WRW4independently selected from optionally substituted hydrogen, C1-C6 Lina�tion or branched alkyl. In some embodiments embodiment, 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-butoxycarbonyl-amino) propyl, or n-pentile.

In one embodiment, 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.]bicyclo-octyl, [2.3.1.]bicyclo-octyl, or a [3.3.1]bicyclo-nonyl.

In some embodiments of the incarnation WRW2represents hydrogen, and WRW4represents a C1-C6 linear or branched alkyl. In some embodiments of the incarnation, WRW4selected from methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl.

In some embodiments of the incarnation WRW4represents hydrogen, and WRW2represents a C1-C6 linear or branched alkyl. In some embodiments of the incarnation, WRW2selected from methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl or n-pentile.

In some embodiments embodiment, each of WRW2and WRW4represents a C1-C6 linear or branched alkyl. Some�the options of the incarnation, each of WRW2and WRW4selected from methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl or pentile.

In one embodiment, WRW5selected from hydrogen, CHF2NH2, CN, NHR', N(R')2, CH2N(R')2, -NHC(O)R', -NHC(O)OR', -OR', C(O)OR' or SO2NHR'. Or WRW5represents-OR',for example, OH.

In some embodiments of the incarnation, WRW5selected from hydrogen, NH2, CN, CHF2NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -CH2NHC(O)O(C1-C6 alkyl), -NHC(O)O(C1-C6 alkyl), -OH, -O(C1-C6 alkyl), C(O)O(C1-C6 alkyl), CH2O(C1-C6 alkyl) or SO2NH2. In another embodiment, WRW5selected from-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, the compound of the formulaVA-1has one, preferably more than one, or more preferably all of the following characteristics:

(i) WRW2represents hydrogen;

(ii) WRW4represents a C1-C6 linear or branched alkyl or monocyclic or bicyclic aliphatic group; and

iii) WRW5selected from hydrogen, CN, CHF2NH2NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -NHC(O)O(C1-C6 alkyl), -CH2C(O)O(C1-C6 alkyl), -OH, -O(C1-C6 alkyl), C(O)O(C1-C6 alkyl) or SO NH2.

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

(i) WRW2represents halogen, C1-C6 alkyl, CF3, CN or phenyl, which optionally has up to 3 substituents selected from C1-C4 alkyl, -O(C1-C4 alkyl) or halogen;

(ii) WRW4is a CF3, halogen, C1-C6 alkyl or C6-C10 cycloaliphatic group; and

iii) WRW5represents OH, NH2NH(C1-C6 alkyl) or N(C1-C6 alkyl).

In one embodiment, X-RXis in position 6 hinolinovogo ring. In some embodiments of the incarnation, X-RXtaken together, represent a C1-C6 alkyl, -O-(C1-C6 alkyl) or halogen.

In one embodiment, X-RXis in position 5 hinolinovogo ring. In some embodiments of the incarnation, X-RXtaken together, represent-OH.

In another embodiment, the present invention provides compounds of the formulaVA-1where WRW4and WRW5taken together, form a 5-7-membered ring containing 0-3 heteroatom selected from N, O or S, where the specified ring optionally has up to three WRWdeputies.

In some embodiments of the incarnation, WRW4and WRW5taken together, form an optionally substituted�th 5-7-membered saturated, unsaturated or aromatic ring containing 0 heteroatoms. In other embodiments of the incarnation, WRW4and WRW5taken together, form an optionally substituted 5-7-membered ring containing 1-3 heteroatom selected from N, O or S. In certain other embodiments of the incarnation, WRW4and WRW5taken together, form a optionally substituted saturated, unsaturated or aromatic 5-7-membered ring containing 1 nitrogen heteroatom. In some other embodiments of the incarnation, WRW4and WRW5taken together, form an optionally substituted 5-7-membered ring containing 1 heteroatom of oxygen.

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

where:

Y represents CH2, C(O)O, C(O) or S(O)2;

m has a value of 0-4; and

X, RX, W, and RWhave the values defined above.

In one embodiment, the compounds of the formulaVA-2have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, Y represents C(O). In another embodiment, Y is C(O)Or O. Y represents S(O)2. Or Y represents CH2.

� one embodiment, m has a value of 1 or 2. Or m has a value of 1. Or m has the value 0.

In one embodiment, W is a bond.

In another embodiment, RWrepresents a C1-C6 aliphatic group, halogen, CF3or phenyl, optionally substituted C1-C6, the alkyl, halogen, cyano or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl optionally substituted by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the above R' is a C1-C4 alkyl.

Examples of embodiments WRWinclude methyl, ethyl, propyl, tert-butyl or 2-ethoxyphenyl.

In another embodiment, RWin the Y-RWrepresents a C1-C6 aliphatic group, optionally substituted with N(R')2where R” represents hydrogen, C1-C6 alkyl, or two R” taken together form a 5-7-membered heterocyclic ring containing up to 2 additional heteroatoms selected from O, S, or NR'. Examples of such heterocyclic rings include pyrrolidinyl, piperidyl, morpholinyl or thiomorpholine.

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

where:

Q represents W;

RQis an RW;

m has a value of 0-4;

n has a value of 0-4; and

X, RX, W, and RWhave the values defined above.

In one embodiment, the compounds of the formulaVA-3have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, n has a value of 0-2.

In another embodiment, m has the value 0-2. In one embodiment, m is 0. In one embodiment, m is set to 1. Or m has a value of 2.

In one embodiment, QRQtaken together, represent halogen, CF3, OCF3, CN, C1-C6 aliphatic group, O-C1-C6 aliphatic group, O-phenyl, NH(C1-C6 aliphatic group), or N(C1-C6 aliphatic group)2where specified, an aliphatic group, and phenyl optionally have up to three substituents selected from C1-C6 alkyl, O-C1-C6 alkyl, halogen, cyano, OH or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl optionally substituted 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 above R' is a C1-C4 alkyl.

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

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

where X, RXand RWhave the values defined above.

In one embodiment, the compounds of the formulaVA-4have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, RWrepresents a C1-C12 aliphatic group, C5-C10 cycloaliphatic group or a C5-C7 heterocyclic ring, where the specified aliphatic group, cycloaliphatic group or a heterocyclic ring optionally has up to three substituents selected from C1-C6 alkyl, halogen, cyano, oxo, OH or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl optionally substituted by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, the above R' is a C1-C4 alkyl.

Examples RWinclude methyl, ethyl, n-propyl, isopr�saws 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 represents a C1-C4 alkyl, methoxyethyl or tetrahydrofuranyl.

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

where:

m has a value of 0-4; and

X, RX, W, RWand R' have the values defined above.

In one embodiment, the compounds of the formulaVA-5have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, m has the value 0-2. Or m has a value of 1. Or m has a value of 2.

In another embodiment, both R' are hydrogen. Or one R' represents hydrogen and the other R' is a C1-C4 alkyl, e.g. methyl. Or both R' are C1-C4 alkyl, e.g. methyl.

In another embodiment, m is 1 or 2, and RWrepresents halogen, CF3, CN, C1-C6 aliphatic group, O-C1-C6 aliphatic group or phenyl, where the specified aliphatic group and a phenyl optionally have up to three substituents selected from C1-C6 alkyl, O-C1-C6 alkyl, Gal�gene cyano, OH or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl optionally substituted by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. In another embodiment, R' above is a C1-C4 alkyl.

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

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

where:

ring B is a 5-7-membered monocyclic or bicyclic, heterocyclic or heteroaryl ring which optionally has up to n present Vice-Q-RQwhere n has a value of 0-4, and Q and RQhave the meaning defined above; and

Q, RQ, X, RX, W, and RWhave the values defined above.

In one embodiment, the compounds of the formulaVA-6have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, m has the value 0-2. Or m has the value 0. Or m has the value 1.

In one�m embodiment, n has a value of 0-2. Or n is 0. Or n has a value of 1.

In another embodiment, ring B is a 5-7-membered monocyclic, heterocyclic ring containing up to 2 heteroatoms selected from O, S or N, which optionally has up to n present Vice-Q-RQ. Examples of heterocyclic rings include N-morpholinyl, N-piperidinyl, 4-benzoyl-piperazine-1-yl, pyrrolidin-1-yl or 4-methyl-piperidine-1-yl.

In another embodiment, ring B represents a 5-6 membered monocyclic, heteroaryl ring containing up to 2 heteroatoms selected from O, S or N, which optionally has up to n present Vice-Q-RQ. Examples of such rings include benzimidazol-2-yl, 5-methyl-furan-2-yl, 2,5-dimethyl-pyrrol-1-yl, pyridin-4-yl, indol-5-yl, indol-2-yl, 2,4-dimethoxy-pyrimidine-5-yl, furan-2-yl, furan-3-yl, 2-acyl-Tien-2-yl, benzothiophen-2-yl, 4-methyl-Thien-2-yl, 5-cyano-Thien-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl.

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

where:

one of Q1and Q3represents N(WRW) and the other of Q1and Q3selected from O, S or N(WRW);

Q2represents C(O) CH2-C(O), C(O)-CH2, CH2, CH2-CH2, CF or CF2-CF2;

m has a value of 0-3; and

X, W, RXand RWhave the values defined above.

In one embodiment, the compounds of the formulaV-B-1have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, Q3represents N(WRW); examples WRWinclude hydrogen, C1-C6 aliphatic group, C(O)C1-C6 aliphatic group or C(O)OC1-C6 aliphatic group.

In another embodiment, Q3represents N(WRW), Q2represents C(O) CH2, CH2-CH2and Q1represents O.

In another embodiment, the present invention provides compounds of the formulaV-B-2:

where:

RW1represents hydrogen or C1-C6 aliphatic group;

each of RW3represents hydrogen or C1-C6 aliphatic group; or

both RW3taken together, form a C3-C6 cycloalkyl or heterocyclic ring containing up to two heteroatoms selected from O, S or NR', where the specified ring optionally has up to two WRWdeputies;

m has a value of 0-4; and

X, RX, W, and RWhave the values defined above.

p> In one embodiment, the compounds of the formulaV-B-2have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, WRW1represents hydrogen, C1-C6 aliphatic group, C(O)C1-C6 aliphatic group or C(O)OC1-C6 aliphatic group.

In another embodiment, each RW3represents hydrogen, C1-C4 alkyl. Or both of RW3taken together form a C3-C6 cycloaliphatic ring or 5-7-membered heterocyclic ring containing up to two heteroatoms selected from O, S or N, where the specified cycloaliphatic or heterocyclic ring optionally has up to three substituents selected from WRW1. Examples of such rings include cyclopropyl, cyclopentyl, optionally substituted piperidyl, etc.

In another embodiment, the present invention provides compounds of the formulaV-B-3:

where:

Q4represents a bond, C(O), C(O)O or S(O)2;

RW1represents hydrogen or C1-C6 aliphatic group;

m has a value of 0-4; and

X, W, RWand RXhave the values defined above.

In one embodiment, the compounds of the formulaV-B-3have y amount�present in the substituents X, R Xwhere y has a value of 0-4. In one embodiment, y is set to 0.

In one embodiment, Q4represents C(O). Or Q4represents C(O)O. In another embodiment, RW1represents a C1-C6 alkyl. Examples RW1include methyl, ethyl or tert-butyl.

In another embodiment, the present invention provides compounds of the formulaV-B-4:

where:

m has a value of 0-4; and

X, RX, W, and RWhave the values defined above.

In one embodiment, the compounds of the formulaV-B-4have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, m has the value 0-2. Or m has the value 0. Or m has the value 1.

In another embodiment, the specified cycloaliphatic ring represents a 5-membered ring. Or the specified ring is a six-membered ring.

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

where:

ring A2represents a phenyl or 5-6-membered heteroaryl ring, where ring A2and phenyl ring, which are Conde�lirovannye, together contain up to 4 substituents independently selected from WRW;

m has a value of 0-4; and

X, W, RWand RXhave the values defined above.

In one embodiment, the compounds of the formulaV-B-5have y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, ring A2represents an optionally substituted 5-membered ring selected from pyrrolyl, furanyl, teinila, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl or triazolyl.

In one embodiment, ring A2represents an optionally substituted 5-membered ring selected from pyrrolyl, pyrazolyl, thiadiazolyl, imidazolyl, oxazolyl or triazolyl. Examples of such rings include:

where the specified ring is optionally substituted as described above.

In another embodiment, ring A2represents an optionally substituted 6-membered ring. Examples of such rings include pyridyl, pyrazinyl or triazinyl. In another embodiment, the ring is neobezatelna pyridyl.

In one embodiment, ring A2ameri� a phenyl.

In another embodiment, ring A2is pyrrolyl, pyrazolyl, pyridyl or thiadiazolyl.

Examples of W in the formulaV-B-5include a bond, C(O), C(O)O or C1-C6 alkylene.

Examples RWin the formulaV-B-5include cyano, halogen, C1-C6 aliphatic group, C3-C6 cycloaliphatic group, an aryl, a 5-7-membered heterocyclic ring containing up to two heteroatoms selected from O, S or N, where the specified aliphatic group, phenyl and heterocyclic group is independently and optionally have up to three substituents selected from C1-C6 alkyl, O-C1-C6 alkyl, halogen, cyano, OH or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl 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 above R' is a C1-C4 alkyl.

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

where:

G4represents hydrogen, halogen, CN, CF3, CHF2, CH2F, optionally substituted C1-C6 aliphatic group, aryl-C1-C6 alkyl or phenyl, where G4optionally has up to 4 substituents WRW; where up to two methylene units in the decree�Noah C1-C6 aliphatic group or C1-C6, the alkyl optionally replaced by-CO-, -CONR'-, -CO2-, -OCO-, -NR'CO2-, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO2or NR'SO2NR'-. ;

G5represents hydrogen or optionally substituted C1-C6 aliphatic group;

where the specified indole ring system optionally has up to 3 additional substituents independently selected from WRW.

In one embodiment, the compounds of the formulaV-B-5-ahave y number of present deputies X-RXwhere y has a value of 0-4. In one embodiment, y has a value of 0. Or y has a value of 1. Or y has a value of 2.

In one embodiment, G4represents hydrogen. Or G5represents hydrogen.

In another embodiment, G4represents hydrogen, and G5represents a C1-C6 aliphatic group, where the specified aliphatic group optionally substituted with C1-C6, the alkyl, halogen, cyano or CF3and where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl 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 above R' is a C1-C4 alkyl.

In another embodiment, G4represents hydrogen, and G5is�Oh, cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyanomethyl, methoxyethyl, CH2C(O)OMe, (CH2)2-NHC(O)O-tert-butyl or cyclopentyl.

In another embodiment, G5represents hydrogen, and G4represents halogen, C1-C6 aliphatic group or phenyl, where the specified aliphatic group or phenyl optionally substituted with C1-C6, the alkyl, halogen, cyano or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl 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 above R' is a C1-C4 alkyl.

In another embodiment, G5represents hydrogen, and G4represents halogen, CF3ethoxycarbonyl, tert-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, (4-C(O)NH(CH2)2-NMe2)-phenyl, 2-methoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminoethyl, ethyl, tert-butyl or piperidine-1-ylcarbonyl.

In another embodiment, G4and G5both represent hydrogen, and ring a nitrogen atom in the specified indole ring substituted C1-C6 aliphatic group, C(O)(C1-C6 aliphatic group) or benzyl, where the specified aliphatic group �whether benzyl optionally substituted C1-C6, the alkyl, halogen, cyano or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl 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 above R' is a C1-C4 alkyl.

In another embodiment, G4and G5Oba represent hydrogen, and ring a nitrogen atom in the specified indole ring is substituted with acyl, benzyl, C(O)CH2N(Me)C(O)CH2NHMe or ethoxycarbonyl.

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

or their pharmaceutically acceptable salts,

where R1, R2, R3, R4, R5, R6, R7and Ar1have the meanings given above for compounds of the formulaI'.

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

Representative compounds of the present invention are presented in Table 1 in the graphic part.

In another embodiment, the present invention provides compounds useful�e as intermediates in the synthesis of compounds of formula I. In one embodiment, such compounds have the formulaA-I:

or a salt of such a compound;

where:

G1represents hydrogen, R', C(O)R', C(S)R', S(O)R', S(O)2R', Si(CH3)2R', P(O)(OR')3P(S)(OR')3or B(OR')2;

G2represents halogen, CN, CF3, isopropyl or phenyl, where the specified isopropyl or phenyl optionally has up to 3 substituents independently selected from WRWwhere W and RWhave the meanings given above for formula I and its embodiments;

G3represents an isopropyl or a C3-C10 cycloaliphatic ring, where the specified G3optionally has up to 3 substituents independently selected from WRWwhere W and RWhave the meanings given above for formula I and its embodiments;

provided that when G1represents methoxy, G3represents a tert-butyl group, then G2cannot be 2-amino-4-methoxy-5-tert-butyl-phenyl.

In one embodiment, the present invention provides compounds of formula A-I, provided that when G2and G3each represents a tert-butyl group, then G1cannot be hydrogen.

In another embodiment:

G1represents hydrogen;

2represents a halogen or isopropyl, where the specified isopropyl optionally has up to 3 substituents independently selected from R'; and

G3represents an isopropyl or a C3-C10 cycloaliphatic ring, where the specified G3optionally has up to 3 substituents independently selected from R'.

In another embodiment:

G1represents hydrogen;

G2represents a halogen, preferably fluorine; and

G3represents a C3-C10 cycloaliphatic ring, where the specified G3optionally has up to 3 substituents independently selected from methyl, ethyl, propyl or butyl.

In another embodiment:

G1represents hydrogen;

G2represents CN, halogen or CF3; and

G3represents an isopropyl or a C3-C10 cycloaliphatic ring, where the specified G3optionally has up to 3 substituents independently selected from R'.

In another embodiment:

G1represents hydrogen;

G2represents phenyl which optionally has up to 3 substituents independently selected from-OC1-C4 alkyl, CF3, halogen or CN; and

G3represents an isopropyl or a C3-C10 cycloaliphatic ring, where the specified G3neobyazatelnoe up to 3 substituents, independently selected from R'.

Examples G3include optionally substituted cyclopentyl, cyclohexyl, cycloheptyl or adamantyl. Or G3 is a C3-C8 branched aliphatic chain. Examples of G3 include isopropyl, tert-butyl, 3,3-diethyl-prop-3-yl or 3,3-diethyl-2,2-dimethyl-prop-3-yl.

In another embodiment:

G1represents hydrogen;

G2represents tert-butyl; and

G3represents a tert-butyl group.

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

or its salt, where:

G4represents hydrogen, halogen, CN, CF3, CHF2, CH2F, optionally substituted C1-C6 aliphatic group, aralkyl or a phenyl ring optionally has up to 4 substituents WRW;

G5represents hydrogen or optionally substituted C1-C6 aliphatic group;

provided that both, G4and G5, cannot simultaneously represent hydrogen;

where the specified indole ring system, moreover, is not necessarily up to 3 additional substituents independently selected from WRW.

In one embodiment, G4represents hydrogen. Or G5represents hydrogen.

In other� embodiment, G4represents hydrogen, and G5represents a C1-C6 aliphatic group, where the specified aliphatic group optionally substituted with C1-C6, the alkyl, halogen, cyano or CF3and where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl 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 above R' is a C1-C4 alkyl.

In another embodiment, G4represents hydrogen, and G5represents cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyanomethyl, methoxyethyl, CH2C(O)OMe, (CH2)2-NHC(O)O-tert-But, or cyclopentyl.

In another embodiment, G5represents hydrogen, and G4represents halogen, C1-C6 aliphatic group or phenyl, where the specified aliphatic group or phenyl optionally substituted with C1-C6, the alkyl, halogen, cyano or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl 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 above R' is a C1-C4 alkyl.

In other� embodiment, G5represents hydrogen, and G4represents a halogen, ethoxycarbonyl, tert-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C(O)NH(CH2)2-NMe2, 2-methoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminoethyl, ethyl, tert-butyl or piperidine-1-ylcarbonyl.

In related embodiments embodiment of formula A-II, the ring nitrogen atom in the specified indole ring substituted C1-C6 aliphatic group, C(O)(C1-C6 aliphatic group) or benzyl, where the specified aliphatic group, or benzyl optionally someseni C1-C6, the alkyl, halogen, cyano or CF3where up to two methylene units in said C1-C6 aliphatic group or C1-C6, the alkyl 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 above R' is a C1-C4 alkyl.

In another embodiment, the ring nitrogen atom in the specified indole ring is substituted with acyl, benzyl, C(O)CH2N(Me)C(O)CH2NHMe or ethoxycarbonyl.

4. General scheme of synthesis

Compounds of the present invention are easily prepared by methods known in the art. Below are illustrated examples of methods for obtaining compounds of the present invention.

Predstavlenna below diagram Il�ustrinum synthesis of acid precursors of the compounds of 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, 130ºC; (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) H2, Raney-Ni

Synthesis of amine precursorP-IV-A:

a) HNO3, Or; b) Na2S2O4, THF/H2O; c) H2, Pd/C.

Synthesis of amine precursorP-V-A-1:

a) KNO3, H2SO4; (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) R2OH, 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; d) HCl

Synthesis of amine precursorP-V-A-1:

(a) HNO3, H2SO4; b) [H]; c) protection; d) R CHO; e) removal of protection; f) [H]; g) Na2S, S, H2O; h) nitration; i) (BOC)2O; j) [H]; k) RX; (l) [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:

(i) NaNO2, HCl; (ii) Na2SO3, CuSO4, HCl; (b) NH4Cl; c) [H]

Synthesis Aminovich predecessorsP-V-A-1:

(a) CHCl2OMe; b) KNO3, H2SO4; (c) Deoxo-Fluoro; (d) Fe

Synthesis Aminovich predecessorsP-V-A-3:

Ar = Aryl or Heteroaryl

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

Synthesis Aminovich predecessorsP-V-B-1:

(a) AcCl; b) DEAD; c) AlCl3; (d) NaOH

Synthesis and�inovah predecessors P-V-B-1:

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

PG=protective group

Synthesis Aminovich predecessorsP-V-B-1:

a) HSCH2CO2H; b) [H]

Synthesis Aminovich predecessorsP-V-B-2:

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

PG=protective group

Synthesis Aminovich predecessorsP-V-B-3:

A) Nitration; b) Protection; c) [H]

PG=protective group

Synthesis Aminovich predecessorsP-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 SnCl2.2H2O, EtOH or SnCl2.2H2Oh, DIEA, EtOH.

Synthesis Aminovich predecessorsP-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, SnCl2.2H2O, H2O; g) MeCOR, EtOH; (h) PPA; (i) LiAlH4, THF or H2, Raney Ni, EtOH or MeOH

Synthesis Aminovich predecessorsV-B-5:

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

Synthesis Aminovich preds�relatives P-V-B-5:

(a) NaNO2, HCl, SnCl2.2H2O, H2O; (b) RCH2COH, AcOH, EtOH; (c) H3PO4, toluene; (d) H2, Pd-C, EtOH

Synthesis Aminovich predecessorsP-V-B-5:

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

Synthesis Aminovich predecessorsP-V-B-5:

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

Synthesis Aminovich predecessorsP-V-B-5:

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

Synthesis Aminovich predecessorsP-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-Ni, MeOH

Synthesis Aminovich predecessorsP-V-A-3andP-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 Aminovich predecessorsP-V-A-4:

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

Synthesis Aminovich predecessorsP-V-A-4:

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

Synthesis Aminovich predecessorsP-V-B-4:

H2, Pd-C, MeOH

Synthesis Aminovich predecessorsP-V-B-4:

(a) NaBH4, MeOH; (b) H2, Pd-C, MeOH; (c) NH2OH, Pyridine; (d) H2, Pd-C, MeOH; e) Boc2O, Et3N, MeOH

The synthesis of compounds of the formula I:

(a) Ar1R7NH linking reagent, base, solvent. Examples of conditions used:

HATU, DIEA; BOP, DIEA, DMF; HBTU, Et3N, CH2Cl2; PFPTFA, pyridine.

The synthesis of compounds of formula I':

R5= aliphatic group:

(a) R5X (X= Br, I), Cs2CO3, DMF

The synthesis of compounds of the formulaV-B-5:

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

The synthesis of compounds of the formulaV-B-5:

WRw= aryl or heteroaryl: (a) ArB(OH)2, (dppf)PdCl2/sub> , K2CO3, DMF

The synthesis of compounds of the formulaV-A-2andV-A-5:

(a) SnCl2.2H2O, EtOH; (b) PG= BOC: TFA, 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: TFA, CH2Cl2; When PG = Ac: NaOH or HCl, EtOH or THF

The synthesis of compounds of the formulaV-A-2:

a) When PG = BOC: TFA, CH2Cl2

a) When PG = BOC: TFA, CH2Cl2; (b) ROCOCl, Et3N, DMF

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

a) When PG = BOC: TFA, CH2Cl2; (b) When Rw= CO2R: ROCOCl, DIEA, MeOH

In the above schemes, the radical R represents a Deputy, for example, RWshall have the meaning given above. Specialists in this field should be clear that the path of synthesis, suitable for different substituents of the present invention are such that ispolzuemye reaction conditions and the stage is not modified prospective deputies.

5. Of application, formulation and introduction

Pharmaceutically acceptable compositions

As discussed above,�this invention provides compounds, which are useful as modulators of ABC transporters and thus are useful in treating diseases, disorders or conditions, such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, disturbances of coagulation-fibrinolysis, such as protein C deficiency, hereditary angioedema type 1, lipid processing, such as familial hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia, disease lysosomal accumulation, such as I-cell disease/pseudo-Hurler, Hurler's disease Sandhof/Tay-Sachs syndrome, crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, dwarfism of Larona, lack of teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, deficiency ACT, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Tooth syndrome, a disease Perlizaeus-Merzbacher, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, pick's disease, some polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar mycheck�I atrophy dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary disease of Creutzfeldt-Jakob disease (due to a defect in the processing of prion protein), Fabry disease, syndrome Straussler-Sheinker, COPD, disease, dry eye or Sjogren's syndrome.

Accordingly, in another aspect of the present invention are provided pharmaceutically acceptable compositions, wherein these compositions comprise any of the compounds described in the present application, and optionally include pharmaceutically acceptable carrier, adjuvant or excipient. In some embodiments, embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

Should also be understood that certain compounds of the present invention can exist in free form for treatment, or, if appropriate, in the form of a 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 product or accession derived, which when administered to a patient in need this, are able to provide, directly and�and indirectly, the compound described in this application, or its metabolite or residue.

Used in the present application, the term "pharmaceutically acceptable salt" refers to those salts which are, in accordance with weighted medical evaluation, are suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable ratio of benefit/risk. "Pharmaceutically acceptable salt" means any non-toxic salt or salt of ester compounds of the present invention, which when administered to the recipient is capable of providing, either directly or indirectly, a compound of the present invention or possessing inhibitory activity metabolite or residue of such connection.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated in this application by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid additive salts include salts of an amino group formed with reorganises�their acids, such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid and Perlina 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 the art 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, lactobionate, 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 metals, ammonium and N+(C1-4alkyl)4. The present invention also envisions the quaternization of any �basic nitrogen-containing groups of the compounds disclosed in the present application. Water - or oil-soluble or dispersible products may be obtained using such quaternization. Representative salts of alkaline or alkaline-earth metals include sodium, lithium, potassium, calcium, magnesium and the like. In addition, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations, Quaternary ammonium and amine formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable carrier, adjuvant or excipient, which, as used in this application includes any and all solvents, diluents, or other liquid carriers, substances that contribute to the dispersion or suspendirovanie, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, as is appropriate for a particular dosage form, which is desirable. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical�and acceptable compositions and known methods for their preparation. Except only in those cases where any traditional environment, Politeama as a carrier, is incompatible with the compounds of the present invention, for example, causing any undesirable biological effect or otherwise interact adverse manner with any other component(components) pharmaceutically acceptable composition, its use is envisaged as covered by the scope of the present 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, secondary sodium acid phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, so�e as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients, such as cocoa butter and waxes for suppositories; oils such as peanut oil, cotton seeds; Safarova oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters, such as ethyloleate and ethyl laurate; agar; buffering 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, as well as dyes, substances that promote the release of shapes, substances, coatings, sweeteners, flavors and fragrances, preservatives and antioxidants can also be present in composite, in accordance with the fact, as deemed necessary by a specialist in the formulation of the composition.

The use of compounds and pharmaceutically acceptable compositions

In another aspect the present invention provides a method of treating or reducing the severity of the condition, disease or disorder associated with CFTR mutation. In some embodiments embodiment, the present invention provides�provides a method of treatment of a condition, disease or disorder associated with a deficiency of the CFTR activity, the method comprises administering a composition comprising a compound of formula 1, to a subject, preferably to a mammal in need of it.

In some embodiments embodiment, the present invention provides a method of treating diseases associated with reduced CFTR function due to mutations in the gene encoding CFTR or environmental factors (e.g., Smoking). These diseases include cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, male infertility caused by congenital bilateral absence of VAS deferens (CBAVD), female infertility caused by congenital absence of the uterus or vagina (CAUV), idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic rhinosinusitis, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eye syndrome, constipation, allergic bronchopulmonary aspergillosis (ABPA), bone diseases (e.g. osteoporosis) and asthma.

In some embodiments embodiment, the present invention provides a method of treating diseases associated with normal CFTR function. These diseases include, chronic obstructive pulmonary disease (COPD), chronic �Rohit, recurrent bronchitis, acute bronchitis, rhinosinusitis, constipation, pancreatitis, including chronic pancreatitis, recurrent pancreatitis, and acute pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of VAS deferens (CBAVD), mild pulmonary form of the disease, idiopathic pancreatitis, liver disease, hereditary emphysema, bile stone disease, gastroesophageal reflux, gastrointestinal tumors, inflammatory bowel disease, constipation, diabetes, arthritis, osteoporosis and osteopenia.

In some embodiments embodiment, the present invention provides a method of treating diseases associated with normal CFTR function, including hereditary hemochromatosis, disturbances of coagulation-fibrinolysis, such as protein C deficiency, hereditary angioedema type 1, lipid processing, such as familial hypercholesterolemia, chylomicronemia type 1, abetalipoproteinemia, disease lysosomal accumulation, such as I-cell disease/pseudo-Hurler, Hurler's disease Sandhof/Tay-Sachs syndrome, crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, diabetes mellitus, dwarfism of Larona, lack of teleoperated, primary hypoparathyroidism, melanoma, glycans CDG type 1, congenital hyperthyroidism, not� "Helion Ukraine" completely osteogenesis, hereditary hypofibrinogenemia, deficiency ACT, diabetes insipidus (DI), neurophysiology DI, nephrogenic DI syndrome Charcot-Marie-Tooth syndrome, a disease Perlizaeus-Merzbacher, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, pick's disease, some polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary disease of Creutzfeldt-Jakob disease (due to a defect in the processing of prion protein)Fabry disease, syndrome Straussler-Sheinker, Gorham's syndrome, chloride channelopathies, congenital myotonia (form Thomson and Becker), a syndrome of Barter type III, dent disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal disease accumulation, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with situs situs inversus (also known as syndrome Kartagener), PCD without situs situs inversus and ciliary aplasia, or Sjogren's syndrome, comprising the stage of introduction of the specified mammal an effective amount of a composition, comprising a compound of the present invention.

In accordance with an alternative preferred embodiment, the present�the present invention provides a method of treating cystic fibrosis, including the stage of introduction of the specified mammal an effective amount of a composition, comprising a compound of the present invention.

In accordance with the present invention, “effective amount” of a compound or pharmaceutically acceptable composition is that amount which is effective for treating or reducing the severity of one or more of the diseases, disorders or conditions mentioned above.

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 for treating or reducing the severity of one or more of the diseases, disorders or conditions mentioned above.

In some embodiments embodiment, the compounds and compositions of the present invention are useful for treating or reducing the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and nerespectarea epithelium. The presence of residual CFTR activity on the surface of the epithelium can be easily determined using methods known in the art, for example, standard electrophysiological, biochemical or histochemical methods. Such methods identify CFTR actively�you using in vivo or ex vivo electrophysiological techniques, measurements of Cl-concentrations in secretions sweaty or salivary glands or by using ex vivo biochemical or histochemical techniques to monitor the density on the cell surface. Using these ways you can easily identify residual CFTR activity in patients homozygous or heterozygous for the most common mutation, ΔF508.

In another embodiment, the compounds and compositions of the present invention are useful for treating or reducing the severity of cystic fibrosis in patients who have residual CFTR activity induced or amplified using pharmacological methods or gene therapy. Such methods increase the amount of CFTR present at the cell surface, inducing thus missing before that CFTR activity in a patient or increasing the existing level of residual CFTR activity in a patient.

In one embodiment, the compounds and compositions of the present invention are useful for treating or reducing the severity of cystic fibrosis in patients within certain genotypes, demonstrating residual CFTR activity, e.g., class III mutations (impaired regulation or Gating mechanism), mutation class IV (change of conductance), or class V mutations (reduced synthesis) (Lee R. Coo-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 mutations that have not been classified.

In one embodiment, the compounds and compositions of the present invention are useful for treating or reducing the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., from 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, demonstrating the insufficiency of the pancreas, or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the VAS deferens, or mild lung disease.

The exact number needed will be different for different subjects, depending on the species, age and General condition of the subject, the severity of the infection, specific means, method of administration, etc. of the Compounds of the present invention preferably �formuliruut in dosage form, contains standard dosing units, for ease of insertion and uniform dosing. The expression "standard unit dosing", as used in this application, refers to a physically discrete unit of a product suitable for the patient to be treated. However, it should be clear that the total daily intake of the compounds and compositions of the present invention determined by the attending physician in accordance with a careful medical evaluation. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder to be treated, and the severity of the disorder; activity of the specific compounds used; the specific composition used; 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 accidentally used with specific connection, and similar factors well known in medicine. The term "patient", as used in this application, means an animal, preferably a mammal, and most preferably human.

Pharmaceutically acceptable compositions according to the present invent�Oia you can enter humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, locally (e.g., powders, ointments, drops or a patch), buccal, in the form of oral or nasal spray or etc., depending on the severity of the infection to be treated. In some embodiments embodiment, the compounds of the present invention can be administered orally or parenterally at dosages from about 0.01 mg/kg to about 50 mg/kg, and preferably from about 1 mg/kg to about 25 mg/kg of body weight of the subject per day, once or several times a day, to produce the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents conventionally used in this field, such as, for example, water or other solvents, solubilizers substances and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, oil of cotton seeds, peanut oil, corn oil, sprouts, seeds, olive oil, Castoro�e oil and sesame oil) glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifiers and suspendresume substances, sweeteners, flavors and fragrances.

Preparations for injection, for example, sterile aqueous or oily suspension for injection can be formulated according to known from the prior art methods using suitable dispersing or wetting agents and suspendida substances. A sterile preparation for injection may also be a sterile solution, suspension or emulsion for injection in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Acceptable fillers and solvents that can be used, you can specify water, ringer's solution U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are traditionally used as the solvent or medium for suspending. For these purposes you can use any light non-volatile oil, including synthetic mono - or diglycerides. In addition, in preparations for injection using fatty acids such as oleic acid.

Song DL� injections 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.

To prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be done using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the connection in this case depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral injectable form of the compound is produced by dissolving or suspending the compounds in the oil filler. The depot form for injection is produced by the formation of matrices for microencapsulation of compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound and the polymer and the nature of the particular polymer used, it is possible to control the rate of release of connection. Examples of other biodegradable polymers include poly(orthoevra) and poly(anhydrides). Footage only�AI depot injection preparations also produced by the conclusion of the compounds in liposomes or microemulsions, which are compatible with body tissues.

Compositions for rectal or vaginal injection are preferably suppositories are, which can be obtained by mixing the compounds of the present invention with suitable non-irritating by excipients or carriers such as cocoa butter, polyethylene glycol or wax for suppositories, which are solid at ambient temperature, but are 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 secondary acidic calcium phosphate and/or a) fillers or bulk agents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, (c) humectants, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapiokovogo starch, alginic acid, certain�e silicates and sodium carbonate, e) slow dissolving substances such as paraffin, f) absorption accelerators such as Quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerylmonostearate, 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 of such substances. In the case of capsules, tablets and pills dosage form may also include buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules, using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be obtained with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation. They do not necessarily contain opaque agents, and can also have a composition which makes possible the release of the active ingredient(ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally delayed about�way. Examples of compositions encapsulating substances which can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers, prisoners in soft and hard 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 such as tablets, dragees, capsules, pills and granules can be obtained with coatings and shells such as enteric coatings that control the release coatings and other coatings well known in the pharmaceutical formulation. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also include, as is the case in normal practice, additional substances than inert diluents, for example lubricants for tableting and other excipients for tableting, such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills such dosage forms can also include buffering agents. They do not necessarily contain opaque agents, and can also have a composition which makes possible the release of the active ingredient(ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally delayed manner. Examples of compositions encapsulating substances which can be used include polymeric substances and waxes.

Dosage forms for administration of the compounds of the present invention, local or percutaneous means include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalations or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers that may be required for this. Eye medications, ear drops and eye drops are also provided as covered by the scope of the present invention. In addition, the present invention provides for the use of transdermal patches, which have the added advantage of providing controlled delivery of compounds into the body. Such dosage forms are obtained by dissolving or dispersing the compound in a suitable environment. You can also use the booster used to increase the penetration soedinenii the skin. Speed can be controlled either by software controlling the speed of the membrane or by dispersing the compound in a polymer matrix or gel.

As described in the General form above, the compounds of the present invention are useful as modulators of ABC transporters. Thus, without wishing to be bound to any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of the disease, condition or disorder where the disease, condition or disorder associated with hyperactivity or inactivity of ABC transporters. When a specific disease, condition or disorder associated with hyperactivity or inactivity of ABC Transporter, such disease, condition or disorder may also be indicated as “ABC Transporter-mediated disease, condition or disorder”. Accordingly, in another aspect the present invention provides a method of treating or reducing the severity of the disease, condition or disorder, in a state where such diseases are involved hyperactivity or inactivity of ABC Transporter.

Analysis of the activity of the compound used in the present invention as modulators of ABC Transporter can be carried out in accordance with FPIC�the means in General described in the prior art and in the Examples presented in this application.

Also it should be clear that the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e. the compounds and pharmaceutically acceptable compositions can be administered simultaneously with the introduction, before or after administration of one or more other desired therapeutics or medical procedures. Specific combination therapies (therapeutic agent or procedure) for use in a combination treatment regimen must take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved in order. Also it should be clear that therapies used can achieve the desired effect for the same disorder (for example, the compound of the present invention can be administered simultaneously with another agent used to treat the same disorder), or they may be designed to achieve different effects (e.g., control of any adverse effects). As used in this application, additional therapeutic agents that are normally administered to treat or prevent a specific disease or condition�, known as "appropriate for the disease or condition being treated".

In one embodiment, the additional agent is selected from mucolytics, bronchodilators, antibiotics, anti-infective tools, protivovospalitelnoe funds, CFTR modulator, different from the compounds of the present invention, or nutrients. In another embodiment, the additional agent is a CFTR modulator, different from the compounds of the present invention.

In one embodiment, the additional agent is an antibiotic. Examples of antibiotics useful in the present invention include tobramycin, including tobramycin powder for inhalation (TIP), azithromycin, aztreonam, including aerosolized form of aztreonam, amikacin, including liposomal composition, ciprofloxacin, including its composition, suitable for administration by inhalation, levofloxacin, including aerosol compositions, and combinations of two antibiotics, for example fosfomycin and tobramycin.

In another embodiment, the additional agent is a mucolytic agent. Examples of mucolytic agents, useful in the present invention include Pulmozyme®.

In another embodiment, an additional tool is�Oh bronchodilator. An example of bronchodilators include albuterol, metaproterenol sulfate, pirbuterol acetate, salmeterol or tetralin sulfate.

In another embodiment, an additional means is effective to restore the surface of the liquid in the Airways in the lungs. Such tools improve the movement of salts into the cells and out of cells, making the mucus in the Airways in the lungs more hydrated, so they are more easily removed. Examples of such funds include hypertonic saline, denufosol tetranitro ([[(3S,5R)-5-(4-amino-2-oxopyrimidine-1-yl)-3-hydroxyanisole-2-yl]methoxy-hydroxyphosphonic][[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidine-1-yl)-3,4-dihydroquinoxaline-2-yl]methoxy-hydroxyphosphonic]oxy hydroxyphosphonic]hydrogen phosphate) or bronchitol (a drug for inhalation using mannitol).

In another embodiment, the additional agent is protivovospalitelnoe tool, i.e. a tool that can reduce inflammation in the lungs. Examples of such tools that are useful in the present invention include ibuprofen, docosahexaenoyl acid (DHA), sildenafil, glutathione for inhalation, pioglitazone, hydroxychloroquine or simvastatin.

In another embodiment, the additional agent reduces the activity of the blocker of epithelial sodium channels (ENaC) or direct�dstone by blocking the channel or indirectly by modulation of the protease, resulting in increased ENaC activity (e.g., serine proteases, channel-activating protease). Examples of such funds include chemostat (inhibitor of trypsin-like proteases), QAU145, 552-02, GS-9411, INO-4995, Aerolytic and amiloride. Additional tools that reduce the activity of the blocker of epithelial sodium channels (ENaC) can be found, e.g., in PCT Publication No. WO2009/074575, the full contents of which are incorporated in this application in its entirety.

Amongst other diseases described in the present application, combinations of CFTR modulators, such as compounds of formula I, and tools that reduce the activity of ENaC are useful for the treatment of syndrome Liddle, inflammatory or allergic condition including cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, respiratory tract infections (acute and chronic; viral and bacterial) and lung carcinoma.

Combinations of CFTR modulators, such as compounds of formula I, and agents that reduce the activity of ENaC are also useful for treating diseases mediated by blockade of the epithelial sodium channel also include diseases, from�ary from respiratory diseases, associated with abnormal regulation of fluid through the epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye syndrome). In addition, blockade of the epithelial sodium channel in the kidney can be used to maintain diuresis inducing, thus, the hypotensive effect.

Asthma includes both hereditary (non-allergic) asthma and acquired (allergic) asthma, mild asthma, moderate form of asthma, severity of asthma, bronchitol asthma, exercise induced asthma, occupational asthma and asthma resulting from bacterial infection. Asthma treatment should also be considered as a treatment of subjects, e.g. of less than 4 or 5 years old who have symptoms of shortness of breath and diagnosed or may be diagnosed, "young children, suffering from shortness of breath ", which represent a category of patients, causing serious health concern, and which is often defined as incipient or asthmatics in the early phase. (For convenience this particular asthmatic condition is specified as a "syndrome of children with shortness of breath"). Evidence of prophylactic efficacy in the treatment of asthma can be reduced in frequency or �ajesty symptomatic seizures, for example, acute asthma or bronchoconstrictor attack, improvement in lung function or improvement of airway hyperresponsiveness. In addition, this can be confirmed by reducing the need for other symptomatic treatment, i.e. the treatment of symptomatic attack when it occurs, or which is intended to limit or prevent such attack, for example, with the use of anti-inflammatory agents (e.g., corticosteroids or bronchodilators. Prophylactic use in asthma, in particular, can be apparent in subjects prone to "morning attack". "Morning attack" is a recognized asthmatic syndrome, which is characteristic for a substantial percentage of asthmatics and characterized by asthma attack, e.g., between 4-6 a.m., i.e., at the time, which is usually quite far removed from any previous admission symptomchecker the treatment of asthma.

Chronic obstructive pulmonary disease includes chronic bronchitis or associated shortness of breath, emphysema, and increased airway hyperresponsiveness as a result of taking the other medicine, in particular, to another drug product for inhalation. In some embodiments, embodiments, combinations of CFTR modulators, t�such as a compound of formula I, and funds that reduce the activity of ENaC are useful for the treatment of bronchitis of any type or Genesis, including, for example, acute, archically, catarrhal, croupous, chronic or phthinoid bronchitis.

In another embodiment, the additional agent is a CFTR modulator, different from that of compound 1, i.e., the agent that has the effect of modulating CFTR activity. Examples of such funds include ataluren (PTC 124®"; 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), sinapultide, lancemate, depeleted (human recombinant inhibitor of neutrophil elastase), cobiprostone (7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-debtor-3-methylpentyl]-2-hydroxy-6-accountpaydayloan[b]PYRAN-5-yl}heptane acid) or(3-(6-(1-(2,2-debtorrent[d][1,3]dioxol-5-yl)cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid. In another embodiment, the additional agent is a(3-(6-(1-(2,2-debtorrent[d][1,3]dioxol-5-yl) cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid.

