RU2525115C2 - Method of modulating transporters of atp-binding cassette - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

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

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

16 cl, 15 tbl

Description

Cross reference to related applications

Pursuant to Section 35 of the Code of the United States Law, paragraph 119, this application claims priority according to provisional application for US patent No. 60/582676, filed June 24, 2004 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", provisional application for US patent No. 60/630127, filed November 22, 2004, entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", provisional application for US patent No. 60/635674, filed December 13, 2004 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", provisional application for US patent No. 60/658219, filed March 3, 2005 and entitled "MODULATORS OF ATP-BINDING CAS SETTE TRANSPORTERS ", and provisional application for US patent No. 60/661311, filed March 11, 2005 and entitled" MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS ", the full contents of each of the above applications are incorporated into this description by reference.

FIELD OF THE INVENTION

The present invention relates to modulators of transporters of ATP-binding cassettes ("ABC") or fragments thereof, including cystic fibrosis transmembrane conductivity regulator ("CFTR"), compositions containing them and methods for their preparation. The present invention also relates to methods for treating diseases mediated by an ABC transporter using such modulators.

BACKGROUND OF THE INVENTION

ABC Transporters are a family of membrane transporter proteins that regulate the transport of a wide range of pharmacological agents, potentially toxic drugs and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) due to their specific activities. Some of these transporters are disclosed as multidrug resistance proteins (like the MDR1-P glycoprotein or the multidrug resistance protein, MRP1) protecting cancer cells from chemotherapeutic agents. To date, 48 ABC transporters have been identified and, based on their sequence and function identity, they are distributed into 7 families.

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

One member of the ABC transporter family, typically associated with the disease, is a cAMP / ATP-mediated transmembrane protein that acts as an anionic “channel”, CFTR. CFTR is expressed in a variety of cell types, including adsorbing and secretory epithelial cells, where it regulates the anion flow through the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, the normal functioning of CFTR is important for maintaining electrolyte transport throughout the body, including respiratory and digestive tract tissue. A CFTR consists of approximately 1,480 amino acids that encode a protein that replenishes the tandem repeat of the transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. Two transmembrane domains are connected by a large polar regulatory (R) -domain with numerous phosphorylation sites that regulate channel activity and cell transport.

The CFTR coding gene is identified and sequenced (see Gregory RJ et al., 347: 382-386 (1990); Rich DP et al., Nature, 347: 358-362 (1990); Riordan JR et al., Sience, 245 : 1066-1073 (1989)). A defect in this gene causes mutations in CFTR, leading to cystic fibrosis (“CF”), the most common deadly genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 children in the United States. Of the entire US population, up to 10 million residents contain one copy of a defective gene without obvious pathological effects. In contrast, individuals with two copies of the CF-associated gene suffer from debilitating and destructive effects of CF, including chronic lung disease.

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

By sequencing the CFTR gene of CF chromosomes, many diseases caused by mutations have been identified (Cutting GR et al., Nature, 346: 366-369 (1990); Dean M. et al., Cell, 61: 863-870 (1990); and Kerem BS. et al., Science, 245: 1073-1080 (1989); Kerem BS. et al., Proc. Natl. Acad. Sci. USA, 87: 8447-8451 (1990)). Currently, more than 1000 diseases caused by mutations in the CF gene have been identified ( http://www.genet.sikkids.on.ca/cftr/ ). The most common mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and it is usually referred to as ΔF508-CFTR. This mutation occurs in approximately 70% of cases of cystic fibrosis and is associated with severe diseases.

The deletion of residue 508 in ΔF508-CFTR prevents the resulting protein from correct folding. This leads to the inability of the mutant protein to exit the ER and directed transport to the cytoplasmic membrane. As a result, the number of channels present in the membrane becomes much smaller than that observed in cells expressing wild-type CFTR. In addition to impaired directional transport, the mutation leads to the opening of a defective membrane channel. The joint reduced number of channels in the membrane and the opening of the defective channel leads to a reduced transport of anions through the epithelium, leading to the transport of defective ions and liquid (Quinton P.M., FASEB J., 4: 2709-2727 (1990)). Studies, however, have shown that reduced amounts of ΔF508-CFTR in the membrane are functional, although to a lesser extent than wild-type CFTR (Dalemans et al., Nature Lond., 354: 526-528 (1991); Dennung et al ., see above; Pasyk Foskett, J. Cell. Biochem., 270: 12347-12350 (1995)). In addition to ΔF508-CFTR, another disease caused by mutations in CFTR that result in defective targeted transport, defective synthesis and / or opening of a defective membrane channel can be controlled in the direction of amplification or attenuation by altering secretion of anions and attenuating progression and / or the severity of the disease.

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

These elements act together to achieve targeted transport through the epithelium due to their selective expression and localization in the cell. Chloride adsorption occurs due to the coordinated activity of ENaC and CFTR present in the apical membrane, and Na ⁺ -K ⁺ -ATPase pump and Cl ^- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal region leads to the accumulation of intracellular chloride, which can then be passively removed through the Cl ^- channels, leading to the transport of infection. A system of Na ⁺ / 2Cl ^- / K ⁺ -cotransporter, Na ⁺ -K ⁺ -ATPase-pump and basolateral membrane K ⁺ channels on the basolateral surface and CFTR in the luminal region coordinate chloride secretion due to CFTR in the luminal region. Since water itself is probably never actively transported, its flow through the epithelium depends on very small transepithelial osmotic gradients generated by a large flow of sodium and chloride.

In addition to cystic fibrosis, modulation of CFTR activity may be useful for other diseases indirectly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome. COPD is characterized by respiratory failure, which is progressive and incompletely reversible. Respiratory failure is caused by hypersecretion of mucus, emphysema and bronchiolitis. Activators of the mutant CFTR or wild-type CFTR contribute to the possible treatment of mucus hypersecretion and impaired clearance of the ciliary epithelium, which is common in COPD. Specifically, increased secretion of anions due to CFTR can facilitate the transport of fluid to the surface of the airways for hydration of the mucus and optimize the viscosity of the periciliary fluid. This should lead to increased clearance of ciliary epithelium and amelioration of symptoms associated with COPD. Dry eye disease is characterized by a decrease in the release of tear fluid and an atypical tear film of lipid, protein and mucin profiles. There are many causes of dry eye disease, some of which are age, Lasik eye surgery, arthritis, drug therapy, chemical / thermal burns, allergies, and diseases like cystic fibrosis and Sjogren's syndrome. Increased secretion of anions due to CFTR should enhance fluid transport from corneal endothelial cells and secretory glands surrounding the eye to enhance corneal hydration. This should help alleviate the symptoms associated with dry eye disease. Sjogren's syndrome is an autoimmune disease in which the immune system acts on the moisture-producing glands throughout the body, including the eyes, oral cavity, skin, respiratory tract tissue, liver, vagina, and intestines. Symptoms include dry eye disease, a disease of the mouth and vagina, as well as the lungs. The disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis / dermatomyositis. It is believed that defective protein transport causes a disease with limited treatment options. Modulators of CFTR activity can hydrate different organs affected by the disease and help alleviate the symptoms associated with the disease.

As discussed above, it is believed that a deletion of residue 508 in ΔF508-CFTR protects the resulting protein from correct folding, leading to the inability of this mutant protein to exit the ER and direct transport to the cytoplasmic membrane. As a result, insufficient amounts of mature protein are present in the cytoplasmic membrane and the transport of chloride to epithelial tissues is significantly reduced. In fact, it was shown that this cellular phenomenon of defective ER processing of ABC transporters due to the ER mechanism is the main basis not only for CF disease, but also for a large number of other "isolated" and hereditary diseases. There are two ways in which the function of the ER mechanism can be disrupted: either due to loss of connection with the ER export of proteins, which leads to degradation, or due to the ER accumulation of these defective proteins with abnormal folding [Aridor M. et al., Nature Med., 5 (7), 745-751 (1999); Shastry BS et al., Neurochem. International, 43 , 1-7 (2003); Rutishauer J. et al., Swiss Med Wkly, 132 , 211-222 (2002); Morello JP et al., TIPS, 21 , 466-469 (2000); Bross P. et al., Human Mut., 14 , 186-198 (1999)]. Diseases associated with the first class of impairment of ER function are cystic fibrosis (due to abnormal folding ΔF508-CFTR, as discussed above), hereditary emphysema (due to α1-antitrypsin; not Piz variants), hereditary hemochromatosis; coagulation-fibrinolysis deficiencies such as protein C deficiency, hereditary type 1 angioedema; lipid processing deficits, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia; lysosomal accumulation diseases such as I-cell inclusions disease / Hurler's pseudosyndrome, mucopolysaccharidosis (due to lysosomal processing enzymes), Sandhoff / Thay-Sachs disease (caused by β-hexosaminidase), Type II Crygler / Nyyar disease (caused by UDP-glucosuron) , polyendocrinopathy / hyperinsulemia, diabetes mellitus (due to the insulin receptor), Laron microsomy (due to the growth hormone receptor), mileoperoxidase deficiency, primary hypoparathyroidism (due to preprop arathyroid hormone), melanoma (due to tyrosinase). Diseases associated with the second class of impaired ER function are CDG type 1 glycanosis, hereditary emphysema (due to α1-antitrypsin; PiZ variant), congenital hyperthyroidism, osteopsatirosis (due to type I, II, IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen ), deficiency of adrenocorticotropic hormone (due to α1-antichymotrypsin), diabetes insipidus (DI), neurophysial DI (due to vasopressin hormone / V2 receptor), non-progenic DI (due to aquaporin II), Charcot-Mar syndrome i-Tooth (due to peripheral myelin protein 22), Perliceus-Merzbacher disease; neurodegenerative diseases such as Alzheimer's disease (due to βAPP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclearplasia, Peak's disease; some neurological disorders, such as Huntington’s disease, type I spinal cerebral ataxia, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian and myotonic dystrophy, as well as spongiform enceopathies, such as hereditary Creutzfeldt-Jacob disease (caused by a defect in protein) lysosomal α-galactosidase A) and Straussler-Scheinker syndrome (due to a processing defect in Prp).

In addition to a high level of regulation of CFTR activity, decreased secretion of anions due to CFTR modulators may be useful for the treatment of secretory diarrhea, in which case the transport of epithelial water dangerously increases as a result of the activation of the secretion-enhancing means of chloride transport. The mechanism includes an increase in cAMP and stimulation of CFTR.

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

Acute and chronic diarrhea is a significant medical problem in many areas of the world. Diarrhea is both a significant factor in malnutrition and a major cause of death (5,000,000 deaths per year) for children under the age of five.

Secretory diarrhea is also a dangerous condition in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). Diarrhea is found in 16 million travelers to developing countries from industrialized countries, and the severity and incidence of diarrhea varies by country and area of travel.

Diarrhea in farm and domestic animals such as cows, pigs and horses, sheep, goats, cats and dogs is the main cause of death of these animals. Diarrhea can occur from any significant change, such as a weaning or physical effect, as well as in response to many bacterial or viral infections and usually occurs in the first five hours of an animal’s life.

The most common diarrhea-causing bacteria is enterotoxogenic E. coli (ETEC), which has the K99 pilus antigen. Common viral causes of diarrhea are rotavirus and coronavirus. Other infectious agents are, among others, cryptosporidia, giardia lamblia and salmonella.

Symptoms of rotavirus infection include excrement of liquid feces, dehydration, and weakness. Coronavirus provokes an even more severe disorder in newborn animals and causes a higher death rate than rotavirus infection. However, often a young animal can be infected with more than one virus, or immediately with a combination of viral and bacterial organisms. This dangerously increases the severity of the disease.

Therefore, there is a need for modulators of ABC transporter activity and compositions containing them, which can be used to modulate ABC transporter activity in the mammalian cytoplasmic membrane.

There is a need for methods of treating diseases mediated by an ABC transporter using such ABC transporter activity modulators.

There is a need for methods of modulating the activity of an ABC transporter in an ex vivo mammalian cytoplasmic membrane.

There is a need for modulators of CFTR activity that can be used to modulate CFTR activity in a mammalian cytoplasmic membrane.

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 an ex vivo mammalian cytoplasmic membrane.

SUMMARY OF THE INVENTION

It has now been found that the compounds of this invention and pharmaceutically acceptable compositions containing them are useful as ABC transporter activity modulators. These compounds correspond to the general formula (I):

or their pharmaceutically acceptable salts, where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Ar ¹ in general terms and by classes and subclasses are indicated below.

These compounds and pharmaceutically acceptable compositions are useful for treating or alleviating the severity of a number of diseases, disorders or conditions, including, but not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; coagulation-fibrinolysis deficiencies such as protein C deficiency, hereditary type 1 angioedema; lipid processing deficits, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia; lysosomal accumulation diseases such as I-cell inclusions disease / Hurler's pseudosyndrome, mucopolysaccharidoses, Sandhoff / Tey-Sachs disease, type II Kriegler-Nayyar’s disease, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron microsomyosoma, myelopherosanosis deficiency, melioperoxidosis deficiency, meloperosis deficiency, Type 1 CDG, hereditary emphysema, congenital hyperthyroidism, osteopsatirosis, hereditary hypofibrinogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysical DI, non-progenic DI, W syndrome bright-Marie-Tooth disease, a disease Perlitseusa-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amphiotrophic lateral sclerosis, progressive supranuclearplasia, Peak's disease; heavy polyglutamine neurological disorders such as Huntington's disease, spinotserebralnaya ataxia type I, spinal and bulbar muscular atrophy, dentatorubalny pallidolyuizian and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Strausslera-Scheinker syndrome, COPD, dry eye disease and Sjogren’s syndrome.

DETAILED DESCRIPTION OF THE INVENTION

I. General Description of the Compounds of the Invention

The present invention relates to compounds of formula (I), useful as modulators of ABC transporter activity:

or their pharmaceutically acceptable salts, where:

Ar ¹ means a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms, where the above ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated or saturated ring where each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms, where Ar ¹ has m substituents, each independently selected from —WR ^W ;

W means a bond or an optionally substituted (C ₁ -C ₆ ) alkylidene chain, where up to two methylene groups of the W residue are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR ', -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, - NR'CO-, -S-, -SO-, -SO ₂ -, -NR'-, -SO ₂ NR'-, -NR'SO ₂ - or -NR'SO ₂ NR'-;

R ^W independently means R ', halogen, NO ₂ , CN, CF ₃ or OCF ₃ ;

m is 0-5;

each of R ¹ , R ² , R ³ , R ⁴ and R ⁵ independently means —X — R ^X ;

X is a bond or an optionally substituted (C ₁ -C ₆ ) alkylidene chain, where up to two methylene groups of the X residue are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR ', -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, - NR'CO-, -S-, -SO-, -SO ₂ -, -NR'-, -SO ₂ NR'-, -NR'SO ₂ - or -NR'SO ₂ NR'-;

R ^X independently means R ', a halogen atom, NO ₂ , CN, CF ₃ or OCF ₃ ;

R ⁶ means a hydrogen atom, CF ₃ , -OR ', -SR' or an optionally substituted C _1-6 aliphatic group;

R ⁷ means a hydrogen atom or a C _1-6 aliphatic group optionally substituted with —X — R ^X ;

R 'is independently selected from a hydrogen atom or an optionally substituted group selected from a (C ₁ -C ₆ ) aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen atoms oxygen or sulfur, or an 8-12 membered saturated, partially unsaturated or completely unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms; or two existing R 'radicals taken together with the atom (s) to which they are bonded form an optionally substituted 3-12 membered saturated, partially unsaturated or completely unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur atoms.

According to some other embodiments, provided are compounds of formula (I):

or their pharmaceutically acceptable salts, where:

Ar ¹ means a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms, where the above ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated or saturated ring where each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms, where Ar ¹ has m substituents, each independently selected from —WR ^W ;

W means a bond or an optionally substituted (C ₁ -C ₆ ) alkylidene chain, where up to two methylene groups of the W residue are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR ', -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, - NR'CO-, -S-, -SO-, -SO ₂ -, -NR'-, -SO ₂ NR'-, -NR'SO ₂ -, -NR'SO ₂ NR'-;

R ^W independently means R ', a halogen atom, NO ₂ , CN, CF ₃ or OCF ₃ ;

m is 0-5;

each of R ¹ , R ² , R ³ , R ⁴ and R ⁵ independently means —X — R ^X ;

X is a bond or an optionally substituted (C ₁ -C ₆ ) alkylidene chain, where up to two methylene groups of the X residue are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR ', -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, - NR'CO-, -S-, -SO-, -SO ₂ -, -NR'-, -SO ₂ NR'-, -NR'SO ₂ - or -NR'SO ₂ NR'-;

R ^X independently means R ', a halogen atom, NO ₂ , CN, CF ₃ or OCF ₃ ;

R ⁶ means a hydrogen atom, CF ₃ , -OR ', -SR' or an optionally substituted (C ₁ -C ₈ ) aliphatic group;

R ⁷ means a hydrogen atom or a (C ₁ -C ₆ ) aliphatic group optionally substituted with —X — R ^X ;

R 'is independently selected from a hydrogen atom or an optionally substituted group selected from a (C ₁ -C ₈ ) aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen atoms oxygen or sulfur, or an 8-12 membered saturated, partially unsaturated or completely unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms; or two existing R 'radicals taken together with the atom (s) to which they are bonded form an optionally substituted 3-12 membered saturated, partially unsaturated or completely unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur atoms;

provided that:

i) when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} hydrogen, then Ar ^{1 is} not phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 2,6-dichlorophenyl , 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5-dicarboxyphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro -4-methylphenyl, 3-carboxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-ethoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 3,4-dimethylphenyl, 2-ethylphenyl-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl-4-phenyl ;

ii) when R ¹ , R ² , R ³ , R ⁵ , R ⁶ and R ^{7 are} hydrogen and R ⁴ is methoxy, then Ar ^{1 is} not 2-fluorophenyl or 3-fluorophenyl;

iii) when R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} hydrogen, R ² is 1,2,3,4-tetrahydroisoquinolin-1-ylsulfonyl, then Ar ^{1 is} not 3-trifluoromethylphenyl;

iv) when R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{7 are} hydrogen, R ⁶ is methyl, then Ar ^{1 is} not phenyl;

v) when R ¹ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} hydrogen, R ² and R ³ taken together are methylenedioxy, then Ar ^{1 is} not 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4 -carboethoxyphenyl, 6-ethoxybenzothiazol-2-yl, 6-carboethoxybenzothiazol-2-yl, 6-halogenbenzothiazol-2-yl, 6-nitrobenzothiazol-2-yl or 6-thiocyanobenzothiazol-2-yl;

vi) when R ¹ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} hydrogen, R ² and R ³ taken together are methylenedioxy, then Ar ^{1 is} not 4-substituted phenyl, where the above substituent is —SO ₂ NHR ^XX , R ^XX means 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl;

vii) when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} hydrogen, then Ar ^{1 is} not thiazol-2-yl, 1H-1,2,4-triazol-3-yl or 1H-1,3,4-triazol-2-yl;

viii) when R ¹ , R ² , R ³ , R ⁵ , R ⁶ and R ^{7 are} hydrogen and R ⁴ is CF ₃ , OMe, a chlorine atom, SCF ₃ or OCF ₃ , then Ar ^{1 is} not 5-methyl-1 , 2-oxazol-3-yl, thiazol-2-yl, 4-fluorophenyl, pyrimidin-2-yl, 1-methyl-1,2- (1H) -pyrazol-5-yl, pyridin-2-yl, phenyl , N-methylimidazol-2-yl, imidazol-2-yl, 5-methylimidazol-2-yl, 1,3-oxazol-2-yl or 1,3,5- (1H) -triazol-2-yl;

ix) when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom, then Ar ^{1 is} not pyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl 4-methoxy-6-methyl-1,3,5-triazin-2-yl, 5-bromopyridin-2-yl, pyridin-2-yl or 3,5-dichloropyridin-2-yl;

x) when R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁷ are each a hydrogen atom, R ⁶ is hydroxyl, then Ar ^{1 is} not 2,6-dichloro-4-aminosulfonylphenyl;

xi) when R ² or R ³ is optionally substituted N-piperazyl, N-piperidyl or N-morpholinyl, then Ar ^{1 is} not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2- sludge or indazolyl;

xii) when R ² is an optionally substituted cyclohexylamino group, then Ar ¹ is not optionally substituted phenyl, pyridyl or thiadiazolyl;

xiii) Ar ¹ is not optionally substituted with tetrazolyl;

xiv) when R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom and R ¹ and R ^{3 are} both CF ₃ , chloro, methyl or methoxy, then Ar ^{1 is} not 4,5- dihydro-1,3-thiazol-2-iom, tizol-2-yl or [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] phenyl;

xv) when R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom and Ar ¹ is thiazol-2-yl, then neither R ² nor R ³ is isopropyl, chlorine or CF ₃ ;

xvi) when Ar ¹ is 4-methoxyphenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, phenyl or 3-chlorophenyl, then:

a) when R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ each represents a hydrogen atom, then R ^{3 is} not a methoxy group; or

b) when R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each represents a hydrogen atom, then R ^{2 is} not chlorine; or

c) when R ¹ , R ² , R ³ , R ⁵ , R ^6, and R ⁷ are each a hydrogen atom, then R ^{4 is} not a methoxy group; or

d) when R ¹ , R ³ , R ⁴ , R ⁶ and R ⁷ are each a hydrogen atom and R ⁵ is ethyl, then R ^{2 is} not a chlorine atom;

e) when R ¹ , R ² , R ⁴ , R ⁵ , R ^6, and R ⁷ are each a hydrogen atom, then R ^{3 is} not a chlorine atom;

xvii) when R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom and R ² is CF ₃ or OCF ₃ , then Ar ^{1 is} not [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] phenyl;

xviii) when R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each a hydrogen atom and R ³ is a hydrogen atom or CF ₃ , then Ar ^{1 is} not phenyl substituted with —OCH ₂ CH ₂ phenyl , -OCH ₂ CH ₂ - (2-trifluoromethylphenyl), -OCH ₂ CH ₂ - (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) or substituted 1H-pyrazol-3-yl;

and

xix) the following two connections are excluded:

2. Compounds and definitions

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

The term "ABC transporter", as used herein, means a protein-ABC transporter or fragment thereof, comprising at least one binding domain, where the aforementioned protein or fragment thereof is in vivo or in vitro. The term “binding domain”, as used herein, means a domain in an ABC transporter that can bind to a modulator; see, for example, Hwang TC et al., J. Gen. Physiol., 111 (3), 477-490 (1998).

The term “CFTR”, as used herein, means a cystic fibrosis transmembrane conductivity regulator or mutation thereof capable of regulatory activity, including, but not limited to, ΔF508-CFTR and G551D-CFTR (see, for example, http: // www. genet.sickkids.on.ca/cftr/ regarding CFTR mutations).

The term “modulating,” as used herein, means increasing or decreasing due to a measurable amount.

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

As described herein, compounds of the invention may be optionally substituted with one or more substituents, as generally illustrated above or exemplified by specific classes, subclasses, and types of the invention. It should be understood that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted”. Usually, the term "substituted", which is preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with a radical of the indicated substituent. Unless otherwise indicated, an optionally substituted group may contain a substituent at any position of a group that may be substituted, and when more than one position in any given structure may be substituted by more than one substituent selected from said group, this substituent may be either one and the same, or another in any position. The combinations of substituents provided according to the present invention are preferably those which result in the formation of stable or chemically possible compounds. The term “stable,” as used herein, refers to compounds that do not substantially change when they are subject to conditions that are acceptable in their preparation, detection, and preferably their conversion, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable or chemically feasible compound is a compound that does not substantially change when it is maintained at a temperature of 40 ° C or lower, in the absence of moisture, or in other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means a linear (ie, unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more unsaturation elements, or monocyclic or bicyclic a hydrocarbon that is fully saturated or that contains one or more unsaturations, but which is not aromatic (also referred to in this description as carbocycle "" cycloaliphatic "or" cycloalkyl "), that has a single binding site with the rest of the molecule. Unless otherwise indicated, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. According to still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms and, according to still other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, the term “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic (C ₃ -C ₈ ) hydrocarbon or a bicyclic or tricyclic (C ₈ -C ₁₄ ) hydrocarbon that is fully saturated or which contains one or more unsaturation elements, but which is not aromatic, which has one binding site to the rest of the molecule, where any single ring in the above bicyclic ring system is 3-7 membered. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and their "hybrids" such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicycloalkyl (e.g. decalin), bridged bicycloalkyl, such as norbornyl or [2,2,2] bicyclooctyl, or bridged tricycloalkyl, such as adamantyl.

The term “heteroaliphatic”, as used herein, means aliphatic groups where one or two carbon atoms are independently replaced by one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon. Heteroaliphatic residues may be substituted or unsubstituted, branched or unbranched, cyclic or alicyclic and include “heterocyclic”, “heterocyclic”, “heterocycloaliphatic” or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic” or “heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems in which one or more members of the ring are independently selected heteroatoms. In some embodiments, a “heterocycle”, “heterocyclyl”, “heterocycloaliphatic” or “heterocyclic” includes from three to fourteen ring members, where one or more ring members are a heteroatom independently selected from oxygen, sulfur, nitrogen or phosphorus atoms, and each ring in the system is 3-7 membered.

The term “heteroatom” means one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; a quaternized form of any basic nitrogen or a substituted nitrogen of a heterocycle, for example, N (as in 3.4 -dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)).

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

The term “alkoxy” or “thioalkyl,” as used herein, refers to an alkyl group, as defined above, bonded to the main carbon chain through an oxygen atom (“alkoxy”) or a sulfur atom (“thioalkyl”).

The terms “haloaliphatic” and “haloalkoxy” mean an aliphatic or alkoxy group, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br or I. Examples of halogen-aliphatic groups include —CHF ₂ , —CH ₂ F, —CF ₃ , —CF ₂ -, or perhaloalkyl, such as —CF ₂ CF ₃ .

The term “aryl”, used individually or as part of a larger residue, as in “aralkyl,” “aralkoxy, or“ aryloxyalkyl, ”refers to monocyclic, bicyclic, and tricyclic ring systems comprising a total of five to fourteen ring members, where at least at least one ring in the system is aromatic and where each ring in the system is 3-7 membered. The term “aryl” may be used interchangeably with the term “aryl ring”. The term “aryl” also refers to heteroaryl ring systems as described hereinbelow.

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

Aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy, and the like) may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl are selected from a halogen atom; -R ^o ; -OR ^o ; -SR ^o ; 1,2-methylenedioxy groups; 1,2-ethylenedioxy groups; phenyl (Ph) optionally substituted with R ^o ; —O (Ph) optionally substituted with R ^o ; - (CH ₂ ) _1-2 (Ph) optionally substituted with R ^o ; —CH = CH (Ph) optionally substituted with R ^o ; -NO ₂ ; -CN; -N (R ^o ) ₂ ; -NR ^o C (O) R ^o ; -NR ^o C (O) N (R ^o ) ₂ ; -NR ^o CO ₂ R ^o ; -NR ^o NR ^o C (O) R ^o ); -NR ^o NR ^o C (O) N (R ^o ) ₂ ; -NR ^o NR ^o CO ₂ R ^o ; -C (O) C (O) R ^o ; -C (O) CH ₂ C (O) R ^o ; -CO ₂ R ^o ; -C (O) R ^o ; -C (O) N (R ^o ) ₂ ; -OC (O) N (R ^o ) ₂ ; -S (O) ₂ R ^o ; -SO ₂ N (R ^o ) ₂ ; -S (O) R ^o ; -NR ^o SO ₂ N (R ^o ) ₂ ; -NR ^o SO ₂ R ^o ; -C (= S) N (R ^o ) ₂ ; —C (═NH) —N (R ^o ) ₂ or - (CH ₂ ) _0-2 NHC (O) R ^o , where each independently available R ^{o is} selected from a hydrogen atom, an optionally substituted C _1-6 aliphatic group, unsubstituted A 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O (Ph) or —CH ₂ (Ph), or, in spite of the above definition, two independently available R ^o in the same substituent or in different substituents taken together atom (s) with whom (which) is connected, each group R ^o, form a 3-8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatom ma independently selected from nitrogen, oxygen or sulfur. Optional substituents on the aliphatic group of R ^o are selected from NH _2, NH (C _1-4 aliphatic), N (C ₁ - ₄ aliphatic) _2, halogen, C _1-4 aliphatic, OH, O (C _1-4 aliphatic group), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic group), O (halogen-C _1-4 aliphatic group) or halogen (C _1-4 aliphatic group), where each of the above With ₁ to ₄ aliphatic groups, R ^o is unsubstituted.

An aliphatic or heteroaliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on a saturated carbon atom of an aliphatic or heteroaliphatic group or a non-aromatic heterocyclic ring are selected from those listed above for an unsaturated carbon atom of an aryl or heteroaryl group, and further include the following: = O, = S, = NNHR *, = NN (R *) ₂ , = NNHC (O) R *, = NNHCO ₂ (alkyl), = NNHSO ₂ (alkyl) or = NR *, where each R * is independently selected from a hydrogen atom or an optionally substituted C _1-6 aliphatic group. Optional substituents for the R * aliphatic group are selected from NH ₂ , NH (C _1-4 aliphatic group), N (C _1-4 aliphatic group) ₂ , a halogen atom, C _1-4 aliphatic group, OH, O (C _{1 -4} aliphatic group), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic group), O (halogen-C _1-4 aliphatic group) or halogen (C _1-4 aliphatic group), where each of the above C _1-4 aliphatic groups, R ^* is unsubstituted.

Optional substituents on the nitrogen atom of the non-aromatic heterocyclic ring are selected from —R ⁺ , —N (R ⁺ ) ₂ , —C (O) R ⁺ , —CO ₂ R *, —C (O) C (O) R ⁺ , —C (O) CH ₂ C (O) R ⁺ , -SO ₂ R ⁺ , -SO ₂ N (R ⁺ ) ₂ , -C (= S) N (R ⁺ ) ₂ , -C (= NH) N (R ⁺ ) ₂ or —NR ⁺ SO ₂ R ⁺ , where R ⁺ is a hydrogen atom, an optionally substituted C _1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted —O (Ph), an optionally substituted —CH ₂ (Ph), optionally substituted - (CH ₂ ) _1-2 (Ph), optionally substituted —CH = CH (Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring containing one to four heteroatoms independently selected from oxygen, nitrogen or sulfur atoms, or, in spite of the above definition, two independently available R ⁺ , in the same substituent or in different substituents taken together with the atom (s) to which each R ⁺ group is attached form a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or EASURES. Optional substituents in the aliphatic group or the phenyl ring R ⁺ are selected from NH ₂ , NH (C _1-4 aliphatic group), N (C _1-4 aliphatic group) ₂ , halogen atom, C _1-4 aliphatic group, OH, O ( C _1-4 aliphatic group), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic group), O (halogen-C _1-4 aliphatic group) or halogen-C _1-4 aliphatic group, where each of the above C _1-4 aliphatic R ⁺ groups is unsubstituted.

The term "alkylidene chain" refers to a linear or branched carbon chain, which may be fully saturated or include one or more elements of unsaturation and has two points of attachment to the rest of the molecule. The term “spirocycloalkylidene” refers to a carbocyclic ring that may be fully saturated or include one or more elements of unsaturation and has two points of attachment at the same carbon atom of the ring to the rest of the molecule.

, эти два имеющихся R^o, взятые вместе с атомами кислорода, с которыми они связаны, образуют конденсированное 6-членное кислородсодержащее кольцо:

. Следует принимать во внимание, что может быть получено множество других колец, когда два независимых имеющихся R^o (или R⁺, или любая другая переменная, также определяемая в данном описании) объединены вместе с атомом(атомами), с которым (которыми) связана каждая переменная, и что примеры, подробно указанные выше, не ограничивают объема изобретения.As described above in detail, in some embodiments, the implementation of two independent available R ^o (or R ⁺ , or any other variable also defined in this description), taken together with the atom (s) to which (each) each variable is associated, form 3 An 8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms. Specific rings that are formed when two independent, available R ^o (or R ⁺ , or any other variable also defined in this description) are combined together with the atom (s) to which each variable is associated, include, but are not limited to by them, the following: a) two independent available R ^o (or R ⁺ , or any other variable also defined in this description) that are associated with the same atom and taken together with this atom form a ring, for example, N ( R ^o) _2, where both the existing R ^o, taken together with the nitrogen atom to form t piperidin-1-yl, piperazin-1-yl or morpholin-4-yl group; and b) two independent available R ^o (or R ⁺ , or any other variable also defined in this description) that are associated with different atoms and taken together with both of these atoms form a ring, for example, where the phenyl group is replaced by two available OR ^o :

, these two available R ^o , taken together with the oxygen atoms to which they are bonded, form a condensed 6-membered oxygen-containing ring:

. It should be borne in mind that many other rings can be obtained when two independent available R ^o (or R ⁺ , or any other variable also defined in this description) are combined with the atom (s) to which each a variable, and that the examples detailed above do not limit the scope of the invention.

The connection of the substituent, for example, with a bicyclic ring system, as shown below, means that the substituent can be attached to any substitutable ring atom of any ring of the bicyclic ring system:

Unless otherwise indicated, it is also understood that the structures provided herein include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, the (Z) and (E) double bond isomers and the conformational (Z) and (E) isomers). Therefore, individual stereochemical isomers, as well as mixtures of enantiomers, diastereomers and geometric (conformational) isomers of the compounds of the present invention are included in the scope of this invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of this invention. For example, when R ⁵ in the compounds of formula (I) means a hydrogen atom, the compounds of formula (I) may exist as tautomers:

Additionally, unless otherwise indicated, it is also understood that the structures provided herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having these structures, with the exception of replacing hydrogen with deuterium or tritium or replacing carbon with ¹³ C or ¹⁴ C enriched carbon, are included in the scope of the present invention. Such compounds are useful, for example, as analytical tools or sensors in biological analyzes.

3. Description of examples of compounds

In some embodiments, implementation of the present invention Ar ¹ selected from:

where ring A ₁ is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms; or

A ₁ and A ₂ together represent an 8-14 membered aromatic, bicyclic or tricyclic aryl ring, where each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms.

In some embodiments, implementation A ₁ means an optionally substituted 6-membered aromatic ring having 0-4 heteroatoms, where the above heteroatom means nitrogen. In some embodiments, A ₁ is optionally substituted phenyl. Or A ₁ is optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl. Or A ₁ is optionally substituted pyrazinyl or triazinyl. Or A ₁ is optionally substituted pyridyl.

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

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

In some embodiments, implementation A ₂ means an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms, where the above heteroatom means nitrogen, oxygen or sulfur. In some embodiments, A ₂ is an optionally substituted 5 membered aromatic ring having 1 to 2 nitrogen atoms. In certain embodiments, A ₂ is optionally substituted pyrrolyl.

In some embodiments, A ₂ is an optionally substituted, 5-7 membered, saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, sulfur, or oxygen. Examples of such rings include piperidyl, piperazyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, etc.

In some embodiments, A ₂ is an optionally substituted, 5-10 membered, saturated or unsaturated carbocyclic ring. In one embodiment, A ₂ means an optionally substituted, 5-10 membered, saturated carbocyclic ring. Examples of such rings include cyclohexyl, cyclopentyl, etc.

In some embodiments, ring A _{2 is} selected from:

where the ring A _{2 is} condensed with the ring A ₁ at two adjacent ring atoms.

In other embodiments, W is a bond or an optionally substituted C _1-6 alkylidene chain, wherein one or two methylene groups are optionally and independently substituted with O, NR ′, S, SO, SO ₂ or COO, CO, SO ₂ NR ′, NR 'SO ₂ , C (O) NR', NR'C (O), OC (O), OC (O) NR ', and R ^W is R' or halogen. In still other embodiments, each of WR ^W independently means —C ₁ -C ₃ alkyl, C ₁ -C ₃ perhaloalkyl, —O (C ₁ -C ₃ alkyl), —CF ₃ , —OCF ₃ , —SCF ₃ , - F, —Cl, —Br or —COOR ′, —COR ′, —O (CH ₂ ) ₂ N (R ′) (R ′), —O (CH ₂ ) N (R ′) (R ′), - CON (R ') (R'), - (CH ₂ ) ₂ OR ', - (CH ₂ ) OR', optionally substituted aromatic monocyclic or bicyclic ring, optionally substituted arylsulfone, optionally substituted 5-membered heteroaryl ring, -N ( R ') (R'), - (CH ₂ ) ₂ N (R ') (R') or - (CH ₂ ) N (R ') (R').

In some embodiments, m is 0 or m is 1, or m is 2. In some embodiments, m is 3. Still in other embodiments, m is 4.

In one embodiment, R ⁵ means X-R ^X. In some embodiments, R ⁵ is hydrogen or R ⁵ is an optionally substituted C _1-8 aliphatic group. In some embodiments, R ⁵ is an optionally substituted C _1-4 aliphatic group or R ⁵ is benzyl.

In some embodiments, R ⁶ is a hydrogen atom or R ⁶ is an optionally substituted C _1-8 aliphatic group. In some embodiments, R ⁶ is an optionally substituted C _1-4 aliphatic group. In certain other embodiments, R ⁶ is - (O-C _1-4 aliphatic group) or - (S-C _1-4 aliphatic group). Preferably, R ⁶ is —OMe or —SMe. In some other embodiments, R ⁶ is CF ₃ .

In one embodiment, according to the present invention, R ¹ , R ² , R ³ and R ⁴ simultaneously mean hydrogen. In another embodiment, R ⁶ and R ⁷ , both simultaneously, are hydrogen.

In another embodiment, according to the present invention, R ¹ , R ² , R ³ , R ⁴ and R ⁵ simultaneously mean hydrogen. In another embodiment, according to the present invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ simultaneously mean hydrogen.

In another embodiment of the present invention, R ² is X-R ^X , where X is SO ₂ NR'- and R ^X is R '; those. R ² is —SO ₂ N (R ′) ₂ . In one embodiment, the two R ′ taken together optionally form a substituted 5-7 membered ring having 0-3 additional heteroatoms selected from nitrogen, oxygen or sulfur atoms; or R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ simultaneously mean hydrogen, and R ² means SO ₂ N (R ') ₂ .

In some embodiments, X is a bond or an optionally substituted C _1-6 alkylidene chain, wherein one or two non-adjacent methylene groups are optionally and independently substituted with O, NR ′, S, SO ₂ or COO, CO, and R ^X is R ′ or halogen . In still other embodiments, each of XR ^X independently means —C _1-3 alkyl, —O (C _1-3 alkyl), —CF ₃ , —OCF ₃ , —SCF ₃ , —F, —Cl, —Br, OH , -COOR ', -COR', -O (CH ₂ ) ₂ N (R ') (R'), -O (CH ₂ ) N (R ') (R'), -CON (R ') (R '), - (CH ₂ ) ₂ OR', - (CH ₂ ) OR ', optionally substituted phenyl, -N (R') (R '), - (CH ₂ ) ₂ N (R') (R ') or - (CH ₂ ) N (R ′) (R ′).

In some embodiments, R ⁷ is a hydrogen atom. In a separate other embodiment, R ⁷ means a linear or branched C _1-4 aliphatic group.

In some embodiments, R ^{W is} selected from the group consisting of a halogen atom, a cyano group, CF ₃ , CHF ₂ , OCHF ₂ , Me,

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

O-fluorophenyl, O-difluorophenyl, O-methoxyphenyl, O-tolyl,

O-benzyl, SMe, SCF ₃ , SCHF ₂ , SEt, CH ₂ CN, NH ₂ , NHMe, N (Me) ₂ , NHEt,

N (Et) ₂ , C (O) CH ₃ , C (O) Ph, C (O) NH ₂ , SPh, SO ₂ - (aminopyridyl),

SO ₂ NH ₂ , SO ₂ Ph, SO ₂ NHPh, SO ₂ —N-morpholino, SO ₂ —N-pyrrolidyl,

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

(cyclohexylmethylamino) methyl,

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

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

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

NHC (O) Ph, NHSO ₂ Me, 2-indolyl, 5-indolyl, —CH ₂ CH ₂ OH, —OCF ₃ ,

O- (2,3-dimethylphenyl), 5-methylfuryl, -SO ₂ -N-piperidyl,

2-tolyl, 3-tolyl, 4-tolyl, O-butyl, NHCO ₂ C (Me) ₃ , CO ₂ C (Me) ₃ ,

isopropenyl, n-butyl, O- (2,4-dichlorophenyl), NHSO ₂ PhMe,

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

2,5-dimethylpyrrolyl, NHCOCH ₂ C (Me) ₃ , O- (2-tert-butyl) phenyl,

2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-hydroxymethylphenyl,

4-dimethylaminophenyl, 2-trifluoromethylphenyl,

3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-cyanomethylphenyl,

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-OCF ₃ -phenyl, 3-trifluoromethoxyphenyl,

4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 4-phenoxyphenyl,

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

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

4-fluorophenyl, 3-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl,

2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,

3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,

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

3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxycarbonylphenyl,

4-methoxycarbonylphenyl, 3-isopropyloxycarbonylphenyl,

3-acetamidophenyl, 4-fluoro-3-methylphenyl, 4-methanesulfinyl phenyl,

4-methanesulfonylphenyl,

4-N- (2-N, N-dimethylaminoethyl) carbamoylphenyl, 5-acetyl-2-thienyl,

2-benzothienyl, 3-benzothienyl, furan-3-yl, 4-methyl-2-thienyl,

5-cyano-2-thienyl, N'-phenylcarbonyl-N-piperazinyl, -NHCO ₂ Et,

-NHCO ₂ Me, N-pyrrolidinyl, -NHSO ₂ (CH ₂ ) ₂ N-piperidine,

-NHSO ₂ (CH ₂ ) ₂ N-morpholine, -NHSO ₂ (CH ₂ ) ₂ N (Me) ₂ , COCH ₂ N (Me) COCH ₂ NHMe,

—CO ₂ Et, O-propyl, —CH ₂ CH ₂ NHCO ₂ C (Me) ₃ , hydroxyl, aminomethyl,

pentyl, adamantyl, cyclopentyl, ethoxyethyl, C (Me) ₂ CH ₂ OH,

C (Me) ₂ CO ₂ Et, -CHOHMe, CH ₂ CO ₂ Et, -C (Me) ₂ CH ₂ NHCO ₂ C (Me) ₃ , O (CH ₂ ) ₂ OEt,

O (CH ₂ ) ₂ OH, CO ₂ Me, hydroxymethyl, 1-methyl-1-cyclohexyl,

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

C (Et) ₃ , CONHCH ₂ CH (Me) ₂ , 2-aminomethylphenyl, ethenyl,

1-piperidinylcarbonyl, ethynyl, cyclohexyl,

4-methylpiperidinyl, -OCO ₂ Me, -C (Me) ₂ CH ₂ NHCO ₂ CH ₂ CH (Me) ₂ ,

-C (Me) ₂ CH ₂ NHCO ₂ CH ₂ CH ₂ CH ₃ , -C (Me) ₂ CH ₂ NHCO ₂ Et, -C (Me) ₂ CH ₂ NHCO ₂ Me,

-C (Me) ₂ CH ₂ NHCO ₂ CH ₂ C (Me) ₃ , -CH ₂ NHCOCF ₃ , -CH ₂ NHCO ₂ C (Me) ₃ ,

-C (Me) ₂ CH ₂ NHCO ₂ (CH ₂ ) ₃ CH ₃ , C (Me) ₂ CH ₂ NHCO ₂ (CH ₂ ) ₂ OMe, C (OH) (CF ₃ ) ₂ ,

-C (Me) ₂ CH ₂ NHCO ₂ CH ₂ -tetrahydrofuran-3-yl, C (Me) ₂ CH ₂ O (CH ₂ ) ₂ OMe or

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

In one embodiment, R ′ is a hydrogen atom.

In one embodiment, R 'is C ₁ -C ₈ aliphatic group optionally substituted with up to 3 substituents selected from halogen, CN, CF _3, CHF _2, OCF ₃ or OCHF _2, wherein two of the methylene groups above C _1- C ₈ aliphatic groups are optionally replaced by -CO-,

-CONH (C ₁ -C ₄ alkyl) -, -CO ₂ -, -OCO-, -N (C ₁ -C ₄ alkyl) CO ₂ -, -O-,

-N (C ₁ -C ₄ alkyl) CON (C ₁ -C ₄ alkyl) -, -OCON (C ₁ -C ₄ alkyl) -,

-N (C ₁ -C ₄ alkyl) CO-, -S-, -N (C ₁ -C ₄ alkyl) -, -SO ₂ N (C ₁ -C ₄ alkyl) -,

—N (C ₁ -C ₄ alkyl) SO ₂ - or —N (C ₁ -C ₄ alkyl) SO ₂ N (C ₁ -C ₄ alkyl) -.

In one embodiment, R ′ is a 3-8 membered saturated, partially unsaturated or completely unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms, where R ′ is optionally substituted with up to 3 substituents selected from halogen atom, CN, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ or C ₁ -C ₆ alkyl, where two methylene groups of the above C ₁ -C ₆ alkyl are optionally replaced by -CO-, -CONH (C ₁ -C ₄ alkyl) -, -CO ₂ -, -OCO-,

-N (C ₁ -C ₄ alkyl) CO ₂ -, -O-, -N (C ₁ -C ₄ alkyl) CON (C ₁ -C ₄ alkyl) -,

-OCON (C ₁ -C ₄ alkyl) -, -N (C ₁ -C ₄ alkyl) CO-, -S-, -N (C ₁ -C ₄ alkyl) -,

-SO ₂ N (C ₁ -C ₄ alkyl) -, N (C ₁ -C ₄ alkyl) SO ₂ - or

-N (C ₁ -C ₄ alkyl) SO ₂ N (C ₁ -C ₄ alkyl) -.