In another embodiment, the additional agent is a nutrient. Examples of such substances include pancrelipase (Deputy pancreatic enzymes), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. � one embodiment, additional nutrient is pancrelipase.

The amount of additional therapeutic agent present in the compositions according to the present invention, should not exceed the quantity, which is normally possible to introduce in a composition comprising that therapeutic agent as the only active substance. Preferably, the amount of additional therapeutic agent in the compositions disclosed in the present invention should be between about 50% to 100% of the amount normally present in a composition comprising that therapeutic agent as the only active substance.

Compounds of the present invention or containing pharmaceutically acceptable compositions can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above and in classes and subclasses described in the present application, and a carrier suitable for coating of specified implanted device. In another aspect,�this invention includes an implantable device having a coating with a composition comprising a compound of the present invention as described generally above and in classes and subclasses described in the present application, and a carrier suitable for coating of specified implanted device. Suitable coatings and the General description of receipt uncoated implantable devices can be found in U.S. patents Nos. 6099562; 5886026; and 5304121. Coverage typically represent a biocompatible polymer material, such as polymeric hydrogels, polymethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating optionally may be additionally coated with a suitable top layer of Versiliana, polysaccharides, polyethylene glycol, phospholipids or a combination of such substances to give the composition of the controlled release characteristics.

Another aspect of the present invention relates to modelirovaniya activity of the ABC Transporter in a biological sample or a patient (e.g., in vitro or in vivo), wherein the method comprises administering to a patient or contacting the specified biological sample with a compound of formula 1 or a composition comprising the specified connection. The term "biological sample" as used in this application includes, without limitation, cellular cult�ry or their extracts; the biopsy material obtained from a mammal or extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

Modulation of activity of ABC Transporter, i.e. CFTR in a biological sample is useful for a variety of purposes that are known to specialists in this field. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena; and the comparative evaluation of new modulators of ABC transporters.

In the following embodiment, is provided a method of modulating the activity of anion channel in vitro or in vivo, comprising the step of contacting the specified channel with a compound of formula I. In preferred embodiments, embodiments, the anion channel is a chloride channel or a bicarbonate channel. In other preferred embodiments, embodiments, the anion channel is a chloride channel.

In accordance with an alternative embodiment, the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting the specified cell with a compound of formula I. the Term “functional ABC Transporter” as used in this application, means an ABC Transporter, which can�to have transport activity. In preferred embodiments, embodiments, the ABC Transporter is a CFTR.

In accordance with another variant embodiment, the activity of the ABC Transporter is determined by measuring transmembrane potential. Means for measuring the potential across the membrane in a biological sample can include any of the methods known in the art, such as optical analysis of membrane potential or other electrophysiological methods.

Optical analysis of membrane potential involves the use of potential-sensitive FRET sensors described by Gonzalez and Tsien (see, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells." Biophys J 69(4): 1272-80 ; Gonzalez, J. E. and R. Y. Tsien (1997); "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with devices for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (see, Gonzalez, je, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439).

These potential-sensitive analyses based on the change of resonant energy transfer fluorescence (FRET) between the membrane-soluble potential-sensitive dye, DiSBAC2(3) and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaf of the plasma membrane and acts as a FRET donor. Changes of membrane potential (Vmcause of redistrib�tion of the negatively charged DiSBAC 2(3) through the plasma membrane, and the amount of transmitted energy from CC2-DMPE changes accordingly. Changes in fluorescence emission can be monitored using VIPR™ II, which is an integrated device comprising a fluid source and a fluorescence detector, intended for the implementation of cellular screening assays in 96 - or 384-well microtiter plates.

In another aspect the present invention provides a kit for use in measuring the activity of a ABC Transporter or a fragment in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound of formula I or any of the above embodiments; and (ii) instructions for a) contacting the composition with the biological sample and b) measuring the activity of the specified ABC Transporter or a fragment. In one embodiment, the kit further comprises instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of the specified ABC Transporter or a fragment in the presence of said additional compound, 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 composition of formula I. In preferred embodiments, embodiments, the set of IP�result to measure the density of CFTR.

In order to better understand the invention described in this application, the following are examples. It should be clear that these examples are presented for illustrative purposes only and should not be construed as in any way limiting the present invention.

EXAMPLES

Example 1:

The General scheme of obtaining the acid groups:

(a) 140-150ºC; b) PPA, POCl3, 70ºC or diphenyl ether, 220ºC; (c) (i) 2n NaOH (ii) 2n HCl

Special example:diethyl ether 2-phenyliminomethyl-malonic acid

A mixture of aniline (up to 25.6 g, 0.28 mol) and diethyl 2-(ethoxymethylene)malonate (62,4 g, 0.29 mole) was heated at 140-150ºC for 2 hours. The mixture was cooled to room temperature and dried under reduced pressure to obtain the diethyl ester of 2-phenyliminomethyl-malonic acid in the form of a solid which was 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

A 1-l three-neck flask equipped with a mechanical stirrer, was loaded diethyl ether 2-phenyliminomethyl-malonic acid (26.3 g, 0.1 mol), polyphosphoric acid (270 g) and phosphorylchloride (750 g). The mixture was heated to about 70ºC and AC�stirred for 4 hours. The mixture was cooled to room temperature and was filtered. The residue was treated with an aqueous solution of Na2CO3that was filtered, washed with water and dried. Ethyl 4-hydroxyquinoline-3-carboxylic acid was obtained as a pale brown solid (15.2 g, 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) was suspended in sodium hydroxide solution (2n, 150 ml) and stirred for 2 hours at the temperature of reflux. After cooling, the mixture was filtered and the filtrate was acidified with to pH 4 2n HCl solution. The precipitate that formed was collected by filtration, washed with water and dried in vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-1) as a pale white solid (10.5 g, 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).

Special example:A-2; 6-Fluoro-4-hydroxy-quinoline-3-carboxylic acid

6-Fluoro-4-hydroxy-quinoline-3-carboxylic acid (A-2) synthesized in accordance with the General scheme presented above, based on 4-fluoro-phenylamine. Overall yield (53%).1H NMR (DMSO-d6) δ 15,2 (lat.s, 1H), 8,89 (s, 1H), 7,93-a 7.85 (m, 2H), 7,80-,74 (m, 1H); ESI-MS 207,9 m/z (MH+).

Example 2:

2-Bromo-5-methoxy-phenylamine

A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and Raney Ni (5 g) in ethanol (100 ml) was stirred under atmosphere of H2(1 ATM) for 4 hours at room temperature. Ni Raney was filtered and the filtrate was concentrated under reduced pressure. The obtained solid substance was purified column chromatography to obtain 2-bromo-5-methoxy-phenylamine (7.5 g, 86%).

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

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

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

Diethyl ether 2-[(2-bromo-5-methoxy-phenylamino)-methylene]-malonic acid (9 g, 24.2 mmol) was slowly added to polyphosphoric acid (30 g) at 120ºC. The mixture was stirred at this temperature for 30 minutes and then cooled to room temperature. Added absolute ethanol (30 ml) and the resulting mixture was boiled with reverse hol�dildocam for 30 minutes. The mixture was podslushivaet aqueous solution of sodium bicarbonate at 25 ° C and extracted using EtOAc (4×100 ml). The organics were combined, dried and the solvent was evaporated with obtaining the ethyl ester of 8-bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2.3 g, 30%).

Ethyl 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid

A mixture of ethyl ester of 8-bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-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 under atmosphere of H2(2.5 ATM) over night. The catalyst was removed by filtration and the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in CH2Cl2(100 ml) and washed with aqueous sodium bicarbonate solution and water. The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography with obtaining the ethyl ester of 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid as a yellow solid (1 g, 57%).

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

A mixture of ethyl ester 5-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (1 g, 7.1 mmol) in 10% NaOH solution (50 ml) was heated to boiling temperature to reflux overnight and then cooled to room�Noah temperature. The mixture was extracted with simple ether. The aqueous phase was separated and made acidic with concentrated HCl solution to pH 1-2. The precipitate that formed was collected by filtration to obtain 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-4) (530 mg, 52%).1H NMR (DMSO) δ: 15,9 (s, 1H), 13,2 (W, 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 2-(merkapto-phenylamino-methylene)-malonic acid

To a suspension of NaH (60% in mineral oil, 6 g, 0.15 mole) in Et2O at room temperature was added dropwise within 30 minutes of ethylmalonate (24 g, 0.15 mole). Was then added dropwise phenylisothiocyanate (20,3 g, 0.15 mole) with stirring for 30 minutes. The mixture was boiled to reflux for 1 hour and then stirred overnight at room temperature. A solid substance was separated, washed with anhydrous ether (200 ml) and dried in vacuum to give diethyl ether sodium 2-(merkapto-phenylamino-methylene)-malonic acid in the form of a pale yellow powder (46 g, 97%).

Diethyl ether 2-(methylsulfanyl-phenylamino-methylene)-malonic acid

During a 30 minute period, methyliodide (17,7 g, 125 mmol) was added dropwise to a solution of diethyl ether sodium 2-(merkapto-phenylamino-methylene)-malonic keys�located the whereabouts of (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 collected by filtration, washed with water and dried with obtaining diethyl ether 2-(methylsulfanyl-phenylamino-methylene)-malonic acid in the form of a pale yellow solid (27 g, 84%).

Ethyl ester of 4-hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid

A mixture of diethyl ether 2-(methylsulfanyl-phenylamino-methylene)-malonic acid (27 g, 87 mmol) in 1,2-dichlorobenzene (100 ml) was heated to boiling temperature to reflux for 1.5 hours. The solvent was removed under reduced pressure and the oily residue was ground into powder with hexane to obtain a pale yellow solid which was purified preparative HPLC with obtaining the ethyl ester of 4-hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid (8 g, 35%).

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

Ethyl ester of 4-hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid (8 g, 30 mmol) was heated at boiling point with 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 collected by filtration, washed with �ode (100 ml) and MeOH (100 ml) to give 2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-16) as a white solid (6 g, 85%).1H NMR (CDCl3) δ 16,4 (lat.s, 1H), 11.1 V (lat.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~200 ºC; (d) 10% NaOH

2,2,2-Cryptor-N-phenyl-acetimidoyl

A mixture of Ph3P (138,0 g, 526 mmol), Et3N (of 21.3 g, 211 mmol), CCl4(170 ml) and TFA (20 g, 175 mmol) was stirred for 10 minutes in an ice bath. Aniline (19,6 g, 211 mmol) was dissolved in CCl4(20 ml) was added. The mixture was stirred at the temperature of reflux for 3 hours. The solvent was removed under vacuum and hexane was added. Precipitated substances (Ph3PO and Ph3P) was filtered and washed with hexane. The filtrate was distilled under reduced pressure to obtain 2,2,2-Cryptor-N-phenyl-acetamidomalonate (19 g), which was used for next step without further purification.

Diethyl ether 2-(2,2,2-Cryptor-1 phenylimino-ethyl)-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 0ºC. The mixture was stirred for 30 minutes at this temperature and was added 2,2,2-Cryptor-N-phenyl-acetimidoyl (19 g, 92 mmol) at 0ºC. The reaction mixture was allowed to warm to room temperature and n�remedial during the night. The mixture was diluted using CH2Cl2, washed with saturated sodium bicarbonate solution and saturated brine. The combined organic layers were dried over Na2SO4, filtered and concentrated to give diethyl ether 2-(2,2,2-Cryptor-1 phenylimino-ethyl)-malonic acid, which was used directly in next step without further purification.

Ethyl ester of 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid

Diethyl ether 2-(2,2,2-Cryptor-1 phenylimino-ethyl)-malonic acid is heated at 210ºC for 1 hour with constant stirring. The mixture was purified by column chromatography (petroleum ether) to give the ethyl ester of 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid (12 g, 24% for stage 3).

A-15; 4-Hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid

A suspension of ethyl ester of 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid (5 g, 17.5 mmol) in 10% aqueous NaOH solution was heated at reflux for 2 hours. After cooling, was added dichloro methaneand the aqueous phase was separated and made acidic with concentrated HCl to pH 4. The precipitate that formed was collected by filtration, washed with water and Et2O obtaining 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid (A-15) (3.6 g, 80%).1H NMR(DMSO-d 6) 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, 130ºC; (c) Ph2O; d) I2Hcl , EtOH; (e) NaOH

3-Amino-cyclohex-2-Aenon

A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH4(38.5 g, 0.5 mol) in toluene was heated at reflux for 5 hours using a Dean stark trap. The obtained oily layer was separated and concentrated under reduced pressure to obtain 3-amino-cyclohex-2-Aenon (49,9 g, 90%) which was used directly in next step without further purification.

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

A mixture of 3-amino-cyclohex-2-Aenon (3.3 g, 29.7 mmol) and diethyl 2-(ethoxymethylene)malonate (6.7 g, 31.2 mmol) was stirred at 130ºC for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, ethyl acetate) to give diethyl ether 2-[(3-oxo-cyclohex-1 enylamine)-methylene]-malonic acid (7.5 g, 90%).

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

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

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

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

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

A mixture of ethyl ester 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (700 mg, 3 mmol) in 10% NaOH (20 ml) was heated at boiling point with reflux during the night. After cooling, the mixture was extracted with simple ether. The aqueous phase was separated and made acidic with using concentrated HCl to pH 1-2. The precipitate that formed was collected by filtration to obtain 5-hydroxy-4-oxo-1,4-DIH�DRO-quinoline-3-carboxylic acid (A-3) (540 mg, 87%).1H NMR (DMSO-d6) δ 13,7 (W, 1H), 13.5 in (W, 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 POCl3was heated at reflux for 2 hours. After cooling, the solvent was removed under reduced pressure to obtain 2,4-dichloraniline, which was 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 was heated at reflux for 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was dissolved in water and extracted using CH2Cl2. The combined organic layers were dried over Na2SO4and concentrated to give 2,4-dimethoxyaniline in the form of a white solid (13 g, 74% over 2 stages).

Ethyl 2,4-dimethoxyaniline-3-carboxylate

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 in hexane, 48.6 ml, 122 mmol) at 0ºC. After stirring for 1.5 hours at 0ºC, and the mixture was added to �Astaro ethyl chloroformate in anhydrous THF and stirred at 0ºC for 30 minutes and then at room temperature overnight. The reaction mixture was poured into water and extracted using CH2Cl2. The organic layer was dried over Na2SO4and concentrated in vacuum. The obtained residue was purified by column chromatography (petroleum ether/EtOAc = 50/1) to give ethyl 2,4-dimethoxyaniline-3-carboxylate (9.6 g, 60%).

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

Ethyl 2,4-dimethoxyaniline-3-carboxylate (1.5 g, 5.7 mmol) was heated at boiling point with reflux in NaOH solution (10%, 100 ml) for 1 hour. After cooling, the mixture was acidified with concentrated HCl to pH 4. The precipitate that formed was collected by filtration and washed with water and simple ether to obtain 2,4-dimethoxyaniline-3-carboxylic acid (A-17) as a white solid (670 mg, 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-dihydro-quinoline-3-carboxylic acid
A-66-[(4-Fluoro-phenyl)-methyl-sulfamoyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-7 6-(4-Methyl-piperidine-1-sulfonyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-84-Oxo-6-(pyrrolidin-1-sulfonyl)-1,4-dihydro-quinoline-3-carboxylic acid
A-106-Ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-116-Ethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-124-Oxo-7-trifluoromethyl-1,4-dihydro-quinoline-3-carboxylic acid
A-137-Chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-144-Oxo-5,7-bis-trifluoromethyl-1,4-dihydro-quinoline-3-carboxylic acid
A-201-Methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-211-Isopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-221,6-Dimethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-231-Ethyl-6-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
A-24 6-Chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid

The amine group

N-1 Substituted 6-aminoindole

Example 1:

General Scheme:

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

Special 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 MeI (is 5.33 g, 37.5 mmol). After stirring at room temperature over night the mixture was poured into water and was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and concentrated in vacuum to give product 1-methyl-6-nitro-1H-indole (4.3 g, 98%).

B-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 under atmosphere of H2(1 ATM) at room temperature over night. After filtration the filtrate was concentrated and acidified with using HCl-MeOH (4 mol/l), to obtain hydrochloride salt 1-methyl-1H-indole-6-ylamine (B-1) (1.74 g, 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-�the Ndola-6-ylamine

1-Benzyl-1H-indol-6-ylamine (B-2) synthesized in accordance with the General scheme presented above, based on 6-of nitroindole and bromide. Overall yield (~40%). HPLC retention time 2.19 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 223,3 m/z (MH+).

B-3; 1-(6-Amino-indol-1-yl)-Etalon

1-(6-Amino-indol-1-yl)-Etalon (B-3) was synthesized in accordance with the General scheme presented above, based on 6-of nitroindole and acetyl chloride. Overall yield (~40%). HPLC retention time 0.54 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 175,1 m/z (MH+).

Example 2:

Ethyl ester {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid

To a stirred solution of (tert-butoxycarbonyl-methyl-amino)-acetic acid (37 g, 0.2 mol) and Et3N (60.6 g, 0.6 mole) in CH2Cl2(300 ml) was added isobutylparaben (27,3 g, 0.2 mmol) dropwise at-20 ° C in argon atmosphere. After stirring for 0.5 hours was added dropwise ethyl ether methylamino-acetic acid hydrochloride (30.5 g, 129 mmol) at-20ºC. The mixture was allowed to warm to room temperature (~1 h) and quenched with water (500 ml). The organic layer was separated, washed with 10% citric acid solution, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (petroleum�th ether/EtOAc 1:1) to give ethyl {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid (12.5 g, 22%).

{[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid

A suspension of ethyl {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid (12.3 g, to 42.7 mmol) and LiOH (8.9 g, 214 mmol) in H2O (20 ml) and THF (100 ml) was stirred over night. Volatile solvent was removed under vacuum and the residue was extracted with simple ether (2×100 ml). The aqueous phase was acidified with to pH 3 with dilute HCl solution and then extracted using CH2Cl2(2×300 ml). The combined organic layers were washed with saturated brine, dried over Na2SO4and concentrated in vacuum to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid as a colorless oil (10 g, 90%).1H NMR (CDCl3) δ 7,17 (lat.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 ether methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamino acids

To a mixture of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-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 minutes. Added a solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 ml) and the reaction mixture was heated �ri 60ºC for 18 hours. The solvent was evaporated and the crude mixture was again partitioned between EtOAc and water. The organic layer was separated, washed with water (×3), dried over Na2SO4and concentrated. Was added diethyl ether, and then EtOAc. The obtained solid substance was collected by filtration, washed with diethyl ether and air dried to obtain tert-butyl ether methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamino acid (6.42 g, 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 3.12 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 405,5 m/z (MH+).

B-26; tert-butyl ether ({[2-(6-amino-indol-1-yl)-2-oxo-ethyl]-methyl-carbamoyl}-methyl)-methyl-carbamino acid

A mixture of tert-butyl ether methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-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) was heated to 70ºC for 3 hours. Was added water and EtOAc and the mixture was filtered through a short plug of Celite. The organic layer was separated, dried over Na2SO4and concentrated to give tert-butyl ether ({[2-(6-amino-indol-1-yl)-2-oxo-ethyl]-methyl-carbamoyl}-methyl)-methyl-car�amine acid (B-26) (11,4 g quantitative). HPLC retention time 2.11 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 375,3 m/z (MH+).

2-Substituted 6-aminoindole

Example 1:

B-4-a; (3-Nitro-phenyl)-hydrazine, hydrochloride salt

3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in a mixture of H2O (40 ml) and 37% HCl (40 ml). Added a solution of NaNO2(13,8 g, 0.2 mol) in H2O (60 ml) at 0ºC followed by the addition of SnCl2.H2O (was 135.5 g, 0.6 mol) in 37% HCl (100 ml) at this temperature. After stirring at 0ºC for 0.5 hours the solid was isolated by filtration and washed with water to obtain (3-nitro-phenyl)-hydrazine in the form hydrochloride salt (B-4-a) (27.6 g, 73%).

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

Hydrochloride salt (3-nitro-phenyl)-hydrazine (B-4-a) (30,2 g, 0.16 mole) and ethyl ester of 2-oxo-propionic 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 was evaporated under reduced pressure, obtaining the ethyl ester of 2-[(3-nitro-phenyl)-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-nitro-phenyl)-hydrazono]-propionic, cyclotis previous stage was dissolved in toluene (300 ml). Added PPA (30 g). The mixture was heated at reflux overnight and then cooled to room temperature. The solvent was removed to give a mixture of the 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, 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 added dropwise a mixture of ethyl ester 4-nitro-1H-indole-2-carboxylic acid and ethyl ester of 6-nitro-1H-indole-2-carboxylic acid (B-4-b) (6g, 25.7 per mmol) in THF (50 ml) at 0ºC in an atmosphere of N2. The mixture was heated at reflux overnight and then cooled to 0ºC. To the mixture was added H2O (7,8 ml) and 10% NaOH (7.8 ml) at 0ºC. The insoluble solid was removed by filtration. The filter was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain 2-methyl-1H-indole-6-ylamine (B-4) (0.3 g, 8%).1H NMR (CDCl3) δ 7.57 the (lat.s, 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 (lat.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�new ester of 6-nitro-1H-indole-2-carboxylic acid (B-4-b) (0.5 g, 2,13 mmol) in 10% NaOH (20 ml) was heated at reflux overnight and then cooled to room temperature. The mixture was extracted with simple ether. The aqueous phase was separated and made acidic with using HCl to pH 1-2. The obtained solid substance was isolated by filtration to provide a mixture of 6-nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid (0.3 g, 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 boiled with reflux for 2 hours. The benzene and excess SOCl2was removed under reduced pressure. The residue was dissolved in CH2Cl2(250 ml). NH4OH (21,76 g 0,32 mol) was added dropwise at 0ºC. The mixture was stirred at room temperature for 1 hour. The obtained solid substance was isolated by filtration to obtain the crude amide mixture of 6-nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H-indole-2-carboxylic acid (9 g, 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�) was dissolved in CH 2Cl2(200 ml). Added Et3N (24,24 g, 0,24 mol) followed by the addition of (CF3CO)2O (51,24 g, 0,24 mol) at room temperature. The mixture was stirred for 1 hour and poured into water (100 ml). The organic layer was separated. The aqueous layer was extracted using EtOAc (100 ml ×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to provide a mixture of 6-nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile (2.5 g, 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 Ni (500 mg) in EtOH (50 ml) was stirred at room temperature in the atmosphere of H2(1 ATM) for 1 hour. Ni Raney was filtered. The filtrate was concentrated under reduced pressure and was purified column chromatography to obtain 6-amino-1H-indole-2-carbonitrile (B-5) (1 g, 49%).1H NMR (DMSO-d6) of 12.75 δ (Shir.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 is 158.2 m/z (MH+).

Example 3:

2,2-Dimethyl-N-o-tolyl-propionamide

To a solution of o-tolylamino (21.4 g, 0.20 mol) and Et3N (of 22.3 g, 0.22 mole) in CH2Cl2added 2,2-dimethyl-propionitrile (25,3 g, 0.21 mole) at 10ºC. The mixture was stirred over night �ri room temperature, was washed with an aqueous solution of HCl (5%, 80 ml), saturated solution of NaHCO3and saturated brine, dried over Na2SO4and concentrated in vacuum to give 2,2-dimethyl-N-o-tolyl-propionamide (35.0 g, 92%).

2-tert-butyl-1H-indole

To a solution of 2,2-dimethyl-N-o-tolyl-propionamide (30,0 g, 159 mmol) in anhydrous THF (100 ml) was added dropwise n-BuLi (2.5 M, in hexane, 190 ml) at 15ºC. The mixture was stirred overnight at 15 ° C, cooled in a bath of ice-water and treated with a saturated solution of NH4Cl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain 2-tert-butyl-1H-indole (23.8 g, 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 10ºC. The mixture was stirred for 20 minutes at 10 ° C, was treated dropwise with the help of H2O under cooling with ice and was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to provide a mixture of original substances, and 2-tert-butyl-2,3-dihydro-1H-indole (4.9 g), which was used directly in the next step.

2-tert-butyl-6-nitro-,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 0ºC. The reaction mixture was stirred at room temperature for 1 hour, carefully poured on crushed ice, podslushivaet with the help of Na2CO3to pH~8 and extracted with ethyl acetate. The combined extracts were washed with saturated brine, dried over anhydrous Na2SO4andconcentrated in vacuo. The residue was purified by column chromatography to obtain 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (4.0 g, 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 was purified by column chromatography to obtain 2-tert-butyl-6-nitro-1H-indole (1.6 g, 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 Ni (0.2 g). The mixture was stirred at room temperature in the atmosphere of H2(1 ATM) for 3 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was washed with petroleum ether to obtain 2-tre�-butyl-1H-indole-6-ylamine (B-6) (1.0 g, 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-Nitro-phenyl)-N'-propylidene-hydrazine

The sodium hydroxide solution (10%, 15 ml) was added slowly to a stirred suspension hydrochloride salt (3-nitro-phenyl)-hydrazine (B-4-a) (1.89 g, 10 mmol) in ethanol (20 ml) until pH 6. To the mixture was added acetic acid (5 ml) followed by the addition of Propionaldehyde (0.7 g, 12 mmol). After stirring for 3 hours at room temperature the mixture was poured into ice water and the resulting precipitate was isolated by filtration, washed with water and air dried to obtain N-(3-nitro-phenyl)-N'-propylidene-hydrazine, 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-nitro-phenyl)-N'-propylidene-hydrazine was dissolved in 85% H3PO4(20 ml) and toluene (20 ml) and heated at 90-100ºC for 2 hours. After cooling, the toluene was removed under reduced pressure. The resulting oil was podslushivaet 10% NaOH to pH 8. The aqueous layer was extracted using EtOAc (100 ml ×3). The combined organic layers were dried, filtered and concentrated under reduced pressure to provide a mixture-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (1.5 g, 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 in an atmosphere of H2(1 ATM) at room temperature. Pd-C was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 3-methyl-1H-indole-6-ylamine (B-7) (0.6 g, 24%).1H NMR (CDCl3) δ RUB 7.59 (lat.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 (lat.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 0ºC . After the addition the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured into ice water, podslushivaet saturated solution NaHCO3to pH 7-8 and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).

B-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 under atmosphere of H 2(1 ATM) at room temperature over night. After filtration the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether/EtOAc = 3/1) to give 6-amino-1H-indole-3-carbonitrile (B-8) (1 g, 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)-amine

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 0ºC for 30 minutes. To this 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 0ºC. The precipitate was collected by filtration and washed with water to obtain dimethyl-(6-nitro-1H-indole-3-ylmethyl)-amine (23 g, 87%).

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

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

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

A mixture of (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (1.5 g, 74,5 ml) and 10% Pd-C (300 mg) in EtOH (50 ml) was stirred at room temperature in the atmosphere of H2(1 ATM) for 5 hours. Pd-C was removed by filtration and the filtrate was concentrated to obtain (6-amino-1H-indol-3-yl)-acetonitrile (B-9) (1.1 g, 90%).1H NMR (DMSO-d6) δ 10,4 (lat.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-a) (8.6 g, 42.8 mmol) in anhydrous THF (200 ml) was added 2 M solution of the complex of borane-dimethyl sulfide in THF (214 ml. of 0.43 mol) at 0ºC. The mixture was heated at reflux overnight in a nitrogen atmosphere. The mixture was then cooled to room temperature and was added a solution of (Boc)2O (14 g, of 64.2 mmol) and Et3N (89,0 ml, 0.64 mole) in THF. The reaction mixture continued to stir overnight and then was poured into ice water. The organic layer was separated and the aqueous phase was extracted using EtOAc (200×3 ml). United �organicheskie layers were washed with water and saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude substance was purified column chromatography to obtain tert-butyl ether [2-(6-nitro-1H-indol-3-yl)-ethyl]-carbamino acid (5 g, 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 Ni (1 g) in EtOH (100 ml) was stirred at room temperature in the atmosphere of H2(1 ATM) for 5 hours. Ni Raney was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified column chromatography to obtain tert-butyl ether [2-(6-amino-1H-indol-3-yl)-ethyl]-carbamino acid (B-10) (3 g, 67%).1H NMR (DMSO-d6) δ 10.1 case (lat.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+).

Example 5:

General scheme:

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

Special 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 TBAI (1.7 g, 5,16 mmol) in anhydrous toluene (11 ml) was added DIEA (1.47 g, to 11.4 mmol) at room�th temperature in a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes at 120ºC, followed by the addition of tert-butylbromide (0,707 g, 5,16 mmol). The resulting mixture was stirred for 45 minutes at 120ºC. The solids were filtered and the filtrate was concentrated to dryness and was purified column chromatography on silica gel (petroleum ether/EtOAc 20:1) to give 3-tert-butyl-6-nitro-1H-indole as a yellow solid (0.25 g, 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 Ni (0.5 g) in ethanol was stirred at room temperature in the atmosphere of H2(1 ATM) for 3 hours. The catalyst was filtered and the filtrate concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc 4:1) to give 3-tert-butyl-1H-indole-6-ylamine (B-11) (2.0 g, 77.3 per cent) 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 (lat.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 in accordance with the General scheme presented above, based on 6-of nitroindole and ethylbromide. Total output (42%). HPLC retention time 1.95 minutes, 10-9% CH 3CN, 5 min cycle; 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 in accordance with the General scheme presented above, based on 6-of nitroindole and isopropylidene. Overall yield (17%). HPLC retention time 2.06 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 175,2 m/z (MH+).

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

3-sec-Butyl-1H-indol-6-ylamine (B-14) was synthesized in accordance with the General scheme presented above, based on 6-of nitroindole and 2-bromobutane. Total output (20%). HPLC retention time 2.32 minutes, 10-99% CH3CN, 5 min cycle; 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 in accordance with the General scheme presented above, based on 6-of nitroindole and iodo-cyclopentane. Total output (16%). HPLC retention time 2,39 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS of 201.5 m/z (MH+).

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

3-(2-Ethoxy-ethyl)-1H-indol-6-ylamine (B-16) was synthesized in accordance with the General scheme presented above, based on 6-of nitroindole and 1-bromo-2-ethoxy-ethane. Overall yield (15%). HPLC retention time 1.56 minutes, 10-99% CH3CN, 5 min cycle; 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 in accordance with the General scheme presented above, based on 6-of nitroindole and ethyl ether iodine-acetic acid. Total output (24%). HPLC retention time 0.95 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 219,2 m/z (MH+).

4-Substituted 6-aminoindole

2-Methyl-3,5-dinitro-benzoic acid

To a mixture of HNO3(95%, 80 ml) and H2SO4(98%, 80 ml) was slowly added 2-methylbenzoic acid (50 g, of 0.37 mol) at 0ºC. After the addition the reaction mixture was stirred for 1.5 hours while maintaining the temperature below 30ºC, poured into ice water and stirred for 15 minutes. The precipitate that formed was collected by filtration and washed with water to obtain 2-methyl-3,5-dinitro-benzoic acid (70 g, 84%).

Ethyl ester of 2-methyl-3,5-dinitro-benzoic acid

A mixture of 2-methyl-3,5-dinitro-benzoic acid (50 g, 0.22 mol) in SOCl2(80 ml) was heated at reflux for 4 hours and then concentrated to dryness. Added CH2Cl2(50 ml) and EtOH (80 ml). The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted using EtOAc (3×100 ml). The combined extract� was washed with a saturated solution of Na 2CO3(80 ml), water (2×100 ml) and saturated brine (100 ml), dried over Na2SO4and concentrated to dryness to obtain ethyl ester of 2-methyl-3,5-dinitro-benzoic acid (50 g, 88%).

Ethyl ether 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid

A mixture of ethyl ester of 2-methyl-3,5-dinitro-benzoic acid (35 g, 0.14 mole) and dimethoxymethyl-dimethyl-amine (32 g, 0.27 mol) in DMF (200 ml) was heated at 100ºC for 5 hours. The mixture was poured into ice water. The precipitate was collected by filtration and washed with water with obtaining the ethyl ester of 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid (11.3 g, 48%).

B-18; ethyl 6-amino-1H-indole-4-carboxylic acid

A mixture of ethyl ester of 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid (11.3 g, 0,037 mol) and SnCl2(83 g, of 0.37 mol) in ethanol was heated at reflux for 4 hours. The mixture was concentrated to dryness and the residue was poured into water and was podslushivaet saturated solution of Na2CO3to pH 8. The precipitate was filtered and the filtrate was extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (2×100 ml) and saturated brine (150 ml), dried over Na2SO4and concentrated to dryness. The residue was purified by column chromatography on silica gel with obtaining the ethyl ester of 6-amino-1H-indol-carboxylic acid (B-18) (3 g, 40%).1H NMR (DMSO-d6) δ 10,76 (lat.s, 1H), 7,11-7,14 (m, 2H), 6,81-about 6,82 (m, 1H), 6,67-6,68 (m, 1H), 4,94 (lat.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:

General scheme:

Special example:

1-Fluoro-5-methyl-2,4-dinitro-benzene

To a stirred solution of HNO3(60 ml) and H2SO4(80 ml), cooled in an ice bath was added 1-fluoro-3-methyl-benzene (27.5 g, 25 mmol) at such a rate that the temperature did not increase above 35ºC. The mixture was left for stirring for 30 minutes at room temperature and was poured into ice water (500 ml). The resulting precipitate (a mixture of desired product and 1-fluoro-3-methyl-2,4-dinitro-benzene, approximately 7:3) was collected by filtration and purified by recrystallization from 50 ml of isopropyl ether to obtain 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%).

[2-(5-Fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine

A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), dimethoxymethyl-dimethylamine (11.9 g, 100 mmol) and DMF (50 ml) was heated at 100ºC for 4 hours. The solution was cooled and poured into water. Red precipitate was collected by filtration, washed with water in sufficient quantity and dried to obtain [2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-�imethyl-amine (8 g, 63%).

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

A suspension of [2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine (8 g, of 31.4 mmol) and Raney Ni (8 g) in EtOH (80 ml) was stirred under atmosphere of H2(40 f/inch (2,812 kg/cm2)) at room temperature for 1 hour. After filtration the filtrate was concentrated and the residue was purified by chromatography (petroleum ether/EtOAc = 5/1) to give 5-fluoro-1H-indole-6-ylamine (B-20) in the form of a brown solid (1 g, 16%).1H NMR (DMSO-d6) δ 10,56 (lat.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 (lat.s, 2H); ESI-MS 150,1 m/z (MH+).

Other examples:

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

5-Chloro-1H-indol-6-ylamine (B-21) was synthesized in accordance with the General scheme above, on the basis of 1-chloro-3-methyl-benzene. Overall yield (7%).1H NMR (CDCl3) δ a 7.85 (lat.s, 1H), 7,52 (s, 1H), 7,03 (s, 1H), of 6.79 (s, 1H), system 6.34 (s, 1H), of 3.91 (lat.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 in accordance with the General scheme above, on the basis of 1-methyl-3-trifluoromethyl-benzene. Overall yield (2%).1H NMR (DMSO-d6) 10,79 (lat.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 with�art 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 a bath of ice-water. After the addition the mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4and concentrated to dryness under reduced pressure to obtain 1-benzolsulfonat-2,3-dihydro-1H-indole (30.9 g, 96%).

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

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

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

To a stirred using a magnetic stirrer TFA (1600 ml) was added at 0ºC sodium borohydride (64 g old, 1.69 mol) over 1 hour. To �the mixture was added dropwise a solution of 1-(1-benzazolyl-2,3-dihydro-1H-indol-5-yl)-ethanone (40 g, Of 0.13 mol) in TFA (700 ml) for 1 hour. The mixture was stirred overnight at 25ºC, was diluted using H2O (1600 ml) and podslushivaet sodium hydroxide in the form of tablets at 0ºC. The organic layer was separated and the aqueous layer was extracted using CH2Cl2. The combined organic layers were washed with saturated brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with obtaining 1-benzolsulfonat-5-ethyl-2,3-dihydro-1H-indole (16,2 g, 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 HBr (48%, 162 ml) was heated at reflux for 6 hours. The mixture was podslushivaet saturated solution of NaOHto pH 9 and was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 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 H2SO4(98%, 20 ml) was slowly added KNO3(1.7 g, 17 mmol) at 0ºC. After the addition the mixture was stirred at 0-10ºC for 10 minutes, carefully poured into ice, pods�lacigale using NaOH solution to pH 9 and was extracted with ethyl acetate. The combined extracts were washed with saturated brine, dried over Na2SO4andconcentrated to dryness. The residue was purified by column chromatography on silica gel to obtain 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 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. The solids were filtered and the filtrate concentrated to dryness to obtain crude 5-ethyl-6-nitro-1H-indole (1.9 g, quantitative).

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

A suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney Ni (1 g) was stirred in the atmosphere of H2(1 ATM) at room temperature for 2 hours. The catalyst was filtered and the filtrate concentrated to dryness. The residue was purified by column chromatography on silica gel to obtain 5-ethyl-1H-indole-6-ylamine (B-23) (760 mg, 48%).1H NMR (CDCl3) δ 7,90 (lat.s, 1H), 7,41 (s, 1H), 7,00 (s, 1H), 6,78 (s, 2H), 6,39 (s, 1H), 3,39 (lat.s, 2H), 2,63 (sq, 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-butyl-phenylamine

To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 ml) was added dropwise NBS (531 g, 3 mol) in DMF (500 ml) at room temperature. After completing�ia added, the reaction mixture was diluted with water and extracted using EtOAc. The organic layer was washed with water, saturated brine, dried over Na2SO4and concentrated. The crude product is directly used for next step without further purification.

2-Bromo-4-tert-butyl-5-nitro-phenylamine

2-Bromo-4-tert-butyl-phenylamine (162 g, 0.71 mole) was added dropwise to H2SO4(410 ml) at room temperature to give a clear solution. This clear solution is then cooled to temperature -5 to-10ºC. Was added dropwise a solution of KNO3(82.5 g., of 0.82 mol) in H2SO4(410 ml) while maintaining the temperature between -5 to-10ºC. After completion of the addition the reaction mixture was poured into ice/water and extracted using EtOAc. The combined organic layers were washed with 5% solution of Na2CO3and saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (EtOAc/petroleum ether 1/10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (152 g, 78%).

4-tert-butyl-5-nitro-2-trimethylsilylethynyl-phenylamine

To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27,3 g, 100 mmol) in toluene (200 ml) and water (100 ml) was 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 mm�l) in a nitrogen atmosphere. The reaction mixture was heated at 70ºC in a tightly closed flask high pressure for 2.5 hours, cooled to room temperature and filtered through a short plug of Celite. The filter cake was washed using EtOAc. The combined filtrate was washed with 5% solution of NH4OH and water, dried over Na2SO4and concentrated. The crude product was purified column chromatography (0-10% EtOAc/petroleum ether) to give 4-tert-butyl-5-nitro-2-trimethylsilylethynyl-phenylamine in the form of a brown viscous liquid (25 g, 81%).

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

To a solution of 4-tert-butyl-5-nitro-2-trimethylsilylethynyl-phenylamine (25 g, 86 mmol) in DMF (100 ml) was added CuI (8.2 g, 43 mmol) under a nitrogen atmosphere. The mixture was heated at 135ºC in a tightly closed flask high pressure over night, cooled to room temperature and filtered through a short plug of Celite. The filter cake was washed using EtOAc. The combined filtrate was washed with water, dried over Na2SO4and concentrated. The crude product was purified by column chromatography (10-20% EtOAc/Hexane) to give 5-tert-butyl-6-nitro-1H-indole as a yellow solid (12.9 g, 69%).

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

Ni Raney (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (14.7 g, 67 mmol) in methanol (100 ml). A mixture of AC�stirred in hydrogen atmosphere (1 ATM) at 30ºC for 3 hours. The catalyst was filtered. The filtrate was dried over Na2SO4and concentrated. The crude dark brown viscous oil was purified by column chromatography (10-20% EtOAc/petroleum ether) to give 5-tert-butyl-1H-indole-6-ylamine (B-24) as a gray solid (11 g, 87%).1H NMR (300 MHz, DMSO-d6) δ 10.3 a (lat.s, 1H), 7,2 (s, 1H), 6,9 (m, 1H), of 6.6 (s, 1H), 6,1 (m, 1H), 4,4 (lat.s, 2H), 1,3 (s, 9H).

Example 4:

5-Methyl-2,4-dinitro-benzoic 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 0ºC. After the addition the mixture was stirred for 1.5 hours while maintaining the temperature below 30ºC. The mixture was poured into ice water and stirred for 15 minutes. The precipitate was collected by filtration and washed with water to provide a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitro-benzoic acid (70 g, 84%). To a solution of this compound in EtOH (150 ml) was added dropwise SOCl2(53.5 g, 0.45 mole). The mixture was heated at reflux for 2 hours and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 ml) and was extracted with 10% solution of Na2CO3(120 ml). It was found that the organic layer contained the ethyl ester 5-methyl-2,4-dinitro-benzoic acid, while water cloisteral 3-methyl-2,6-dinitro-benzoic acid. The organic layer was washed with saturated brine (50 ml), dried over Na2SO4and concentrated to dryness to obtain ethyl 5-methyl-2,4-dinitro-benzoic acid (20 g, 20%).

Ethyl ester 5-(2-dimethylamino-vinyl)-2,4-dinitro-benzoic acid

A mixture of ethyl ester 5-methyl-2,4-dinitro-benzoic acid (39 g, 0.15 mole) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 ml) was heated at 100ºC for 5 hours. The mixture was poured into ice water. The precipitate was collected by filtration and washed with water to obtain ethyl 5-(2-dimethylamino-vinyl)-2,4-dinitro-benzoic acid (15 g, 28%).

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

A mixture of ethyl ester 5-(2-dimethylamino-vinyl)-2,4-dinitro-benzoic acid (15 g, 0.05 mol) and Raney Ni (5 g) in EtOH (500 ml) was stirred under atmosphere of H2(50 f/inch2(3,515 kg/cm2)) at room temperature for 2 hours. The catalyst was filtered and the filtrate concentrated to dryness. The residue was purified by column chromatography on silica gel with obtaining the ethyl ester of 6-amino-1H-indole-5-carboxylic acid (B-25) (3 g, 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 (sq, J=7.2 Hz, 2H), 1,32-of 1.27 (t, J=7,2 Hz, 3H).

Example 5:

1-(2,3-Dihydro-indol-1-yl)-Etalon

To susp�nsii NaHCO 3(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, was added dropwise acetyl chloride (of 78.5 g, 1.0 mol). The mixture was stirred at room temperature for 2 hours. The solids were filtered and the filtrate concentrated to give 1-(2,3-dihydro-indol-1-yl)-ethanone (82 g, 100%).

1-(5-Bromo-2,3-dihydro-indol-1-yl)-Etalon

To a solution of 1-(2,3-dihydro-indol-1-yl)-ethanone (58,0 g, 0.36 mole) in acetic acid (3000 ml) was added Br2(87.0 g, of 0.54 mol) at 10ºC. The mixture was stirred at room temperature for 4 hours. The precipitate was collected by filtration to obtain crude 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanone (100 g, 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-dihydro-indol-1-yl)-ethanone (100 g, 0.34 mol) in HCl (20%, 1200 ml) was heated at reflux for 6 hours. The mixture was podslushivaet with the help of Na2CO3to pH of 8.5-10 and then was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 5-bromo-2,3-dihydro-1H-indole (37 g, 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 H2SO4(98%, 200 ml) was slowly added KNO3(23,5 g, 0,23 mol) at 0ºC. After the addition the mixture was stirred at 0-10ºC for 4 hours, carefully poured into ice, podslushivaet with the help of Na2CO3to pH 8 and was extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over Na2SO4and concentrated to dryness. The residue was purified by column chromatography on silica gel to obtain 5-bromo-6-nitro-2,3-dihydro-1H-indole (42 g, 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 80ºC for 2 hours. The solids were filtered and the filtrate concentrated to dryness. The residue was purified by column chromatography on silica gel to obtain 5-bromo-6-nitro-1H-indole (7.5 g, 38%).

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

A mixture of 5-bromo-6-nitro-1H-indole (7.5 g, 31,1 mmol) and Raney Ni (1 g) in ethanol was stirred under atmosphere of H2(1 ATM) at room temperature for 2 hours. The catalyst was filtered and the filtrate concentrated to dryness. The residue was purified by column chromatography on silica gel to obtain 5-bromo-1H-indole-6-ylamine (B-27) (2 g, 30%).1H NMR (DMSO-d6) δ is 10.6 (s, 1H), 7,49 (s, 1H), of 6.79-7,02 (m, 1H), of 6.79 (�, 1H), 6,14-USD 6.16 (m, 1H), to 4.81 (s, 2H).

7-Substituted 6-aminoindole

3-Methyl-2,6-dinitro-benzoic 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 0ºC. After the addition the mixture was stirred for 1.5 hours while maintaining the temperature below 30ºC. The mixture was poured into ice water and stirred for 15 minutes. The precipitate was collected by filtration and washed with water to provide a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitro-benzoic acid (70 g, 84%). To a solution of this compound in EtOH (150 ml) was added dropwise SOCl2(53.5 g, 0.45 mole). The mixture was heated to boiling temperature with reflux for 2 hours and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 ml) and was extracted with 10% solution of Na2CO3(120 ml). It was found that the organic layer contained the ethyl ester 5-methyl-2,4-dinitro-benzoic acid. The aqueous layer was acidified with using HCl to pH 2~3, and the resulting precipitate was collected by filtration, washed with water and air dried to obtain 3-methyl-2,6-dinitro-benzoic acid (39 g, 47%).

Ethyl ester of 3-methyl-2,6-dinitro-benzoic acid

A mixture of 3-methyl-2,6-dinitro-benzoic acid (39 g, 0.15 mole) and SOCl2(80 ml) was heated at a temperature to�singing to reflux for 4 hours. The excess SOCl2was removed 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 20ºC for 1 hour and concentrated to dryness. The residue was dissolved in EtOAc (100 ml), washed with a solution of Na2CO3(10%, 40 ml ×2), water (50 ml ×2) and saturated brine (50 ml), dried over Na2SO4and concentrated to give the ethyl ester of 3-methyl-2,6-dinitro-benzoic acid (20 g, 53%).

Ethyl ester of 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid

A mixture of ethyl ester of 3-methyl-2,6-dinitro-benzoic acid (35 g, 0.14 mole) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 ml) was heated at 100ºC for 5 hours. The mixture was poured into ice water and the precipitate was collected by filtration and washed with water with obtaining the ethyl ester of 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid (25 g, 58%).

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

A mixture of ethyl ester of 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid (30 g, 0,097 mol) and Raney Ni (10 g) in EtOH (1000 ml) was stirred under atmosphere of H2(50 f/inch2(3,515 kg/cm2)) for 2 hours. The catalyst was filtered and the filtrate concentrated to dryness. The residue was purified by column chromatography on silica gel with obtaining the ethyl ester of 6-amino-1H-indole-7-carboxylic acid (B-19) in view of� not quite white solid (3.2 g, 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 (sq, 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) was added dropwise 2-tert-butyl-phenylamine (4.5 g, 30 mmol) at 0ºC. Was added potassium nitrate (4.5 g, 45 mmol) in portions at 0ºC. The reaction mixture was stirred at 0-5ºC for 5 minutes, poured into ice water and then extracted using EtOAc three times. The combined organic layers were washed with saturated brine and dried over Na2SO4. After removal of solvent, the residue was purified by recrystallization using 70% EtOH-H2O obtaining 2-tert-butyl-5-nitroaniline (3.7 g, 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 minutes, 10-99% CH3CN, 5 min cycle; 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 15% solution of H2SO4was added dropwise a solution of NaNO2(763 mg, 11.0 mmol) in water (3 ml) at 0ºC. The resulting mixture was stirred at 0-5ºC for 5 minutes. An excess of NaNO2neutralized with the help of urea was then added 5 ml H2SO4-H O (V/V 1:2) and the mixture was boiled to reflux for 5 minutes. Added three additional 5 ml aliquots of H2SO4-H2O (V/V 1:2) when heated at boiling point with reflux. The reaction mixture was cooled to room temperature and extracted using EtOAc twice. The combined organic layers were washed with saturated brine and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-5-NITROPHENOL (C-1-a) (1.2 g, 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 3.46 in minutes, 10-99% CH3CN, 5 min cycle.

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

To be heated at the temperature of reflux to a solution of 2-tert-butyl-5-NITROPHENOL (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 ml) was added ammonium formate (200 mg, 3.1 mmol) followed by the addition of 140 mg of 10% Pd-C. the Reaction mixture was boiled to reflux for 30 minutes, cooled to room temperature and was filtered through a layer of Celite. The filtrate was concentrated to dryness and purified column chromatography (20-30% EtOAc-hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 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 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS to 166.1 m/z (MH+).

Example 2:

General scheme:

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

Special example:

1-tert-butyl-2-methoxy-4-nitrobenzene

To a mixture of 2-tert-butyl-5-NITROPHENOL (C-1-a) (100 mg, 0.52 mmol) and K2CO3(86 mg, 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 using EtOAc. The combined organic layers were washed with saturated brine and dried over MgSO4. After filtration the filtrate was evaporated to dryness to obtain 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 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 be heated at the temperature of reflux to 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), followed by the addition of 10% Pd-C (15 mg). The reaction mixture was boiled with reverse refrigerator and stove� within 60 minutes was cooled to room temperature and filtered through Celite. The filtrate was concentrated to dryness to obtain 4-tert-butyl-3-methoxyaniline (C-2) (52 mg, 72%) which was used without further purification. HPLC retention time 2.29 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 180,0 m/z (MH+).

Other examples:

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

3-(2-Ethoxyethoxy)-4-tert-butylbenzylamine (C-3) was synthesized in accordance with the General scheme above, on the basis of 2-tert-butyl-5-NITROPHENOL (C-1-a) and 1-bromo-2-ethoxyethane.1H NMR (400 MHz, CDCl3) δ 6,97 (d, J=7.9 Hz, 1H), 6,17 (s, 1H), 6,14 (d, J=2,3 Hz, 1H), 4,00 (t, J=5,2 Hz, 2H), 3,76 (t, J=5,2 Hz, 2H), 3,53 (sq, J=7,0 Hz, 2H), of 1.27 (s, 9H), of 1.16 (t, J=7,0 Hz, 3H); HPLC retention time 2.55 per minute, 10-99% CH3CN, 5 min cycle; 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 in accordance with the General scheme above, on the basis of 2-tert-butyl-5-NITROPHENOL (C-1-a) and 2-bromoethanol. HPLC retention time 2.08 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 210,3 m/z (MH+).

Example 3:

N-(3-hydroxy-phenyl)-acetamide and 3-formylamino-phenyl ester of acetic acid

To the thoroughly stirred suspension of 3-amino-phenol (50 g, 0.46 mole) and NHCO 3(193,2 g, 2.3 mol) in chloroform (1 l) was added dropwise chlorocatechol (46,9 g, 0.6 mole) during 30 minutes at 0ºC. After completion of the addition the reaction mixture was heated to reflux overnight and then cooled to room temperature. An excess of NaHCO3was removed by filtration. The filtrate was poured into water and extracted using EtOAc (300×3 ml). The combined organic layers were washed with saturated brine (500 ml), dried over anhydrous Na2SO4and concentrated under reduced pressure to provide a mixture of N-(3-hydroxy-phenyl)-acetamide and 3-formylamino-phenyl acetic acid ester (35 g, 4:1 according to NMR analysis). The mixture was used directly in the next step.

N-[3-(3-Methyl-but-3-enyloxy)-phenyl]-acetamide

A suspension mixture of N-(3-hydroxy-phenyl)-acetamide and 3-formylamino-phenyl acetic acid ester (18,12 g, 0.12 mole), 3-methyl-but-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 at reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted using EtOAc (300×3 ml). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4and to�have centriole. The residue was purified by column chromatography to obtain N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (11 g, 52%).

N-(4,4-Dimethyl-chroman-7-yl)-acetamide

A mixture of N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (2.5 g, to 11.4 mmol) and AlCl3(4,52 g, to 34.3 mmol) in fluoro-benzene (50 ml) was heated at boiling point with reflux during the night. After cooling, the reaction mixture was poured into water. The organic layer was separated and the aqueous phase was extracted using EtOAc (40×3 ml). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4and concentrated in vacuum. The residue was purified by column chromatography to obtain N-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 54%).

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

A mixture of N-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 6.2 mmol) in 20% rectorem HCl (30 ml) was heated at reflux for 3 hours and then cooled to room temperature. The reaction mixture was podslushivaet 10% aqueous NaOH to pH 8 and extracted using EtOAc (30×3 ml). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4and concentrated to give 3,4-dihydro-4,4-dimethyl-2H-chromen-7-amine (C-5) (1 g, 92%).1H NMR (DMSO-d6) δ of 6.87 (d, J=8.4 Hz, 1H), 6,07 (DD, J=8,4, 2.4 GHz �C, 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:

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 SnCl2·2H2O, EtOH or H2, Pd-C, MeOH.

A special example

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 the help of NaHCO3, dried over MgSO4and concentrated. The residue was purified by column chromatography (5-15% EtOAc-hexane)to give 2-tert-butyl-4-terfenol (3.12 g, 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 was removed by filtration. The filtrate is then diluted with water and was extracted with simple ether. The ether extract was washed with water and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography to obtain 2-tert-butyl-4-performancebut (2.08 g, 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-a) and 2-tert-butyl-4-fluoro-6-nitrophenylarsonic (C-6-a)

To a solution of 2-tert-butyl-4-performancebut (1,81 g, 8 mmol) in H2SO4(98%, 1 ml) was added slowly a cooled mixture of H2SO4(1 ml) and HNO3(1 ml) at 0ºC. The mixture was stirred for 2 hours while warming to room temperature, poured into ice and was extracted with diethyl ether. The ether extract was washed with saturated brine, dried over MgSO4and concentrated. The residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-4-fluoro-5-nitrophenylarsonic (C-7-a) (1.2 g, 55%) and 2-tert-butyl-4-fluoro-6-nitrophenylacetate (C-6-a) (270 mg, 12%). 2-tert-butyl-4-fluoro-5-nitrophenylarsonic (C-7-a):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-6-nitrophenylarsonic (C-6-a):1H NMR (400 MHz, DMSO-d6) δ and 8.04 (DD, J=7,6, Of 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-a) (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 was extracted with 1N NaOH (3×). The aqueous layer was acidified with 1N HCl solution and was extracted with diethyl ether. The ether extract was washed with saturated brine, dried (MgSO4) and concentrated to give 2-tert-butyl-4-fluoro-5-NITROPHENOL (530 mg, 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 be heated at the temperature of reflux to a solution of 2-tert-butyl-4-fluoro-5-NITROPHENOL (400 mg, at 1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) in EtOH (20 ml) was added 5% Pd-C (260 mg). The mixture was boiled to reflux for a further 1 hour, cooled and filtered through Celite. The solvent was removed by evaporation to obtain 2-tert-butyl-5-amino-4-terfenol (C-7) (550 mg, 83%).1H NMR (400 MHz, DMSO-d6) δ 8,83 (lat.s, 1H), 6,66 (d, J=13,7 Hz, 1H), from 6.22 (d, J=8,5 Hz, 1H), 4,74 (lat.s, 2H), 1.26 in (s, 9H); HPLC retention time of 2.58 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 184,0 m/z (MH+).

Other examples:

C-10; 2-tert-butyl-5-amino-4-chlorp�Nol

2-tert-butyl-5-amino-4-chlorophenol (C-10) was synthesized in accordance with the General scheme above, on the basis of 4-chlorophenol and tert-butanol. Overall yield (6%). HPLC retention time 3.07 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS of 200.2 m/z (MH+).

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

5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-13) was synthesized in accordance with the General scheme presented above, based on 4-of terfenol and 1-methylcyclohexanol. Overall yield (3%). HPLC retention time of 3.00 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 224,2 m/z (MH+).

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

5-Amino-2-(3-ethylpent-3-yl)-4-fluoro-phenol (C-19) was synthesized in accordance with the General scheme presented above, based on 4-of terfenol and 3-ethyl-3-pentothal. Total output (1%).

C-20; 2-Adamantyl-5-amino-4-fluoro-phenol

2-Adamantyl-5-amino-4-fluoro-phenol (C-20) was synthesized in accordance with the General scheme presented above, based on 4-of terfenol and adamantane-1-ol.

C-21; 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol

5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-21) was synthesized in accordance with the General scheme presented above, based on 4-of terfenol and 1-methyl-cycloheptanol.

C-22; 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol

5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-22) was synthesized in accordance with the General scheme presented above, based on 4-of terfenol and 1-methyl-cyclooctanol.

C-23; 5-Amino-2-(3-ethyl-2,2-dimethylpentan-3-yl)-4-fluoro-phenol

5-Amino-2-(3-ethyl-2,2-dimethylpentan-3-yl)-4-fluoro-phenol (C-23) was synthesized in accordance with the General scheme presented above, based on 4-of terfenol and 3-ethyl-2,2-dimethyl-pentane-3-ol.

Example 5:

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

To be heated at the temperature of reflux to 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 was boiled to reflux for a further 1 hour, cooled and filtered through Celite. The solvent was removed by evaporation and the residue was purified by column chromatography (0-15%, EtOAc-hexane) to give 2-tert-butyl-4-fluoro-6-aminophenylalanine (C-6) (60 mg, 27%). HPLC retention time 3.35 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 242,0 m/z (MH+).

Example 6:

2,4-di-tert-butyl-phenyl ester methyl ester of carbonic acid

Methylchloroform (58 ml, 750 mmol) was added to�include to a solution of 2,4-di-tert-butyl-phenol (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 to 0ºC. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approximately 1 l) using a mixture of 10% ethyl acetate-hexane (~4 l) as eluent. The combined filtrates were concentrated to give 2,4-di-tert-butyl-phenyl ester methyl ester of carbonic acid as a yellow oil (132 g, quantitative).1H NMR (400 MHz, DMSO-d6) δ 7,35 (d, J=2.4 Hz, 1H), 7,29 (DD, J=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).

2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester of carbonic acid and 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester of carbonic acid

To a stirred mixture of 2,4-di-tert-butyl-phenyl ester methyl ester of carbonic acid (4,76 g, 18 mmol) in concentrated sulfuric acid (2 ml), cooled in a bath of ice-water, was added a cooled mixture of sulfuric acid (2 ml) and nitric acid (2 ml). The addition was carried out slowly so that the reaction temperature does not exceed 50ºC. The reaction mixture was allowed to stir for 2 hours while warming to room temperature. The reaction mixture was then added to ice water and extracted into diethyl ether. The ether layer was dried (MgSO4), close�was narrowly and was purified column chromatography (0-10% ethyl acetate-hexane) to give a mixture of 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester of carbonic acid and 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ether of carbonic acid in the form of a pale yellow solid (4,28 g) which was used directly in the next step.

2,4-Di-tert-butyl-5-nitro-phenol and 2,4-Di-tert-butyl-6-nitro-phenol

A mixture of carbonic acids 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester of carbonic acid and 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester of carbonic acid (4.2 g, 12.9 mmol) was dissolved in MeOH (65 ml) was added KOH (2.0 g, 36 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then acidified with (pH 2-3) by adding concentrated HCl and partitioned between water and diethyl ether. The ether layer was dried (MgSO4), concentrated and purified column chromatography (0-5% ethyl acetate-hexane) to give 2,4-di-tert-butyl-5-nitro-phenol (1.31 g, 29% over 2 stages) and 2,4-di-tert-butyl-6-nitro-phenol. 2,4-Di-tert-butyl-5-nitro-phenol: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-5-nitro-phenol: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).

C-9; 5-Amino-2,4-di-tert-butyl-phenol

At the temperature of reflux to a solution of 2,4-di-tert-butyl-5-nitro-phenol (1,86 g, 7.4 mmol) and ammonium formate (1,86 g) in ethanol (75 ml) was added Pd-5% wt. on charcoal (900 mg). Reactio�ing mixture was stirred at the temperature of reflux for 2 hours, was cooled to room temperature and filtered through Celite. Celite was washed with methanol and the combined filtrates concentrated to give 5-amino-2,4-di-tert-butyl-phenol in the form of a grey solid (1.66 g, quantitative).1H NMR (400 MHz, DMSO-d6) δ 8,64 (s, 1H, OH), at 6.84 (s, 1H), 6,08 (s, 1H), 4,39 (s, 2H, NH2), Of 1.27 (m, 18H); HPLC retention time 2.72 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 222,4 m/z (MH+).

C-8; 6-Amino-2,4-di-tert-butyl-phenol

A solution of 2,4-di-tert-butyl-6-nitro-phenol (27 mg, 0.11 mmol) and SnCl2·2H2O (121 mg, 0,54 mmol) in EtOH (1.0 ml) was heated in a microwave oven at 100ºC for 30 minutes. The mixture was diluted with EtOAc and water, podslushivaet saturated solution NaHCO3and filtered through Celite. The organic layer was separated and dried over Na2SO4. The solvent was removed by evaporation to obtain 6-amino-2,4-di-tert-butyl-phenol (C-8), which was used without further purification. HPLC retention time of 2.74 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 222,5 m/z (MH+).

Example 7:

4-tert-butyl-2-chloro-phenol

To a solution of 4-tert-butyl-phenol (40,0 g, 0.27 mole) and SO2Cl2(37,5 g, 0.28 mole) in CH2Cl2was added MeOH (9.0 g, 0.28 mol) at 0ºC. After completion of the addition the mixture was stirred over night at room temperature and then added water (200 �l). The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc, 50:1) to give 4-tert-butyl-2-chloro-phenol (47,0 g, 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 0ºC. The reaction mixture was allowed to warm to room temperature and stirred for another 30 minutes. The reaction mixture was washed using H2O and the organic layer was dried over Na2SO4and concentrated to give 4-tert-butyl-2-chlorophenylalanine (56.6 g, 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 0ºC. KNO3(Of 0.53 g, 5.2 mmol) was added in portions over 25 minutes. The reaction mixture was stirred for 1.5 hours and poured into ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with aqueous solution of NaHCO3, dried over Na2SO4and concentrated under vacuum to obtain� 4-tert-butyl-2-chloro-5-nitrophenylarsonic (41,0 g), which was used without further purification.

4-tert-butyl-2-chloro-5-nitro-phenol

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 minutes the reaction mixture was acidified with 1N HCl solution and was extracted with dichloromethane. The combined organic layers were pooled, dried over Na2SO4and concentrated in vacuum. The crude residue was purified by column chromatography (petroleum ether/EtOAc, 30:1) to give 4-tert-butyl-2-chloro-5-nitro-phenol (23,0 g, 68% over 2 stages).

C-11; 4-tert-butyl-2-chloro-5-amino-phenol

To a solution of 4-tert-butyl-2-chloro-5-nitro-phenol (12.6 g, 54,9 mmol) in MeOH (50 ml) was added Ni (1.2 g). The reaction mixture was shaken in an atmosphere of H2(1 ATM) for 4 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc, 20:1) to give 4-tert-butyl-2-chloro-5-amino-phenol (C-11) (8.5 g, 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-methyl-phenylethylamine

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 dichloro methane� (8 ml), chilled in a bath of ice-water to 0ºC. The mixture was allowed to warm to room temperature while stirring overnight, then filtered and the filtrate concentrated. The residue was purified by column chromatography (10-20% ethyl acetate-hexane) to give 2-adamantyl-4-methyl-phenylethylamine in the form of a yellow oil (1,32 g, 94%).

2-Adamantyl-4-methyl-5-nitrophenylarsonic

To a chilled solution of 2-adamantyl-4-methyl-phenylethylamine (1,32 g, 4.2 mmol) in H2SO4(98%, 10 ml) was added KNO3(510 mg, 5.0 mmol) in small portions at 0ºC. The mixture was stirred for 3 hours while warming to room temperature, poured into ice and then extracted with dichloromethane. The combined organic layers were washed with NaHCO3and saturated brine, dried over MgSO4and concentrated to dryness. The residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-adamantyl-4-methyl-5-nitrophenylacetate (378 mg, 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, were absorbed on silica gel under reduced pressure and was purified flash chromatography on silica gel (0-15%, EtOAc-hexane) to give 2-adamantyl-4-m�Teal-5-NITROPHENOL (231 mg, 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 Pd-5% wt. on carbon (10 mg). The mixture was stirred in the atmosphere of H2(1 ATM) overnight and then filtered through Celite. The filtrate was evaporated to dryness to obtain 2-adamantyl-4-methyl-5-aminophenol (C-12), which was used without further purification. HPLC retention time 2,52 minutes, 10-99% CH3CN, 5 min cycle; 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 the addition the mixture was stirred at room temperature overnight and then the solvent was removed. Was added petroleum ether (1000 ml) and the resulting white precipitate was filtered. The filtrate was concentrated under reduced pressure to obtain crude 2-tert-butyl-4-bromophenol (380 g), which was 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 this solution was added dropwise methylchloroform (155 ml) at 0ºC. After the addition the mixture was stirred at 0ºC for chasov, was quenched with saturated aqueous ammonium chloride and diluted with water. The organic layer was separated and washed with water and saturated brine, dried over Na2SO4and concentrated to give crude methyl (2-tert-butyl-4-bromophenyl)carbonate (470 g), which was 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 0ºC. Was added in portions KNO3(253 g, 2.5 mol) in 90 minutes. The reaction mixture was stirred at 0ºC for 2 hours and poured into ice water (20 l). The precipitate that formed was collected by filtration and thoroughly washed with water, dried and recrystallized from simple ether to obtain methyl (2-tert-butyl-4-bromo-5-nitrophenyl)carbonate (332 g, 60% for stage 3).

C-14-a; 2-tert-butyl-4-bromo-5-nitro-phenol

To a solution of methyl (2-tert-butyl-4-bromo-5-nitrophenyl)carbonate (121,5 g, 0,366 mol) in methanol (1000 ml) was added potassium hydroxide (30.75 per g, 0,549 mol) in portions. After the addition the mixture was stirred at room temperature for 3 hours and acidified with 1N HCl solution to pH 7. The methanol was removed and water was added. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over Na2SO4and concentrated to give tert-butyl-4-bromo-5-nitro-phenol (C-14-a) (100 g, 99%).

1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene

To a mixture of 2-tert-butyl-4-bromo-5-NITROPHENOL (C-14-a) (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 the help of H2O and extracted twice using EtOAc. The combined organic layers were washed with saturated brine and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography (0-5% EtOAc-hexane) to give 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (1.37 g, 94%).1H NMR (400 MHz, CDCl3) A 7.62 (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 125ºC in a sealed tube overnight, cooled to room temperature, diluted with water and extracted three times using EtOAc. The combined organic layers were washed with saturated brine and dried over anhydrous MgSO4. After removal of solvent, the residue was purified by column chromatography (0-5% EtOAc-hexane) to give 1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-�of nitrobenzol (591 mg, 67%).1H NMR (400 MHz, CDCl3) 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-trifluoromethyl-phenol

To be heated at the temperature of reflux to a solution of 1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (353 mg, 1.0 mmol) and ammonium formate (350 mg, 5.4 mmol) in EtOH (10 ml) was added 10% Pd-C (245 mg). The mixture was boiled to reflux for 2 hours, cooled to room temperature and filtered through Celite. After removal of solvent, the residue was purified by column chromatography to obtain 5-amino-2-tert-butyl-4-trifluoromethyl-phenol (C-14) (120 mg, 52%).1H NMR (400 MHz, CDCl3) δ 7,21 (s, 1H), to 6.05 (s, 1H), of 1.28 (s, 9H); HPLC retention time 3,46 min, 10-99 % CH3CN, 5 min. cycle; ESI-MS 234,1 m/z (MH+).

Example 10:

General scheme:

a) ArB(OH)2, K2CO3, Pd(PPh3)4, H2O, DMF or ArB(OH)2, (dppf)PdCl2, K2CO3Hcl , EtOH; (b) H2, Raney-Ni, MeOH or HCO2NH4, Pd-C, EtOH or SnCl2.2H2O.

Special example:

2-tert-butyl-4-(2-ethoxyphenyl)-5-NITROPHENOL

To a solution of 2-tert-butyl-4-bromo-5-NITROPHENOL (C-14-a) (8,22 g, 30 mmol) in DMF (90 ml) was added 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 90ºC for 3 hours in a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was distributed between water and ethyl acetate. The combined organic layers were washed with water and saturated brine, dried and purified by column chromatography (petroleum ether-ethyl acetate, 10:1) to give 2-tert-butyl-4-(2-ethoxyphenyl)-5-NITROPHENOL (9,2 g, 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 (square, 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+).

C-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 Ni (300 mg). The mixture was stirred in the atmosphere of H2(1 ATM) at room temperature for 2 hours. The catalyst was filtered and the filtrate concentrated. The residue was purified by column chromatography (petroleum ether-etoac 6:1) to give 2-tert-butyl-4-(2-ethoxyphenyl)-5-aminophenol (C-15) (2.35 g, 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 (square, 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 examples:

C-16; 2-tert-butyl-4-(3-ethoxyphenyl)-5-aminophenol

2-tert-butyl-4-(3-idoxifene�)-5-aminophenol (C-16) was synthesized in accordance with the General scheme, presented above, based on 2-tert-butyl-4-bromo-5-NITROPHENOL (C-14-a) and 3-ethoxypropionate acid. HPLC retention time 2.77 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 286,1 m/z (MH+).

C-17; 2-tert-butyl-4-(3-ethoxycarbonylphenyl)-5-aminophenol (C-17)

2-tert-butyl-4-(3-ethoxycarbonylphenyl)-5-aminophenol (C-17) was synthesized in accordance with the General scheme above, on the basis of 2-tert-butyl-4-bromo-5-NITROPHENOL (C-14-a) and 3-(methoxycarbonyl)phenylboronic acid. HPLC retention time 2.70 minutes, 10-99% CH3CN, 5 min cycle; 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-a) (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 the help of H2O and extracted twice using EtOAc. The combined organic layers were washed with saturated brine and dried over MgSO4. After removal of solvent, the residue was washed with hexane to obtain 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (1.1 g, 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

The mixture Tret-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 125ºC in a sealed tube overnight, cooled to room temperature, diluted with water and extracted three times using EtOAc. The combined organic layers were washed with saturated brine and dried over anhydrous MgSO4. After removal of solvent, the residue was purified by column chromatography (0-5% EtOAc-hexane) to give 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene (512 mg, 61%).1H NMR (400 MHz, CDCl3) δ 7,60 (s, 1H), 7,29 (s, 1H), 3,90 (s, 3H), of 1.33 (s, 9H).

C-18; 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-aminobenzoyl

To be heated at the temperature of reflux to a solution of 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene (473 mg, 1.7 mmol) and ammonium formate (473 mg, 7.3 mmol) in EtOH (10 ml) was added 10% Pd-C (200 mg). The mixture was boiled to reflux for 1 hour, cooled and filtered through Celite. The solvent was removed by evaporation to obtain 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-aminobenzene (C-18) (403 mg, 95%).1H NMR (400 MHz, CDCl3) δ of 7.19 (s, 1H), 6,14 (s, 1H), was 4.02 (lat.s, 2H), 3,74 (s, 3H), 1,24 (s, 9H).

Example 12:

C-27; 2-tert-butyl-4-bromo-5-amino-phenol

To a solution of 2-tert-butyl-4-bromo-5-nitrophen�La (C-14-a) (12 g, To 43.8 mmol) in MeOH (90 ml) was added Ni (2.4 g). The reaction mixture was stirred in the atmosphere of H2(1 ATM) for 4 hours. The mixture was filtered and the filtrate concentrated. The crude product is recrystallized from ethyl acetate and petroleum ether to obtain 2-tert-butyl-4-bromo-5-amino-phenol (C-27) (7.2 g, 70%).1H NMR (DMSO-d6) δ 9.15, with (s, 1H), 6,91 (s, 1H), for 6.24 (s, 1H), 4,90 (lat.s, 2H), 1,22 (s, 9H); ESI-MS 244,0 m/z (MH+).

Example 13:

C-24; 2,4-Di-tert-butyl-6-(N-methylamino)phenol

A mixture of 2,4-di-tert-butyl-6-amino-phenol (C-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 at reflux for 3 hours. After removal of solvent, the residue was purified by column chromatography (petroleum ether-EtOAc, 30:1) to give 2,4-di-tert-butyl-6-(N-methylamino)phenol (C-24) (800 mg, 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-phenyl-propane-1-ol

To a solution of 2-methyl-2-phenyl-propionic acid (82 g, 0.5 mol) in THF (200 ml) was added dropwise borane-dimethyl sulfide (2M, 100 ml) at 0-5ºC. The mixture was stirred at this temperature for 30 minutes and then heated at the boiling point with reverse �holodilnik for 1 hour. After cooling, was added methanol (150 ml) and water (50 ml). The mixture was extracted using EtOAc (100 ml ×3) and combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated to give 2-methyl-2-phenyl-propane-1-ol as an oil (70 g, 77%).

2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-benzene

To a suspension of NaH (29 g, 0.75 mol) in THF (200 ml) was added dropwise a solution of 2-methyl-2-phenyl-propane-1-ol (75 g, 0.5 mol) in THF (50 ml) at 0ºC. The mixture was stirred at 20ºC for 30 minutes and then was added dropwise a solution of 1-bromo-2-methoxy-ethane (104 g, 0.75 mol) in THF (100 ml) at 0ºC. The mixture was stirred at 20 ° C overnight, poured into water (200 ml) and extracted using EtOAc (100 ml ×3). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to give 2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-benzene as an oil (28 g, 27%).

1-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-4-nitro-benzene

To a solution of 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-benzene (52 g, 0.25 mol) in CHCl3(200 ml) was added KNO3(50.5 g, 0.5 mol) and TMSCl (54 g, 0.5 mol). The mixture was stirred at 20ºC for 30 minutes and then was added AlCl3(95 g, 0.7 mole). The reaction mixture was stirred at 20ºC in those�Linux 1 hour and poured into ice water. The organic layer was separated and the aqueous layer was extracted with using CHCl3(50 ml ×3). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to give 1-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-4-nitro-benzene (6 g, 10%).

4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine

A suspension of 1-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-4-nitro-benzene (8.1 g, 32 mmol) and Raney Ni (1 g) in MeOH (50 ml) was stirred under atmosphere of H2(1 ATM) at room temperature for 1 hour. The catalyst was filtered and the filtrate concentrated to give 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine (5.5 g, 77%).

4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine

To a solution of 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine (5.8 g, 26 mmol) in H2SO4(20 ml) was added KNO3(2,63 g, 26 mmol) at 0ºC. After completion of the addition the mixture was stirred at this temperature for 20 minutes and then was poured into ice water. The mixture was extracted using EtOAc (50 ml ×3). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to give 4-[2(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5 g, 71%).

N-{4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide

To a suspension of NaHCO3(10 g, 0.1 mol) in dichloromethane (50 ml) was added 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5 g, 30 mmol) and acetyl chloride (3 ml, 20 mmol) at 0-5ºC. The mixture was stirred overnight at 15 ° C and then poured into water (200 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 ml ×2). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated to dryness to obtain N-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide (5.0 g, 87%).

N-{3-Amino-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide

A mixture of N-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide (5 g, 16 mmol) and Raney Ni (1 g) in MeOH (50 ml) was stirred under atmosphere of H2(1 ATM) at room temperature for 1 hour. The catalyst was filtered and the filtrate concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to give N-{3-amino-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (1.6 g, 35%).

N-{3-Hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide

To a solution of N-{3-amino-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (1.6 g, 5.7 mmol) in H2SO4(15%, 6 ml) was added NaNO2at 0-5ºC. Mixture� stirred at this temperature for 20 minutes and then was poured into ice water. The mixture was extracted using EtOAc (30 ml ×3). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to give N-{3-hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (0.7 g, 38%).

C-25; 2-(1-(2-Methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol

A mixture of N-{3-hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (1 g, 3.5 mmol) and HCl (5 ml) was heated at boiling point with reflux for 1 hour. The mixture was podslushivaet solution of Na2CO3to pH 9 and then extracted using EtOAc (20 ml ×3). The combined organic layers were washed with water and saturated brine, dried over Na2SO4and concentrated to dryness. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to give 2-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol (C-25) (61 mg, 6%).1H NMR (CDCl3) δ 9,11 (lat.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) slowly add�ulali HNO 3(15 ml). The mixture was heated at 60ºC for 40 minutes, then poured into H2O (50 ml). The mixture was allowed to stand at room temperature for 2 hours, then placed in an ice bath for 1 hour. The solid is collected and washed with water to obtain 4,6-di-tert-butyl-3-nitrocyclohexane-3,5-diene-1,2-dione (1.2 g, 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

In the separating funnel was placed THF/H2O (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 separating funnel was corked and shaken for 2 minutes. The mixture was diluted using EtOAc (20 ml). The layers were separated and the organic layer was washed with saturated brine, dried over MgSO4and concentrated to give 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (3.4 g, 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 Pd-5% wt. on carbon (200 mg). The mixture was stirred in the atmosphere of H2(1 ATM) for 2 hours. In the reaction mixture is again loaded Pd-5% wt. on carbon (200 mg) and stirred in the atmosphere of H2 (1 ATM) for 2 hours. The mixture was filtered through Celite and the filtrate was concentrated and was purified column chromatography (10-40% ethyl acetate-hexane) to give 4,6-di-tert-butyl-3-aminobenzene-1,2-diol (C-26) (560 mg, 33%).1H NMR (400 MHz, CDCl3) δ 7,28 (s, 1H), of 1.42 (s, 9H), to 1.38 (s, 9H).

Aniline

Example 1:

General diagram

Special example:

D-1; 4-Chloro-benzene-1,3-diamine

A mixture of 1-chloro-2,4-dinitro-benzene (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. Added water and then the mixture was podslushivaet to pH 7-8 with a saturated solution NaHCO3. The solution was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered and concentrated to give 4-chloro-benzene-1,3-diamine (D-1) (79 mg, quantitative). HPLC retention time 0,38 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS of 143.1 m/z (MH+)

Other examples:

D-2; 4,6-Dichloro-benzene-1,3-diamine

4,6-Dichloro-benzene-1,3-diamine (D-2) was synthesized in accordance with the General scheme above, on the basis of 1,5-dichloro-2,4-dinitro-benzene. Yield (95%). HPLC retention time 1.88 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 177,1 m/z (MH+/sup> ).

D-3; 4-Methoxy-benzene-1,3-diamine

4-Methoxy-benzene-1,3-diamine (D-3) was synthesized in accordance with the General scheme above, on the basis of 1-methoxy-2,4-dinitro-benzene. Output (quantitative). HPLC retention time 0,31 minutes, 10-99% CH3CN, 5 min cycle.

D-4; 4-Triptoreline-benzene-1,3-diamine

4 Triptoreline-benzene-1,3-diamine (D-4) was synthesized in accordance with the General scheme above, on the basis of 2,4-dinitro-1-triptoreline-benzene. Output (89%). HPLC retention time of 0.91 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 193,3 m/z (MH+).

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

4-Propoxybenzene-1,3-diamine (D-5) was synthesized in accordance with the General scheme presented above, based on 5-nitro-2-propoxy-phenylamine. Output (79%). HPLC retention time 0.54 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 167,5 m/z (MH+).

Example 2:

General diagram

(a) HNO3, H2SO4; (b) SnCl2.2H2O, EtOH or H2, Pd-C, MeOH

Special example:

2,4-Dinitro-propylbenzene

A solution of propylbenzene (10 g, 83 mmol) in concentrated H2SO4(50 ml) was cooled at 0ºC for 30 minutes and was added in portions a solution of kontsentrirovano�th H 2SO4(50 ml) and fuming HNO3(25 ml), previously cooled to 0ºC for 15 minutes. The mixture was stirred at 0ºC for 30 minutes and then allowed to warm to room temperature. The mixture was poured into ice (200 g) - water (100 ml) and was extracted with simple ether (2×100 ml). The combined extracts were washed with H2O (100 ml) and saturated brine (100 ml), dried over MgSO4, filtered and concentrated to give 2,4-dinitro-propylbenzene (15.6 g, 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-Propyl-benzene-1,3-diamine

To a solution of 2,4-dinitro-propylbenzene (2,02 g, 9.6 mmol) in ethanol (100 ml) was added SnCl2(9,9 g, 52 mmol) followed by the addition of concentrated HCl (10 ml). The mixture was boiled to reflux for 2 hours, poured into ice water (100 ml) and neutralized with solid sodium bicarbonate. The solution was further podslushivaet 10% NaOH to pH~10 and extracted with simple ether (2×100 ml). The combined organic layers were washed with saturated brine (100 ml), dried over MgSO4, filtered and concentrated to give 4-propyl-benzene-1,3-diamine (D-6) (1.2 g, 83%). Not required no further purification for use at the next stage; however, the product has not been with�abellinum over an extended 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 (lat.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 in accordance with 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 in accordance with the General scheme above, on the basis of isopropylbenzene. Overall yield (78%).

D-9; 4-tert-butylbenzoyl-1,3-diamine

4-tert-butylbenzoyl-1,3-diamine (D-9) was synthesized in accordance with 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 (W, 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:

General diagram

a) KNO3, H2SO4; (b) (i) HNO3, H2SO4; (ii) Na2S, S, H2O; c) Boc2O, NaOH, THF; (d) H2, Pd-C, MeOH

Special example:

4-tert-butyl-3-nitro-phenylamine

To a mixture of tert-butyl phenylamine (10.0 g, 67,01 mmol) dissolved in H2SO4(98%, 60 ml), was slowly added KNO3(8.1 g, 80,41 mmol) at 0ºC. After the addition the reaction mixture was allowed to warm to room temperature and stirred over night. The mixture then was poured into ice water and was podslushivaet saturated solution NaHCO3to pH 8. The mixture was extracted several times with CH2Cl2. The combined organic layers were washed with saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10:1) to give 4-tert-butyl-3-nitro-phenylamine (10 g, 77%).

tert-butyl ether (4-tert-butyl-3-nitro-phenyl)-carbamino acid

A mixture of 4-tert-butyl-3-nitro-phenylamine (4.0 g, 20.6 mmol) and Boc2O (4,72 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 using CH2Cl2. The organic layer was washed with NaHCO3andsaturated brine, dried over Na2SO4and concentrated to give tert-butyl ether (4-tert-butyl-3-nitro-phenyl)-carbamino acid (4.5 g, 74%).

D-10; tert-butyl methyl ether (3-amino-4-tert-butyl-phenyl)-carbamino acid

A suspension of tert-butyl methyl ether (4-tert-butyl-3-n�tro-phenyl)-carbamino acid (3.0 g, 10,19 mol) and 10% Pd-C (1 g) in MeOH (40 ml) was stirred under atmosphere of H2(1 ATM) at room temperature over night. After filtration the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether-EtOAc, 5:1) to give tert-butyl methyl ether (3-amino-4-tert-butyl-phenyl)-carbamino acid (D-10) in the form of a brown oil (2.5 g, 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 (lat.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-amino-4-isopropyl-phenyl)-carbamino acid

tert-Butyl methyl ether (3-amino-4-isopropyl-phenyl)-carbamino acid (D-11) was synthesized in accordance with the General scheme above, on the basis of isopropylbenzene. Overall yield (56%).

D-12; tert-butyl methyl ether (3-amino-4-ethyl-phenyl)-carbamino acid

tert-Butyl methyl ether (3-amino-4-ethyl-phenyl)-carbamino acid (D-12) was synthesized in accordance with 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), is 6.81 (d, J=2,2 Hz, 1H), 6,63 (DD, J=8,1, J=2,2, 1H), 2,47 (sq, J=7,4 Hz, 2H), 1,50 (s, 9H), 1,19 (t, J=7,4 Hz, 3H); ESI-MS 237,1 m/z (MH+).

D-13; tert-butyl methyl ether (3-amino-4-propyl-phenyl)-carbamino�th acid

tert-Butyl methyl ether (3-amino-4-propyl-phenyl)-carbamino acid (D-13) was synthesized in accordance with the General scheme presented above, based on propylbenzene. Overall yield (48%).

Example 4:

Benzyl ether (3-amino-4-tert-butyl-phenyl)-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 CH2Cl2/MeOH (12/1, 8 ml) was cooled to 0ºC was added dropwise a solution of benzylchloride (of 0.51 ml, 3.6 mmol) in CH2Cl2(8 ml) for 10 minutes. The mixture was stirred at 0ºC for 15 minutes, then was warmed to room temperature. After 1 hour the mixture was washed with a solution of 1M citric acid (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-butyl-phenyl)-carbamino acid in the form of a brown viscous resin (0,97 g), which was 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 (lat.s, 1H), to 6.57 (DD, J=2,3, 8,5 Hz, 1H), 5,17 (s, 2H), 3,85 (lat.s, 2H), 1,38 (s, 9H);13C NMR (100 MHz, CDCl3, rotameric) δ 153,3 (Shire.), 145,3, 136,56, 136,18, 129,2, 128,73, 128,59, 128,29, 128,25, 127,14, 108,63 (Shir.), 107,61 (W), 66,86, 33,9, 29,7; ESI-MS 299,1 m/z (MH+).

Benzyl ether (4-tert-butyl-3-formylamino-Hairdryer�l) is carbamino acid

A solution of benzyl ether (3-amino-4-tert-butyl-phenyl)-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 0ºC was added dropwise a solution of 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.) pure and ageing for 1 hour) in CH2Cl2(2.5 ml) for 2 minutes. After completion of the addition the mixture was allowed to warm to room temperature, there was a formation of precipitate, and the resulting suspension was stirred over night. The mixture was washed with a solution of 1 M citric acid (2×20 ml), saturated aqueous sodium bicarbonate solution (20 ml), dried (Na2SO4) and was filtered. From turbid mixture was deposited a thin layer of solids on the dehumidifier, HPLC analysis showed that it is desired formamide. The filtrate was concentrated to approximately 5 ml and diluted with hexane (15 ml) to precipitate further quantities of formamide. Dehumidifier (Na2SO4) suspended with methanol (50 ml), filtered, and the filtrate was combined with the substance of recrystallization from CH2Cl2/hexane. The resulting mixture was concentrated to give benzyl ester (4-tert-butyl-3-formylamino-phenyl)-carbamino acid as an off-b�logo solid (650 mg, 50% over 2 stages).1H and13C NMR (CD3OD) showed a product in the form retornou mixture.1H NMR (400 MHz, CD3OD, rotameric) 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, rotameric) δ 1636,9, 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 (Shir.), 118,7 (Shire.), 67,80, 67,67, 35,78, 35,52, 31,65, 31,34; ESI-MS of 327.5 m/z (MH+).