In one embodiment, R ′ is an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R ′ is optionally substituted with up to 3 substituents selected from halogen, CN, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ or C ₁ -C ₆ alkyl, where two methylene groups of the above C ₁ -C ₆ alkyl are optionally replaced with -CO-, -CONH (C ₁ -C ₄ alkyl ) -, -CO ₂ -, -OCO-,

-N (C ₁ -C ₄ alkyl) CO ₂ -, -O-, -N (C ₁ -C ₄ alkyl) CON (C ₁ -C ₄ alkyl) -,

-OCON (C ₁ -C ₄ alkyl) -, -N (C ₁ -C ₄ alkyl) CO-, -S-, -N (C ₁ -C ₄ alkyl) -,

-SO ₂ N (C ₁ -C ₄ alkyl) -, N (C ₁ -C ₄ alkyl) SO ₂ - or

-N (C ₁ -C ₄ alkyl) SO ₂ N (C ₁ -C ₄ alkyl) -.

In one embodiment, the two available R ′, taken together with the atom (s) to which they are bonded, form an optionally substituted 3-12 membered saturated, partially unsaturated or completely unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms, where R 'is optionally substituted with up to 3 substituents selected from a halogen atom, CN, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ or C ₁ -C ₆ alkyl, where two methylene groups of the above C ₁ -C ₆ alkyl are optionally replaced with -CO-, -CONH (C ₁ -C ₄ alkyl) -, -CO ₂ -, -OCO-,

-N (C ₁ -C ₄ alkyl) CO ₂ -, -O-, -N (C ₁ -C ₄ alkyl) CON (C ₁ -C ₄ alkyl) -,

-OCON (C ₁ -C ₄ alkyl) -, -N (C ₁ -C ₄ alkyl) CO-, -S-, -N (C ₁ -C ₄ alkyl) -,

-SO ₂ N (C ₁ -C ₄ alkyl) -, N (C ₁ -C ₄ alkyl) SO ₂ - or

-N (C ₁ -C ₄ alkyl) SO ₂ N (C ₁ -C ₄ alkyl) -.

According to one embodiment, the present invention relates to compounds of formula IIA or formula IIB :

According to another variant implementation, the present invention relates to compounds of formula IIIA , formula IIIB , formula IIIC , formula IIID or formula IIIE :

where each of X ₁ , X ₂ , X ₃ , X ₄ and X _{5 are} independently selected from CH or N; and X ₆ means O, S or NR '.

In one embodiment, compounds of Formula IIIA , Formula IIIB , Formula IIIC , Formula IIID, or Formula IIIE have y occurrences of X — R ^X where y is 0-4; or y is 1; or y is 2.

In some embodiments of Formula IIIA, X ₁ , X ₂ , X ₃ , X _4, and X ₅ , taken together with WR ^W and m, are optionally substituted phenyl.

In some embodiments of Formula IIIA, X ₁ , X ₂ , X ₃ , X _4, and X ₅ taken together mean an optionally substituted ring selected from:

In some embodiments, the implementation of formula IIIB , formula IIIC , formula IIID or formula IIIE X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ taken together with ring A ₂ , mean an optionally substituted ring selected from:

In some embodiments, R ^{W is} selected from the group consisting of halogen atom, cyano, CF ₃ , CHF ₂ , OCHF ₂ , Me, Et, CH (Me) ₂ , CHMeEt, n-propyl, tert-butyl, OMe, OEt, OPh, O-fluorophenyl, O-difluorophenyl, O-methoxyphenyl, O-tolyl, O-benzyl, SMe, SCF ₃ , SCHF ₂ , SEt, CH ₂ CN, NH ₂ , NHMe, N (Me) ₂ , NHEt, N (Et) ₂ , C (O) CH ₃ , C (O) Ph, C (O) NH ₂ , SPh, SO ₂ - (aminopyridyl), SO ₂ NH ₂ , SO ₂ Ph, SO ₂ NHPh, SO ₂ - N-morpholino groups, SO ₂ -N-pyrrolidyl, N-pyrrolyl, N-morpholino groups, 1-piperidyl, phenyl, benzyl, (cyclohexylmethylamino) methyl, 4-methyl-2,4-dihydropyrazol-3-one-2-yl, benzimidazol-2-yl, furan-2-yl, 4-methyl-4H- [l, 2,4] triazol-3-yl, 3- (4'-chlorfe nyl) - [l, 2,4] oxadiazol-5-yl, NHC (O) Me, NHC (O) Et, NHC (O) Ph or NHSO ₂ Me.

In some embodiments, X and R ^X , taken together, are Me, Et, halogen, CN, CF ₃ , OH, OMe, OEt, SO ₂ N (Me) (fluorophenyl), SO ₂ - (4-methylpiperidin-1- il) or SO ₂ -N-pyrrolidinyl.

According to another embodiment, the present invention relates to compounds of formula IVA , formula IVB or formula IVC :

In one embodiment, compounds of formula IVA , formula IVB, and formula IVC have X — R ^X at occurrences of the substituent, where y is 0-4; or y is 1; or y is 2.

In one embodiment, the present invention relates to compounds of formula IVA , formula IVB and formula IVC , wherein X is a bond and R ^X is a hydrogen atom.

In one embodiment, the present invention relates to compounds of formula IVA , formula IVB, and formula IVC , wherein A ₂ ring is an optionally substituted, saturated, unsaturated, or aromatic 7-membered ring having 0-3 heteroatoms selected from O, S, or N atoms Examples of rings include azepanil, 5,5-dimethylazepanyl, etc.

In one embodiment, the present invention relates to compounds of formula IVB and formula IVC , wherein A ₂ ring is an optionally substituted, saturated, unsaturated, or aromatic 6 membered ring having 0-3 heteroatoms selected from O, S, or N atoms. Examples of rings include piperidinyl, 4,4-dimethylpiperidinyl, etc.

In one embodiment, the present invention relates to compounds of formula IVB and formula IVC , wherein A ₂ ring is an optionally substituted, saturated, unsaturated, or aromatic 5-membered ring having 0-3 heteroatoms selected from O, S, or N.

In one embodiment, the present invention relates to compounds of formula IVB and formula IVC , wherein A ₂ ring is an optionally substituted 5 membered ring with one nitrogen atom, for example pyrrolyl or pyrrolidinyl.

In one embodiment of formula IVA , the following compound of formula VA-1 is provided :

where each of WR ^W2 and WR ^{W4 is} independently selected from a hydrogen atom, CN, CF ₃ , halogen, linear or branched C ₁ -C ₆ alkyl, 3-12 membered cycloaliphatic group, phenyl, C ₅ -C ₁₀ heteroaryl or C ₃ -C ₇ heterocyclic groups, where the aforementioned heteroaryl or heterocyclic group has up to 3 heteroatoms selected from O, S or N atoms, where the above WR ^W2 and WR ^{W4 are} independently and optionally substituted with up to three substituents selected from the group consisting of -OR ', -CF ₃ , -OCF ₃ , SR', S (O) R ', SO ₂ R', -SCF ₃ , halogen, CN, -COOR ', -COR', -O (CH ₂ ) ₂ N ( R ') (R'), -O (CH ₂ ) N (R ') (R'), -CON (R ') (R'), - ( CH ₂ ) ₂ OR ', - (CH ₂ ) OR', CH ₂ CN, optionally substituted phenyl or phenoxy groups, -N (R ') (R'), -NR'C (O) OR ', -NR'C (O) R ', - (CH ₂ ) ₂ N (R') (R ') or - (CH ₂ ) N (R') (R '); and

WR ^{W5 is} selected from the group consisting of hydrogen atom, —OH, NH ₂ , CN, CHF ₂ , NHR ′, N (R ′) ₂ , —NHC (O) R ′, —NHC (O) OR ′, NHSO ₂ R ', -OR', CH ₂ OH, CH ₂ N (R ') ₂ , C (O) OR', SO ₂ NHR ', SO ₂ N (R') ₂ or CH ₂ NHC (O) OR '; or WR ^W4 and WR ^W5 taken together form a 5-7 membered ring containing 0-3 heteroatoms selected from N, O and S atoms, wherein the above ring is optionally substituted with up to three WR ^W substituents.

In one embodiment, the compounds of formula VA-1 have the occurrence of a substituent X-R ^X , where y is 0-4. In one embodiment, y is 0.

In one embodiment, the present invention relates to compounds of formula VA-1 , wherein X is a bond and R ^X is a hydrogen atom.

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

each of WR ^W2 and WR ^{W4 is} independently selected from the group consisting of hydrogen atom, CN, CF ₃ , halogen atom, linear or branched C ₁ -C ₆ alkyl, 3-12 membered cycloaliphatic group or phenyl, where the above WR ^W2 and WR ^{W4 are} independently and optionally substituted with up to three substituents selected from the group consisting of —OR ′, —CF ₃ , —OCF ₃ , —SCF ₃ , halogen atom, —COOR ′, —COR ′, —O (CH ₂ ) ₂ N (R ') (R'), -O (CH ₂ ) N (R ') (R'), -CON (R ') (R'), - (CH ₂ ) ₂ OR ', - (CH ₂ ) OR ', optionally substituted phenyl, -N (R') (R '), -NR'C (O) OR', -NR'C (O) R ', - (CH ₂ ) ₂ N (R' ) (R ') or - (CH ₂ ) N (R') (R '); and

WR ^{W5 is} selected from the group consisting of a hydrogen atom, —OH, NH ₂ , CN, NHR ′, N (R ′) ₂ , —NHC (O) R ′, —NHC (O) OR ′, NHSO ₂ R ′, -OR ', CH ₂ OH, C (O) OR', SO ₂ NHR 'or CH ₂ NHC (O) O- (R').

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

WR ^W2 means a phenyl ring optionally substituted with up to three substituents selected from the group consisting of —OR ′, —CF ₃ , —OCF ₃ , SR ′, S (O) R ′, SO ₂ R ′, —SCF ₃ , halogen, CN, —COOR ′, —COR ′, —O (CH ₂ ) ₂ N (R ′) (R ′), —O (CH ₂ ) N (R ′) (R ′), —CON (R ′ ) (R '), - (CH ₂ ) ₂ OR', - (CH ₂ ) OR ', CH ₂ CN, optionally substituted phenyl or phenoxy groups, -N (R') (R '), -NR'C (O ) OR ', -NR'C (O) R', - (CH ₂ ) ₂ N (R ') (R') or - (CH ₂ ) N (R ') (R');

WR ^W4 is linear or branched C ₁ -C ₆ alkyl; and

WR ^W5 means OH.

In one embodiment, each of WR ^W2 and WR ^{W4 is} independently selected from CF ₃ or a halogen atom. In one embodiment, each of WR ^W2 and WR ^{W4 is} independently selected from a hydrogen atom, an optionally substituted linear or branched C ₁ -C ₆ alkyl. In certain embodiments, each of WR ^W2 and WR ^{W4 is} independently selected from optionally substituted n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl- 2- (ethoxycarbonyl) ethyl, 1,1-dimethyl-3- (tert-butoxycarbonylamino) propyl or n-pentyl.

In one embodiment, each of WR ^W2 and WR ^{W4 is} independently selected from an optionally substituted 3-12 membered cycloaliphatic group. Examples of embodiments of such cycloaliphatic groups include cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, [2,2,2] bicyclooctyl, [2,3,1] bicyclooctyl or [3,3,1] bicyclononyl.

In certain embodiments, WR ^W2 is a hydrogen atom and WR ^W4 is a linear or branched C ₁ -C ₆ alkyl. In certain embodiments, WR ^{W4 is} selected from methyl, ethyl, propyl, n-butyl, sec-butyl or tert-butyl.

In certain embodiments, WR ^W4 is a hydrogen atom and WR ^W2 is a linear or branched C ₁ -C ₆ alkyl. In certain embodiments, WR ^{W2 is} selected from methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl or n-pentyl.

In certain embodiments, each of WR ^W2 and WR ^W4 is a linear or branched C ₁ -C ₆ alkyl. In certain embodiments, each of WR ^W2 and WR ^{W4 is} selected from methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl or pentyl.

In one embodiment, WR ^{W5 is} selected from the group consisting of hydrogen atom, CHF ₂ , NH ₂ , CN, NHR ′, N (R ′) ₂ , CH ₂ N (R ′) ₂ , —NHC (O) R ′, -NHC (O) OR ', -OR', C (O) OR 'or SO ₂ NHR'; or WR ^W5 is —OR ′, for example, OH.

In certain embodiments, WR ^{W5 is} selected from the group consisting of a hydrogen atom, NH ₂ , CN, CHF ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) ( C ₁ -C ₆ alkyl), -CH ₂ NHC (O) O (C ₁ -C ₆ alkyl), -NHC (O) O (C ₁ -C ₆ alkyl), -OH, -O (C ₁ -C ₆ alkyl), C (O) O (C ₁ -C ₆ alkyl), CH ₂ O (C ₁ -C ₆ alkyl) or SO ₂ NH ₂ . In another embodiment, WR ^{W5 is} selected from the group consisting of —OH, OMe, NH ₂ , —NHMe, —N (Me) ₂ , —CH ₂ NH ₂ , CH ₂ OH, NHC (O) OMe, NHC (O) OEt, CN, CHF ₂ , —CH ₂ NHC (O) O (tert-butyl), —O- (ethoxyethyl), —O- (hydroxyethyl), —C (O) OMe, or —SO ₂ NH ₂ .

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

i) WR ^W2 is hydrogen;

ii) WR ^W4 means a linear or branched C ₁ -C ₆ alkyl or aliphatic monocyclic or bicyclic group; and

iii) WR ^{W5 is} selected from the group consisting of a hydrogen atom,

CN, CHF ₂ , NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ ,

-NHC (O) (C ₁ -C ₆ alkyl), -NHC (O) O (C ₁ -C ₆ alkyl),

-CH ₂ C (O) O (C ₁ -C ₆ alkyl), -OH, -O (C ₁ -C ₆ alkyl), C (O) O (C ₁ -C ₆ alkyl)

or SO ₂ NH ₂ .

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

i) WR ^W2 is a halogen atom, C ₁ -C ₆ alkyl, CF ₃ , CN or phenyl optionally substituted with up to 3 substituents selected from C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl) or an atom halogen;

ii) WR ^W4 is CF ₃ , a halogen atom, a C ₁ -C ₆ alkyl or a C ₆ -C ₁₀ cycloaliphatic group; and

iii) WR ^W5 is OH, NH ₂ , NH (C ₁ -C ₆ alkyl) or N (C ₁ -C ₆ alkyl).

In one embodiment, X-R ^X is at position 6 of the quinolinyl ring. In certain embodiments, X-R ^X taken together means C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl) or a halogen atom.

In one embodiment, X-R ^X is at position 5 of the quinolinyl ring. In certain embodiments, X-R ^X taken together means —OH.

In another embodiment, the present invention relates to compounds of formula VA-1 , where WR ^W4 and WR ^W5 , taken together, form a 5-7 membered ring containing 0-3 heteroatoms selected from N, O or S atoms, where the above ring optionally substituted with up to three WR ^W substituents.

In certain embodiments, WR ^W4 and WR ^W5 taken together form an optionally substituted, 5-7 membered, saturated, unsaturated, or aromatic ring containing 0 heteroatoms. In other embodiments, the implementation of WR ^W4 and WR ^W5 , taken together, form an optionally substituted, 5-7 membered ring containing 1-3 heteroatoms selected from N, O or S. In other embodiments, the implementation of WR ^W4 and WR ^W5 , taken together form an optionally substituted, saturated, unsaturated or aromatic 5-7 membered ring containing 1 nitrogen atom as a heteroatom. In certain other embodiments, the implementation of WR ^W4 and WR ^W5 , taken together, form an optionally substituted, 5-7 membered ring containing 1 oxygen atom as a heteroatom.

In another embodiment, the present invention relates to compounds of formula VA-2:

Where:

Y is CH ₂ , C (O) O, C (O) or S (O) ₂ ;

m is 0-4; and

X, R ^X , W and R ^W have the meanings as described above.

In one embodiment, compounds of formula VA-2 have y occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

In one embodiment, Y is C (O). In another embodiment, Y is C (O) O; or Y is S (O) ₂ ; or Y is CH ₂ .

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

In one embodiment, W is a bond.

In another embodiment, R ^W is a C ₁ -C ₆ aliphatic group, a halogen atom, CF ₃ or phenyl optionally substituted with C ₁ -C ₆ alkyl, a halogen atom, a cyano group or CF ₃ , where up to two methylene groups of the above C ₁ - C ₆ aliphatic groups or C ₁ -C ₆ alkyl are optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl. Examples of embodiments of WR ^W include methyl, ethyl, propyl, tert-butyl or 2-ethoxyphenyl.

In another embodiment, R ^W in YR ^W is a C _l -C ₆ aliphatic group optionally substituted with N (R ”) ₂ , where R” is a hydrogen atom, C _l -C ₆ alkyl or two R ”, taken together, form 5 -7 membered heterocyclic ring with 2 additional heteroatoms selected from O, S, or NR ′ atoms. Examples of such heterocycles include pyrrolidinyl, piperidyl, morpholinyl or thiomorpholinyl.

In another embodiment, the present invention relates to compounds of formula VA-3:

Where:

Q is W;

R ^Q means R ^W ;

m is 0-4;

n is 0-4; and

X, R ^X , W and R ^W have the meanings as described above.

In one embodiment, compounds of formula VA-3 have occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

In one embodiment, n is 0-2.

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

In one embodiment, QR ^Q , taken together, means a halogen atom, CF ₃ , OCF ₃ , CN, C ₁ -C ₆ aliphatic group, O-C ₁ -C ₆ aliphatic group, O-phenyl, NH (C ₁ -C ₆ aliphatic group) or N (C ₁ -C ₆ aliphatic group) ₂ , where the above aliphatic group and phenyl are optionally substituted with up to three substituents selected from C ₁ -C ₆ alkyl, O-C ₁ -C ₆ alkyl, a halogen atom , cyano groups, OH or CF ₃ , where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl are optionally replaced by —CO—, —CONR′—, —CO ₂ -, —OCO—, -NR'CO ₂ -, -O-, -NR'C ONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, SOR ', SO ₂ R', -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

Examples of QR ^Q include methyl, isopropyl, sec-butyl, hydroxymethyl, CF ₃ , NMe ₂ , CN, CH ₂ CN, fluorine atom, chlorine atom, OEt, OMe, SMe, OCF ₃ , OPh, C (O) OMe, C (O) O-iPr, S (O) Me, NHC (O) Me or S (O) ₂ Me.

In another embodiment, the present invention relates to compounds of formula VA-4:

where X, R ^X and R ^W have the meanings as described above.

In one embodiment, compounds of formula VA-4 have occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

In one embodiment, R ^W is a C ₁ -C ₁₂ aliphatic group, a C ₅ -C ₁₀ cycloaliphatic or C ₅ -C ₇ heterocyclic ring, wherein the above aliphatic group, cycloaliphatic or heterocyclic ring is optionally substituted with up to three substituents selected from C _l -C ₆ alkyl, halogen atom, cyano group, oxo group, OH or CF ₃ , where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl are optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'S O ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

Examples of R ^W include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, vinyl, cyanomethyl, hydroxymethyl, hydroxyethyl, hydroxybutyl, cyclohexyl, adamantyl or —C (CH ₃ ) _2- NHC (O) O-T, where T is C ₁ -C ₄ alkyl, methoxyethyl or tetrahydrofuranylmethyl.

In another embodiment, the present invention relates to compounds of formula VA-5:

Where:

m is 0-4; and

X, R ^X , W, R ^W and R 'are as defined above.

In one embodiment, the compounds of formula VA-5 have y occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

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

In another embodiment, both R ′ are a hydrogen atom; or one R ′ is a hydrogen atom and the other R ′ is C ₁ -C ₄ alkyl, for example methyl; or both R 'are C ₁ -C ₄ alkyl, for example methyl.

In another embodiment, m is 1 or 2, and R ^W is a halogen atom, CF ₃ , CN, C ₁ -C ₆ aliphatic group, O-C ₁ -C ₆ aliphatic group or phenyl, where the above aliphatic group and phenyl are optionally substituted up to three substituents selected from C ₁ -C ₆ alkyl, O-C ₁ -C ₆ alkyl, a halogen atom, cyano group, OH or CF ₃ , where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl is optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR 'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

Examples of embodiments of R ^W include a chlorine atom, CF ₃ , OCF ₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, propyloxy or 2-ethoxyphenyl.

In another embodiment, the present invention relates to compounds of formula VA-6:

Where:

ring B means a 5-7 membered monocyclic or bicyclic, heterocyclic or heteroaryl ring optionally substituted with up to n occurrences with the substituent —QR ^Q -, where n is 0-4 and Q and R ^Q are as defined above; and

Q, R ^Q , X, R ^X , W and R ^W have the meanings as described above.

In one embodiment, the compounds of formula VA-6 have y occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

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

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

In another embodiment, ring B means a 5-7 membered monocyclic heterocyclic ring having up to 2 heteroatoms selected from O, S or N atoms, optionally substituted, up to n occurrences, with a -QR ^Q substituent. Examples of heterocycles include N-morpholinyl, N-piperidinyl, 4-benzoylpiperazin-1-yl, pyrrolidin-1-yl or 4-methylpiperidin-1-yl.

In another embodiment, ring B means a 5-6 membered monocyclic, heteroaryl ring having up to 2 heteroatoms selected from O, S or N atoms, optionally substituted, up to n occurrences, with a -QR ^Q substituent. Such particular rings include benzimidazol-2-yl, 5-methylfuran-2-yl, 2,5-dimethylpyrrol-1-yl, pyridin-4-yl, indol-5-yl, indol-2-yl, 2,4- dimethoxypyrimidin-5-yl, furan-2-yl, furan-3-yl, 2-acylthien-2-yl, benzothiophen-2-yl, 4-methylthien-2-yl, 5-cyanothien-2-yl, 3- chloro-5-trifluoromethylpyridin-2-yl.

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

Where:

one of Q ₁ and Q ₃ is N (WR ^W ), and the other of Q ₁ and Q _{3 is} selected from O, S or N (WR ^W );

Q ₂ is C (O), CH ₂ —C (O), C (O) —CH ₂ , CH ₂ , CH ₂ —CH ₂ , CF ₂ or CF ₂ —CF ₂ ;

m is 0-3; and

X, W, R ^X and R ^W have the meanings as described above.

In one embodiment, compounds of formula V-B-1 have occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

In one embodiment, Q ₃ is N (WR ^W ); examples of WR ^W include a hydrogen atom, a C ₁ -C ₆ aliphatic group, a C (O) C ₁ -C ₆ aliphatic group, or a C (O) OC ₁ -C ₆ aliphatic group.

In another embodiment, Q ₃ is N (WR ^W ), Q ₂ is C (O), CH ₂ , CH _{2 is} CH ₂ , and Q ₁ is O.

In another embodiment, the present invention relates to compounds of formula V-B-2:

Where:

R ^W1 means a hydrogen atom or a C ₁ -C ₆ aliphatic group;

each of R ^W3 is a hydrogen atom or a C ₁ -C ₆ aliphatic group; or

both R ^W3 together form a C ₃ -C ₆ cycloalkyl or heterocyclic ring having up to two heteroatoms selected from O, S or NR 'atoms, where the above ring is optionally substituted with up to two WR ^W substituents;

m is 0-4; and

X, R ^X , W and R ^W have the meanings as described above.

In one embodiment, the compounds of formula V-B-2 have y occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

In one embodiment, WR ^W1 is a hydrogen atom, a C ₁ -C ₆ aliphatic group, a C (O) C ₁ -C ₆ aliphatic group, or a C (O) OC ₁ -C ₆ aliphatic group.

In another embodiment, each of R ^W3 is a hydrogen atom, C ₁ -C ₄ alkyl; or both R ^W3 taken together form a C ₃ -C ₆ cycloaliphatic group or a 5-7 membered heterocyclic ring having up to two heteroatoms selected from O, S or N atoms, where the above cycloaliphatic group or heterocyclic ring is optionally substituted up to three substituents selected from WR ^W1 . Such particular rings include cyclopropyl, cyclopentyl, optionally substituted piperidyl, etc.

In another embodiment, the present invention relates to compounds of formula V-B-3:

Where:

Q ₄ means a bond, C (O), C (O) O or S (O) ₂ ;

R ^W1 means a hydrogen atom or a C ₁ -C ₆ aliphatic group;

m is 0-4; and

X, W, R ^W and R ^X are as defined above.

In one embodiment, the compounds of formula V-B-3 have occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0.

In one embodiment, Q ₄ is C (O); or Q ₄ means C (O) O. In another embodiment, R ^W1 is C ₁ -C ₆ alkyl. Examples of R ^W1 include methyl, ethyl or tert-butyl.

In another embodiment, the present invention relates to compounds of formula V-B-4:

Where:

m is 0-4; and

X, R ^X , W and R ^W have the meanings as described above.

In one embodiment, the compounds of formula V-B-4 have y occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

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

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

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

Where:

A ₂ ring means phenyl or a 5-6 membered heteroaryl ring, where A ₂ ring and the phenyl ring fused to it together have up to 4 substituents independently selected from WR ^W ;

m is 0-4; and

X, W, R ^W and R ^X are as defined above.

In one embodiment, the compounds of formula V-B-5 have y occurrences of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

In one embodiment, ring A ₂ means an optionally substituted 5-membered ring selected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl or triazolyl.

In one embodiment, ring A ₂ means an optionally substituted 5-membered ring selected from pyrrolyl, pyrazolyl, thiadiazolyl, imidazolyl, oxazolyl or triazolyl. Examples of such rings include:

where the above ring is optionally substituted as described above.

In another embodiment, ring A ₂ is an optionally substituted 6 membered ring. Examples of rings include pyridyl, pyrazinyl or triazinyl. In another embodiment, the above ring is optionally substituted pyridyl.

In one embodiment, ring A ₂ is phenyl.

In another embodiment, ring A ₂ is pyrrolyl, pyrazolyl, pyridyl or thiadiazolyl.

Examples of W in the formula V-B-5 include a bond, C (O), C (O) O or C ₁ -C ₆ alkylene.

Examples of R ^W in the formula V-B-5 include a cyano group, a halogen atom, a C ₁ -C ₆ aliphatic group, a C ₃ -C ₆ cycloaliphatic group, aryl, a 5-7 membered heterocyclic ring having up to two heteroatoms selected from O, S or N atoms, where the above aliphatic group, phenyl and heterocyclic ring are independently and optionally substituted with up to three substituents selected from C ₁ -C ₆ alkyl, O-C ₁ -C ₆ alkyl, halogen atom, cyano group, OH or CF ₃ , where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO- , -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

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

Where:

G ₄ means a hydrogen atom, a halogen atom, CN, CF ₃ , CHF ₂ , CH ₂ F, an optionally substituted C ₁ -C ₆ aliphatic group, an aryl C ₁ -C ₆ alkyl or phenyl, where G _{4 is} optionally substituted up to 4 substituents WR ^W ; where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl are optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, - O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR ' -.

G ₅ means a hydrogen atom or an optionally substituted C ₁ -C ₆ aliphatic group;

where the above indole ring system is additionally optionally substituted with up to 3 substituents independently selected from WR ^W.

In one embodiment, the compounds of formula V-B-5-a have y occurrence of the substituent X-R ^X , where y is 0-4. In one embodiment, y is 0; or y is 1; or y is 2.

In one embodiment, G ₄ means a hydrogen atom. Or G ₅ means a hydrogen atom.

In another embodiment, G ₄ is a hydrogen atom, and G ₅ is a C ₁ -C ₆ aliphatic group, where the above aliphatic group is optionally substituted with C ₁ -C ₆ alkyl, a halogen atom, a cyano group or CF ₃ , where up to two methylene groups of the above C ₁ -C ₆ aliphatic groups or C ₁ -C ₆ alkyl are optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR '-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

In another embodiment, G ₄ is a hydrogen atom and G ₅ is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyanomethyl, methoxyethyl, CH ₂ C (O) OMe, (CH ₂ ) _2- NHC (O) O-tert-butyl or cyclopentyl.

In another embodiment, G ₅ is a hydrogen atom and G ₄ is a halogen atom, a C ₁ -C ₆ aliphatic group or phenyl, wherein the above aliphatic group or phenyl is optionally substituted with C ₁ -C ₆ alkyl, a halogen atom, a cyano group or CF ₃ , where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl are optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, - O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR ' -. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

In another embodiment, G ₅ is a hydrogen atom and G ₄ is a halogen atom, CF ₃ , ethoxycarbonyl, tert-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, (4-C (O) NH (CH ₂ ) ₂ -NMe ₂ ) phenyl, 2-methoxy-4-chlorophenyl, pyridin-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, tert-butyl or piperidin-1-ylcarbonyl.

In another embodiment, G ₄ and G ₅ are both hydrogen and the nitrogen atom of the above indole ring is substituted with a C ₁ -C ₆ aliphatic group, C (O) (C ₁ -C ₆ aliphatic group) or benzyl, where the above aliphatic group or benzyl is optionally substituted with C ₁ -C ₆ alkyl, a halogen atom, a cyano group or CF ₃ where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl are optionally replaced with -CO-, -CONR'- , -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, -NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

In another embodiment, G ₄ and G ₅ are both hydrogen and the nitrogen atom of the above indole ring is substituted with acyl, benzyl, C (O) CH ₂ N (Me) C (O) CH ₂ NHMe or ethoxycarbonyl.

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

or their pharmaceutically acceptable salts,

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Ar ¹ have the meanings as described above for compounds of formula I.

In one embodiment, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Ar ¹ in the compounds of formula I ′ independently has the meanings as described above for any embodiments of the compounds of formula I.

Particular compounds of the present invention are those shown in Table 1 below.

Table 1 Connection No. Title one N- [5- (5-chloro-2-methoxyphenyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 2 N- (3-methoxy-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 3 N- [2- (2-methoxyphenoxy) -5- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide four N- (2-morpholinophenyl) -4-oxo-1H-quinoline-3-carboxamide 5 N- [4- (2-hydroxy-1,1-dimethylethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 6 N- [3- (hydroxymethyl) -4-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide 7 N- (4-benzoylamino-2,5-diethoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 8 N- (3-amino-4-ethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 9 4-oxo-N- (3-sulfamoylphenyl) -1H-quinoline-3-carboxamide 10 1,4-dihydro-N- (2,3,4,5-tetrahydro-1H-benzo [b] azepin-8-yl) -4-oxoquinoline-3-carboxamide

eleven 4-oxo-N- [2- [2- (trifluoromethyl) phenyl] phenyl] -1H-quinoline-3-carboxamide 12 N- [2- (4-dimethylaminophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 13 N- (3-cyano-4-tert-butylphenyl) -4-oxo-1H-quinolin-3-
carboxamide fourteen [5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -2-tert-butylphenyl] amino formic acid methyl ester fifteen N- (2-methoxy-3-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 16 4-oxo-N- (2-propylphenyl) -1H-quinoline-3-carboxamide 17 N- (5-amino-2-propoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide eighteen N- (9H-fluoren-1-yl) -4-oxo-1H-quinoline-3-carboxamide 19 4-oxo-N- (2-quinolyl) -1H-quinoline-3-carboxamide twenty N- [2- (2-methylphenoxy) phenyl] -4-oxo-1H-quinoline-3-carboxamide 21 4-oxo-N- [4- (2-pyridylsulfamoyl) phenyl] -1H-quinoline-3-carboxamide 22 N- (1 ', 2'-dihydrospiro [cyclopropane-1,3' - [3H] indole] -
4'-yl) amide 4-oxo-l, 4-dihydroquinoline-3-carboxylic acid 23 N- [2- (2-ethoxyphenyl) -5-hydroxy-4-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide 24 4-oxo-N- (3-pyrrolidin-1-ylsulfonylphenyl) -1H-quinoline-3-carboxamide 25 N- [2- (3-acetylaminophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 26 4-oxo-N- [2- (1-piperidyl) phenyl] -1H-quinoline-3-carboxamide 27 N- [1- [2- [methyl (2-methylaminoacetyl) amino] acetyl] -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 28 [2-Methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid 2-methoxyethyl ester 29th 1-isopropyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide thirty [2-Isopropyl-5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid methyl ester 31 4-oxo-N- (p-tolyl) -1H-quinoline-3-carboxamide 32 N- (5-chloro-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 33 N- (1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 34 N- [4- (1,1-diethylpropyl) -2-fluoro-5-hydroxyphenyl] -4-hydroxyquinoline-3-carboxamide 35 1,4-dihydro-N- (2,3,4,5-tetrahydro-5,5-dimethyl-1H-benzo [b] azepin-8-yl) -4-oxoquinoline-3-carboxamide 36 N- (2-isopropylphenyl) -4-oxo-1H-quinoline-3-carboxamide 37 N- (1H-indol-7-yl) -4-oxo-1H-quinoline-3-carboxamide 38 N- [2- (1H-indol-2-yl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 39 [3 - [(2,4-Dimethoxy-3-quinolyl) carbonylamino] -4-tert-butylphenyl] amino formic acid tert-butyl ester

40 N- [2- (2-hydroxyethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 41 N- (5-amino-2-propylphenyl) -4-oxo-1H-quinoline-3-carboxamide 42 N- [2 - [[3-chloro-5- (trifluoromethyl) -2-pyridyl] oxy] phenyl] -4-oxo-1H-quinoline-3-carboxamide 43 N- [2- (3-ethoxyphenyl) -5-hydroxy-4-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide 44 N- (2-methylbenzothiazol-5-yl) -4-oxo-1H-quinoline-3-carboxamide 45 N- (2-cyano-3-fluorophenyl) -4-oxo-1H-quinoline-3-carboxamide 46 N- [3-chloro-5- (2-morpholinoethylsulfonylamino) phenyl] -4-oxo-1H-quinoline-3-carboxamide 47 N- [4-isopropyl-2- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 48 N- (5-chloro-2-fluorophenyl) -4-oxo-1H-quinoline-3-carboxamide 49 N- [2- (2,6-dimethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide fifty 4-oxo-N- (2,4,6-trimethylphenyl) -1H-quinoline-3-carboxamide 51 6 - [(4-methyl-1-piperidyl) sulfonyl] -4-oxo-N- (5-tert-butyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 52 N- [2- (m-tolyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 53 4-oxo-N- (4-pyridyl) -1H-quinoline-3-carboxamide 54 4-oxo-N- (8-thia-7,9-diazabicyclo [4.3.0] nona-2,4,6,9-tetraen-5-yl) -1H-quinoline-3-carboxamide 55 N- (3-amino-2-methoxy-5-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 56 1,4-dihydro-N- (1,2,3,4-tetrahydro-6-hydroxynaphthalen-7-yl) -4-oxoquinoline-3-carboxamide 57 N- [4- (3-ethyl-2,6-dioxo-3-piperidyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 58 N- [3-amino-4- (trifluoromethoxy) phenyl] -4-oxo-1H-quinoline-3-carboxamide 59 N- [2- (5-Isopropyl-2-methoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 60 [4-Isopropyl-3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid tert-butyl ester 61 N- (2,3-dimethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 62 4-oxo-N- [3- (trifluoromethoxy) phenyl] -1H-quinoline-3-carboxamide 63 N- [2- (2,4-difluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 64 4-oxo-N- (2-oxo-1,3-dihydrobenzoimidazol-5-yl) -1H-quinoline-3-carboxamide 65 4-oxo-N- [5- (3-pyridyl) -1H-indol-6-yl] -1H-quinoline-3-carboxamide 66 N- (2,2-difluorobenzo [1,3] dioxol-5-yl) -4-oxo-1H-quinoline-3-carboxamide 67 6-ethyl-4-hydroxy-N- (1H-indol-6-yl) quinoline-3-carboxamide 68 3- [2 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] benzoic acid methyl ester

69 N- (3-amino-4-isopropylphenyl) -4-oxo-1H-quinoline-3-carboxamide 70 4-oxo-N- [2- (4-pyridyl) phenyl] -1H-quinoline-3-carboxamide 71 3- [2 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] benzoic acid isopropyl ester 72 N- (2-ethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 73 4-oxo-N- (2-phenyl-3H-benzoimidazol-5-yl) -1H-quinoline-3-carboxamide 74 4-oxo-N- [5- (trifluoromethyl) -2-pyridyl] -1H-quinoline-3-carboxamide 75 4-oxo-N- (3-quinolyl) -1H-quinoline-3-carboxamide 76 N- [2- (3,4-difluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 77 N- (5-fluoro-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 78 4-oxo-N- (2-sulfamoylphenyl) -1H-quinoline-3-carboxamide 79 N- [2- (4-fluoro-3-methylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 80 N- (2-methoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 81 4-oxo-N- (3-propionylaminophenyl) -1H-quinoline-3-carboxamide 82 N- (4-diethylamino-2-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 83 N- [2- (3-cyanophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 84 N- (4-methyl-2-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 85 N- [2- (3,4-dichlorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 86 N- [4- [2- (aminomethyl) phenyl] phenyl] -4-oxo-1H-quinoline-3-carboxamide 87 4-oxo-N- (3-phenoxyphenyl) -1H-quinoline-3-carboxamide 88 [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid tert-butyl ester 89 N- (2-cyano-5-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 90 4-oxo-N- (2-tert-butylphenyl) -1H-quinoline-3-carboxamide 91 N- (3-chloro-2,6-diethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 92 N- [2-fluoro-5-hydroxy-4- (1-methylcyclohexyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 93 N- [2- (5-cyano-2-thienyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 94 N- (5-amino-2-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 95 N- (2-cyanophenyl) -4-oxo-1H-quinoline-3-carboxamide 96 N- [3- (cyanomethyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 97 N- [2- (2,4-Dimethoxypyrimidin-5-yl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 98 N- (5-Dimethylamino-2-propylphenyl) -4-oxo-1H-quinoline-3-carboxamide 99 4-oxo-N- (4-pentylphenyl) -1H-quinoline-3-carboxamide one hundred N- (1H-indol-4-yl) -4-oxo-1H-quinoline-3-carboxamide 101 N- (5-amino-2-isopropylphenyl) -4-oxo-1H-quinoline-3-carboxamide

102 N- [2- [3- (4-chlorophenyl) -1,2,4-oxadiazol-5-yl] phenyl] -4-oxo-1H-quinoline-3-carboxamide 103 6-fluoro-N- (5-hydroxy-2,4-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 104 N- (2-methyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 105 1,4-dihydro-N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-yl) -4-oxoquinoline-3-carboxamide 106 N- (2-cyano-4,5-dimethoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 107 7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester 108 4,4-dimethyl-7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester 109 N- (1-acetyl-2,3,4,5-tetrahydro-5,5-dimethyl-1H-benzo [b] azepin-8-yl) -1,4-dihydro-4-oxoquinoline-3-carboxamide 110 N- [4- (cyanomethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 111 4-oxo-N- [2- (trifluoromethyl) phenyl] -1H-quinoline-3-carboxamide 112 6-ethoxy-4-hydroxy-N- (1H-indol-6-yl) quinoline-3-carboxamide 113 N- (3-methyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 114 [4- (2-Ethoxyphenyl) -3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid tert-butyl ester 115 N- [2- (2-furyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 116 5-hydroxy-N- (1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 117 N- (3-Dimethylamino-4-isopropylphenyl) -4-oxo-1H-quinoline-3-carboxamide 118 N- [2- (1H-indol-5-yl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 119 [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid ethyl ester 120 N- (2-methoxy-5-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 121 N- (3,4-dichlorophenyl) -4-oxo-1H-quinoline-3-carboxamide 122 N- (3,4-dimethoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 123 N- [2- (3-furyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 124 6-fluoro-4-oxo-N- (5-tert-butyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 125 N- (6-ethyl-2-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 126 N- [3-hydroxy-4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] phenyl] -4-oxo-1H-quinoline-3-carboxamide 127 [5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -2-tert-butylphenyl] amino formic acid ethyl ester 128 1,6-dimethyl-4-oxo-N- (2-phenylphenyl) -1H-quinoline-3-carboxamide

129 [2-ethyl-5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid methyl ester 130 4-hydroxy-N- (1H-indol-6-yl) -5,7-bis (trifluoromethyl) quinoline-3-carboxamide 131 N- (3-amino-5-chlorophenyl) -4-oxo-1H-quinoline-3-carboxamide 132 N- (5-acetylamino-2-ethoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 133 N- [3-chloro-5- [2- (1-piperidyl) ethylsulfonylamino] phenyl] -4-oxo-1H-quinoline-3-carboxamide 134 N- [2- (4-methylsulfinyl phenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 135 N- (2-benzo [1,3] dioxol-5-ylphenyl) -4-oxo-1H-quinoline-3-carboxamide 136 N- (2-hydroxy-3,5-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 137 6 - [(4-fluorophenyl) methylsulfamoyl] -N- (5-hydroxy-2,4-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 138 N- [2- (3,5-difluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 139 N- [2- (2,4-Dichlorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 140 N- (4-cyclohexylphenyl) -4-oxo-1H-quinoline-3-carboxamide 141 [2-methyl-5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid ethyl ester 142 4-oxo-N- (2-sec-butylphenyl) -1H-quinoline-3-carboxamide 143 N- (2-fluoro-5-hydroxy-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 144 N- (3-hydroxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 145 6 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-4-carboxylic acid ethyl ester 146 4-oxo-N- (1,7,9-triazabicyclo [4.3.0] nona-2,4,6,8-tetraen-5-yl) -1H-quinoline-3-carboxamide 147 N- [2- (4-fluorophenoxy) -3-pyridyl] -4-oxo-1H-quinoline-3-carboxamide 148 4-oxo-N- [5- (1-piperidylcarbonyl) -1H-indol-6-yl] -1H-quinoline-3-carboxamide 149 N- (3-Acetylamino-4-ethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 150 4-oxo-N- [4- [2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl] phenyl] -1H-quinoline-3-carboxamide 151 N- [2- (4-methyl-2-thienyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 152 4-oxo-N- (2-oxo-3H-benzoxazol-6-yl) -1H-quinoline-3-carboxamide 153 N- [4- (1,1-diethyl-2,2-dimethylpropyl) -2-fluoro-5-hydroxyphenyl] -4-hydroxyquinoline-3-carboxamide 154 N- [3,5-bis (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 155 4-oxo-N- (2-pyridyl) -1H-quinoline-3-carboxamide 156 4-oxo-N- [2- [2- (trifluoromethoxy) phenyl] phenyl] -1H-quinoline-3-carboxamide

157 N- (2-ethyl-5-methylaminophenyl) -4-oxo-1H-quinoline-3-carboxamide 158 4-oxo-N- (5-phenyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 159 [7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid methyl ester 160 N- (3-amino-4-propylphenyl) -4-oxo-1H-quinoline-3-carboxamide 161 N- [3- (2-ethoxyethoxy) -4-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide 162 N- (6-methoxy-3-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 163 N- [5- (aminomethyl) -2- (2-ethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 164 4-oxo-N- [3- (trifluoromethyl) phenyl] -1H-quinoline-3-carboxamide 165 4-oxo-N- (4-sulfamoylphenyl) -1H-quinoline-3-carboxamide 166 4- [2 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] benzoic acid methyl ester 167 N- (3-amino-4-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 168 4-oxo-N- (3-pyridyl) -1H-quinoline-3-carboxamide 169 N- (1-methyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 170 N- (5-chloro-2-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 171 N- [2- (2,3-Dichlorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 172 N- (2- (Benzo [b] thiophen-2-yl) phenyl) -1,4-dihydro-4-oxoquinoline-3-carboxamide 173 N- (6-methyl-2-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 174 N- [2- (5-acetyl-2-thienyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 175 N- (1'-acetyl-1 ', 2'-dihydrospiro [cyclopropane-1,3'-
3H-indole] -6'-yl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid amide 176 4-oxo-N- [4- (trifluoromethoxy) phenyl] -1H-quinoline-3-carboxamide 177 N- (2-butoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 178 4-oxo-N- [2- (2-tert-butylphenoxy) phenyl] -1H-quinoline-3-carboxamide 179 N- (3-carbamoylphenyl) -4-oxo-1H-quinoline-3-carboxamide 180 N- (2-ethyl-6-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 181 4-oxo-N- [2- (p-tolyl) phenyl] -1H-quinoline-3-carboxamide 182 N- [2- (4-fluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 183 7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester 184 N- (1H-indol-6-yl) -4-oxo-2- (trifluoromethyl) -1H-quinoline-3-carboxamide 185 N- (3-morpholinosulfonylphenyl) -4-oxo-1H-quinoline-3-carboxamide 186 N- (3-cyclopentyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide

187 N- (1-acetyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 188 6 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-5-carboxylic acid ethyl ester 189 N- (4-benzyloxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 190 N- [2- (3-chloro-4-fluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 191 4-oxo-N- (5-quinolyl) -1H-quinoline-3-carboxamide 192 N- (3-methyl-2-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 193 N- (2,6-dimethoxy-3-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 194 N- (4-cyanophenyl) -4-oxo-1H-quinoline-3-carboxamide 195 N- (5-methyl-2-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 196 N- [5- (3,3-dimethylbutanoylamino) -2-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide 197 4-oxo-N- [6- (trifluoromethyl) -3-pyridyl] -1H-quinoline-3-carboxamide 198 N- (4-fluorophenyl) -4-oxo-1H-quinoline-3-carboxamide 199 N- [2- (o-tolyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 200 1,4-dihydro-N- (1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl) -4-oxoquinoline-3-carboxamide 201 N- (2-cyano-3-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 202 N- [2- (5-chloro-2-methoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 203 N- (1-benzyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 204 N- (4,4-dimethylchroman-7-yl) -4-oxo-1H-quinoline-3-carboxamide 205 N- [2- (4-methoxyphenoxy) -5- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 206 N- [2- (2,3-dimethylphenoxy) -3-pyridyl] -4-oxo-1H-quinoline-3-carboxamide 207 2- [6 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1H-indol-3-yl] acetic acid ethyl ester 208 N- [4- (2-adamantyl) -5-hydroxy-2-methylphenyl] -4-oxo-1H-quinoline-3-carboxamide 209 N- [4- (hydroxymethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 210 2,4-dimethoxy-N- (2-phenylphenyl) quinoline-3-carboxamide 211 N- (2-methoxy-5-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 212 N- [3- (3-methyl-5-oxo-1,4-dihydropyrazol-1-yl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 213 N- [2- (2,5-Dichlorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 214 N- (3-methylsulfonylaminophenyl) -4-oxo-1H-quinoline-3-carboxamide 215 4-oxo-N-phenyl-1H-quinoline-3-carboxamide 216 N- (3H-benzimidazol-2-yl) -4-oxo-1H-quinoline-3-carboxamide 217 N- (1H-indazol-5-yl) -4-oxo-1H-quinoline-3-carboxamide 218 6-fluoro-N- [2-fluoro-5-hydroxy-4- (1-methylcyclohexyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide

219 4-oxo-N-pyrazin-2-yl-1H-quinoline-3-carboxamide 220 N- (2,3-dihydroxy-4,6-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 221 [5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -2-propylphenyl] amino formic acid methyl ester 222 N- (3-chloro-2-cyanophenyl) -4-oxo-1H-quinoline-3-carboxamide 223 N- [2- (4-methylsulfanylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 224 4-oxo-N- [4- [2 - [(2,2,2-trifluoroacetyl) aminomethyl] phenyl] phenyl] -1H-quinoline-3-carboxamide 225 [2-isopropyl-5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid ethyl ester 226 4-oxo-N- (4-propylphenyl) -1H-quinoline-3-carboxamide 227 N- [2- (3H-benzimidazol-2-yl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 228 N- [2- (Hydroxyphenylmethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 229 N- (2-methylsulfanylphenyl) -4-oxo-1H-quinoline-3-carboxamide 230 N- (2-methyl-1H-indol-5-yl) -4-oxo-1H-quinoline-3-carboxamide 231 3- [4-hydroxy-2 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -5-tert-butylphenyl] benzoic acid methyl ester 232 N- (5-Acetylamino-2-propylphenyl) -4-oxo-1H-quinoline-3-carboxamide 233 N- (1-Acetylindolin-6-yl) -4-oxo-1H-quinoline-3-carboxamide 234 4-oxo-N- [5- (trifluoromethyl) -1H-indol-6-yl] -1H-quinoline-3-carboxamide 235 N- (6-Isopropyl-3-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 236 4-oxo-N- [4- (trifluoromethyl) phenyl] -1H-quinoline-3-carboxamide 237 N- [5- (2-methoxyphenyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 238 7 '- [(4-oxo-1H-quinolin-3-ylcarbonyl) amino] spiro [piperidin-4,4' (1'H) -quinoline] -2 ', 3'-dihydrocarboxylic acid tert-butyl ester 239 [4-Isopropyl-3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid methyl ester 240 N- (2-benzyloxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 241 4-oxo-N- (8-quinolyl) -1H-quinoline-3-carboxamide 242 N- (5-amino-2,4-dichlorophenyl) -4-oxo-1H-quinoline-3-carboxamide 243 N- (5-acetylamino-2-isopropylphenyl) -4-oxo-1H-quinoline-3-carboxamide 244 4-oxo-N- (6,7,8,9-tetrahydro-5H-carbazol-2-yl) -1H-quinoline-3-carboxamide 245 N- [2- (2,4-Dichlorophenoxy) phenyl] -4-oxo-1H-quinoline-3-carboxamide 246 N- (3,4-dimethylphenyl) -4-oxo-1H-quinoline-3-carboxamide

247 4-oxo-N- [2- (2-phenoxyphenyl) phenyl] -1H-quinoline-3-carboxamide 248 N- (3-Acetylamino-4-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 249 [4-ethyl-3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid methyl ester 250 N- (5-acetylamino-2-methoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 251 [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid isobutyl ester 252 N- (2-benzoylphenyl) -4-oxo-1H-quinoline-3-carboxamide 253 4-oxo-N- [2- [3- (trifluoromethoxy) phenyl] phenyl] -1H-quinoline-3-carboxamide 254 6-fluoro-N- (5-fluoro-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 255 N- (5-hydroxy-2,4-di-tert-butylphenyl) -4-oxo-6-pyrrolidin-1-ylsulfonyl-1H-quinoline-3-carboxamide 256 N- (1H-benzotriazol-5-yl) -4-oxo-1H-quinoline-3-carboxamide 257 N- (4-fluoro-3-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 258 N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide 259 4-oxo-N- (3-sec-butyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 260 N- (5-amino-2-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 261 N- [2- (3,4-dimethylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 262 1,4-dihydro-N- (3,4-dihydro-3-oxo-2H-benzo [b] [1,4] thiazin-6-yl) -4-oxoquinoline-3-carboxamide 263 N- (4-bromo-2-ethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 264 N- (2,5-diethoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 265 N- (2-benzylphenyl) -4-oxo-1H-quinoline-3-carboxamide 266 N- [5-hydroxy-4-tert-butyl-2- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 267 4-oxo-N- (4-phenoxyphenyl) -1H-quinoline-3-carboxamide 268 4-oxo-N- (3-sulfamoyl-4-tert-butylphenyl) -1H-quinoline-3-carboxamide 269 [4-isopropyl-3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid ethyl ester 270 N- (2-cyano-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 271 N- (3-amino-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 272 N- [3- (2-morpholinoethylsulfonylamino) -5- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 273 [7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid tert-butyl ester 274 4-oxo-6-pyrrolidin-1-ylsulfonyl-N- (5-tert-butyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 275 4-benzyloxy-N- (3-hydroxy-4-tert-butylphenyl) quinoline-3-carboxamide 276 N- (4-morpholinosulfonylphenyl) -4-oxo-1H-quinoline-3-carboxamide

277 N- [2- (3-fluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 278 4-oxo-N- [2- [3- (trifluoromethyl) phenyl] phenyl] -1H-quinoline-3-carboxamide 279 N- [2- (2-methylsulfanylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 280 4-oxo-N- (6-quinolyl) -1H-quinoline-3-carboxamide 281 N- (2,4-Dimethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 282 N- (5-amino-2-ethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 283 N- [2- (3-methoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 284 N- (1H-indazol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 285 N- [2- (2,3-difluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 286 1,4-dihydro-N- (1,2,3,4-tetrahydronaphthalen-5-yl) -4-oxoquinoline-3-carboxamide 287 N- [2-fluoro-5-hydroxy-4- (1-methylcyclohexyl) phenyl] -5-hydroxy-4-oxo-1H-quinoline-3-carboxamide 288 N- (5-fluoro-2-methoxycarbonyloxy-3-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 289 N- (2-fluoro-4-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 290 N- [2- (3-isopropylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 291 N- (2-chloro-5-hydroxy-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 292 N- (5-chloro-2-phenoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 293 4-oxo-N- [2- (1H-pyrrol-1-yl) phenyl] -1H-quinolin-3-carboxamide 294 N- (1H-indol-5-yl) -4-oxo-1H-quinoline-3-carboxamide 295 4-oxo-N- (2-pyrrolidin-1-ylphenyl) -1H-quinoline-3-carboxamide 296 2,4-dimethoxy-N- (2-tert-butylphenyl) quinoline-3-carboxamide 297 N- [2- (2,5-dimethyl-1H-pyrrol-1-yl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 298 [2-ethyl-5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid ethyl ester 299 4-oxo-N- (1,2,3,4-tetrahydroquinolin-7-yl) -1H-quinoline-3-carboxamide 300 N- (4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl) -4-oxo-1H-quinoline-3-carboxamide 301 N- [4- (4-methyl-4H-1,2,4-triazol-3-yl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 302 N- [2- [4- (hydroxymethyl) phenyl] phenyl] -4-oxo-1H-quinoline-3-carboxamide 303 N- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-oxo-1H-quinoline-3-carboxamide 304 [4- (2-Ethoxyphenyl) -3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenylmethyl] amino formic acid tert-butyl ester 305 N- [2- (4-methoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide

306 N- [2- (3-ethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 307 N- [2- (3-chlorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 308 N- [2- (cyanomethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 309 N- (3-isoquinolyl) -4-oxo-1H-quinoline-3-carboxamide 310 4-oxo-N- (4-sec-butylphenyl) -1H-quinoline-3-carboxamide 311 N- [2- (5-methyl-2-furyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 312 N- [2- (2,4-Dimethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 313 N- [2- (2-fluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 314 N- (2-ethyl-6-isopropylphenyl) -4-oxo-1H-quinoline-3-carboxamide 315 N- (2,6-dimethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 316 N- (5-acetylamino-2-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 317 N- (2,6-dichlorophenyl) -4-oxo-1H-quinoline-3-carboxamide 318 4-oxo-N- [3- [2- (1-piperidyl) ethylsulfonylamino] -5- (trifluoromethyl) phenyl] -1H-quinoline-3-carboxamide 319 6-fluoro-N- (2-fluoro-5-hydroxy-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 320 4-oxo-N- (2-tert-butyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 321 N- [2- (4-benzoylpiperazin-1-yl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 322 N- (2-ethyl-6-sec-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 323 [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid methyl ester 324 N- (4-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 325 N- (2,6-diethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 326 N- [2- (4-methylsulfonylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 327 N- [5- (2-ethoxyphenyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 328 N- (3-acetylphenyl) -4-oxo-1H-quinoline-3-carboxamide 329 N- [2- (o-tolyl) benzoxazol-5-yl] -4-oxo-1H-quinoline-3-carboxamide 330 N- (2-chlorophenyl) -4-oxo-1H-quinoline-3-carboxamide 331 N- (2-carbamoylphenyl) -4-oxo-1H-quinoline-3-carboxamide 332 N- (4-ethynylphenyl) -4-oxo-1H-quinoline-3-carboxamide 333 N- [2- [4- (cyanomethyl) phenyl] phenyl] -4-oxo-1H-quinoline-3-carboxamide 334 7 '- [(4-oxo-1H-quinolin-3-ylcarbonyl) amino] spiro [piperidin-4,4' (1'H) -1-acetylquinoline] -2 ', 3'-dihydrocarboxylic acid tert-butyl ester 335 N- (2-carbamoyl-5-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 336 N- (2-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 337 N- (5-hydroxy-2,4-di-tert-butylphenyl) -N-methyl-4-oxo-1H-quinoline-3-carboxamide

338 N- (3-methyl-1H-indol-4-yl) -4-oxo-1H-quinoline-3-carboxamide 339 N- (3-cyano-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 340 N- (3-methylsulfonylamino-4-propylphenyl) -4-oxo-1H-quinoline-3-carboxamide 341 [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid neopentyl ester 342 N- [5- (4-Isopropylphenyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 343 N- [5- (Isobutylcarbamoyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 344 N- [2- (2-ethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 345 6-fluoro-4-hydroxy-N- (1H-indol-6-yl) quinoline-3-carboxamide 346 4-oxo-N-phenyl-7- (trifluoromethyl) -1H-quinoline-3-carboxamide 347 N- [5- [4- (2-dimethylaminoethylcarbamoyl) phenyl] -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 348 N- [2- (4-ethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 349 4-oxo-N- (2-phenylsulfonylphenyl) -1H-quinoline-3-carboxamide 350 N- (1-naphthyl) -4-oxo-1H-quinoline-3-carboxamide 351 N- (5-ethyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 352 2- [6 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1H-indol-3-yl] ethylamino formic acid tert-butyl ester 353 [3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -4-tert-butylphenyl] amino formic acid tert-butyl ester 354 N- [2 - [(cyclohexylmethylamino) methyl] phenyl] -4-oxo-1H-quinoline-3-carboxamide 355 N- [2- (2-methoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 356 N- (5-methylamino-2-propylphenyl) -4-oxo-1H-quinoline-3-carboxamide 357 N- (3-Isopropyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 358 6-chloro-4-hydroxy-N- (1H-indol-6-yl) quinoline-3-carboxamide 359 N- [3- (2-Dimethylaminoethylsulfonylamino) -5- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 360 N- [4- (difluoromethoxy) phenyl] -4-oxo-1H-quinoline-3-carboxamide 361 N- [2- (2,5-dimethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 362 N- (2-chloro-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 363 N- [2- (2-fluoro-3-methoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 364 N- (2-methyl-8-quinolyl) -4-oxo-1H-quinoline-3-carboxamide 365 N- (2-acetylphenyl) -4-oxo-1H-quinoline-3-carboxamide

366 4-oxo-N- [2- [4- (trifluoromethyl) phenyl] phenyl] -1H-quinoline-3-carboxamide 367 N- [2- (3,5-Dichlorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 368 N- (3-amino-4-propoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 369 N- (2,4-Dichloro-6-cyanophenyl) -4-oxo-1H-quinoline-3-carboxamide 370 N- (3-chlorophenyl) -4-oxo-1H-quinoline-3-carboxamide 371 4-oxo-N- [2- (trifluoromethylsulfanyl) phenyl] -1H-quinoline-3-carboxamide 372 N- [2- (4-methyl-1-piperidyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 373 N-indan-4-yl-4-oxo-1H-quinoline-3-carboxamide 374 4-hydroxy-N- (1H-indol-6-yl) -2-methylsulfanylquinoline-3-carboxamide 375 1,4-dihydro-N- (1,2,3,4-tetrahydronaphthalen-6-yl) -4-oxoquinoline-3-carboxamide 376 4-oxo-N- (2-phenylbenzoxazol-5-yl) -1H-quinoline-3-carboxamide 377 6,8-difluoro-4-hydroxy-N- (1H-indol-6-yl) quinoline-3-carboxamide 378 N- (3-amino-4-methoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 379 N- [3-Acetylamino-5- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 380 N- (2-ethoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 381 4-oxo-N- (5-tert-butyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 382 [5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -2-propylphenyl] amino formic acid ethyl ester 383 N- (3-ethyl-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide 384 N- [2- (2,5-difluorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 385 N- [2- (2,4-difluorophenoxy) -3-pyridyl] -4-oxo-1H-quinoline-3-carboxamide 386 N- (3,3-dimethylindolin-6-yl) -4-oxo-1H-quinoline-3-carboxamide 387 N- [2-methyl-3- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 388 4-oxo-N- [2- [4- (trifluoromethoxy) phenyl] phenyl] -1H-quinoline-3-carboxamide 389 N- (3-benzylphenyl) -4-oxo-1H-quinoline-3-carboxamide 390 N- [3- (aminomethyl) -4-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide 391 N- [2- (4-isobutylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 392 N- (6-chloro-3-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 393 N- [5-amino-2- (2-ethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 394 1,6-dimethyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide

395 N- [4- (1-adamantyl) -2-fluoro-5-hydroxyphenyl] -4-hydroxyquinoline-3-carboxamide 396 [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid tetrahydrofuran-3-ylmethyl ester 397 4-oxo-N- (4-phenylphenyl) -1H-quinoline-3-carboxamide 398 4-oxo-N- [2- (p-tolylsulfonylamino) phenyl] -1H-quinoline-3-carboxamide 399 N- (2-Isopropyl-5-methylaminophenyl) -4-oxo-1H-quinoline-3-carboxamide 400 N- (6-morpholino-3-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 401 N- [2- (2,3-dimethylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 402 4-oxo-N- (5-phenyl-2-pyridyl) -1H-quinoline-3-carboxamide 403 N- [2-fluoro-5-hydroxy-4- (1-methylcyclooctyl) phenyl] -4-hydroxyquinoline-3-carboxamide 404 N- [5- (2,6-dimethoxyphenyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 405 N- (4-chlorophenyl) -4-oxo-1H-quinoline-3-carboxamide 406 6 - [(4-fluorophenyl) methylsulfamoyl] -4-oxo-N- (5-tert-butyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 407 N- (2-fluoro-5-hydroxy-4-tert-butylphenyl) -5-hydroxy-4-oxo-1H-quinoline-3-carboxamide 408 N- (3-methoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 409 N- (5-Dimethylamino-2-ethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 410 4-oxo-N- [2- (4-phenoxyphenyl) phenyl] -1H-quinoline-3-carboxamide 411 7-chloro-4-oxo-N-phenyl-1H-quinoline-3-carboxamide 412 6 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-7-carboxylic acid ethyl ester 413 4-oxo-N- (2-phenoxyphenyl) -1H-quinoline-3-carboxamide 414 N- (3H-benzimidazol-5-yl) -4-oxo-1H-quinoline-3-carboxamide 415 N- (3-hydroxy-4-tert-butylphenyl) -4-methoxyquinoline-3-carboxamide 416 [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid propyl ester 417 N- (2- (Benzo [b] thiophen-3-yl) phenyl) -1,4-dihydro-4-oxoquinoline-3-carboxamide 418 N- (3-dimethylaminophenyl) -4-oxo-1H-quinoline-3-carboxamide 419 N- (3-acetylaminophenyl) -4-oxo-1H-quinoline-3-carboxamide 420 2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propanoic acid ethyl ester 421 N- [5-methoxy-4-tert-butyl-2- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 422 N- (5,6-dimethyl-3H-benzoimidazol-2-yl) -4-oxo-1H-quinoline-3-carboxamide 423 N- [3- (2-ethoxyethyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide 424 N- [2- (4-chlorophenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 425 N- (4-isopropylphenyl) -4-oxo-1H-quinoline-3-carboxamide

426 N- (4-chloro-5-hydroxy-2-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 427 5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester 428 N- (3-hydroxy-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 429 N- [3-amino-5- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 430 N- (2-Isopropyl-6-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide 431 N- (3-aminophenyl) -4-oxo-1H-quinoline-3-carboxamide 432 N- [2- (4-isopropylphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 433 N- (5-hydroxy-2,4-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 434 N- (2,5-Dimethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 435 N- [2- (2-fluorophenoxy) -3-pyridyl] -4-oxo-1H-quinoline-3-carboxamide 436 N- [2- (3,4-dimethoxyphenyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 437 N-benzo [1,3] dioxol-5-yl-4-oxo-1H-quinoline-3-carboxamide 438 N- [5- (difluoromethyl) -2,4-di-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide 439 N- (4-methoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide 440 N- (2,2,3,3-tetrafluoro-2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -1,4-dihydro-4-oxoquinoline-3-carboxamide 441 N- [3-methylsulfonylamino-5- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 442 4-oxo-N- [3- (1-piperidylsulfonyl) phenyl] -1H-quinoline-3-carboxamide 443 4-oxo-N-quinoxaline-6-yl-1H-quinoline-3-carboxamide 444 5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -2-tert-butylbenzoic acid methyl ester 445 N- (2-isopropenylphenyl) -4-oxo-1H-quinoline-3-carboxamide 446 N- (1,1-dioxobenzothiophen-6-yl) -4-oxo-1H-quinoline-3-carboxamide 447 N- (3-cyanophenyl) -4-oxo-1H-quinoline-3-carboxamide 448 4-oxo-N- (4-tert-butylphenyl) -1H-quinoline-3-carboxamide 449 N- (m-tolyl) -4-oxo-1H-quinoline-3-carboxamide 450 N- [4- (1-hydroxyethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 451 N- (4-cyano-2-ethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 452 4-oxo-N- (4-vinylphenyl) -1H-quinoline-3-carboxamide 453 N- (3-amino-4-chlorophenyl) -4-oxo-1H-quinoline-3-carboxamide 454 N- (2-methyl-5-phenylphenyl) -4-oxo-1H-quinoline-3-carboxamide 455 N- [4- (1-adamantyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide 456 4-oxo-N- [3- (trifluoromethylsulfanyl) phenyl] -1H-quinoline-3-carboxamide 457 N- (4-morpholinophenyl) -4-oxo-1H-quinoline-3-carboxamide 458 N- [3- (2-hydroxyethoxy) -4-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide

459 N- (o-tolyl) -4-oxo-1H-quinoline-3-carboxamide 460 [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid butyl ester 461 4-oxo-N- (2-phenylphenyl) -1H-quinoline-3-carboxamide 462 N- (3-Dimethylamino-4-propylphenyl) -4-oxo-1H-quinoline-3-carboxamide 463 N- (4-ethylphenyl) -4-oxo-1H-quinoline-3-carboxamide 464 5-hydroxy-N- (5-hydroxy-2,4-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 465 [5 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -2-tert-butylphenylmethyl] amino formic acid tert-butyl ester 466 N- (2,6-diisopropylphenyl) -4-oxo-1H-quinoline-3-carboxamide 467 N- (2,3-dihydrobenzofuran-5-yl) -4-oxo-1H-quinoline-3-carboxamide 468 1-methyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide 469 4-oxo-N- (2-phenylphenyl) -7- (trifluoromethyl) -1H-quinoline-3-carboxamide 470 4-oxo-N- (4-phenylsulfanylphenyl) -1H-quinoline-3-carboxamide 471 [3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -4-propylphenyl] amino formic acid methyl ester 472 [4-ethyl-3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] amino formic acid ethyl ester 473 1-isopropyl-4-oxo-N- (2-tert-butylphenyl) -1H-quinoline-3-carboxamide 474 N- (3-methyl-2-oxo-3H-benzooxazol-5-yl) -4-oxo-1H-quinoline-3-carboxamide 475 N- (2,5-Dichloro-3-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 476 N- (2-cyano-5-hydroxy-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 477 N- (5-fluoro-2-pyridyl) -4-oxo-1H-quinoline-3-carboxamide 478 4-oxo-N- (3-tert-butyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide 479 N- (1H-indol-6-yl) -5-methoxy-4-oxo-1H-quinoline-3-carboxamide 480 1-ethyl-6-methoxy-4-oxo-N-phenyl-1H-quinoline-3-carboxamide 481 N- (2-naphthyl) -4-oxo-1H-quinoline-3-carboxamide 482 [7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid ethyl ester 483 N- [2-fluoro-5-hydroxy-4- (1-methylcycloheptyl) phenyl] -4-hydroxyquinoline-3-carboxamide 484 N- (3-methylamino-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide 485 N- (3-dimethylamino-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide

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

or their salts;

Where:

G ₁ means a hydrogen atom, R ', C (O) R', C (S) R ', S (O) R', S (O) ₂ R ', Si (CH ₃ ) ₂ R', P (O ) (OR ') ₃ , P (S) (OR') ₃ or B (OR ') ₂ ;

G ₂ means a halogen atom, CN, CF ₃ , isopropyl or phenyl, where the above isopropyl or phenyl is optionally substituted with up to 3 substituents independently selected from WR ^W , where W and R ^W have the meanings as described above for formula I and its variants implementation;

G ₃ means isopropyl or a C ₃ -C ₁₀ cycloaliphatic ring, wherein the above G _{3 is} optionally substituted with up to 3 substituents independently selected from WR ^W , where W and R ^W are as defined above for formula I and its embodiments;

with the proviso that when G ₁ is methoxy, G ₃ is tert-butyl, then G _{2 is} not 2-amino-4-methoxy-5-tert-butylphenomel.

In one embodiment, the present invention relates to compounds of formula AI, provided that when G ₂ and G ₃ are each tert-butyl, then G _{1 is} not a hydrogen atom.

In another embodiment:

G ₁ means a hydrogen atom;

G ₂ means a halogen atom or isopropyl, where the aforementioned isopropyl is optionally substituted with up to 3 substituents independently selected from R '; and

G ₃ is isopropyl or a C ₃ -C ₁₀ cycloaliphatic ring, wherein the above G _{3 is} optionally substituted with up to 3 substituents independently selected from R ′;

In another embodiment:

G ₁ means a hydrogen atom;

G ₂ means a halogen atom, preferably a fluorine atom; and

G ₃ means a C ₃ -C ₁₀ cycloaliphatic ring, wherein the above G _{3 is} optionally substituted with up to 3 substituents independently selected from methyl, ethyl, propyl or butyl.

In another embodiment:

G ₁ means a hydrogen atom;

G ₂ means CN, a halogen atom or CF ₃ ; or

G ₃ means isopropyl or a C ₃ -C ₁₀ cycloaliphatic ring, wherein the above G _{3 is} optionally substituted with up to 3 substituents independently selected from R ′.

In another embodiment:

G ₁ means a hydrogen atom;

G ₂ is phenyl optionally substituted with up to 3 substituents independently selected from —O — C ₁ –C ₄ alkyl, CF ₃ , a halogen atom, or CN; and

G ₃ means isopropyl or a C ₃ -C ₁₀ cycloaliphatic ring, wherein the above G _{3 is} optionally substituted with up to 3 substituents independently selected from R ′.

Examples of G ₃ include optionally substituted cyclopentyl, cyclohexyl, cycloheptyl or adamantyl. Or G ₃ means a branched C ₃ -C ₈ aliphatic chain. Examples of G ₃ include isopropyl, tert-butyl, 3,3-diethylprop-3-yl or 3,3-diethyl-2,2-dimethylprop-3-yl.

In another embodiment:

G ₁ means a hydrogen atom;

G ₂ means tert-butyl; and

G ₃ means tert-butyl.

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

or its salt, where:

G ₄ means a hydrogen atom, a halogen atom, CN, CF ₃ , CHF ₂ , CH ₂ F, an optionally substituted C ₁ -C ₆ aliphatic group, an aralkyl or phenyl ring optionally substituted with up to 4 WR ^W substituents;

G ₅ means a hydrogen atom or an optionally substituted C ₁ -C ₆ aliphatic group;

provided that both G ₄ and G ₅ are not simultaneously hydrogen;

where the above indole ring is optionally further substituted with up to 3 substituents independently selected from WR ^W.

In one embodiment, G ₄ means a hydrogen atom. Or G ₅ means a hydrogen atom.

In another embodiment, G ₄ is a hydrogen atom and G ₅ is a C ₁ -C ₆ aliphatic group, where the above aliphatic group is optionally substituted with C ₁ -C ₆ alkyl, halogen, cyano or CF ₃ , where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR ' -, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

In another embodiment, G ₄ is a hydrogen atom and G ₅ is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyanomethyl, methoxyethyl, CH ₂ C (O) OMe, (CH ₂ ) _2- NHC (O) O-tert-butyl or cyclopentyl.

In another embodiment, G ₅ is a hydrogen atom and G ₄ is a halogen atom, a C ₁ -C ₆ aliphatic group or phenyl, where the above aliphatic group or phenyl is optionally substituted (substituted) with C ₁ -C ₆ alkyl, a halogen atom, a cyano group, or CF ₃ , where up to two methylene groups of the above C ₁ -C ₆ aliphatic group or C ₁ -C ₆ alkyl are optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

In another embodiment, G ₅ is a hydrogen atom, and G ₄ is a halogen atom, ethoxycarbonyl, tert-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C (O) NH (CH ₂ ) ₂ -NMe ₂ , 2-methoxy -4-chlorophenyl, pyridin-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, tert-butyl or piperidin-1-ylcarbonyl.

In the embodiment associated with Formula A-II, the nitrogen atom of the above indole ring is substituted with a C ₁ -C ₆ aliphatic group, C (O) (C ₁ -C ₆ aliphatic group) or benzyl, where the above aliphatic group or benzyl is optionally substituted (substituted) C ₁ -C ₆ alkyl, halogen, cyano or CF _3, wherein up to two methylene groups above C _1- C ₆ aliphatic group or a C ₁ -C ₆ alkyl optionally replaced by -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR ' -, NR'SO ₂ - or -NR'SO ₂ NR'-. In another embodiment, the above R 'is C ₁ -C ₄ alkyl.

In another embodiment, the nitrogen atom of the above indole ring is substituted with acyl, benzyl, C (O) CH ₂ N (Me) C (O) CH ₂ NHMe, or ethoxycarbonyl.

4. General synthesis schemes

The compounds of the present invention are readily prepared by methods known in the art. The methods illustrated below are examples of processes for preparing the compounds of the present invention.

The scheme below illustrates the synthesis of acid precursors of the compounds of the present invention.

Synthesis of P-IV-A, P-IV-B, or P-IV-C Precursor Acids

a) (CO ₂ Et) ₂ CH ₂ ; b) (CO ₂ Et) ₂ CH = CH (OEt); c) CF ₃ CO ₂ H, PPh ₃ , CCl ₄ , Et ₃ N; d) MeI; e) PPA or diphenyl ether; f) NaOH.

Synthesis of P-IV-A, P-IV-B, or P-IV-C Precursor Acids

a) AcONH ₄ ; b) EtOCHC (CO ₂ Et) ₂ , 130 ^O C; c) Ph ₂ O, ΔT; d) I ₂ , EtOH; e) NaOH.

Synthesis of P-IV-A, P-IV-B, or P-IV-C Precursor Acids

a) POCl ₃ ; b) R'ONa; c) n-BuLi, ClCO ₂ Et; d) NaOH.

Synthesis of P-III-A Precursor Amine :

a) (CH ₃ ) ₂ SO ₄ ; b) K ₃ Fe (CN) ₆ , NaOH, H ₂ O; c) HNO ₃ , H ₂ SO ₄ ; d) RCOCH ₃ , MeOH, NH ₃ ; e) H ₂ , Raney nickel.

Synthesis of P-IV-A Precursor Amine :

a) HNO ₃ , HOAc; b) Na ₂ S ₂ O ₄ , THF / H ₂ O; c) H ₂ , Pd / C.

Synthesis of amine precursor PVA-1 :

a) KNO ₃ , H ₂ SO ₄ ; b) NaNO ₂ , H ₂ SO ₄ —H ₂ O; c) NH ₄ CO ₂ H, Pd-C; d) R'X; e) NH ₄ CO ₂ H, Pd-C.

Synthesis of amine precursor PVA-1 :

a) SO ₂ Cl ₂ , R2 = Cl; b) R2OH, R2 = alkyl; c) NBS, R1 = Br; d) ClCO ₂ R, TEA; e) HNO ₃ , H ₂ SO ₄ ; f) base; g) ArB (OH) ₂ , R1 = Br; h) [H]; i) R'X, R1 = Br; j) ClCF ₂ CO ₂ Me; k) [H]; l) [H].

Synthesis of amine precursor PVA-1 :

a) KNO ₃ ; b) [H]; c) KNO ₃ ; d) AcCl; e) [H]; f) i) NaNO ₂ ; ii) H ₂ O; g) HCl.

Synthesis of amine precursor PVA-1 :

a) HNO ₃ , H ₂ SO ₄ ; b) [H]; c) protection; d) R'CHO; e) deprotection; f) [H]; g) Na ₂ S, S, H ₂ O; h) nitration; i) (Boc) ₂ O; j) [H]; k) RX; 1) [H]; PG = protecting group.

Synthesis of PVA-1 or PVA-2 amine precursors:

a) Br ₂ ; b) Zn (CN) ₂ , Pd (PPh) ₃ ; c) [H]; d) BH ₃ ; e) (Boc) ₂ O; f) [H]; g) H ₂ SO ₄ , H ₂ O; h) R'X; i) [H]; j) LiAlH ₄ .

Synthesis of PVA-1 or PVA-2 amine precursors:

a) (i) NaNO ₂ , HCl; ii) Na ₂ SO ₃ , CuSO ₄ , HCl; b) NH ₄ Cl; c) [H].

Synthesis of amine precursor PVA-1 :

a) CHCl ₂ OMe; b) KNO ₃ , H ₂ SO ₄ ; c) Deoxofluoride; d) Fe.

Synthesis of amine precursor PVA-3 :

Ar = aryl or heteroaryl

a) nitration; b) ArB (OH) ₂ , Pd; c) BH ₃ ; d) (Boc) ₂ O.

Synthesis of the amine precursor PV-B-1 :

a) AcCl; b) DEAD; c) AlCl ₃ ; d) NaOH.

Synthesis of the amine precursor PV-B-1 :

a) ClCH ₂ COCl; b) [H]; c) protection; d) [H];

PG = protecting group.

Synthesis of the amine precursor PV-B-1 :

a) HSCH ₂ CO ₂ H; b) [H].

Synthesis of the amine precursor PV-B-2 :

a) AlCl ₃ ; b) [H]; c) i) R1R2CHCOCH ₂ CH ₂ Cl; ii) NaBH ₄ ; d) NH ₂ OH; e) DIBAL-H; f) nitration; g) protection; h) [H];

PG = protecting group.

Synthesis of the amine precursor PV-B-3 :

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

PG = protecting group.

Synthesis of the amine precursor PV-B-5 :

a) when X = Cl, Br, I: RX, K ₂ CO ₃ , DMF or CH ₃ CN; when X = OH: RX, TFFH, DIEA, THF; b) H ₂ , Pd-C, EtOH or SnCl ₂ · 2H ₂ O, EtOH or SnCl ₂ · 2H ₂ O, DIEA, EtOH.

Synthesis of the amine precursor PV-B-5 :

a) RCOCl, Et ₃ N, CH ₂ Cl ₂ ; b) n-BuLi, THF; c) NaBH ₄ , AcOH; d) KNO ₃ , H ₂ SO ₄ ; e) DDQ, 1,4-dioxane; f) NaNO ₂ , HCl, SnCl ₂ · 2H ₂ O, H ₂ O; g) MeCOR, EtOH; h) PPA; i) LiAlH ₄ , THF or H ₂ , Raney nickel, EtOH or MeOH.

Synthesis of the amine precursor PV-B-5 :

a) NaNO ₂ , HCl, SnCl ₂ · 2H ₂ O, H ₂ O; b) RCH ₂ COR, AcOH, EtOH; c) H ₃ PO ₄ , toluene; d) H ₂ , Pd-C, EtOH.

Synthesis of the amine precursor P-V-B-5 :

a) NaNO ₂ , HCl, SnCl ₂ · 2H ₂ O, H ₂ O; b) RCH ₂ COH, AcOH, EtOH; c) H ₃ PO ₄ , toluene; d) H ₂ , Pd-C, EtOH.

Synthesis of the amine precursor P-V-B-5 :

a) RX (X = Br, I), zinc triflate, TBAI, DIEA, toluene; b) H ₂ , Raney nickel, EtOH or H ₂ , Pd-C, EtOH or SnCl ₂ · 2H ₂ O, EtOH; c) ClSO ₂ NCO, DMF, CH ₃ CN; d) Me ₂ NH, H ₂ CO, AcOH; e) MeI, DMF, THF, H ₂ O; f) MNu (M = Na, K, Li; Nu = nucleophile).

Synthesis of the amine precursor P-V-B-5 :

a) HNO ₃ , H ₂ SO ₄ ; b) Me ₂ NCH (OMe) ₂ , DMF; c) H ₂ , Raney Nickel, EtOH.

Synthesis of the amine precursor P-V-B-5 :

but) when PG = SO₂Ph: PhSO₂Cl, Et₃N, DMAP, CH₂Cl₂; when PG = Ac: AcCl, NaHCO₃, CH₂Cl₂; b) when R = RCO: (RCO)₂O, AlCl₃, CH₂Cl₂; when R = Br: Br₂AcOH; c) HBr or HCl; d) KNO₃, H₂SO_four; e) MnO₂, CH₂Cl₂ or DDQ, 1,4-dioxane; f) H₂Raney Nickel, EtOH.

Synthesis of the amine precursor P-V-B-5 :

a) NBS, DMF; b) KNO ₃ , H ₂ SO ₄ ; c) HC = CSiMe ₃ , Pd (PPh ₃ ) ₂ Cl ₂ , CuI, Et ₃ N, toluene, H ₂ O; d) CuI, DMF; e) H ₂ , Raney Nickel, MeOH.

Synthesis of the amine precursor P-V-A-3 or P-V-A-6 :

Ar = aryl or heteroaryl;

a) ArB (OH) ₂ , Pd (PPh ₃ ) ₄ , K ₂ CO ₃ , H ₂ O, THF or ArB (OH) ₂ , Pd ₂ (dba) ₃ , P (tBu) ₃ , KF, THF.

Synthesis of the amine precursor P-V-A-4 :

R = CN, CO ₂ Et; a) MeI, NaOtBu, DMF; b) HCO ₂ K, Pd-C, EtOH or HCO ₂ NH ₄ , Pd-C, EtOH.

Synthesis of the amine precursor P-V-A-4 :

a) ArBr, Pd (OAc) ₂ , PS-PPh ₃ , K ₂ CO ₃ , DMF.

Synthesis of the amine precursor P-V-B-4 :

a) H ₂ , Pd-C, MeOH.

Synthesis of the amine precursor P-V-B-4 :

a) NaBH ₄ , MeOH; b) H ₂ , Pd-C, MeOH; c) NH ₂ OH, pyridine; d) H ₂ , Pd-C, MeOH; e) Boc ₂ O, Et ₃ N, MeOH.

The synthesis of compounds of formula I

a) Ar ₁ R7NH, coupling agent, base, solvent. Examples of conditions used: HATU, DIEA; BOP, DIEA, DMF; HBTU, Et ₃ N, CH ₂ Cl ₂ ; PFPTFA, pyridine.

The synthesis of compounds of formula I '

R ⁵ = aliphatic group: a) R ⁵ X (X = Br, I), Cs ₂ CO ₃ , DMF.

Synthesis of compounds of formula VB-5

a) NaOH, THF; b) HNR ₂ , HATU, DIEA, DMF.

Synthesis of compounds of formula VB-5

WR ^W = aryl or heteroaryl: a) ArB (OH) ₂ , (dppf) PdCl ₂ , K ₂ CO ₃ , DMF.

The synthesis of compounds of the formulaV-A-2and formulasV-A-5

a) SnCl ₂ · 2H ₂ O, EtOH; b) PG = Boc: TFA, CH ₂ Cl ₂ ; c) CH ₂ O, NaBH ₃ CN, CH ₂ Cl ₂ , MeOH; d) RXCl, DIEA, THF or RXCl, NMM, 1,4-dioxane or RXCl, CH ₂ Cl ₂ , DMF; e) R'R "NH, LiClO ₄ , CH ₂ Cl ₂ , iPrOH.

Synthesis of compounds of formula V-B-2

a) when PG = Boc: TFA, CH ₂ Cl ₂ ; when PG = Ac: NaOH or HCl, EtOH or THF.

Synthesis of compounds of formula V-A-2

a) when PG = Boc: TFA, CH ₂ Cl ₂ .

a) when PG = Boc: TFA, CH ₂ Cl ₂ ; b) ROCOCl, Et ₃ N, DMF.

Synthesis of compounds of formula VA-4 :

a) when PG = BOC: TFA, CH ₂ Cl ₂ ; b) when R ^W = CO ₂ R: ROCOCl, DIEA, MeOH

In the above schemes, the radical R used is a substituent, for example, R ^W , as defined hereinabove. One skilled in the art will recognize that synthetic routes suitable for the various substituents of the present invention are such that the reaction conditions and steps used do not cause modifications of the substituents in mind.

5. Applications, finished dosage form and administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention relates to compounds that are useful as modulators of ABC transporters and, thus, are useful in the treatment of diseases, disorders or conditions, such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; coagulation-fibrinolysis deficiencies such as protein C deficiency, hereditary type 1 angioedema; lipid processing deficits, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia; lysosomal accumulation diseases such as I-cell inclusions disease / Hurler's pseudosyndrome, mucopolysaccharidoses, Sandhoff / Tey-Sachs disease, type II Kriegler-Nayyar’s disease, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron microsomyosoma, myelopherosanosis deficiency, melioperoxidosis deficiency, meloperosis deficiency, Type 1 CDG, congenital hyperthyroidism, osteopsatirosis, hereditary hypofibrigenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysical DI, non-progenic DI, Charcot-Marie-Tooth syndrome, Pearl disease tseusa-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amphiotrophic lateral sclerosis, progressive supranuclearplasia, Peak's disease; severe polyglutamine neurological disorders, such as Huntington’s disease, type I spinal cerebral ataxia, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Kreutzfeldton disease, Protein-prone disease, defect protein-producing disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's syndrome.

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

It should also be appreciated that some of the compounds of the present invention may exist in free form for treatment or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof or a prodrug thereof. In accordance with the present invention, a pharmaceutically acceptable derivative or prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative that (which), after administration to a patient in need thereof, capable of producing, directly or indirectly, a compound, otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, as part of a medical health assessment, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction and the like, and correspond acceptable benefit / risk ratio. The term “pharmaceutically acceptable salt” means any non-toxic salt or ester salt of a compound of the present invention which, upon administration to a recipient, is capable of producing, directly or indirectly, a compound of the present invention or its active inhibitory metabolite or residue.

Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences, 66 , 1-19 (1977), incorporated herein 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 addition salts are those formed by the amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid , tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in this field, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentapropionate, digluconate, dodecyl sulfate, ethanesulfonate, hemo glufonate, glucose glucose, glucose glucose, glucose glucose, , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectin, , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from the corresponding bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of compounds disclosed herein. Water or oil soluble or dispersible products can be obtained by such quaternization. Examples of alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additionally, pharmaceutically acceptable salts include, where appropriate, non-toxic cations of ammonium, quaternary ammonium and amine formed using counterions such as halide ion, hydroxyl ion, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant or excipient, which, as used herein, includes any or all of the solvents, diluents, or other liquid excipient auxiliary to the dispersion or suspension of the agent, surfactants substances, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, depending on the desired co specific dosage form. In Remington's Pharmaceutical Sciences, sixteenth edition, E.W. Martin (Mack Publishing Co, Easton, Pa, 1980) describes various carriers used in the preparation of pharmaceutically acceptable compositions and known methods for their preparation. Except when any conventional carrier medium is incompatible with the compounds of the invention, such as causing an undesirable biological effect or otherwise interacting harmful with any other component (s) of a pharmaceutically acceptable composition, it is contemplated that its use is included to the scope of this invention. Some examples of substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid or potassium sorbate, mixtures of incomplete glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal ioksid silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, bloksposolimery with polyethylene and polyoxypropylene blocks, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and candle waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethyl alcohol and phosphate buffered saline, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring and flavoring agents, preservatives and antioxidants, may be present in the composition according to manufacturer’s assessment.

The use of compounds and pharmaceutically acceptable compositions

According to another aspect, the present invention relates to a method for treating a condition, disease and disorder in which an ABC transporter activity, for example, CFTR, is involved. According to some embodiments, the present invention relates to a method for treating a condition, disease or disorder in which an ABC transporter activity deficiency is involved, comprising administering a composition containing a compound of formula (I) to a subject, preferably a mammal, in need of such treatment.

According to some variants of implementation, the present invention relates to a method for the treatment of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary type 1 angioedema; lipid processing deficits, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia; lysosomal accumulation diseases such as I-cell inclusions disease / Hurler's pseudosyndrome, mucopolysaccharidoses, Sandhoff / Tey-Sachs disease, type II Kriegler-Nayyar disease, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron microsomy, glomerosicanosis, mileopenosis deficiency, meloperosanosis, Type 1 CDG, congenital hyperthyroidism, osteopsatyrosis, hereditary hypofibrogenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysical DI, non-progenic DI, Charcot-Marie-Tooth syndrome, Per disease itseusa-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amphiotrophic lateral sclerosis, progressive supranuclearplasia, Peak's disease; severe polyglutamine neurological disorders, such as Huntington’s disease, type I spinal cerebral ataxia, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Kreitzfeldt-Disease-like disease) Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's syndrome; comprising the step of administering to the aforementioned mammal an effective amount of a composition comprising a compound of the present invention.

According to an alternative preferred embodiment, the present invention relates to a method for treating cystic fibrosis, comprising the step of administering to the above mammal an effective amount of a composition comprising a compound of the present invention.

According to the present invention, an “effective amount” of a compound or a pharmaceutically acceptable composition is an amount effective to treat or ameliorate the severity of one or more diseases, such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; coagulation-fibrinolysis deficiencies such as protein C deficiency, hereditary type 1 angioedema; lipid processing deficits, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia; lysosomal accumulation diseases such as I-cell inclusions disease / Hurler's pseudosyndrome, mucopolysaccharidoses, Sandhoff / Tey-Sachs disease, type II Kriegler-Nayyar’s disease, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron microsomyosoma, myelopherosanosis deficiency, melioperoxidosis deficiency, meloperosis deficiency, Type 1 CDG, congenital hyperthyroidism, osteopsatirosis, hereditary hypofibrigenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysical DI, non-progenic DI, Charcot-Marie-Tooth syndrome, Pearl disease tseusa-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amphiotrophic lateral sclerosis, progressive supranuclearplasia, Peak's disease; severe polyglumine neurological disorders, such as Huntington’s disease, type I spinal cerebral ataxia, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Kreutzfeldton disease (Protein disease, Protein-defect disease), Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's syndrome.

Compounds and compositions, in accordance with the method according to the present invention, can be administered using any number and any route of administration effective in treating or alleviating the severity of one or more diseases, such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis; coagulation-fibrinolysis deficiencies such as protein C deficiency, hereditary type 1 angioedema; lipid processing deficits, such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia; lysosomal accumulation diseases such as I-cell inclusions disease / Hurler's pseudosyndrome, mucopolysaccharidoses, Sandhoff / Tey-Sachs disease, type II Kriegler-Nayyar’s disease, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron microsomyosoma, myelopherosanosis deficiency, melioperoxidosis deficiency, meloperosis deficiency, Type 1 CDG, congenital hyperthyroidism, osteopsatirosis, hereditary hypofibrigenemia, adrenocorticotropic hormone deficiency, diabetes insipidus (DI), neurophysical DI, non-progenic DI, Charcot-Marie-Tooth syndrome, Pearl disease tseusa-Merzbacher; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amphiotrophic lateral sclerosis, progressive supranuclearplasia, Peak's disease; severe polyglutamine neurological disorders, such as Huntington’s disease, type I spinal cerebral ataxia, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Kreutzfeldton disease, Protein-prone disease, defect protein-producing disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's syndrome.

In accordance with one embodiment, the compounds and compositions of the present invention are useful for treating or alleviating the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of the respiratory and non-respiratory epithelium. The presence of residual CFTR activity on the epithelial surface can be easily determined using methods known in the art, for example, standard electrophysiological, biochemical or histochemical methods. Using such methods, CFTR activity is identified using in vivo or ex vivo electrophysiological methods, by measuring Cl ^- concentrations in sweat or saliva, or ex vivo biochemical or histochemical methods, by monitoring cell surface density. Using such methods, the residual activity of CFTR can be easily determined in heterozygous or homozygous patients for many different mutations, including homozygous or heterozygous patients with the most common mutation, ΔF508.

According to another embodiment, the compounds and compositions of the present invention are useful for treating or alleviating the severity of cystic fibrosis in patients who have induced or increased residual CFTR activity using pharmacological methods or gene therapy. Such methods increase the amount of CFTR located on the surface of the cell, thereby inducing thus far the absence of CFTR activity in the patient or increasing the existing level of residual CFTR activity in the patient.