N-(5-Amino-2-tert-butyl-phenyl)-formamide

In a 100 ml flask was loaded with benzyl ether (4-tert-butyl-3-formylamino-phenyl)-carbamino acid (650 mg, 1.99 mmol), methanol (30 ml) and 10% Pd-C (50 mg) and stirred in the atmosphere of H2(1 ATM) for 20 hours. Added CH2Cl2(5 ml) to quench the catalyst and the mixture then filtered through Celite and concentrated to give N-(5-amino-2-tert-butyl-phenyl)-formamide as an off-white solid (366 mg, 96%). Rotameric according to the data1H and13C NMR (DMSO-d6).1H NMR (400 MHz, DMSO-d6, rotameric) 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-d6, rotamer) 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 -methyl-benzene-1,3-diamine

In a 100 ml flask was loaded with N-(5-amino-2-tert-butyl-phenyl)-formamide (340 mg, 1,77 mmol) and purged with nitrogen. Was added THF (10 ml) and the solution was cooled to 0ºC. Added a solution of hydride in THF (4.4 ml, 1M solution) for 2 minutes. The mixture was then allowed to warm to room temperature. After boiling to reflux for 15 hours yellow suspension was cooled to 0ºC, was quenched with water (170 μl), 15% aqueous NaOH (170 ml) and water (510 μl) were added sequentially, and stirred at room temperature for 30 minutes. The mixture was filtered through Celite and the filter cake was washed with methanol (50 ml). The combined filtrates were concentrated in vacuum to give a gray-brown solid which was partitioned between chloroform (75 ml) and water (50 ml). The organic layer was separated, washed with water (50 ml), dried (Na2SO4), filtered and concentrated to give 4-tert-butyl-N3-methyl-benzene-1,3-diamine (D-14) in the form of a brown oil, which hardens when left standing (313 mg, 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 (lat.s, 1H), 3,52 (lat.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:

General scheme:

Special example:

2,4-Dinitro-propylbenzene

A solution of propylbenzene (10 g, 83 mmol) in concentrated H2SO4(50 ml) was cooled at 0ºC for 30 minutes and was added in portions a solution of concentrated H2SO4(50 ml) and fuming HNO3(25 ml), previously cooled to 0ºC for 15 minutes. The mixture was stirred at 0ºC for 30 minutes and then allowed to warm to room temperature. The mixture was poured into ice (200 g) - water (100 ml) and was extracted with simple ether (2×100 ml). The combined extracts were washed with H2O (100 ml) and saturated brine (100 ml), dried over MgSO4, filtered and concentrated to give 2,4-dinitro-propylbenzene (15.6 g, 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-dinitro-propylbenzene (2 g, 9.5 mmol) in H2O (100 ml) was heated at a temperature of about the boiling point with reflux and intensively stirred. Was added dropwise transparent orange-red solution of polysulfide (300 ml (10 EQ.), pre-obtained by heating sodium sulfide of managerat (10.0 g), sulfur powder (2,60 g) and (H2O (400 ml) for 45 minutes. The red-brown solution was heated at those�the temperature of reflux for 1.5 hours. The mixture was cooled to 0ºC and then was extracted with simple ether (2×200 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to obtain 4-propyl-3-nitroaniline (1.6 g, 93%) which was used without further purification.

tert-butyl methyl ether (3-nitro-4-propyl-phenyl)-carbamino acid

4-Propyl-3-nitroaniline (1,69 g, 9.4 mmol) was dissolved in pyridine (30 ml) with stirring. Was added Boc anhydride (2.05 g, 9.4 mmol). The mixture was stirred and heated at boiling point with reflux for 1 hour, then the solvent was removed under vacuum. The resulting oil was again dissolved in CH2Cl2(300 ml) and washed with water (300 ml) and saturated brine (300 ml), dried over Na2SO4, filtered and concentrated. Crude oil, which contained both mono-and bis-acylated microproduct, was purified column chromatography (0-10% CH2Cl2-MeOH) to give tert-butyl methyl ether (3-nitro-4-propyl-phenyl)-carbamino acid (2.3 g, 87%).

tert-butyl ether methyl-(3-nitro-4-propyl-phenyl)-carbamino acid

To a solution of tert-butyl methyl ether (3-nitro-4-propyl-phenyl)-carbamino acid (200 mg, 0.71 mmol) in DMF (5 ml) was added Ag2O (1.0 g, 6.0 mmol) followed by the addition of methyliodide (0.20 ml, 3.2 mmol). Paul�Chennai suspension was stirred at room temperature for 18 hours and was filtered through a layer of Celite. The filter cake was washed using CH2Cl2(10 ml). The filtrate was concentrated in vacuum. The crude oil was purified column chromatography (0-10% CH2Cl2-MeOH) to obtain tert-butyl ether methyl-(3-nitro-4-propyl-phenyl)-carbamino acid as a yellow oil (110 mg, 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), of 0.97 (t, J=7,4 Hz, 3H).

D-15; tert-butyl methyl ether (3-amino-4-propyl-phenyl)-methyl-carbamino acid

To a solution of tert-butyl methyl ether-(3-nitro-4-propyl-phenyl)-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. Rasva of the reaction was monitored using TLC. After completion of the addition the reaction mixture was filtered through a layer of Celite. The filtrate was concentrated in vacuum to give tert-butyl methyl ether (3-amino-4-propyl-phenyl)-methyl-carbamino acid (D-15) as a colorless crystalline compound (80 mg, 81%). ESI-MS 265,3 m/z (MH+).

Other examples:

D-16; tert-butyl methyl ether (3-amino-4-ethyl-phenyl)-methyl-carbamino acid

tert-Butyl methyl ether (3-amino-4-ethyl-phenyl)-methyl-carbamino acid (D-16) sintezirovan�and in accordance with the General scheme, presented above, on the basis of ethylbenzene. Overall yield (57%).

D-17; tert-butyl methyl ether (3-amino-4-isopropyl-phenyl)-methyl-carbamino acid

tert-Butyl methyl ether (3-amino-4-isopropyl-phenyl)-methyl-carbamino acid (D-17) was synthesized in accordance with the General scheme above, on the basis of isopropylbenzene. Overall yield (38%).

Example 6:

2'-Ethoxy-2,4-dinitro-biphenyl

The flask high pressure loaded 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-dinitro-Brabanthal (0,99 g, 4.0 mmol) in THF (5 ml). The vessel was purged with argon for 1 minute followed by the addition of tri-tert-butylphosphine (0.15 ml, 0.48 mmol, 10% solution in hexane). The reaction vessel was purged with argon for a further 1 minute, tightly closed and heated at 80ºC overnight. After cooling to room temperature the solution was filtered through a layer of Celite. The filter cake was washed using CH2Cl2(10 ml) and the combined organic extracts were concentrated under reduced pressure to obtain crude product of 2'-ethoxy-2,4-dinitro-biphenyl (0.95 g, 82%). Do not carry out any further purification.1H NMR (300 MHz, CDCl3) δ of 8.75 (s, 1H), 8,43 (d, J=to 8.7 Hz, 1H), 7,60 (d, J=84 Hz, 1H), 7,40 (t, J=7,8 Hz, 1H), 7,31 (d, J=7.5 Hz, 1H), was 7.08 (t, J=7.5 Hz, 1H), to 6.88 (d, J=8.4 Hz, 1H), 3,44 (kV, J=6,6 Hz, 2H), 1,24 (t, J=6,6 Hz, 3H); HPLC retention time 3.14 minutes, 10-100% CH3CN, 5 min gradient.

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

Transparent orange-red solution of polysulfide (120 ml, 7.5 EQ.), pre-obtained by heating sodium sulfide monohydrate (10 g), sulfur (1.04 g) and water (160 ml) was added dropwise at 90ºC for 45 minutes to a suspension of 2'-ethoxy-2,4-dinitro-biphenyl (1.2 g, 4.0 mmol) in water (40 ml). The red-brown solution was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and was added solid NaCl (5 g). The solution was extracted using CH2Cl2(3×50 ml) and the combined organic extracts were concentrated to give 2'-ethoxy-2-nitrobiphenyl-4-ylamine (0,98 g, 95%) which was 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 2.81 minutes, 10-100% CH3CN, 5 min gradient; 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 Boc2O (2.6 g, 12 mmol) was heated with a hair dryer. After the starting material was consumed, as shown by TLC analysis, 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, 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 (sq, J=6,9 Hz, 2H), 1,50 (s, 9H), of 1.18 (t, J=6,9 Hz, 3H); HPLC retention time 3,30 minutes, 10-100% CH3CN, 5 min gradient.

D-18; tert-butyl ether (2'-ethoxy-2-aminobiphenyl-4-yl)-carbamino acid

To a solution of NiCl2.6H2O (0.26 g, 1.1 mmol) in EtOH (5 ml) was added NaBH4(40 mg, 1.1 mmol) at-10ºC. Watched the evolution of gas, and there was a formation of a black precipitate. After stirring for 5 minutes 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). Added additional amount of NaBH4(80 mg, 60 mmol) in 3 portions over 20 minutes. The reaction mixture was stirred at 0ºC for 20 minutes followed by the addition of NH4OH (4 ml, 25% aqueous solution). The resulting solution was stirred for 20 minutes. The crude mixture was filtered through a short plug of silica. The cake of silica was washed with 5% solution of MeOH in CH2Cl2(10 ml) and the combined organic extracts were concentrated under reduced pressure to obtain tert-butyl�vågå ether (2'-ethoxy-2-aminobiphenyl-4-yl)-carbamino acid (D-18) (0.36 g, quantitative) which was used without further purification. HPLC retention time 2.41 minutes, 10-100% CH3CN, 5 min gradient; ESI-MS 329,3 m/z (MH+).

Example 7:

D-19; N-(3-Amino-5-trifluoromethyl-phenyl)-methanesulfonamide

A solution of 5-trifluoromethyl-benzene-1,3-diamine (250 mg, of 1.42 mmol) in pyridine (0,52 ml) and CH2Cl2(6.5 ml) was cooled to 0ºC. Was slowly added methanesulfonamide (171 mg, 1,49 mmol) at such a rate that the solution temperature remained below 10ºC. The mixture was stirred at ~8ºC and then after 30 minutes, allowed to warm to room temperature. After stirring at room temperature for 4 hours the reaction was practically completed, as shown by LCMS analysis. The reaction was quenched with a saturated aqueous solution of NH4Cl (10 ml), was extracted using CH2Cl2(4×10 ml), dried over Na2SO4, filtered and concentrated to give N-(3-amino-5-trifluoromethyl-phenyl)-methanesulfonamide (D-19) as a reddish semi-solid substances (0.35 g, 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-tetrahydro-quinoline

To a mixture of 1,2,3,4-tetrahydro-quinoline (20.0 g, 0.15 m�l), dissolved in H2SO4(98%, 150 ml) was slowly added KNO3With 18.2 g, 0.18 mol) at 0ºC. The reaction mixture was allowed to warm to room temperature and stirred over night. The mixture then was poured into ice water and was podslushivaet saturated solution NaHCO3to pH 8. After extraction using CH2Cl2the combined organic layers were washed with saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10:1) to give 7-nitro-1,2,3,4-tetrahydro-quinoline (6.6 g, 25%).

tert-butyl ester of 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid

A mixture of 7-nitro-1,2,3,4-tetrahydro-quinoline (4.0 g, 5,61 mmol), Boc2O (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 using CH2Cl2. The combined organic layers were washed with NaHCO3and saturated brine, dried over Na2SO4and concentrated to give crude 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 methyl ether 7-�Jethro-3,4-dihydro-2H-quinoline-1-carboxylic acid (4.5 g, The 16.2 mol) and 10% Pd-C (0.45 g) in MeOH (40 ml) was stirred under atmosphere of H2(1 ATM) at room temperature over night. After filtration the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether-EtOAc, 5:1) to give tert-butyl 7-amino-3,4-dihydroquinoline-1(2H)-carboxylate (DC-1) as a brown solid (1.2 g, 22% over 2 stages).1H NMR (CDCl3) 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 (lat.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-Hydroxy-ethyl)-1,3-dihydro-indol-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 was triturated to powder with hexane to obtain 3-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one as a colorless crystalline solid (4.6 g, 70%).

1,2-Dihydro-3-Spiro-1'-cyclopropyl-1H-indol-2-he

To a solution of 3-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (4.6 g, 26 mmol) and triethylamine (10 ml) in CH2Cl2(100 ml) was added MsCl (3.4 g, 30 mmol) dropwise at-20ºC. The mixture was then allowed to warm to room temperature and stirred over night. The mixture was filtered and the filtrate concentrated under vacuum the Residue was purified by column chromatography to obtain the crude 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indol-2-one as 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, crude) in THF (50 ml) was added LiAlH4(2 g, 52 mmol) in portions. After heating the mixture to a temperature of reflux the mixture was poured into crushed ice, podslushivaet aqueous solution of ammonia to pH 8 and extracted using EtOAc. The combined organic layers were washed with saturated brine, dried over Na2SO4and concentrated to give 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 the cooled solution (-5ºC to-10ºC) NaNO3(1.3 g, of 15.3 mmol) in H2SO4(98%, 30 ml) was added 1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (2 g, neocidin) dropwise over 20 minutes. After the addition the reaction mixture was stirred for 40 minutes and poured into crushed ice (20 g). The cooled mixture was then podslushivaet using NH4OH and extracted using EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated under reduced pressure to obtain 6-nitro-1,2-dihydro-3-SP�ro-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). Under vigorous stirring was added dropwise acetyl chloride (720 mg). The mixture was stirred for 1 hour and was filtered. The filtrate was concentrated in vacuum. The residue was purified column flash chromatography on silica gel to obtain 1-acetyl-6-nitro-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (0.9 g, 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 and the filtrate was concentrated under reduced pressure. The residue was processed using HCl/MeOH to obtain 1-acetyl-6-amino-1,2-dihydro-3-Spiro-1'-cyclopropyl-1H-indole (DC-2) (300 mg, 90%) in the form hydrochloride salt.

Example 3:

Phenylamide 3-methyl-but-2-envoy acid

A mixture of 3-methyl-but-2-envoy acid (100 g, 1 mol) and SOCl2(119 g, 1 mol) was heated at reflux for 3 hours. The excess SOCl2was removed under reduced pressure. Added CH2 Cl2(200 ml) followed by the addition of aniline (93 g, 1.0 mol) in Et3N (101 g, 1 mol) at 0ºC. The mixture was stirred at room temperature for 1 hour and quenched with the help of HCl (5%, 150 ml). The aqueous layer was separated and extracted using CH2Cl2.The combined organic layers were washed with water (2×100 ml) and saturated brine (100 ml), dried over Na2SO4and concentrated to give phenylamide 3-methyl-but-2-envoy acid (120 g, 80%).

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

AlCl3(500 g, 3.8 mol) was carefully added to a suspension of 3-phenylamino methyl-but-2-envoy acid (105 g, 0.6 mol) in benzene (1000 ml). The reaction mixture was stirred at 80ºC overnight and poured into ice water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (250 ml ×3). The combined organic layers were washed with water (200 ml ×2) and saturated brine (200 ml), dried over Na2SO4and concentrated to give 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (90 g, 86%).

4,4-Dimethyl-1,2,3,4-tetrahydro-quinoline

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 0ºC. After the addition the mixture was stirred at room temperature for 30 minutes and then slowly heated to the boiling point of�Ratna refrigerator for 1 hour. The mixture was then cooled to 0ºC. Was carefully added water (18 ml) and NaOH (10%, 100 ml) to quench the reaction. The solids were filtered and the filtrate was concentrated to give 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline.

4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline

To a mixture of 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (33 g, 0.2 mol) in H2SO4(120 ml) was slowly added KNO3(20.7 g, 0.2 mol) at 0ºC. After the addition the mixture was stirred at room temperature for 2 hours, carefully poured into ice water and was podslushivaet with the help of Na2CO3to pH 8. The mixture was extracted with ethyl acetate (3×200 ml). The combined extracts were washed with water and saturated brine, dried over Na2SO4and concentrated to give 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (21 g, 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-tetrahydro-quinoline (25 g, 0.12 mole) and Boc2O (55 g, 0.25 mol) was stirred at 80ºC for 2 days. The mixture was purified by chromatography on silica gel to obtain tert-butyl ether 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid (8 g, 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 �of islote (8.3 g, Of 0.03 mol) and Pd-C (0.5 g) in methanol (100 ml) was stirred under atmosphere of H2(1 ATM) at room temperature over night. The catalyst was filtered and the filtrate concentrated. The residue was washed with petroleum ether to obtain tert-butyl 7-amino-3,4-dihydro-4,4-dimethylindoline-1(2H)-carboxylate (DC-3) (7.2 g, 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 was passed 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 5ºC. 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 using CH2Cl2. The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered and concentrated to give the crude 1-chloro-4-methylpentan-3-it, 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 at the boiling point from about�atna fridge over night. After cooling, the insoluble salt was filtered and the filtrate concentrated. The residue was diluted using CH2Cl2, washed with 10% HCl solution (100 ml) and saturated brine, dried over Na2SO4, filtered and concentrated to give crude 4-methyl-1-(phenylamino)-pentane-3-it.

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

At-10ºC, 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 the addition the reaction mixture was allowed to warm to room temperature and stirred for 20 minutes. The solvent was removed and the residue was again partitioned between water and CH2Cl2. The organic phase was separated, washed with saturated brine, dried over Na2SO4, filtered and concentrated. The resulting resin was ground to powder with simple ether to obtain 4-methyl-1-(phenylamino)-pentane-3-ol as a white solid (22 g, 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 50ºC for 30 minutes. The reaction mixture was poured into ice water, podslushivaet saturated solution of NaOH to pH 8 and extracted using CH2Cl2. The combined organic phases were washed with us�saturated saline solution, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (petroleum ether) to give 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine in the form of a brown oil (1.5 g, 8%).

5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin

At 0ºC, KNO3(0,76 g, 7,54 mmol) was added in portions to a solution of 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.1 g, 6,28 mmol) in H2SO4(15 ml). After stirring for 15 minutes at this temperature, the mixture was poured into ice water, podslushivaet saturated solution NaHCO3to pH 8 and extracted using EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated to give 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 was heated at boiling point with reflux for 1 hour. After cooling, the mixture was poured into water and extracted using CH2Cl2.Body�ical layer was washed with saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography to obtain 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone (1.05 g, 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-tetrahydrobenzo[b]azepin-1-yl)ethanone (1.05 g, 40 mmol) and 10% Pd-C (0.2 g) in MeOH (20 ml) was stirred under atmosphere of H2(1 ATM) at room temperature for 4 hours. After filtration the filtrate was concentrated to give 1-(8-amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo[b]azepin-1-yl)ethanone in the form of a white solid (DC-4) (880 mg, 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 (lat.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:

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

A mixture of Spiro[1H-indene-1,4'-piperidine]-1'-carboxylic acid, 2,3-dihydro-3-oxo-, 1,1-dimethylethylene ether (9,50 g, 31,50 mmol) in a saturated solution of HCl/MeOH (50 ml) was stirred at 25ºC during the night. The solvent was removed under reduced pressure to obtain an off-white solid (7,50 g). To a solution of this solid in anhydrous CH3CN (30 ml) was added anhydrous K2CO3(7.85 g, 56,80 mmol). Suspension pyo�amichevoli for 5 minutes and added dropwise to the bromide (5,93 g, 34,65 mmol) at room temperature. The mixture was stirred for 2 hours, then poured into crushed ice and extracted using CH2Cl2. The combined organic layers were dried over Na2SO4and concentrated in vacuum to give crude Spiro[1H-indene-1,4'-piperidine]-3(2H)-it, 1'-benzyl (of 7.93 g, 87%) which was used without further purification.

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

To a solution of Spiro[1H-indene-1,4'-piperidine]-3(2H)-it, 1'-benzyl (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 was boiled to reflux for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and added with 200 ml of water. The mixture was extracted using CH2Cl2. The combined organic layers were dried over Na2SO4and concentrated to give Spiro[1H-indene-1,4'-piperidine]-3(2H)-he, 1'-benzyl, oxime (7.57 the g, 91%) which was used without further purification.

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

To a solution of Spiro[1H-indene-1,4'-piperidine]-3(2H)-he, 1'-benzyl, oxime (7.57 the g, 24,74 mmol) in anhydrous CH2Cl2(150 ml) was added dropwise DIBAL-H (of 135.7 ml, 1M in toluene) at 0ºC. The mixture was stirred at 0ºC for 3 hour�in, was diluted using CH2Cl2(100 ml) and quenched using NaF (20,78 g, 495 mmol) and water (6.7 g, 372 mmol). The resulting suspension was intensively stirred at 0ºC for 30 minutes. After filtration the residue was washed using CH2Cl2. The combined filtrates were concentrated in vacuum to give a brownish oil, which was purified column chromatography on silica gel (CH2Cl2-MeOH, 30:1) to give 1,2,3,4-tetrahydroquinolin-4-Spiro-4'-(N'-benzyl-piperidine) (2.72 g, 38%).

1,2,3,4-Tetrahydroquinolin-4-Spiro-4'-piperidine

A suspension of 1,2,3,4-Tetrahydroquinolin-4-Spiro-4'-(N'-benzyl-piperidine) (300 mg, of 1.03 mmol) and Pd(OH)2-C (30 mg) in MeOH (3 ml) was stirred under atmosphere of H2(55 f/inch2(3,867 kg/cm2)) at 50 ° C over night. After cooling, the catalyst was filtered and washed using MeOH. The combined filtrates were concentrated under reduced pressure to obtain 1,2,3,4-tetrahydroquinolin-4-Spiro-4'-piperidine as a white solid (176 mg, 85%) which was used without further purification.

tert-butyl ether 7'-Nitro-Spiro[piperidine-4,4'(1'H)-quinoline], 2',3'-dihydro-carboxylic acid

KNO3(69,97 mg, 0.69 mmol) was added in portions to a suspension of 1,2,3,4-tetrahydroquinolin-4-Spiro-4'-piperidine (133 mg, 0.66 mmol) in 98% H2SO4(2 ml) at 0ºC. After zabavljanjeasian the mixture was allowed to warm to room temperature and stirred for another 2 hours. The mixture then was poured onto crushed ice and podslushivaet 10% NaOH to pH~8. Was added dropwise Boc2O (172 mg, 0.79, which mmol) and the mixture stirred at room temperature for 1 hour. The mixture was then extracted using EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated to give crude tert-butyl ether 7'-nitro-Spiro[piperidine-4,4'(1'H)-quinoline], 2',3'-dihydro-carboxylic acid (230 mg), which was used for next step without further purification.

tert-butyl ether 7'-nitro-Spiro[piperidine-4,4'(1'H)-1-acetyl-quinoline], 2',3'-dihydro-carboxylic acid

Acetyl chloride (260 mg, 3,30 mmol) was added dropwise to a suspension of tert-butyl methyl ether 7'-nitro-Spiro[piperidine-4,4'(1'H)-quinoline], 2',3'-dihydro-carboxylic acid (230 mg) and NaHCO3(1.11 g, 13,17 mmol) in MeCN (5 ml) at room temperature. The reaction mixture was boiled with reflux for 4 hours. After cooling, the suspension was filtered and the filtrate concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10:1) to give tert-butyl ether 7'-nitro-Spiro[piperidine-4,4'(1'H)-1-acetyl-quinoline], 2',3'-dihydro-carboxylic acid (150 mg, 58% over 2 stages).

DC-5; tert-butyl ether 7'-Amino-Spiro[piperidine-4,4'(1'H)-1-acetyl-quinoline], 2',3'-dihydro-carboxylic acid

�Uspenskiy tert-butyl ether 7'-nitro-Spiro[piperidine-4,4'(1'H)-1-acetyl-quinoline], 2',3'-dihydro-carboxylic acid (150 mg, 0,39 mmol) and Raney Ni (15 mg) in MeOH (2 ml) was stirred under atmosphere of H2(1 ATM) at 25 ° C during the night. The catalyst was removed by filtration and washed using MeOH. The combined filtrates were dried over Na2SO4, filtered and concentrated to give tert-butyl ether 7'-amino-Spiro[piperidine-4,4'(1'H)-1-acetyl-quinoline], 2',3'-dihydro-carboxylic acid (DC-5) (133 mg, 96%).

Example 7:

2-(2,4-Dinitrophenyl)-acetic acid

Et3N (1.5 g, 15 mmol) and merkapto-acetic 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 was added H2O (100 ml). The resulting suspension was extracted with ethyl acetate (100 ml ×3). Ethylacetate the extract was washed with water and saturated brine, dried over Na2SO4and concentrated to give 2-(2,4-dinitrophenyl)-acetic acid (2.3 g, 74%) which was 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 tin chloride(II) dihydrate (22.6 g, 0.1 mol) in ethanol (30 ml) was heated to reflux over night. After removal of the solvent in Pont�located the pressure of the remaining slurry was diluted with water (100 ml) and podslushivaet 10% solution of Na 2CO3to pH 8. The resulting suspension was extracted with ethyl acetate (3×100 ml). Ethylacetate the extract was washed with water and saturated brine, dried over Na2SO4and concentrated. The residue was washed using CH2Cl2obtaining 6-amino-2H-benzo[b][1,4]thiazin-3(4H)-she (DC-7) as a yellow powder (1 g, 52%)1H NMR (DMSO-d6) δ 10.24 per (s, 1H), to 6.88 (d, 1H, J=6 Hz), 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 25ºC. The reaction mixture was stirred at room temperature overnight and then poured into water. The precipitate was collected by filtration, washed with water and dried in vacuum to give N-(2-bromo-5-nitrophenyl)acetamide as an off-white solid (3.6 g, 90%).

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

At 25ºC, the 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 25ºC during the night. The reaction mixture then was filtered and the filtrate is processed by�and a saturated solution of Na 2CO3. The organic layer was separated and the aqueous layer was extracted using EtOAc. The combined organic extracts were washed with water and saturated brine, dried over MgSO4, filtered and concentrated in vacuum to give N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide in the form of a Golden solid (3.1 g, 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 80ºC for 15 hours in an atmosphere of N2. After cooling, the mixture was filtered through Celite. Celite was washed with the aid of EtOAc and the combined filtrates were washed with saturated solution of NaHCO3. The separated organic layer was washed with water and saturated brine, dried over MgSO4,was filtered and concentrated under reduced pressure to obtain 1-(3,3-dimethyl-6-nitroindoline-1-yl)ethanone in the form of a brown solid (2.1 g, 88%).

DC-8; 1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-Etalon

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 is�re H 2(40 f/inch2(2,812 kg/cm2)) at room temperature over night. Pd-C was filtered and the filtrate was concentrated in vacuum to give crude product, which was purified column chromatography to obtain 1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (DC-8) (1.3 g, 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-oxime (3 g, 18 mmol) in dichloromethane (50 ml) at 0ºC. The mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with dichloromethane (30 ml), followed by processing with NaF (2 g, 0.36 mole) and H2O (5 ml, 0.27 mole). Intensive stirring of the obtained suspension was kept at 0ºC for 30 minutes. After filtration the filtrate is concentrated. The residue was purified column flash chromatography with getting 2,3,4,5-tetrahydro-1H-benzo[b]azepine in the form of a colorless oil (1.9 g, 70%).

8-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepin

At-10ºC, 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 minutes, then poured into crushed ice, podslushivaet aqueous ammonia solution to pH 13 and extracted using EtOAc. The combined organic phases washed�and saturated brine, dried over Na2SO4and concentrated to give 8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine as a black solid (1.3 g, 51%) which was used without further purification.

1-(8-Nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-Etalon

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 CH2Cl2was washed with saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography to obtain 1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone as a yellow solid (1.3 g, 80%).

DC-9; 1-(8-Amino-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-Etalon

A mixture of 1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (1.3 g, 5.4 mmol) and Pd-C (10%, 100 mg) in EtOH (200 ml) was stirred under atmosphere of H2(1 ATM) at room temperature for 1.5 hours. The mixture was filtered through a layer of Celite and the filtrate concentrated to give 1-(8-amino-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (DC-9) as a white solid (1 g, 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 (lat.s, 2H), 2,64-by 2.55 (m, 3H), 1,94-1,9 (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-one

At 0ºC, 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) for 30 minutes. After the addition the reaction mixture was stirred at 0ºC for 1 hour, then at 50 ° C over night. The solvent was removed under reduced pressure and the residue treated with water (50 ml). The solid is collected by filtration, washed with water and recrystallized from ethanol to obtain 6-nitro-4H-benzo[1,4]oxazine Serie-3-it is in the form of a pale yellow solid (8 g, 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 the aid of MeOH (5 ml) at 0ºC and then added water (20 ml). The mixture was extracted with using the Et2O and the combined organic layers were washed with saturated brine, dried over Na2SO4and concentrated to give 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine Serie a red solid (0.5 g, 89%), and�used without further purification.

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

Under vigorous stirring at room temperature, acetyl chloride (1.02 g, 13 mmol) was added dropwise 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 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 processed with the help of Et2O:hexane (1:2, 50 ml) with stirring for 30 minutes and then filtered to obtain 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine Serie in the form of a pale yellow solid (2 g, 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 under atmosphere of H2(1 ATM) over night. The catalyst was filtered and the filtrate concentrated. The residue was processed using HCl/MeOH to obtain 4-acetyl-6-amino-3,4-dihydro-2H-benzo[1,4]oxazine Serie hydrochloride (DC-10) as an off-white solid (1.1 g, 85%).1H NMR (DMSO-d6)δ 10,12 (lat.s, 2H), 8,08 (lat.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:

1,2,3,4-Tetrahydro-7-nitroisoquinoline hydrochloride

1,2,3,4-Tetrahydro�isoquinoline (6,3 ml 50,0 mmol) was added dropwise to a stirred cooled with ice to a solution of concentrated H2SO4(25 ml). Was added in portions KNO3(5.6 g, 55,0 mmol) while maintaining the temperature below 5ºC. The mixture was stirred at room temperature over night, carefully poured into a chilled ice solution kontsentrirovannoe NH4OH and then extracted three times using CHCl3. The combined organic layers were washed with saturated brine, dried over Na2SO4and concentrated. The obtained dark brown oil was taken for absorption of EtOH, cooled in an ice bath and treated with concentrated HCl. The yellow precipitate was collected by filtration and recrystallized from methanol to obtain 1,2,3,4-tetrahydro-7-nitroisoquinoline hydrochloride as a yellow solid (2.5 g, 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,1H), of 4.38 (s, 2H), 3,38 (s, 2H), 3,17-3,14 (m, 2H); HPLC retention time 0.51 minutes, 10-99% CH3CN, 5 min cycle; 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 (12 ml) was cooled in an ice bath and was added Boc2O (2.8 g, 12.8 mmol). The mixture was stirred at room temperature for 2.5 h�in, was acidified with 5% aqueous KHSO4to pH 2-3 and then extracted using EtOAc. The organic layer was dried over MgSO4and concentrated to give tert-butyl 3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, quantitative) 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 minutes, 10-99% CH3CN, 5 min cycle; 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 an atmosphere of N2. The reaction mixture was stirred in the atmosphere of H2(1 ATM) at room temperature for 72 hours. The solid was removed by filtration through Celite. The filtrate was concentrated and was purified column chromatography (15-35% EtOAc-hexane) to give tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (DC-6) as a pink oil (2.0 g, 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 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 249,0 m/z (MH+).

Other amines

Example 1:

4-Bromo-3-nitrobenzonitrile

To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in concentrated H2SO4(10 ml) was added dropwise at 0ºC nitric acid (6 ml). The reaction mixture was stirred at 0ºC for 30 minutes and then at room temperature for 2.5 hours. The resulting solution was poured into ice water. White precipitate was collected by filtration and washed with water until until the washing became neutral. The solid is recrystallized from a mixture of ethanol/water (1:1, 20 ml) twice to obtain 4-bromo-3-nitrobenzonitrile in the form of a white crystalline solid (2.8 g, 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 1.96 minutes, 10-100% CH3CN, 5 min gradient; ESI-MS 227,1 m/z (MH+).

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

In a 50 ml round bottom flask was loaded with 4-bromo-3-nitrobenzonitrile (1.0 g, 4.4 mmol), 2-ethoxypropionate acid (731 mg, 4.4 mmol), Pd2(dba)3(18 mg, 0,022 mmol) and potassium fluoride (786 mg, 13.5 mmol). In the reaction vessel has created a vacuum and filled with argon. Added anhydrous THF (300 ml) followed by the addition of P(t-Bu)3(0,11 ml, 10% wt. in hexane). The reaction mixture was stirred at room temperature for 30 minutes and then n�gravely at 80ºC for 16 hours. After cooling to room temperature the mixture was filtered through a layer of Celite and concentrated. 2'-Ethoxy-2-nitrobiphenyl-4-carbonitrile was isolated as a yellow solid (1.12 g, 95%).1H NMR (300 MHz, DMSO-d6) δ 8,51 (s, 1H), 8,20 (d, 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 minutes 10-100% CH3CN, 5 min gradient; ESI-MS 269,3 m/z (MH+).

4-Aminomethyl-2'-ethoxy-biphenyl-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 0ºC for 30 minutes. The reaction mixture was stirred at 0ºC for 3 hours and then at room temperature for 15 hours. The reaction solution was cooled to 0ºC and added a mixture of H2O/THF (3 ml). After stirring at room temperature for 6 hours the volatiles removed under reduced pressure. The residue was dissolved in EtOAc (100 ml) and was extracted with 1N HCl solution (2×100 ml). The aqueous phase was podslushivaet 1N NaOH to pH 1 and extracted using EtOAc (3×50 ml). The combined organic layers were washed with water (50 ml), dried over Na2SO4, was filtered and was evaporated.After drying in vacuo 4-aminomethyl-2'-ethoxy-biphenyl-2-ylamine was isolated as brown oil (370 mg, 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 1.54 minutes, 10-100% CH3CN, 5 min gradient; ESI-MS 243,3 m/z (MH+).

E-1; tert-butyl ether (2-Amino-2'-ethoxy-biphenyl-4-ylmethyl)carbamino acid

A solution of Boc2O (123 mg, 0,565 mmol) in 1,4-dioxane (10 ml) was added over 30 minutes to a solution of 4-aminomethyl-2'-ethoxy-biphenyl-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 were removed on a rotary evaporator. The residue was purified by flash chromatography (silica gel, EtOAc-CH2Cl2, 1:4) to give tert-butyl ether (2-Amino-2'-ethoxy-biphenyl-4-ylmethyl)carbamino acid (E-1) in the form of a pale yellow oil (119 mg, 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 (sq, J=7.2 Hz, 2H), 1,38 (s, 9H), of 1.20 (t, J=7,2 Hz, 3H); HPLC retention time 2.34 minutes, 10-100% CH3CN, 5 min gradient; 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 (,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). The stirring was continued at room temperature overnight and then the mixture was poured into dilute solution of sodium hydrosulfite and extracted using EtOAc three times. The combined organic layers were washed with saturated brine and dried over MgSO4. After filtration the filtrate was concentrated to give 2-bromo-1-tert-butyl-4-nitrobenzene (12.7 g, 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 4.05 minutes, 10-100% CH3CN, 5 min gradient.

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 container at 205ºC for 5 hours. After cooling to room temperature the mixture was diluted with water and extracted using EtOAc twice. The combined organic layers were washed with saturated brine and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-5-nitrobenzonitrile (1.33 g, 80%).1/sup> H 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 minutes, 10-100% CH3CN, 5 min gradient.

E-2; 2-tert-butyl-5-aminobenzonitrile

To be heated at the temperature of reflux to 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 the addition of 10% Pd-C (570 mg). The reaction mixture was boiled to reflux for 90 minutes, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give 2-tert-butyl-5-aminobenzonitrile (E-2) (630 mg, 91%) which was used without further purification. HPLC retention time 2.66 minutes, 10-99% CH3CN, 5 min cycle; 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 in THF, 12.0 mmol) in a nitrogen atmosphere. The reaction mixture was stirred at 70ºC overnight and cooled to 0ºC. Was added methanol (2 ml) followed by the addition of 1N HCl solution (2 ml). After boiling to reflux for 30 minutes the solution was diluted with water and extracted using EtOAc. The aqueous layer was podslushivaet 1N NaOH and extragere�do with EtOAc twice. The combined organic layers were washed with saturated brine and dried over Mg2SO4. After removal of solvent, the residue was purified by column chromatography (0-10% MeOH-CH2Cl2) to give (2-tert-butyl-5-nitrophenyl)methanamine (268 mg, 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 2.05 minutes, 10-100% CH3CN, 5 min gradient; 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 minutes. After cooling to room temperature the solution was diluted with water and extracted using EtOAc. The combined organic layers were washed with saturated brine and dried over MgSO4. After filtration the filtrate was concentrated to give tert-butyl 2-tert-butyl-5-nitrobenzylamine (240 mg, 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 minutes, 10-100% CH3CN, 5 min gradient.

E-4; tert-butyl 2-tert-butyl-5-aminobenzylidene

To a solution of tert-butyl 2-tert-booth�l-5-nitrobenzylamine (20 mg, 0,065 mmol) in 5% AcOH-MeOH (1 ml) was added 10% Pd-C (14 mg) in a nitrogen atmosphere. The mixture was stirred in the atmosphere of H2(1 ATM) at room temperature for 1 hour. The catalyst was removed by filtration through Celite and the filtrate concentrated to give tert-butyl 2-tert-butyl-5-aminobenzoylglutamate (E-4), which was 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 (lat.s, 1H), 4,40 (d, J=5.1 Hz, 2H), 4,15 (lat.s, 2H), of 1.39 (s, 9H), of 1.29 (s, 9H); HPLC retention time 2,47 minutes, 10-100% CH3CN, 5 min gradient; 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% H2SO4was heated in a microwave oven at 200 ºC for 30 minutes. The reaction mixture was poured onto ice, extracted using EtOAc, washed with saturated brine and dried over MgSO4. After filtration the filtrate was concentrated to give 2-tert-butyl-5-nitrobenzoic acid (200 mg, 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) of 1.51 (s, 9H); HPLC retention time 2.97 minutes, 10-100% CH3CN, 5 min gradient.

Methyl 2-tert-butyl-5-nitrobenzoate

To a mixture of 2-tert-butyl-5-n�trobenzene 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 minutes, diluted with water and extracted using EtOAc. The combined organic layers were washed with saturated brine and dried over MgSO4. After filtration the filtrate was concentrated to give methyl 2-tert-butyl-5-nitrobenzoate, which was 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 be heated at the temperature of reflux to 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), followed by the addition of 20 mg of 10% Pd-C. the Reaction mixture was boiled to reflux for 40 minutes, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give methyl 2-tert-butyl-5-aminobenzoate (E-6) (76 mg, 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 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS to 208.2 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 5-10 ° C and added dropwise a solution of NaNO2(0,433 g, 6.3 mmol) in H2O (0,83 ml). The stirring was continued for 0.5 hours, the mixture is then pulled vacuum filtration. The filtrate was 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 3-5ºC. The stirring was continued for 0.5 hours and the resulting precipitate was filtered, washed with water and dried to obtain 2-tert-butyl-5-nitrobenzene-1-sulphonylchloride (0,235 g, 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 a simple ether (2 ml) was added an aqueous solution of NH4OH (128 μl, 3.6 mmol) at 0ºC. The mixture was stirred at room temperature overnight, diluted with water and was extracted with simple ether. The combined ether extracts were washed with saturated brine and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (0-50% EtOAc-g�Xan), to obtain 2-tert-butyl-5-nitrobenzene-1-sulfonamide (of 31.6 mg, 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 SnCl2.2H2O (138 mg, 0.61 mmol) in EtOH (1.5 ml) was heated in a microwave oven at 100ºC for 30 minutes. The mixture was diluted with EtOAc and water, podslushivaet saturated solution NaHCO3and filtered through Celite. The organic layer was separated from water and dried over Na2SO4. The solvent was removed by evaporation to obtain 2-tert-butyl-5-aminobenzoyl-1-sulfonamida (E-7) (28 mg, 100%) which was used without further purification. HPLC retention time 1.99 minutes, 10-99% CH3CN, 5 min cycle; 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 in THF, 1.4 mmol) at 0ºC. The reaction mixture was boiled with reflux for 2 hours, was diluted using H2O and extracted using EtOAc. The combined organic layers were washed with saturated brine and dried over MgSO4. After filtration the filtrate was concentrated to give (2-tert-butyl-5-Dapsone base)methanol (E-8) (25 mg, 20%) which was used 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), ,56 (DD, J=an 8.4, 2.7 Hz, 1H), a 4.83 (s, 2H), of 1.36 (s, 9H).

Example 7:

1-Methyl-pyridine, salt monomethyltin acid

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 minutes, then at 100ºC for 2 hours. The mixture was cooled to room temperature to obtain crude 1-methyl-pyridinium salts monomethyltin acid (64,7 g, quantitative) which was used without further purification.

1-Methyl-2-pyridon

The salt solution monomethyltin acid 1-methyl-pyridinium (50 g, 0,243 mol) in water (54 ml) was cooled to 0ºC. Received separate solutions of potassium ferricyanide (160 g, 0,486 mol) in water (320 ml) and sodium hydroxide (40 g, 1,000 mol) in water (67 ml) and added dropwise from a separatory funnels to the thoroughly stirred solution of salt monomethyltin acid 1-methyl-pyridinium at such a rate that the temperature of the reaction mixture never rose above 10ºC. The speed of adding these two solutions was regulated so that the sodium hydroxide solution was introduced into the reaction mixture when it was added to half of a solution of potassium ferricyanide. After completion of the addition the reaction mixture was allowed to warm to room temperature and stirred over night. Was added anhydrous Carbo�at sodium (91,6 g) and the mixture was stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted using CH2Cl2(100 ml ×3). The combined organic layers were dried and concentrated to give 1-methoxy-2-pyridone (25,0 g, 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 0ºC. After stirring for 5 minutes was added dropwise nitric acid (200 ml) at 0ºC. After the addition the reaction temperature was slowly raised to 100ºC and then maintained for 5 hours. The reaction mixture was poured onto ice, podslushivaet using potassium carbonate to pH 8 and extracted using CH2Cl2(100 ml ×3). The combined organic layers were dried over Na2SO4and concentrated to give 1-methyl-3,5-dinitro-2-pyridone (12.5 g, 28%) which was used without further purification.

2-Isopropyl-5-nitro-pyridine

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), followed by the addition of ammonia solution in methanol (10.0 g, 17%, 100 mmol). The reaction mixture was heated at 70ºC for 2.5 hours at atmospheric pressure. The solvent was removed in vacuo and the residual oil was dissolved in CH2Cl2and then was filtered. The filtrate was dried in� Na 2SO4and concentrated to give 2-isopropyl-5-nitro-pyridine (1.88 g, 28%).

E-9; 2-Isopropyl-5-amino-pyridine

2-Isopropyl-5-nitro-pyridine (1,30 g, of 7.82 mmol) was dissolved in methanol (20 ml) was added Raney-Ni (0.25 g). The mixture was stirred in the atmosphere of H2(1 ATM) at room temperature for 2 hours. The catalyst was filtered and the filtrate was concentrated in vacuum to give 2-isopropyl-5-amino-pyridine (E-9) (0.55 g, 52%).1H NMR (CDCl3) δ with 8.05 (s, 1H), 6,93-of 6.99 (m, 2H), 3,47 (lat.s, 2H), 2,92-3,02 (m, 1H), 1,24-1,26 (m, 6H), ESI-MS 137,2 m/z (MH+).

Example 8:

2,4-di-tert-butyl-phenyl ester diethyl 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 0ºC. The mixture was stirred at 0ºC for 15 minutes and was then added dropwise diethyl ether phosphorochloridate acid (of 30.15 g, 174,7 mmol) at 0ºC. After the addition the mixture was stirred at this temperature for 15 minutes. The reaction mixture was quenched with a saturated solution of NH4Cl (300 ml). The organic layer was separated and the aqueous phase was extracted with using the Et2O (350 ml ×2). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4and conc�Wali in vacuum to give crude 2,4-di-tert-butyl-phenyl ester diethyl ester of phosphoric acid as a yellow oil (51 g, with some admixture of mineral oil), which was used directly in the next step.

1,3-Di-tert-butyl-benzene

NH3(liquid, 250 ml) was added a solution of 2,4-di-tert-butyl-phenyl ester diethyl ether phosphoric acid (51 g, crude from last step, about 0.2 mol) in Et2O (anhydrous, 150 ml) at-78ºC in the atmosphere of N2. To the solution was added lithium metal in small pieces to obtain a persistent blue color. The reaction mixture was stirred at-78ºC for 15 minutes and then quenched with a saturated solution of NH4Cl until the mixture became colorless. Liquid NH3evaporated and the residue was dissolved in water, extracted with the help of Et2O (300 ml ×2). The combined organic phases were dried over Na2SO4andconcentrated to give crude 1,3-di-tert-butyl-benzene as a yellow oil (30.4 g, 94% over 2 stages, with some admixture of mineral oil), which was used directly in the next step.

2,4-Di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde

To a stirred solution of 1,3-di-tert-butyl-benzene (30 g, 157,6 mmol) in anhydrous CH2Cl2(700 ml) was added TiCl4(A 37.5 g, 197 mmol) at 0ºC, followed by the addition dropwise MeOCHCl2(27,3 g, 236,4 mmol). The reaction mixture was allowed to warm to room� temperature and stirred for 1 hour. The mixture was poured into ice water and extracted using CH2Cl2. The combined organic phases were washed with NaHCO3and saturated brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde (21 g, 61%).

2,4-Di-tert-butyl-5-nitro-benzaldehyde and 3,5-di-tert-butyl-2-nitro-benzaldehyde

To a mixture of 2,4-di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde in H2SO4(250 ml) was added KNO3(Of 7.64 g, to 75.6 mmol) in portions at 0ºC. The reaction mixture was stirred at this temperature for 20 minutes and then was poured into crushed ice. The mixture was podslushivaet NaOH to pH 8 and extracted with the help of Et2O (10 ml ×3). The combined organic layers were washed with water and saturated brine and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-tert-butyl-5-nitro-benzaldehyde and 3,5-di-tert-butyl-2-nitro-benzaldehyde (2:1 according to NMR) as a yellow solid (14.7 g, 82%). Further purified column chromatography (petroleum ether) was isolated 2,4-di-tert-butyl-5-nitro-benzaldehyde (2.5 g, containing 10% 3,5-di-tert-butyl-2-nitro-benzaldehyde).

1,5-Di-tert-butyl-2-ditto�methyl-4-nitro-benzene and 1,5-Di-tert-butyl-3-deformity-2-nitro-benzene

2,4-Di-tert-butyl-5-nitro-benzaldehyde (2.4 g, of 9.11 mmol, with an admixture of 10% solution of 3,5-di-tert-butyl-2-nitro-benzaldehyde) in a solution of pure diakopter stirred at room temperature for 5 hours. The reaction mixture was poured into a cooled saturated solution of NaHCO3and was extracted with dichloromethane. Combined organic layers were dried over Na2SO4was concentrated and was purified column chromatography (petroleum ether) to give 1,5-di-tert-butyl-2-deformity-4-nitro-benzene (1.5 g) and a mixture of 1,5-di-tert-butyl-2-deformity-4-nitro-benzene and 1,5-di-tert-butyl-3-deformity-2-nitro-benzene (0.75 g, contains 28% of 1,5-di-tert-butyl-3-deformity-2-nitro-benzene).

E-10; 1,5-Di-tert-butyl-2-deformity-4-amino-benzene

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-nitro-benzene (1.3 g, 4,56 mmol). The reaction mixture was heated at 115ºC for 15 minutes. The solids were filtered, washed with acetic acid and CH2Cl2. The combined filtrate was concentrated and treated using HCl/MeOH. The precipitate was collected by filtration, washed using MeOH and dried with obtaining 1,5-di-tert-butyl-2-deformity-4-amino-benzene in the form of HCl salt (E-10) as a white solid (1.20 g, 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

General scheme:

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

Method A

In a vessel with a capacity of 2 drachmas, 2-bromoaniline (100 mg, of 0.58 mmol) and the appropriate arylboronic acid (0,82 mmol) was dissolved in THF (1 ml). Added H2O (500 μl) followed by the addition of K2CO3(200 mg, 1.0 mmol) and Pd(PPh3)4(100 mg, 0.1 mmol). The vessel was purged with argon and sealed closed. The vessel was then heated at 75ºC for 18 hours. The crude sample was diluted in EtOAc and filtered through a plug of silica gel. The organics were concentrated using Savant Speed-vac. The crude amine was used without further purification.

Method B

In a vessel with a capacity of 2 drachmas was added the appropriate arylboronic acid (0,58 mmol) followed by the addition of KF (110 mg, 1.9 mmol). Solids suspended in THF (2 ml) and then was added 2-bromoaniline (70 μl, of 0.58 mmol). The vessel was purged with argon for 1 minute. Added P(tBu)3(100 μl, 10% solution in hexane) followed by the addition of Pd2(dba)3(900 μl of 0.005 M in THF). The vessel was again purged with argon and sealed closed. The vessel was shaken on an orbital shaking device at room �temperature for 30 minutes and heated in a heating block at 80ºC for 16 hours. The vessel was then cooled to 20 ° C and the suspension was passed through a layer of Celite. Layer was washed using EtOAc (5 ml). The organic layers were combined and concentrated in vacuum to give the crude amine which was used without further purification.

The table below includes the amines obtained in accordance with the General scheme shown above.

ProductNameMethod
F-14'-Methyl-biphenyl-2-ylamineA
F-23'-Methyl-biphenyl-2-ylamineA
F-32'-Methyl-biphenyl-2-ylamineA
F-42',3'-Dimethyl-biphenyl-2-ylamineA
F-5(2'-Amino-biphenyl-4-yl)-methanolA
F-6N*4'*,N*4'*-Dimethyl-biphenyl-2,4'-diamineB
F-72'-Trifluoromethyl-biphenyl-2-ylamine B
F-8(2'-Amino-biphenyl-4-yl)-acetonitrileA
F-94'-Isobutyl-biphenyl-2-ylamineA
F-103'-Trifluoromethyl-biphenyl-2-ylamineB
F-112-Pyridin-4-yl-phenylamineB
F-122-(1H-Indol-5-yl)-phenylamineB
F-133',4'-Dimethyl-biphenyl-2-ylamineA
F-144'-Isopropyl-biphenyl-2-ylamineA
F-153'-Isopropyl-biphenyl-2-ylamineA
F-164'-Trifluoromethyl-biphenyl-2-ylamineB
F-174'-Methoxy-biphenyl-2-ylamineB
F-183'-Methoxy-biphenyl-2-ylamineB
F-192-Benzo[1,3]dioxol-5-yl-phenylamineB
F-203'-Ethoxy-biphenyl-2-ylamineB
F-214'-Ethoxy-biphenyl-2-ylamineB
F-222'-Ethoxy-biphenyl-2-ylamineB
F-234'-Methylsulfanyl-biphenyl-2-ylamineB

F-243',4'-Dimethoxy-biphenyl-2-ylamineB
F-252',6'-Dimethoxy-biphenyl-2-ylamineB
F-262',5'-Dimethoxy-biphenyl-2-ylamineB
F-272',4'-Dimethoxy-biphenyl-2-ylamineB
F-285'-Chloro-2'-methoxy-biphenyl-2-ylamineB
F-294'-Triptoreline-biphenyl-2-ylamine B
F-30The 3'Triptoreline-biphenyl-2-ylamineB
F-314'-Phenoxy-biphenyl-2-ylamineB
F-322'-Fluoro-3'-methoxy-biphenyl-2-ylamineB
F-332'-Phenoxy-biphenyl-2-ylamineB
F-342-(2,4-Dimethoxy-pyrimidine-5-yl)-phenylamineB
F-355'-Isopropyl-2'-methoxy-biphenyl-2-ylamineB
F-362'-Triptoreline-biphenyl-2-ylamineB
F-374'-Fluoro-biphenyl-2-ylamineB
F-383'-Fluoro-biphenyl-2-ylamineB
F-392'-Fluoro-biphenyl-2-ylamineB
F-402'-Amino-biphenyl-3-carbonitrileB
F-414'-Fluoro-3'-methyl-biphenyl-2-ylamineB
F-424'-Chloro-biphenyl-2-ylamineB
F-433'-Chloro-biphenyl-2-ylamineB
F-443',5'-Debtor-biphenyl-2-ylamineB
F-452',3'-Debtor-biphenyl-2-ylamineB
F-463',4'-Debtor-biphenyl-2-ylamineB
F-472',4'-Debtor-biphenyl-2-ylamineB
F-482',5'-Debtor-biphenyl-2-ylamineB

F-493'-Chloro-4'-fluoro-biphenyl-2-ylamineB
F-503',5'-Dichloro-biphenyl-2-ylamineB
F-512',5'-Dichloro-biphenyl-2-ylamine B
F-522',3'-Dichloro-biphenyl-2-ylamineB
F-533',4'-Dichloro-biphenyl-2-ylamineB
F-54methyl ester of 2'-amino-biphenyl-4-carboxylic acidB
F-55methyl ester of 2'-amino-biphenyl-3-carboxylic acidB
F-562'-Methylsulfanyl-biphenyl-2-ylamineB
F-57N-(2'-Amino-biphenyl-3-yl)-acetamideB
F-584'-Methanesulfonyl-biphenyl-2-ylamineB
F-592',4'-Dichloro-biphenyl-2-ylamineB
F-604'-Methanesulfonyl-biphenyl-2-ylamineB
F-61isopropyl ester of 2'-amino-biphenyl-2-carboxylic acidB
F-62 2-Furan-2-yl-phenylamineB
F-631-[5-(2-Amino-phenyl)-thiophene-2-yl]-alanonB
F-642-Benzo[b]thiophene-2-yl-phenylamineB
F-652-Benzo[b]thiophene-3-yl-phenylamineB
F-662-Furan-3-yl-phenylamineB
F-672-(4-Methyl-thiophene-2-yl)-phenylamineB
F-685-(2-Amino-phenyl)-thiophene-2-carbonitrileB

Example 10:

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

tert-Butoxide sodium (466 mg, is 4.85 mmol) was added to DMF (20 ml) at 0ºC. The cloudy solution was again cooled to 5ºC. Was added ethyl 4-nitrophenylacetate (1.0 g, 4,78 mmol). The purple slurry was cooled to 5ºC and added methyliodide (0,688 ml, is 4.85 mmol) for 40 minutes. The mixture was stirred at 5-10ºC for 20 minutes and then re-uploaded tert-butoxide sodium (466 mg, is 4.85 mmol) and methyliodide (read 0.699 ml, is 4.85 mmol). The mixture was stirred at 5-10ºC for 20 minutes and add�ulali third download of tert-butoxide sodium (47 mg, 0,48 mmol) followed by the addition of methyliodide (0,057 ml, 0.9 mmol). Was added ethyl acetate (100 ml) and HCl (0.1 n, 50 ml). The organic layer was separated, washed with saturated brine and dried over Na2SO4. After filtration the filtrate was concentrated to give ethyl 2-(4-nitrophenyl)-2-methylpropanoate (900 mg, 80%) which was used without further purification.

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

A solution of ethyl 2-(4-nitrophenyl)-2-methylpropanoate (900 mg, 3.8 mmol) in EtOH (10 ml) was treated with 10% solution of Pd-C (80 mg) and heated to 45ºC. Added a solution of potassium formate (4.10 g, and 48.8 mmol) in H2O (11 ml) for 15 minutes. The reaction mixture was stirred at 65ºC for 2 hours and then treated with an additional 300 mg of Pd/C. the Reaction mixture was stirred for 1.5 hours and then filtered through Celite. The volume of solvent was reduced by approximately 50% under reduced pressure and extracted using EtOAc. The organic layers were dried over Na2SO4and the solvent was removed under reduced pressure to obtain ethyl 2-(4-Dapsone base)-2-methylpropanoate (G-1) (670 mg, 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-m�of dipropanoat (30 mg, 0,145 mmol) in THF (1 ml) were processed using LiAlH4(1M solution in THF, 0,226 ml, 0,226 mmol) at 0ºC and stirred for 15 minutes. The reaction mixture was treated with 0.1 n NaOH, extracted using EtOAc, and the organic layers were dried over Na2SO4. The solvent was removed under reduced pressure to obtain 2-(4-Dapsone base)-2-methylpropan-1-ol (G-2), which was 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 0ºC was treated with 4-nitrophenylacetonitrile (1000 mg, 6.18 of mmol) and stirred for 10 minutes. Was added dropwise methyliodide (400 μl, 6,47 mmol) for 15 minutes. The solution was stirred at 0-10ºC for 15 minutes and then at room temperature for 15 minutes. To this purple solution was added tert-butoxide sodium (662 mg, 6,47 mmol) and the solution was stirred for 15 minutes. Was added dropwise methyliodide (400 μl, 6,47 mmol) for 15 minutes and the solution was stirred over night. Was added tert-butoxide sodium (192 mg, 1,94 mmol) and the reaction mixture was stirred at 0ºC for 10 minutes. Added 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 1 n HCl solution and saturated brine, dried over Na2SO4and concentrated to give 2-methyl-2-(4-nitrophenyl)propanenitrile as a green waxy solid (1.25 g, 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 BH3(1M in THF, 14 ml, 14 mmol) dropwise at 0ºC. The mixture was heated to room temperature and heated at 70ºC for 2 hours. Was added 1N HCl solution (2 ml) followed by the addition of NaOH until pH >7. The mixture was extracted with simple ether and the ether extract concentrated to give 2-methyl-2-(4-nitrophenyl)propane-1-amine (610 mg, 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 1N NaOH (3 ml, 3 mmol) in 1,4-dioxane (6 ml) and water (3 ml) was added Boc2O (742 mg, 3.4 mmol) at 0ºC. The reaction mixture was allowed to warm to room temperature and was stirred for but�I. The reaction mixture was acidified with 5% aqueous KHSO4and then was extracted with ethyl acetate. The organic layer was dried over MgSO4and concentrated to give tert-butyl 2-methyl-2-(4-nitrophenyl)propylgallate (725 mg, 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 be heated at the temperature of reflux to a solution of tert-butyl 2-methyl-2-(4-nitrophenyl)propylgallate (725 mg, 2.5 mmol) and ammonium formate (700 mg, 10.9 mmol) in EtOH (25 ml) was added Pd-5% wt. on carbon (400 mg). The mixture was boiled to reflux for 1 hour, cooled and filtered through Celite. The filtrate was concentrated to give tert-butyl 2-methyl-2-(4-Dapsone base)propylgallate (G-3) (550 mg, 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), of 1.12 (s, 6H); HPLC retention time 2.02 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 265,2 m/z (MH+).

Example 13:

7-Nitro-1,2,3,4-tetrahydro-naphthalene-1-ol

7-Nitro-3,4-dihydro-2H-naphthalene-1-he (200 mg, 1.05 mmol) was dissolved in methanol (5 ml) was added in portions NaBH4((78 mg, 2,05 mmol). Reaction with�ect stirred at room temperature for 20 minutes and then concentrated and was purified column chromatography (10-50% ethyl acetate-hexane) to give 7-nitro-1,2,3,4-tetrahydro-naphthalene-1-ol (163 mg, 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 2.32 minutes, 10-99% CH3CN, 5 min cycle.

H-1; 7-Amino-1,2,3,4-tetrahydro-naphthalene-1-ol

7-nitro-1,2,3,4-tetrahydro-naphthalene-1-ol (142 mg, 0,73 mmol) was dissolved in methanol (10 ml) and the flask was washed using N2(gas). Was added 10% Pd-C (10 mg) and the reaction mixture was stirred in the atmosphere of H2(1 ATM) at room temperature over night. The reaction mixture was filtered and the filtrate concentrated to give 7-amino-1,2,3,4-tetrahydro-naphthalene-1-ol (H-1) (113 mg, 95%). HPLC retention time 0,58 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 164,5 m/z (MH+).

Example 14:

7-Nitro-3,4-dihydro-2H-naphthalene-1-he oxime

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 was purified column chromatography (10-50% ethyl acetate-hexane) to give 7-nitro-3,4-dihydro-2H-naphthalene-1-oxime (471 mg, 88%). HPLC retention time 2.67 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 207,1 m/z (MH+).

1,2,3,4-Tetrahydro-naphthalene-1,7-diamine

7-Nitro-3,4-dihydro-2H-naphthalene-1-it ACS�m (274 mg, Of 1.33 mmol) was dissolved in methanol (10 ml) and the flask was washed using N2(gas). Was added 10% Pd-C (50 mg) and the reaction mixture was stirred in the atmosphere of H2(1 ATM) at room temperature over night. The reaction mixture was filtered and the filtrate concentrated to give 1,2,3,4-tetrahydro-naphthalene-1,7-diamine (207 mg, 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-tetrahydro-naphthalene-1-yl)-carbamino acid

To a solution of 1,2,3,4-tetrahydro-naphthalene-1,7-diamine (154 mg, 0.95 mmol) and triethylamine (139 µl, 1.0 mmol) in methanol (2 ml), cooled to 0ºC, was added di-tert-BUTYLCARBAMATE (207 mg, 0.95 mmol). The reaction mixture was stirred at 0ºC and then concentrated and was purified column chromatography (5-50% methanol-dichloro methane) to give tert-butyl ether (7-amino-1,2,3,4-tetrahydro-naphthalene-1-yl)-carbamino acid (H-2) (327 mg, quantitative). HPLC retention time 1.95 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 263,1 m/z (MH+).

Example 15:

N-(2-Bromo-benzyl)-2,2,2-Cryptor-acetamide

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 �eremetical at room temperature for 1 hour. The reaction mixture was then concentrated in vacuum to give N-(2-bromo-benzyl)-2,2,2-Cryptor-acetamide (3,15 g, quantitative). HPLC retention time 2.86 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 283,9 m/z (MH+).

I-1; N-(4'-Amino-biphenyl-2-ylmethyl)-2,2,2-Cryptor-acetamide

A mixture of N-(2-bromo-benzyl)-2,2,2-Cryptor-acetamide (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) was added 4M K2CO3the solution (0.5 ml). The reaction mixture was heated at 80ºC overnight. The mixture was filtered, concentrated and purified column chromatography (0-50% ethyl acetate-hexane) to give N-(4'-amino-biphenyl-2-ylmethyl)-2,2,2-Cryptor-acetamide (I-1) (143 mg, 49%). HPLC retention time 1.90 minutes, 10-99% CH3CN, 5 min cycle; 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'-Aminomethyl-biphenyl-4-ylamine
J-161H-Indazol-6-ylamine
J-172-(2-methoxyphenoxy)-5-(trifluoromethyl)benzolamide
J-182-tert-butylbenzylamine
J-192,4,6-Tr�methylbenzenamine
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'-Methoxy-biphenyl-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-(benzilic�and)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-Methyl-biphenyl-3-ylamine
J-48pyridin-3-amine
J-493,4-dimethoxybenzoate
-50 3H-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-herperidin-2-amine
J-644-cyclohexylbenzene
J-65 4-Amino-benzolsulfonat
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-yl-phenylamine
J-743-amino-5,6,7,8-tetrahydronaphthalen-2-ol
J-75benzo[d][1,3]dioxol-5-amine
J-765-chloro-2-phenoxybenzamine
J-77N-1-torbenson-1,2-diamine
J-783,4-dimethylbenzenamine
J-792-(triptoreline)benzoylamine
J-80Nindel-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-Amino-benzolsulfonat
J-931-(2-Dapsone base)alanon
J-94m-toluidine
J-952-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)benzo�Lamine
J-962-amino-6-methylbenzonitrile
J-972-(prop-1-EN-2-yl)benzoylamine
J-984-Amino-N-pyridin-2-yl-benzolsulfonat
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-1073,5-bis(trifluoromethyl)benzolamide
J-1084-vinylbenzoate
J-1094-(trifluoromethyl)benzolamide

J-110 2-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-Diokso-1H-lambda*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)-carboxyl�
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-136aniline
J-1373-(triptoreline)benzoylamine
J-1382-(2,5-dimethyl-1H-pyrrol-1-yl)benzoylamine
J-1394-(Morpholine-4-sulfonyl)-f�nilamon
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-ylamine
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-�AMINOPHENYL)(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-(trifluoromethyl)benzolamide
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-[(Cyclohexyl-methyl-amino)-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-Amino-benzolsulfonat
J-1982-ethyl-6-methylbenzenamine
J-199Biphenyl-4-ylamine
J-2002-(o-tolyloxy)benzenes�
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-2092-(4-demerol-1-yl)benzoylamine
J-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 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-Amino-phenyl)-methanesulfonamide
J-222N-(3-Dapsone base)propionamide
J-223N1,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-Indo�-6-amine
J-2311H-indol-6-amine
J-2321H-indol-6-amine
J-2331H-indol-6-amine
J-2341H-indol-6-amine
J-2351H-indol-6-amine

J-2361H-indol-6-amine
J-2371H-indol-6-amine
J-2381H-indol-6-amine
J-2391-(6-Amino-2,3-dihydro-indol-1-yl)-Etalon
J-2405-Chloro-benzene-1,3-diamine

Amides (Compounds of formula (I)

General scheme:

(a) Ar1R7NH linking reagent, base, solvent. Examples of conditions used: HATU, DIEA, DMF; BOP, DIEA, DMF; HBTU, Et3N, CH2Cl2; PFP-TFA, pyridine

Special example:

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

To a solution of 4-hydroxy-quinoline-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 using HPLC (10-99% CH3CN/H2O) to give 4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, 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), 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); HPLC retention time 3.02 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 265,1 m/z (MH+).

The Table below lists other examples synthesized in accordance with the General scheme shown above.

tr>
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

tr>
29A-21J-208
31A-1J-87
32A-1B-21
33A-1J-227
34A-1C-19
36A-1J-203
37A-1J-80
38A-1J-46
39A-17D-10
40A-1J-125
42A-1J-95
43A-1C-16
44A-1 J-140
45A-1J-205
47A-1J-102
48A-1J-181
49A-1F-25
50A-1J-19
51A-7B-24
52A-1F-2
53A-1J-178
54A-1J-26
55A-1J-219
56A-1J-74
57A-1J-61
58A-1D-4
59A-1F-35
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
74 A-1J-104
75A-1J-195
76A-1F-46
77A-1B-20
78A-1J-92
79A-1F-41
80A-1J-30
81A-1J-222
82A-1J-190
83A-1F-40
84A-1J-32
85A-1F-53
86A-1J-15
87A-1J-39
88A-1 G-3
89A-1J-134
90A-1J-18
91A-1J-38
92A-1C-13
93A-1F-68
95A-1J-189
96A-1B-9
97A-1F-34
99A-1J-4
100A-1J-182
102A-1J-117
103A-2C-9
104A-1B-4

F-59
106 A-1J-11
107A-1DC-6
108A-1DC-3
109A-1DC-4
110A-1J-84
111A-1J-43
112A-11J-235
113A-1B-7
114A-1D-18
115A-1F-62
116A-3J-229
118A-1F-12
120A-1J-1
121A-1J-130
122A-1 J-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-1
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
156 A-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-1 F-63
175A-1DC-2
176A-1J-212
177A-1J-57
178A-1J-153
179A-1J-154
180A-1J-198
181A-1F-1
182A-1F-37
183A-1DC-1
184A-15J-231
185A-1J-173

td align="center"> A-1
186A-1B-15
187A-1B-3
188A-1B-25
189A-1J-24
190A-1F-49
191A-1J-23
192A-1J-36
193A-1J-68
194A-1J-37
195A-1J-127
197A-1J-167
198A-1J-210
199A-1F-3
200A-1H-1
201A-1J-96
202A-1F-28
203 A-1B-2
204A-1C-5
205A-1J-179
206A-1J-8
207A-1B-17
208A-1C-12
209A-1J-126
210A-17J-101
211A-1J-152
212A-1J-217
213A-1F-51
214A-1J-221
215A-1J-136
216A-1J-147
217J-185
218A-2C-13
219A-1J-114
220A-1C-26

234
222A-1J-35
223A-1F-23
224A-1I-1
226A-1J-129
227A-1J-120
228A-1J-169
229A-1J-59
230A-1J-145
231A-1C-17
233A-1J-239
A-1B-22
235A-1E-9
236A-1J-109
240A-1J-34
241A-1J-82
242A-1D-2
244A-1J-228
245A-1J-177
246A-1J-78
247A-1F-33
250A-1J-224
252A-1J-135
253A-1F-30
254A-2B-20
255/td> A-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-1 D-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
302A-1F-5
303A-1J-13
304A-1E-1
305A-1F-17
306A-1F-20
307A-1F-43

308A-1J-206
309A-1J-5
310A-1J-70
311A-1J-60
312A-1F-27
313A-1F-39
314A-1J-116
315A-1J-58
317A-1J-85
319A-2C-7
320A-1B-6
321 A-1J-44
322A-1J-22
324A-1J-172
325A-1J-103
326A-1F-60
328A-1J-115
329A-1J-148
330A-1J-133
331A-1J-105
332A-1J-9
333A-1F-8
334A-1DC-5
335A-1J-194
336A-1J-192
337-1 C-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

A-1
351A-1B-23
352A-1B-10
353A-1D-10
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-141
370A-1J-90
371A-1J-79
372/td> A-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
389J-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
423A-1B-16
424A-1F-42
42 A-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
437A-1J-75
438A-1 E-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
451A-1J-31
452A-1J108
453A-1D-1
454A-1J-47
455A-1J-73
456A-1J-137
457A-1J-155
458A-1C-4
459A-1J-53
461A-1J-150
463A-1J-202
464A-3C-9
465A-1E-4
466A-1J-2
467A-1J-86

468 A-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-IA-1B-26
B-27-I A-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:

General scheme:

Special 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-carboxylic acid (188) (450 mg, 1.2 mmol) and 1N NaOH solution (5 ml) in THF (10 ml) was heated at 85ºC during the night. The reaction AGR�ü distributed between EtOAc and water. The aqueous layer was acidified with 1N HCl solution to pH 5 and the precipitate was filtered, washed with water and air dried to obtain 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-5-carboxylic acid (188-I) (386 mg, 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, 1H); HPLC retention time 2.95 minutes 10-99% CH3CN, 5 min cycle; 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 isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65ºC overnight. The resulting solution was filtered and purified using HPLC (10-99% CH3CN/H2O) to give product, N-[5-(isobutylamino)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (343) (20 mg, 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 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 403,3 m/z (MH+).

Another example:

148; 4-Oxo-N-[5-(1-piperidinylcarbonyl)-1H-�Dol-6-yl]-1H-quinoline-3-carboxamide

4-Oxo-N-[5-(1-piperidinylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide (148) was synthesized in accordance with the General scheme presented above, linking acid (188-I) with piperidine. Total output (12%). HPLC retention time 2.79 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 415,5 m/z (MH+).

Example 2:

General scheme:

Special 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 (B-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 180ºC for 10 minutes. The reaction mixture was filtered and purified using HPLC (10-99% CH3CN/H2O) to give product, 4-oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide (158) (5 mg, 13%). HPLC retention time of 3.05 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS USD 380.2 m/z (MH+).

The Table below lists other examples synthesized in accordance with the General scheme shown above.

The compound of the formula IBaronova acid
2372-methoxyphenylalanine Ki�lot size
3272-ethoxypropionate acid

4042,6-dimethoxyaniline acid
15-chloro-2-methoxy-phenylboronic 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-dihydro-quinoline-3-carbonyl)-amino]-indol-1-yl}-ethyl)-carbamoyl]-methyl}-carbamino acid (B-26-I) (2.0 g, 3.7 mmol) dissolved in a mixture of CH2Cl2(50 ml) and methanol (15 ml) was added HCl solution (60 ml of 1.25 M in methanol). The reaction mixture was stirred at room temperature for 64 hours. The precipitated product was collected by filtration, washed with diethyl ether and dried under high vacuum to give the HCl salt of the product, 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, 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 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 446,5 m/z (MH+).

Phenols

Example 1:

General scheme:

Special example:

275; 4 Benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide

To a mixture of N-(3-hydroxy-4-tert-butyl-phenyl)-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 to obtain 4-benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide (275).1H 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). HPLC retention time 3.93 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 427,1 m/z (MH+).

Another example:

415; N-(3-Hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide

N(3-Hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide (415) was synthesized in accordance with the General scheme, presented above, interacting N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (428) 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 3.46 in minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 351,5 m/z (MH+).

Example 2:

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(CN)2(14 mg, 0.12 mmol) in NMP (1 ml) was added Pd(PPh3)4(16 mg, of 0.014 mmol) in a nitrogen atmosphere. The mixture was heated in a microwave oven at 200 ºC for 1 hour, was filtered and was purified using preparative HPLC to obtain 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), 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); HPLC retention time 3.42 minutes, 10-100% CH3CN, 5 min gradient; ESI-MS to 362.1 m/z (MH+).

Aniline

Example 1:

General scheme:

Special example:

p> 260; N-(5-Amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

A mixture of tert-butyl methyl ether [3-[(4-oxo-1H-quinoline-3-yl)carbylamine]-4-tert-butyl-phenyl]his aminoarabinose acid (353) (33 mg, 0.08 mmol), TFA (1 ml) and CH2Cl2(1 ml) was stirred at room temperature over night. The solution was concentrated and the residue was dissolved in DMSO (1 ml) and purified using HPLC (10-99% CH3CN/H2O) to give product, N-(5-amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (260) (15 mg, 56%).1H NMR (400 MHz, DMSO-d6) ∆ 13,23 (d, J=6,6 Hz, 1H), 12,20 (s, 1H), 10,22 (lat.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 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 336,3 m/z (MH+).

The Table below lists other examples synthesized in accordance with the General scheme shown above.

Initial intermediate connectionProduct
60101
D-12-I282
D-13-I41
114393
D-16-I157

D-15-I356D-17-I399

Example 2:

General scheme:

Special example:

485; N-(3-Dimethylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

To a suspension of N-(3-amino-4-tert-butyl-phenyl)-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 the water). After 10 minutes added cyanoborohydride sodium (407 mg, 6.5 mmol) in one portion. Added additional formaldehyde (135 μl, 1.8 mmol, 37% wt. in water) 1.5 and 4.2 h. After 4.7 hours, the mixture was diluted simple ether (40 ml), washed with water (25 ml) and saturated brine (25 ml), dried (Na2SO4), filtered and concentrated. The obtained red-brown foamy substance was purified preparative HPLC to obtain N-(3-dimethylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (485) (108 mg, 17%).1H NMR (300 MHz, CDCl3) ∆ 13,13 (lat.s, 1H), of 12.78 (s, 1H), 8,91 (lat.s, 1H), to 8.42 (lat.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 2.15 min, 10-100% CH3CN, 5 min cycle; ESI-MS 364,3 m/z (MH+).

The Table below, the references�s other examples synthesized in accordance with the General scheme shown above.

Initial intermediate connectionProduct
69117
160462
282409
4198

Example 3:

General scheme:

Special example:

94; N-(5-Amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

To a solution of 4-hydroxy-quinoline-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-nitro-phenylamine (40 mg, 0,26 mmol). The mixture was heated at 150ºC in a microwave oven for 20 minutes and the resulting solution concentrated. The residue was dissolved in EtOH (2 ml) was added SnCl2.2H2O (293 mg, 1.3 mmol). The reaction mixture was stirred at room temperature over night. The reaction mixture was podslushivaet saturated solution NaHCO3to pH 7-8 and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4that was filtered � concentrated. The residue was dissolved in DMSO and purified using HPLC (10-99% CH3CN/H2O) to give product, N-(5-amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (94) (6 mg, 8%). HPLC retention time 2.06 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 294,2 m/z (MH+).

Another example:

17; N-(5-Amino-2-propoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide

N-(5-Amino-2-propoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide (17) was obtained in accordance with the General scheme presented above, based on 4-hydroxy-quinoline-3-carboxylic acid (A-1) and 5-nitro-2-propoxy-phenylamine. Output (9%). HPLC retention time 3.74 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 338,3 m/z (MH+).

Example 4:

General scheme:

X= CO, CO2, SO2: a) R2XCl, DIEA, THF or R2XCl, NMM, 1,4-dioxane or R2XCl, Et3N, CH2Cl2, DMF.

Special example:

248; N-(3-Acetylamino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

To a solution of N-(3-amino-4-methyl-phenyl)-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 minutes. LCMS analysis showed that there was Vallirana. Added a solution of piperidine (81 μl, 0,82 mmol) in CH2Cl2(2 ml) and reactio�ing mixture was stirred for 30 minutes, after that only the desired product was determined by LCMS analysis. The reaction solution was concentrated and the residue was dissolved in DMSO and purified using HPLC (10-99% CH3CN/H2O) to give product, N-(3-acetylamino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (248) (4 mg, 11%).1H 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); HPLC retention time 2.46 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 336,3 m/z (MH+).

The Table below lists other examples synthesized in accordance with the General scheme shown above.

Based onXR2Product
260COMe316
260COneopentyl196
429COMe379
41COMe 232
101COMe243
8COMe149
271CO2Et127
271CO2Me14
167CO2Et141
69CO2Me30
160CO2Me221
160CO2Et382
69CO2Et225
282CO2Me249
282 CO2Et472
41CO2Me471
101CO2Me239
101CO2Et269
8CO2Me129
8CO2Et298
160SO2Me340

Example 5:

General scheme:

Special 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). Added β-Kharatishvili (0.16 ml of 1.51 mmol) in argon atmosphere. The mixture was stirred at room Tempe�the atur for 6 ½ hours after which TLC analysis (CH2Cl2-EtOAc, 8:2) showed a new spot with very similar Rfthe original substance. Added another 0.5 EQ. NMM and the mixture was stirred at room temperature over night. LCMS analysis of the crude mixture showed >85% conversion to the desired product. The mixture was concentrated, treated with a solution of 1M HCl (5 ml) and extracted using EtOAc (3×10 ml) and CH2Cl2(3×10 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonate)phenyl]-1,4-dihydroquinoline-3-carboxamide as an orange foamy substance (0,495 g, 79%) which was 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 (lat.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 1:1 solution of CH2Cl2:isopropanol (1.5 ml). The mixture was boiled to reflux at 75ºC for 18 hours. After that, LCMS analysis showed > 95% CONV�this in the desired product. The crude mixture was purified by reversed-phase HPLC to obtain 4-oxo-N-[3-[2-(1-piperidyl)ethylsulfanyl]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide (318) as yellowish solid (15 mg, 25%).1H-NMR (d6-Acetone, 300 MHz) δ 8,92 (lat.s, 1H), and 8.4 (d, J=8,1 Hz, 1H), 8,05 (lat.s, 1H), 7,94 (lat.s, 1H), 7,78 (lat.s, 2H), 7,53-751 (m, 1H), of 7.36 (lat.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 lists other examples synthesized in accordance with the General scheme shown above.

Initial intermediate connectionAminProduct
429the morpholine272
429dimethylamine359

131the piperidine133
131the morpholine46

Example 6:

General scheme:

Special example:

258; N-Indolin-6-yl-4-oxo-1H-�inolin-3-carboxamide

A mixture of N-(1-acetylindole-6-yl)-4-oxo-1H-quinoline-3-carboxamide (233) (43 mg, 0.12 mmol), 1N NaOH solution (0.5 ml) and ethanol (0.5 ml) was heated to boiling temperature to reflux for 48 hours. The solution was concentrated and the residue was dissolved in DMSO (1 ml) and purified using HPLC (10-99% CH3CN-H2O) to give product, N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide (258) (10 mg, 20%). HPLC retention time of 2.05 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 306,3 m/z (MH+).

The Table below lists other examples synthesized in accordance with the General scheme shown above.

Based onProductConditionsSolvent
DC-8-I386NaOHEtOH
DC-9-I10HClEtOH
17522HClEtOH
10935HClEtOH
334 238NaOHEtOH
DC-10-I105NaOHTHF

Example 2:

General scheme:

Special 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), TFA (1 ml) and CH2Cl2(1 ml) was stirred at room temperature over night. The solution was concentrated and the residue was dissolved in DMSO (1 ml) and purified using HPLC (10-99% CH3CN-H2O) to give product, 4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide (299) (7 mg, 32%). HPLC retention time 2.18 minutes, 10-99% CH3CN, 5 min cycle; 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 in accordance with the General scheme presented above, based on 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%). 1H 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 2.40 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 348,2 m/z (MH+).

Other

Example 1:

General scheme:

Special example:

163; 4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid (4-aminomethyl-2'-ethoxy-biphenyl-2-yl)-amide

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 CH2Cl2/TFA mixture (3:1, 20 ml) at room temperature for 1 hour. Volatiles were removed on a rotary evaporator. The crude product was purified preparative HPLC to obtain (4-aminomethyl-2'-ethoxymethyl-2-yl)amine 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (163) in the form of a yellowish-brown solid (14 mg, 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 (lat.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 minutes, 10-100% CH3CN, 5 min gradient; ESI-MS 414,1 m/z (MH+).

Another example:

390; N-[3-(Aminomethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide

N-[3-(Aminomethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide (390) was synthesized in accordance with the General scheme presented above, based on tert-butyl ether [5-[(4-oxo-1H-quinoline-3-yl)carbylamine]-2-tert-butyl-phenyl]his methylaminoethanol acid (465). HPLC retention time 2.44 minutes, 10-99% CH3CN, 5 min gradient; ESI-MS m/z 350,3 (M + H)+.

Example 2:

General scheme:

Special 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-dihydro-quinoline-3-yl)-ethyl]-phenyl}-propyl)-carbamino acid (88) (0.50 g, 1.15 mmol), TFA (5 ml) and CH2Cl2(5 ml) were combined and stirred at room temperature over night. The reaction mixture was then neutralized with 1N NaOH. The precipitate was collected by filtration to give product 3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H)-it is in the form of a brown solid (651 mg, 91%). HPLC retention time 2.26 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 336,5 m/z (MH+).

323; methyl ester [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]-propyl]his 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)acetyl)quinolin-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 minutes. The reaction mixture was filtered and purified preparative HPLC (10-99% CH3CN-H2O) to give product methyl ester [2-methyl-2-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]phenyl]-propyl]his aminoarabinose acid (323).1H NMR (400 MHz, DMSO-d6) δ 12,94 (lat.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 2,93 minutes, 10-99% CH3CN, 5 min cycle; ESI-MS 394,0 m/z (MH+).

The Table below lists other examples synthesized in accordance with the General scheme shown above.

ProductCharformat
119Ethylchloride
416Propylchloride
460Butylchloroformate
251Isobutylparaben
341N�opentarget
282-methoxyethylamine
396(tetrahydrofuran-3-yl)methylchloroform

Example 3:

General scheme:

Special 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 TFA (2 ml). The reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was again added dichloro methane (10 ml) and the solution was washed with saturated solution of NaHCO3(5 ml). Began formation of a precipitate in the organic layer, therefore, the combined organic layers were concentrated to give N-(1-aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (273-I) (185 mg, 93%). HPLC retention time 1.94 minutes, 10-99% CH3CN, 5 min cycle; 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-yl)-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 shuffle�Wali at room temperature for 1 hour. LCMS analysis of the reaction mixture showed peaks corresponding to both products and only bis accession. Added piperidine (2 ml) and the reaction mixture was stirred overnight, after which observed only the product is the only connection. The resulting solution was filtered and purified using HPLC (10-99% CH3CN-H2O) to give product, methyl ester [7-[(4-oxo-1H-quinoline-3-yl)carbylamine]tetralin-1-yl]his aminoarabinose acid (159) (27 mg, 35%). HPLC retention time 2.68 minutes, 10-99% CH3CN, 5 min cycle; 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 in accordance with the General scheme presented above, based on the amine (273-I) and ethylchloride. Overall yield (18%). HPLC retention time 2.84 per minute, 10-99% CH3CN, 5 min cycle; ESI-MS 406,5 m/z (MH+).

Additional examples

The acid intermediate of the compound of Example 1:Synthesis of 7-fluoro-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A mixture of 3-fluoro-4-methoxy-aniline (0.7 g, 4.96 mmol) and diethyl 2-(ethoxymethylene)propanoate (1.1 g, 4.96 mmol) was heated at 100ºC for 4 h�owls. The mixture was cooled to room temperature and concentrated under reduced pressure and then was purified column chromatography on silica gel using 1% to 60% EtOAc in hexane to obtain diethyl 2-((3-fluoro-4-methoxybenzylamine)methylene)malonate (1.2 g, 78%). LC/MS: m/z 312,3 (M+H)+at 1.69 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

A flask containing diethyl 2-((3-fluoro-4-methoxybenzylamine)methylene)malonate (1.2 g, 3,86 mmol) and polyphosphoric acid (4.8 g), heated at 120ºC for 4 hours. The reaction mixture was then cooled to room temperature and was filtered. The residue was treated with aqueous solution of NaHCO3that was filtered, washed with water and dried. The solid is then purified column chromatography on silica gel using 20 to 70% EtOAc in hexane to obtain ethyl 7-fluoro-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (410 mg, 40%). LC/MS: m/z 266,3 (M+H)+to of 0.91 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Ethyl 7-fluoro-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (409 mg, 1.54 mmol) was suspended in NaOH solution (3.55 ml 4% wt/V, 3,55 mmol) and the reaction mixture was stirred at the temperature of reflux for 2 hours. After cooling, the reaction mixture was acidified with using concentrated HCl. The precipitate that formed was collected by filtration, washed with water and dried to obtain 7-fluoro-6-�ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 mg, 14%). LC/MS: m/z 238,3 (M+H)+at 0.95 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

6-fluoro-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

6-fluoro-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid can be synthesized in accordance with the General scheme presented above, based on 4-fluoro-3-methoxyaniline

The acid intermediate of the compound of Example 2:Synthesis of 5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A mixture of 2-bromo-5-methyl-aniline (1.0 g, of 5.34 mmol) and diethyl 2-(ethoxymethylene)propanoate (1,23 g, 5,90 mmol) was heated at 100ºC for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel using 1% to 60% EtOAc in hexane to obtain diethyl 2-[[(2-bromo-5-methyl-phenyl)amino]methylene]propanoate (1.6 g, 84%).1H NMR (300 MHz, CDCl3) δ 11,19 (d, J=13.2 Hz, 1H), 8.48 to (d, J=13.2 Hz, 1H), 7,43 (d, J=8,1 Hz, 1H), was 7.08 (s, 1H), is 6.81 (d, J=8,1 Hz, 1H), 4,37-to 4.23 (m, 4H), 2,35 (s, 3H), 1,42-1,25 (m, 6H).

A flask containing diethyl 2-[[(2-bromo-5-methyl-phenyl)amino]methylene]propanedioic (1.6 g, 4,49 mmol) and polyphosphoric acid (5.6 g), heated at 120ºC for 4 hours. The reaction mixture was then cooled to room temperature and was filtered. The residue was treated with aqueous solution of NaHCO3,filtered, was washed with water and dried. The residue was then purified by column chromatography on silica gel using 20 to 70% EtOAc in hexane to obtain ethyl 8-bromo-5-methyl-4-oxo-1H-quinoline-3-carboxylate (895 mg, 64%).1H NMR (300 MHz, DMSO-d6) δ 11,22 (s, 1H), 8,32 (s, 1H), 7,82 (d, J=7,8 Hz, 1H), to 7.04 (d, J=7,8 Hz, 1H), 4,19 (sq, J=7.2 V, 14.4 Hz, 2H), of 2.72 (s, 3H), 1,23 (t, J=10,2 Hz, 3H).

A flask containing ethyl 8-bromo-5-methyl-4-oxo-1H-quinoline-3-carboxylate (895 mg, 2,89 mmol), sodium acetate (237 mg, 2,89 mmol) and Pd/C (180 mg, 1,69 mmol), washed in the atmosphere of N2with the subsequent removal of gas in vacuum. Was added acetic acid (21 ml) under an inert atmosphere followed by removal of gas in vacuum. The reaction mixture is then stirred for 4 hours in the atmosphere of H2. The reaction mixture was filtered to remove the Pd catalyst and the solvent was evaporated to obtain ethyl 5-methyl-4-oxo-1H-quinoline-3-carboxylate (145 mg, 22%).

Ethyl 5-methyl-4-oxo-1H-quinoline-3-carboxylate (142 mg, 0.61 mmol) was suspended in aqueous NaOH (1,54 ml of 4% wt/V, 1.54 mmol) and the reaction mixture was stirred at the temperature of reflux for 2 hours. After cooling, the reaction mixture was acidified with using concentrated HCl. The precipitate that formed was collected by filtration, washed with water and dried to obtain 5-methyl-4-oxo-1H-quinoline-3-carboxylic acid (42 mg, 34%).1H I�R (400 MHz, DMSO-d6) δ 15,69 (lat.s, 1H), 13,81 (lat.s, 1H), 8,68 (d, J=6,4 Hz, 1H), 7,70-of 7.64 (m, 2H), 7,27(d, J=6,4 Hz, 1H), 2,84 (s, 3H), MS (ESI) m/z: 202,2 [M-H]-.

7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid can be synthesized in accordance with the General scheme above, on the basis of 2-bromo-3-methylaniline. Total output (16%).1H NMR (400 MHz, DMSO-d6) with 15.24 δ (s, 1H), 12,30 (s, 1H), 8,63 (s, 1H), 8,07 (d, J=8,0 Hz, 2H), 7,28 (d, J=8,0 Hz, 1H), 2,85 (s, 3H).