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

In accordance with one embodiment, the compounds and compositions of the present invention are useful for treating or alleviating the severity of cystic fibrosis in patients with certain clinical phenotypes, such as a moderate to weak clinical phenotype, which usually correlates with the amount of residual CFTR activity in the apical epithelial membrane . Such phenotypes include patients with pancreatic insufficiency, or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the excretory vessel, or with mild lung disease.

The exact amount required varies from subject to subject, depending on the kind, age, and general condition of the subject, the severity of the infection, the specific agent, the route of administration, and the like. The compounds of the invention are preferably used to prepare a medicament in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form", as used herein, refers to a physically discrete unit of the corresponding agent for the patient being treated. However, it should be understood that the total daily dose of the compounds and compositions according to the present invention should be determined by a staff doctor as part of a medical health assessment. The level of a specific effective dose for any particular patient or organism depends on a number of factors, including the disorder to be treated and the severity of the disorder, the activity of the particular compound used, the particular composition used; age, body weight, general health, gender and diet of the patient; time of administration, route of administration and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or simultaneously with the particular compound used, and the like, well known in medicine. The term “patient,” as used herein, means an animal, preferably a mammal, and, most preferably, a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistinally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccally, in the form of an oral or nasal spray, or the like, depending from the severity of the infection that needs to be treated. In accordance with some embodiments, the compounds of the invention can be administered orally or parenterally at a dosage level of from about 0.01 mg / kg to about 50 mg / kg, and preferably from about 1 mg / kg to about 25 mg / kg, based on the patient’s body weight, per day, one or more times a day, to achieve the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, etragidrofurfurilovy alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors and flavors.

Injectable preparations, for example, sterile injectable aqueous or oily suspensions, may be prepared according to the prior art using suitable dispersants or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Suitable excipients and solvents that can be used are water, Ringer's solution according to the US Pharmacopeia, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. For this purpose, any tasteless fixed oils may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in injection preparations.

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

In order to prolong the effect of the compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with low solubility in water. The absorption rate of the compound then depends on its dissolution rate, which, in turn, may depend on the size of the crystal and crystalline form. Alternatively, the delayed absorption of the form of the parenterally administered compound is completed by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by creating matrices for microencapsulation of a compound from biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot compositions are also prepared by incorporating the compound into liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or candle wax, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) excipients or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants, such as glycerin, d) disintegrants, such as agar agar, calcium carbonate, tofile or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coated coatings and coatings, such as enteric coatings or other coatings well known in the pharmaceutical art. They may optionally contain opacifying components and may also be of such a composition that they release only the active ingredient (s) or preferably in a certain part of the gastrointestinal tract, optionally, in a delayed manner. Examples of formulations that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more excipients, as described above. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings, such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical art. 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 may also include, as is common practice, additional substances other than inert diluents, for example, tabletting lubricants and other tabletting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also include buffering agents. They may optionally contain opacifying components and may also be of such a composition that they release only the active ingredient (s) or preferably in a certain part of the gastrointestinal tract, optionally, in a delayed manner. Examples of formulations that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhaled dosage forms or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as may be required. Ophthalmic composition, ear drops and eye drops are also contemplated as being within the scope of the present invention. Additionally, according to the present invention, it is contemplated to use transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers may also be used to increase the flow of the compound through the skin. The speed can be controlled either by controlling the speed of the membrane, or by dispersing the compound in a polymer matrix or gel.

As generally described above, the compounds of the invention are useful as ABC transporter modulators. Thus, not wishing to resort to any particular theory, the compounds and compositions are particularly useful in treating or alleviating the severity of a disease, condition or disorder, where the hyperactivity or inactivity of ABC transporters is involved in the disease, condition or disorder. When an ABC transporter hyperactivity or inactivity is implicated in a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as an “ABC transporter mediated disease, condition or disorder”. Accordingly, according to another aspect, the present invention relates to a method for treating or alleviating the severity of a disease, condition or disorder, wherein an ABC transporter hyperactivity or inactivity is involved in a disease state.

The activity of the compound used according to the present invention as an ABC transporter modulator can be determined in accordance with methods commonly described in the art and in the examples of this description.

It should also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, that is, the compounds and pharmaceutically acceptable compositions can be administered simultaneously with, before or after one or more other desired therapeutic agents or therapeutic procedures. A particular combination of therapies (therapeutic agents or procedures) for use in combination regimens is selected based on the compatibility of the desired therapeutic agents and / or procedures and the achievement of the desired therapeutic effect. It should also be taken into account that in the case of therapies used, the desired effect can be achieved for the same disorder (for example, the compound of the invention can be administered simultaneously with another agent used to treat the same disorder) or different effects can be achieved ( for example, controlling any side effects). As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease or condition are known as “suitable for the disease or condition that is being treated”.

According to one embodiment, the additional agent is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infectious agent, an anti-inflammatory agent, a CFTR modulator, other than the compound of the present invention, or a nutrition-related agent.

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

The compounds of the present invention, or pharmaceutically acceptable compositions containing them, can also be formulated for coating an implantable medical device, such as prostheses, artificial valves, vascular implants, stents and catheters. Accordingly, the present invention, in accordance with another aspect, relates to an implantable coating composition comprising a compound according to the present invention, as generally described above, and according to the classes and subclasses described herein, and a carrier that is suitable for coating to the above implantable device. According to another aspect, the present invention relates to an implantable device, which is coated using a composition containing a compound according to the present invention, as generally described above, and according to the classes and subclasses specified in this description, and a carrier that is suitable for application coatings on the above implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Pat. Coatings may optionally be further protected with a suitable topcoated coating of fluorosilicon, polysaccharides, polyethylene glycol, phospholipids, or a combination thereof, to impart controlled release characteristics to the composition.

Another aspect of the invention relates to modulating the activity of an ABC transporter in a biological sample or in a patient (e.g., in vitro or in vivo) by a method that comprises administering to a patient or contacting with the above biological sample a compound of formula (I) or a composition containing the above compound. The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from mammals, or extracts from it; and blood, saliva, urine, excrement, semen, lacrimal fluid or other body fluids, or extracts from them.

The modulation of the activity of the ABC transporter, for example, CFTR, in a biological sample is suitable for many purposes that are known to the person skilled in the art. Examples of such goals include, but are not limited to, the study of ABC transporters in relation to biological and pathological phenomena and a comparative assessment of new modulators of ABC transporters.

According to yet another embodiment, a method of modulating anion channel activity, in vitro or in vivo, comprises the step of contacting the aforementioned channel with a compound of formula (I). According to preferred embodiments, the anion channel is a chloride channel or a bicarbonate channel. According to other preferred embodiments, the anion channel is a chloride channel.

According to an alternative embodiment, the present invention relates to a method for increasing the number of functional ABC transporters in a cell membrane, comprising the step of contacting said cell with a compound of formula (I). The term “functional ABC transporter,” as used herein, means an ABC transporter that has transport activity. According to preferred embodiments, the aforementioned functional ABC transporter is CFTR.

According to another preferred embodiment, the activity of the ABC conveyor is determined by measuring the transmembrane voltage potential. To measure the voltage potential across the membrane in a biological sample, any of the methods known in the art can be used, such as optical analysis of the transmembrane potential or other electrophysiological methods.

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

The given potential-sensitive tests are based on changing the resonance with fluorescence energy transfer (FRET) between the membrane-soluble, potential-sensitive dye, DiSBAC ₂ (3), and the fluorescent phospholipid, CC2-DMPE, which is associated with the outer “leaf” of the cytoplasmic membrane and acts as a donor FR. Changes in the transmembrane potential (V _m ) cause the redistribution of the negatively charged DiSBAC ₂ (3) in the cytoplasmic membrane and, accordingly, the amount of energy transferred from CC2-DMPE changes. Changes in fluorescence emission can be controlled using the VIPR ^™ II device, which is an integrated fluid manipulator and fluorescence detector designed to perform cell-based screening using 96- or 384-well microtiter plates.

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

In order to better understand the invention described herein, the following examples are provided. It is intended that these examples are provided for illustrative purposes only and cannot be construed as limiting the invention in any way.

EXAMPLES

Example 1

General scheme for producing acidic components:

a) 140-150 ^about C; b) PPA, POCl _3, 70 ° C or diphenyl ether, 220 ^C; c) i) 2n. NaOH ii) 2n. HCl.

Specific example

2-Phenylaminomethylene malonic acid diethyl ester

A mixture of aniline (25.6 g, 0.28 mol) and diethyl 2- (ethoxymethylene) malonate (62.4 g, 0.29 mol) is heated at a temperature of 140-150 ° C for 2 hours. The mixture was cooled to room temperature and dried under reduced pressure to obtain 2-phenylaminomethylene malonic acid diethyl ester as a solid, which was used in the next step without further purification.

¹ H NMR (d-DMSO) δ 11.00 (d, 1H), 8.54 (d, J = 13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13 -7.17 (m, 3H); 4.17-4.33 (m, 4H); 1.18-1.40 (m, 6H).

4-hydroxyquinoline-3-carboxylic acid ethyl ester

2-phenylaminomethylene malonic acid diethyl ester (26.3 g, 0.1 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g) are introduced into a 1-liter three-necked flask equipped with a mechanical stirrer. The mixture is heated at a temperature of about 70 ° C and stirred for 4 hours. The mixture was cooled to room temperature and filtered. The residue is treated with an aqueous solution of Na ₂ CO ₃ , filtered, washed with water and dried. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a pale brown solid (15.2 g, 70% yield). The crude product is used in the next step without further purification.

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

4-hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 ml) and stirred for 2 hours at reflux temperature. After cooling, the mixture was filtered and the filtrate was acidified to pH = 4-2N. HCl solution. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( A-1 ) as a dull white solid (10.5 g, 92% yield).

¹ H NMR (d-DMSO) δ 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H ), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).

Specific example

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

6-Fluoro-4-hydroxyquinoline-3-carboxylic acid ( A-2 ) is synthesized according to the general scheme given above based on 4-fluorophenylamine. Total yield (53%).

¹ H-NMR (DMSO-d ₆ ): δ 15.2 (br s, 1H), 8.89 (s, 1H), 7.93-7.85 (m, 2H), 7.80-7 74 (m, 1H).

ESI-MS: 207.9 m / z (MH ⁺ ).

Example 2

2-bromo-5-methoxyphenylamine

A mixture of 1-bromo-4-methoxy-2-nitrobenzene (10 g, 43 mmol) and Raney nickel (5 g) in ethanol (100 ml) was stirred under a hydrogen atmosphere (1 atm.) For 4 hours at room temperature. Raney nickel is filtered off and the filtrate is concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxyphenylamine (7.5 g, 86% yield).

2 - [(2-Bromo-5-methoxyphenylamino) methylene] malonic acid diethyl ether

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

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

2 - [(2-Bromo-5-methoxyphenylamino) methylene] malonic acid diethyl ether (9 g, 24.2 mmol) is slowly added to polyphosphoric acid (30 g) at a temperature of 120 ° C. The mixture was stirred at this temperature for 30 minutes and then cooled to room temperature. Absolute ethanol (30 ml) was added and the resulting mixture was refluxed for 30 minutes. The mixture was made basic with an aqueous solution of sodium bicarbonate at a temperature of 25 ° C. and extracted with EtOAc (4 times, 100 ml each). The organic layers were combined, dried and the solvent was evaporated, yielding 8-bromo-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (2.3 g, 30% yield).

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

A mixture of 8-bromo-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (2.3 g, 7.1 mmol), sodium acetate (580 mg, 7.1 mmol) and 10 % Pd / C (100 mg) in glacial acetic acid (50 ml) was stirred in an atmosphere of hydrogen (2.5 atm.) overnight. The catalyst was removed by filtration and the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in CH ₂ Cl ₂ (100 ml) and washed with aqueous sodium bicarbonate and water. The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography to give 5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester as a yellow solid (1 g, 57% yield).

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

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

¹ H-NMR (DMSO) δ 15.9 (s, 1H), 13.2 (broad, 1H), 8.71 (s, 1H), 7.71 (t, J = 8.1 Hz, 1H ), 7.18 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H).

ESI-MS: 219.9 m / z (MH ⁺ ).

Example 3

2- (mercaptophenylaminomethylene) malonic acid sodium diethyl ether

To a suspension of NaH (60% in mineral oil, 6 g, 0.15 mol) in Et ₂ O at ethyl temperature, ethyl malonate (24 g, 0.15 mol) was added dropwise over 30 minutes. Then phenylisothiocyanate (20.3 g, 0.15 mol) is added dropwise with stirring for 30 minutes. The mixture was refluxed for 1 hour and then stirred overnight at room temperature. The solid was separated, washed with anhydrous diethyl ether (200 ml) and dried in vacuo to give diethyl ether of the sodium salt of 2- (mercaptophenylaminomethylene) malonic acid as a pale yellow powder (46 g, yield 97%).

2- (Methylsulfanylphenylaminomethylene) malonic acid diethyl ether

Methyl iodide (17.7 g, 125 mmol) was added dropwise over 30 minutes to a solution of 2- (mercaptophenylaminomethylene) sodium malonic acid diethyl ether (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 resulting solid was separated by filtration, washed with water and dried to give 2- (methylsulfanylphenylaminomethylene) malonic acid diethyl ester as a pale yellow solid (27 g, 84% yield).

4-hydroxy-2-methylsulfanylquinoline-3-carboxylic acid ethyl ester

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

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

4-Hydroxy-2-methylsulfanylquinoline-3-carboxylic acid ethyl ester (8 g, 30 mmol) was refluxed in a NaOH solution (10%, 100 ml) for 1.5 hours. After cooling, the mixture was acidified with concentrated HCl to pH = 4. The resulting solid was separated by filtration, washed with water (100 ml) and MeOH (100 ml) to obtain 2-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( A-16 ) as a white solid (6 g, yield 85%).

¹ H-NMR (CDCl ₃ ) δ 16.4 (br s, 1H), 11.1 (br s, 1H), 8.19 (d,

J = 8 Hz, 1H), 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) PPh ₃ , Et ₃ N, CCl ₄ , CF ₃ CO ₂ H; b) diethyl malonate; c) T ~ 200 ^O C; d) 10% NaOH.

2,2,2-Trifluoro-N-phenylacetylamidoyl chloride

A mixture of Ph ₃ P (138.0 g, 526 mmol), Et ₃ N (21.3 g, 211 mmol), CCl ₄ (170 ml) and TFA (20 g, 175 mmol) was stirred for 10 minutes in an ice bath . Aniline (19.6 g, 211 mmol) dissolved in CCl ₄ (20 ml) was added. The mixture was stirred at reflux for 3 hours. The solvent was removed in vacuo and hexane was added. Precipitation (Ph ₃ PO and Ph ₃ P) is filtered off and washed with hexane. The filtrate was distilled under reduced pressure to obtain 2,2,2-trifluoro-N-phenylacetylamidoyl chloride (19 g), which was used in the next step without further purification.

2- (2,2,2-Trifluoro-1-phenyliminoethyl) malonic acid diethyl ether

To a suspension of NaH (3.47 g, 145 mmol, 60% in mineral oil) in THF (200 ml) was added diethyl malonate (18.5 g, 116 mmol) at a temperature of 0 ° C. The mixture was stirred for 30 minutes at this temperature and 2,2,2-trifluoro-N-phenylacetylamidoyl chloride (19 g, 92 mmol) was added at a temperature of 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The mixture was diluted with CH ₂ Cl ₂ , washed with saturated sodium bicarbonate solution and brine. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 2- (2,2,2-trifluoro-1-phenyliminoethyl) malonic acid diethyl ether, which was used directly in the next step without further purification.

4-hydroxy-2-trifluoromethylquinoline-3-carboxylic acid ethyl ester

2- (2,2,2-Trifluoro-1-phenyliminoethyl) malonic acid diethyl ether is heated at a temperature of 210 ° C. for 1 hour with continuous stirring. The mixture was purified by column chromatography (petroleum ether) to give 4-hydroxy-2-trifluoromethylquinoline-3-carboxylic acid ethyl ester (12 g, 24% yield in 3 steps).

A-15 ; 4-hydroxy-2-trifluoromethylquinoline-3-carboxylic acid

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

¹ H-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) 7.79-7.83 (t, J = 14.4 Hz, 1H); 7.50-7.53 (t, J = 15 Hz, 1H).

ESI-MS: 257.0 m / z (MH ⁺ ).

Example 5

a) CH ₃ C (O) ONH ₄ , toluene; b) EtOCHC (CO ₂ Et) ₂ , 130 ^O C; c) Ph ₂ O; d) I ₂ , EtOH; e) NaOH.

3-aminocyclohex-2-enon

A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH ₄ (38.5 g, 0.5 mol) in toluene is refluxed for 5 hours using a Dean-Stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-aminocyclohex-2-enone (49.9 g, 90% yield), which was used directly in the next step without further purification.

2 - [(3-Oxocyclohex-1-enylamino) methylene] malonic acid diethyl ether

A mixture of 3-aminocyclohex-2-enone (3.3 g, 29.7 mmol) and diethyl 2- (ethoxymethylene) malonate (6.7 g, 31.2 mmol) was stirred at 130 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, ethyl acetate) to obtain 2 - [(3-oxocyclohex-1-enylamino) methylene] malonic acid diethyl ester (7.5 g, 90% yield).

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

A mixture of 2 - [(3-oxocyclohex-1-enylamino) methylene] malonic acid diethyl ether (2.8 g, 1 mmol) and diphenyl ether (20 ml) was refluxed for 15 minutes. After cooling, n-hexane (80 ml) was added. The resulting solid was isolated by filtration and recrystallized from methanol to give 4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (1.7 g, 72% yield).

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

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

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

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

¹ H-NMR (DMSO-d ₆ ) δ 13.7 (broad, 1H), 13.5 (broad, 1H), 12.6 (s, 1H), 8.82 (s, 1H), 7 68 (t, J = 8.1 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H).

ESI-MS: 205.9 m / z (MH ⁺ ).

Example 6

a) POCl ₃ ; b) MeONa; c) n-BuLi, ClCO ₂ Et; d) NaOH.

2,4-Dichloroquinoline

A suspension of quinoline-2,4-diol (15 g, 92.6 mmol) in POCl _{3 was} refluxed for 2 hours. After cooling, the solvent was removed under reduced pressure to obtain 2,4-dichloroquinoline, which was used without further purification.

2,4-dimethoxyquinoline

Sodium methoxide (50 g) was added to a suspension of 2,4-dichloroquinoline in MeOH (100 ml). The mixture was refluxed for 2 days. After cooling, the mixture is filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was dissolved in water and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 2,4-dimethoxyquinoline as a white solid (13 g, 74% yield in 2 steps).

2,4-Dimethoxyquinoline-3-ethylcarboxylate

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

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

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

¹ H-NMR (CDCl ₃ ) δ 8.01-8.04 (d, J = 12 Hz, 1H), 7.66-7.76 (m, 2H), 7.42-7.47 (t, J = 22 Hz, 2H), 4.09 (s, 3H), 3.97 (s, 3H).

ESI-MS: 234.1 m / z (MH ⁺ ).

Commercially Available Acids Acid Title A-5 6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A-6 6 - [(4-fluorophenyl) methylsulfamoyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-7 6- (4-methylpiperidin-1-sulfonyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-8 4-oxo-6- (pyrrolidin-1-sulfonyl) -1,4-dihydroquinoline-3-carboxylic acid A-10 6-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-11 6-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-12 4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid A-13 7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-14 4-oxo-5,7-bistrifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid A-20 1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-21 1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-22 1,6-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-23 1-ethyl-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid A-24 6-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Amine components

N-1-Substituted 6-aminoindoles

Example 1

The general scheme :

a) RX (X = Cl, Br, I), K ₂ CO ₃ , DMF or CH ₃ CN; b) H ₂ , Pd / C, EtOH or SnCl ₂ · 2H ₂ O, EtOH.

Specific example

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

To a solution of 6-nitroindole (4.05 g, 25 mmol) in DMF (50 ml) was added K ₂ CO ₃ (8.63 g, 62.5 mmol) and MeI (5.33 g, 37.5 mmol). After stirring at room temperature overnight, the mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to afford 1-methyl-6-nitro-1H-indole (4.3 g, 98% yield).

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

A suspension of 1-methyl-6-nitro-1H-indole (4.3 g, 24.4 mmol) and 10% Pd / C (0.43 g) in EtOH (50 ml) was stirred under a hydrogen atmosphere (1 atm .) at room temperature overnight. After filtration, the filtrate was concentrated and acidified with a solution of HCl-MeOH (4 mol / L) to obtain 1-methyl-1H-indol-6-ylamine hydrochloride ( B-1 ) (1.74 g, 49% yield) as a gray powder .

¹ H-NMR (DMSO-d ₆ ): 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), 6.84 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 2.8 Hz, 1H), 3.72 (s, 3H).

ESI-MS: 146.08 m / z (MH ⁺ ).

Other examples

IN 2 ; 1-benzyl-1H-indol-6-ylamine

1-Benzyl-1H-indol-6-ylamine ( B-2 ) is synthesized according to the general scheme given above based on 6-nitroindole and benzyl bromide. Total yield (~ 40%). HPLC: retention time 2.19 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 223.3 m / z (MH ⁺ ).

IN 3 ; 1- (6-aminoindol-1-yl) ethanone

1- (6-aminoindol-1-yl) ethanone ( B-3 ) is synthesized according to the general scheme presented above, starting from 6-nitroindole and acetyl chloride. Total yield (~ 40%). HPLC: retention time 0.54 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 175.1 m / z (MH ⁺ ).

Example 2

{[2- (tert-Butoxycarbonylmethylamino) acetyl] methylamino} acetic acid ethyl ester

To a stirred solution of (tert-butoxycarbonylmethylamino) acetic acid (37 g, 0.2 mol) and Et ₃ N (60.6 g, 0.6 mol) in CH ₂ Cl ₂ (300 ml) isobutyl chloroformate was added dropwise (27, 3 g, 0.2 mmol) at a temperature of -20 ° C in an argon atmosphere. After stirring for 0.5 hours, methylaminoacetic acid ethyl ester hydrochloride (30.5 g, 129 mmol) was added dropwise at a temperature of -20 ° C. The mixture was allowed to warm to room temperature (about 1 hour) and quenched with water (500 ml). The organic layer was separated, washed with 10% citric acid solution, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 1: 1) to obtain {[2- (tert-butoxycarbonylmethylamino) acetyl] methylamino} acetic acid ethyl ester (12.5 g, 22% yield).

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

Suspension of {[2- (tert-butoxycarbonylmethylamino) acetyl] methylamino} acetic acid ethyl ester (12.3 g, 42.7 mmol) and LiOH (8.9 g, 214 mmol) in H ₂ O (20 ml) and THF (100 ml) was stirred overnight. The volatile solvent was removed in vacuo and the residue was extracted with diethyl ether (2 times 100 ml). The aqueous phase is acidified to pH = 3 with a dilute HCl solution and then extracted with CH ₂ Cl ₂ (2 times 300 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give {[2- (tert-butoxycarbonylmethylamino) acetyl] methylamino} acetic acid as a colorless oil (10 g, 90% yield).

¹ H-NMR (CDCl ₃ ): δ 7.17 (br s, 1H), 4.14-4.04 (m, 4H), 3.04-2.88 (m, 6H), 1.45 -1.41 (m, 9H).

ESI-MS: 282.9 m / z (M + Na ⁺ ).

methyl ({methyl [2- (6-nitroindol-1-yl) -2-oxoethyl] carbamoyl} methyl) carbamic acid tert-butyl ester

To a mixture of {[2- (tert-butoxycarbonylmethylamino) acetyl] methylamino} acetic acid (13.8 g, 53 mmol) and TFFH (21.0 g, 79.5 mmol) in anhydrous THF (125 ml) was added DIEA (27 , 7 ml, 159 mmol) at room temperature in a nitrogen atmosphere. The solution was stirred at room temperature for 20 minutes. A solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 ml) was added and the reaction mixture was heated at a temperature of 60 ° C for 18 hours. The solvent was evaporated and the crude mixture was redistributed between EtOAc and water. The organic layer was separated, washed with water (3 times), dried over Na ₂ SO ₄ and concentrated. Then diethyl ether and EtOAc are added. The resulting solid was separated by filtration, washed with diethyl ether and dried in air to give tert-butyl ether methyl ({methyl [2- (6-nitroindol-1-yl) -2-oxoethyl] carbamoyl} methyl) carbamic acid (6.42 g, yield 30%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 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, 0.6H), 4.18 (d, J = 12.0 Hz, 1.4H), 4.92 (d, J = 3.4 Hz, 1.4H), 5.08 (d, J = 11.4 Hz, 0.6H), 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 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 405.5 m / z (MH ⁺ ).

B-26 ; ({[2- (6-aminoindol-1-yl) -2-oxoethyl] methylcarbamoyl} methyl) methylcarbamic acid tert-butyl ester

Mixture of tert-butyl ether methyl ({methyl [2- (6-nitroindol-1-yl) -2-oxoethyl] carbamoyl} methyl) carbamic acid (12.4 g, 30.6 mmol), SnCl ₂ · 2H ₂ O (34.5 g, 153.2 mmol) and DIEA (74.8 ml, 429 mmol) in ethanol (112 ml) are heated at 70 ° C. for 3 hours. Water and EtOAc were added and the mixture was filtered through a small pad of celite. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give tert-butyl ether ({[2- (6-aminoindol-1-yl) -2-oxoethyl] methylcarbamoyl} methyl) methylcarbamic acid ( B-26 ) (11 4 g, quantitative yield).

HPLC: retention time 2.11 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 375.3 m / z (MH ⁺ ).

2-Substituted 6-aminoindoles

Example 1

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

3-Nitrophenylamine (27.6 g, 0.2 mol) was dissolved in a mixture of H ₂ O (40 ml) and 37% HCl solution (40 ml). A solution of NaNO ₂ (13.8 g, 0.2 mol) in H ₂ O (60 ml) was added at a temperature of 0 ° C, then SnCl ₂ · H ₂ O (135.5 g, 0.6 mol) in 37% solution of HCl (100 ml) at the same temperature. After stirring at 0 ° C for 0.5 hours, the solid was isolated by filtration and washed with water to obtain (3-nitrophenyl) hydrazine hydrochloride ( B-4-a ) (27.6 g, 73% yield).

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

(3-Nitrophenyl) hydrazine hydrochloride ( B-4-a ) (30.2 g, 0.16 mol) and 2-oxopropionic acid ethyl ester (22.3 g, 0.19 mol) are dissolved in ethanol (300 ml) . The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to obtain 2 - [(3-nitrophenyl) hydrazono] propionic acid ethyl ester, which was used directly in the next step.

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

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

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

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

¹ H-NMR (CDCl ₃ ): δ 7.57 (br s,; 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.62 (s, 1H), 6.51 -6.53 (m, 1H), 6.07 (s, 1H), 3.59-3.25 (br s, 2H), 2.37 (s, 3H).

ESI-MS: 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 4-nitro-1H-indole-2-carboxylic acid ethyl ester and 6-nitro-1H-indole-2-carboxylic acid ethyl ester ( B-4-b ) (0.5 g, 2.13 mmol) in 10 % NaOH solution (20 ml) is refluxed overnight and then cooled to room temperature. The mixture was extracted with diethyl ether. The aqueous phase is separated and acidified with HCl to pH = 1-2. The resulting solid was isolated by filtration to obtain a mixture of 6-nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid (0.3 g, 68% yield).

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

A mixture of 6-nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid (12 g, 58 mmol) and SOCl ₂ (50 ml, 64 mmol) in benzene (150 ml) is boiled under reflux for 2 hours. Benzene and excess SOCl ₂ are removed under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (250 ml). NH ₄ OH (21.76 g, 0.32 mol) was added dropwise at a temperature of 0 ° C. The mixture was stirred at room temperature for 1 hour. The resulting solid was isolated by filtration to obtain a crude mixture of 6-nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H-indole-2-carboxylic acid amide (9 g, 68% yield), which was used directly in the next stage.

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

A mixture of 6-nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H-indole-2-carboxylic acid amide (5 g, 24 mmol) was dissolved in CH ₂ Cl ₂ (200 ml). Et ₃ N (24.24 g, 0.24 mol) was added, then (CF ₃ CO) ₂ O (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 is separated. The aqueous layer was extracted with EtOAc (3 times 100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give a mixture of 6-nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile (2.5 g, 55% yield).

AT 5 ; 6-amino-1H-indole-2-carbonitrile

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

¹ H-NMR (DMSO-d ₆ ): δ 12.75 (br s, 1H), 7.82 (d, J = 8 Hz, 1H), 7.57 (s, 1H), 7.42 ( s, 1H), 7.15 (d, J = 8 Hz, 1H).

ESI-MS: 158.2 m / z (MH ⁺ ).

Example 3

2,2-Dimethyl-N-o-tolylpropionamide

To a solution of o-tolylamine (21.4 g, 0.20 mol) and Et ₃ N (22.3 g, 0.22 mol) in CH ₂ Cl ₂ , 2,2-dimethylpropionyl chloride (25.3 g, 0, 21 mol) at a temperature of 10 ° C. The mixture was stirred overnight at room temperature, washed with aqueous HCl (5%, 80 ml), saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 2,2-dimethyl- N-o-tolylpropionamide (35.0 g, yield 92%).

2-tert-butyl-1H-indole

To a solution of 2,2-dimethyl-N-o-tolylpropionamide (30.0 g, 159 mmol) in anhydrous THF (100 ml) was added dropwise n-BuLi (2.5 M, in hexane, 190 ml) at a temperature of 15 ° C. The mixture was stirred overnight at a temperature of 15 ° C, cooled in a bath with ice water and treated with a saturated solution of NH ₄ Cl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to give 2-tert-butyl-1H-indole (23.8 g, 88% yield).

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 NaBH ₄ at a temperature of 10 ° C. The mixture was stirred for 20 minutes at 10 ° C., treated with dropwise H ₂ O under ice-cooling, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a mixture of the starting material 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-2,3-dihydro-1H-indole

To a solution of a mixture of 2-tert-butyl-2,3-dihydro-1H-indole and 2-tert-butyl-1H-indole (9.7 g) in H ₂ SO ₄ (98%, 80 ml) was slowly added KNO ₃ (5.6 g, 55.7 mmol) at a temperature of 0 ° C. The reaction mixture was stirred at room temperature for 1 hour, carefully poured onto crushed ice, basified with Na ₂ CO ₃ to pH = ~ 8 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated 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% yield in 2 steps).

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 refluxing for 2.5 hours, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-1H-indole (1.6 g, 80% yield).

AT 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), Raney nickel (0.2 g) was added. The mixture was stirred at room temperature in a hydrogen atmosphere (1 atm.) For 3 hours. The resulting mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-1H-indol-6-ylamine ( B-6 ) (1.0 g, 89% yield).

¹ H-NMR (DMSO-d ₆ ) δ 10.19 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.46 (s, 1H), 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-aminoindoles

Example 1

N- (3-Nitrophenyl) -N'-propylidenehydrazine

A solution of sodium hydroxide (10%, 15 ml) is slowly added to a stirred suspension of (3-nitrophenyl) hydrazine hydrochloride ( B-4-a ) (1.89 g, 10 mmol) in ethanol (20 ml) until pH = 6. Acetic acid (5 ml) was added to the mixture, followed by propionic aldehyde (0.7 g, 12 mmol). After stirring for 3 hours at room temperature, the mixture was poured into ice water and the resulting precipitate was isolated by filtration, washed with water and dried in air to obtain N- (3-nitrophenyl) -N'-propylidenehydrazine, which was used directly in the next step.

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

A mixture of N- (3-nitrophenyl) -N'-propylidenehydrazine dissolved in 85% H ₃ PO ₄ (20 ml) and toluene (20 ml) is heated at a temperature of 90-100 ° C for 2 hours. After cooling, toluene is removed under reduced pressure. The resulting oil is made alkaline with 10% NaOH to pH = 8. The aqueous layer was extracted with EtOAc (3 times 100 ml). The combined organic layers were dried, filtered and concentrated under reduced pressure to give a mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (1.5 g, 86% yield in two steps) which is used directly in the next step.

AT 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 ) stirred overnight in a hydrogen atmosphere (1 atm.) at room temperature. Pd / C was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 3-methyl-1H-indol-6-ylamine ( B-7 ) (0.6 g, 24% yield).

¹ H-NMR (CDCl ₃ ): δ 7.59 (br s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 6.64 ( s, 1H), 6.57 (m, 1H), 3.57 (br s, 2H), 2.28 (s, 3H).

ESI-MS: 147.2 m / z (MH ⁺ ).

Example 2

6-nitro-1H-indole-3-carbonitrile

To a solution of 6-nitroindole (4.86 g, 30 mmol) in DMF (24.3 ml) and CH ₃ CN (243 ml) was added dropwise a solution of ClSO ₂ NCO (5 ml, 57 mmol) in CH ₃ CN (39 ml) at a temperature of 0 ° C. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured into ice water, made basic with saturated NaHCO ₃ solution to pH = 7-8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82% yield).

AT 8 ; 6-amino-1H-indole-3-carbonitrile

A suspension of 6-nitro-1H-indole-3-carbonitrile (4.6 g, 24.6 mmol) and 10% Pd / C (0.46 g) in EtOH (50 ml) was stirred under a hydrogen atmosphere (1 atm .) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether / EtOAc = 3/1) to obtain 6-amino-1H-indole-3-carbonitrile ( B-8 ) (1 g, 99% yield) as a pink powder .

¹ H-NMR (DMSO-d ₆ ): 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-indol-3-ylmethyl) amine

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

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

To a mixture of DMF (35 ml) and MeI (74.6 g, 0.53 mol) in water (35 ml) and THF (400 ml), dimethyl (6-nitro-1H-indol-3-ylmethyl) amine (23 g, 0.105 mol). The reaction mixture was then refluxed for 10 minutes, potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was continued to reflux overnight. Then the mixture was cooled to room temperature and filtered. The filtrate was washed with brine (3 times 300 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to give (6-nitro-1H-indol-3-yl) acetonitrile ( B-9-a ) (7.5 g, 36% yield).

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

¹ H-NMR (DMSO-d ₆ ): δ 10.4 (br s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 6, 52 (s, 1H), 6.42 (dd, J = 8.4, 1.8 Hz, 1H), 4.76 (s, 2H), 3.88 (s, 2H).

ESI-MS: 172.1 m / z (MH ⁺ ).

Example 4

[2- (6-Nitro-1H-indol-3-yl) ethyl] carbamic acid tert-butyl ester

To a solution of (6-nitro-1H-indol-3-yl) acetonitrile ( B-9 ) (8.6 g, 42.8 mmol) in anhydrous THF (200 ml) was added a 2M solution of the borane-dimethyl sulfide complex in THF (214 ml, 0.43 mol) at a temperature of 0 ° C. The mixture was refluxed overnight under nitrogen. The mixture was then cooled to room temperature and a solution of (Boc) ₂ O (14 g, 64.2 mmol) and Et ₃ N (89.0 ml, 0.64 mol) in THF were added. The reaction mixture was allowed to stir overnight and then poured into ice water. The organic layer was separated and the aqueous phase was extracted with EtOAc (3 times 200 ml). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give [2- (6-nitro-1H-indol-3-yl) ethyl] carbamic acid tert-butyl ester (5 g, 38% yield).

AT 10 ; [2- (6-amino-1H-indol-3-yl) ethyl] carbamic acid tert-butyl ester

A mixture of [2- (6-nitro-1H-indol-3-yl) ethyl] carbamic acid tert-butyl ester (5 g, 16.4 mmol) and Raney nickel (1 g) in EtOH (100 ml) was stirred at room temperature temperature in a hydrogen atmosphere (1 atm.) for 5 hours. Raney nickel was filtered off and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography to give [2- (6-amino-1H-indol-3-yl) ethyl] carbamic acid tert-butyl ester ( B-10 ) (3 g, yield 67;).

¹ H-NMR (DMSO-d ₆ ) δ 10.1 (br s, 1H), 7.11, (d, J = 8.4 Hz, 1H), 6.77-6.73 (m, 2H ), 6.46 (d, J = 1.5 Hz, 1H), 6.32 (dd, J = 8.4, 2.1 Hz, 1H), 4.62 (s, 2H), 3.14 -3.08 (m, 2H); 2.67-2.62 (m, 2H); 1.35 (s, 9H).

ESI-MS: 275.8 m / z (MH ⁺ ).

Example 5

General scheme

a) RX (X = Br, I), zinc triflate, TBAI, DIEA, toluene; b) H ₂ , Raney nickel, EtOH or SnCl ₂ · 2H ₂ O, EtOH.

Specific example

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

To a mixture of 6-nitroindole (1 g, 6, 2 mmol), zinc triflate (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, 11.4 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 10 min at a temperature of 120 ° C, then tert-butyl bromide (0.707 g, 5.16 mmol) was added. The resulting mixture was stirred for 45 minutes at a temperature of 120 ° C. The solid is filtered off, the filtrate is concentrated to dryness and purified by silica gel column chromatography (petroleum ether / EtOAc = 20: 1) to obtain 3-tert-butyl-6-nitro-1H-indole as a yellow solid (0.25 g, yield 19%).

¹ H-NMR (CDCl ₃ ): δ 8.32 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 2.1, 14.4 Hz, 1H), 7.85 ( d, J = 8.7 Hz, 1H), 7.25 (s, 1H), 1.46 (s, 9H).

AT 11 ; 3-tert-butyl-1H-indol-6-ylamine

A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 13.7 mmol) and Raney nickel (0.5 g) in ethanol was stirred at room temperature in a hydrogen atmosphere (1 atm.) For 3 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 4: 1) to obtain 3-tert-butyl-1H-indol-6-ylamine ( B-11 ) (2.0 g, yield 77.3%) as gray solid.

¹ H-NMR (CDCl ₃ ): δ 7.58 (m, 2H), 6.73 (d, J = 1.2 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J = 0.8, 8.6 Hz, 1H), 3.60 (br s, 2H), 1.42 (s, 9H).

Other examples

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

3-Ethyl-1H-indol-6-ylamine ( B-12 ) is synthesized according to the general scheme given above starting from 6-nitroindole and ethyl bromide. Total yield (42%).

HPLC: retention time 1.95 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 161.3 m / z (MH ⁺ ).

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

3-Isopropyl-1H-indol-6-ylamine ( B-13 ) is synthesized according to the general scheme given above based on 6-nitroindole and isopropyl iodide. Total yield (17%).

HPLC: retention time 2.06 min, 10-99% CH ₃ CN, analysis time 5 min.

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 ) is synthesized according to the general scheme given above starting from 6-nitroindole and 2-bromobutane. Total yield (20%).

HPLC: retention time 2.32 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 189.5 m / z (MH ⁺ ).

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

3-Cyclopentyl-1H-indol-6-ylamine ( B-15 ) is synthesized following the general scheme given above based on 6-nitroindole and iodocyclopentane. Total yield (16%).

HPLC: retention time 2.39 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 201.5 m / z (MH ⁺ ).

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

3- (2-Ethoxyethyl) -1H-indol-6-ylamine ( B-16 ) is synthesized according to the general scheme given above starting from 6-nitroindole and 1-bromo-2-ethoxyethane. Total yield (15%).

HPLC: retention time 1.56 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 205.1 m / z (MH ⁺ ).

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

Ethyl (6-amino-1H-indol-3-yl) acetic acid ( B-17 ) is synthesized according to the general scheme given above starting from 6-nitroindole and ethyl iodoacetic acid. Total yield (24%).

HPLC: retention time 0.95 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 219.2 m / z (MH ⁺ ).

4-Substituted 6-aminoindoles

2-methyl-3,5-dinitrobenzoic acid

To a mixture of HNO ₃ (95%, 80 ml) and H ₂ SO ₄ (98%, 80 ml) 2-methylbenzoic acid (50 g, 0.37 mol) was slowly added at a temperature of 0 ° C. After completion of the addition, the reaction mixture was stirred for 1.5 hours while maintaining the temperature below 30 ° C, poured into ice water and stirred for 15 minutes. The resulting precipitate was filtered off and washed with water to give 2-methyl-3,5-dinitrobenzoic acid (70 g, 84% yield).

2-methyl-3,5-dinitrobenzoic acid ethyl ester

A mixture of 2-methyl-3,5-dinitrobenzoic acid (50 g, 0.22 mol) in SOCl ₂ (80 ml) was refluxed for 4 hours and then concentrated to dryness. CH ₂ Cl ₂ (50 ml) and EtOH (80 ml) were added. The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with EtOAc (3 times 100 ml). The combined extracts were washed with saturated Na ₂ CO ₃ solution (80 ml), water (2 times 100 ml) and brine (100 ml), dried over Na ₂ SO ₄ and concentrated to dryness to give 2-methyl-3 ethyl ether, 5-dinitrobenzoic acid (50 g, 88% yield).

2- (2-Dimethylaminovinyl) -3,5-dinitrobenzoic acid ethyl ester

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

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

A mixture of 2- (2-dimethylaminovinyl) -3,5-dinitrobenzoic acid ethyl ester (11.3 g, 0.037 mol) and SnCl ₂ (83 g, 0.37 mol) in ethanol is refluxed for 4 hours. The mixture was concentrated to dryness, the residue was poured into water and made basic with a saturated solution of Na ₂ CO ₃ to pH = 8. The precipitate was filtered off and the filtrate was extracted with ethyl acetate (3 times 100 ml). The combined extracts were washed with water (2 times 100 ml) and brine (150 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 6-amino-1H-indole-4-carboxylic acid ethyl ester (B-18) (3 g, yield 40%).

¹ H-NMR (DMSO-d ₆ ) δ 10.76 (br s, 1H), 7.11-7.14 (m, 2H), 6.81-6.82 (m, 1H), 6, 67-6.68 (m, 1H), 4.94 (br s, 2H), 4.32-4.25 (q, J = 7.2 Hz, 2H), 1.35-1.31 ( t, J = 7.2, 3H).

ESI-MS: 205.0 m / z (MH ⁺ ).

5-Substituted 6-aminoindoles

Example 1

General scheme

Specific example

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

To a stirred solution of HNO ₃ (60 ml) and H ₂ SO ₄ (80 ml), cooled in an ice bath, 1-fluoro-3-methylbenzene (27.5 g, 25 mmol) was added so that the temperature did not exceed 35 ° FROM. The mixture was allowed to stir for 30 minutes at room temperature and poured into ice water (500 ml). The resulting precipitate (a mixture of the desired product and 1-fluoro-3-methyl-2,4-dinitrobenzene, approximately 7: 3) was separated by filtration and purified by recrystallization from 50 ml of diisopropyl ether to obtain 1-fluoro-5-methyl-2,4- dinitrobenzene as a white solid (18 g, 36% yield).

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

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

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

A suspension of [2- (5-fluoro-2,4-dinitrophenyl) vinyl] dimethylamine (8 g, 31.4 mmol) and Raney nickel (8 g) in EtOH (80 ml) was stirred under a hydrogen atmosphere (40 psi). inch) 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 obtain 5-fluoro-1H-indol-6-ylamine ( B-20 ) as a brown solid (1 g, 16% yield).

¹ H-NMR (DMSO-d ₆ ): δ 10.56 (br s, 1H), 7.07 (d, J = 12 Hz, 1H), 7.02 (m, 1H), 6.71 ( d, J = 8 Hz, 1H), 6.17 (s, 1H), 3.91 (br s, 2H).

ESI-MS: 150.1 m / z (MH ⁺ ).

Other examples

AT 21 ; 5-chloro-1H-indol-6-ylamine

5-Chloro-1H-indol-6-ylamine ( B-21 ) is synthesized according to the general scheme given above starting from 1-chloro-3-methylbenzene. Total yield (7%).

¹ H-NMR (CDCl ₃ ): δ 7.85 (br s, 1H), 7.52 (s, 1H), 7.03 (s, 1H), 6.79 (s, 1H), 6, 34 (s, 1H); 3.91 (br 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 ) is synthesized according to the general scheme given above starting from 1-methyl-3-trifluoromethylbenzene. Total yield (2%).

¹ H-NMR (DMSO-d ₆ ): 10.79 (br s, 1H), 7.55 (s, 1H), 7.12 (s, 1H), 6.78 (s, 1H), 6 27 (s, 1H); 4.92 (s, 2H).

ESI-MS: 200.8 m / z (MH ⁺ ).

Example 2

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

To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24 g, 136 mmol) and 2,3-dihydro-1H-indole (14.7 g, 124 mmol) in CH ₂ Cl ₂ (200 ml) was added dropwise Et ₃ N (19 g, 186 mmol) in an ice-water bath. After complete addition, the mixture was stirred at room temperature overnight, washed with water, dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure to obtain 1-benzenesulfonyl-2,3-dihydro-1H-indole (30.9 g, yield 96 %).

1- (1-Benzenesulfonyl-2,3-dihydro-1H-indol-5-yl) ethanone

Acetic anhydride (54 ml) was added to a stirred suspension of AlCl ₃ (144 g, 1.08 mol) in CH ₂ Cl ₂ (1070 ml). The mixture is stirred for 15 minutes. A solution of 1-benzenesulfonyl-2,3-dihydro-1H-indole (46.9 g, 0.18 mol) in CH ₂ Cl ₂ (1070 ml) was added dropwise. The mixture was stirred for 5 hours and quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 1- (1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl) ethanone (42 6 g, yield 79%).

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

Sodium borohydride (64 g, 1.69 mol) was added to a TFUK (1600 ml) stirring magnetic stirrer over 1 hour at a temperature of 0 ° C. To the resulting mixture was added dropwise a solution of 1- (1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl) ethanone (40 g, 0.13 mol) in TFA (700 ml) over 1 hour. The mixture was stirred overnight at 25 ° C, diluted with H ₂ O (1600 ml) and made basic with sodium hydroxide granules at 0 ° C. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (16.2 g, yield 43%).

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

A mixture of 1-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (15 g, 0.05 mol) in HBr (48%, 162 ml) was refluxed for 6 hours. The mixture was made basic with saturated NaOH to pH = 9 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 32% yield).

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 H ₂ SO ₄ (98%, 20 ml), KNO ₃ (1.7 g, 17 mmol) is slowly added. ) at a temperature of 0 ° C. After complete addition, the mixture is stirred at a temperature of 0-10 ° C for 10 min, carefully poured onto ice, made basic with a NaOH solution to pH = 9 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, yield 58%).