8-bromo-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

8-bromo-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid can be synthesized in accordance with the General scheme above, on the basis of 2-bromo-5-nitroaniline. LC/MS: m/z 314,9 (M+H)+1.0 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

The acid intermediate of the compound of Example 3:Synthesis of 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid

2-chloro-5-(trifluoromethyl)aniline (52 g, 260 mmol) and diethyl 2-(ethoxymethylene)propanedioic (85 g, 389 mmol) were combined in a 250 ml flask and the flask was supplied with a trap Dean-stark. The mixture was heated to 110ºC for 4 hours. The reaction mixture was cooled to ~80ºC and was slowly added hexane (~150 ml). The resulting precipitate was stirred until reaching room temperature�URS, then was filtered to give a white crystalline solid. The solid is washed with hexane and air dried (93 g, 94%).1H NMR (400 MHz, DMSO-d6) δ 11,28 (d, J=13,0 Hz, 1H), 8,63 (d, J=13,0 Hz, 1H), 8,10 (s, 1H), 7,80 (d, J=8,3 Hz, 1H), 7,50 (DD, J=8,4, 1.5 Hz, 1H), 4,21 (d. sq, J=28,3, a 7.1 Hz, 4H), 1.27 mm (TD, J=7,1, 2,9 Hz, 6H).

6 ml of Dowtherm was added to dinagalu 25 ml flask equipped with a reflux condenser. Dowtherm heated to 200ºC and degassed for 20 minutes. Was then added diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino)methylene)malonate (1 g, 2,73 mmol) and the solution was then heated to boiling temperature to reflux for 2.5 hours in an atmosphere of N2. The reaction mixture was cooled in 2.5 hours, then diluted with hexane (12 ml) with a fine light brown precipitate. The reaction mixture was filtered and the precipitate was washed with hexane until the disappearance of the color. The product was air dried to obtain ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate as a light brown solid (0,57 g, 65%).1H NMR (400 MHz, DMSO-d6) δ 11,91 (s, 1H), of 8.39 (s, 1H), 8,06 (d, J=8,3 Hz, 1H), 7,81 (d, J=8.4 Hz, 1H), 4,24 (kV, J=7,1 Hz, 2H), of 1.29 (t, J=7,1 Hz, 3H).

Ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate (500 mg, 1.56 mmol) was dissolved in NaOH (16 ml of 2.0 M, 31 mmol) and ethanol (3 ml) and heated to 100ºC for 2 hours. Transparent light W�lty the solution was cooled to 50ºC, the reaction mixture was degassed using N2and then was treated with 10% solution of Pd/C (65 mg, 0,03 mmol). The reaction mixture was heated at 70ºC for 3 hours in the atmosphere of H2. The reaction mixture was cooled and then filtered, using acidified with concentrated HCl until a white precipitate, was then left to stir over night. The reaction mixture was filtered, washed with water and dried using CH3CN to give a white powder (350 mg, 87%).1H NMR (400 MHz, DMSO-d6) δ 15,26 (s, 1H), 13,68 (s, 1H), 8,98 (s, 1H), 8,16-8,09 (m, 1H), 8,08-7,97 (m, 2H).

Commercially available acids and esters

8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
4-oxo-6-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid
8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

4-oxo-7-(triptoreline)-1,4-dihydroquinoline-3-carboxylic acid
Ethyl 5,8-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylate
5-PIF�-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
4-oxo-8-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid
8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Ethyl 8-cyano-4-oxo-1,4-dihydroquinoline-3-carboxylate
7-cyano-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
8-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
6-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
8-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Ethyl 7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate
6-(dimethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
6-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
7-acetyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Amine intermediate Example 1:Synthesis of 5-amino-2-(trifluoromethyl)phenol

A mixture of 1-bromo-2-methoxy-4-nitro-benzene (20 g, of 86.2 mmol), methyl 2,2-debtor-2-persulfuric-acetate (100 g, 520,5 mmol) and CuI (65 g, 341,3 mmol) in anhydrous DMF (200 ml) was stirred at 75ºC in the atmosphere of N2in the course of the night. The solvent was evaporated under reduced pressure. To the residue was added EtOAc and the solid was removed by filtration. The filtrate was washed with water (100 ml ×2), saturated brine (100 ml), dried over anhydrous Na2SO4and was purified column chromatography on silica gel (petroleum ether as eluent) to give a mixture of 1-bromo-2-methoxy-4-nitro-benzene and 2-methoxy-4-nitro-1-(trifluoromethyl)benzene (16 g).1H NMR (300 MHz, CDCl3) δ 7,90-7,86 (m, 1H), a 7.85 (s, 1H), to 7.77-7,69 (m, 1H), was 4.02 (s, H).

A mixture of 2-methoxy-4-nitro-1-(trifluoromethyl)benzene and 1-bromo-2-methoxy-4-nitro-benzene (16 g, 72 mmol) and pyridinecarboxamide (100 g, 865,3 mmol) was stirred at 210ºC for 40 minutes. Then the reaction mixture was poured into ice water and extracted using EtOAc (80 ml ×3). The combined organic layers were washed with water (100 ml ×2) and saturated brine (50 ml), dried over anhydrous Na2SO4, filtered, concentrated and was purified column chromatography on silica gel (5% EtOAc in petroleum ether as eluent) to give a mixture of 5-nitro-2-(trifluoromethyl)phenol and 2-bromo-5-nitro-phenol (10 g).1H NMR (400 MHz, CDCl3) δ 9,16 (s, 1H), 7,00 (d, J=8.4 Hz, 1H), of 6.06 (s, 1H), 5,95 (d, J=8.4 Hz, 1H), 4,07 (lat.s, 1H).

To a solution of 5-nitro-2-(trifluoromethyl)phenol and 2-bromo-5-nitro-phenol (10 g, 48,28 mmol) in methanol (60 ml) was added Raney-Nickel (2,83 g, 318 μl 48,28 mmol) in a nitrogen atmosphere. The reaction mixture is then stirred for 4 hours at room temperature in hydrogen atmosphere (1 ATM). The catalyst was removed by filtration through a layer of Celite and the filtrate was concentrated in vacuum. The crude product was purified preparative HPLC to obtain 5-amino-2-(trifluoromethyl)phenol (1.7 g, 20%).1H NMR (400 MHz, DMSO-d6) δ 9,79 (s, 1H), to 7.04 (d, J=8,8 Hz, 1H), 6,10 (s, 1H), 6,01 (d, J=8.4 Hz, 1H), 5,58 (lat.s, 2H).

Amine intermediate Example 2:Synthesis of 5-amino-2-(trif�ormetal)phenol

2-Isopropylaniline (13.5 g, 99,85 mmol) was added in portions to concentrated H2SO4(100 ml) to obtain a yellow homogeneous solution. The solution was then cooled to 0ºC and added in portions KNO3(15.2 g, to 150.3 mmol), maintaining the internal temperature below 5ºC. The reaction mixture was stirred for 2 hours and then was poured onto ice water, then podslushivaet 10% NaOH. The aqueous layer was extracted using EtOAc, dried over MgSO4, filtered and concentrated to give 2-isopropyl-5-nitroaniline (14,9 g, 83%).1H NMR (400 MHz, CDCl3) δ 7,60 (DD, J=8,4, and 2.2 Hz, 1H), 7,50 (d, J=2.4 Hz, 1H), 7,27-7,21 (m, 1H), 3,96 (s, 2H), 2,98-2,79 (m, 1H), of 1.29 (d, J=6,8 Hz, 6H).

2-Isopropyl-5-nitro-aniline (1.89 g, 10,49 mmol) was added dropwise to a mixture of concentrated H2SO4(9 ml) and H2O (50 ml). This reaction mixture was cooled to 0ºC was added a solution of NaNO2(763 mg, 11,06 mmol) in H2O (2 ml). The reaction mixture was stirred for 10 minutes and then was added 1 g of urea was added to decompose the excess NaNO2with the subsequent addition of 10 ml of 1:2 with concentrated H2SO4:H2O. the Reaction mixture was then heated to reflux for 10 minutes, cooled to room temperature and extracted using EtOAc, washed with saturated brine, sushi�and over MgSO 4, filtered and concentrated. The residue was then purified by column chromatography on silica gel using 10 to 20% EtOAc in hexane to obtain 2-isopropyl-5-methyl-phenol (1.41 g, 89%).1H NMR (400 MHz, CDCl3) δ 7,79 (DD, J=8,5, and 2.3 Hz, 1H), 7,63 (d, J=2,3 Hz, 1H), to 7.33 (d, J=8,5 Hz, 1H), 7,26 (s, 1H), 3,39-3,18 (m, 1H), 1,29-of 1.26 (m, 6H).

To be heated at the temperature of reflux to a solution of 2-isopropyl-5-methyl-phenol (1.3 g, 8,65 mmol) and ammonium formate (1.3 g, 20,62 mmol) in ethanol (50 ml) was added 10% Pd/C (887 mg, of 8.33 mmol). The mixture was boiled to reflux for 5 minutes, cooled and filtered through a layer of Celite. The solvent was removed by evaporation to obtain 5-amino-2-isopropylphenol, which was used without further purification.1H NMR (400 MHz, DMSO-d6) δ to 8.70 (s, 1H), 6,71 (d, J=8,1 Hz, 1H), 6,04 (d, J=2,2 Hz, 1H), 5,97 (DD, J=8,1, 2,2 Hz, 1H), 4,65 (s, 2H), is 3.08-to 2.94 (m, 1H), of 1.07 (d, J=6,9 Hz, 6H).

3-amino-4-tert-butylphenol

3-amino-4-tert-butylphenol can be synthesized in accordance with the General scheme presented above, based on 4-tert-butylaniline.

Amine intermediate Example 3:Synthesis of 5-amino-2-cyclohexylphenol

4-cyclohexylaniline (15 g, 85,58 mmol) was added in portions to concentrated sulfuric acid (85 ml, 1.6 mol) to obtain homogeneously. The solution was then cooled to 0ºC and added in portions KNO3(13 g, of 128.6 mmol), maintaining the internal temperature below 5ºC. The reaction mixture was stirred for 5 minutes at-10ºC and then was poured onto ice water, podslushivaet 6N NaOH and the aqueous layer was extracted using EtOAc, dried over MgSO4, filtered and concentrated to give 4-cyclohexyl-3-nitroaniline (17 g, 921%).1H NMR (400 MHz, CDCl3) δ 7,20 (d, J=8,5 Hz, 1H), 6,97 (d, J=2.5 Hz, 1H), about 6,82 (DD, J=8,4, 2.5 Hz, 1H), 2,85 (DDD, J=11,4, 8,3, a 3.2 Hz, 1H), 1,89-to 1.69 (m, 6H), 1,49-of 1.29 (m, 4H).

To a solution of 4-cyclohexyl-3-nitro-aniline (1,54 g, of 6.99 mmol) in DCM (15 ml) was added Et3N (1.9 ml, is 13.63 mmol), followed by the addition of acetic anhydride (3.3 ml, 34,98 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with water, the layers were separated and the organic layer was washed with 0.1 n HCl solution, followed by rinsing by using H2O. the Organic layer was dried over MgSO4, filtered and concentrated to give N-(4-cyclohexyl-3-nitrophenyl)acetamide (1.7 g, 93%).1H NMR (400 MHz, CDCl3) δ 7,91 (d, J=2,2 Hz, 1H), 7,69 (DD, J=8,6, and 2.2 Hz, 1H), 7,52 (s, 1H), 7,40 (d, J=8,6 Hz, 1H), 3,01-2,87 (m, 1H), 2,22 (s, 3H), 1,95-1,78 (m, 5H), of 1.42 (t, J=10.4 Hz, 4H), 1,32-to 1.21 (m, 1H).

To be heated at the boiling temperature to reflux a solution of N-(4-cyclohexyl-3-nitro-phenyl)acetamide (1.8 g, 6.86 mmol) and formate um�onium (1.8 g, 28,55 mmol) in ethanol (50 ml) was added 10% Pd/C (1.3 g, 12,22 mmol). The mixture was boiled to reflux for 5 minutes, cooled and filtered through a layer of Celite. The solvent was removed by evaporation to obtain N-(3-amino-4-cyclohexylphenol)acetamide (1.4 g, 90%) which was used without further purification.1H NMR (400 MHz, CDCl3) δ 7,15 (d, J=2,1 Hz, 2H), 7,03 (d, J=8,3 Hz, 1H), to 6.67 (DD, J=8,2, and 2.1 Hz, 1H), and 3.72 (d, J=9,8 Hz, 2H), 2,42 (d, J=8,5 Hz, 1H), 2,15 (s, 3H), of 1.88 (d, J=9,5 Hz, 4H), 1,78 (d, J=12.1 Hz, 1H), 1,51-of 1.33 (m, 5H).

N-(3-amino-4-cyclohexyl-phenyl)acetamide (696 mg, 3.0 mmol) was added dropwise to a mixture of concentrated H2SO4(3 ml, 56,28 mmol) and H2O (17 ml). This reaction mixture was cooled to 0ºC was added a solution of NaNO2(229 mg, of 3.32 mmol) in H2O (2 ml). The reaction mixture was stirred for 5 minutes at 0ºC and then was added 1 g of urea followed by the addition of 10 ml of 1:2 H2SO4:H2O. the Reaction mixture was then heated to reflux for 1 hour, cooled to room temperature and extracted using EtOAc. The aqueous layer was podslushivaet solid NaOH and extracted using EtOAc. The combined organic layer was washed with saturated brine, dried over MgSO4, filtered and concentrated to give 5-amino-2-cyclohexylphenol (426 mg, 74%) which was used without further purification.

Amine intermediate Example 4:Synthesis of 5-amino-2-tert-butyl-4-ethylphenol

To a solution of 2-tert-butyl-4-ethyl-phenol (10 g, was 56.1 mmol) in DCM (50 ml) was added Et3N (17 g, 168,0 mmol) and methylchloroform (11 g, 116,4 mmol) at 0ºC. The mixture was stirred over night at room temperature. Was added water to quench the reaction and the mixture extracted using EtOAc (200 MLS). The combined organic layers were dried over anhydrous Na2SO4, was filtered and was evaporated in vacuum to give 2-tert-butyl-4-ethylphenethylamine (12 g, 91%).1H NMR (300 MHz, CDCl3), 7,06-7,02 (m, 2H), 7,02 (s, 1H), 3,92 (s, 3H), of 2.64 (q, J=7.5 Hz, 2H), of 1.37 (s, 9H), 1,54 (t, J=7.5 Hz, 3H).

To a solution of KNO3(3.9 g, 38,57 mmol) in DCM (50 ml) was added TMSCl (5.5 g, 50,62 mmol) and 2-tert-butyl-4-ethylphenethylamine (6 g, 25,39 mmol) at 0ºC. After stirring for 15 minutes was added AlCl3(10 g, 0,08 mol) and then the reaction mixture was stirred for 2 hours. The reaction mixture was poured onto ice water and extracted using EtOAc (50 MLS). The combined organic layers were dried over anhydrous Na2SO4, was filtered and was evaporated in vacuum to give the crude compound which was purified by column chromatography on silica gel (10-15% EtOAc in petroleum ether as eluent) to give 2-tert-butyl-4-ethyl-5-nitrophe�of ilmestyskirjasta (5 g, 70%).1H NMR (400 MHz, CDCl3) 7,69 (s, 1H), 7,25 (s, 1H), 3,82 (s, 3H), of 2.54 (q, J=7,6 Hz, 2H), 1.26 in (s, 9H), of 1.15 (d, J=7,6 Hz, 3H).

To a solution of (2-tert-butyl-4-ethyl-5-nitro-phenyl)methylcarbamate (3.9 g, 13,86 mmol) in methanol (100 ml) was added KOH (1.8 g, of 32.08 mmol) at room temperature. The mixture was stirred over night. Added water and the reaction mixture was extracted using EtOAc (50 MLS). The combined organic layers were dried over anhydrous Na2SO4, was filtered and was evaporated in vacuum to give 2-tert-butyl-4-ethyl-5-NITROPHENOL (2.8 g, 91%) which was used for next step without further purification.

To a solution of 2-tert-butyl-4-ethyl-5-nitro-phenol (3.2 g, and 14.3 mmol) in methanol (20 ml) was added Raney Nickel (200 mg, 3.4 mmol) in a nitrogen atmosphere. The reaction mixture was then stirred over night at room temperature in hydrogen atmosphere (1 ATM). The catalyst was removed by filtration through a layer of Celite and the filtrate was concentrated in vacuum to give 5-amino-2-tert-butyl-4-ethyl-phenol (1.2 g, 43%).1H NMR (400 MHz, CDCl3) δ at 6.92 (s, 1H), of 6.06 (s, 1H), 2,45 (sq, J=7,6 Hz, 2H), of 1.37 (s, 9H), to 1.21 (t, J=7,6 Hz, 3H), MS (ESI) m/e (M+H+) 194,2.

5-amino-2-tert-butyl-4-METHYLPHENOL

5-amino-2-tert-butyl-4-METHYLPHENOL can be synthesized in accordance with the General scheme above, on the basis of 2-tert-butyl-4-METHYLPHENOL.1 H NMR (400 MHz, CDCl3) δ 6,91 (s, 1H), to 6.05 (s, 1H), 4,73 (lat.s, 1H), 3,44 (lat.s, 2H), 2,09 (s, 3H), of 1.37 (s, 9H), MS (ESI) m/z (M+H+) 179,3.

Amine intermediate Example 5:Synthesis of 4-tert-butyl-3-ftoranila

KNO3(7.5 g, 74,18 mmol) in concentrated H2SO4(50 ml) was slowly added to a mixture of 2-tert-butylaniline (11 g, 73,71 mmol) in concentrated H2SO4(50 ml) at-10ºC. The mixture was stirred at -10 OC for 1 hour and poured into ice water. The mixture was extracted using EtOAc (150 ml ×3). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4and was purified column chromatography on silica gel to obtain 2-tert-butyl-5-nitro-aniline (9 g, 63%).1H NMR (400 MHz, CDCl3) δ 7,53 (DD, J=2,8, 8,8 Hz, 1H), of 7.46 (d, J=2,8 Hz, 1H), 7,34 (d, J=8,8 Hz, 1H), 4,12 (lat.s, 2H), of 1.44 (s, 9H).

To a stirred solution of 2-tert-butyl-5-nitro-aniline (5.0 g, 25,74 mmol) in H2O (20 ml) was added concentrated HCl (10 ml). After dissolution, the mixture was cooled to 0ºC, followed by the slow addition of NaNO2(1.8 g, 819 μl 25,74 mmol) in H2O (10 ml). The reaction mixture was stirred at 0ºC for another 0.5 hours. Then was added a solution of HPF6(2×20 ml) batches. The resulting precipitate was isolated by filtration, then was heated under conditions of infrared radiation when�to be about 130-150ºC. The gray solid was slowly turned into a dark viscous oil, which was purified column chromatography on silica gel to obtain 1-tert-butyl-2-fluoro-4-nitrobenzene (0.6 g, 12%).1H NMR (400 MHz, CDCl3) δ 7,96 (DD, J=2,4, 8,8 Hz, 1H), a 7.87 (DD, J=2,4, and 12.0 Hz, 1H), of 7.48 (t, J=8,0 Hz, 1H), 1,43 (s, 9H).

NaBH4(144 mg, 152 μl, 3.8 mmol) was added to a solution of 1-tert-butyl-2-fluoro-4-nitro-benzene (750 mg, 3.8 mmol) and NiCl2.6H2O (2.6 g, 11 mmol) in methanol (15 ml) at-15. After the addition the mixture was stirred for 2 minutes and water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (50 ml ×3). The combined organic layers were dried over anhydrous Na2SO4and was evaporated in vacuum to give 4-tert-butyl-3-fluoro-aniline (470 mg, 74%) which was used without further purification.1H NMR (300 MHz, CDCl3) δ 7,08-7,02 (m, 1H), to 6.42-system 6.34 (m, 2H), 1,32 (s, 9H), MS (ESI) m/z: 168,2 [M+H].

Amine intermediate Example 6:Synthesis of 4-tert-butyl-3-foronline

Concentrated nitric acid (15.8 ml, 376,9 mmol) was added to a solution of 4-bromoaniline (40 g, to 232.5 mmol) in H2SO4/CH2Cl2(400 ml, 1:1, V/V) dropwise at 0ºC in an atmosphere of N2. Cooling bath was removed and the mixture was stirred at 20ºC until then, until the starting material was consumed (about 1 hour). Reactio�ing mixture was poured onto water and neutralized with NaOH solution to pH=9 and extracted using DCM. The organic layer was dried, filtered and evaporated in vacuum to give crude product 4-bromo-3-nitro-aniline, which was used directly in the next step.

2,2-dimethylpropanoate (28 g, 232,2 mmol) was added to a stirred solution of 4-bromo-3-nitro-aniline (42 g, to 193.5 mmol) and Et3N (51 ml, 366 mmol) in anhydrous DCM (200 ml) at 0ºC in an atmosphere of N2. Cooling bath was removed and stirring was continued at room temperature for 2 hours. The reaction mixture was poured onto ice (500 g) and extracted using CH2Cl2. The combined organic layer was dried over Na2SO4and was evaporated in vacuum to give crude product N-(4-bromo-3-nitrophenyl)palamida (55 g, 94%) which was used directly in the next step.1H NMR (300 MHz, CDCl3) δ: 8,18-8,17 (m, 1H), of 7.64-7,63 (m, 2H), 7,50 (lat.s, 1H), 1,32 (s, 9H).

CuI (69,8 g, 366,5 mmol) and methyl 2,2-debtor-2-persulfuric-acetate (70,4 g, 366,4 mmol) was added to a stirred solution of N-(4-bromo-3-nitro-phenyl)-2,2-dimethyl-propanamide (55,0 g, USD 182.6 mmol) in anhydrous DMF (300 ml) at room temperature. The reaction mixture was stirred at 100ºC until then, until the starting material was consumed (about 12 hours). The solvent was evaporated in vacuum to give crude product N-(3-nitro-4-(trifluoromethyl)phenyl)palamida (45,0 g, 85%)), to�which was used directly in next step without purification. 1H NMR (400 MHz, CDCl3) δ: 8,21 (d, J=2,0 Hz, 1H), a 7.87 (DD, J=2,0, 8,8 Hz, 1H), 7,74 (d, J=8,8 Hz, 1H), of 7.64 (lat.s, 1H), of 1.34 (s, 9H),19F NMR (282,4 MHz, CDCl3): -60,62 (S).

2,2-dimethyl-N-[3-nitro-4-(trifluoromethyl)phenyl]propanamide (45,0 g, 155,0 mmol) in 6N HCl (200 ml) was stirred at 100ºC overnight. The reaction mixture was cooled to room temperature and carefully neutralized with solid NaHCO3to pH=9. The reaction mixture was extracted using CH2Cl2and dried over Na2SO4. The solvent was evaporated in vacuum to give crude product 3-nitro-4-(trifluoromethyl)aniline (31.0 g, 97%) which was used directly in the next step.

To a solution of 3-nitro-4-(trifluoromethyl)aniline (31.0 g, 150,4 mmol) in Or (200 ml) was added bromine (9,3 ml of 180.5 mmol) at 0ºC in an atmosphere of N2. Cooling bath was removed and the mixture was stirred at 20ºC for 1 hour. The solvent was removed in vacuum to give crude product 2-bromo-5-nitro-4-(trifluoromethyl)aniline (40,0 g, 93%) which was used directly in the next step.

To a solution of 2-bromo-5-nitro-4-(trifluoromethyl)aniline (10.0 g, 35.1 per mmol) in toluene/H2O (100 ml, 1:1, V/V) was added CuI (0.4 g, 2.10 mmol), Et3N (9.5 ml, 68,16 mmol), Pd(PPh3)2Cl2(5.0 g, 7.12 mmol) and amenitieseven (5.2 g, 53 mmol) successively under a nitrogen atmosphere at room temperature�ré. The reaction mixture was transferred into a sealed flask high pressure and heated at 70ºC for 10 hours. The reaction mixture was cooled to room temperature, was filtered, was evaporated in vacuo and was purified column chromatography on silica gel (1% to 20% EtOAc in petroleum ether as eluent) to give 5-nitro-4-(trifluoromethyl)-2-((trimethylsilyl)ethinyl)aniline (6.0 g, 57%) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 7.67 per (s, 1H), 7,13 (s, 1H), with 4.86 (lat.s, 2H), of 0.29 (s, 9H).

To a solution of 5-nitro-4-(trifluoromethyl)-2-((trimethylsilyl)ethinyl)aniline (6.0 g, 19,85 mmol) in DMF (30 ml) was added CuI (1.9 g, 9,976 mmol) in a nitrogen atmosphere. The reaction mixture was heated at 135ºC in a tightly closed flask high pressure over night. The reaction mixture then was filtered and the filtrate was washed with water, dried over Na2SO4and concentrated. The crude product was purified column chromatography on silica gel (5 to 20% EtOAc in petroleum ether as eluent) to give 6-nitro-5-(trifluoromethyl)-1H-indole (1.4 g, 31%).1H NMR (400 MHz, CDCl3): δ 8,83 (lat.s, 1H), 8,15 (s, 1H), 8,11 (s, 1H), 7,58-EUR 7.57 (m, 1H), 6,80-of 6.79 (m, 1H);19F NMR (282,4 MHz, CDCl3) : δ -57,82; MS (ESI): m/z [M-H]-229.

In a microwave vessel was loaded with 6-nitro-5-(trifluoromethyl)-1H-indole (100 mg, 0.43 mmol), tert-butylbromide (30 mg, 0,22 mmol), triflic zinc (95 mg, 0,26 mmol), TBAI(80 mg, 0,22 mmol), DIEA (63 mg, 0.49 mmol) and toluene (1 ml), hermetically closed and heated in the microwave for 10 minutes at 120ºC. The reaction mixture was quenched with water, the layers were separated and the aqueous layer was extracted using DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated. The mixture was then purified by column chromatography on silica gel using 0 to 20% EtOAc in hexane to obtain 3-tert-butyl-6-nitro-5-(trifluoromethyl)-1H-indole.1H NMR (400,0 MHz, CDCl3) δ of 8.25 (s, 1H), 8,10 (s, 1H), to 7.33 (d, J=2.5 Hz, 1H), 7,28 (s, 1H) and 1.50 (s, 9H), M. D.

In a microwave vessel was loaded with 3-tert-butyl-6-nitro-5-(trifluoromethyl)-1H-indole (95 mg, 0,3319 mmol), SnCl2.2H2O (375 mg, of 1.66 mmol) and ethanol (1 ml), was hermetically closed and heated at 62ºC for 3 hours. The reaction mixture was cooled to room temperature, was diluted using EtOAc and quenched with saturated solution of NaHCO3until a pH of 7. The reaction mixture was then filtered through a layer of Celite. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using 0 to 40% EtOAc in hexane to obtain 3-tert-butyl-5-(trifluoromethyl)-1H-indol-6-amine. LC/MS: m/z 257,3 (M+H)+at 1.54 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

The General scheme of: Receiving a meta-Thames�nnyh anilines

Suitable solvents include: benzene, toluene, DMSO; suitable cyclization conditions include: NaOAc, Ac2O or thionylchlorid, NaOAc; suitable conditions 1 recovery include: BH3or LiALH4in Et2O or THF; a suitable nitration conditions include: HNO3, H2SO4or KNO3, H2SO4;suitable conditions 2 recovery include: Pd/C, H2or Zn, or Fe AcOH, AcOH

3-(pyrrolidin-1-yl)-5-(trifluoromethyl)aniline

3-(pyrrolidin-1-yl)-5-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme presented above, based on 3-nitro-5-(trifluoromethyl)aniline and tetrahydrofuran-2,5-Dion. LC/MS: m/z 230,9 (M+H)+at 1.22 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA))

3-(piperidine-1-yl)-5-(trifluoromethyl)aniline

3-(piperidine-1-yl)-5-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme presented above, based on 4-nitro-3-(trifluoromethyl)aniline and dihydro-2H-PYRAN-2,6(3H)-dione. LC/MS: m/z 245,1 (M+H)+to 0,77 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

3-(piperidine-1-yl)-4-(triptoreline)aniline

3-(piperidine-1-yl)-4-(triptoreline)aniline can be synthesized in accordance with the General scheme presented above, the outcome� of 4-(triptoreline)benzene-1,3-diamine and dihydro-2H-PYRAN-2,6(3H)-dione. LC/MS: m/z 361,3 (M+H)+at 1.15 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

3-(pyrrolidin-1-yl)-4-(triptoreline)aniline

3-(pyrrolidin-1-yl)-4-(triptoreline)aniline can be synthesized in accordance with the General scheme presented above, based on 4-(triptoreline)benzene-1,3-diamine and tetrahydrofuran-2,5-Dion. LC/MS: m/z 247,1 (M+H)+when 1,13 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Amine intermediate Example 7:Synthesis of 4-tert-butyl-3-(pyrrolidin-1-yl)aniline

To a solution of 2-tert-butylaniline (1.0 g, 6.7 mmol) in toluene (15 ml) was added tetrahydrofuran-2,5-dione (0,81 g, 8.1 mmol) and the reaction mixture was boiled to reflux for 1 hour. The reaction mixture was cooled and filtered to obtain 4-(2-tert-butylbenzylamine)-4-oxobutanoic acid, which was dissolved in acetic acid (20 ml) and sodium acetate (3,02 g, 36,86 mmol) and stirred at 80ºC overnight. The reaction mixture was quenched with water, the layers were separated and the aqueous layer was extracted using DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The obtained solid substance was recrystallized from ethanol to give pure 1-(2-tert-butylphenyl)pyrrolidin-2,5-dione (930 mg, 60%). LC/MS: m/z of 232.3 (M+H)+when 1,264 min (10%-99% CH3CN (0,05% TFA)/H 2O (0,05% TFA)).

To a solution of 1-(2-tert-butylphenyl)pyrrolidin-2,5-dione (500 mg, 2.16 mmol) in THF (10 ml) was added BH3in toluene (350 mg, 1,72 mmol) dropwise and the reaction mixture was heated to boiling temperature to reflux over night. The reaction mixture was cooled to room temperature and quenched with methanol (until the evolution of H2). The solvent was evaporated to obtain 1-(2-tert-butylphenyl)pyrrolidine (350 mg, 80%) as an oil.1H NMR (400 MHz, CDCl3) δ 7,30 (s, 1H), 7,28 (s, 1H), 7,15 (d, J=0.9 Hz, 1H), 7,07-7,01 (m, 1H), 2,90 (s, 4H), 1,88-1,78 (m, 4H), of 1.35 (s, 9H). LC/MS: m/z 204,1 (M+H)+when 0,88 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

1-(2-tert-butylphenyl)pyrrolidine (350 mg, 1,72 mmol) was added in portions to concentrated H2SO4(1 ml) to produce a yellow homogeneous solution. The solution was then cooled to 0ºC and added in portions KNO3(191 mg, 1.9 mmol), maintaining the internal temperature below 5ºC. The reaction mixture was stirred for 2 hours and then was poured onto ice water and extracted using DCM, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to obtain 1-(2-tert-butyl-5-nitrophenyl)pyrrolidine (325 mg, 76%). LC/MS: m/z 248,9 (M+H)+when 2,39 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

A flask containing 1-(2-tert-butyl-5-nitro�Neal)pyrrolidine (150 mg, Of 0.60 mmol) and Pd/C (15 mg, 0.14 mmol), washed in the atmosphere of N2with the subsequent removal of gas in vacuum. Was added methanol (2 ml) under an inert atmosphere followed by removal of gas in vacuum. The reaction mixture was stirred overnight in an atmosphere of H2. The reaction mixture was filtered and the solvent was evaporated to obtain 4-tert-butyl-3-(pyrrolidin-1-yl)aniline (119 mg, 90%). LC/MS: m/z 218,5 (M+H)+at 2 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-tert-butyl-3-(piperidine-1-yl)aniline

4-tert-butyl-3-(piperidine-1-yl)aniline can be synthesized in accordance with the General scheme above, on the basis of 2-tert-butylaniline and dihydro-2H-PYRAN-2,6(3H)-dione. LC/MS: m/z 232,9 (M+H)+when 1,23 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Obtaining para-substituted anilines

Suitable solvents include: benzene, toluene, DMSO; suitable cyclization conditions include: NaOAc, Ac2O or thionylchlorid, NaOAc; suitable conditions 1 recovery include: BH3or LiALH4in Et2O or THF; a suitable nitration conditions include: HNO3, H2SO4or KNO3, H2SO4; suitable conditions 2 recovery include: Pd/C, H2or Zn, or Fe AcOH, AcOH.

Obtaining para-substituted anilines via SNAr chemistry

Suitable bases include: triethylamine, potassium tert-butoxide, diisopropylethylamine, potassium carbonate; suitable solvents include DMSO, DMF, CH3CN, THF; suitable conditions for recovery include: Pd/C, H2; Zn, AcOH, Fe, AcOH.

Amine intermediate Example 8:Synthesis of 4-(pyrrolidin-1-yl)-2-(trifluoromethyl)aniline

To a solution of 4-nitro-3-(trifter)aniline (2.0 g, 9.7 mmol) in toluene (30 ml) was added dihydrofuran-2,5-dione (1.16 g, 11.6 mmol) and the reaction mixture was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and was filtered. The precipitate was washed with simple ether and dried to obtain 4-(4-nitro-3-(trifluoromethyl)phenylamino)-4-oxobutanoic acid (1.1 g, 37%). LC/MS: m/z 307,3 (M+H)+.

A solution of 4-(4-nitro-3-(trifluoromethyl)phenylamino)-4-oxobutanoic acid (1.1 g, 3.6 mmol) and NaOAc (1.62 g, 19,75 mmol) in acetic anhydride (15 ml) was stirred overnight at 80ºC. The reaction mixture was diluted with water and extracted twice with dichloromethane. The organic layers were combined and washed using NaOH (1 n) until pH 9. The organic layer was separated, dried using MgSO4,was filtered and concentrated in vacuum to give 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2,5-dione (0.4 g, 39%). LC/MS: m/z 288,9 (M+H)+.

To a solution of 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2,5-dione (400 mg, 1,38 mmol) in THF (10 ml) was added a solution of 1 M BH3in THF (11,10 ml) dropwise over 5 minutes. The reaction mixture was boiled to reflux for 16 hours in an inert atmosphere, cooled, then quenched with the aid of MeOH and concentrated in vacuo. The crude product was used for next step without purification. LC/MS: m/z 261,1 (M+H)+.

A solution of 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (350 mg, of 1.34 mmol) in methanol (2 ml) and Pd/C (30 mg, 0.3 mmol) was stirred for 16 hours in an atmosphere of H2. The reaction mixture was filtered and the solvent evaporated in vacuum to give 4-(pyrrolidin-1-yl)-2-(trifluoromethyl)aniline (0.3 g, 97%). LC/MS: m/z 231.3 of which (M+H)+.1H NMR (400 MHz, DMSO-d6) δ at 6.84 (d, J=8,8 Hz, 1H), 6,72 (DD, J=8,8, 2.5 Hz, 1H), a 6.53 (d, J=2.7 Hz, 1H), 4,74 (s, 2H), 3,21-3,11 (m, 4H), 2.00 in of 1.93 (m, 4H).

4-(piperidine-1-yl)-2-(trifluoromethyl)aniline

4-(piperidine-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme presented above, based on 4-nitro-3-(trifluoromethyl)aniline and dihydro-2H-PYRAN-2,6(3H)-dione.1H NMR (400,0 MHz, DMSO-d6) δ was 7.08 (DD, J=2.7 and 8.8 Hz, 1H), to 6.88 (d, J=2,8 Hz, 1H), 6,83 (d, J=8,9 Hz, 1H), 5,09 (s, 2H), 2,96 (t, J=5.4 Hz, 4H), 1,67 (sq, J=5,5 Hz, 4H) and 1.55-of 1.42 (m, 2H) M. D. LC/MS: m/z 244,9 (M+H)+when 0,67 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

2-methyl-4-(pyrrolidin-1-yl)aniline

2-methyl-4-(pyrrolidin-1-yl)aniline can be synthesized in accordance with the General scheme presented above, based on 3-methyl-4-nitroaniline and tetrahydrofuran-2,5-Dion.1H NMR (400,0 MHz, DMSO-d6) δ 6,56 (d, J=8.4 Hz, 1H), 6,33 (d, J=2,6 Hz, 1H), 6,27 (DD, J=2.7 and 8.4 Hz, 1H), 4,10 (s, 2H), 3,13 (t, J=6,5 Hz, 4H), 2,09-2,04 (m, 3H) and 1,99-1,90 (m, 4H) M. D. LC/MS: m/z 177,3 (M+H)+when 0,35 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Amine intermediate Example 8:Synthesis of 1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-amine

To a solution of tert-butyl 7-amino-4,4-dimethyl-2,3-dihydroquinoline-1-carboxylate (100 mg, 0.36 mmol) in THF (2.2 ml) under an inert atmosphere was added LiAlH4(1.8 ml of a solution 1 M, 1.8 mmol) dropwise. The reaction mixture was heated to boiling temperature to reflux and stirred for 4 hours. The reaction mixture was cooled to room temperature and quenched with a solution of 0.4 M NaOH (0.6 ml), the aqueous layer was extracted using DCM, dried over Na2SO4, filtered and concentrated to give an orange oil. The residue was purified by reversed-phase HPLC. LC/MS: m/z 191,5 (M+H)+when 0,92 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Amine intermediate Example 9:Synthesis of 5-(benzyloxy)-4-cyclohexyl-2-(trifluoromethyl)aniline

To a stirred solution of 2-cyclo�of existenoe (26,0 g, 146,8 mmol) in glacial acetic acid (100 ml) was added HBr in acetic acid (150 ml of a 33% mass/mass) and H2O (52 ml), followed by the addition dropwise DMSO (100 ml) for 10 minutes. The reaction mixture was then carefully quenched with saturated solution of NaHCO3and concentrated in vacuum. The residue was treated with simple ether(400 ml), washed with water (2×100 ml) and saturated brine (1×100 ml) and dried over anhydrous Na2SO4, filtered and concentrated to give crude oil which was purified by column chromatography on silica gel using a gradient of 15-30% EtOAc/hexane to obtain 4-bromo-2-cyclohexyl-phenol (35.0 g, 93%)

4-Bromo-2-cyclohexyl-phenol (35.0 g, 137,2 mmol) was dissolved in DCM (200 ml) and Et3N (38 ml, this amounted to 272.6 mmol), cooled to 0ºC, then processed by methylchloroform (15.0 g, 153,4 mmol) and allowed to warm to room temperature for 16 hours. The reaction mixture was quenched with 30 ml of a saturated solution of NaHCO3, washed with 50% saturated solution of NaHCO3(1×100 ml) and saturated brine (1×100 ml), then dried over anhydrous Na2SO4, filtered and concentrated to give crude oil which was purified by column chromatography on silica gel, using a gradient of 20% EtOAc/hexane to obtain (4-bromo-2-cyclohexyl-phenyl)methylcarbamate (38,0 g, 88%) as colorless�about oil. 1H NMR (400 MHz, CDCl3) δ 7,41 (d, J=2,3 Hz, 1H), 7,32-7,29 (m, 1H), 6,98 (d, J=8,6 Hz, 1H), 3,92 (s, 3H), 2,71-of 2.64 (m, 1H), 1.85 to of 1.74 (m, 5H), 1,39-of 1.20 (m, 5H).

(4-Bromo-2-cyclohexyl-phenyl) methylcarbamate (5.0 g, 15,96 mmol) was added in portions to concentrated H2SO4(15 ml) to obtain colorless homogeneous solution. This solution is then cooled to 0ºC and added in portions KNO3(1,77 g, 17,51 mmol), maintaining the internal temperature below 5ºC. The reaction mixture was stirred for 2 hours and then was poured onto ice water and the aqueous layer was extracted using DCM (3×10 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was then purified by column chromatography on silica gel using a gradient of 10% EtOAc/hexane to obtain 4-bromo-2-cyclohexyl-5-nitro-phenylmercuriborate (3.25 g, 58%).1H NMR (400 MHz, CDCl3) δ 7,80 (s, 1H), 7,69 (s, 1H), 3,98 (s, 3H), 2,81-of 2.75 (m, 1H), 1,90-to 1.79 (m, 5H), 1,44-of 1.26 (m, 5H).

To a solution of (4-bromo-2-cyclohexyl-5-nitro-phenyl)-methylcarbamate (1.5 g, 4.2 mmol) in methanol (15 ml) was added KOH (353 mg, 6.3 mmol) in portions at 0ºC. After the addition the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was acidified using 1N HCl solution. The solvent was evaporated and water was added. The aqueous layer was extracted using DCM (3×10 ml). Associations�tion the organic layer was dried over Na 2SO4, filtered and concentrated to give 4-bromo-2-cyclohexyl-5-NITROPHENOL (1.2 g, 95%).1H NMR (400 MHz, CDCl3) δ 7,50 (s, 1H), 7,39 (s, 1H), 5,10 (s, 1H), 2,90-2,83 (m, 1H), 1,91-1,89 (m, 4H), 1,83-of 1.80 (m, 1H), 1,51-1,24 (m, 5H).

To a solution of 4-bromo-2-cyclohexyl-5-nitro-phenol (1.19 g, 4.0 mmol) and Cs2CO3(1,54 g, 4,72 mmol) in DMF (10 ml) was added the bromide (1.02 g, 707 µl, 6.0 mmol) dropwise. The reaction mixture was stirred at room temperature under an inert atmosphere for 2 hours. The reaction mixture was quenched with water and the aqueous layer was extracted using EtOAc (3×10 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using a gradient of 5% EtOAc/hexane to obtain 1-(benzyloxy)-4-bromo-2-cyclohexyl-5-nitrobenzene (1.35 g, 87%).1H NMR (400 MHz, CDCl3) δ of 7.42 (s, 1H), 7,39 (s, 1H), of 7.36-7,25 (m, 5H), of 5.06 (s, 2H), 2,99-of 2.93 (m, 1H), 1,79 (d, J=11.5 Hz, 4H), of 1.70 (d, J=13,4 Hz, 1H), 1,39-to 1.14 (m, 5H).

To a solution of 1-benzyloxy-4-bromo-2-cyclohexyl-5-nitro-benzene (500 mg, 1,28 mmol) and CuI (487,0 mg, 2.56 mmol) in DMF (5 ml) at room temperature was added methyl 2,2-debtor-2-persulfuric-acetate (492 mg, 326,0 ml, 2.56 mmol) dropwise in an inert atmosphere. The reaction mixture was then heated at 105ºC for 2 hours. The reaction mixture was cooled to room temperature, quenched with the help of NaHCO3 and filtered through a layer of Celite (to remove Cu salts). The aqueous layer was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using a gradient of 10% EtOAc/hexane to obtain 1-(benzyloxy)-2-cyclohexyl-5-nitro-4-(trifluoromethyl)benzene (435 mg, 90%).1H NMR (400 MHz, CDCl3) δ of 7.77 (s, 1H), 7.62 mm (s, 1H), of 7.42-7,28 (m, 5H), 5,27 (s, 2H), 2,98-of 2.92 (m, 1H), 1,75-1,62 (m, 5H), 1,47-of 1.13 (m, 5H).

To a solution of 1-(benzyloxy)-2-cyclohexyl-5-nitro-4-(trifluoromethyl)benzene (250 mg, 0,66 mmol) and NiCl2(170 mg, 1,31 mmol) in methanol (2.5 ml) was added NaBH4(50 mg, 1,32 mmol) in portions at 0ºC. The reaction mixture became black after 5 minutes. The reaction mixture was quenched using NaHCO3and was diluted using EtOAc. The reaction mixture was filtered through a layer of Celite, the layers were separated and the aqueous layer was extracted using EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was then purified by column chromatography on silica gel using a gradient of 10% EtOAc/hexane to obtain 5-benzyloxy-4-cyclohexyl-2-(trifluoromethyl)aniline (150 mg, 65%). LC/MS: m/z 350,3 (M+H)+when 2,40 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

5-(benzyloxy)-4-isopropyl-2-(trifluoromethyl)aniline

5-(benzyloxy)4-isopropyl-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme, presented above, based on 2-isopropylphenol. LC/MS: m/z 310,3 (M+H)+when 2,21 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-bromo-2-cyclopentyl-5-nitrophenylarsonic

4-bromo-2-cyclopentyl-5-nitrophenylarsonic can be synthesized in accordance with the General scheme presented above, based on 2-cyclopentylphenol).1H NMR (400,0 MHz, DMSO-d6) δ 8,12 (s, 1H), of 7.88 (s, 1H), 3,88 (d, J=5,7 Hz, 3H), 3,13 (DD, J=9,4, and 17.2 Hz, 1H), 1,96-of 1.92 (m, 2H), 1,80-of 1.75 (m, 2H), 1,68-of 1.54 (m, 4H).

Amine intermediate Example 10:Synthesis of 5-(benzyloxy)-2-fluoro-4-(trifluoromethyl)aniline

A solution of 2-bromo-4-fluoro-phenol (7.0 g, 36,65 mmol) and DMAP (224 mg, to 1.83 mmol) in DCM (15 ml) and Et3N (of 7.42 g, 10 ml, 73,30 mmol) was cooled to 0ºC, then processed by methylchloroform (14.5 g, 153,4 mmol) dropwise and allowed to warm to room temperature for 16 hours. The reaction mixture was quenched with 30 ml of a saturated solution of NaHCO3, washed with 50% saturated solution of NaHCO3(1×100 ml) and saturated brine (1×100 ml). The organic layer is then dried over anhydrous Na2SO4, filtered and concentrated to give crude oil which was purified by column chromatography on silica gel, using a gradient of 15% EtOAc/hexane to obtain (2-bromo-4-fluoro-phenyl)metalcarbon�TA (8,25 g, 90%).1H NMR (400 MHz, CDCl3) δ 7,38 (DD, J=7,7, 2,9 Hz, 1H), 7.23 percent (DD, J=9,0, 5,0 Hz, 1H), was 7.08 (DDD, J=9,0, 7,6, 2,9 Hz, 1H), 3,97 (s, 3H).19F NMR (376 MHz, CDCl3) δ -113,78 (TD, J=7,9, 5,2 Hz, 1H).

(2-Bromo-4-fluoro-phenyl)methylcarbamate (8,25 g, 33,13 mmol) was added in portions to concentrated H2SO4(45 ml) to obtain colorless homogeneous solution. This solution is then cooled to 0ºC and added in portions KNO3(3.7 g, 36,44 mmol), maintaining the internal temperature below 5ºC. The reaction mixture was stirred for 2 hours and then was poured onto ice water and the aqueous layer was extracted using DCM (3×10 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was then purified by column chromatography on silica gel using a gradient of 15% EtOAc/hexane to obtain 2-bromo-4-fluoro-5-nitrophenylarsonic (8,93 g, 92%).1H NMR (400 MHz, CDCl3) δ with 8.05 (d, J=6,7 Hz, 1H), 7,65 (d, J=9,6 Hz, 1H), 4,01 (s, 3H).

To a solution of 2-bromo-4-fluoro-5-nitrophenylarsonic (8,90 g, 30,27 mmol) in methanol (100 ml) was added KOH (4.25 g, 75,68 mmol) in portions at 0ºC. After completion of the addition the reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was acidified using 1N HCl solution. The solvent was evaporated and water was added. The aqueous layer was extracted using DCM (3×10ml). The combined organic layer was dried over Na2SO4, filtered and concentrated to give 2-bromo-4-fluoro-5-nitro-phenol (7,05 g, 99%).1H NMR (400 MHz, CDCl3) δ of 7.75 (d, J=6,6 Hz, 1H), 7,51 (d, J=9,6 Hz, 1H), to 5.62 (s, 1H).

To a solution of 2-bromo-4-fluoro-5-nitro-phenol (3.5 g, 14,83 mmol) and Cs2CO3(5,80 g, 17,80 mmol) in DMF (26 ml) was added the bromide (2.80 g, 1,94 ml, 16,31 mmol) dropwise. The reaction mixture was stirred at room temperature under an inert atmosphere for 2 hours. The reaction mixture was quenched with water and the aqueous layer was extracted using EtOAc (3×10 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using a gradient of 40% DCM/hexane to obtain 1-(benzyloxy)-2-bromo-4-fluoro-5-nitrobenzene.1H NMR (400 MHz, CDCl3) δ 7,65 (d, J=6,4 Hz, 1H), members, 7.59 (d, J=9.9 Hz, 1H), 7,52-7,34 (m, 5H), 5,23 (s, 2H).

To a solution of 1-benzyloxy-2-bromo-4-fluoro-5-nitro-benzene (500 mg, 1,53 mmol) and CuI (584 mg, of 3.07 mmol) in DMF (5 ml) at room temperature was added methyl 2,2-debtor-2-persulfuric-acetate (589,0 mg, of 3.07 mmol) dropwise in an inert atmosphere. The reaction mixture was then heated at 105ºC for 3 hours, then cooled to room temperature, quenched with the help of NaHCO3and filtered through a layer of Celite (to remove Cu salts). The aqueous layer extrage�up with ethyl acetate, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using a gradient of 10% EtOAc/hexane to obtain 1-(benzyloxy)-4-fluoro-5-nitro-2-(trifluoromethyl)benzene (400 mg, 83%).1H NMR (400 MHz, CDCl3) δ 7,71 (d, J=5.7 Hz, 1H), 7,62-EUR 7.57 (m, 1H), of 7.48-value of 7, 37 (m, 5H), 5,27 (s, 2H).19F NMR (376 MHz, CDCl3) δ -63,28 (s, 3H), -126,02 (DD, J=10,2, a 5.7 Hz, 1H).

To a solution of 1-(benzyloxy)-4-fluoro-5-nitro-2-(trifluoromethyl)benzene (382 mg, to 1.21 mmol) and NiCl2(314 mg, 2,42 mmol) in methanol (40 ml) was added NaBH4(50 mg, 1,32 mmol) in portions at 0ºC. The reaction mixture was black in 20 minutes. The reaction mixture was quenched using NaHCO3and was diluted using EtOAc. The reaction mixture was then filtered through a layer of Celite, the layers were separated and the aqueous layer was extracted using EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was then purified by column chromatography on silica gel using a gradient of 15% EtOAc/hexane to obtain 5-(benzyloxy)-2-fluoro-4-(trifluoromethyl)aniline (150 mg, 43%). LC/MS: m/z 286,1 (M+H)+when 1,89 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Amine intermediate Example 11:Synthesis of (1S,4R)-2-azabicyclo[2,2,1]heptane

The cooled solution of (1S)-1-fenilalanina (19.0 g, 156,8 mmol in H 2O (60 ml) at 0ºC was treated with a solution of glacial acetic acid (9 ml) in water (20 ml), followed by the addition of freshly distilled cyclopentadiene (is 20.73 g, 26,01 ml, 313,6 mmol) and formaldehyde (7,06 g, 6.5 ml, 235,2 mmol). The obtained reaction mixture was stirred for 48 hours at 5ºC. The reaction mixture then was poured onto ice water (100 ml) and 50% ethyl acetate in hexane (100 ml) and then was podslushivaet pills NaOH (pH ≈10) at 0ºC. The layers were separated and the aqueous layer was extracted using 50% ethyl acetate/hexane (2×100 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide a mixture of (1R,4R)-2-((S)-1-phenylethyl)-2-azabicyclo[2,2,1]hept-5-s and (1S,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2,2,1]hept-5-ena in the form of oil (33,0 g). The product has a tendency to react retro-Diels-alder reaction, so it is used directly in the next step. LC/MS: m/z 199,8 (M+H)+when 0,38 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

To a solution of (2R,3R)-2,3-dibenzoylresorcinol acid (55,75 g of 155.6 mmol) in acetone (500 ml) was added a solution of (1R,4R)-5-[(1S)-1-phenylethyl]-5-azabicyclo[2,2,1]hept-2-s and (1S,4S)-5-[(1S)-1-phenylethyl]-5-azabicyclo[2,2,1]hept-2-ena (31,01 g of 155.6 mmol) in acetone (200 ml) dropwise. The reaction mixture was stirred for 15 hours at room temperature. The precipitate that formed was collected, filtered�eat and washed with acetone (2×75 ml) and dried under reduced pressure. The residue was slowly added to a chilled (0ºC) 10% NaOH solution (350 ml) and ethyl acetate (300 ml) and stirred for 15 min (pH 10). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×150 ml). The combined organic layer was dried over Na2SO4,was filtered and concentrated under reduced pressure to obtain (1R,4R)-2-((S)-1-phenylethyl)-2-azabicyclo[2,2,1]hept-5-ena, which was used directly used in the next step. LC/MS: m/z 199,8 (M+H)+when 0,38 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

A flask containing (1R,4R)-5-[(1S)-1-phenylethyl]-5-azabicyclo[2,2,1]hept-2-ene (19 g, 95,34 mmol) and palladium on carbon (4 g, 133,0 mmol), purged using N2with the subsequent removal of gas in vacuum. EtOAc (50 ml) and EtOH (200 ml) was added under an inert atmosphere followed by removal of gas in vacuum. The reaction mixture was then stirred overnight in an atmosphere of H2. Was added AcOH (60 ml) and then the reaction mixture was stirred overnight at 55ºC in the atmosphere of H2.The reaction mixture was cooled to room temperature and was filtered through a layer of Celite to remove the palladium catalyst, washed with ethyl acetate, concentrated under vacuum and the residue treated with 1N HCl solution in ether. The solvent was evaporated under reduced pressure to obtain (1S,4R)-2-azabicyclo[2,2,1]heptane.

Amine intermediate �the connection Example 12: Synthesis of (S)-4-(2-methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline

To a solution of 5-fluoro-2-nitrobenzotrifluoride (2.0 g, of 9.56 mmol) in CH3CN (20 ml) was added Et3N (2,41 g, 23,90 mmol) followed by the addition of (S)-2-methylpyrrolidinium (3,18 g, of 12.43 mmol). The reaction mixture was stirred at 80ºC overnight. The reaction mixture was then quenched with water and the aqueous layer was extracted using DCM. The combined organic layers were washed with 1N HCl solution, dried over MgSO4, filtered and concentrated to give (S)-2-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (2,45 g, 94% yield).1H NMR (400 MHz, DMSO-d6) δ 8,11 (d, J=9.1 Hz, 1H), to 6.88 (s, 1H), of 6.85 (d, J=2,6 Hz, 1H), 4,17-4,13 (m, 1H), 3,59-3,54 (m, 1H), 3,33-or 3.28 (m, 1H), 2,14-2,00 (m, 3H), 1,80-1,71 (m, 1H), 1.14 in (d, J=6.3 Hz, 3H). LC/MS: m/z 275,3 (M+H)+at 1.98 m min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

A flask containing (S)-2-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin (2,45 g, 8,9 mmol) and palladium on carbon (245 mg, 10% wt.), purged using N2with the subsequent removal of gas in vacuum. Was added methanol (15 ml) under an inert atmosphere followed by removal of gas in vacuum. The reaction mixture was stirred overnight in an atmosphere of H2. Palladium catalyst was removed by filtration and the solvent was removed under reduced pressure to obtain (S)-4-(2-methylpyrrolidine-1-yl)-2-(triform�Teal)aniline with a quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 6,78 (d, J=8,8 Hz, 1H), 6,70-6,67 (m, 1H), 6,47 (d, J=2.7 Hz, 1H), 4,68 (s, 2H), 3,76-of 3.69 (m, 1H), 3,32-3,27 (m, 1H), 3,02-2,96 (m, 1H), 2,05-1,94 (m, 2H), 1.93 and-of 1.84 (m, 1H), 1,64-1,58 (m, 1H), of 1.05 (d, J=6.1 Hz, 3H). LC/MS: m/z 245,1 (M+H)+when 0,48 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

The following compounds can be obtained in accordance with the General scheme shown above.

(R)-4-(2-Methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline

(R)-4-(2-Methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (R)-2-methylpyrrolidine.1H NMR (400,0 MHz, DMSO-d6) δ of 6.79 (d, J=8,8 Hz, 1H), 6,68 (DD, J=2,3, to 8.7 Hz, 1H), 6,47 (d, J=2.5 Hz, 1H), 4,69 (s, 2H), 3,73 (t, J=5.6 Hz, 1H), of 3.33 3.27 per (m, 1H), 2,99 (sq, J=8,0 Hz, 1H), 2,03-to 1.87 (m, 3H), of 1.64 to 1.60 (m, 1H) and 1.05 (d, J=6.1 Hz, 3H). LC/MS: m/z of 245.3 (M+H)+at 0.57 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-Morpholino-2-(trifluoromethyl)aniline

4-Morpholino-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and morpholine.1H NMR (400,0 MHz, DMSO-d6) δ to 7.04 (DD, J=2,6, 8,9 Hz, 1H), 6,84-of 6.79 (m, 2H), 5,07 (s, 2H), 3,71 (t, J=4,7 Hz, 4H) and 2.93 (t, J=4,7 Hz, 4H). LC/MS: m/z 247,1 (M+H)+when 0,43 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-(3,3-Dimethylpiperidin-1-yl)-2-(three�tormentil)aniline

4-(3,3-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and 3.3-dimethylpyrimidine. LC/MS: m/z 259,1 (M+H)+when 1,18 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-(3-Methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline

4-(3-Methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and 3-methylpyrrolidine.1H NMR (400,0 MHz, DMSO-d6) δ 6,78 (d, J=8,8 Hz, 1H), only 6.64 (DD, J=2,5, 8,8 Hz, 1H), 6,44 (d, J=2.7 Hz, 1H), 4,67 (s, 2H), and 3.31 (t, J=7,6 Hz, 1H), 3,20-3,15 (m, 2H), 2,73-2,69 (m, 1H), 2,33 (DD, J=7,0, of 15.1 Hz, 1H), 2,10-2,04 (m, 1H), 1,54 (TD, J=8,2, 4.0 Hz, 1H) and 1.06 (d, J=6,7 Hz, 3H) M. D. LC/MS: m/z 245,1 (M+H)+when 0,94 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-(Azetidin-1-yl)-2-(trifluoromethyl)aniline

4-(Azetidin-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and azetidine. LC/MS: m/z 217,3 (M+H)+when 0,34 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(R)-1-(4-Amino-3-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine

(R)-1-(4-Amino-3-(trifluoromethyl)phenyl)-N,N-dimethylpyridin-3 min can be synthesized in accordance with the General scheme, presented above, based on 5-fluoro-2-nitrobenzotrifluoride and (R)-N,N-dimethylpiperidin-3-amine. LC/MS: m/z 274,5 (M+H)+when 1,32 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(R)-tert-butyl 1-(4-amino-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylate

(R)-tert-butyl 1-(4-amino-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (R)-tert-butyl pyrrolidin-2-carboxylate. LC/MS: m/z 331,5 (M+H)+when 1,70 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-tert-butyl 1-(4-amino-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylate

(S)-tert-butyl 1-(4-amino-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-tert-butyl pyrrolidin-2-carboxylate. LC/MS: m/z 331,5 (M+H)+when 1,70 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-(4-Isopropylpiperazine-1-yl)-2-(trifluoromethyl)aniline

4-(4-Isopropylpiperazine-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and 1-isopropylpiperazine.1H NMR (400,0 MHz, DMSO-d6) δ 7,02 (DD, J=2,6, 8,8 Hz,1H), About 6,82-was 6.77 (m, 2H), of 5.03 (s, 2H), 2,95-2,92 (m, 4H), 2,65 (t, J=6,5 Hz, 1H), 2,56-of 2.50 (m, 4H) and 0.99 (d, J=6,5 Hz, 6H) M. D. LC/MS: m/z 288,3 (M+H)+when 0,97 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(R)-(1-(4-amino-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol

(R)-(1-(4-amino-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (R)-pyrrolidin-2-ylmethanol. LC/MS: m/z 261,1 (M+H)+when 0,90 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-(1-(4-Amino-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol

(S)-(1-(4-Amino-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-pyrrolidin-2-ylmethanol. LC/MS: m/z 261,1 (M+H)+when 0,91 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(1-(4-Amino-3-(trifluoromethyl)phenyl)piperidine-4-yl)methanol

(1-(4-Amino-3-(trifluoromethyl)phenyl)piperidine-4-yl)methanol can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and piperidine-4-ylmethanol. LC/MS: m/z 275,3 (M+H)+when 0,91 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-1-(4-Amino-3-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine

(S)-1-(4-Amino-3-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-N,N-dimethylpiperidin-3-amine. LC/MS: m/z of 274.1 (M+H)+when 0,78 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-1-(4-Amino-3-(trifluoromethyl)phenyl)pyrrolidin-3-ol

(S)-1-(4-Amino-3-(trifluoromethyl)phenyl)pyrrolidin-3-ol can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-pyrrolidin-3-ol. LC/MS: m/z 277,1 (M+H)+when 1,28 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(R)-1-(4-Amino-3-(trifluoromethyl)phenyl)pyrrolidin-3-ol

(R)-1-(4-Amino-3-(trifluoromethyl)phenyl)pyrrolidin-3-ol can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (R)-pyrrolidin-3-ol. LC/MS: m/z 277,1 (M+H)+when 1,28 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-4-(2-Demerol-1-yl)-2-(trifluoromethyl)aniline

(S)-4-(2-Demerol-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-2-methylpiperidine. LC/MS: m/z 259,1 (M+H)+when 0,66 min (10%-99% CH3 CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-Ethyl 1-(4-amino-3-(trifluoromethyl)phenyl)piperidine-3-carboxylate

(S)-Ethyl 1-(4-amino-3-(trifluoromethyl)phenyl)piperidine-3-carboxylate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-ethyl piperidine-3-carboxylate. LC/MS: m/z 317,1 (M+H)+when 1,01 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-(3,3-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline

4-(3,3-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and 3.3-dimethylpiperidine. LC/MS: m/z 273,1 (M+H)+when 0,96 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(R)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)piperidine-2-carboxylate

(R)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)piperidine-2-carboxylate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (R)-methyl piperidine-2-carboxylate. LC/MS: m/z 303,3 (M+H)+when 1,03 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)piperidine-2-carboxylate

(S)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)piperidine-2-carbox�ilat can be synthesized in accordance with the General scheme, presented above, based on 5-fluoro-2-nitrobenzotrifluoride and (S)-methyl piperidine-2-carboxylate. LC/MS: m/z 303,3 (M+H)+when 1,03 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)-2-methylpyrrolidine-2-carboxylate

(S)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)-2-methylpyrrolidine-2-carboxylate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-methyl 2-methylpyrrolidine-2-carboxylate. LC/MS: m/z 303,1 (M+H)+when 1,27 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(2S,3S)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)-3-methylpyrrolidine-2-carboxylate

(2S,3S)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)-3-methylpyrrolidine-2-carboxylate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (2S,3S)-methyl 3-methylpyrrolidine-2-carboxylate. LC/MS: m/z 303,3 (M+H)+at 1.30 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(1R,2R,5S)-Methyl 3-(4-amino-3-(trifluoromethyl)phenyl)-3-azabicyclo[3,1,0]hexane-2-carboxylate

(1R,2R,5S)-Methyl 3-(4-amino-3-(trifluoromethyl)phenyl)-3-azabicyclo[3,1,0]hexane-2-carboxylate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride� and (1R,2R,5S)-methyl 3-azabicyclo[3,1,0]hexane-2-carboxylate. LC/MS: m/z figure of $ 301.5 (M+H)+when 1,31 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(2S,4R)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)-4-tert-butoxypropan-2-carboxylate

(2S,4R)-Methyl 1-(4-amino-3-(trifluoromethyl)phenyl)-4-tert-butoxypropan-2-carboxylate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (2S,4R)-methyl 4-tert-butoxypropan-2-carboxylate. LC/MS: m/z figure of $ 301.5 (M+H)+when 1,31 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

N-(4-Amino-3-(trifluoromethyl)phenyl)pivalue

N-(4-Amino-3-(trifluoromethyl)phenyl)pivalate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and palamida. LC/MS: m/z 261,1 (M+H)+when 1,28 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

tert-butyl 4-amino-3-(trifluoromethyl)phenylcarbamate

tert-butyl 4-amino-3-(trifluoromethyl)phenylcarbamate can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and tert-butyl carbamate. LC/MS: m/z 277,3 (M+H)+when 1,56 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(R)-4-(3-Ftorpirimidinu-1-yl)-2-(trifluoromethyl)aniline

(R)-4-(3-Ftorpirimidinu-1-yl)-2-(triptime�l)aniline can be synthesized in accordance with the General scheme, presented above, based on 5-fluoro-2-nitrobenzotrifluoride and (R)-3-terpinolene. LC/MS: m/z 249,3 (M+H)+when 0,92 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-4-(3-Ftorpirimidinu-1-yl)-2-(trifluoromethyl)aniline

(S)-4-(3-Ftorpirimidinu-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-3-terpinolene.1H NMR (400,0 MHz, DMSO-d6) δ is 6.81 (d, J=8,8 Hz, 1H), 6,72 (DD, J=2,6, 8,8 Hz, 1H), is 6.51 (d, J=2,8 Hz, 1H), 5,48 (d, J=3.1 Hz, 1H), to 4.76 (s, 2H), 3,50 (DD, J=3,9, and 11.8 Hz, 1H), 3.43 points-to 3.38 (m, 1H), 3,33-3,24 (m, 2H), 2,24-of 2.21 (m, 1H) and 2.15 (DD, J=3,9, and 7.9 Hz, 1H), M. D. LC/MS: m/z 249,2 (M+H)+when 0,92 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(R)-4-(3-Methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline

(R)-4-(3-Methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (R)-3-methylpyrrolidine. LC/MS: m/z 245,1 (M+H)+when 0,92 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-4-(3-Methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline

(S)-4-(3-Methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (S)-3-methylpyrrolidine. LCMS: m/z 245,1 (M+H) +when 0,93 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-((2R,5R)-2,5-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline

4-((2R,5R)-2,5-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (2R,5R)-2,5-dimethylpyrimidine.1H NMR (400,0 MHz, DMSO-d6) δ was 6.77 (d, J=8,8 Hz, 1H), 6,70 (d, J=9,0 Hz, 1H), of 6.49 (s, 1H), 4,70 (s, 2H), 3,88 (t, J=5,9 Hz, 2H), 2,18-to 2.14 (m, 2H), of 1.56 (s, 2H) and 0.96 (d, J=6.1 Hz, 6H) M. D. LC/MS: m/z 259,3 (M+H)+when 0,66 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-(3,3-Giftability-1-yl)-2-(trifluoromethyl)aniline

4-(3,3-Giftability-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and 3.3-giftability.1H NMR (400,0 MHz, DMSO-d6) δ 6,83-6,76 (m, 2H), to 6.58 (d, J=2,6 Hz, 1H), 4,89 (s, 2H) and 3.59 (t, J=13.5 Hz, 2H), 3,36 (sq, J=7,0 Hz, 3H) and 1.18 (t, J=7,3 Hz, 1H), M. D. LC/MS: m/z 267,2 (M+H)+at 1.35 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-((2S,5S)-2,5-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline

4-((2S,5S)-2,5-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (2S,5S)-2,5-dimethyl�of irreligion. LC/MS: m/z 259,1 (M+H)+when 0,79 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-((2S,5R)-2,5-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline

4-((2S,5R)-2,5-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (2S,5R)-2,5-dimethylpyrimidine. LC/MS: m/z 259,1 (M+H)+when 0,79 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-((2S,5R)-2,5-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline

4-((2S,5R)-2,5-Dimethylpiperidin-1-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (2S,5R)-2,5-dimethylpyrimidine. LC/MS: m/z 259,1 (M+H)+when 0,79 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-(Cyclopentyloxy)-2-(trifluoromethyl)aniline

4-(Cyclopentyloxy)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and Cyclopentanol.1H NMR (400,0 MHz, CDCl3) δ of 6.96 (d, J=2,8 Hz, 1H), to 6.88 (DD, J=2,8, to 8.7 Hz, 1H), 6,69 is 6.67 (m, 1H), 4,68-4,63 (m, 1H), 4,12 (d, J=7,1 Hz, 2H) and 1,90-of 1.56 (m, 8H), M. D.

4 Isopropoxy-2-(trifluoromethyl)aniline

4 Isopropoxy-2-(trifluoromethyl)aniline can be Synthe�graded in accordance with the General scheme, presented above, based on 5-fluoro-2-nitrobenzotrifluoride and propan-2-ol.1H NMR (400,0 MHz, CDCl3) δ of 6.99 (d, J=2,8 Hz, 1H), 6,90 (DD, J=2.7, and an 8.7 Hz, 1H), 6,68 (d, J=to 8.7 Hz, 1H), 4,39 (t, J=6.1 Hz, 1H), 3,88 (s, 2H) and 1,30-of 1.26 (m, 6H), M. D.

2-Amino-5-(pyrrolidin-1-yl)benzonitrile

2-Amino-5-(pyrrolidin-1-yl)benzonitrile can be synthesized in accordance with the General scheme above, on the basis of 2-amino-5-perbenzoate and pyrrolidine.1H NMR (400,0 MHz, DMSO-d6) δ 6,74 (d, J=1.1 Hz, 2H), 6,48 (s, 1H), 5,16 (s, 2H), 3,10 (m, 4H), 1,90 (m, 4H). LC/MS: m/z 188,5 (M+H)+when 0,44 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

2-Methoxy-4-(pyrrolidin-1-yl)aniline

2-Methoxy-4-(pyrrolidin-1-yl)aniline can be synthesized in accordance with the General scheme presented above, based on 4-fluoro-2-methoxyaniline and pyrrolidine.1H NMR (400,0 MHz, DMSO-d6) δ is 6.51 (d, J=8,3 Hz, 1H), 6,14 (d, J=2.4 Hz, 1H), 5,95 (DD, J=2,4, 8,3 Hz, 1H), of 3.91 (s, 2H), 3,74 (s, 3H), 3,11 (m, 4H), 1,90 (m, 4H). LC/MS: m/z 193,5 (M+H)+when 1,06 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-(3-Demerol-1-yl)-2-(trifluoromethyl)aniline

2-Methoxy-4-(pyrrolidin-1-yl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and 3-methylpiperidine.1H NMR (400 MHz, CDCl3)δ 7,05-6,93 (m, 2H), 6,69 (d, J=to 8.7 Hz, 1H), 3,85 (s, 2H), 3,42-3,29 (m, 2H), 2,52 (TD, J=11,5, at 3.1 Hz, 1H), 2,25-of 2.15 (m, 1H), 1,86-1,62 (m, 5H), were 0.94 (d, J=6,4 Hz, 3H). LC/MS: m/z 259,0 (M+H)+when 0,79 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

4-((1S,4R)-2-Azabicyclo[2,2,1]heptane--2-yl)-2-(trifluoromethyl)aniline

4-((1S,4R)-2-Azabicyclo[2,2,1]heptane--2-yl)-2-(trifluoromethyl)aniline can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and (1S,4R)-2-azabicyclo[2,2,1]heptane.1H NMR (400 MHz, CDCl3) δ 6,68 (d, J=8,5 Hz, 1H), to 6.58 (dt, J=to 8.7, 2.5 Hz, 2H), was 4.02 (s, 1H), 3,65 (s, 2H), 3,49 (dt, J=5,9, and 3.2 Hz, 1H), 2,64 (d, J=8,0 Hz, 1H), 2,56 (s, 1H), 1,83-of 1.53 (m, 5H), of 1.48 (d, J=9,3 Hz, 1H), 1,37-1,22 (m, 2H).

2-(4-(4-Amino-3-(trifluoromethyl)phenyl)piperazine-1-yl)ethanol

2-(4-(4-Amino-3-(trifluoromethyl)phenyl)piperazine-1-yl)ethanol can be synthesized in accordance with the General scheme above, on the basis of 5-fluoro-2-nitrobenzotrifluoride and 2-(piperazine-1-yl)ethanol.

Amine intermediate Example 13:Synthesis of 5-amino-2-isopropoxyphenol

To a stirred solution of sodium hydroxide (387 mg, 9,67 mmol) in anhydrous DMSO was added 4-nitrobenzene-1,2-diol (500 mg, up 3.22 mmol) at 0ºC. After stirring for 5 minutes was added dropwise 2-iodo-propane (603 mg, 3,55 mmol). The obtained dark mixture was stirred for 1 hour� at room temperature. The reaction mixture was quenched with water and then using acidified with 1M HCl (pH=4) and then the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layer was washed with saturated NaCl solution and then dried over MgSO4, filtered and concentrated under reduced pressure to dryness. The crude product was purified column chromatography on silica gel using a gradient of 0-20% EtOAc in hexane to obtain 2-isopropoxy-5-nitro-phenol (163 mg, 51%).1H NMR (400,0 MHz, CDCl3) δ 7,86 (DD, J=2,5, 8,8 Hz, 1H), 7,76 (d, J=2.5 Hz, 1H), 6,99 (d, J=8,8 Hz, 1H), 4,73 (Quin., J=6.1 Hz, 1H) and 1.43 (d, J=6.1 Hz, 6H).

A flask containing 2-isopropoxy-5-nitro-phenol (100 mg, 0.47 mmol) and palladium on carbon (50 mg, 0.47 mmol), purged using N2with the subsequent removal of gas in vacuum. Was added EtOAc (2 ml) and methanol (2 ml) under an inert atmosphere followed by removal of gas in vacuum. The reaction mixture was then stirred overnight in a hydrogen atmosphere. Palladium catalyst was removed by filtration and the solvent was removed under reduced pressure to obtain 5-amino-2-isopropoxyphenol (65 mg, 76%).1H NMR (400,0 MHz, CDCl3) δ 6,73 (d, J=8,3 Hz, 1H), of 6.31 (d, J=2.5 Hz, 1H), from 6.22 (DD, J=2,5, 8,3 Hz, 1H), 5,22 (s, 1H), 4,50 (Quin., J=6.1 Hz, 1H), 3,37 (s, 2H) and 1.37-of 1.26 (m, 6H), M. D.

Amine intermediate Example 14:Synthesis of 6-methoxy-5-(trifluoromethyl)pyridin-2-amine

A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (1.0 g, 4,63 mmol), dibenzylamine (913 mg, 890 μl, 4,63 mmol), triethylamine (1.2 ml, 8,61 mmol) and 1-methyl-2-pyrrolidone (6 ml, 62,22 mmol) was heated at 120ºC for 9 hours. The reaction mixture was cooled to room temperature and poured into ice water, extracted using EtOAc (20 ml ×3), combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and was purified column chromatography on silica gel (2%-10% EtOAc in petroleum ether as eluent) to give N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2-amine (1.5 g, 86%) as an oil.1H NMR (300 MHz, CDCl3) δ members, 7.59 (d, J=to 8.7 Hz, 1H), value of 7, 37-7,21 (m, 10H), 6.32 per (d, J=to 8.7 Hz, 1H), 4,80 (s, 4H).

To a stirred solution of N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2-amine (100 mg, 0.27 mmol) in THF (5 ml) was added their CH3ONa (42 mg, 0,78 mmol) at room temperature. The mixture was heated to boiling temperature with reflux for 10 hours and then cooled to room temperature, diluted with water (5 ml) and extracted using CH2Cl2(6 ml ×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of 2%-10% EtOAc in petroleum ether in the quality�e eluent to obtain N,N-dibenzyl-6-methoxy-5-(trifluoromethyl)pyridin-2-amine (90 mg, 91%).1H NMR (400 MHz, CDCl3) δ 7,53 (d, J=8.4 Hz, 1H), 7,35-7,22 (m, 10H), of 6.02 (d, J=8.4 Hz, 1H), 4,79 (s, 4H), 3,90 (s, 3H).

To a solution of N,N-dibenzyl-6-methoxy-5-(trifluoromethyl)pyridin-2-amine (3.0 g, 8,056 mmol) in a mixture of methanol (30 ml) and AcOH (3 ml) was added palladium hydroxide (0.3 g, 0.43 mmol) in a nitrogen atmosphere. The mixture was stirred in hydrogen atmosphere (55 f/inch2(3,867 kg/cm2), 25 ºC) overnight. The catalyst was removed by filtration through a layer of Celite and the filtrate neutralized with a saturated solution of Na2CO3.The aqueous layer was extracted using CH2Cl2(30 ml ×3) and combined organic layers were concentrated in vacuum to give 6-methoxy-5-(trifluoromethyl)pyridin-2-amine (1.4 g, 90%) as pale-yellow solids.1H NMR (400 MHz, CDCl3) δ 7,56 (d, J=8.4 Hz, 1H), 6,03 (d, J=8,0 Hz, 1H), a 4.64 (lat.s, 2H), 3,93 (s, 3H), MS (ESI) m/e (M+H+) 193,13C NMR (100 MHz, CDCl3) 159,4, 138,0 (d, J=5,9 Hz), to 125.9, 122,3, to 101.9 (d, J=44,4 Hz), 98,3, 53,6,19F NMR (282,4 MHz, CDCl3) -62,6.

Amine intermediate Example 15: Synthesis of (R)-4-(4,4-debtor-2-methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline

(S)-2-(methyl bromide)-4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin

(R)-4-(4,4-debtor-2-methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline

(S)-1-(tert-butoxycarbonyl)-4,4-giftability-2-carboxylic Ki�lot (500 mg, 2.0 mmol) was dissolved in dichloromethane and treated dropwise with the help of TFA (227 mg, 153 μl, 2 mmol). The reaction mixture was stirred for 3 hours at room temperature, the solvent was evaporated to obtain (S)-4,4-giftability-2-carboxylic acid, which was used for next step without further purification. LC/MS: m/z 152,2 (M+H)+when 0,53 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

To 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (416 mg, 2 mmol), (S)-4,4-giftability-2-carboxylic acid (301 mg, 2 mmol) and sodium carbonate (633 mg, 574 μl, 6.0 mmol) was added 1:1 water/ethanol (8 ml) and the reaction mixture was heated at 90ºC for 72 hours. The reaction mixture was diluted with water (50 ml) then acidified with 1 n HCl solution and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain (S)-4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylic acid in the form of a brown oil (600 mg, 89%) which was used directly in the next reaction. LC/MS: m/z 341,00 (M+H)+when 1,49 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

(S)-4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylic acid (600 mg, of 1.76 mmol) was dissolved in methanol (10 ml), cooled to 0ºC and treated dropwise with thionylchloride (840 mg, 515 μl, was 7.08 mmol). Reactio�ing mixture was heated at 50ºC for 48 hours. The reaction mixture was evaporated in vacuum and the residue was purified column chromatography on silica gel (0-60% ethyl acetate in hexane) to give (S)-methyl 4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylate (300 mg, 48% yield).1H NMR (400 MHz, DMSO-d6) δ 8,12 (d, J=9,2 Hz, 1H), to 7.04 (d, J=2,6 Hz, 1H), 6,97 (DD, J=9,2, of 2.7 Hz, 1H), 5,19 (DD, J=9,8, a 1.9 Hz, 1H), 4,14-3,99 (m, 2H), 3,69 (s, 3H), 3,11-2,95 (m, 1H), 2,78 (t, J=14.6 Hz, 1H).

To a suspension of LiBH4(55 mg, 2.54 mmol) in anhydrous THF (3 ml) was added a solution of (S)-methyl 4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylate (300 mg, 0.85 mmol) in anhydrous THF at 0ºC. The reaction mixture was stirred at 0ºC for 20 minutes, then allowed to warm to room temperature and stirred over night. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (50 ml) and then saturated brine. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to give (S)-(4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol as a yellow viscous oil (275 mg, 100%). LC/MS: m/z 327,2 (M+H)+when a 1.54 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

To a solution of (S)-(4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol (275 mg, 0,84 mmol) in anhydrous DCM was added triethylamine (171 mg, 235 µl, 1.7 mmol) followed by the addition of methanesulfonanilide (106 m�, 72 μl, 0.93 mmol) at 0ºC. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was diluted using DCM and quenched with 3 ml of a saturated solution of NaHCO3. The organic layer was separated and washed with saturated brine, dried over Na2SO4, filtered and concentrated to give (S)-(4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methylmethanesulfonate as a yellow solid (330 mg, 96%). LC/MS: m/z 405 (M+H)+when 1,71 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

NaBr (420 mg, 131 μl, 4,08 mmol) was added to a solution of (S)-(4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methylmethanesulfonate (330 mg, 0,82 mmol) in acetonitrile (2.0 ml) and heated at 80ºC for 16 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and water (5 ml). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (15-50% ethyl acetate/hexane) to give (S)-2-(methyl bromide)-4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (230 mg, 72%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8,14 (d, J=to 8.7 Hz, 1H), 7,09-7,07 (m, 2H), 4,76-4,71 (m, 1H), 4,16-3,99 (m, 2H), 3,74 (DD, J=10,6, and 3.0 Hz, 1H), 3,60 (t, J=9,7 Hz, 1H), 2,94-2,80 (m, 1H), 2,66-by 2.55 (m, 1H).

(S)-2-(methyl bromide)-4,4-debtor-1-(4-nitro-3-(trifluoromethyl)phenyl)feast�oliden (230 mg, 0,59 mmol) was dissolved in ethyl acetate (5 ml) and TEA (90 mg, 124 μl of 0.89 mmol) and the flask flushed with nitrogen. Was added 10% Pd/C (58 mg, 0.05 mmol), the catalyst and the reaction mixture was stirred overnight in a hydrogen atmosphere. The reaction mixture was filtered, treated with 50% saturated solution of NaHCO3and was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to give (R)-4-(4,4-debtor-2-methylpyrrolidine-1-yl)-2-(trifluoromethyl)aniline in the form of a purple oil (164 mg, 99% yield).1H NMR (400 MHz, DMSO-d6) δ is 6.81 (s, 2H), to 6.58 (s, 1H), to 4.92 (s, 2H), 4,07-4,01 (m, 1H), 3,74-3,63 (m, 1H), 3,60-3,50 (m, 1H), 2,75-2,60 (m, 1H), 2,22-2,11 (m, 1H), 1,10 (d, J=6.2 Hz, 3H).

Amine intermediate Example 16:Synthesis of 1-(2-methoxyethyl)-5-(trifluoromethyl)-1H-indol-6-amine

6-nitro-5-(trifluoromethyl)-1H-indole (50 mg, 0,22 mmol) was dissolved in DMF (2 ml) and treated with sodium hydride (35 mg, 0.87 mmol) to form a dark red opaque solution. The solution was stirred for 20 minutes and was then added dropwise to a solution of 2-pomatoleios ether (121 mg, 82 μl, 0.87 mmol) in 1 ml DMF. The reaction mixture was heated at 50ºC for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with 50% saturated solution of NaHCO3(2×10 ml) and saturated brine. The organic layer was dried over Na2 SO4that was filtered and dried to obtain 1-(2-methoxyethyl)-6-nitro-5-(trifluoromethyl)-1H-indole, which was used for next step without further purification.

1-(2-methoxyethyl)-6-nitro-5-(trifluoromethyl)-1H-indole was dissolved in 10 ml of EtOH and gidrirovanie using Raney Ni as a catalyst (H-cube:1.2 ml/min 30ºC) to give 1-(2-methoxyethyl)-5-(trifluoromethyl)-1H-indol-6-amine with a quantitative yield. LC/MS: m/z 259,0 (M+H)+when 1,12 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Amine intermediate Example 17:Synthesis of N-(4-amino-3-(trifluoromethyl)phenyl)palamida

To a solution of 4-nitro-3-(trifluoromethyl)aniline (1.0 g, is 4.85 mmol) in CH2Cl2(15 ml) and TEA (2,95 g, and 4.1 ml, 29,11 mmol) in round bottom flask at 0ºC was added trimethylacetaldehyde (1,75 g, 1.8 ml, 14,55 mmol) dropwise. The reaction mixture was warmed to room temperature and quenched by pouring into water. The layers were separated and the aqueous layer was extracted using DCM. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was then purified by column chromatography on silica gel using a gradient (0-100% EtOAc/Hex.) obtaining N-(4-nitro-3-(trifluoromethyl)phenyl)palamida (1.64 g, 81%). LC/MS: m/z 291,1 (M+H)+when 1,83 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

To a solution of 2,2-dimethyl-n-(4-nitro--trifluoromethyl-phenyl)-propionamide (1.64 g, 5,65 mmol) in MeOH (50 ml) was added Pd/C (150 mg, 0.14 mmol) in a nitrogen atmosphere. The mixture was stirred in hydrogen atmosphere for 4 hours. The catalyst was removed by filtration through a layer of Celite and the solvent was evaporated in vacuum to give N-(4-amino-3-(trifluoromethyl)phenyl)palamida (1.2 g, 78%). LC/MS: m/z of 261.5 (M+H)+when 1,83 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

tert-butyl 4-amino-3-(trifluoromethyl)phenylcarbamate

tert-butyl 4-amino-3-(trifluoromethyl)phenylcarbamate can be synthesized in accordance with the General scheme presented above, based on 4-nitro-3-(trifluoromethyl)aniline and di-tert-BUTYLCARBAMATE. LC/MS: m/z 277,35 (M+H)+when 1,56 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Amine intermediate Example 18:Synthesis of (S)-6-(2-methylpyrrolidine-1-yl)-2-(trifluoromethyl)pyridin-3-amine.

To a solution of 2,6-dibromopyridine (10.0 g, of 42.6 mmol) in anhydrous CH3CN (100 ml) was slowly added NO2+BF4(11.3 g, of 85.2 mmol). The reaction mixture was heated to 80ºC in a nitrogen atmosphere for 24 hours. The mixture then was evaporated in vacuum to give crude product. The residue was purified by column chromatography on silica gel with obtaining 2,6-dibrom-3-nitropyridine (5.7 g, 48%).1H NMR (400 MHz, CDCl3) δ 8,03 (d, J=8.4 Hz, 1H), 7,65 (d, J=8.4 Hz, 1H).

To Rast�Ouro 2,6-dibrom-3-nitropyridine (5.7 g, 20,4 mmol) in DMF (40 ml) was added CuI (3.9 g, of 20.4 mmol) and FSO2CF2CO2Me (4.7 g, 24.5 mmol). The reaction mixture was stirred at 80ºC for 1 hour. After cooling to room temperature the reaction mixture was poured into water (100 ml) and extracted using EtOAc (100 ml ×3). The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4and was purified column chromatography on silica gel to obtain 6-bromo-3-nitro-2-(trifluoromethyl)pyridine (3.0 g, 53%, purity 70%).1H NMR (400 MHz, CDCl3) δ 8,12 (d, J=8.4 Hz, 1H), 7,94 (d, J=8.4 Hz, 1H).

A suspension of 6-bromo-3-nitro-2-(trifluoromethyl)pyridine (400 mg, 1.5 mmol), tosylate salt (S)-2-methylpyrrolidine (381 mg, 1.5 mmol) and K2CO3(620 mg, 4.5 mmol) in H2O (4 ml) was heated at 140ºC under conditions of microwave irradiation for 30 minutes. The solution was extracted using EtOAc (50 ml ×3) and combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4and was purified column chromatography on silica gel with obtaining (S)-6-(2-methylpyrrolidine-1-yl)-3-nitro-2-(trifluoromethyl)pyridine (350 mg, 88% yield).1H NMR (400 MHz, CDCl3) δ 8,14 (d, J=9,2 Hz, 1H), 6,44 (d, J=8.4 Hz, 1H), 4,55-4,42 (m, 1H), was 4.02-3,30 (m, 2H), 2,30-2,00 (m, 3H), 1,81 (lat.s, 1H), 1.27 mm (d, J=6,4 Hz, 3H).

To a solution of (S)-6-(2-methylpyrrolidine-1-yl)-3-nitro-2-(trifluoromethyl)pyridine (300, 1.1 mmol) in 5 ml of methanol was added NiCl2∙6H2O (772 mg, 3.3 mmol). After stirring for 5 minutes was added dropwise NaBH4(84 mg, 2.2 mmol) in three portions at 0ºC. The reaction mixture was stirred for 5 minutes, quenched with water (10 ml) and extracted using EtOAc (15 ml ×3). The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, concentrated and purified by chromatography on silica gel with obtaining (S)-6-(2-methylpyrrolidine-1-yl)-2-(trifluoromethyl)pyridin-3-amine (260 mg, 92.6% of the output).

Amine intermediate Example 19:Synthesis of 3-amino-2,6-di-tert-butylphenol

DMAP (885 mg, of 7.24 mmol) was added to a solution of 2,6-di-tert-butylphenol (30 g, 145,4 mmol) and di-tert-BUTYLCARBAMATE (38 g, 174,1 mmol) in Et3N (29,43 g, 40,5 ml, 290,8 mmol) and hexane (700 ml). The reaction mixture was stirred overnight and was quenched with water and extracted using EtOAc. The organic layer was washed with aqueous solution of NaHCO3, dried over Na2SO4and concentrated in vacuum. The crude product was purified column chromatography on silica gel (petroleum ether as eluent) to give tert-butyl (2,6-di-tert-butylphenyl)carbonate (30 g, 67%).1H NMR (400 MHz, CDCl3) δ: 7,31 (d, J=8,0 Hz, 2H), 7,12 (t, J=8,0 Hz, 1H), 1,54 (s, 9H), 1,38 (s, 8H).