5-Ethyl-6-nitro-1H-indole

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

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

A suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney nickel (1 g) was stirred under a hydrogen atmosphere (1 atm.) At room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 5-ethyl-1H-indol-6-ylamine ( B-23 ) (760 mg, 48% yield).

¹ H-NMR (CDCl ₃ ) δ 7.90 (br s, 1H), 7.41 (s, 1H), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3.39 (br s, 2H), 2.63 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H).

ESI-MS: 161.1 m / z (MH ⁺ ).

Example 3

2-bromo-4-tert-butylphenylamine

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

2-bromo-4-tert-butyl-5-nitrophenylamine

2-Bromo-4-tert-butylphenylamine (162 g, 0.71 mol) was added dropwise to H ₂ SO ₄ (410 ml) at room temperature to give a clear solution. The resulting clear solution is then cooled to a temperature in the range from -5 ° C to -10 ° C. A solution of KNO ₃ (82.5 g, 0.82 mol) in H ₂ SO ₄ (410 ml) was added dropwise, maintaining the temperature in the range from -5 to -10 ° C. After complete addition, the reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with 5% Na ₂ CO ₃ solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (EtOAc / petroleum ether = 1/10) to obtain 2-bromo-4-tert-butyl-5-nitrophenylamine as a yellow solid (152 g, 78% yield).

4-tert-butyl-5-nitro-2-trimethylsilanylethynylphenylamine

To a mixture of 2-bromo-4-tert-butyl-5-nitrophenylamine (27.3 g, 100 mmol) in toluene (200 ml) and water (100 ml) in a nitrogen atmosphere, Et ₃ N (27.9 ml, 200 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (2.11 g, 3 mmol), CuI (950 mg, 0.5 mmol) and trimethylsilylacetylene (21.2 ml, 150 mmol). The reaction mixture is heated at a temperature of 70 ° C in a sealed flask for 2.5 hours, cooled to room temperature and filtered through a small layer of celite. The filter cake was washed with EtOAc. The combined filtrate was washed with 5% NH ₄ OH solution and water, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (0-10% EtOAc / petroleum ether) to give 4-tert-butyl-5-nitro-2-trimethylsilanylenethyl phenylamine as a viscous brown liquid (25 g, 81% yield).

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

To a solution of 4-tert-butyl-5-nitro-2-trimethylsilanylethinyl phenylamine (25 g, 86 mmol) in DMF (100 ml) under a nitrogen atmosphere, CuI (8.2 g, 43 mmol) was added. The mixture is heated at 135 ° C in a sealed flask overnight, cooled to room temperature and filtered through a small layer of celite. The filter cake was washed with EtOAc. The combined filtrate was washed with water, dried over Na ₂ SO ₄ and 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% yield).

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

Raney Nickel (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (14.7 g, 67 mmol) in methanol (100 ml). The mixture is stirred in a hydrogen atmosphere (1 atm.) At a temperature of 30 ° C for 3 hours. The catalyst is filtered off. The filtrate was dried over Na ₂ SO ₄ and concentrated. The crude viscous dark brown oil was purified by column chromatography (10-20% EtOAc / petroleum ether) to give 5-tert-butyl-1H-indol-6-ylamine ( B-24 ) as a gray solid (11 g, yield 87 %).

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 10.3 (br s, 1H), 7.2 (s, 1H), 6.9 (m, 1H), 6.6 (s, 1H), 6.1 (m, 1H), 4.4 (br s, 2H), 1.3 (s, 9H).

Example 4

5-methyl-2,4-dinitrobenzoic acid

To a mixture of HNO ₃ (95%, 80 ml) and H ₂ SO ₄ (98%, 80 ml) 3-methylbenzoic acid (50 g, 0.37 mol) was slowly added at a temperature of 0 ° C. After complete addition, the mixture is stirred for 1.5 hours, maintaining the temperature below 30 ° C. The mixture was poured into ice water and stirred for 15 minutes. The precipitate was separated by filtration and washed with water to obtain a mixture of 3-methyl-2,6-dinitrobenzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, 84% yield). To a solution of the resulting mixture in EtOH (150 ml) was added dropwise SOCl ₂ (53.5 g, 0.45 mol). The mixture was refluxed for 2 hours and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 ml) and extracted with 10% Na ₂ CO ₃ solution (120 ml). It was found that the organic layer contains 5-methyl-2,4-dinitrobenzoic acid ethyl ester, while the aqueous layer contains 3-methyl-2,6-dinitrobenzoic acid. The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated to dryness to give 5-methyl-2,4-dinitrobenzoic acid ethyl ester (20 g, 20% yield).

5- (2-Dimethylaminovinyl) -2,4-dinitrobenzoic acid ethyl ester

A mixture of 5-methyl-2,4-dinitrobenzoic acid ethyl ester (39 g, 0.15 mol) and dimethoxymethyldimethylamine (32 g, 0.27 mol) in DMF (200 ml) is heated at 100 ° C. for 5 hours. The mixture is poured into ice water. The precipitate was filtered off and washed with water to give 5- (2-dimethylaminovinyl) -2,4-dinitrobenzoic acid ethyl ester (15 g, 28% yield).

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

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

¹ H-NMR (DMSO-d ₆ ) δ 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 (q, J = 7.2 Hz, 2H), 1.32-1.27 (t, J = 7.2 Hz, 3H).

Example 5

1- (2,3-dihydroindol-1-yl) ethanone

To a suspension of NaHCO ₃ (504 g, 6.0 mol) and 2,3-dihydro-1H-indole (60 g, 0.5 mol) in CH ₂ Cl ₂ (600 ml), cooled in an ice-water bath, acetyl chloride (78.5 g, 1.0 mol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The solid was filtered off and the filtrate was concentrated to give 1- (2,3-dihydroindol-1-yl) ethanone (82 g, 100% yield).

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

To a solution of 1- (2,3-dihydroindol-1-yl) ethanone (58.0 g, 0.36 mol) in acetic acid (3000 ml), Br ₂ (87.0 g, 0.54 mol) is added at a temperature 10 ° C. The mixture was stirred at room temperature for 4 hours. The precipitate was collected by filtration to obtain crude 1- (5-bromo-2,3-dihydroindol-1-yl) ethanone (100 g, 96% yield), which was used directly in the next step.

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

A mixture of the crude 1- (5-bromo-2,3-dihydroindol-1-yl) ethanone (100 g, 0.34 mol) in HCl (20%, 1200 ml) was refluxed for 6 hours. The mixture was made basic with a Na ₂ CO ₃ solution to pH 8.5-10 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-bromo-2,3-dihydro-1H-indole (37 g, 55% yield).

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 H ₂ SO ₄ (98%, 200 ml) KNO ₃ (23.5 g, 0.23 mol) is slowly added. ) at a temperature of 0 ° C. After complete addition, the mixture was stirred at a temperature of 0-10 ° C for 4 hours, carefully poured onto ice, made basic with a solution of Na ₂ CO ₃ to pH = 8 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 5-bromo-6-nitro-2,3-dihydro-1H-indole (42 g, 76% yield).

5-bromo-6-nitro-1H-indole

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

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 nickel (1 g) in ethanol was stirred under a hydrogen atmosphere (1 atm.) At room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 5-bromo-1H-indol-6-ylamine ( B-27 ) (2 g, 30% yield).

¹ H-NMR (DMSO-d ₆ ): δ 10.6 (s, 1H), 7.49 (s, 1H), 6.79-7.02 (m, 1H), 6.79 (s, 1H ), 6.14-6.16 (m, 1H); 4.81 (s, 2H).

7-Substituted 6-aminoindoles

3-methyl-2,6-dinitrobenzoic acid

To a mixture of HNO ₃ (95%, 80 ml) and H ₂ SO ₄ (98%, 80 ml) 3-methylbenzoic acid (50 g, 0.37 mol) was slowly added at a temperature of 0 ° C. After complete addition, the mixture is stirred for 1.5 hours, maintaining the temperature below 30 ° C. The mixture was poured into ice water and stirred for 15 minutes. The precipitate was separated by filtration and washed with water to obtain a mixture of 3-methyl-2,6-dinitrobenzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, 84% yield). To a solution of the resulting mixture in EtOH (150 ml) was added dropwise SOCl ₂ (53.5 g, 0.45 mol). The mixture was refluxed for 2 hours and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 ml) and extracted with 10% Na ₂ CO ₃ solution (120 ml). The organic layer was found to contain 5-methyl-2,4-dinitrobenzoic acid ethyl ester. The aqueous layer was acidified with HCl to pH = 2 ~ 3 and the resulting precipitate was separated by filtration, washed with water and dried in air, obtaining 3-methyl-2,6-dinitrobenzoic acid (39 g, 47% yield).

3-methyl-2,6-dinitrobenzoic acid ethyl ester

A mixture of 3-methyl-2,6-dinitrobenzoic acid (39 g, 0.15 mol) and SOCl ₂ (80 ml) was refluxed for 4 hours. Excess SOCl _{2 was} removed under reduced pressure, and the residue was added dropwise to a solution of EtOH (100 ml) and Et ₃ N (50 ml). The mixture was stirred at 20 ° C. for 1 hour and concentrated to dryness. The residue was dissolved in EtOAc (100 ml), washed with a solution of Na ₂ CO ₃ (10%, 2 times 40 ml), water (2 times 50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated to give 3-methyl-2,6-dinitrobenzoic acid ethyl ester (20 g, 53% yield).

3- (2-Dimethylaminovinyl) -2,6-dinitrobenzoic acid ethyl ester

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

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

A mixture of 3- (2-dimethylaminovinyl) -2,6-dinitrobenzoic acid ethyl ester (30 g, 0.097 mol) and Raney nickel (10 g) in EtOH (1000 ml) was stirred under a hydrogen atmosphere (50 psi) in within 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 6-amino-1H-indole-7-carboxylic acid ethyl ester ( B-19 ) as an off-white solid (3.2 g, 16% yield).

¹ H-NMR (DMSO-d ₆ ) δ 10.38 (s, 1H), 7.44-7.41 (d, J = 8.7 Hz, 1H), 6.98 (t, 1H), 6 65 (s, 2H), 6.50-6.46 (m, 1H), 6.27-6.26 (m, 1H), 4.43-4.36 (q, J = 7.2 Hz , 2H), 1.35 (t, J = 7.2 Hz, 3H).

Phenols

Example 1

2-tert-butyl-5-nitroaniline

To a cooled solution of sulfuric acid (90%, 50 ml), 2-tert-butylphenylamine (4.5 g, 30 mmol) was added dropwise at a temperature of 0 ° C. Potassium nitrate (4.5 g, 45 mmol) was added in portions at 0 ° C. The reaction mixture was stirred at 0-5 ° C for 5 minutes, poured into ice water and then extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . After removing the solvent, the residue was purified by recrystallization using 70% EtOH-H ₂ O to give 2-tert-butyl-5-nitroaniline (3.7 g, 64% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.56 (dd, J = 8.7, 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7 36 (d, J = 8.7 Hz, 1H); 4.17 (s, 2H); 1.46 (s, 9H).

HPLC: retention time 3.27 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 195.3 m / z (MH ⁺ ).

S-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% H ₂ SO ₄ was added dropwise a solution of NaNO ₂ (763 mg, 11.0 mmol) in water (3 ml) at a temperature of 0 ° C. The resulting mixture was stirred at a temperature of 0-5 ° C for 5 minutes Excess NaNO _{2 is} neutralized with urea, then 5 ml of a mixture of H ₂ SO ₄ —H ₂ O (w / w = 1: 2) are added and the mixture is refluxed for 5 minutes. Then add three aliquots of 5 ml of a mixture of H ₂ SO ₄ -H ₂ O (wt./mass. = 1: 2) while boiling under reflux. The reaction mixture was cooled to room temperature and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After removing the solvent, the residue was purified by column chromatography (0-10% EtOAc-hexane) to obtain 2-tert-butyl-5-nitrophenol ( C-1-a ) (1.2 g, yield 62%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.76 (dd, J = 8.6, 2.2 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7 43 (d, J = 8.6 Hz, 1H), 5.41 (s, 1H), 1.45 (s, 9H).

HPLC: retention time 3.46 min, 10-99% CH ₃ CN, analysis time 5 min.

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

To a refluxing 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), then 140 mg of 10% Pd / C. Then the reaction mixture was refluxed for 30 minutes, cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc-hexane) to give 2-tert-butyl-5-aminophenol ( C-1 ) (144 mg, 87% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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 (s, 9H).

HPLC: retention time 2.26 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 166.1 m / z (MH ⁺ ).

Example 2

General scheme

a) RX (X = Br, I), K ₂ CO ₃ or Cs ₂ CO ₃ , DMF; b) HCO ₂ NH ₄ or HCO ₂ K, Pd / C, EtOH.

Specific example

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

To a mixture of 2-tert-butyl-5-nitrophenol ( C-1-a ) (100 mg, 0.52 mmol) and K ₂ CO ₃ (86 mg, 0.62 mmol) in DMF (2 ml) was added CH ₃ I (40 μl, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was evaporated to dryness to give 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 76% yield), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.77 (t, J = 4.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.40 (d , J = 8.6 Hz, 1H), 3.94 (s, 3H), 1.39 (s, 9H).

S-2 ; 4-tert-butyl-3-methoxyaniline

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

HPLC: retention time 2.29 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 180.0 m / z (MH ⁺ ).

Other examples

S-3 ; 3- (2-Ethoxyethoxy) -4-tert-butylbenzeneamine

3- (2-Ethoxyethoxy) -4-tert-butylbenzeneamine ( C-3 ) is synthesized according to the general scheme given above, starting from 2-tert-butyl-5-nitrophenol ( C-1-a ) and 1-bromo- 2-ethoxyethane.

¹ H-NMR (400 MHz, CDCl ₃ ) 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 (q, J = 7.0 Hz, 2H) 1.27 (s, 9H); 1.16 (t, J = 7.0 Hz, 3H).

HPLC: retention time 2.55 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 238.3 m / z (MH ⁺ ).

S-4 ; 2- (2-tert-butyl-5-aminophenoxy) ethanol

2- (2-tert-Butyl-5-aminophenoxy) ethanol ( C-4 ) is synthesized according to the general scheme given above, starting from 2-tert-butyl-5-nitrophenol ( C-1-a ) and 2-bromoethanol .

HPLC: retention time 2.08 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 210.3 m / z (MH ⁺ ).

Example 3

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

To an intensively stirred suspension of 3-aminophenol (50 g, 0.46 mol) and NaHCO ₃ (193.2 g, 2.3 mol) in chloroform (1 L), chloroacetyl chloride (46.9 g, 0.6 mol) was added dropwise. ) for 30 minutes at a temperature of 0 ° C. After complete addition, the reaction mixture was refluxed overnight and then cooled to room temperature. Excess NaHCO _{3 was} removed by filtration. The filtrate was poured into water and extracted with EtOAc (3 times 300 ml). The combined organic layers were washed with brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a mixture of N- (3-hydroxyphenyl) acetamide and 3-formylaminophenyl ester of acetic acid (35 g, 4: 1, according to NMR analysis). The mixture is used directly in the next step.

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

Suspension of a mixture of N- (3-hydroxyphenyl) acetamide and 3-formylaminophenyl ester of acetic acid (18.12 g, 0.12 mol), 3-methylbut-3-en-1-ol (8.6 g, 0.1 mol ), DEAD (87 g, 0.2 mol) and Ph ₃ P (31.44 g, 0.12 mol) in benzene (250 ml) were refluxed overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase is extracted with EtOAc (3 times 300 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to obtain N- [3- (3-methylbut-3-enyloxy) phenyl] acetamide (11 g, yield 52%).

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

A mixture of N- [3- (3-methylbut-3-enyloxy) phenyl] acetamide (2.5 g, 11.4 mmol) and AlCl ₃ (4.52 g, 34.3 mmol) in fluorobenzene (50 ml) is boiled reflux overnight. After cooling, the reaction mixture was poured into water. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 times 40 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography to obtain N- (4,4-dimethylchroman-7-yl) acetamide (1.35 g, yield 54%).

S-5 ; 3,4-dihydro-4,4-dimethyl-2H-chromene-7-amine

A mixture of N- (4,4-dimethylchroman-7-yl) acetamide (1.35 g, 6.2 mmol) in a 20% HCl solution (30 ml) was refluxed for 3 hours and then cooled to room temperature temperature. The reaction mixture was made basic with a 10% aqueous NaOH solution to pH = 8 and extracted with EtOAc (3 times 30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 3,4-dihydro-4,4-dimethyl-2H-chromene-7-amine ( C-5 ) (1 g, 92% yield) )

¹ H-NMR (DMSO-d ₆ ) δ 6.87 (d, J = 8.4 Hz, 1H), 6.07 (dd, J = 8.4, 2.4 Hz, 1H), 5.87 (d, J = 2.4 Hz, 1H), 4.75 (s, 2H), 3.99 (t, J = 5.4 Hz, 2H), 1.64 (t, J = 5.1 Hz , 2H), 1.15 (s, 6H).

ESI-MS: 178.1 m / z (MH ⁺ ).

Example 4

General scheme

X = F, Cl; a) ROH, H ₂ SO ₄ or MeSO ₃ H, CH ₂ Cl ₂ ; b) R'CO ₂ Cl, Et ₃ N, 1,4-dioxane or CHCl ₃ ; c) HNO ₃ , H ₂ SO ₄ or KNO ₃ , H ₂ SO ₄ or HNO ₃ , AcOH; d) piperidine, CH ₂ Cl ₂ ; e) HCO ₂ NH ₄ , Pd / C, EtOH or SnCl ₂ · 2H ₂ O, EtOH or H ₂ , Pd / C, MeOH.

Specific example

2-tert-butyl-4-fluorophenol

4-Fluorophenol (5 g, 45 mmol) and tert-butanol (5.9 ml, 63 mmol) were dissolved in CH ₂ Cl ₂ (80 ml) and treated with concentrated sulfuric acid (98%, 3 ml). The mixture was stirred at room temperature overnight. The organic layer was washed with water, neutralized with NaHCO ₃ , dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (5-15% EtOAc-hexane) to give 2-tert-butyl-4-fluorophenol (3.12 g, 42% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.32 (s, 1H), 6.89 (dd, J = 11.1, 3.1 Hz, 1H), 6.84-6, 79 (m, 1H), 6.74 (dd, J = 8.7, 5.3 Hz, 1H), 1.33 (s, 9H).

2-tert-butyl-4-fluorophenylmethyl carbonate

To a solution of 2-tert-butyl-4-fluorophenol (2.63 g, 15.7 mmol) and NEt ₃ (3.13 ml, 22.5 mmol) in dioxane (45 ml) was added methyl chloroformate (1.27 ml, 16.5 mmol). The mixture was stirred at room temperature for 1 hour. The precipitate was removed by filtration. The filtrate was then diluted with water and extracted with diethyl ether. The diethyl ether extract was washed with water and dried over MgSO ₄ . After removing the solvent, the residue was purified by column chromatography to obtain 2-tert-butyl-4-fluorophenylmethyl carbonate (2.08 g, 59% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.24 (dd, J = 8.8, 5.4 Hz, 1H), 7.17-7.10 (m, 2H), 3, 86 (s, 3H); 1.29 (s, 9H).

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

To a solution of 2-tert-butyl-4-fluorophenylmethyl carbonate (1.81 g, 8 mmol) in H ₂ SO ₄ (98%, 1 ml), a cooled mixture of H ₂ SO ₄ (1 ml) and HNO ₃ (slowly 1 ml) at a temperature of 0 ° C. The mixture was stirred for 2 hours until it warmed to room temperature, poured onto ice and extracted with diethyl ether. The diethyl ether extract was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-4-fluoro-5-nitrophenylmethyl carbonate ( C-7-a ) (1.2 g, 55% yield) and 2-tert- butyl-4-fluoro-6-nitrophenylmethyl carbonate ( C-6-a ) (270 mg, 12% yield).

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

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.24 (d, J = 7.1 Hz, 1H), 7.55 (d, J = 13.4 Hz, 1H), 3.90 (s, 3H); 1.32 (s, 9H).

2-tert-Butyl-4-fluoro-6-nitrophenylmethyl carbonate ( C-6-a ):

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.04 (dd, J = 7.6, 3.1 Hz, 1H), 7.69 (dd, J = 10.1, 3.1 Hz, 1H), 3.91 (s, 3H), 1.35 (s, 9H).

2-tert-butyl-4-fluoro-5-nitrophenol

To a solution of 2-tert-butyl-4-fluoro-5-nitrophenylmethyl carbonate ( C-7-a ) (1.08 g, 4 mmol) in CH ₂ Cl ₂ (40 ml), piperidine (3.94 ml, 10 mmol) was added ) The mixture was stirred at room temperature for 1 hour and extracted with 1N. NaOH solution (3 times). The aqueous layer is acidified with 1N. HCl solution and extracted with diethyl ether. The diethyl ether extract was washed with brine, dried (MgSO ₄ ) and concentrated to give 2-tert-butyl-4-fluoro-5-nitrophenol (530 mg, 62% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.40 (s, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.25 (d, J = 13, 7 Hz, 1H); 1.36 (s, 9H).

S-7 ; 2-tert-butyl-5-amino-4-fluorophenol

To a refluxing solution of 2-tert-butyl-4-fluoro-5-nitrophenol (400 mg, 1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) was added 5% Pd / C (260 mg). Then the mixture is refluxed for 1 hour, cooled and filtered through celite. The solvent was removed by evaporation to give 2-tert-butyl-5-amino-4-fluorophenol ( C-7 ) (550 mg, 83% yield).

^oneH-NMR (400 MHz, DMSO-d₆): δ 8.83 (br s, 1H), 6.66 (d, J = 13.7 Hz, 1H), 6.22 (d, J = 8.5 Hz, 1H), 4.74 (br s, 2H), 1.26 (s, 9H).

HPLC: retention time 2.58 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 184.0 m / z (MH ⁺ ).

Other examples

S-10 ; 2-tert-butyl-5-amino-4-chlorophenol

2-tert-Butyl-5-amino-4-chlorophenol ( C-10 ) is synthesized according to the general scheme given above based on 4-chlorophenol and tert-butanol. Total yield (6%).

HPLC: retention time 3.07 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 200.2 m / z (MH ⁺ ).

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

5-amino-4-fluoro-2- (1-methylcyclohexyl) phenol ( C-13 ) is synthesized according to the general scheme given above based on 4-fluorophenol and 1-methylcyclohexanol. Total yield (3%).

HPLC: retention time 3.00 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 224.2 m / z (MH ⁺ ).

S-19 ; 5-amino-2- (3-ethylpentan-3-yl) -4-fluorophenol

5-amino-2- (3-ethylpentan-3-yl) -4-fluorophenol ( C-19 ) is synthesized according to the general scheme given above starting from 4-fluorophenol and 3-ethyl-3-pentanol. Total yield (1%).

S-20 ; 2-adamantyl-5-amino-4-fluorophenol

2-Adamantyl-5-amino-4-fluorophenol ( C-20 ) is synthesized according to the general scheme given above based on 4-fluorophenol and adamantan-1-ol.

S-21 ; 5-amino-4-fluoro-2- (1-methylcycloheptyl) phenol

5-amino-4-fluoro-2- (1-methylcycloheptyl) phenol ( C-21 ) is synthesized according to the general scheme given above based on 4-fluorophenol and 1-methylcycloheptanol.

S-22 ; 5-amino-4-fluoro-2- (1-methylcyclooctyl) phenol

5-amino-4-fluoro-2- (1-methylcyclooctyl) phenol ( C-22 ) is synthesized according to the general scheme given above based on 4-fluorophenol and 1-methylcyclooctanol.

S-23 ; 5-amino-2- (3-ethyl-2,2-dimethylpentan-3-yl) -4-fluorophenol

5-amino-2- (3-ethyl-2,2-dimethylpentan-3-yl) -4-fluorophenol ( C-23 ) is synthesized according to the general scheme given above starting from 4-fluorophenol and 3-ethyl-2 , 2-dimethylpentan-3-ol.

Example 5

S-6 ; 2-tert-butyl-4-fluoro-6-aminophenylmethyl carbonate

To a refluxing solution of 2-tert-butyl-4-fluoro-6-nitrophenylmethyl carbonate (250 mg, 0.92 mmol) and ammonium formate (250 mg, 4 mmol) in EtOH (10 ml) was added 5% Pd / C (170 mg). Then the mixture is refluxed for 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-aminophenylmethyl carbonate ( C-6 ) (60 mg, 27% yield).

HPLC: retention time 3.35 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 242.0 m / z (MH ⁺ ).

Example 6

Carbonic acid 2,4-di-tert-butylphenyl ester methyl ester

Methyl chloroformate (58 ml, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butylphenol (103.2 g, 500 mmol), Et ₃ N (139 ml, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 ml), ice-water cooled in a bath at a temperature of 0 ° С. The mixture was allowed to warm to room temperature with stirring overnight, then was filtered through silica gel (approximately 1 L) using a mixture of 10% ethyl acetate-hexanes (~ 4 L) as eluent. The combined filtrates were concentrated to give methyl carbonate 2,4-di-tert-butylphenyl ester as a yellow oil (132 g, quantitative yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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), 1.30 (s, 9H), 1.29 (s, 9H).

2,4-di-tert-butyl-5-nitrophenyl carbonate methyl ester and 2,4-di-tert-butyl-6-nitrophenyl carbonate methyl ester

To a stirred mixture of methyl carbonate 2,4-di-tert-butylphenyl ester of carbonic acid (4.76 g, 18 mmol) in concentrated sulfuric acid (2 ml), cooled in a water-ice bath, add a cooled mixture of sulfuric acid (2 ml ) and nitric acid (2 ml). Addition is carried out slowly, so that the reaction temperature does not exceed 50 ° C. The reaction mixture was allowed to stir for 2 hours until it warmed to room temperature. The reaction mixture was then introduced into ice water and extracted with diethyl ether. The diethyl ether layer was dried (MgSO ₄ ), concentrated and purified by column chromatography (0-10% ethyl acetate-hexanes) to give a mixture of 2,4-di-tert-butyl-5-nitrophenyl carbonate methyl ester and 2,4 methyl ester di-tert-butyl-6-nitrophenyl ester of carbonic acid as a pale yellow solid (4.28 g), which is used directly in the next step.

2,4-di-tert-butyl-5-nitrophenol and 2,4-di-tert-butyl-6-nitrophenol

A mixture of 2,4-di-tert-butyl-5-nitrophenyl carbonate methyl ester and 2,4-di-tert-butyl-6-nitrophenyl carbonate methyl ester (4.2 g, 12.9 mmol) was dissolved in MeOH (65 ml) and KOH (2.0 g, 36 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture is then acidified (pH = 2-3) by adding concentrated HCl and partitioned between water and diethyl ether. The diethyl ether layer was dried (MgSO ₄ ), concentrated and purified by column chromatography (0-5% ethyl acetate-hexanes) to obtain 2,4-di-tert-butyl-5-nitrophenol (1.31 g, 29% yield in 2 steps) ) and 2,4-di-tert-butyl-6-nitrophenol.

2,4-di-tert-butyl-5-nitrophenol:

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H).

2,4-di-tert-butyl-6-nitrophenol:

¹ H-NMR (400 MHz, CDCl ₃ ): δ 11.48 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.4 Hz , 1H), 1.47 (s, 9H), 1.34 (s, 9H).

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

To a refluxing solution of 2,4-di-tert-butyl-5-nitrophenol (1.86 g, 7.4 mmol) and ammonium formate (1.86 g) in ethanol (75 ml) was added 5% by weight. palladium on carbon (Pd / C) (900 mg). The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature and filtered through celite. The celite was washed with methanol and the combined filtrates were concentrated to give 5-amino-2,4-di-tert-butylphenol as a gray solid (1.66 g, quantitative yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.64 (s, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, NH ₂ ), 1.27 (m, 18H).

HPLC: retention time 2.72 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 222.4 m / z (MH ⁺ ).

S-8 ; 6-amino-2,4-di-tert-butylphenol

A solution of 2,4-di-tert-butyl-6-nitrophenol (27 mg, 0.11 mmol) and SnCl ₂ · 2H ₂ O (121 mg, 0.54 mmol) in EtOH (1.0 ml) is heated in a microwave furnace at a temperature of 100 ° C for 30 minutes The mixture was diluted with EtOAc and water, basified with saturated NaHCO ₃ solution and filtered through celite. The organic layer was separated and dried over Na ₂ SO ₄ . The solvent was removed by evaporation to give 6-amino-2,4-di-tert-butylphenol ( C-8 ), which was used without further purification.

HPLC: retention time 2.74 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 222.5 m / z (MH ⁺ ).

Example 7

4-tert-butyl-2-chlorophenol

To a solution of 4-tert-butylphenol (40.0 g, 0.27 mol) and SO ₂ Cl ₂ (37.5 g, 0.28 mol) in CH ₂ Cl _{2 is} added MeOH (9.0 g, 0.28 mol) at a temperature of 0 ° C. After complete addition, the mixture was stirred overnight at room temperature and then water (200 ml) was added. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc = 50: 1) to obtain 4-tert-butyl-2-chlorophenol (47.0 g, 95% yield).

4-tert-butyl-2-chlorophenylmethyl carbonate

To a solution of 4-tert-butyl-2-chlorophenol (47.0 g, 0.25 mol) in dichloromethane (200 ml) was added Et ₃ N (50.5 g, 0.50 mol), DMAP (1 g) and methyl chloroformate (35.4 g, 0.38 mol) at a temperature of 0 ° C. The reaction mixture was allowed to warm to room temperature and then stirred for 30 minutes. The reaction mixture was washed with H ₂ O, the organic layer was dried over Na ₂ SO ₄ and concentrated to give 4-tert-butyl-2-chlorophenylmethyl carbonate (56.6 g, yield 92%), which was used directly in the next step.

4-tert-butyl-2-chloro-5-nitrophenylmethyl carbonate

4-tert-Butyl-2-chlorophenylmethyl carbonate (36.0 g, 0.15 mol) was dissolved in concentrated H ₂ SO ₄ (100 ml) at a temperature of 0 ° C. KNO ₃ (0.53 g, 5.2 mmol) was added portionwise over 25 minutes. The reaction mixture was stirred for 1.5 hours and poured onto ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with an aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated in vacuo to give 4-tert-butyl-2-chloro-5-nitrophenylmethyl carbonate (41.0 g), which was used without further purification.

4-tert-butyl-2-chloro-5-nitrophenol

Potassium hydroxide (10.1 g, 181 mmol) was added to 4-tert-butyl-2-chloro-5-nitrophenylmethyl carbonate (40.0 g, 139 mmol) in MeOH (100 ml). After 30 minutes, the reaction mixture was acidified with 1N. HCl solution and extracted with dichloromethane. The combined organic layers are combined, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by column chromatography (petroleum ether / EtOAc = 30: 1) to give 4-tert-butyl-2-chloro-5-nitrophenol (23.0 g, 68% yield in 2 steps).

S-11 ; 4-tert-butyl-2-chloro-5-aminophenol

To a solution of 4-tert-butyl-2-chloro-5-nitrophenol (12.6 g, 54.9 mmol) in MeOH (50 ml) Ni (1.2 g) was added. The reaction mixture is shaken in a hydrogen atmosphere (1 atm.) For 4 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 20: 1) to give 4-tert-butyl-2-chloro-5-aminophenol ( C-11 ) (8.5 g, 78% yield).

¹ H-NMR (DMSO-d ₆ ): δ 9.33 (s, 1H), 6.80 (s, 1H), 6.22 (s, 1H), 4.76 (s, 1H), 1, 23 (s, 9H).

ESI-MS: 200.1 m / z (MH ⁺ ).

Example 8

2-Adamantyl-4-methylphenylethyl carbonate

Ethyl chloroformate (0.64 ml, 6.7 mmol) was added dropwise to a solution of 2-adamantyl-4-methylphenol (1.09 g, 4.5 mmol), Et ₃ N (1.25 ml, 9 mmol) and DMAP (catalytic amount) in dichloromethane (8 ml), cooled in a bath of ice water, at a temperature of 0 ° C. The mixture was allowed to warm to room temperature with stirring overnight, then filtered and the filtrate was concentrated. The residue was purified by column chromatography (10-20% ethyl acetate-hexanes) to give 2-adamantyl-4-methylphenylethyl carbonate as a yellow oil (1.32 g, yield 94%).

2-Adamantyl-4-methyl-5-nitrophenylethyl carbonate

To a cooled solution of 2-adamantyl-4-methylphenylethyl carbonate (1.32 g, 4.2 mmol) in H ₂ SO ₄ (98%, 10 ml), KNO ₃ (510 mg, 5.0 mmol) was added in small portions at temperature 0 ° С. The mixture was stirred for 3 hours until it warmed to room temperature, poured onto ice and then extracted with dichloromethane. The combined organic layers were washed with NaHCO ₃ solution and brine, dried over MgSO ₄ and concentrated to dryness. The residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-adamantyl-4-methyl-5-nitrophenylethyl carbonate (378 mg, 25% yield).

2-adamantyl-4-methyl-5-nitrophenol

To a solution of 2-adamantyl-4-methyl-5-nitrophenylethyl carbonate (378 mg, 1.05 mmol) in CH ₂ Cl ₂ (5 ml), piperidine (1.0 ml) was added. The solution was stirred at room temperature for 1 hour, adsorbed on silica gel under reduced pressure, and purified by flash chromatography on silica gel (0-15% EtOAc-hexanes) to give 2-adamantyl-4-methyl-5-nitrophenol (231 mg, yield 77%).

S-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) add 5% of the mass. palladium on charcoal (10 mg). The mixture was stirred under an atmosphere of hydrogen (1 atm.) Overnight and then filtered through celite. The filtrate was evaporated to dryness to give 2-adamantyl-4-methyl-5-aminophenol ( C-12 ), which was used without further purification.

HPLC: retention time 2.52 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 258.3 m / z (MH ⁺ ).

Example 9

2-tert-butyl-4-bromophenol

To a solution of 2-tert-butylphenol (250 g, 1.67 mol) in CH ₃ CN (1500 ml) was added NBS (300 g, 1.67 mol) at room temperature. After complete addition, the mixture was stirred at room temperature overnight and then the solvent was removed. Petroleum ether (1000 ml) was added and the resulting white precipitate was filtered off. 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 Et ₃ N (202 g, 2 mol) at room temperature. Methyl chloroformate (155 ml) was added dropwise to the above solution at a temperature of 0 ° C. After complete addition, the mixture is stirred at 0 ° C for 2 hours, quenched with a saturated solution of ammonium chloride and diluted with water. The organic layer was separated and washed with water and brine, dried over Na ₂ SO ₄ and 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 H ₂ SO ₄ (1000 ml) at a temperature of 0 ° C. KNO ₃ (253 g, 2.5 mol) was added portionwise over 90 minutes. The reaction mixture was stirred at 0 ° C for 2 hours and poured into ice water (20 L). The resulting precipitate was separated by filtration and washed thoroughly with water, dried and recrystallized from diethyl ether to obtain methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate (332 g, 60% yield in 3 stages).

S-14-a ; 2-tert-butyl-4-bromo-5-nitrophenol

To a solution of methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate (121.5 g, 0.366 mol) in methanol (1000 ml), potassium hydroxide (30.75 g, 0.549 mol) is added in portions. After complete addition, the mixture was stirred at room temperature for 3 hours and acidified with 1N. HCl solution to pH = 7. Methanol is removed and water is added. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give 2-tert-butyl-4-bromo-5-nitrophenol ( C-14-a ) (100 g, 99% yield).

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 Cs ₂ CO ₃ (1.56 g, 4.8 mmol) in DMF ( 8 ml) benzyl bromide (500 μl, 4.2 mmol) is added. The mixture was stirred at room temperature for 4 hours, diluted with H ₂ O and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After removing the solvent, the residue was purified by column chromatography (0-5% EtOAc-hexane) to obtain 1-tert-butyl-2- (benzyloxy) -5-bromo-4-nitrobenzene (1.37 g, yield 94%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.62 (s, 1H), 7.53 (s, 1H), 7.43 (m, 5H), 5.22 (s, 2H), 1 42 (s, 9H).

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

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), methylchlorodifluoroacetate (1.6 ml, 15 mmol) and DMF (5 ml) were stirred at 125 ° C in a sealed tube overnight, cooled to room temperature, diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine and dried over anhydrous MgSO ₄ . After removing the solvent, the residue was purified by column chromatography (0-5% EtOAc-hexane) to obtain 1-tert-butyl-2- (benzyloxy) -5- (trifluoromethyl) -4-nitrobenzene (591 mg, 67% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.66 (s, 1H), 7.37 (m, 5H), 7.19 (s, 1H), 5.21 (s, 2H), 1 32 (s, 9H).

S-14 ; 5-amino-2-tert-butyl-4-trifluoromethylphenol

To a refluxing 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) add 10% Pd / C (245 mg). Then the mixture was refluxed for 2 hours, cooled to room temperature and filtered through celite. After removing the solvent, the residue was purified by column chromatography to obtain 5-amino-2-tert-butyl-4-trifluoromethylphenol ( C-14 ) (120 mg, 52% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.21 (s, 1H), 6.05 (s, 1H), 1.28 (s, 9H).

HPLC: retention time 3.46 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 234.1 m / z (MH ⁺ ).

Example 10

General scheme

a) ArB (OH) ₂ , K ₂ CO ₃ , Pd (PPh ₃ ) ₄ , H ₂ O, DMF or ArB (OH) ₂ , (dppf) PdCl ₂ , K ₂ CO ₃ , EtOH; b) H ₂ , Raney nickel, MeOH or HCO ₂ NH ₄ , Pd / C, EtOH or SnCl ₂ · 2H ₂ O.

Specific 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-ethoxyphenylboronic acid (5.48 g, 33 mmol) ), potassium carbonate (4.56 g, 33 mmol), water (10 ml) and Pd (PPh ₃ ) ₄ (1.73 g, 1.5 mmol). The mixture is heated at a temperature of 90 ° C for 3 hours in a nitrogen atmosphere. The solvent is removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried and purified by column chromatography (petroleum ether-ethyl acetate = 10: 1) to obtain 2-tert-butyl-4- (2-ethoxyphenyl) -5-nitrophenol (9.2 g, yield 92%).

¹ H-NMR (DMSO-d ₆ ) δ 10.38 (s, 1H), 7.36 (s, 1H), 7.28 (m, 2H), 7.08 (s, 1H), 6.99 (t, 1H, J = 7.35 Hz), 6.92 (d, 1H, J = 8.1 Hz), 3.84 (q, 2H, J = 6.6 Hz), 1.35 (s , 9H), 1.09 (t, 3H, J = 6.6 Hz).

ESI-MS: 314.3 m / z (MH ⁺ ).

S-15 ; 2-tert-butyl-4- (2-ethoxyphenyl) -5-aminophenol

To a solution of 2-tert-butyl-4- (2-ethoxyphenyl) -5-nitrophenol (3.0 g, 9.5 mmol) in methanol (30 ml), Raney nickel (300 mg) was added. The mixture was stirred in a hydrogen atmosphere (1 atm.) At room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether-ethyl acetate = 6: 1) to obtain 2-tert-butyl-4- (2-ethoxyphenyl) -5-aminophenol ( C-15 ) (2.35 g, yield 92%).

¹ H-NMR (DMSO-d ₆ ) δ 8.89 (s, 1H), 7.19 (t, 1H, J = 4.2 Hz), 7.10 (d, 1H, J = 1.8 Hz ), 7.08 (d, 1H, J = 1.8 Hz), 6.94 (t, 1H, J = 3.6 Hz), 6.67 (s, 1H), 6.16 (s, 1H ), 4.25 (s, 1H), 4.00 (q, 2H, J = 6.9 Hz), 1.26 (s, 9H), 1.21 (t, 3H, J = 6.9 Hz )

ESI-MS: 286.0 m / z (MH ⁺ ).

Other examples

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

2-tert-Butyl-4- (3-ethoxyphenyl) -5-aminophenol ( C-16 ) is synthesized according to the general scheme given above, starting from 2-tert-butyl-4-bromo-5-nitrophenol ( C-14 -a ) and 3-ethoxyphenylboronic acid.

HPLC: retention time 2.77 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 286.1 m / z (MH ⁺ ).

S-17 ; 2-tert-Butyl-4- (3-methoxycarbonylphenyl) -5-aminophenol

2-tert-Butyl-4- (3-methoxycarbonylphenyl) -5-aminophenol ( C-17 ) is synthesized according to the general scheme given above based on 2-tert-butyl-4-bromo-5-nitrophenol ( C-14 a ) and 3- (methoxycarbonyl) phenylboronic acid.

HPLC: retention time 2.70 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 300.5 m / z (MH ⁺ ).

Example 11

1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene

To a mixture of 2-tert-butyl-4-bromo-5-nitrophenol ( C-14-a ) (1.5 g, 5.5 mmol) and Cs ₂ CO ₃ (2.2 g, 6.6 mmol) in DMF (6 ml) was added methyl iodide (5150 μl, 8.3 mmol). The mixture was stirred at room temperature for 4 hours, diluted with H ₂ O and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After removing the solvent, the residue was washed with hexane to obtain 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (1.1 g, yield 69%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.58 (s, 1H), 7.44 (s, 1H), 3.92 (s, 3H), 1.39 (s, 9H).

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

Mixture of 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (867 mg, 3.0 mmol), KF (348 mg, 6 mmol), KBr (714 mg, 6 mmol), CuI (684 mg , 3.6 mmol), methylchlorodifluoroacetate (2.2 ml, 21.0 mmol) in DMF (5 ml) was stirred at 125 ° C in a sealed tube overnight, cooled to room temperature, diluted with water and extracted three times with extraction EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO ₄ . After removing the solvent, the residue was purified by column chromatography (0-5% EtOAc-hexane) to obtain 1-tert-butyl-2-methoxy-5- (trifluoromethyl) -4-nitrobenzene (512 mg, 61% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.60 (s, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 1.33 (s, 9H).

S-18 ; 1-tert-Butyl-2-methoxy-5- (trifluoromethyl) -4-aminobenzene

To a refluxing 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) add 10% Pd / C (200 mg). The mixture was refluxed for 1 hour, cooled and filtered through celite. The solvent was removed by evaporation to give 1-tert-butyl-2-methoxy-5- (trifluoromethyl) -4-aminobenzene ( C-18 ) (403 mg, 95% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.19 (s, 1H), 6.14 (s, 1H), 4.02 (br s, 2H), 3.74 (s, 3H) 1.24 (s, 9H).

Example 12

S-27 ; 2-tert-butyl-4-bromo-5-aminophenol

To a solution of 2-tert-butyl-4-bromo-5-nitrophenol ( C-14-a ) (12 g, 43.8 mmol) in MeOH (90 ml) Ni (2.4 g) was added. The reaction mixture was stirred in a hydrogen atmosphere (1 atm.) For 4 hours. The mixture was filtered and the filtrate was concentrated. The crude product was recrystallized from ethyl acetate and petroleum ether to give 2-tert-butyl-4-bromo-5-aminophenol ( C-27 ) (7.2 g, 70% yield).

¹ H-NMR (DMSO-d ₆ ): δ 9.15 (s, 1H), 6.91 (s, 1H), 6.24 (s, 1H), 4.90 (br s, 2H), 1.22 (s, 9H).

ESI-MS: 244.0 m / z (MH ⁺ ).

Example 13

S-24 ; 2,4-di-tert-butyl-6- (N-methylamino) phenol

A mixture of 2,4-di-tert-butyl-6-aminophenol ( C-9 ) (5.08 g, 23 mmol), NaBH ₃ CN (4.41 g, 70 mmol) and paraformaldehyde (2.1 g, 70 mmol) in methanol (50 ml) was stirred at the boil under reflux for 3 hours. After removing the solvent, the residue was purified by column chromatography (petroleum ether-EtOAc = 30: 1) to obtain 2,4-di-tert-butyl-6- (N-methylamino) phenol ( C-24 ) (800 mg, 15% yield) .

¹ H-NMR (DMSO-d ₆ ): δ 8.67 (s, 1H), 6.84 (s, 1H), 5.99 (s, 1H), 4.36 (q, J = 4, 8 Hz, 1H), 2.65 (d, J = 4.8 Hz, 3H), 1.23 (s, 18H).

ESI-MS: 236.2 m / z (MH ⁺ ).

Example 14

2-methyl-2-phenylpropan-1-ol

To a solution of 2-methyl-2-phenylpropionic acid (82 g, 0.5 mol) in THF (200 ml), borane dimethyl sulfide (2M, 100 ml) was added dropwise at a temperature of 0-5 ° C. The mixture was stirred at this temperature for 30 minutes and then refluxed for 1 hour. After cooling, methanol (150 ml) and water (50 ml) are added. The mixture was extracted with EtOAc (3 times 100 ml) and the combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give 2-methyl-2-phenylpropan-1-ol as an oil (70 g, yield 77%).

2 - [(2-Methoxyethoxy) -1,1-dimethylethyl] benzene

To a suspension of NaH (29 g, 0.75 mol) in THF (200 ml) was added dropwise a solution of 2-methyl-2-phenylpropan-1-ol (75 g, 0.5 mol) in THF (50 ml) at a temperature 0 ° C. The mixture was stirred at 20 ° C. for 30 minutes and then a solution of 1-bromo-2-methoxyethane (104 g, 0.75 mol) in THF (100 ml) was added dropwise at 0 ° C. The mixture was stirred at 20 ° C. overnight, poured into water (200 ml) and extracted with EtOAc (3 times 100 ml). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to give 2 - [(2-methoxyethoxy) -1,1-dimethylethyl] benzene as an oil (28 g, 27% yield).

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

To a solution of 2 - [(2-methoxyethoxy) -1,1-dimethylethyl] benzene (52 g, 0.25 mol) in CHCl ₃ (200 ml) was added KNO ₃ (50.5 g, 0.5 mol) and TMSCl (54 g, 0.5 mol). The mixture was stirred at 20 ° C. for 30 minutes and then AlCl ₃ (95 g, 0.7 mol) was added. The reaction mixture was stirred at 20 ° C for 1 hour and poured into ice water. The organic layer was separated and the aqueous layer was extracted with CHCl ₃ (3 times 50 ml). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to give 1- [2- (2-methoxyethoxy) -1,1-dimethylethyl] -4-nitrobenzene (6 g, 10% yield).

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

A suspension of 1- [2- (2-methoxyethoxy) -1,1-dimethylethyl] -4-nitrobenzene (8.1 g, 32 mmol) and Raney nickel (1 g) in MeOH (50 ml) was stirred under a hydrogen atmosphere (1 atm.) at room temperature for 1 hour. The catalyst was filtered off and the filtrate was concentrated to give 4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] phenylamine (5.5 g, 77% yield).

4- [2- (2-Methoxyethoxy) -1,1-dimethylethyl] -3-nitrophenylamine

To a solution of 4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] phenylamine (5.8 g, 26 mmol) in H ₂ SO ₄ (20 ml) was added KNO ₃ (2.63 g, 26 mmol) at a temperature of 0 ° C. After complete addition, the mixture is stirred at this temperature for 20 minutes and then poured into ice water. The mixture was extracted with EtOAc (3 times 50 ml). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc = 100: 1) to give 4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] -3-nitrophenylamine (5 g, 71% yield).

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

To a suspension of NaHCO ₃ (10 g, 0.1 mol) in dichloromethane (50 ml) was added 4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] -3-nitrophenylamine (5 g, 30 mmol) and acetyl chloride (3 ml, 20 mmol) at a temperature of 0-5 ° C. 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 (2 times 50 ml). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to dryness to give N- {4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] -3-nitrophenyl} acetamide (5, 0 g, yield 87%).

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

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

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

To a solution of N- {3-amino-4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] phenyl} acetamide (1.6 g, 5.7 mmol) in H ₂ SO ₄ (15% , 6 ml) add NaNO ₂ at a temperature of 0-5 ° C. The mixture was stirred at this temperature for 20 minutes and then poured into ice water. The mixture was extracted with EtOAc (3 times 30 ml). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc = 100: 1) to obtain N- {3-hydroxy-4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] phenyl} acetamide (0.7 g, yield 38%).

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

A mixture of N- {3-hydroxy-4- [2- (2-methoxyethoxy) -1,1-dimethylethyl] phenyl} acetamide (1 g, 3.5 mmol) and HCl (5 ml) was refluxed for 1 hours. The mixture was made basic with a Na ₂ CO ₃ solution to pH = 9 and then extracted with EtOAc (3 times with 20 ml). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column chromatography (petroleum ether-EtOAc = 100: 1) to obtain 2- (1- (2-methoxyethoxy) -2-methylpropan-2-yl) -5-aminophenol ( C-25 ) (61 mg, yield 6 %).

¹ H-NMR (CDCl ₃ ) δ 9.11 (br s, 1H), 6.96-6.98 (d, J = 8 Hz, 1H), 6.26-6.27 (d, J = 4 Hz, 1H), 6.17-6.19 (m, 1H), 3.68-3.69 (m, 2H), 3.56-3.59 (m, 4H), 3.39 (s , 3H); 1.37 (s, 6H).

ESI-MS: 239.9 m / z (MH ⁺ ).

Example 15

4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione

To a solution of 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (4.20 g, 19.1 mmol) in acetic acid (115 ml), HNO ₃ (15 ml) was slowly added. The mixture is heated at a temperature of 60 ° C for 40 minutes before pouring into H ₂ O (50 ml). The mixture is left to stand at room temperature for 2 hours, then placed for 1 hour in an ice bath. The solid was collected and washed with water to give 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (1.2 g, 24% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 6.89 (s, 1H), 1.27 (s, 9H), 1.24 (s, 9H).

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

A THF / H ₂ O mixture (1: 1, 400 ml), 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (4.59 g, 17.3 mmol) and Na ₂ S ₂ O ₄ (3 g, 17.3 mmol). Clog the separatory funnel and shake for 2 minutes. The mixture was diluted with EtOAc (20 ml). The layers were separated and the organic layer was washed with brine, dried over MgSO ₄ and concentrated to give 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (3.4 g, 74% yield), which was used without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.24 (s, 1H), 8.76 (s, 1H), 6.87 (s, 1H), 1.35 (s, 9H) 1.25 (s, 9H).

S-26 ; 4,6-di-tert-butyl-3-aminobenzene-1,2-diol

To a solution of 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (1.92 g, 7.2 mmol) in EtOH (70 ml) was added 5% by weight. palladium on charcoal (200 mg). The mixture was stirred in an atmosphere of hydrogen (1 atm.) For 2 hours. 5% of the mass are re-added to the reaction mixture. palladium-on-charcoal (200 mg) and stirred in a hydrogen atmosphere (1 atm.) for the next 2 hours. The mixture was filtered through celite, the filtrate was concentrated and purified by column chromatography (10-40% ethyl acetate-hexanes) to give 4,6-di-tert-butyl-3-aminobenzene-1,2-diol ( C-26 ) (560 mg, yield 33%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.28 (s, 1H), 1.42 (s, 9H), 1.38 (s, 9H).

Anilines

Example 1

General scheme

Specific example

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

A mixture of 1-chloro-2,4-dinitrobenzene (100 mg, 0.5 mmol) and SnCl ₂ · 2H ₂ O (1.12 g, 5 mmol) in ethanol (2.5 ml) was stirred at room temperature overnight . Water was added and then the mixture was alkalinized to pH = 7-8 with saturated NaHCO ₃ solution. The solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 4-chlorobenzene-1,3-diamine ( D-1 ) (79 mg, quantitative yield).

HPLC: retention time 0.38 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 143.1 m / z (MH ⁺ ).

Other examples

D-2 ; 4,6-Dichlorobenzene-1,3-diamine

4,6-Dichlorobenzene-1,3-diamine ( D-2 ) is synthesized according to the general scheme given above based on 1,5-dichloro-2,4-dinitrobenzene. Yield (95%).

HPLC: retention time 1.88 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 177.1 m / z (MH ⁺ ).

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

4-Methoxybenzene-1,3-diamine ( D-3 ) is synthesized according to the general scheme given above based on 1-methoxy-2,4-dinitrobenzene. Yield (quantitative).

HPLC: retention time 0.31 min, 10-99% CH ₃ CN, analysis time 5 min.

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

4-Trifluoromethoxybenzene-1,3-diamine ( D-4 ) is synthesized according to the general scheme given above based on 2,4-dinitro-1-trifluoromethoxybenzene. Yield (89%).

HPLC: retention time 0.91 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 193.3 m / z (MH ⁺ ).

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

4-Propoxybenzene-1,3-diamine ( D-5 ) is synthesized according to the general scheme given above based on 5-nitro-2-propoxyphenylamine. Yield (79%).

HPLC: retention time 0.54 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 167.5 m / z (MH ⁺ ).

Example 2

General scheme

a) HNO ₃ , H ₂ SO ₄ ; b) SnCl ₂ · 2H ₂ O, EtOH or H ₂ , Pd / C, MeOH.

Specific example

2,4-dinitropropylbenzene

A solution of propylbenzene (10 g, 83 mmol) in concentrated H ₂ SO ₄ (50 ml) was cooled to 0 ° C over 30 minutes and a solution of H ₂ SO ₄ (50 ml) and fuming HNO ₃ (25 ml) was added portionwise. pre-cooled to a temperature of 0 ° C, for 15 minutes Next, the mixture was stirred at 0 ° C. for 30 minutes and then allowed to warm to room temperature. The mixture was poured into a mixture of ice (200 g) with water (100 ml) and extracted with diethyl ether (2 times 100 ml). The combined extracts were washed with H ₂ O (100 ml) and brine (100 ml), dried over MgSO ₄ , filtered and concentrated to give 2,4-dinitropropylbenzene (15.6 g, 89% yield).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.73 (d, J = 2.2 Hz, 1H), 8.38 (dd, J = 8.3, J = 2.2, 1H), 7 6 (d, J = 8.5 Hz, 1H), 2.96 (dd, 2H), 1.73 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).

D-6 ; 4-propylbenzene-1,3-diamine

To a solution of 2,4-dinitropropylbenzene (2.02 g, 9.6 mmol) in ethanol (100 ml) was added SnCl ₂ (9.9 g, 52 mmol), then concentrated HCl (10 ml). The mixture was refluxed for 2 hours, poured into ice water (100 ml) and neutralized with solid sodium bicarbonate. Then the solution was alkalinized with a 10% NaOH solution to pH ~ 10, extracted with diethyl ether (2 times 100 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO ₄ , filtered and concentrated to give 4-propylbenzene-1,3-diamine ( D-6 ) (1.2 g, 83% yield). No further cleaning is necessary for use in the next step; however, the product is not stable for a long period of time.

¹ H-NMR (CDCl ₃ , 300 MHz) δ 6.82 (d, J = 7.9 Hz, 1H), 6.11 (dd, J = 7.5, J = 2.2 Hz, 1H), 6.06 (d, J = 2.2 Hz, 1H), 3.49 (br s, 4H, NH ₂ ), 2.38 (t, J = 7.4 Hz, 2H), 1.58 ( m, 2H), 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 ) is synthesized according to the general scheme given above starting from ethylbenzene. Total yield (76%).

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

4-Isopropylbenzene-1,3-diamine ( D-8 ) is synthesized according to the general scheme given above based on isopropylbenzene. Total yield (78%).

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

4-tert-Butylbenzene-1,3-diamine ( D-9 ) is synthesized according to the general scheme given above based on tert-butylbenzene. Total yield (48%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.01 (d, J = 8.3 Hz, 1H), 6.10 (dd, J = 2.4, 8.3 Hz, 1H), 6 01 (d, J = 2.4 Hz, 1H); 3.59 (br., 4H); 1.37 (s, 9H);

¹³ C-NMR (100 MHz, CDCl ₃ ): 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 scheme

a) KNO ₃ , H ₂ SO ₄ ; b) (i) HNO ₃ , H ₂ SO ₄ ; (ii) Na ₂ S, S, H ₂ O; c) Boc ₂ O, NaOH, THF; d) H ₂ , Pd / C, MeOH.

Specific example

4-tert-butyl-3-nitrophenylamine

To a mixture of 4-tert-butylphenylamine (10.0 g, 67.01 mmol) dissolved in H ₂ SO ₄ (98%, 60 ml), KNO ₃ (8.1 g, 80.41 mmol) was slowly added. at a temperature of 0 ° C. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was then poured into ice water and made basic with saturated NaHCO ₃ solution to pH = 8. The mixture was extracted several times with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc = 10: 1) to give 4-tert-butyl-3-nitrophenylamine (10 g, 77% yield).

(4-tert-butyl-3-nitrophenyl) carbamic acid tert-butyl ester

A mixture of 4-tert-butyl-3-nitrophenylamine (4.0 g, 20.6 mmol) and Boc ₂ O (4.72 g, 21.6 mmol) in a solution of NaOH (2N, 20 ml) and THF (20 ml) was stirred at room temperature overnight. THF is removed under reduced pressure. The residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was washed with NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to give tert-butyl ether (4-tert-butyl-3-nitrophenyl) carbamic acid (4.5 g, 74% yield).

D-10 ; (3-amino-4-tert-butylphenyl) carbamic acid tert-butyl ester

A suspension of tert-butyl ether (4-tert-butyl-3-nitrophenyl) carbamic acid (3.0 g, 10.19 mol) and 10% Pd / C (1 g) in MeOH (40 ml) was stirred in the atmosphere hydrogen (1 atm.) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether-EtOAc = 5: 1) to obtain (3-amino-4-tert-butylphenyl) carbamic acid tert-butyl ester ( D-10 ) as a brown oil (2, 5 g, yield 93%).

¹ H-NMR (CDCl ₃ ) δ 7.10 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 6.50-6.53 (m, 1H), 6.36 (s, 1H), 3.62 (br s, 2H), 1.50 (s, 9H), 1.38 (s, 9H).

ESI-MS: 528.9 m / z (2M + H ⁺ ).

Other examples

D-11 ; (3-amino-4-isopropylphenyl) carbamic acid tert-butyl ester

(3-Amino-4-isopropylphenyl) carbamic acid tert-butyl ester ( D-11 ) is synthesized according to the general scheme given above based on isopropylbenzene. Total yield (56%).

D-12 ; (3-amino-4-ethylphenyl) carbamic acid tert-butyl ester

(3-Amino-4-ethyl-phenyl) -carbamic acid tert-butyl ester ( D-12 ) is synthesized according to the general scheme given above starting from ethylbenzene. Total yield (64%).

¹ H-NMR (CD ₃ OD 300 MHz) δ 6.87 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 2.2 1H), 6.63 (dd, J = 8.1 J = 2.2 1H), 2.47 (q, J = 7.4 Hz, 2H).

ESI-MS: 237.1 m / z (MH ⁺ ).

D-13 ; (3-amino-4-propylphenyl) carbamic acid tert-butyl ester

(3-Amino-4-propylphenyl) carbamic acid tert-butyl ester ( D-13 ) is synthesized according to the general scheme given above based on propylbenzene. Total yield (48%).

Example 4

(3-amino-4-tert-butylphenyl) carbamic acid benzyl ester

A solution of 4-tert-butylbenzene-1,3-diamine ( D-9 ) (657 mg, 4 mmol) and pyridine (0.39 ml, 4.8 mmol) in a mixture of CH ₂ Cl ₂ / MeOH (12/1, 8 ml) was cooled to a temperature of 0 ° C and a solution of benzyl chloroformate (0.51 ml, 3.6 mmol) in CH ₂ Cl ₂ (8 ml) was added dropwise over 10 minutes. The mixture was stirred at 0 ° C. for 15 minutes, then warmed to room temperature. After 1 hour, the mixture was washed with 1M citric acid solution (2 times in 20 ml), saturated aqueous sodium bicarbonate solution (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give crude benzyl ether (3-amino -4-tert-butylphenyl) carbamic acid as a brown viscous resin (0.97 g), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.41-7.32 (m, 6H,), 7.12 (d, J = 8.5 Hz, 1H) 6.89 (br s, 1H ), 6.57 (dd, J = 2.3, 8.5 Hz, 1H), 5.17 (s, 2H), 3.85 (broad s, 2H), 1.38 (s, 9H) .

¹³ C-NMR (100 MHz, CDCl ₃ , mixture of rotamers) δ 153.3 (broad), 145.3, 136.56, 136.18, 129.2, 128.73, 128.59, 128.29 , 128.25, 127.14, 108.63 (broad), 107.61 (broad), 66.86, 33.9, 29.7.

ESI-MS: 299.1 m / z (MH ⁺ ).

(4-tert-butyl-3-formylaminophenyl) carbamic acid benzyl ester

A solution of benzyl ether (3-amino-4-tert-butylphenyl) carbamic acid (0.97 g, 3.25 mmol) and pyridine (0.43 ml, 5.25 mmol) in CH ₂ Cl ₂ (7.5 ml ) is cooled to a temperature of 0 ° C and a solution of mixed formic acetic anhydride (3.5 mmol, obtained by mixing formic acid (158 μl, 4.2 mmol, 1.3 equiv.) and acetic anhydride) is added dropwise over 2 minutes 0.32 ml, 3.5 mmol, 1.1 eq.), Undiluted and aged for 1 hour) in CH ₂ Cl ₂ (2.5 ml). After completion of the addition, the mixture was allowed to warm to room temperature, after which a precipitate formed in it, and the resulting suspension was stirred overnight. The mixture was washed with 1M citric acid solution (2 times 20 ml), saturated aqueous sodium bicarbonate solution (20 ml), dried (Na ₂ SO ₄ ) and filtered. A thin layer of solid is deposited from the turbid mixture on top of the desiccant, and HPLC analysis indicates that this is the desired formamide. The filtrate was concentrated to a volume of approximately 5 ml and diluted with hexane (15 ml) to further precipitate formamide. The desiccant (Na ₂ SO ₄ ) is suspended in methanol (50 ml), filtered and the filtrate combined with the substance recrystallized from a mixture of CH ₂ Cl ₂ / hexane. The resulting mixture was concentrated to give (4-tert-butyl-3-formylaminophenyl) carbamic acid benzyl ester as an off-white solid (650 mg, 50% yield in 2 steps). ¹ H and ¹³ C-NMR (CD ₃ OD) indicate that the product is in the form of a mixture of rotamers.

¹ H-NMR (400 MHz, CD ₃ OD, mixture of rotamers) δ 8.27 (s, 1H-a), 8.17 (s, 1H-b), 7.42-7.26 (m, 8H) 5.17 (s, 1H-a), 5.15 (s, 1H-b), 4.86 (s, 2H), 1.37 (s, 9H-a), 1.36 (s, 9H -b)

¹³ C-NMR (100 MHz, CD ₃ OD, mixture of rotamers) δ 163.9, 163.5, 155.8, 141.40, 141.32, 139.37, 138.88, 138.22, 138, 14, 136.4, 135.3, 129.68, 129.65, 129.31, 129.24, 129.19, 129.13, 128.94, 128.50, 121.4 (broad), 118.7 (broad), 67.80, 67.67, 35.78, 35.52, 31.65, 31.34.

ESI-MS: 327.5 m / z (MH ⁺ ).

N- (5-amino-2-tert-butylphenyl) formamide

Benzyl ester (4-tert-butyl-3-formylaminophenyl) carbamic acid (650 mg, 1.99 mmol), methanol (30 ml) and 10% Pd / C (50 mg) are introduced into a 100 ml flask. in a hydrogen atmosphere (1 atm.) for 20 hours. CH ₂ Cl ₂ (5 ml) was added to quench the catalyst, the mixture was then filtered through celite and concentrated to give N- (5-amino-2-tert-butylphenyl) formaldehyde as an off-white solid (366 mg, 96% yield) ) Rotamer mixture according to ¹ H and ¹³ C-NMR (DMSO-d ₆ ).

¹ H-NMR (400 MHz, DMSO-d ₆ , mixture of rotamers) δ 9.24 (d, J = 10.4 Hz, 1H), 9.15 (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), 6.51 (d, J = 2.5 Hz, 1H), 6.46 (dd, J = 2.5, 8.5 Hz, 1H), 6.39 (dd, J = 2.5, 8.5 Hz, 1H), 6.29 (d, J = 2.5 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 1.27 ( s, 9H).

¹³ C-NMR (100 MHz, DMSO-d ₆ , mixture of rotamers) δ 164.0, 160.4, 147.37, 146.74, 135.38, 135.72, 132.48, 131.59, 127 , 31, 126.69, 115.15, 115.01, 112.43, 112.00, 33.92, 33.57, 31.33, 30.92.

ESI-MS: 193.1 m / z (MH ⁺ ).

D-14 ; 4-tert-butyl-N ³ methylbenzene-1,3-diamine

N- (5-amino-2-tert-butylphenyl) formamide (340 mg, 1.77 mmol) was introduced into a 100 ml flask and purged with nitrogen. THF (10 ml) was added and the solution was cooled to 0 ° C. A solution of lithium aluminum hydride in THF (4.4 ml, 1M solution) was added over 2 minutes. Then the mixture was allowed to warm to room temperature. After refluxing for 15 hours, the yellow suspension was cooled to 0 ° C, quenched with water (170 μl), 15% aqueous NaOH solution (170 μl) and water (510 μl), which 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 vacuo to give a tan solid, which was partitioned between chloroform (75 ml) and water (50 ml). The organic layer was separated, washed with water (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give 4-tert-butyl-N ^3- methylbenzene-1,3-diamine ( D-14 ) as a brown oil, which cures upon standing (313 mg, 98% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.01 (d, J = 8.1 Hz, 1H), 6.05 (dd, J = 2.4, 8.1 Hz, 1H), 6, 03 (d, J = 2.4 Hz, 1H), 3.91 (broad s, 1H), 3.52 (broad s, 2H), 2.86 (s, 3H), 1.36 (s , 9H).

¹³ C-NMR (100 MHz, CDCl ₃ ): 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

Specific example

2,4-dinitropropylbenzene

A solution of propylbenzene (10 g, 83 mmol) in concentrated H ₂ SO ₄ (50 ml) was cooled to 0 ° C over 30 minutes and a solution of concentrated H ₂ SO ₄ (50 ml) and fuming HNO ₃ (25 ml) was added portionwise. , pre-cooled to a temperature of 0 ° C, for 15 minutes The mixture was stirred at 0 ° C. for an additional 30 minutes and then allowed to warm to room temperature. The mixture was poured into a mixture of ice (200 g) with water (100 ml) and extracted with diethyl ether (2 times 100 ml). The combined extracts were washed with H ₂ O (100 ml) and brine (100 ml), dried over MgSO ₄ , filtered and concentrated to give 2,4-dinitropropylbenzene (15.6 g, 89% yield).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.73 (d, J = 2.2 Hz, 1H), 8.38 (dd, J = 8.3, 2.2 Hz, 1H), 7, 6 (d, J = 8.5 Hz, 1H), 2.96 (m, 2H), 1.73 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).

4-propyl-3-nitroaniline

A suspension of 2,4-dinitropropylbenzene (2 g, 9.5 mmol) in H ₂ O (100 ml) is refluxed and vigorously stirred. A clear orange-red polysulfide solution (300 ml, 10 equiv.), Previously obtained by heating sodium sulfide nanohydrate (10.0 g), sulfur powder (2.60 g) and H ₂ O (400 ml) was added dropwise over 45 minutes. ) The red-brown solution was refluxed for 1.5 hours. The mixture is cooled to a temperature of 0 ° C and then extracted with diethyl ether (2 times 200 ml). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 4-propyl-3-nitroaniline (1.6 g, 93% yield), which was used without further purification.

(3-Nitro-4-propylphenyl) carbamic acid tert-butyl ester

4-Propyl-3-nitroaniline (1.69 g, 9.4 mmol) was dissolved in pyridine (30 ml) with stirring. Boc anhydride (2.05 g, 9.4 mmol) was added. The mixture was stirred and refluxed for 1 hour, then the solvent was removed in vacuo. The resulting oil was again dissolved in CH ₂ Cl ₂ (300 ml) and washed with water (300 ml) and brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude oil, which contains both mono-acylated and bis-acylated nitro products, is purified by column chromatography (0-10% CH ₂ Cl ₂ -MeOH) to obtain tert-butyl ester of (3-nitro-4-propylphenyl) carbamic acid (2, 3 g, 87% yield).

methyl (3-nitro-4-propylphenyl) carbamic acid tert-butyl ester

To a solution of (3-nitro-4-propylphenyl) carbamic acid tert-butyl ester (200 mg, 0.71 mmol) in DMF (5 ml) was added Ag ₂ O (1.0 g, 6.0 mmol), then methyl iodide (0.20 ml, 3.2 mmol). The resulting suspension was stirred at room temperature for 18 hours and filtered through a pad of celite. The filter cake was washed with CH ₂ Cl ₂ (10 ml). The filtrate was concentrated in vacuo. The crude oil was purified by column chromatography (0-10% CH ₂ Cl ₂ -MeOH) to give methyl (3-nitro-4-propylphenyl) carbamic acid tert-butyl ester as a yellow oil (110 mg, 52% yield).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.78 (d, J = 2.2 Hz, 1H), 7.42 (dd, J = 8.2, 2.2 Hz, 1H), 7, 26 (d, J = 8.2 Hz, 1H), 3.27 (s, 3H), 2.81 (t, J = 7.7 Hz, 2H), 1.66 (m, 2H), 1, 61 (s, 9H), 0.97 (t, J = 7.4 Hz, 3H).

D-15 ; (3-amino-4-propylphenyl) methylcarbamic acid tert-butyl ester

To a solution of methyl (3-nitro-4-propylphenyl) carbamic acid tert-butyl ester (110 mg, 0.37 mmol) in EtOAc (10 ml) was added 10% Pd / C (100 mg). The resulting suspension was stirred at room temperature in an atmosphere of H ₂ (1 atm.) For 2 days. The progress of the reaction is controlled by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to give (3-amino-4-propylphenyl) methylcarbamic acid tert-butyl ester ( D-15 ) as a colorless crystalline compound (80 mg, 81% yield).

ESI-MS: 265.3 m / z (MH ⁺ ).

Other examples

D-16 ; (3-amino-4-ethylphenyl) methylcarbamic acid tert-butyl ester

(3-Amino-4-ethylphenyl) methylcarbamic acid tert-butyl ester ( D-16 ) is synthesized according to the general scheme given above starting from ethylbenzene. Total yield (57%).

D-17 ; (3-amino-4-isopropylphenyl) methylcarbamic acid tert-butyl ester

(3-Amino-4-isopropylphenyl) methylcarbamic acid tert-butyl ester ( D-17 ) is synthesized according to the general scheme given above based on isopropylbenzene. Total yield (38%).

Example 6

2'-Ethoxy-2,4-dinitrobiphenyl

2-ethoxyphenylboronic acid (0.66 g, 4.0 mmol), KF (0.77 g, 13 mmol), Pd ₂ (dba) ₃ (16 mg, 0.02 mmol) and 2, are introduced into the pressure vessel 4-dinitrobromobenzene (0.99 g, 4.0 mmol) in THF (5 ml). The vessel was purged with argon for 1 min, then tri-tert-butylphosphine (0.15 ml, 0.48 mmol, 10% solution in hexanes) was added. The reaction vessel was purged with argon for an additional 1 min, sealed, and heated at 80 ° C. overnight. After cooling to room temperature, the solution was filtered through a pad of celite. The filter cake was washed with CH ₂ Cl ₂ (10 ml) and the combined organic extracts were concentrated under reduced pressure to obtain the crude product, 2'-ethoxy-2,4-dinitrobiphenyl (0.95 g, 82% yield). Further purification is not carried out.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 8.43 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H) 6.88 (d, J = 8.4 Hz, 1H); 3.44 (q, 7 = 6.6 Hz, 2H); 1.24 (t, J = 6.6 Hz, 3H).

HPLC: retention time 3.14 min, 10-100% CH ₃ CN, gradient 5 min.

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

A clear orange-red polysulfide solution (120 ml, 7.5 equiv.), Previously obtained by heating sodium sulfide monohydrate (10 g), sulfur (1.04 g) and water (160 ml), was added dropwise at a temperature of 90 ° C. within 45 minutes, to a suspension of 2'-ethoxy-2,4-dinitrobiphenyl (1.2 g, 4.0 mmol) in water (40 ml). The red-brown solution was refluxed for 1.5 hours. The mixture was cooled to room temperature and solid NaCl (5 g) was added. The solution was extracted with CH ₂ Cl ₂ (3 times 50 ml) and the combined organic extracts concentrated to give 2'-ethoxy-2-nitrobiphenyl-4-ylamine (0.98 g, 95% yield), which was used in the next step without further cleaning up.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.26 (m, 2H), 7.17 (d, J = 2.7 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.00 (t, J = 6.9 Hz, 1H), 6.83 (m, 2H), 3.91 (q, J = 6.9 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H).

HPLC: retention time 2.81 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 259.1 m / z (MH ⁺ ).

(2'-Ethoxy-2-nitrobiphenyl-4-yl) carbamic acid tert-butyl ester

A mixture of 2'-ethoxy-2-nitrobiphenyl-4-ylamine (0.98 g, 4.0 mmol) and Boc ₂ O (2.6 g, 12 mmol) was heated with a jet air dryer. After the starting materials were consumed, according to TLC, the crude mixture was purified by flash chromatography (silica gel, CH ₂ Cl ₂ ) to give tert-butyl ether (2'-ethoxy-2-nitrobiphenyl-4-yl) carbamic acid (1.5 g yield 83%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.25 (m, 3H), 6.99 ( t, J = 7.5 Hz, 1H), 6.82 (m, 2H), 3.88 (q, J = 6.9 Hz, 2H), 1.50 (s, 9H), 1.18 ( t, J = 6.9 Hz, 3H).

HPLC: retention time 3.30 min, 10-100% CH ₃ CN, gradient 5 min.

D-18 ; (2'-Ethoxy-2-aminobiphenyl-4-yl) carbamic acid tert-butyl ester

To a solution of NiCl ₂ · 6H ₂ O (0.26 g, 1.1 mmol) in EtOH (5 ml) was added NaBH ₄ (40 mg, 1.1 mmol) at a temperature of -10 ° C. Gas evolution is observed and a black precipitate forms. After stirring for 5 minutes, a solution of (2'-ethoxy-2-nitrobiphenyl-4-yl) carbamic acid tert-butyl ester (0.50 g, 1.1 mmol) in EtOH (2 ml) was added. Additional NaBH ₄ (80 mg, 60 mmol) was then added in 3 portions over 20 minutes. The reaction mixture was stirred at 0 ° C. for 20 minutes, then NH ₄ OH (4 ml, 25% aqueous solution) was added. The resulting solution was stirred for 20 minutes. The crude mixture is filtered through a small layer of silica gel. The silica gel layer was washed with a 5% solution of MeOH in CH ₂ Cl ₂ (10 ml) and the combined organic extracts were concentrated under reduced pressure to obtain tert-butyl ether (2'-ethoxy-2-aminobiphenyl-4-yl) carbamic acid ( D -18 ) (0.36 g, quantitative yield), which is used without further purification.

HPLC: retention time 2.41 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 329.3 m / z (MH ⁺ ).

Example 7

D-19 ; N- (3-amino-5-trifluoromethylphenyl) methanesulfonamide

A solution of 5-trifluoromethylbenzene-1,3-diamine (250 mg, 1.42 mmol) in pyridine (0.52 ml) and CH ₂ Cl ₂ (6.5 ml) was cooled to 0 ° C. Methanesulfonyl chloride (171 mg, 1.49 mmol) is added slowly at such a rate that the temperature of the solution remains below 10 ° C. The mixture is stirred at a temperature of ~ 8 ° C and then, after 30 minutes, left to warm to room temperature. After stirring at room temperature for 4 hours, the reaction was almost complete, according to LCMS analysis. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (10 ml), extracted with CH ₂ Cl ₂ (4 times 10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give N- (3-amino-5-trifluoromethylphenyl) methanesulfonamide ( D-19 ) as a reddish semi-solid (0.35 g, 97% yield), which was used without further purification.

^oneH-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-tetrahydroquinoline

To a mixture of 1,2,3,4-tetrahydroquinoline (20.0 g, 0.15 mol) dissolved in H ₂ SO ₄ (98%, 150 ml), KNO ₃ (18.2 g, 0) was slowly added. , 18 mol) at a temperature of 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Then the mixture was poured into ice water and made basic with saturated NaHCO ₃ solution to pH = 8. After extraction with CH ₂ Cl _{2, the} combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10: 1) to give 7-nitro-1,2,3,4-tetrahydroquinoline (6.6 g, 25% yield).

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

A mixture of 7-nitro-1,2,3,4-tetrahydroquinoline (4.0 g, 5.61 mmol), Boc ₂ O (1.29 g, 5.89 mmol) and DMAP (0.4 g) in CH ₂ Cl _{2 was} stirred at room temperature overnight. After dilution with water, the mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to give 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester, which was used in the next step without further cleaning.

DC-1 ; tert-butyl-7-amino-3,4-dihydroquinolin-1 (2H) -carboxylate

Suspension of crude 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (4.5 g, 16.2 mol) and 10% Pd / C (0.45 g) in Meon (40 ml) was stirred in an atmosphere of H ₂ (1 ATM.) At room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether-EtOAc, 5: 1) to obtain tert-butyl-7-amino-3,4-dihydroquinoline-1 (2H) -carboxylate ( DC-1 ) as a brown solid substances (1.2 g, yield 22% in 2 stages).

¹ H-NMR (CDCl ₃ ) δ 7.15 (d, J = 2 Hz, 1H), 6.84 (d, J = 8 Hz, 1H), 6.36-6.38 (m, 1H), 3.65-3.68 (m, 2H), 3.10 (br s, 2H), 2.66 (t, J = 6.4 Hz, 2H), 1.84-1.90 (m, 2H), 1.52 (s, 9H).

ESI-MS: 496.8 m / z (2M + H ⁺ ).

Example 2

3- (2-Hydroxyethyl) -1,3-dihydroindol-2-one

A stirred mixture of oxyindole (5.7 g, 43 mmol) and Raney nickel (10 g) in ethane-1,2-diol (100 ml) is heated in an autoclave. After completion of the reaction, the mixture was filtered and excess diol was removed in vacuo. The residual oil was triturated in hexane to give 3- (2-hydroxyethyl) -1,3-dihydroindol-2-one as a colorless crystalline solid (4.6 g, 70% yield).

1,2-dihydro-3-spiro-1'-cyclopropyl-1H-indol-2-one

To a solution of 3- (2-hydroxyethyl) -1,3-dihydroindol-2-one (4.6 g, 26 mmol) and triethylamine (10 ml) in CH ₂ Cl ₂ (100 ml), MsCl is added dropwise (3, 4 g, 30 mmol) at a temperature of -20 ° C. Then the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to obtain 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), LiAlH ₄ (2 g, 52 mmol) was added in portions. After refluxing the mixture, it was poured onto crushed ice, made basic with aqueous ammonia to pH = 8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give crude 1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole as a yellow solid (about 2 g), which was used directly to the next stage.

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

To a cooled solution (temperature of -5 ° C to ^-10 ° C) NaNO ₃ (1.3 g, 15.3 mmol) in H ₂ SO ₄ (98% cent, 30 ml) was added dropwise 1,2- dihydro-3-spiro-1'-cyclopropyl-1H-indole (2 g, crude) for 20 minutes After complete addition, the reaction mixture was stirred for another 40 minutes and poured onto crushed ice (20 g). The cooled mixture was then made basic with NH ₄ OH and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain 6-nitro-1,2-dihydro-3-spiro-1'-cyclopropyl-1H-indole as a dark gray solid ( 1.3 g).

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

NaHCO ₃ (5 g) was suspended in a solution of 6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (1.3 g, crude) in CH ₂ Cl ₂ (50 ml). During vigorous stirring, acetyl chloride (720 mg) was added dropwise. The mixture was stirred for 1 hour and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give 1-acetyl-6-nitro-1,2-dihydro-3-spiro-1'-cyclopropyl-1H-indole (0.9 g, 15% yield in 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 an atmosphere of H ₂ (1 atm.) For 1.5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was treated with HCl / MeOH to give 1-acetyl-6-amino-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole ( DC-2 ) (300 mg, 90% yield) as the hydrochloride .

Example 3

3-methylbut-2-enoic acid phenylamide

A mixture of 3-methylbut-2-enoic acid (100 g, 1 mol) and SOCl ₂ (119 g, 1 mol) was refluxed for 3 hours. Excess SOCl _{2 is} removed under reduced pressure. CH ₂ Cl ₂ (200 ml) was added, then aniline (93 g, 1.0 mol) in Et ₃ N (101 g, 1 mol) at 0 ° C. The mixture was stirred at room temperature for 1 hour and quenched with a HCl solution (5%, 150 ml). The aqueous layer was separated and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (2 times 100 ml) and brine (100 ml), dried over Na ₂ SO ₄ and concentrated to give 3-methylbut-2-enoic acid phenylamide (120 g, 80% yield).

4,4-Dimethyl-3,4-dihydro-1H-quinolin-2-one

AlCl ₃ (500 g, 3.8 mol) was carefully added to a suspension of 3-methylbut-2-enoic acid phenylamide (105 g, 0.6 mol) in benzene (1000 ml). The reaction mixture was stirred at 80 ° C. overnight and poured into ice water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 times 250 ml). The combined organic layers were washed with water (2 times 200 ml) and brine (200 ml), dried over Na ₂ SO ₄ and concentrated to give 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (90 g, 86% yield).

4,4-Dimethyl-1,2,3,4-tetrahydroquinoline

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 LiAlH ₄ (18 g, 0.47 mol) ) in THF (200 ml) at a temperature of 0 ° C. After complete addition, the mixture was stirred at room temperature for 30 minutes and then slowly heated to reflux for 1 hour. Then the mixture is cooled to a temperature of 0 ° C. Water (18 ml) and a NaOH solution (10%, 100 ml) are carefully added to quench the reaction. The solid was filtered off and the filtrate was concentrated to give 4,4-dimethyl-1,2,3,4-tetrahydroquinoline.

4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline

To a mixture of 4,4-dimethyl-1,2,3,4-tetrahydroquinoline (33 g, 0.2 mol) in H ₂ SO ₄ (120 ml) KNO ₃ (20.7 g, 0.2 mol) is slowly added. at a temperature of 0 ° C. After complete addition, the mixture was stirred at room temperature for 2 hours, carefully poured into ice water and made basic with Na ₂ CO ₃ to pH = 8. The mixture was extracted with ethyl acetate (3 times 200 ml). The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline (21 g, 50% yield).

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

A mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline (25 g, 0.12 mol) and Boc ₂ O (55 g, 0.25 mol) was stirred at a temperature of 80 ° C for 2 days. The mixture was purified by silica gel chromatography to give 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (8 g, 22% yield).

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

A mixture of 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (8.3 g, 0.03 mol) and Pd / C (0.5 g) in methanol (100 ml) was stirred in a hydrogen atmosphere (1 atm.) at room temperature overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was washed with petroleum ether to give tert-butyl-7-amino-3,4-dihydro-4,4-dimethylquinolin-1 (2H) -carboxylate ( DC-3 ) (7.2 g, 95% yield).

¹ H-NMR (CDCl ₃ ) δ 7.11-7.04 (m, 2H), 6.45-6.38 (m, 1H), 3.71-3.67 (m, 2H), 3, 50-3.28 (m, 2H), 1.71-1.67 (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 isobutyryl chloride (50 g, 0.5 mol) and AlCl ₃ (68.8 g, 0.52 mol) in anhydrous CH ₂ Cl ₂ (700 ml) at a temperature of 5 ° C. After 4 hours, the absorption of ethylene ceases and the mixture is stirred at room temperature overnight. The mixture was poured into a cold dilute HCl solution and extracted with CH ₂ Cl ₂ . The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give crude 1-chloro-4-methylpentan-3-one, which is used directly in the next step without further purification.

4-methyl-1- (phenylamino) pentan-3-one

A suspension of crude 1-chloro-4-methylpentan-3-one (about 60 g), aniline (69.8 g, 0.75 mol) and NaHCO ₃ (210 g, 2.5 mol) in CH ₃ CN (1000 ml ) are refluxed overnight. After cooling, the insoluble salt was filtered off and the filtrate was concentrated. The residue was diluted with CH ₂ Cl ₂ , washed with 10% HCl (100 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give crude 4-methyl-1- (phenylamino) pentan-3-one .

4-methyl-1- (phenylamino) pentan-3-ol

At a temperature of -10 ° C, NaBH ₄ (56.7 g, 1.5 mol) is gradually added to a mixture of crude 4-methyl-1- (phenylamino) pentan-3-one (about 80 g) in MeOH (500 ml) . After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for 20 minutes. The solvent was removed and the residue was redistributed between water and CH ₂ Cl ₂ . The organic phase is separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting resin was triturated in diethyl ether to give 4-methyl-1- (phenylamino) pentan-3-ol as a white solid (22 g, 23% yield).

5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo [b] azepine

A mixture of 4-methyl-1- (phenylamino) pentan-3-ol (22 g, 0.11 mol) in 98% H ₂ SO ₄ (250 ml) was stirred at 50 ° C for 30 minutes. The reaction mixture was poured into ice water, made basic with a saturated NaOH solution to pH = 8, and extracted with CH ₂ Cl ₂ . The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , 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 as a brown oil (1.5 g, 8% yield).

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

At a temperature of 0 ° C, KNO ₃ (0.76 g, 7.54 mmol) is added portionwise to a solution of 5.5-dimethyl-2,3,4,5-tetrahydro-1H-benzo [b] azepine (1,1 g, 6.28 mmol) in H ₂ SO ₄ (15 ml). After stirring for 15 minutes at this temperature, the mixture was poured into ice water, made basic with saturated NaHCO ₃ solution to pH = 8 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give crude 5.5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo [b] azepine (1.2 g ), which is used directly in the next step without further purification.

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

Acetyl chloride (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, 5.45 mmol) and NaHCO ₃ (1.37 g, 16.3 mmol) in CH ₂ Cl ₂ (20 ml). The mixture was refluxed for 1 hour. After cooling, the mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic layer was washed with brine, dried over Na ₂ SO ₄ and 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% yield in two steps )

DC-4 ; 1- (8-amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo [b] azepin-1-yl) ethanone

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 in an atmosphere of H ₂ (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 as a white solid ( DC-4 ) (880 mg, yield 94%).

¹ H-NMR (CDCl ₃ ) δ 7.06 (d, J = 8.0 Hz, 1H), 6.59 (dd, J = 8.4, 2.4 Hz, 1H), 6.50 (broad s, 1H), 4.18-4.05 (m, 1H), 3.46-3.36 (m, 1H), 2.23 (s, 3H), 1.92-1.85 (m , 1H), 1.61-1.51 (m, 3H), 1.21 (s, 3H), 0.73 (t, J = 7.2 Hz, 3H).

ESI-MS: 233.0 m / z (MH ⁺ ).

Example 5

1'-Benzyl-spiro [1H-inden-1,4'-piperidine] -3 (2H) -one

A mixture of 2,3-dihydro-3-oxospiro [1H-inden-1,4'-piperidine] -1'-carboxylic acid 1,1-dimethylethyl ester (9.50 g, 31.50 mmol) in a saturated HCl solution in MeOH (50 ml) was stirred at 25 ° C. overnight. The solvent was removed under reduced pressure to give an off-white solid (7.50 g). To a solution of a solid in anhydrous CH ₃ CN (30 ml) was added anhydrous K ₂ CO ₃ (7.85 g, 56.80 mmol). The suspension was stirred for 5 minutes and benzyl bromide (5.93 g, 34.65 mmol) was added dropwise at room temperature. The mixture was stirred for 2 hours, poured onto crushed ice and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give crude 1'-benzylspiro [1H-indene-1,4'-piperidine] -3 (2H) -one (7.93 g, 87% yield), which is used without further purification.

Oxime 1'-benzylspiro [1H-inden-1,4'-piperidine] -3 (2H) -one

To a solution of 1'-benzylspiro [1H-inden-1,4'-piperidine] -3 (2H) -one (7.93 g, 27.25 mmol) in EtOH (50 ml) is 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 refluxed for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and 200 ml of water was added. The mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 1'-benzylspiro [1H-inden-1,4'-piperidine] -3 (2H) -one oxime (7.57 g, 91% yield), which was used without further purification.

1,2,3,4-Tetrahydroquinoline-4-spiro-4 '- (N'-benzylpiperidine)

To a solution of 1'-benzylspiro [1H-indene-1,4'-piperidine] -3 (2H) -one oxime (7.57 g, 24.74 mmol) oxime in anhydrous CH ₂ Cl ₂ (150 ml) was added dropwise DIBAL-H (135.7 ml, 1M solution in toluene) at a temperature of 0 ° C. The mixture was stirred at 0 ° C for 3 hours, diluted with CH ₂ Cl ₂ (100 ml) and quenched with NaF (20.78 g, 495 mmol) and water (6.7 g, 372 mmol). The resulting suspension was vigorously stirred at a temperature of 0 ° C for 30 minutes After filtration, the residue was washed with CH ₂ Cl ₂ . The combined filtrates were concentrated in vacuo to give an off-brown oil, which was purified by silica gel column chromatography (CH ₂ Cl ₂ -MeOH, 30: 1) to obtain 1,2,3,4-tetrahydroquinoline-4-spiro-4 '- ( N'-benzylpiperidine) (2.72 g, 38% yield).

1,2,3,4-Tetrahydroquinoline-4-spiro-4'-piperidine

Suspension of 1,2,3,4-tetrahydroquinolin-4-spiro-4 '- (N'-benzylpiperidine) (300 mg, 1.03 mmol) and Pd (OH) ₂ / C (30 mg) in MeOH (3 ml ) stirred in an atmosphere of H ₂ (55 psi) at a temperature of 50 ° C during the night. After cooling, the catalyst was filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure to obtain 1,2,3,4-tetrahydroquinoline-4-spiro-4'-piperidine as a white solid (176 mg, 85% yield), which was used without further purification.

7'-nitrospiro [piperidin-4,4 '(1'H) -quinoline] -2', 3'-dihydrocarboxylic acid tert-butyl ester

KNO ₃ (69.97 mg, 0.69 mmol) is added in portions to a suspension of 1,2,3,4-tetrahydroquinolin-4-spiro-4'-piperidine (133 mg, 0.66 mmol) in 98% H ₂ SO ₄ (2 ml) at a temperature of 0 ° C. After complete addition, the reaction mixture was allowed to warm to room temperature and then stirred for 2 hours. Then the mixture was poured onto crushed ice and made basic with 10% NaOH to pH ~ 8. Boc ₂ O (172 mg, 0.79 mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The mixture was then extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the crude 7'-nitrospiro [piperidin-4,4 '(1'H) -quinoline] -2', 3 ' -dihydrocarboxylic acid (230 mg), which is used in the next step without further purification.

7'-nitrospiro [piperidin-4,4 '(1'H) -1-acetylquinoline] -2', 3'-dihydrocarboxylic acid tert-butyl ester

Acetyl chloride (260 mg, 3.30 mmol) was added dropwise to a suspension of 7'-nitrospiro [piperidin-4,4 '(1'H) -quinoline] -2', 3'-dihydrocarboxylic acid tert-butyl ester (230 mg ) and NaHCO ₃ (1.11 g, 13.17 mmol) in MeCN (5 ml) at room temperature. The reaction mixture was refluxed for 4 hours. After cooling, the suspension is filtered and the filtrate is concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10: 1) to obtain 7'-nitrospiro [piperidin-4,4 '(1'H) -1-acetylquinoline] -2', 3'-dihydrocarboxylic acid tert-butyl ester (150 mg, 58% yield in 2 steps).

DC-5 ; 7'-aminospyro [piperidin-4,4 '(1'H) -1-acetylquinoline] tert-butyl ester - 2', 3'-dihydrocarboxylic acid

Suspension of 7'-nitrospiro [piperidin-4,4 '(1'H) -1-acetylquinoline] -2', 3'-dihydrocarboxylic acid tert-butyl ester (150 mg, 0.39 mmol) and Raney nickel (15 mg ) in MeOH (2 ml) was stirred in an atmosphere of H ₂ (1 ATM.) at a temperature of 25 ° C during the night. The catalyst was removed by filtration and washed with MeOH. The combined filtrates were dried over Na ₂ SO _4, filtered and concentrated to afford tert-butyl ester 7'-aminospiro [piperidine-4,4 '(1'N) -1-atsetilhinolin] -2', 3'-digidrokarbonovoy acid (DC -5 ) (133 mg, 96% yield).