TMSCl (8.5 g,78,24 mmol) and tert-butyl (2,6-di-tert-butylphenyl)carbonate (12.0 g, 39,16 mmol) was added to a suspension of KNO3(5.9 g, 58,36 mmol) in CHCl3(100 ml) successively at 0ºC. The reaction mixture was stirred for 0.5 hours and was added AlCl3(15.5 g, 116,20 mmol). The stirring was continued for 2 hours and the resulting mixture was poured into ice water and extracted using CH2Cl2. The combined organic layers were washed with saturated solution of NaHCO3and saturated brine, dried over Na2SO4and was evaporated in vacuum. The crude product was purified column chromatography on silica gel (petroleum ether) to give 2,6-di-tert-butyl-3-NITROPHENOL (2.5 g, 25%).1H NMR (300 MHz, CDCl3) δ 7,18 (d, J=8.4 Hz, 1H), of 6.79 (d, J=8.4 Hz, 1H), to 5.57 (s, 1H), 1,51 (s, 9H), of 1.44 (s, 9H).

NaBH4(433 mg, of 11.45 mmol) was added to a solution of 2,6-di-tert-butyl-3-NITROPHENOL (950 mg, 3,780 mmol) and NiCl2(1,24 g, 9,568 mmol) in methanol (15 ml) at-15. After completion of the addition the reaction mixture was stirred for 20 seconds and immediately water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4and was evaporated in vacuum to give 3-amino-2,6-di-tert-butyl-phenol (650 mg, 78%).1H NMR (300 MHz, CDCl3) δ at 6.92 (d, J=8.4 Hz, 1H), for 6.24 (d, J=8.4 Hz, 1H), 5,39 (s, 1H), 1,62 (s, 9H), of 1.39 (s, 9H); MS (ESI) m/z: 222,2 [M+H+].

Amine intermediate soedineniyami 20: Synthesis of 3-(trifluoromethyl)-1H-indol-6-amine

To a solution of 1,4-dinitrobenzene (2,12 g, 7,21 mmol) in tetrahydrofuran (11 ml) at-78ºC in the atmosphere of N2added phenylmagnesium (2M in THF) (4 ml, 8.0 mmol, 1.1 EQ.) dropwise. The dark red solution was stirred for 30 minutes at-78ºC, was then added dropwise methyltryptophan (0.75 ml, 8,65 mmol). The reaction mixture was stirred for 30 minutes at-78ºC and then for 2 hours at room temperature. The reaction mixture was cooled to-10ºC and was quenched by adding 1 M HCl (6 ml). The reaction mixture was diluted with water (10 ml) and dichloromethane (30 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (3×30 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (0.5 to 30% ethyl acetate/hexane) to give methyl 2-(2,4-dinitrophenyl)-3,3,3-Cryptor-2-hydroxypropanoate (of 1.34 g, 60%)

To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-Cryptor-2-hydroxypropanoate (1.3 g, 4,01 mmol) in ethyl acetate (18 ml) was added (pH3) HCl (5.2 ml) followed by the addition of 10% Pd/C (350 mg) in ethyl acetate (3 ml). The reaction mixture was stirred overnight in an atmosphere of H2. The reaction mixture was filtered through a layer of Celite and the filtrate concentrated in vacuo. Received neocis�nny residue was partitioned between dichloromethane (25 ml) and a saturated aqueous solution of NaHCO 3(15 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×25 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (50-100% ethyl acetate/hexane) to give 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%)

To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0.5 ml) at 0ºC was added dropwise a complex of BH3.THF (1 M in THF, 1 ml, 0.95 mmol). The reaction mixture was stirred for 5 minutes at 0ºC, and then for 3 hours at room temperature. The reaction mixture was quenched by adding carefully 6M HCl (3.5 ml) until gas evolution ceased. The reaction mixture was then stirred at 80ºC for 2 hours. The solvent was removed under reduced pressure and the resulting solid residue was dissolved in DMF (3 ml), was filtered and was purified using reverse-phase HPLC (10-99% CH3CN/H2O), to obtain 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).

Amine intermediate Example 21:Synthesis of 2-(trifluoromethyl)-1H-indol-6-amine

To a solution of 4-methylbenzo-1,3-diamine (500 mg, 4.1 mmol) in anhydrous pyridine (25 ml) at 0ºC in an atmosphere of N2was added trifluoroacetic anhydride (1.2 ml) by the drop�. Cooling bath was removed and the reaction mixture was stirred at room temperature to achieve complete conversion of the original substance into the desired product. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (10-45% AcOEt in hexane) to give N,N'-(4-methyl-1,3-phenylene)bis(2,2,2-triptorelin) (807 mg, 63%). LC/MS: m/z 315,3 (M+H)+when 1,39 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

A mixture of N,N'-(4-methyl-1,3-phenylene)bis(2,2,2-triptorelin) (1,02 g, 3.25 mmol), NBS (0.80 g, 4.5 mmol) in CCl4(6 ml) was stirred overnight at room temperature under conditions of irradiation of 300 W lamp. The precipitate that formed was collected by filtration and washed with the help of CCl4. The crude residue was taken for absorption in anhydrous toluene (9,7 ml) in the presence of PPh3(1.3 g, 4.96 mmol) and stirred at 60oC for 16 hours. Postnewly precipitate was collected by filtration, then dissolved in anhydrous DMF (10 ml) and stirred at 165ºC to achieve complete conversion to the product (6.5 hours). The solvent was removed in vacuum and the obtained residue was purified column chromatography on silica gel (5-25% AcOEt in hexane) to give 2,2,2-Cryptor-N-(2-(trifluoromethyl)-1H-indol-6-yl)acetamide (243 mg, 25%). LC/MS: m/z 297,3 (M+H)+when 1,68 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

2,2,2-Cryptor-N-(2-(three�tormentil)-1H-indol-6-yl)acetamide (28 mg, 0,09 mmol) was dissolved in MeOH (0.9 ml) and water (0.4 ml) in th (K2CO3(90 mg, of 0.65 mmol) and stirred overnight at room temperature. Purification (10 to 99% ACN in water) using LC-MS gave 3-(trifluoromethyl)-1H-indol-6-amine 2,2,2-triptorelin (30 mg, quantitative yield). LC/MS: m/z 201,1 (M+H)+when 0,90 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Amine intermediate Example 22:Synthesis of 4-(3-methyloxiran-3-yl)aniline

To a solution of diethyl 2-methylpropanoate (21.8 g, 125,0 mmol) in anhydrous DMF (125 ml) was slowly added NaH (5.2 g, 130 mmol) at 0ºC under an atmosphere of nitrogen. The obtained reaction mixture was left for stirring for 10 minutes at 0ºC and then at room temperature for 10 minutes. Quickly added 2-bromo-1-fluoro-4-nitro-benzene (25.0 g, to 113.6 mmol) and the reaction mixture became bright red. After stirring for 10 minutes at room temperature the crude mixture was evaporated to dryness and then partitioned between dichloromethane and saturated brine. The layers were separated and the combined organic layers were dried over anhydrous Na2SO4and was evaporated in vacuum to give crude product, which was purified column chromatography on silica gel (petroleum ether/EtOAc 10:1) to give diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (33,0 g, 78%)

To a solution of diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (7.5 g, 20.0 mmol) in anhydrous tetrahydrofuran (80 ml) was slowly added a solution of hydride (22 ml, 22,0 mmol, 1.0 M in THF) at 0ºC under an atmosphere of nitrogen. After stirring for 10 minutes the reaction was completed. The reaction was quenched by slow addition of methanol at 0ºC. The reaction mixture was then partitioned between dichloromethane and 1 n hydrochloric acid solution. The layers were separated and the aqueous layer was extracted with three times dichloromethane. The combined organic layers were dried over anhydrous Na2SO4and was evaporated in vacuum to give crude products which was purified by column chromatography on silica gel (petroleum ether/EtOAc 2:1) to give 2-(2-bromo-4-nitrophenyl)-2-methylpropan-1,3-diol (1.4 g, 24%) as red solids.1H NMR (400 MHz, DMSO-d6) δ 8,31 (d, J=2.4 Hz, 1H), 8,13 (DD, J=2,4, 8,8 Hz, 1H), 7,74 (d, J=8,8 Hz, 1H), 4,74 (t, J=5,2 Hz, 2H), 3,93 (sq, J=5,2 Hz, 2H), 3,79 (m, sq, J=5,2 Hz, 2H), 1,38 (s, 3H).

To a solution of 2-(2-bromo-4-nitrophenyl)-2-methylpropan-1,3-diol (7.2 g, 24,82 mmol) in anhydrous benzene (75 ml) was added cyanomethaemoglobin (9.0 g, 37,29 mmol) at room temperature. The reaction mixture was stirred for 72 hours, then was evaporated to dryness, and again dissolved in ethanol (100 ml). Then was added tin chloride(II) dihydrate (28 g, 94,42 mmol) and obtained p�the target was heated to 70ºC for 1 hour. The reaction mixture was cooled to room temperature and then quenched with a saturated aqueous solution of sodium bicarbonate. The reaction mixture was then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4and was evaporated in vacuum to give crude product, which was purified using reverse-phase HPLC to obtain 3-bromo-4-(3-methyloxiran-3-yl)aniline (1.5 g, 18%) TFA salt.1H NMR (400 MHz, CD3CN) δ 6,93 (d, J=2.4 Hz, 1H), 6,78 (d, J=8.4 Hz, 1H), 6,71 (DD, J=2,4, and 8.4 Hz, 1H), 4,94 (d, J=5.6 Hz, 2H), 4,46 (d, J=6,0 Hz, 2H), of 1.70 (s, 3H).

To be heated at the temperature of reflux to a solution of 3-(2-bromo-4-nitrophenyl)-3-methyloxirane (68 mg, 0,2499 mmol) in ethanol (5 ml) was added ammonium formate (68 mg, 1,078 mmol) followed by the addition of Pd/C (32 mg, 0,3007 mmol). The reaction mixture was boiled to reflux for 5 minutes, cooled to room temperature and was filtered through a layer of Celite. The solvent was evaporated to obtain 4-(3-methyloxiran-3-yl)aniline.1H NMR (400 MHz, DMSO-d6) δ 6,93-6,90 (m, 2H), 6,56 (d, J=8,5 Hz, 2H), 4,70 (d, J=5.4 Hz, 2H), of 4.45 (d, J=5.6 Hz, 2H), of 1.55 (s, 3H).

Amine intermediate Example 23:Synthesis of 2-(4-Dapsone base)-2-methylpropan-1,3-diol

To be heated at the temperature of reflux to a solution of 2-(2-bromo-nitrophenyl)-2-methylpropan-1,3-diol (211 mg, 0,73 mmol) in ethanol (15.5 ml) was added ammonium formate (211 mg, 3.35 mmol) followed by the addition of Pd/C (140 mg, 1,32 mmol). The reaction mixture was boiled to reflux for 10 minutes, cooled to room temperature and was filtered through a layer of Celite. The solvent was evaporated under reduced pressure to obtain 2-(4-Dapsone base)-2-methylpropan-1,3-diol (112 mg, 85%).

Special examples

Synthesis of 4-oxo-N-(3-tert-butylphenyl)-1H-quinoline-3-carboxamide (table 1, Compound 603)

A flask containing 4-oxo-1H-quinoline-3-carboxylic acid (38 mg, 0.20 mmol), HBTU (76 mg, 0.20 mmol), Et3N (61 mg, 84 μl, of 0.60 mmol) and DMF (2 ml), heated at 60ºC for 15 minutes. To the reaction mixture was then added 3-tert-butylaniline (of 29.98 mg, 0,2009 mmol) and the reaction mixture was stirred at 60ºC for 30 minutes. The reaction mixture was cooled to room temperature, was filtered and was purified by reversed-phase HPLC using 10 to 99% CH3CN in H2O obtaining N-(3-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.1H NMR (400 MHz, DMSO-d6) δ 12,94 (s, 1H), 12,45 (s, 1H), 8,89 (s, 1H), of 8.34 (DD, J=1,1, 8,2 Hz, 1H), 7,84-7,80 (m, 1H), 7,76-7,71 (m, 2H), 7,62-7,53 (m, 2H), 7,29 (t, J=7.9 Hz, 1H), 7,15-7,12 (m, 1H), 1,31 (s, 9H). LC/MS: m/z 321,5 (M+H)+at 1.8 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of N-[4-cyclopentyl-5-hydroxy-2-(3-hydroxyprop-1-inyl)Fe�yl]-4-oxo-1H-quinoline-3-carboxamide (table 1, Connection 512)

4-bromo-2-cyclopentyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)fenilmetilketenom (50 mg, 0.10 mmol), Pd(PPh3)2Cl2(4 mg, of 0.005 mmol) and copper iodide (1 mg, 0,10 μl of 0.003 mmol) was added in a microwave vessel, which was purged using N2and closed the lid. Added degassed DMF solution (1 ml), triethylamine (2 ml) and prop-2-yn-1-ol (57,75 mg, 59,97 μl 1,030 mmol) and the reaction mixture was heated at 80ºC for 16 hours. The reaction mixture was filtered and purified using HPLC (20-99% CH3CN/0,05% TFA) to give 2-cyclopentyl-4-(3-hydroxyprop-1-inyl)-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenylmercuriborate/N-(4-cyclopentyl-5-hydroxy-2-(3-hydroxyprop-1-inyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide. These product containing fractions were pooled, concentrated to remove acetonitrile and treated with 5N NaOH (2 ml). the pH of the solution was adjusted to 7 and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 50% saturated sodium bicarbonate solution (2×20 ml) and saturated brine. The solution was dried over anhydrous Na2SO4that was filtered and dried to obtain N-(4-cyclopentyl-5-hydroxy-2-(3-hydroxyprop-1-inyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide. LC/MS: m/z 403,2 (M+H)+when 0,92 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA).

Synthesis of N-(4-cyclohexyl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (table 1, Compound 648)

To N-(4-bromo-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (50 mg, 0.14 mmol), cyclohexene-1-Voronovo acid (35 mg, 0,28) and Pd(dppf)Cl2-DCM (11 mg, 0.01 mmol) was added Na2CO3(980 µl of 2 M solution of 1.96 mmol) and acetonitrile (2 ml). The reaction mixture was heated under conditions of microwave irradiation for 10 minutes at 150ºC in the atmosphere of N2. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 ml), water and saturated brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified column chromatography on silica gel (30-100% ethyl acetate/hexane) to give N-(4-cyclohexene-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide in the form of a white solid (35 mg, 70%). N-(4-cyclohexene-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (35 mg, 0.10 mmol) was intensively stirred with a 10% solution of Pd/C (wet) (30 mg, 0.01 mmol) in the atmosphere of H2for 30 minutes at 50ºC. The reaction mixture was filtered, concentrated in vacuo and purified using HPLC (30-95% CH3CN/5 mm HCl) to give N-(4-cyclohexyl-2-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (20 mg, 57% o�d). LC/MS m/z 361,4 [M+H]+.1H NMR (400,0 MHz, DMSO-d6) δ 12,94 (d, J=6,0 Hz, 1H), to 12.24 (s, 1H), 8,89 (d, J=6,5 Hz, 1H), 8,35 (d, J=7,7 Hz, 1H), 8,22 (d, J=8,3 Hz, 1H), of 7.82 (t, J=7,6 Hz, 1H), 7,76 (d, J=7,8 Hz, 1H), 7,55-7,51 (m, J=7,6 Hz, 1H), 7,11 (s, 1H), 7,05 (d, J=8.4 Hz, 1H), 2,45 (m, 1H), of 2.38 (s, 3H), 1,80-to 1.69 (m, 5H), 1,42-to 1.21 (m, 5H).

Synthesis of N-(4-hydroxy-2-naphthyl)-4-oxo-1H-quinoline-3-carboxamide (table 1, Compound 552)

To a solution of N-(4-methoxy-2-naphthyl)-4-oxo-1H-quinoline-3-carboxamide (73 mg, 0.21 mmol) in DCM (4 ml) was added BBr3(1.1 ml, 11,64 mmol) dropwise at-78ºC. After completion of the addition the cooling bath was removed and the reaction mixture obtained was warmed to room temperature and then heated to 50ºC for 2 hours, cooled to -10 OC and quenched with saturated solution of NaHCO3. The aqueous layer was extracted using DCM and combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by reversed-phase HPLC to obtain N-(4-hydroxy-2-naphthyl)-4-oxo-1H-quinoline-3-carboxamide. LC/MS: m/z 331 (M+H)+when 1,47 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of N-[5-hydroxy-4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide (table 1, Compound 497)

A flask containing N-[5-benzyloxy-4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide (118 mg, 0.25 mmol) and Pd/C (12 mg, 011 mmol), was razziali in vacuum, followed by purging using N2. Was added methanol (2 ml) under an inert atmosphere, followed by removal of gas in vacuum. The reaction mixture was stirred overnight in a hydrogen atmosphere, filtered through a layer of Celite and concentrated to give N-[5-hydroxy-4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide.1H NMR (400,0 MHz, DMSO-d6) δ 12,93 (s, 1H), of 12.59 (s, 1H), 10,29 (s, 1H), 8,87 (s, 1H), 8,32 (DD, J=1,0, 8,1 Hz, 1H), 7,95 (s, 1H), 7,83-7,74 (m, 2H), 7,52 (t, J=8,0 Hz, 1H), of 7.36 (s, 1H), 3,20 (Quin., J=6,9 Hz, 1H) and 1.24-1,19 (m, 6H) M. D. LC/MS: m/z 391,36 (M+H)+when a 1.77 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of N-[4-cyclohexyl-5-hydroxy-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide (table 1, Compound 620)

(N-(4-cyclohexyl-5-hydroxy-2-(trifluoromethyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide can be synthesized in accordance with the General scheme presented above, proceeding from N-(5-(benzyloxy)-4-cyclohexyl-2-(trifluoromethyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.1H NMR (400 MHz, DMSO-d6) δ 12,93 (d, J=6,6 Hz, 1H), 12,54 (s, 1H), 10,28 (s, 1H), 8,87 (d, J=6,8 Hz, 1H), 8,32 (d, J=7,3 Hz, 1H), 7,95 (s, 1H), 7,81 (DDD, J=23,1, 15,0, 4,7 Hz, 2H), 7,53 (DD, J=11,5, 4.6 Hz, 1H), 7,34 (s, 1H), 2,84 (s, 1H), 1.85 to to 1.69 (m, 5H), 1,38 (t, J=10.3 Hz, 5H). LC/MS: m/z 431,5 (M+H)+when 2,01 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of N-[2-fluoro-5-hydroxy-4-(trif�ormetal)phenyl]-4-oxo-1H-quinoline-3-carboxamide (table 1, Connection 501)

N-(2-fluoro-5-hydroxy-4-(trifluoromethyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide can be synthesized in accordance with the General scheme presented above, proceeding from N-(5-(benzyloxy)-2-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide. LC/MS: m/z 367,10 (M+H)+when 1,65 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of 6-[(4-oxo-1H-quinoline-3-yl)carbylamine]-1H-indole-4-carboxylic acid (table 1, Compound 712)

Ethyl 6-(4-oxo-1,4-dihydroquinoline-3-carboxamido)-1H-indole-4-carboxylate (6 mg, 0.02 mmol) was suspended in 1 M NaOH (400 μl, 0,40 mmol) and heated to 50ºC for 30 minutes. Transparent brown solution was diluted with water (1 ml) and made acidic with 1N HCl solution (450 μl). The solution was washed with water (3×1 ml) and purified by reversed-phase HPLC (75% acetonitrile/water) to give 6-(4-oxo-1,4-dihydroquinoline-3-carboxamido)-1H-indole-4-carboxylic acid. LC/MS: m/z 347,8 (M+H)+when 1,07 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA))

Synthesis of 5-amino-N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (table 1, Link 586)

A flask containing 8-bromo-N-(2,4-di-tert-butyl-5-hydroxyphenyl)-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxamide (430 mg, 0.83 mmol) and Pd/C (60 mg, 0,56 mmol), razziali in a vacuum, with subsequent�ing scavenging using N 2. Was added EtOAc (4 ml) and HCl (1 ml of 1 M, 1,000 mmol) followed by removal of gas in vacuum. The reaction mixture was stirred overnight in a hydrogen atmosphere, filtered through a layer of Celite and concentrated to give 5-amino-N-(2,4-di-tert-butyl-5-hydroxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide (164 mg, 48%). LC/MS: m/z 408,5 (M+H)+at 1.98 m min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-5-methylamino-4-oxo-1H-quinoline-3-carboxamide (table 1, Link 543)

A flask containing 5-amino-N-(2,4-di-tert-butyl-5-hydroxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide (23 mg, 0,06 mmol), Pd/C (5 mg, 0.05 mmol) and formaldehyde (5 ál 38% wt/V, 0,06 mmol), razziali in vacuum, followed by purging using N2. Was added methanol (1 ml) followed by removal of gas in vacuum. The reaction mixture was stirred overnight in a hydrogen atmosphere, filtered through a layer of Celite and concentrated to give N-(2,4-di-tert-butyl-5-hydroxy-phenyl)-5-methylamino-4-oxo-1H-quinoline-3-carboxamide. LC/MS: m/z 422,5 (M+H)+when 2,24 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of N-(2,4-di-tert-butyl-5-hydroxy-phenyl)-7-hydroxy-4-oxo-1H-quinoline-3-carboxamide (table 1, Compound 653)

To a solution of N-(2,4-di-tert-butyl-5-hydroxy-phenyl)-7-methoxy-4-ox�-1H-quinoline-3-carboxamide (120 mg, 0.28 mmol) in DCM (1.5 ml) was added BBr3(1.5 ml, 15,23 mmol) dropwise at-78ºC. After completion of the addition the cooling bath was removed and the reaction mixture obtained was warmed to room temperature and stirred over night. The reaction was quenched with saturated solution of NaHCO3. The aqueous layer was extracted using DCM and the combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by reversed-phase HPLC to obtain N-(2,4-di-tert-butyl-5-hydroxy-phenyl)-7-hydroxy-4-oxo-1H-quinoline-3-carboxamide . LC/MS: m/z of 409.5 (M+H)+when 1,83 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of 6-hydroxy-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide (table 1, Compound 680)

6-hydroxy-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide can be synthesized in accordance with the General scheme presented above, proceeding from N-(5-tert-butyl-1H-indol-6-yl)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide. LC/MS: m/z 378,00 (M+H)+when 1,38 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of 6-hydroxy-N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (table 1, Compound 703)

6-hydroxy-N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide can be synthesized in accordance with General�increasing, presented above, proceeding from N-(2,4-di-tert-butyl-5-hydroxyphenyl)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide. LC/MS: m/z 409,00 (M+H)+when 1,73 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of (R)-1-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]-3-(trifluoromethyl)phenyl]pyrrolidin-2-carboxylic acid (table 1, Compound 699)

To a solution of tert-butyl (2R)-1-[4-[(4-oxo-1H-quinoline-3-carbonyl)amino]-3-(trifluoromethyl)phenyl]pyrrolidin-2-carboxylate (35 mg, 0,06979 mmol) in DCM (500 ml) was added TFA (1 ml) at room temperature and the reaction mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure and the residue was purified by reversed-phase HPLC with the receipt of (2R)-1-[4-[(4-oxo-1H-quinoline-3-carbonyl)amino]-3-(trifluoromethyl)phenyl]pyrrolidin-2-carboxylic acid. LC/MS: m/z 466,3 (M+H)+when 1,46 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

Synthesis of (S)-1-[4-[(4-oxo-1H-quinoline-3-yl)carbylamine]-3-(trifluoromethyl)phenyl]pyrrolidin-2-carboxylic acid (table 1, Compound 568)

(S)-1-(4-(4-oxo-1,4-dihydroquinoline-3-carboxamido)-3-(trifluoromethyl)phenyl)pyrrolidin-2-carboxylic acid can be synthesized in accordance with the General scheme above, on the basis of tert-butyl (2S)-1-[4-[(4-oxo-1H-quinoline-3-carbonyl)amino]-3-(trifluoromethyl)phenyl]pyrrolidin-2-carboxylate. LC/MS: /z 466,3 (M+H) +when 1,47 min (10%-99% CH3CN (of 0.035% TFA)/H2O (0,05% TFA)).

In table 2, are shown in the graphical part presents data characterizing the compounds of the present invention obtained in the above Examples .

NMR data for selected compounds are presented in Table 2 And shown in the graphic part.

(B) Assays for detecting and measuring corrective properties of the compounds in respect of ΔF508-CFTR

(I) Optical methods for determination of membrane potential for the analysis of properties of compounds aimed at modulating ΔF508-CFTR

Optical analysis of membrane potential involves the use of potential-sensitive FRET sensors described by Gonzalez and Tsien (see, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells." Biophys J 69(4): 1272-80 ; Gonzalez, J. E. and R. Y. Tsien (1997); "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with devices for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (see, Gonzalez, je, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439).

These potential-sensitive analyses based on the change of resonant energy transfer fluorescence (FRET) between the membrane-soluble potential-sensitive dye, DiSBAC2(3) and a fluorescent phospholipid, CC2-DMPE, which is attached to the external target�e plasma membrane and acts as a FRET donor. Changes of membrane potential (Vm) cause a redistribution of the negatively charged DiSBAC2(3) through the plasma membrane, and the amount of transmitted energy from CC2-DMPE changes accordingly. Changes in fluorescence emission can be monitored using VIPR™ II, which is an integrated device comprising a fluid source and a fluorescence detector, intended for the implementation of cellular screening assays in 96 - or 384-well microtiter plates.

Identification of correction compounds

To identify small molecules that correct the defect of traffic associated with ΔF508-CFTR, was developed by the analysis in the format of one HTS add. Cells were incubated in serum-free medium for 16 hours at 37ºC in th or in the absence (negative control) of the test compounds. As a positive control, cells were seeded in 384 well plates and incubated for 16 hours at 27ºC for “temperature correction” ΔF508-CFTR. Cells were then washed 3× with a solution of Krebs-ringer and loaded with potential-sensitive dyes. To activate ΔF508-CFTR to each well was added with 10 μm Forskolin and the CFTR-potentiating means of genistein (20 μm) together with do not contain Cl-environment. Add not containing Cl-environment �was romotional outflow of Cl -in response to the activation of ΔF508-CFTR, the resulting membrane depolarization was measured optically using the potential-sensitive dye-based FRET.

Identification potentionally compounds

To determine potentiation ΔF508-CFTR, was developed by the analysis in the format of double HTS add. When you first add not containing Cl-the medium with or without test compounds was added to each well. After 22 h was carried out by second Addendum containing Cl-medium containing 2-10 μm Forskolin, to activate ΔF508-CFTR. Extracellular Cl-concentration after both additions was 28 mm, which promoted the outflow of Cl-in response to the activation of ΔF508-CFTR, and the resulting membrane depolarization was measured optically using the potential-sensitive dye-based FRET.

Solutions

The solution is in
the bath
#1: (in mm)
NaCl 160, KCl 4.5 And CaCl22, MgCl21, HEPES 10, pH to 7.4 using NaOH.
The solution is in
the bath
without chlorides:
Chloride salt in solution in the bath #1 replaced gluconate salts.
CC2-DMPE: Received as 10 mm stock solution in DMSO and stored at-20ºC.

DiSBAC2(3):Received as 10 mm stock solution in DMSO and stored at-20ºC.

Cell culture

Murine NIH3T3 fibroblasts stably expressing ΔF508-CFTR were used for optical measurements of membrane potential. Cells were maintained at 37ºC in 5% CO2and 90% humidity in a modified Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal bovine serum, 1× NEAA, β-ME, 1× pen/strep, and 25 mm HEPES in 175 cm2flasks for cultivation. For all optical assays, the cells were seeded at a density of 30,000/well in 384-well Matrigel-coated plates and cultured for 2 hours at 37ºC, and then were cultured at 27ºC for 24 hours for analysis potentiating funds. For the correction assays, the cells were cultured at 27ºC or 37ºC with and without compounds for 16-24 hours.

Electrophysiological analyses to determine the ΔF508-CFTR-modulating properties of the compounds.

1. Analysis using the Ussing chamber

Experiments using the Ussing chamber was performed on polarized epithelial cells of the respiratory tract, expressing ΔF508-CFTR to further care.�th characterization of modulators of ΔF508-CFTR, identified in the optical assays. Epithelial FRT cells?F5O8-CFTRgrown on the inclusions of the cell culture Costar Snapwell, were placed in an Ussing chamber (Physiologic Instruments, Inc., San Diego, CA) and constantly carried a short circuit in the monolayers using fixation systems capacity (Department of Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured by applying a 2-mV pulse. In these conditions, the FRT epithelia demonstrated resistance 4Ω/cm2or more. The solutions were maintained at 27AboutC and flushed with air. The bias voltage on the electrode and the resistance of the liquid was adjusted with the use of acellular inclusion. Under these conditions, the current reflects the flow of Cl-through ΔF508-CFTR expressed in the apical membrane. Data ISCreceived in digital format using MRA-CE interface and program AcqKnowledge (ν3.2.6; BIOPAC Systems, Santa Barbara, CA).

Identification of corrective connections

A typical Protocol included the use of a gradient of concentration of Cl-from the basolateral to the apical membrane. To establish this gradient at the basolateral membrane used normal ringer's solutions, whereas apical NaCl was replaced with equimolar amounts of sodium gluconate (titrated to pH to 7.4 using NaOH) with getting too high�on the concentration gradient of Cl -through the epithelium. All experiments were carried out with intact monolayer. Added fully activated ΔF508-CFTR, Forskolin (10 μm) and the PDE inhibitor, IBMX (100 μm), followed by the addition of potentiator 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 37ºC and then washed with 3× until registration. cAMP - and genistein-mediated ISCin treated compound cells normalized to 27ºC and 37ºC controls and expressed as percent activity. Pre-incubation of cells with the correction compound significantly increased the cAMP - and genistein-mediated ISCcompared to 37ºC controls.

Identification of potentiator compounds

A typical Protocol included the use of a gradient of concentration of Cl-from the basolateral to the apical membrane. To establish this gradient at the basolateral membrane used normal ringer solution and membrane permeability using nystatin (360 μg/ml), whereas apical NaCl was replaced with equimolar amounts of glucono�and sodium (titrated to a pH of 7.4 using NaOH) to produce high concentration gradient of Cl -through the epithelium. All experiments were carried out 30 minutes after treatment with nystatin for membrane permeability. Forskolin (10 μm) and all test compounds were added on both sides of inclusions in cell culture. The effectiveness of the proposed funding potentiating ΔF508-CFTR, were compared with the known potentiating means genistein.

Solutions

Basolateral solution (in mm):NaCl (135), CaCl2(1,2), MgCl (1,2) K2HPO4(0,6), KHPO4N-2-hydroxyethylpiperazine-N'-2-econsultancy acid (HEPES) (10), and dextrose (10). The solution was titrated to a pH of 7.4 using NaOH.
The apical solution (in mm):Same as basolateral solution, but with replacement of NaCl with Na gluconate (135).

Cell culture

Epithelial cells of rats Fisher (FRT) expressing ΔF508-CFTR (FRT?F5O8-CFTR),used to experiment with using the camera for alleged modulators of ΔF508-CFTR identified in the optical assays. Cells were cultured on the inclusions of the cell culture Costar Snapwell and were cultured for five days at 37ºC and 5% CO2inmodified Coon environment hamF-12, medium supplemented with 5% fetal calf�La serum 100 Units./ml of penicillin and 100 µg/ml streptomycin. Before using them to characterize the potentiating activity of the compounds, the cells were incubated at 27ºC for 16-48 hours for the correction of ΔF508-CFTR. To determine the activity of correction compounds, the cells were incubated at 27ºC or 37ºC with and without the compounds for 24 hours.

2. Registration is in the format “a cell”

Macroscopic ΔF508-CFTR current (IΔF508) in temperature - and test compound-corrected NIH3T3 cells stably expressing ΔF508-CFTR were monitored using the perforated-patch method in the format “a cell”. In short, current-clamp registration of IΔF508carried out at room temperature using the Axopatch 200B patch clamp amplifier (Axon Instruments Inc., Foster City, CA). All registrations were carried out at a 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 insulating resistance >20GΩ and series resistance <15 GΩ. Pulse generation, data collection and analysis was carried out using a personal computer equipped with a Digidata 1320 A/D interface VM�side with Clampex 8 (Axon Instruments Inc.). The bath contained < 250 μl of physiological saline, and provided ongoing perponderance at a speed of 2 ml/min using a gravity-driven perfusion system.

Identification of corrective connections

To determine the activity of correction compounds for increasing the density of ΔF508-CFTR in the plasma membrane, was used as described above, medota perforated-patch-registration to measure the current density following 24-hour treatment corrective compounds. Fully activated ΔF508-CFTR, 10 μm Forskolin and 20 μm genistein were added to the cells. In these conditions of registration, the current density after 24-hour incubation at 27ºC was higher than the current density observed after 24 hours incubation at 37ºC. 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 37ºC and the current density was compared to 27ºC and 37ºC controls (% activity). Before initiating registration, the cells were washed 3× extracellular environment to register to remove any residue of the test compound. Pre-incubation with 10 μm of corrective connections su�significantly increased cAMP - and genistein-dependent current compared to 37ºC controls.

Identification potentiating compounds

The ability of ΔF508-CFTR-potentiating compounds to increase the macroscopic ΔF508-CFTR current (IΔF508) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using perforated-patch method. Potentiating the funds identified in the optical assays evoked a dose-dependent increase in IΔF508with the same potency and efficacy that was observed in the optical assays. In all the studied cells, the potential reversion to and in the process of applying potentiating funds was around -30 mV, which represents the calculated value of ECl(-28 mV).

Solutions

Intracellular solution (in mm):Cs-aspartate (90), CsCl (50), MgCl2(1), HEPES (10), and 240 µg/ml amphotericin-B (pH adjusted to 7.35 using CsOH).
Extracellular solution (in mm):N-methyl-D-glucamine (NMDG)-Cl (150), MgCl2(2), CaCl2(2), HEPES (10) (pH adjusted to 7.35 using HCl).

Cell culture

Murine NIH3T3 fibroblasts stably expressing ΔF508-CFTR, used to register in the format “a cell”. Cells were maintained at 37ºC in 5% CO2and 90% humidity in the modified Dolbec�about the environment of the Needle, supplemented with 2 mm glutamine, 10% fetal bovine serum, 1× NEAA, β-ME, 1× pen/strep, and 25 mm HEPES in 175 cm2flasks for cultivation. To register in the format “a cell” 2500-5000 cells were seeded on coated with poly-L-lysine cover glasses and cultured for 24-48 hours at 27ºC before using for the test potentiating activity funds; and incubated with or without the correction compound at 37ºC for measuring the activity of correction compounds.

3. Registration of single channels

Activity single channel temperature-corrected ΔF508-CFTR, expressed in NIH3T3 cells, were observed using isolated areas(patches) of the membranes in the configuration of the “internal side out. In short, current-clamp registration activity of single channels was carried out at room temperature using the Axopatch 200B patch clamp amplifier (Axon Instruments Inc.). All registrations were carried out at a frequency of 10 kHz using a low pass filter at 400 Hz. Patch-pipettes were made from glass Corning Kovar Sealing #7052 (World Precision Instruments, Inc., Sarasota, FL) and 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. Madisn, WI). After stabilization of the activity of the channel, patch was perpendicularly using gravity-driven microperfusion system. Incoming solution was in close proximity to the patch, which ensured complete exchange of solutions within 1-2 seconds. To maintain ΔF508-CFTR activity during the rapid perfusion, the nonspecific phosphatase inhibitor F-(10 mm NaF) was added to the solution in the bath. In these conditions of registration, the channel activity remained constant throughout the patch-registration (up to 60 min). The currents formed by a positive charge moving from intra - to extracellular solutions (anions move in the opposite direction) is represented as a positive current. The potential of the pipette (Vp) maintained at 80 mV.

The channel activity was analyzed from membrane patches containing ≤2 active channel. The maximum number of simultaneous discoveries determined the number of active channels during the experiment. To determine the amplitude of single channel current, the data obtained from 120 sec of activity of ΔF508-CFTR, was filtered “off-line” at 100 Hz and then used to make histograms of the amplitude by using all of the points that are customized using multihousing functions and using Bio-Patch Analysis (Bio-Logic Comp. France). The total microscopic�the first current and the possibility of opening (P o) was determined from 120 sec channel activity. Powas determined using the Bio-Patch or from Po= I/i(N), where I = mean current, i = the amplitude of single channel current 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 adjusted to 7.35 using Tris base).
Intracellular solution (in mm):NMDG-Cl (150), MgCl2(2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 by the introduction of HCl).

Cell culture

Murine NIH3T3 fibroblasts stably expressing ΔF508-CFTR were used for patch clamp register using isolated sites. Cells were maintained at 37ºC in 5% CO2and 90% humidity in a modified Dulbecco environment, Needle, supplemented with 2 mm glutamine, 10% fetal bovine serum, 1× NEAA, β-ME, 1× pen/strep, and 25 mm HEPES in 175 cm2flasks for cultivation. To register single channel 2500-5000 cells were seeded on coated with poly-L-lysine cover glasses and cultured for 24-48 hours at 27ºC before use.

Compounds of the present invention are useful�and as modulators of ATP-binding cassette transporters. Table 3 below illustrates the EC50 and relative efficacy of certain embodiments, are presented in Table 1.

In Table 3, are shown in the graphic part, the symbols used have the following meanings:

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%.

1. A method of treating or reducing the severity of cystic fibrosis in a patient, where the patient has a transmembrane receptor cystic fibrosis (CFTR) R117H mutation, comprising the step of introducing a specified patient an effective amount of N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

2. A method according to claim 1, wherein the patient is heterozygous for R117H mutation.

3. A method according to claim 1, wherein the patient is homozygous for the R117H mutation.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: second amines are N-alkylated by cis-2,3-dichlormethyl-hem-dichlorcyclopropane in the presence of the phase transfer catalyst triethylbenzylammonium chloride at 75°C for 8 hours in the presence of the following components, wt %: diethylamine 4.7; cis-2,3-dichloromethyl-hem-dichlorcyclopropane 6.7; dimethylsulphoxide 87.8; triethylbenzyl ammonium chloride 0.26; potassium hydroxide 0.54; a dibutylamine reaction is carried out in the following proportions, wt %: dibutylamine 8; -2,3-dichloromethyl-hem-dichlorcyclopropane 6.45; dimethylsulphoxide 84.8; ammonium chloride 0.25; potassium hydroxide 0.5.

EFFECT: higher target product yield and higher quality.

2 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining N,N'-di(1-adamantyl)bispidin-9-ones, where R=R'=methyl (1a), R=R'=ethyl (1b), R=R'=propyl (1c), R=methyl and R'=1-adamantylaminomethyl (2), R=R'=1-adamantylaminomethyl (3). Method is realised by two-stage condensation, at the first stage condensed is 1-aminoadamantane with formaldehyde, at the second stage formed product is condensed with ketones in the same reactor with heating in butanol or other alcohols. Obtained products are extracted after condensing reaction mass under vacuum with hot toluene and re-crystallised from toluene.

EFFECT: N,N'-di(1-adamantyl)bispidin-9-ones, which can be used as substances for medications and as initial substances for obtaining novel derivatives of N,N'-di(1-adamantyl)bispidine .

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a biologically active analgesic with non-opioid action 2-[3'-(6'-chloropyridyl)]-7-azabicyclo[2.2.1]-haptane, and specifically to a method of producing an exo-isomer thereof via isomerisation of an endo-isomer in the presence of strong bases in an aprotic solvent solution at room temperature. The disclosed method is easily implemented in industrial conditions and enables to obtain 2-exo-[3'-(6'-chloropyridyl)]-7-azabicyclo[2.2.1]-haptane with high output.

EFFECT: high output.

4 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula I: where n has values 0 or 1, and Cy represents a heteroaryl group, selected from such groups as 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl and 4-pyridinyl, where heteroaryl groups are optionally substituted by up to 3 substituents, different from hydrogen, independently selected fromC1-6alkyl, C2-6alkenyl, C2-6alkinyl, C3-8cycloalkyl, substituted phenyl, furyl, halogen, -OR', -CF3, -CN, -NO2, -SO2R', -SO2NR'R″, -R'SO2R″, where R' and R″ are independently selected from hydrogen, C1-6alkyl, where the term "substituted", applicable with respect to substituted phenyl, relates to substitution with one or several halogens, and their pharmaceutically acceptable salts, as well as to pharmaceutical compositions based on the said compounds.

EFFECT: application of the said compounds for treatment and/or prevention of wide spectrum of CNS diseases and disorders.

13 cl, 2 dwg, 1 tbl, 11 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to new positively charged NSAIA prodrugs of a common formula (1, 2a, 2b, 2c or 2d) of "1, 2a, 2b, 2c or 2d structure"

Structure 1, Structure 2a,

Structure 2b, Structure 2c, Structure 2d. Values of R, R1, R2, R3, R4, R5, Ary, X radicals are presented in Claims 1,2.

EFFECT: increasing agent penetration speed.

22 cl, 14 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to 1,5-bis[(tert-butylamino)methyl]-N,N'-di-tert-butylbispidin-9-one and a method for production thereof. 1,5-bis[(tert-butylamino)methyl]-N,N'-di-tert-butylbispidin-9-one is obtained by condensation of acetone with 1,3,5-tri-(tert-butyl)-1,3,5-triazacyclohexane while heating in an alcohol in the presence of acetic acid. The reaction is carried out while heating in ethanol or another alcohol. The obtained product is extracted after condensation of the reaction mass in a vacuum with hot toluene and recrystallised from ethyl alcohol.

EFFECT: obtaining a novel compound which can be used as a starting substance when producing bispidine and 1,3-diazaadamantane derivatives.

2 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds in the form of a free base or a pharmaceutically acceptable acid addition salt specified in a group including: (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-azabicyclo[3.3.1]nonane, 5-{2-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydroindol-2-one, (4S,5R)-4-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-1-azabicyclo[3.3.1]nonane, (4S,5R)-4-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-azabicyclo[3.3.1]nonane, (4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-azabicyclo[1.3.1]nonane and 5-{6-[(4S,5R)-(1-azabicyclo[3,3,1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydroindol-2-one, possess nAChR α7 agonist activity.

EFFECT: using them in pharmaceutical compositions and for preparing a drug applicable for preventing and treating a memory disorder.

21 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), having antibacterial properties, a method for synthesis thereof, use thereof and a pharmaceutical composition based on said compounds. In general formula (I) R1 is a (CH2)n-NH2 or (CH2)n-NHR radical, where R is (C1-C6)alkyl and n equals 1 or 2; R2 is a hydrogen atom; R3 and R4 together form a nitrogen-containing aromatic 5-member heterocycle with 1, 2 or 3 nitrogen atoms, possibly substituted with one or more R' groups, where R' is selected from a group consisting of a hydrogen atom and alkyl radicals with 1-6 carbon atoms.

EFFECT: improved method.

13 cl, 4 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: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,3,5-dithiazinanes of formula (1): wherein diphenylenediamine (diaminodiphenylmethane, diaminodiphenyl oxide) reacts with N-tert-butyl-1,3,5-dithiazinane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine: N-tert-butyl-1,3,5-dithiazinane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system (1:1, by volume) for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as antimicrobial and antifungual agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method for selective production of 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes of formula (1) where R = 4-C6H4-CH2-C6H4-4', 4-C6H4-O-C6H4-4', 4-H3COC6H3-C6H3OCH3-4', where diphenylenediamines (diaminodiphenylmethane, diaminodiphenyl oxide, dimethoxybenzidine) react with 1-oxa-3,6-dithiacycloheptane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine:1-oxa-3,6-dithiacycloheptane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system for 2.5-3.5 hours.

EFFECT: novel method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes, which can be used as antimicrobial, antifungal and anti-inflammatory agents, sorbents and extractants of precious metals and selective complexing agents.

1 tbl, 1 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

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