Example 6

2- (2,4-dinitrophenylthio) acetic acid

Et ₃ N (1.5 g, 15 mmol) and mercaptoacetic acid (1 g, 11 mmol) are 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, H ₂ O (100 ml) was added. The resulting suspension was extracted with ethyl acetate (3 times in 100 ml). The ethyl acetate extract was washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give 2- (2,4-dinitrophenylthio) acetic acid (2.3 g, 74% yield), which was used without further purification.

DC-7 ; 6-amino-2H-benzo [b] [1,4] thiazin-3 (4H) -one

A solution of 2- (2,4-dinitrophenylthio) acetic acid (2.3 g, 9 mmol) and tin- (II) chloride dihydrate (22.6 g, 0.1 mol) in ethanol (30 ml) is refluxed during the night. After removing the solvent under reduced pressure, the residual suspension was diluted with water (100 ml) and made basic with a 10% Na ₂ CO ₃ solution to pH = 8. The resulting suspension was extracted with ethyl acetate (3 times in 100 ml). The ethyl acetate extract was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was washed with CH ₂ Cl ₂ to give 6-amino-2H-benzo [b] [1,4] thiazin-3 (4H) -one ( DC-7 ) as a yellow powder (1 g, yield 52%).

^oneH-NMR (DMSO-d₆): δ 10.24 (s, 1H), 6.88 (d, 1H),J = 6 Hz), 6.19-6.21 (m, 2H), 5.15 (s, 2H), 3.28 (s, 2H).

ESI-MS: 181.1 m / z (MH ⁺ ).

Example 7

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

Acetic anhydride (1.4 ml, 13.8 mmol) was added dropwise to a stirred solution of 2-bromo-5-nitroaniline (3 g, 13.8 mmol) in glacial acetic acid (30 ml) at a temperature of 25 ° C. The reaction mixture was stirred at room temperature overnight and then poured into water. The precipitate was filtered off, washed with water and dried in vacuo to give N- (2-bromo-5-nitrophenyl) acetamide as an off-white solid (3.6 g, 90% yield).

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

At 25 ° C., a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) in anhydrous DMF (30 ml) was added dropwise to a solution of N- (2-bromo-5-nitrophenyl) acetamide (3 6 g, 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 ml). The reaction mixture was stirred at 25 ° C. overnight. The reaction mixture was then filtered and the filtrate was treated with saturated Na ₂ CO ₃ solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give N- (2-bromo-5-nitrophenyl) -N- (2-methylprop-2-enyl) acetamide as a golden solid substances (3.1 g, yield 85%).

ESI-MS: 313 m / z (MH ⁺ ).

1- (3,3-Dimethyl-6-nitroindolin-1-yl) ethanone

Solution of N- (2-bromo-5-nitrophenyl) -N- (2-methylprop-2-enyl) acetamide (3.1 g, 10.2 mmol), tetraethylammonium chloride hydrate (2.4 g, 149 mmol), formate sodium (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) are stirred at a temperature of 80 ° C for 15 hours in a nitrogen atmosphere. After cooling, the mixture was filtered through celite. Celite was washed with EtOAc and the combined filtrates were washed with saturated NaHCO ₃ solution. The separated organic layer was washed with water and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 1- (3,3-dimethyl-6-nitroindolin-1-yl) ethanone as a brown solid (2.1 g, yield 88%).

DC-8 ; 1- (6-amino-3,3-dimethyl-2,3-dihydroindol-1-yl) ethanone

10% Pd / C (0.2 g) was added to a suspension of 1- (3,3-dimethyl-6-nitroindolin-1-yl) ethanone (2.1 g, 9 mmol) in MeOH (20 ml). The reaction mixture was stirred in an atmosphere of H ₂ (40 psi) at room temperature overnight. Pd / C was filtered and the filtrate was concentrated in vacuo to give a crude product, which was purified by column chromatography to give 1- (6-amino-3,3-dimethyl-2,3-dihydroindol-1-yl) ethanone ( DC-8 ) ( 1.3 g, 61% yield).

Example 8

2,3,4,5-Tetrahydro-1H-benzo [b] azepine

DIBAL (90 ml, 90 mmol) was added dropwise to a solution of 4-dihydro-2H-naphthalen-1-one-oxime (3 g, 18 mmol) in dichloromethane (50 ml) at a temperature of 0 ° C. The mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with dichloromethane (30 ml), then treated with NaF (2 g, 0.36 mol) and H ₂ O (5 ml, 0.27 mol). Vigorous stirring of the resulting suspension is continued at a temperature of 0 ° C for 30 minutes After filtration, the filtrate was concentrated. The residue was purified by flash column chromatography to give 2,3,4,5-tetrahydro-1H-benzo [b] azepine as a colorless oil (1.9 g, 70% yield).

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

At a temperature of −10 ° C., 2,3,4,5-tetrahydro-1H-benzo [b] azepine (1.9 g, 13 mmol) was added dropwise to a solution of KNO ₃ (3 g, 30 mmol) in H ₂ SO ₄ (50 ml). The mixture was stirred for 40 minutes, poured onto crushed ice, made basic with aqueous ammonia to pH = 13 and extracted with EtOAc. The combined organic phases are washed with brine, dried over Na ₂ SO ₄ and concentrated to give 8-nitro-2,3,4,5-tetrahydro-1H-benzo [b] azepine as a black solid (1.3 g, yield 51%), which is used without further purification.

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

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 NaHCO ₃ (1 g, 12 mmol) in CH ₂ Cl ₂ (50 ml). After stirring for 1 hour, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH ₂ Cl ₂ , washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give 1- (8-nitro-2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) ethanone as a yellow solid (1.3 g, 80% yield).

DC-9; 1- (8-amino-2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) ethanone

A mixture of 1- (8-nitro-2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) ethanone (1.3 g, 5.4 mmol) and Pd / C (10%, 100 mg ) in EtOH (200 ml) was stirred in an atmosphere of H ₂ (1 ATM.) at room temperature for 1.5 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give 1- (8-amino-2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) ethanone ( DC-9 ) as a white solid (1 g, yield 90%).

¹ H-NMR (CDCl ₃ ) δ 7.01 (d, J = 6.0 Hz, 1H), 6.56 (dd, J = 6.0, 1.8 Hz, 1H), 6.50 (d , J = 1.8 Hz, 1H), 4.66-4.61 (m, 1H), 3.50 (br s, 2H), 2.64-2.55 (m, 3H), 1, 94-1.91 (m, 5H), 1.77-1.72 (m, 1H), 1.32-1.30 (m, 1H).

ESI-MS: 204.1 m / z (MH ⁺ ).

Example 9

6-Nitro-4H-benzo [1,4] oxazin-3-one

At 0 ° C, chloroacetyl chloride (8.75 ml, 0.11 mol) was added dropwise to a mixture of 4-nitro-2-aminophenol (15.4 g, 0.1 mol), benzyltrimethylammonium chloride (18.6 g, 0 , 1 mol) and NaHCO ₃ (42 g, 0.5 mol) in chloroform (350 ml) for 30 minutes. After complete addition, the reaction mixture was stirred at 0 ° C. for 1 hour, then at 50 ° C. overnight. The solvent was removed under reduced pressure and the residue was treated with water (50 ml). The solid was separated by filtration, washed with water and recrystallized from ethanol to give 6-nitro-4H-benzo [1,4] oxazin-3-one as a pale yellow solid (8 g, 41% yield).

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

A solution of BH ₃ · Me ₂ S in THF (2 M, 7.75 ml, 15.5 mmol) was added dropwise to a suspension of 6-nitro-4H-benzo [1,4] oxazin-3-one (0.6 g 3.1 mmol) in THF (10 ml). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH (5 ml) at 0 ° C. and then water (20 ml) was added. The mixture was extracted with Et ₂ O and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give 6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine as a red solid (0 5 g, yield 89%), which is used without further purification.

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

With vigorous stirring and at room temperature, acetyl chloride (1.02 g, 13 mmol) is added dropwise to a mixture of 6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine (1.8 g, 10 mmol) ) and NaHCO ₃ (7.14 g, 85 mmol) in CH ₂ Cl ₂ (50 ml). After complete addition, the reaction mixture is stirred for 1 hour at this temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with a mixture of Et ₂ O: hexane (1: 2, 50 ml) with stirring for 30 minutes and then filtered to give 4-acetyl-6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine as a pale yellow solid (2 g, 90% yield).

DC-10 ; 4-Acetyl-6-amino-3,4-dihydro-2H-benzo [1,4] oxazine

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

¹ H-NMR (DMSO-d ₆ ) δ 10.12 (br s, 2H), 8.08 (br s, 1H), 6.90-7.03 (m, 2H), 4.24 ( t, J = 4.8 Hz, 2H), 3.83 (t, J = 4.8 Hz, 2H), 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-Tetrahydroisoquinoline (6.3 ml, 50.0 mmol) was added dropwise to a stirred, ice-cooled, concentrated H ₂ SO ₄ solution (25 ml). KNO ₃ (5.6 g, 55.0 mmol) was added in portions, keeping the temperature below 5 ° C. The mixture was stirred at room temperature overnight, carefully poured into an ice-cold concentrated NH ₄ OH solution, and then extracted three times with CHCl ₃ . The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The resulting dark brown oil was added to EtOH, cooled in an ice bath, and treated with concentrated HCl. The yellow precipitate was separated by filtration and recrystallized from methanol to obtain 1,2,3,4-tetrahydro-7-nitroisoquinoline hydrochloride as a yellow solid (2.5 g, 23% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 2H), 8.22 (d, J = 1.6 Hz, 1H), 8.11 (dd, J = 8.5 , 2.2 Hz, 1H), 7.53 (d, J = 8.5 Hz, lH), 4.38 (s, 2H), 3.38 (s, 2H), 3.17-3.14 (m, 2H).

HPLC: retention time 0.51 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 179.0 m / z (MH ⁺ ).

tert-butyl-3,4-dihydro-7-nitroisoquinoline-2 (1H) -carboxylate

A mixture of 1,2,3,4-tetrahydro-7-nitroisoquinoline (2.5 g, 11.6 mmol), 1,4-dioxane (24 ml), H ₂ O (12 ml) and 1N. NaOH solution (12 ml) was cooled in an ice bath and Boc ₂ O (2.8 g, 12.8 mmol) was added. The mixture was stirred at room temperature for 2.5 hours, basified with a 5% KHSO ₄ solution to pH = 2-3, and then extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated to give tert-butyl-3,4-dihydro-7-nitroisoquinoline-2 (1H) -carboxylate (3.3 g, quantitative yield), which was used without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 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), 3.60-3.57 (m, 2H), 2.90 (t, J = 5.9 Hz , 2H); 1.44 (s, 9H).

HPLC: retention time 3.51 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 279.2 m / z (MH ⁺ ).

DC-6 ; tert-butyl-7-amino-3,4-dihydroisoquinoline-2 (1H) -carboxylate

Pd (OH) ₂ (330.0 mg) was added to a stirred solution of tert-butyl-3,4-dihydro-7-nitroisoquinoline-2 (1H) -carboxylate (3.3 g, 12.0 mmol) in MeOH (56 ml) in an atmosphere of nitrogen. The reaction mixture was stirred in a hydrogen atmosphere (1 atm.) At room temperature for 72 hours. The solid is removed by filtration through celite. The filtrate was concentrated and purified by column chromatography (15-35% EtOAc-hexanes) to obtain tert-butyl-7-amino-3,4-dihydroisoquinoline-2 (1H) -carboxylate ( DC-6 ) as a pink oil (2.0 g, yield 69%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 6.79 (d, J = 8.1 Hz, 1H), 6.40 (dd, J = 8.1, 2.3 Hz, 1H), 6.31 (s, 1H), 4.88 (s, 2H), 4.33 (s, 2H), 3.48 (t, J = 5.9 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H); 1.42 (s, 9H).

HPLC: retention time 2.13 min, 10-99% CH ₃ CN, analysis time 5 min.

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 H ₂ SO ₄ (10 ml), nitric acid (6 ml) was added dropwise at a temperature of 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 2.5 hours. The resulting solution was poured into ice water. The white precipitate was separated by filtration and washed with water until the wash water became neutral. The solid was recrystallized twice from ethanol / water (1: 1, 20 ml) to give 4-bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56% yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.54 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8, 4 Hz, 1H).

¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6.

HPLC: retention time 1.96 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 227.1 m / z (MH ⁺ ).

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

4-Bromo-3-nitrobenzonitrile (1.0 g, 4.4 mmol), 2-ethoxyphenylboronic acid (731 mg, 4.4 mmol), Pd ₂ (dba) ₃ (18 mg, 0.022 mmol) and potassium fluoride (786 mg, 13.5 mmol). The reaction vessel is evacuated and filled with argon. Anhydrous THF (300 ml) was added, followed by P (t-Bu) ₃ (0.11 ml, 10% by weight in hexane). The reaction mixture was stirred at room temperature for 30 minutes and then heated at 80 ° C. for 16 hours. After cooling to room temperature, the resulting mixture was filtered through a celite pad and concentrated. 2'-Ethoxy-2-nitrobiphenyl-4-carbonitrile was isolated as a yellow solid (1.12 g, 95% yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ) 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), 7.37 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 3.91 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H) .

¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 154.9, 149.7, 137.3, 137.2, 134.4, 131.5, 130.4, 128.4, 125.4 , 121.8, 117.6, 112.3, 111.9, 64.1, 14.7.

HPLC: retention time 2.43 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 269.3 m / z (MH ⁺ ).

4-aminomethyl-2'-ethoxybiphenyl-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 BH ₃ · THF (5.6 ml, 10% wt. In THF, 5, 6 mmol) at a temperature of 0 ° C for 30 minutes The reaction mixture was stirred at 0 ° C. for 3 hours and then at room temperature for 15 hours. The reaction mixture was cooled to 0 ° C. and a mixture of H ₂ O / THF (3 ml) was added. After shaking at room temperature for 6 hours, volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (100 ml) and extracted with 1N. HCl solution (2 times in 100 ml). The aqueous phase is alkalinized with 1N. NaOH solution to pH = 1 and extracted with EtOAc (3 times 50 ml). The combined organic layers were washed with water (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated. After drying in vacuo, 4-aminomethyl-2'-ethoxybiphenyl-2-ylamine was isolated as a brown oil (370 mg, 82% yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.28 (dt, J = 7.2 Hz, J = 1.8 Hz, 1H), 7.09 (dd, J = 7.2 Hz, J = 1.8 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 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), 6.57 (dd, J = 7.5 Hz, J = 1.5 Hz , 1H), 4.29 (s, 2H), 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 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 243.3 m / z (MH ⁺ ).

E-1 ; (2-amino-2'-ethoxybiphenyl-4-ylmethyl) carbamic acid tert-butyl ester

A solution of Boc ₂ O (123 mg, 0.565 mmol) in 1,4-dioxane (10 ml) was added over 30 minutes to a solution of 4-aminomethyl-2'-ethoxybiphenyl-2-ylamine (274 mg, 1.13 mmol) in 1,4-dioxane (10 ml). The reaction mixture was stirred at room temperature for 16 hours. Volatiles are removed on a rotary evaporator. The residue was purified by flash chromatography (silica gel, EtOAc-CH ₂ Cl ₂ , 1: 4) to give (2-amino-2'-ethoxybiphenyl-4-ylmethyl) carbamic acid ( E-1 ) tert-butyl ester as a pale yellow oil (119 mg, 31% yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ) 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), 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 (q, J = 7.2 Hz, 2H), 1.38 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H).

HPLC: retention time 2.34 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 343.1 m / z (MH ⁺ ).

Example 2

2-bromo-1-tert-butyl-4-nitrobenzene

To a solution of 1-tert-butyl-4-nitrobenzene (8.95 g, 50 mmol) and silver sulfate (10 g, 32 mmol) in 50 ml of 90% sulfuric acid was added dropwise bromine (7.95 g, 50 mmol). Stirring was continued at room temperature overnight, then the mixture was poured into a dilute sodium hydrogen sulfite solution and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to give 2-bromo-1-tert-butyl-4-nitrobenzene (12.7 g, yield 98%), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.47 (d, J = 2.5 Hz, 1H), 8.11 (dd, J = 8.8, 2.5 Hz, 1H), 7 63 (d, J = 8.8 Hz, 1H); 1.57 (s, 9H).

HPLC: retention time 4.05 min, 10-100% CH ₃ CN, gradient 5 min.

2-tert-butyl-5-nitrobenzonitrile

To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (2.13 g, 8.2 mmol) and Zn (CN) ₂ (770 mg, 6.56 mmol) in DMF (10 ml) was added Pd ( PPh ₃ ) ₄ (474 mg, 0.41 mmol) in a nitrogen atmosphere. The mixture is heated in a hermetically sealed vessel at a temperature of 205 ° C for 5 hours. After cooling to room temperature, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After removing the solvent, the residue was purified by column chromatography (0-10% EtOAc-hexane) to obtain 2-tert-butyl-5-nitrobenzonitrile (1.33 g, 80% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.55 (d, J = 2.3 Hz, 1H), 8.36 (dd, J = 8.8, 2.2 Hz, 1H), 7 73 (d, J = 8.9 Hz, 1H); 1.60 (s, 9H).

HPLC: retention time 3.42 min, 10-100% CH ₃ CN, gradient 5 min.

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

To a refluxing solution of 2-tert-butyl-5-nitrobenzonitrile (816 mg, 4.0 mmol) in EtOH (20 ml) is added ammonium formate (816 mg, 12.6 mmol), then 10% Pd / C (570 mg). Then the reaction mixture was refluxed 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% yield), which was used without further purification.

HPLC: retention time 2.66 min, 10-99% CH ₃ CN, gradient 5 min.

ESI-MS: 175.2 m / z (MH ⁺ ).

Example 3

(2-tert-Butyl-5-nitrophenyl) methanamine

To a solution of 2-tert-butyl-5-nitrobenzonitrile (612 mg, 3.0 mmol) in THF (10 ml) was added a solution of BH ₃ · THF (12 ml, 1M solution in THF, 12.0 mmol) in a nitrogen atmosphere. The reaction mixture was stirred at 70 ° C. overnight and cooled to 0 ° C. Methanol (2 ml) was added, followed by 1N. HCl solution (2 ml). After refluxing for 30 minutes, the solution was diluted with water and extracted with EtOAc. The aqueous layer is alkalinized with 1N. NaOH solution and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After removing the solvent, the residue was purified by column chromatography (0-10% MeOH-CH ₂ Cl ₂ ) to give (2-tert-butyl-5-nitrophenyl) methanamine (268 mg, 43% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) 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 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 209.3 m / z (MH ⁺ ).

tert-butyl-2-tert-butyl-5-nitrobenzylcarbamate

A solution of (2-tert-butyl-5-nitrophenyl) methanamine (208 mg, 1 mmol) and Boc ₂ O (229 mg, 1.05 mmol) in THF (5 ml) is refluxed for 30 minutes. After cooling to room temperature, the solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to obtain tert-butyl-2-tert-butyl-5-nitrobenzylcarbamate (240 mg, 78% yield), which was used without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 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), 1, 48 (s, 18H).

HPLC: retention time 3.72 min, 10-100% CH ₃ CN, gradient 5 min.

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

To a solution of tert-butyl-2-tert-butyl-5-nitrobenzylcarbamate (20 mg, 0.065 mmol) in a mixture of 5% AcOH-MeOH (1 ml) was added 10% Pd / C (14 mg) in a nitrogen atmosphere. The mixture was stirred in a hydrogen atmosphere (1 atm.) At room temperature for 1 hour. The catalyst was removed by filtration through celite, and the filtrate was concentrated to obtain tert-butyl-2-tert-butyl-5-aminobenzylcarbamate ( E-4 ), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 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 (broad s, 1H), 4.40 (d, J = 5.1 Hz, 2H), 4.15 (broad s, 2H ), 1.39 (s, 9H), 1.29 (s, 9H).

HPLC: retention time 2.47 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 279.3 m / z (MH ⁺ ).

Example 4

2-tert-butyl-5-nitrobenzoic acid

A solution of 2-tert-butyl-5-nitrobenzonitrile (204 mg, 1 mmol) in 5 ml of 75% H ₂ SO ₄ was microwaved at 200 ° C for 30 minutes. The reaction mixture was poured onto ice, extracted with EtOAc, washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to give 2-tert-butyl-5-nitrobenzoic acid (200 mg, 90% yield), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.36 (d, J = 2.6 Hz, 1H), 8.24 (dd, J = 8.9, 2.6 Hz, 1H), 7 72 (d, J = 8.9 Hz, 1H); 1.51 (s, 9H).

HPLC: retention time 2.97 min, 10-100% CH ₃ CN, gradient 5 min.

Methyl 2-tert-butyl-5-nitrobenzoate

To a mixture of 2-tert-butyl-5-nitrobenzoic acid (120 mg, 0.53 mmol) and K ₂ CO ₃ (147 mg, 1.1 mmol) in DMF (5.0 ml) was added CH ₃ I (40 μl 0.64 mmol). The reaction mixture was stirred at room temperature for 10 minutes, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to give methyl 2-tert-butyl-5-nitrobenzoate, which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): 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 a refluxing solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38 mmol) in EtOH (2.0 ml) was added potassium formate (400 mg, 4.76 mmol) in water (1 ml) then 20 mg of 10% Pd / C. Then the reaction mixture was refluxed 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% yield), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.24 (d, J = 8.6 Hz, 1H), 6.67 (dd, J = 8.6, 2.7 Hz, 1H), 6 60 (d, J = 2.7 Hz, 1H); 3.86 (s, 3H); 1.34 (s, 9H).

HPLC: retention time 2.19 min, 10-99% CH ₃ CN, gradient 5 min.

ESI-MS: 208.2 m / z (MH ⁺ ).

Example 5

2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride

A suspension of 2-tert-butyl-5-nitrobenzeneamine (0.971 g, 5 mmol) in concentrated HCl (5 ml) was cooled to 5-10 ° C and a solution of NaNO ₂ (0.433 g, 6.3 mmol) in H was added dropwise. ₂ O (0.83 ml). Stirring is continued for 0.5 hours, then the mixture is filtered in vacuo. The filtrate was added simultaneously with a solution of Na ₂ SO ₃ (1.57 g, 12.4 mmol) in H ₂ O (2.7 ml) to a stirred solution of CuSO ₄ (0.190 g, 0.76 mmol) and Na ₂ SO ₃ ( 1.57 g, 12.4 mmol) in HCl (11.7 ml) and H ₂ O (2.7 ml) at a temperature of 3-5 ° C. Stirring was continued for 0.5 hours and the resulting precipitate was filtered off, washed with water and dried to give 2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride (0.235 g, 17% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.13 (d, J = 2.5 Hz, 1H), 8.36 (dd, J = 8.9, 2.5 Hz, 1H) 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-sulfonyl chloride (100 mg, 0.36 mmol) in diethyl ether (2 ml) was added aqueous NH ₄ OH (128 μl, 3.6 mmol) at a temperature of 0 ° C . The mixture was stirred at room temperature overnight, diluted with water and extracted with diethyl ether. The combined diethyl ether extracts were washed with brine and dried over Na ₂ SO ₄ . After removing the solvent, the residue was purified by column chromatography (0-50% EtOAc-hexane) to obtain 2-tert-butyl-5-nitrobenzene-1-sulfonamide (31.6 mg, 34% yield).

E-7 ; 2-tert-butyl-5-aminobenzene-1-sulfonamide

A solution of 2-tert-butyl-5-nitrobenzene-1-sulfonamide (32 mg, 0.12 mmol) and SnCl ₂ · 2H ₂ O (138 mg, 0.61 mmol) in EtOH (1.5 ml) is heated in microwave furnace at a temperature of 100 ° C for 30 minutes The mixture was diluted with EtOAc and water, basified with saturated NaHCO ₃ solution and filtered through celite. The organic layer was separated from water and dried over Na ₂ SO ₄ . The solvent was removed by evaporation to give 2-tert-butyl-5-aminobenzene-1-sulfonamide ( E-7 ) (28 mg, 100% yield), which was used without further purification.

HPLC: retention time 1.99 min, 10-99% CH ₃ CN, gradient 5 min.

ESI-MS: 229.3 m / z (MH ⁺ ).

Example 6

E-8 ; (2-tert-Butyl-5-aminophenyl) methanol

To a solution of methyl 2-tert-butyl-5-aminobenzoate (159 mg, 0.72 mmol) in THF (5 ml) was added dropwise LiAlH ₄ (1.4 ml, 1M solution in THF, 1.4 mmol) at temperature 0 ° С. The reaction mixture was refluxed for 2 hours, diluted with H ₂ O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to obtain (2-tert-butyl-5-aminophenyl) methanol ( E-8 ) (25 mg, 20% yield), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.17 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 2.6 Hz, 1H), 6.56 (dd , J = 8.4, 2.7 Hz, 1H), 4.83 (s, 2H), 1.36 (s, 9H).

Example 7

1-Methylpyridinium monomethyl sulfate

Methyl sulfate (30 ml, 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 100 ° C. for 2 hours. The mixture was cooled to room temperature to give crude 1-methylpyridinium monomethyl sulfate (64.7 g, quantitative yield), which was used without further purification.

1-methyl-2-pyridone

A solution of 1-methylpyridinium monomethyl sulfate (50 g, 0.243 mol) in water (54 ml) is cooled to a temperature of 0 ° C. Separate solutions of potassium ferricyanide (160 g, 0.486 mol) in water (320 ml) and sodium hydroxide (40 g, 1000 mol) in water (67 ml) are prepared and two dropwise funnels are added dropwise to a well-mixed solution of 1-methylpyridinium monomethyl sulfate, at such a rate that the temperature of the reaction mixture does not exceed 10 ° C. The rate of addition of the two solutions is adjusted so that the entire sodium hydroxide solution is introduced into the reaction mixture when only half of the potassium ferricyanide solution is added. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. Anhydrous sodium carbonate (91.6 g) was added and the mixture was stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3 times 100 ml). The combined organic layers were dried and concentrated to give 1-methyl-2-pyridone (25.0 g, 94% yield), which was used without further purification.

1-methyl-3,5-dinitro-2-pyridone

1-Methyl-2-pyridone (25.0 g, 0.229 mol) was added to sulfuric acid (500 ml) at a temperature of 0 ° C. After stirring for 5 minutes, nitric acid (200 ml) was added dropwise at a temperature of 0 ° C. After complete addition, the reaction temperature is slowly raised to 100 ° C and then maintained for 5 hours. The reaction mixture was poured onto ice, made basic with potassium carbonate solution to pH = 8, and extracted with CH ₂ Cl ₂ (3 times, 100 ml each). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 1-methyl-3,5-dinitro-2-pyridone (12.5 g, 28% yield), which was used without further purification.

2-Isopropyl-5-nitropyridine

To a solution of 1-methyl-3,5-dinitro-2-pyridone (8.0 g, 40 mmol) in methyl alcohol (20 ml) 3-methyl-2-butanone (5.1 ml, 48 mmol) was added dropwise. , then a solution of ammonia in methyl alcohol (10.0 g, 17%, 100 mmol). The reaction mixture is heated at a temperature of 70 ° C for 2.5 hours at atmospheric pressure. The solvent was removed in vacuo, the residual oil was dissolved in CH ₂ Cl ₂ and then filtered. The filtrate was dried over Na ₂ SO ₄ and concentrated to give 2-isopropyl-5-nitropyridine (1.88 g, 28% yield).

E-9 ; 2-Isopropyl-5-aminopyridine

2-Isopropyl-5-nitropyridine (1.30 g, 7.82 mmol) was dissolved in methyl alcohol (20 ml) and Raney nickel (0.25 g) was added. The mixture was stirred in a hydrogen atmosphere (1 atm.) At room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give 2-isopropyl-5-aminopyridine ( E-9 ) (0.55 g, 52% yield).

¹ H-NMR (CDCl ₃ ): δ 8.05 (s, 1H), 6.93-6.99 (m, 2H), 3.47 (br s, 2H), 2.92-3.02 (m, 1H); 1.24-1.26 (m, 6H).

ESI-MS: 137.2 m / z (MH ⁺ ).

Example 8

Phosphoric acid 2,4-di-tert-butylphenyl ether diethyl ether

To a suspension of NaH (60% in mineral oil, 6.99 g, 174.7 mmol) in THF (350 ml) was added dropwise a solution of 2,4-di-tert-butylphenol (35 g, 169.6 mmol) in THF (150 ml) at a temperature of 0 ° C. The mixture was stirred at 0 ° C. for 15 minutes, and then phosphorochloride acid diethyl ether (30.15 g, 174.7 mmol) was added dropwise at a temperature of 0 ° C. After complete addition, the mixture is stirred at this temperature for 15 minutes. The reaction mixture was quenched with saturated NH ₄ Cl solution (300 ml). The organic layer was separated and the aqueous phase was extracted with Et ₂ O (2 times 350 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give crude phosphoric acid 2,4-di-tert-butylphenyl ether as a yellow oil (51 g, contaminated with some mineral oil) which is used directly in the next step.

1,3-di-tert-butylbenzene

To NH ₃ (liquid, 250 ml) was added a solution of diethyl ether of 2,4-di-tert-butylphenyl ether of phosphoric acid (51 g, crude, obtained in the previous step, about 0.2 mol) in Et ₂ O (anhydrous, 150 ml) at a temperature of -78 ° C in a nitrogen atmosphere. Lithium metal is added in small pieces to the solution until the blue color of the solution remains. The reaction mixture was stirred at −78 ° C. for 15 minutes and then quenched with saturated NH ₄ Cl solution until the mixture became colorless. The liquid NH _{3 was} evaporated and the residue was dissolved in water, extracted with Et ₂ O (2 times 300 ml). The combined organic phases are dried over Na ₂ SO ₄ and concentrated, obtaining the crude 1,3-di-tert-butylbenzene as a yellow oil (30.4 g, 94% yield in 2 steps, contaminated with a small amount of mineral oil), which is used directly in the next stage.

2,4-di-tert-butylbenzaldehyde and 3,5-di-tert-butylbenzaldehyde

To a stirred solution of 1,3-di-tert-butylbenzene (30 g, 157.6 mmol) in anhydrous CH ₂ Cl ₂ (700 ml) was added TiCl ₄ (37.5 g, 197 mmol) at a temperature of 0 ° C, then MeOCHCl ₂ (27.3 g, 236.4 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic phases are washed with NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-tert-butylbenzaldehyde and 3,5-di-tert-butylbenzaldehyde (21 g, 61% yield).

2,4-di-tert-butyl-5-nitrobenzaldehyde and 3,5-di-tert-butyl-2-nitrobenzaldehyde

To a mixture of 2,4-di-tert-butylbenzaldehyde and 3,5-di-tert-butylbenzaldehyde in H ₂ SO ₄ (250 ml), KNO ₃ (7.64 g, 75.6 mmol) was added in portions at a temperature of 0 ° C. . The reaction mixture was stirred at this temperature for 20 minutes and then poured onto crushed ice. The mixture was basified with NaOH solution to pH = 8 and extracted with Et ₂ O (3 times, 10 ml each). The combined organic layers were washed with water and brine and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-tert-butyl-5-nitrobenzaldehyde and 3,5-di-tert-butyl-2-nitrobenzaldehyde (2: 1 by NMR) as a yellow solid substances (14.7 g, yield 82%). After further purification by column chromatography (petroleum ether), 2,4-di-tert-butyl-5-nitrobenzaldehyde was isolated (2.5 g, containing 10% 3,5-di-tert-butyl-2-nitrobenzaldehyde).

1,5-di-tert-butyl-2-difluoromethyl-4-nitrobenzene and 1,5-di-tert-butyl-3-difluoromethyl-2-nitrobenzene

2,4-di-tert-butyl-5-nitrobenzaldehyde (2.4 g, 9.11 mmol, contains 10% 3,5-di-tert-butyl-2-nitrobenzaldehyde) in a clear deoxofluoride solution is stirred at room temperature within 5 hours. The reaction mixture was poured into a cooled saturated solution of NaHCO ₃ and extracted with dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether) to give 1,5-di-tert-butyl-2-difluoromethyl-4-nitrobenzene (1.5 g) and a mixture of 1.5- di-tert-butyl-2-difluoromethyl-4-nitrobenzene and 1,5-di-tert-butyl-3-difluoromethyl-2-nitrobenzene (0.75 g, contains 28% of 1,5-di-tert-butyl- 3-difluoromethyl-2-nitrobenzene).

E-10 ; 1,5-di-tert-butyl-2-difluoromethyl-4-aminobenzene

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-difluoromethyl-4-nitrobenzene (1.3 g, 4.56 mmol). The reaction mixture is heated at a temperature of 115 ° C for 15 minutes The solid is filtered off, washed with acetic acid and CH ₂ Cl ₂ . The combined filtrate was concentrated and treated with a solution of HCl in MeOH. The precipitate was separated by filtration, washed with MeOH and dried, yielding 1,5-di-tert-butyl-2-difluoromethyl-4-aminobenzene hydrochloride ( E-10 ) as a white solid (1.20 g, 90% yield).

¹ H-NMR (DMSO-d ₆ ): δ 7.35-7.70 (t, J = 53.7 Hz, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 1.33-1.36 (d, J = 8.1 Hz, 1H).

ESI-MS: 256.3 m / z (MH ⁺ ).

Example 9

General scheme

A ) Pd (PPh ₃ ) ₄ , K ₂ CO ₃ , H ₂ O, THF; B ) Pd ₂ (dba) ₃ , P (tBu) ₃ , KF, THF.

Method A

In a test tube of 2 drachmas, 2-bromoaniline (100 mg, 0.58 mmol) and the corresponding arylboronic acid (0.82 mmol) were dissolved in THF (1 ml). H ₂ O (500 μl) was added, followed by K ₂ CO ₃ (200 mg, 1.0 mmol) and Pd (PPh ₃ ) ₄ (100 mg, 0.1 mmol). The tube is purged with argon and sealed. Then the tube is heated at a temperature of 75 ° C for 18 hours. The crude sample was diluted with EtOAc and filtered through a pad of silica gel. The organic layers are concentrated by Savant Speed-evacuation. The crude amine is used without further purification.

Method B

The corresponding arylboronic acid (0.58 mmol), then KF (110 mg, 1.9 mmol), is introduced into a 2 drachma tube. The solids were suspended in THF (2 ml) and then 2-bromaniline (70 μl, 0.58 mmol) was added. The tube was purged with argon for 1 min. P (tBu) ₃ (100 μl, 10% solution in hexanes) was added, then Pd ₂ (dba) ₃ (900 μl, 0.005 M solution in THF). The tube is again purged with argon and sealed. The tube is shaken on an orbital shaker at room temperature for 30 minutes and heated in a heating module at 80 ° C for 16 hours. Then the tube is cooled to a temperature of 20 ° C and the suspension is passed through a layer of celite. This layer was washed with EtOAc (5 ml). The organic layers were combined and concentrated in vacuo to give the crude amine, which was used without further purification.

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

Product Title Way F-1 4'-methylbiphenyl-2-ylamine A F-2 3'-methylbiphenyl-2-ylamine A F-3 2'-methylbiphenyl-2-ylamine A F-4 2 ', 3'-dimethylbiphenyl-2-ylamine A F-5 (2'-aminobiphenyl-4-yl) methanol A F-6 N * 4 '*, N * 4' * - dimethylbiphenyl-2,4'-diamine B F-7 2'-trifluoromethylbiphenyl-2-ylamine B F-8 (2'-aminobiphenyl-4-yl) acetonitrile A F-9 4'-isobutylbiphenyl-2-ylamine A F-10 3'-trifluoromethylbiphenyl-2-ylamine B F-11 2-pyridin-4-ylphenylamine B F-12 2- (1H-indol-5-yl) phenylamine B F-13 3 ', 4'-dimethylbiphenyl-2-ylamine A F-14 4'-isopropylbiphenyl-2-ylamine A F-15 3'-isopropylbiphenyl-2-ylamine A F-16 4'-trifluoromethylbiphenyl-2-ylamine B F-17 4'-methoxybiphenyl-2-ylamine B F-18 3'-methoxybiphenyl-2-ylamine B F-19 2-benzo [1,3] dioxol-5-ylphenylamine B F-20 3'-ethoxybiphenyl-2-ylamine B F-21 4'-ethoxybiphenyl-2-ylamine B F-22 2'-ethoxybiphenyl-2-ylamine B F-23 4'-methylsulfanylbiphenyl-2-ylamine B F-24 3 ', 4'-dimethoxybiphenyl-2-ylamine B F-25 2 ', 6'-dimethoxybiphenyl-2-ylamine B F-26 2 ', 5'-dimethoxybiphenyl-2-ylamine B F-27 2 ', 4'-dimethoxybiphenyl-2-ylamine B F-28 5'-Chloro-2'-methoxybiphenyl-2-ylamine B F-29 4'-trifluoromethoxybiphenyl-2-ylamine B F-30 3'-trifluoromethoxybiphenyl-2-ylamine B F-31 4'-phenoxybiphenyl-2-ylamine B F-32 2'-fluoro-3'-methoxybiphenyl-2-ylamine B

F-33 2'-phenoxybiphenyl-2-ylamine B F-34 2- (2,4-dimethoxypyrimidin-5-yl) phenylamine B F-35 5'-isopropyl-2'-methoxybiphenyl-2-ylamine B F-36 2'-trifluoromethoxybiphenyl-2-ylamine B F-37 4'-fluorobiphenyl-2-ylamine B F-38 3'-fluorobiphenyl-2-ylamine B F-39 2'-fluorobiphenyl-2-ylamine B F-40 2'-aminobiphenyl-3-carbonitrile B F-41 4'-fluoro-3'-methylbiphenyl-2-ylamine B F-42 4'-chlorobiphenyl-2-ylamine B F-43 3'-chlorobiphenyl-2-ylamine B F-44 3 ', 5'-difluorobiphenyl-2-ylamine B F-45 2 ', 3'-difluorobiphenyl-2-ylamine B F-46 3 ', 4'-difluorobiphenyl-2-ylamine B F-47 2 ', 4'-difluorobiphenyl-2-ylamine B F-48 2 ', 5'-difluorobiphenyl-2-ylamine B F-49 3'-chloro-4'-fluorobiphenyl-2-ylamine B F-50 3 ', 5'-dichlorobiphenyl-2-ylamine B F-51 2 ', 5'-dichlorobiphenyl-2-ylamine B F-52 2 ', 3'-dichlorobiphenyl-2-ylamine B F-53 3 ', 4'-dichlorobiphenyl-2-ylamine B F-54 2'-aminobiphenyl-4-carboxylic acid methyl ester B F-55 2'-aminobiphenyl-3-carboxylic acid methyl ester B F-56 2'-methylsulfanylbiphenyl-2-ylamine B F-57 N- (2'-aminobiphenyl-3-yl) acetamide B F-58 4'-methanesulfinylbiphenyl-2-ylamine B F-59 2 ', 4'-dichlorobiphenyl-2-ylamine B F-60 4'-methanesulfonylbiphenyl-2-ylamine B F-61 2'-aminobiphenyl-2-carboxylic acid isopropyl ester B F-62 2-furan-2-ylphenylamine B F-63 1- [5- (2-aminophenyl) thiophen-2-yl] ethanone B F-64 2-benzo [b] thiophen-2-ylphenylamine B F-65 2-benzo [b] thiophen-3-ylphenylamine B F-66 2-furan-3-ylphenylamine B F-67 2- (4-methylthiophen-2-yl) phenylamine B F-68 5- (2-aminophenyl) thiophene-2-carbonitrile B

Example 10

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

Sodium tert-butoxide (466 mg, 4.85 mmol) was added to DMF (20 ml) at 0 ° C. The turbid solution is re-cooled to a temperature of 5 ° C. Ethyl 4-nitrophenyl acetate (1.0 g, 4.78 mmol) was added. The purple suspension was cooled to 5 ° C and methyl iodide (0.688 ml, 4.85 mmol) was added over 40 minutes. The mixture was stirred at 5-10 ° C. for 20 minutes and then sodium tert-butoxide (466 mg, 4.85 mmol) and methyl iodide (0.699 ml, 4.85 mmol) were added repeatedly. The mixture is stirred at a temperature of 5-10 ° C. for 20 minutes and sodium tert-butoxide (47 mg, 0.48 mmol) is added a third time, followed by methyl iodide (0.057 ml, 0.9 mmol). Ethyl acetate (100 ml) and HCl (0.1 N, 50 ml) were added. The organic layer was separated, washed with brine and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated to obtain ethyl 2- (4-nitrophenyl) -2-methylpropanoate (900 mg, 80% yield), which was used without further purification.

G-1 ; Ethyl 2- (4-aminophenyl) -2-methylpropanoate

A solution of ethyl 2- (4-nitrophenyl) -2-methylpropanoate (900 mg, 3.8 mmol) in EtOH (10 ml) was treated with 10% Pd / C (80 mg) and heated to a temperature of 45 ° C. A solution of potassium formate (4.10 g, 48.8 mmol) in H ₂ O (11 ml) was added over 15 minutes. The reaction mixture was stirred at 65 ° C for 2 hours and then treated with 300 mg of Pd / C. The reaction mixture was stirred for 1.5 hours and then filtered through celite. The solvent volume was reduced to approximately 50% under reduced pressure and extracted with EtOAc. The organic layers were dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to obtain ethyl 2- (4-aminophenyl) -2-methylpropanoate ( G-1 ) (670 mg, 85% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.14 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 4.10 (q ., J = 7.1 Hz, 2H), 1.53 (s, 6H), 1.18 (t, J = 7.1 Hz, 3H).

Example 11

G-2 ; 2- (4-aminophenyl) -2-methylpropan-1-ol

A solution of ethyl 2- (4-aminophenyl) -2-methylpropanoate (30 mg, 0.145 mmol) in THF (1 ml) is treated with LiAlH ₄ (1 M solution in THF, 0.226 ml, 0.226 mmol) at a temperature of 0 ° C and stirred in for 15 minutes The reaction mixture is treated with 0.1N. NaOH solution, extracted with EtOAc and the organic layers dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to obtain 2- (4-aminophenyl) -2-methylpropan-1-ol ( G-2 ), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.17 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 8.5 Hz, 2H), 3.53 (s , 2H); 1.28 (s, 6H).

Example 12

2-methyl-2- (4-nitrophenyl) propannitrile

A suspension of sodium tert-butoxide (662 mg, 6.47 mmol) in DMF (20 ml) at 0 ° C was treated with 4-nitrophenylacetonitrile (1000 mg, 6.18 mmol) and stirred for 10 minutes. Methyl iodide (400 μl, 6.47 mmol) was added dropwise over 15 minutes. The solution was stirred at a temperature of 0-10 ° C for 15 minutes and then at room temperature for the next 15 minutes. Sodium tert-butoxide (662 mg, 6.47 mmol) was added to the resulting purple solution, and the solution was stirred for 15 minutes. Methyl iodide (400 μl, 6.47 mmol) was added dropwise over 15 minutes and the solution was stirred overnight. Sodium tert-butoxide (192 mg, 1.94 mmol) was added and the reaction mixture was stirred at 0 ° C for 10 minutes. Methyl iodide (186 μl, 2.98 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was then partitioned between 1N. HCl solution (50 ml) and EtOAc (75 ml). The organic layer was washed with 1N. HCl solution and brine, dried over Na ₂ SO ₄ and concentrated to give 2-methyl-2- (4-nitrophenyl) propannitrile as a green waxy solid (1.25 g, 99% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.24 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.9 Hz, 2H), 1.77 (s , 6H).

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

To a cooled solution of 2-methyl-2- (4-nitrophenyl) propannitrile (670 mg, 3.5 mmol) in THF (15 ml) was added dropwise BH ₃ (1M solution in THF, 14 ml, 14 mmol) at a temperature of 0 ° C. The mixture was warmed to room temperature and heated at 70 ° C. for 2 hours. Add 1N. HCl solution (2 ml), then NaOH, until the pH reaches> 7. The mixture was extracted with diethyl ether and the extract in diethyl ether concentrated to give 2-methyl-2- (4-nitrophenyl) propan-1-amine (610 mg, 90% yield), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): 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) propyl carbamate

To a cooled solution of 2-methyl-2- (4-nitrophenyl) propan-1-amine (600 mg, 3.1 mmol) and 1N. a solution of NaOH (3 ml, 3 mmol) in 1,4-dioxane (6 ml) and water (3 ml) was added Boc ₂ O (742 mg, 3.4 mmol) at a temperature of 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was acidified with 5% KHSO ₄ solution and then extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated to give tert-butyl-2-methyl-2- (4-nitrophenyl) propyl carbamate (725 mg, 80% yield), which was used without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.11 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 3.63 (s , 2H), 1.31-1.29 (m, 15H).

G-3 ; tert-butyl-2-methyl-2- (4-aminophenyl) propyl carbamate

To a refluxing solution of tert-butyl-2-methyl-2- (4-nitrophenyl) propyl carbamate (725 mg, 2.5 mmol) and ammonium formate (700 mg, 10.9 mmol) in EtOH (25 ml) was added 5% of the mass. Pd / C (400 mg). The mixture was refluxed for 1 hour, cooled and filtered through celite. The filtrate was concentrated to give tert-butyl-2-methyl-2- (4-aminophenyl) propyl carbamate ( G-3 ) (550 mg, 83% yield), which was used without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 6.99 (d, J = 8.5 Hz, 2H), 6.49 (d, J = 8.6 Hz, 2H), 4.85 ( s, 2H), 3.01 (d, J = 6.3 Hz, 2H), 1.36 (s, 9H).

HPLC: retention time 2.02 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 265.2 m / z (MH ⁺ ).

Example 13

7-nitro-1,2,3,4-tetrahydronaphthalen-1-ol

7-Nitro-3,4-dihydro-2H-naphthalen-1-one (200 mg, 1.05 mmol) was dissolved in methanol (5 ml) and NaBH ₄ (78 mg, 2.05 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 20 minutes, then concentrated and purified by column chromatography (10-50% ethyl acetate-hexanes) to give 7-nitro-1,2,3,4-tetrahydronaphthalen-1-ol (163 mg, yield 80%).

¹ H-NMR (400 MHz, CD ₃ CN) δ 8.30 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 8.5, 2.5 Hz, 1H), 7 33 (d, J = 8.5 Hz, 1H), 4.76 (t, J = 5.5 Hz, 1H), 2.96-2.80 (m, 2H), 2.10-1, 99 (m, 2H); 1.86-1.77 (m, 2H).

HPLC: retention time 2.32 min, 10-99% CH ₃ CN, analysis time 5 min.

N-1 ; 7-amino-1,2,3,4-tetrahydronaphthalen-1-ol

7-Nitro-1,2,3,4-tetrahydronaphthalen-1-ol (142 mg, 0.73 mmol) was dissolved in methanol (10 ml) and the flask was purged with N ₂ (gaseous). 10% Pd / C (10 mg) was added and the reaction mixture was stirred in a hydrogen atmosphere (1 atm.) At room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give 7-amino-1,2,3,4-tetrahydronaphthalen-1-ol ( H-1 ) (113 mg, 95% yield).

HPLC: retention time 0.58 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 164.5 m / z (MH ⁺ ).

Example 14

Oxime 7-nitro-3,4-dihydro-2H-naphthalene-1-one

To a solution of 7-nitro-3,4-dihydro-2H-naphthalen-1-one (500 mg, 2.62 mmol) in pyridine (2 ml) is added a solution of hydroxylamine (1 ml, ~ 50% solution in water) . The reaction mixture was stirred at room temperature for 1 hour, then concentrated and purified by column chromatography (10-50% ethyl acetate-hexanes) to give 7-nitro-3,4-dihydro-2H-naphthalen-1-one oxime (471 mg, yield 88%).

HPLC: retention time 2.67 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 207.1 m / z (MH ⁺ ).

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

Oxime 7-nitro-3,4-dihydro-2H-naphthalen-1-one (274 mg, 1.33 mmol) was dissolved in methanol (10 ml) and the flask was purged with N ₂ (gaseous). 10% Pd / C (50 mg) was added and the reaction mixture was stirred in a hydrogen atmosphere (1 atm.) At room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give 1,2,3,4-tetrahydronaphthalene-1,7-diamine (207 mg, 96% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 6.61-6.57 (m, 2H), 6.28 (dd, J = 8.0, 2.4 Hz, 1H), 4.62 (s, 2H), 3.58 (m, 1H), 2.48-2.44 (m, 2H), 1.78-1.70 (m, 2H), 1.53-1.37 (m , 2H).

N-2 ; (7-amino-1,2,3,4-tetrahydronaphthalen-1-yl) carbamic acid tert-butyl ester

To a solution of 1,2,3,4-tetrahydronaphthalene-1,7-diamine (154 mg, 0.95 mmol) and triethylamine (139 μl, 1.0 mmol) in methanol (2 ml), cooled to 0 ° C di-tert-butyl dicarbonate (207 mg, 0.95 mmol) was added. The reaction mixture was stirred at 0 ° C and then concentrated and purified by column chromatography (5-50% methanol-dichloromethane) to give tert-butyl ether (7-amino-1,2,3,4-tetrahydronaphthalen-1-yl) carbamic acid ( H-2 ) (327 mg, quantitative yield).

HPLC: retention time 1.95 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 263.1 m / z (MH ⁺ ).

Example 15

N-(2-Бромбензил)-2,2,2-трифторацетамид

N- (2-Bromobenzyl) -2,2,2-trifluoroacetamide

To a solution of 2-bromobenzylamine (1.3 ml, 10.8 mmol) in methanol (5 ml) was added ethyl trifluoroacetate (1.54 ml, 21.6 mmol) and triethylamine (1.4 ml, 10.8 mmol) in the atmosphere. nitrogen. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo to give N- (2-bromobenzyl) -2,2,2-trifluoroacetamide (3.15 g, quantitative yield).

HPLC: retention time 2.86 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 283.9 m / z (MH ⁺ ).

I-1 ; N- (4'-Aminobiphenyl-2-ylmethyl) -2,2,2-trifluoroacetamide

A mixture of N- (2-bromobenzyl) -2,2,2-trifluoroacetamide (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-PPh ₃ (40 mg, 3 mmol / g, 0.12 mmol) are dissolved in DMF (5 ml) and add 4M solution of K ₂ CO ₃ (0.5 ml). The reaction mixture is heated at 80 ° C. overnight. The mixture was filtered, concentrated and purified by column chromatography (0-50% ethyl acetate-hexanes) to give N- (4'-aminobiphenyl-2-ylmethyl) -2,2,2-trifluoroacetamide ( I-1 ) (143 mg, 49 yield) %).

HPLC: retention time 1.90 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 295.5 m / z (MH ⁺ ).

Commercially Available Amines

Amine Title J-1 2-methoxy-5-methylbenzolamine J-2 2,6-diisopropylbenzeneamine

J-3 pyridin-2-amine J-4 4-pentylbenzolamine J-5 isoquinolin-3-amine J-6 aniline J-7 4-phenoxybenzolamine J-8 2- (2,3-dimethylphenoxy) pyridin-3-amine J-9 4-ethynylbenzenamine J-10 2-sec-butylbenzeneamine J-11 2-amino-4,5-dimethoxybenzonitrile J-12 2-tert-butylbenzolamine J-13 1- (7-amino-3,4-dihydroisoquinolin-2 (1H) -yl) ethanone J-14 4- (4-methyl-4H-1,2,4-triazol-3-yl) benzolamine J-15 2'-aminomethylbiphenyl-4-ylamine J-16 1H-indazol-6-ylamine J-17 2- (2-methoxyphenoxy) -5- (trifluoromethyl) benzeneamine J-18 2-tert-butylbenzolamine J-19 2,4,6-trimethylbenzolamine J-20 5,6-dimethyl-1H-benzo [d] imidazole-2-amine J-21 2,3-dihydro-1H-inden-4-amine J-22 2-sec-butyl-6-ethylbenzolamine J-23 quinoline-5-amine J-24 4- (benzyloxy) benzenamine J-25 2'-methoxybiphenyl-2-ylamine J-26 benzo [c] [1,2,5] thiadiazole-4-amine J-27 3-benzylbenzolamine J-28 4-isopropylbenzeneamine J-29 2- (phenylsulfonyl) benzeneamine J-30 2-methoxybenzolamine J-31 4-amino-3-ethylbenzonitrile J-32 4-methylpyridin-2-amine J-33 4-chlorobenzolamine J-34 2- (benzyloxy) benzenamine J-35 2-amino-6-chlorobenzonitrile J-36 3-methylpyridin-2-amine J-37 4-aminobenzonitrile J-38 3-chloro-2,6-diethylbenzolamine J-39 3-phenoxybenzolamine J-40 2-benzylbenzolamine J-41 2- (2-fluorophenoxy) pyridin-3-amine J-42 5-chloropyridin-2-amine J-43 2- (trifluoromethyl) benzeneamine J-44 (4- (2-aminophenyl) piperazin-1-yl) (phenyl) methanone J-45 1H-benzo [d] [1,2,3] triazole-5-amine J-46 2- (1H-indol-2-yl) benzeneamine J-47 4-methylbiphenyl-3-ylamine J-48 pyridin-3-amine J-49 3,4-dimethoxybenzolamine J-50 3H-benzo [d] imidazole-5-amine J-51 3-aminobenzonitrile J-52 6-chloropyridin-3-amine

J-53 o-toluidine J-54 1H-indole-5-amine J-55 [1,2,4] triazolo [1,5-a] pyridin-8-amine J-56 2-methoxypyridin-3-amine J-57 2-butoxybenzolamine J-58 2,6-dimethylbenzolamine J-59 2- (methylthio) benzeneamine J-60 2- (5-methylfuran-2-yl) benzeneamine J-61 3- (4-aminophenyl) -3-ethylpiperidin-2,6-dione J-62 2,4-dimethylbenzolamine J-63 5-fluoropyridin-2-amine J-64 4-cyclohexylbenzenamine J-65 4-aminobenzenesulfonamide J-66 2-ethylbenzolamine J-67 4-fluoro-3-methylbenzolamine J-68 2,6-dimethoxypyridin-3-amine J-69 4-tert-butylbenzolamine J-70 4-sec-butylbenzeneamine J-71 5,6,7,8-tetrahydronaphthalene-2-amine J-72 3- (pyrrolidin-1-sulfonyl) phenylamine J-73 4-adamantan-1-ylphenylamine J-74 3-amino-5,6,7,8-tetrahydronaphthalen-2-ol J-75 benzo [d] [1,3] dioxol-5-amine J-76 5-chloro-2-phenoxybenzolamine J-77 N1-tosylbenzene-1,2-diamine J-78 3,4-dimethylbenzolamine J-79 2- (trifluoromethylthio) benzeneamine J-80 1H-indole-7-amine J-81 3-methoxybenzolamine J-82 quinoline-8-amine J-83 2- (2,4-difluorophenoxy) pyridin-3-amine J-84 2- (4-aminophenyl) acetonitrile J-85 2,6-dichlorobenzeneamine J-86 2,3-dihydrobenzofuran-5-amine J-87 p-toluidine J-88 2-methylquinolin-8-amine J-89 2-tert-butylbenzolamine J-90 3-chlorobenzolamine J-91 4-tert-butyl-2-chlorobenzolamine J-92 2-aminobenzenesulfonamide J-93 1- (2-aminophenyl) ethanone J-94 m-toluidine J-95 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yloxy) benzeneamine J-96 2-amino-6-methylbenzonitrile J-97 2- (prop-1-en-2-yl) benzeneamine J-98 4-amino-N-pyridin-2-ylbenzenesulfonamide J-99 2-ethoxybenzolamine J-100 naphthalene-1-amine J-101 biphenyl-2-ylamine J-102 2- (trifluoromethyl) -4-isopropylbenzeneamine

J-103 2,6-diethylbenzolamine J-104 5- (trifluoromethyl) pyridin-2-amine J-105 2-aminobenzamide J-106 3- (trifluoromethoxy) benzeneamine J-107 3,5-bis (trifluoromethyl) benzeneamine J-108 4-vinylbenzeneamine J-109 4- (trifluoromethyl) benzeneamine J-110 2-morpholinobenzeneamine J-111 5-amino-1H-benzo [d] imidazole-2 (3H) -one J-112 quinoline-2-amine J-113 3-methyl-1H-indol-4-amine J-114 pyrazin-2-amine J-115 1- (3-aminophenyl) ethanone J-116 2-ethyl-6-isopropylbenzeneamine J-117 2- (3- (4-chlorophenyl) -1,2,4-oxadiazol-5-yl) benzeneamine J-118 N- (4-amino-2,5-diethoxyphenyl) benzamide J-119 5,6,7,8-tetrahydronaphthalene-1-amine J-120 2- (1H-benzo [d] imidazol-2-yl) benzolamine J-121 1,1-dioxo-1H-1λ * 6 * -benzo [b] thiophen-6-ylamine J-122 2,5-diethoxybenzolamine J-123 2-isopropyl-6-methylbenzolamine J-124 tert-butyl-5-amino-3,4-dihydroisoquinoline-2 (1H) -carboxylate J-125 2- (2-aminophenyl) ethanol J-126 (4-aminophenyl) methanol J-127 5-methylpyridin-2-amine J-128 2- (pyrrolidin-1-yl) benzeneamine J-129 4-propylbenzeneamine J-130 3,4-dichlorobenzeneamine J-131 2-phenoxybenzolamine J-132 biphenyl-2-ylamine J-133 2-chlorobenzolamine J-134 2-amino-4-methylbenzonitrile J-135 (2-aminophenyl) (phenyl) methanone J-136 aniline J-137 3- (trifluoromethylthio) benzeneamine J-138 2- (2,5-dimethyl-1H-pyrrol-1-yl) benzeneamine J-139 4- (morpholine-4-sulfonyl) phenylamine J-140 2-methylbenzo [d] thiazol-5-amine J-141 2-amino-3,5-dichlorobenzonitrile J-142 2-fluoro-4-methylbenzolamine J-143 6-ethylpyridin-2-amine J-144 2- (1H-pyrrole-1-yl) benzeneamine J-145 2-methyl-1H-indol-5-amine J-146 quinoline-6-amine J-147 1H-benzo [d] imidazole-2-amine J-148 2-o-tolylbenzo [d] oxazole-5-amine J-149 5-phenylpyridin-2-amine J-150 biphenyl-2-ylamine J-151 4- (difluoromethoxy) benzeneamine

J-152 5-tert-butyl-2-methoxybenzolamine J-153 2- (2-tert-butylphenoxy) benzenamine J-154 3-aminobenzamide J-155 4-morpholinobenzeneamine J-156 6-aminobenzo [d] oxazole-2 (3H) -one J-157 2-phenyl-3H-benzo [d] imidazole-5-amine J-158 2,5-dichloropyridin-3-amine J-159 2,5-dimethylbenzolamine J-160 4- (phenylthio) benzeneamine J-161 9H-fluoren-1-amine J-162 2- (4-aminophenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol J-163 4-bromo-2-ethylbenzolamine J-164 4-methoxybenzolamine J-165 3- (piperidin-1-sulfonyl) phenylamine J-166 quinoxaline-6-amine J-167 6- (trifluoromethyl) pyridin-3-amine J-168 3- (trifluoromethyl) -2-methylbenzolamine J-169 (2-aminophenyl) (phenyl) methanol J-170 aniline J-171 6-methoxypyridin-3-amine J-172 4-butylbenzolamine J-173 3- (morpholine-4-sulfonyl) phenylamine J-174 2,3-dimethylbenzolamine J-175 aniline J-176 biphenyl-2-ylamine J-177 2- (2,4-dichlorophenoxy) benzeneamine J-178 pyridin-4-amine J-179 2- (4-methoxyphenoxy) -5- (trifluoromethyl) benzeneamine J-180 6-methylpyridin-2-amine J-181 5-chloro-2-fluorobenzolamine J-182 1H-indole-4-amine J-183 6-morpholinopyridin-3-amine J-184 aniline J-185 1H-indazole-5-amine J-186 2 - [(cyclohexylmethylamino) methyl] phenylamine J-187 2-phenylbenzo [d] oxazole-5-amine J-188 naphthalene-2-amine J-189 2-aminobenzonitrile J-190 N1, N1-diethyl-3-methylbenzene-1,4-diamine J-191 aniline J-192 2-butylbenzolamine J-193 1- (4-aminophenyl) ethanol J-194 2-amino-4-methylbenzamide J-195 quinoline-3-amine J-196 2- (piperidin-1-yl) benzeneamine J-197 3-aminobenzenesulfonamide J-198 2-ethyl-6-methylbenzolamine J-199 biphenyl-4-ylamine J-200 2- (o-tolyloxy) benzeneamine J-201 5-amino-3-methylbenzo [d] oxazole-2 (3H) -one

J-202 4-ethylbenzolamine J-203 2-isopropylbenzeneamine J-204 3- (trifluoromethyl) benzeneamine J-205 2-amino-6-fluorobenzonitrile J-206 2- (2-aminophenyl) acetonitrile J-207 2- (4-fluorophenoxy) pyridin-3-amine J-208 aniline J-209 2- (4-methylpiperidin-1-yl) benzeneamine J-210 4-fluorobenzeneamine J-211 2-propylbenzeneamine J-212 4- (trifluoromethoxy) benzeneamine J-213 3-aminophenol J-214 2,2-difluorobenzo [d] [1,3] dioxol-5-amine J-215 2,2,3,3-tetrafluoro-2,3-dihydrobenzo [b] [1,4] dioxin-6-amine J-216 N- (3-aminophenyl) acetamide J-217 1- (3-aminophenyl) -3-methyl-1H-pyrazol-5 (4H) -one J-218 5- (trifluoromethyl) benzene-1,3-diamine J-219 5-tert-butyl-2-methoxybenzene-1,3-diamine J-220 N- (3-amino-4-ethoxyphenyl) acetamide J-221 N- (3-aminophenyl) methanesulfonamide J-222 N- (3-aminophenyl) propionamide J-223 N1, N1-dimethylbenzene-1,3-diamine J-224 N- (3-amino-4-methoxyphenyl) acetamide J-225 benzene-1,3-diamine J-226 4-methylbenzene-1,3-diamine J-227 1H-indol-6-amine J-228 6,7,8,9-tetrahydro-5H-carbazole-2-amine J-229 1H-indol-6-amine J-230 1H-indol-6-amine J-231 1H-indol-6-amine J-232 1H-indol-6-amine J-233 1H-indol-6-amine J-234 1H-indol-6-amine J-235 1H-indol-6-amine J-236 1H-indol-6-amine J-237 1H-indol-6-amine J-238 1H-indol-6-amine J-239 1- (6-amino-2,3-dihydroindol-1-yl) ethanone J-240 5-chlorobenzene-1,3-diamine

Amides (compounds of formula I)

General scheme

a) Ar ₁ R7NH, coupling agent, base, solvent. Examples of conditions used: HATU, DIEA, DMF; BOP, DIEA, DMF; HBTU, Et ₃ N, CH ₂ Cl ₂ ; PFP-TFA, pyridine.

Specific example

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

To a solution of 4-hydroxyquinoline-3-carboxylic acid ( A-1 ) (19 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (34.9 μl, 0.2 mmol) in DMF (1 ml) add aniline (18.2 μl, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The resulting solution was filtered and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give 4-oxo-N-phenyl-1H-quinoline-3-carboxamide ( 215 ) (12 mg, 45% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 12.50 (s, 1H) 8.89 (s, 1H), 8.34 (dd, J = 8, 1, 1.1 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H) 7.75 (m, 3H) 7.55 (t, J = 8.1 Hz, 1H), 7 37 (t, J = 7.9 Hz, 2H); 7.10 (t, J = 6.8 Hz, 1H).

HPLC: retention time 3.02 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 265.1 m / z (MH ⁺ ).

The table below provides a list of other examples of substances synthesized according to the general scheme given above.

The compound of formula I Acid Amine 2 A-1 C-2 3 A-1 J-17 four A-1 J-110 5 A-1 G-2 6 A-1 E-8 7 A-1 J-118 8 A-1 D-7 9 A-1 J-197 eleven A-1 F-7 12 A-1 F-6 13 A-1 E-2 fifteen A-1 J-56 16 A-1 J-211 eighteen A-1 J-161 19 A-1 J-112 twenty A-1 J-200 21 A-1 J-98 23 A-1 C-15 24 A-1 J-72 25 A-1 F-57 26 A-1 J-196 29th A-21 J-208 31 A-1 J-87 32 A-1 B-21 33 A-1 J-227 34 A-1 C-19 36 A-1 J-203 37 A-1 J-80 38 A-1 J-46 39 A-17 D-10 40 A-1 J-125 42 A-1 J-95 43 A-1 C-16 44 A-1 J-140 45 A-1 J-205 47 A-1 J-102 48 A-1 J-181 49 A-1 F-25 fifty A-1 J-19 51 A-7 B-24 52 A-1 F-2 53 A-1 J-178 54 A-1 J-26 55 A-1 J-219 56 A-1 J-74 57 A-1 J-61 58 A-1 D-4 59 A-1 F-35

60 A-1 D-11 61 A-1 J-174 62 A-1 J-106 63 A-1 F-47 64 A-1 J-111 66 A-1 J-214 67 A-10 J-236 68 A-1 F-55 69 A-1 D-8 70 A-1 F-11 71 A-1 F-61 72 A-1 J-66 73 A-1 J-157 74 A-1 J-104 75 A-1 J-195 76 A-1 F-46 77 A-1 B-20 78 A-1 J-92 79 A-1 F-41 80 A-1 J-30 81 A-1 J-222 82 A-1 J-190 83 A-1 F-40 84 A-1 J-32 85 A-1 F-53 86 A-1 J-15 87 A-1 J-39 88 A-1 G-3 89 A-1 J-134 90 A-1 J-18 91 A-1 J-38 92 A-1 C-13 93 A-1 F-68 95 A-1 J-189 96 A-1 B-9 97 A-1 F-34 99 A-1 J-4 one hundred A-1 J-182 102 A-1 J-117 103 A-2 C-9 104 A-1 B-4 106 A-1 J-11 107 A-1 DC-6 108 A-1 DC-3 109 A-1 DC-4 110 A-1 J-84 111 A-1 J-43 112 A-11 J-235 113 A-1 B-7 114 A-1 D-18

115 A-1 F-62 116 A-3 J-229 118 A-1 F-12 120 A-1 J-1 121 A-1 J-130 122 A-1 J-49 123 A-1 F-66 124 A-2 B-24 125 A-1 J-143 126 A-1 C-25 128 A-22 J-176 130 A-14 J-233 131 A-1 J-240 132 A-1 J-220 134 A-1 F-58 135 A-1 F-19 136 A-1 C-8 137 A-6 C-9 138 A-1 F-44 139 A-1 F-59 140 A-1 J-64 142 A-1 J-10 143 A-1 C-7 144 A-1 J-213 145 A-1 B-18 146 A-1 J-55 147 A-1 J-207 150 A-1 J-162 151 A-1 F-67 152 A-1 J-156 153 A-1 C-23 154 A-1 J-107 155 A-1 J-3 156 A-1 F-36 160 A-1 D-6 161 A-1 C-3 162 A-1 J-171 164 A-1 J-204 165 A-1 J-65 166 A-1 F-54 167 A-1 J-226 168 A-1 J-48 169 A-1 B-1 170 A-1 J-42 171 A-1 F-52 172 A-1 F-64 173 A-1 J-180 174 A-1 F-63 175 A-1 DC-2 176 A-1 J-212

177 A-1 J-57 178 A-1 J-153 179 A-1 J-154 180 A-1 J-198 181 A-1 F-1 182 A-1 F-37 183 A-1 DC-1 184 A-15 J-231 185 A-1 J-173 186 A-1 B-15 187 A-1 B-3 188 A-1 B-25 189 A-1 J-24 190 A-1 F-49 191 A-1 J-23 192 A-1 J-36 193 A-1 J-68 194 A-1 J-37 195 A-1 J-127 197 A-1 J-167 198 A-1 J-210 199 A-1 F-3 200 A-1 H-1 201 A-1 J-96 202 A-1 F-28 203 A-1 B-2 204 A-1 C-5 205 A-1 J-179 206 A-1 J-8 207 A-1 B-17 208 A-1 C-12 209 A-1 J-126 210 A-17 J-101 211 A-1 J-152 212 A-1 J-217 213 A-1 F-51 214 A-1 J-221 215 A-1 J-136 216 A-1 J-147 217 A-1 J-185 218 A-2 C-13 219 A-1 J-114 220 A-1 C-26 222 A-1 J-35 223 A-1 F-23 224 A-1 1-1 226 A-1 J-129 227 A-1 J-120 228 A-1 J-169 229 A-1 J-59

230 A-1 J-145 231 A-1 C-17 233 A-1 J-239 234 A-1 B-22 235 A-1 E-9 236 A-1 J-109 240 A-1 J-34 241 A-1 J-82 242 A-1 D-2 244 A-1 J-228 245 A-1 J-177 246 A-1 J-78 247 A-1 F-33 250 A-1 J-224 252 A-1 J-135 253 A-1 F-30 254 A-2 B-20 255 A-8 C-9 256 A-1 J-45 257 A-1 J-67 259 A-1 B-14 261 A-1 F-13 262 A-1 DC-7 263 A-1 J-163 264 A-1 J-122 265 A-1 J-40 266 A-1 C-14 267 A-1 J-7 268 A-1 E-7 270 A-1 B-5 271 A-1 D-9 273 A-1 H-2 274 A-8 B-24 276 A-1 J-139 277 A-1 F-38 278 A-1 F-10 279 A-1 F-56 280 A-1 J-146 281 A-1 J-62 283 A-1 F-18 284 A-1 J-16 285 A-1 F-45 286 A-1 J-119 287 A-3 C-13 288 A-1 C-6 289 A-1 J-142 290 A-1 F-15 291 A-1 C-10 292 A-1 J-76

293 A-1 J-144 294 A-1 J-54 295 A-1 J-128 296 A-17 J-12 297 A-1 J-138 301 A-1 J-14 302 A-1 F-5 303 A-1 J-13 304 A-1 E-1 305 A-1 F-17 306 A-1 F-20 307 A-1 F-43 308 A-1 J-206 309 A-1 J-5 310 A-1 J-70 311 A-1 J-60 312 A-1 F-27 313 A-1 F-39 314 A-1 J-116 315 A-1 J-58 317 A-1 J-85 319 A-2 C-7 320 A-1 B-6 321 A-1 J-44 322 A-1 J-22 324 A-1 J-172 325 A-1 J-103 326 A-1 F-60 328 A-1 J-115 329 A-1 J-148 330 A-1 J-133 331 A-1 J-105 332 A-1 J-9 333 A-1 F-8 334 A-1 DC-5 335 A-1 J-194 336 A-1 J-192 337 A-1 C-24 338 A-1 J-113 339 A-1 B-8 344 A-1 F-22 345 A-2 J-234 346 A-12 J-6 348 A-1 F-21 349 A-1 J-29 350 A-1 J-100 351 A-1 B-23 352 A-1 B-10 353 A-1 D-10 354 A-1 J-186 355 A-1 J-25

357 A-1 B-13 358 A-24 J-232 360 A-1 J-151 361 A-1 F-26 362 A-1 J-91 363 A-1 F-32 364 A-1 J-88 365 A-1 J-93 366 A-1 F-16 367 A-1 F-50 368 A-1 D-5 369 A-1 J-141 370 A-1 J-90 371 A-1 J-79 372 A-1 J-209 373 A-1 J-21 374 A-16 J-238 375 A-1 J-71 376 A-1 J-187 377 A-5 J-237 378 A-1 D-3 380 A-1 J-99 381 A-1 B-24 383 A-1 B-12 384 A-1 F-48 385 A-1 J-83 387 A-1 J-168 388 A-1 F-29 389 A-1 J-27 391 A-1 F-9 392 A-1 J-52 394 A-22 J-170 395 A-1 C-20 397 A-1 J-199 398 A-1 J-77 400 A-1 J-183 401 A-1 F-4 402 A-1 J-149 403 A-1 C-22 405 A-1 J-33 406 A-6 B-24 407 A-3 C-7 408 A-1 J-81 410 A-1 F-31 411 A-13 J-191 412 A-1 B-19 413 A-1 J-131 414 A-1 J-50 417 A-1 F-65 418 A-1 J-223

419 A-1 J-216 420 A-1 G-1 421 A-1 C-18 422 A-1 J-20 423 A-1 B-16 424 A-1 F-42 425 A-1 J-28 426 A-1 C-11 427 A-1 J-124 428 A-1 C-1 429 A-1 J-218 430 A-1 J-123 431 A-1 J-225 432 A-1 F-14 433 A-1 C-9 434 A-1 J-159 435 A-1 J-41 436 A-1 F-24 437 A-1 J-75 438 A-1 E-10 439 A-1 J-164 440 A-1 J-215 441 A-1 D-19 442 A-1 J-165 443 A-1 J-166 444 A-1 E-6 445 A-1 J-97 446 A-1 J-121 447 A-1 J-51 448 A-1 J-69 449 A-1 J-94 450 A-1 J-193 451 A-1 J-31 452 A-1 J-108 453 A-1 D-1 454 A-1 J-47 455 A-1 J-73 456 A-1 J-137 457 A-1 J-155 458 A-1 C-4 459 A-1 J-53 461 A-1 J-150 463 A-1 J-202 464 A-3 C-9 465 A-1 E-4 466 A-1 J-2 467 A-1 J-86 468 A-20 J-184 469 A-12 J-132 470 A-1 J-160

473 A-21 J-89 474 A-1 J-201 475 A-1 J-158 477 A-1 J-63 478 A-1 B-11 479 A-4 J-230 480 A-23 J-175 481 A-1 J-188 483 A-1 C-21 484 A-1 D-14 B-26-I A-1 B-26 B-27-I A-1 B-27 C-27-I A-1 C-27 D-12-I A-1 D-12 D-13-I A-1 D-13 D-15-I A-1 D-15 D-16-i A-1 D-16 D-17-i A-1 D-17 DC-10-I A-1 DC-10 DC-8-I A-1 DC-8 DC-9-I A-1 DC-9

Indoles

Example 1

General scheme

Specific example

188-I ; 6 - [(4-Oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-5-carboxylic acid

A mixture of 6 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-5-carboxylic acid ethyl ester ( 188 ) (450 mg, 1.2 mmol) and 1N. a solution of NaOH (5 ml) in THF (10 ml) is heated at a temperature of 85 ° C overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer is acidified with 1N. HCl solution to pH = 5 and the precipitate is filtered off, washed with water and dried in air, obtaining 6 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-5-carboxylic acid ( 188-I ) (386 mg, 93% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.92-12.75 (m, 2H), 11.33 (s, 1H), 8.84 (s, 1H), 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), 6.51 (m, H).

HPLC: retention time 2.95 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 376.2 m / z (MH ⁺ ).

343 ; N- [5- (Isobutylcarbamoyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide

To a solution of 6 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -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) isobutylamine (7 mg, 0.1 mmol) is added and the reaction mixture is stirred at 65 ° C. overnight. The resulting solution was filtered and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product, N- [5- (isobutylcarbamoyl) -1H-indol-6-yl] -4-oxo-1H-quinolin-3 -carboxamide ( 343 ) (20 mg, 66% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) 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), 8.47 (s, 1H), 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), 1.88 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H).

HPLC: retention time 2.73 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 403.3 m / z (MH ⁺ ).

Another example

148 ; 4-Oxo-N- [5- (1-piperidylcarbonyl) -1H-indol-6-yl] -1H-quinoline-3-carboxamide

4-Oxo-N- [5- (1-piperidylcarbonyl) -1H-indol-6-yl] -1H-quinoline-3-carboxamide ( 148 ) is synthesized according to the general scheme given above, linking the acid ( 188-I ) with piperidine. Total yield (12%).

HPLC: retention time 2.79 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 415.5 m / z (MH ⁺ ).

Example 2

General scheme

Specific example

158 ; 4-oxo-N- (5-phenyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide

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) PdCl ₂ (catalytic amount) and K ₂ CO ₃ (100 μl, 2M solution) in DMF (1 ml) are heated in a microwave oven at 180 ° C for 10 minutes. The reaction mixture was filtered and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product, 4-oxo-N- (5-phenyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide ( 158 ) (5 mg, 13% yield).

HPLC: retention time 3.05 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 380.2 m / z (MH ⁺ ).

The table below lists other examples of substances synthesized according to the above general scheme.

The compound of formula I Boronic acid 237 2-methoxyphenylboronic acid 327 2-ethoxyphenylboronic acid 404 2,6-dimethoxyphenylboronic acid one 5-chloro-2-methoxyphenylboronic acid 342 4-isopropylphenylboronic acid 347 4- (2-dimethylaminoethylcarbamoyl) phenylboronic acid 65 3-pyridinylboronic acid

Example 3

27 ; N- [1- [2- [Methyl (2-methylaminoacetyl) amino] acetyl] -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide

To a solution of tert-butyl ether methyl {[methyl (2-oxo-2- {6 - [(4-oxo-1,4-dihydroquinoline-3-carbonyl) amino] indol-1-yl} ethyl) carbamoyl] methyl} carbamic acid ( B-26-I ) (2.0 g, 3.7 mmol) dissolved in a mixture of CH ₂ Cl ₂ (50 ml) and methanol (15 ml) add HCl solution (60 ml, 1.25 M solution in methanol). The reaction mixture was stirred at room temperature for 64 hours. The precipitated product was separated by filtration, washed with diethyl ether and dried under high vacuum to give N- [1- [2- [methyl (2-methylaminoacetyl) amino] acetyl] -1H-indol-6-yl] -4-oxo-1H hydrochloride -quinoline-3-carboxamide ( 27 ) as a grayish-white solid (1.25 g, 70% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.20 (d, J = 6.7 Hz, 1H), 12.68 (s, 1H), 8.96-8.85 (m, 1H ), 8.35 (d, J = 7.9 Hz, 1H), 7.91-7.77 (m, 3H), 7.64-7.54 (m, 3H), 6.82 (m, 1H), 5.05 (s, 0.7H), 4.96 (s, 1.3H), 4.25 (t, J = 5.6 Hz, 1.3H), 4.00 (t, J = 5.7 Hz, 0.7H), 3.14 (s, 2H), 3.02 (s, 1H), 2.62 (t, J = 5.2 Hz, 2H), 2.54 (t , J = 5.4 Hz, 1H).

HPLC: retention time 2.36 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 446.5 m / z (MH ⁺ ).

Phenols

Example 1

General scheme

Specific example

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

To a mixture of N- (3-hydroxy-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide ( 428 ) (6.7 mg, 0.02 mmol) and Cs ₂ CO ₃ (13 mg, 0.04 mmol) in DMF (0.2 ml) add BnBr (10 μl, 0.08 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and purified using HPLC to give 4-benzyloxy-N- (3-hydroxy-4-tert-butylphenyl) quinoline-3-carboxamide ( 275 ).

^lH-NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 9.47 (s, 1H), 9.20 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H), 7.79 (t , J = 2.0 Hz, 2H), 7.56 (m, 1H), 7.38-7.26 (m, 6H), 7.11 (d, J = 8.4 Hz, 1H), 6 99 (dd, J = 8.4, 2.1 Hz, 1H), 5.85 (s, 2H), 1.35 (s, 9H).

HPLC: retention time 3.93 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 427.1 m / z (MH ⁺ ).

Another example

415 ; N- (3-Hydroxy-4-tert-butylphenyl) -4-methoxyquinolin-3-

carboxamide

N- (3-Hydroxy-4-tert-butylphenyl) -4-methoxyquinoline-3-carboxamide ( 415 ) is synthesized following the general scheme above by reacting N- (3-hydroxy-4-tert-butylphenyl) -4 -oxo-1H-quinoline-3-carboxamide ( 428 ) with methyl iodide.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 9.46 (s, 1H), 8.99 (s, 1H), 8.42 (t, J = 4 , 2 Hz, 1H), 7.95-7.88 (m, 2H), 7.61-7.69 (m, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7 10 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.1 Hz, 1H), 4.08 (s, 3H), 1.35 (s, 9H).

HPLC: retention time 3.46 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 351.5 m / z (MH ⁺ ).

Example 2

Where

NMP = 2-nitro-2-methyl-1-propanol

476 ; N- (4-tert-Butyl-2-cyano-5-hydroxyphenyl) -1,4-dihydro-4-oxoquinoline-3-carboxamide

To a suspension of N- (4-tert-butyl-2-bromo-5-hydroxyphenyl) -1,4-dihydro-4-oxoquinoline-3-carboxamide ( C-27-I ) (84 mg, 0.2 mmol), Zn (CN) ₂ (14 mg, 0.12 mmol) in NMP (1 ml) was added under nitrogen atmosphere Pd (PPh ₃ ) ₄ (16 mg, 0.014 mmol). The mixture is heated in a microwave oven at 200 ° C. for 1 hour, filtered and purified using preparative HPLC to give N- (4-tert-butyl-2-cyano-5-hydroxyphenyl) -1,4-dihydro-4- oxoquinoline-3-carboxamide ( 476 ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (d, J = 6.4 Hz, 1H), 12.91 (s, 1H), 8.89 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.16 (s, 1H), 7.85-7.75 (m, 2H), 7.56-7.54 (m, 1H), 7.44 (s, 1H), 1.35 (s, 9H).

HPLC: retention time 3.42 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 362.1 m / z (MH ⁺ ).

Anilines

Example 1

General scheme

Specific example

260 ; N- (5-amino-2-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide

Mixture of tert-butyl ether [3 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -4-tert-butylphenyl] amino formic acid ( 353 ) (33 mg, 0.08 mmol), TFA (1 ml ) and CH ₂ Cl ₂ (1 ml) were stirred at room temperature overnight. The solution was concentrated and the residue was dissolved in DMSO (1 ml) and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product N- (5-amino-2-tert-butylphenyl) -4-oxo-1H -quinoline-3-carboxamide ( 260 ) (15 mg, 56% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.23 (d, J = 6.6 Hz, 1H), 12.20 (s, 1H), 10.22 (br s, 2H), 8.88 (d, J = 6.8 Hz, 1H) 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 2.33 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 336.3 m / z (MH ⁺ ).

The table below lists other examples of substances synthesized according to the above general scheme.

Source Intermediate Product 60 101 D-12-I 282 D-13-I 41 114 393 D-16-i 157 D-15-I 356 D-17-i 399

Example 2

General scheme

Specific example

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

To a suspension of N- (3-amino-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide ( 271 ) (600 mg, 1.8 mmol) in CH ₂ Cl ₂ (15 ml) and methanol (5 ml) add acetic acid (250 μl) and formaldehyde (268 μl, 3.6 mmol, 37% wt. In water.). After 10 minutes, sodium cyanoborohydride (407 mg, 6.5 mmol) was added in one portion. Additional formaldehyde (135 μl, 1.8 mmol, 37% wt. In water) was added after 1.5 hours and 4.2 hours. After 4.7 hours, the mixture was diluted with diethyl ether (40 ml), washed with water (25 ml) and brine (25 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting red-brown foam was purified by preparative HPLC to give N- (3-dimethylamino-4-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide ( 485 ) (108 mg, 17% yield).

^l H-NMR (300 MHz, SDS1 ₃ ) δ 13.13 (br s, 1H), 12.78 (s, 1H), 8.91 (br.s, 1H), 8.42 (br.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% CH ₃ CN, analysis time 5 min.

ESI-MS: 364.3 m / z (MH ⁺ ).

The table below lists other examples of substances synthesized according to the above general scheme.

Source Intermediate Product 69 117 160 462 282 409 41 98

Example 3

General scheme

Specific example

94;  N- (5-amino-2-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide

To a solution of 4-hydroxyquinoline-3-carboxylic acid ( A-1 ) (50 mg, 0.26 mmol), HBTU (99 mg, 0.26 mmol) and DIEA (138 μl, 0.79 mmol) in THF (2 6 ml) 2-methyl-5-nitrophenylamine (40 mg, 0.26 mmol) is added. The mixture was heated at 150 ° C. in the microwave for 20 minutes and the resulting solution was concentrated. The residue was dissolved in EtOH (2 ml) and SnCl ₂ · 2H ₂ O (293 mg, 1.3 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was made basic with a NaHCO ₃ solution to pH = 7-8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product N- (5-amino-2-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide ( 94 ) (6 mg, 8% yield).

HPLC: retention time 2.06 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 294.2 m / z (MH ⁺ ).

Another example

17 ; N- (5-amino-2-propoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide

N- (5-amino-2-propoxyphenyl) -4-oxo-1H-quinoline-3-carboxamide ( 17 ) is prepared following the general scheme given above starting from 4-hydroxyquinoline-3-carboxylic acid ( A-1 ) and 5-nitro-2-propoxyphenylamine. Yield (9%).

HPLC: retention time 3.74 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 338.3 m / z (MH ⁺ ).

Example 4

General scheme

X = CO, CO ₂ , SO ₂ : a) R2XC1, DIEA, THF or R2XC1, NMM, 1,4-dioxane or R2XC1, Et ₃ N, CH ₂ Cl ₂ , DMF.

Specific example

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

To a solution of N- (3-amino-4-methylphenyl) -4-oxo-1H-quinoline-3-carboxamide ( 167 ) (33 mg, 0.11 mmol) and DIEA (49 μl, 0.28 mmol) in THF (1 ml) acetyl chloride (16 μl, 0.22 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. LCMS analysis indicates that diacylation has occurred. A solution of piperidine (81 μl, 0.82 mmol) in CH ₂ Cl ₂ (2 ml) was added and then the reaction mixture was stirred for 30 minutes, after which only the desired product was found by LCMS analysis. The reaction solution was concentrated and the residue was dissolved in DMSO and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product N- (3-acetylamino-4-methylphenyl) -4-oxo-1H-quinolin-3- carboxamide ( 248 ) (4 mg, 11% yield).

^oneH-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), 8.33 (dd, J = 8.1 , 1.3 Hz, 1H), 7.85-7.81 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.1 Hz , 1H), 7.49 (dd, J = 8.2, 2.2 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 2.18 (s, 3H), 2 08 (s, 3H).

HPLC: retention time 2.46 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 336.3 m / z (MH ⁺ ).

The table below lists other examples of substances synthesized according to the above general scheme.

Based X R ² Product 260 With Me 316 260 With neopentyl 196 429 With Me 379 41 With Me 232 101 With Me 243 8 With Me 149 271 CO ₂ Et 127 271 CO ₂ Me fourteen 167 CO ₂ Et 141 69 CO ₂ Me thirty 160 CO ₂ Me 221 160 CO ₂ Et 382 69 CO ₂ Et 225 282 CO ₂ Me 249 282 CO ₂ Et 472 41 CO ₂ Me 471 101 CO ₂ Me 239 101 CO ₂ Et 269 8 CO ₂ Me 129 8 CO ₂ Et 298 160 SO ₂ Me 340

Example 5

General scheme

Specific example

4-oxo-N- [3- (trifluoromethyl) -5- (vinylsulfonamido) 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) NMM (0.4 ml, 3.6 mmol) was added. Β-Chloroethylsulfonyl chloride (0.16 ml, 1.51 mmol) was added under argon. The mixture was stirred at room temperature for 6.5 hours, after which thin-layer chromatography (CH ₂ Cl ₂ -EtOAc 8: 2 mixture) showed a new spot with a very similar R _{f of the} starting material. An additional 0.5 eq. NMM and the mixture was stirred at room temperature overnight. LCMS analysis of the crude mixture shows conversion to the desired product> 85%. The mixture was concentrated, treated with 1M HCl (5 ml) and extracted with EtOAc (3 times 10 ml) and CH ₂ Cl ₂ (3 times 10 ml). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give 4-oxo-N- [3- (trifluoromethyl) -5- (vinylsulfonamido) phenyl] -1,4-dihydroquinoline-3-carboxamide as an orange foam ( 0.495 g, yield 79%), which is used in the next step without further purification.

¹ H-NMR (d ₆ -acetone, 300 MHz) δ 8.92 (s, 1H), 8.41-8.38 (m, 1H), 7.94 (m, 2H), 7.78 (broad s, 2H), 7.53-7.47 (m, 1H), 7.30 (s, 1H), 6.87-6.79 (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) ethylsulfonylamino] -5- (trifluoromethyl) phenyl] -1H-quinoline-3-carboxamide

A mixture of 4-oxo-N- [3- (trifluoromethyl) -5- (vinylsulfonamido) phenyl] -1,4-dihydroquinoline-3-carboxamide (50 mg, 0.11 mmol), piperidine (18 μl, 1.6 equiv .) and LiClO ₄ (20 mg, 1.7 equiv.) are suspended in a solution of CH ₂ Cl ₂ : isopropanol (1: 1, 1.5 ml). The mixture was refluxed at 75 ° C. for 18 hours. After this time, LCMS analysis shows the conversion to the desired product> 95%. The crude mixture was purified by reverse phase HPLC to give 4-oxo-N- [3- [2- (1-piperidyl) ethylsulfonylamino] -5- (trifluoromethyl) phenyl] -1H-quinoline-3-carboxamide ( 318 ) as yellowish solid (15 mg, 25% yield).

¹ H-NMR (d ₆ -acetone, 300 MHz) δ 8.92 (br s, 1H), 8.4 (d, J = 8.1 Hz, 1H), 8.05 (br s, 1H ), 7.94 (br s, 1H), 7.78 (br s, 2H), 7.53-7.51 (m, 1H), 7.36 (br s, 1H), 3, 97 (t, J = 7.2 Hz, 2H), 3.66 (t, J = 8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36-1.31 (m , 4H).

ESI-MS: 489.1 m / z (MH ⁺ ).

The table below lists other examples of substances synthesized according to the above general scheme.

Source Intermediate Amine Product 429 morpholine 272 429 dimethylamine 359 131 piperidine 133 131 morpholine 46

Example 6

General scheme

Specific example

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

A mixture of N- (1-acetylindolin-6-yl) -4-oxo-1H-quinoline-3-carboxamide ( 233 ) (43 mg, 0.12 mmol), 1N. a solution of NaOH (0.5 ml) and ethanol (0.5 ml) is refluxed for 48 hours. The solution was concentrated and the residue was dissolved in DMSO (1 ml) and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product, N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide ( 258 ) (10 mg, 20% yield).

HPLC: retention time 2.05 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 306.3 m / z (MH ⁺ ).

The table below lists other examples of substances synthesized according to the above general scheme.

Based Product Conditions Solvent DC-8-I 386 NaOH EtOH DC-9-I 10 HC1 EtOH 175 22 HC1 EtOH 109 35 HC1 EtOH 334 238 NaOH EtOH DC-10-I 105 NaOH THF

Example 2

General scheme

Specific example

299 ; 4-Oxo-N- (1,2,3,4-tetrahydroquinolin-7-yl) -1H-quinoline-3-carboxamide

Mixture of 7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester ( 183 ) (23 mg, 0.05 mmol) , TFA (1 ml) and CH ₂ Cl ₂ (1 ml) were stirred at room temperature overnight. The solution was concentrated and the residue was dissolved in DMSO (1 ml) and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product, 4-oxo-N- (1,2,3,4-tetrahydroquinoline-7- il) -1H-quinoline-3-carboxamide ( 299 ) (7 mg, 32% yield).

HPLC: retention time 2.18 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 320.3 m / z (MH ⁺ ).

Another example

300 ; N- (4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl) -4-oxo-1H-quinoline-3-carboxamide

N- (4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl) -4-oxo-1H-quinoline-3-carboxamide ( 300 ) is synthesized according to the general scheme given above, starting from tert 4,4-dimethyl-7-butyl ether - [(4-oxo-1H-quinolin-3-yl) carbonylamino] -1,2,3,4-tetrahydroquinoline-1-carboxylic acid ( 108 ). Yield (33%).

^l H-NMR (400 MHz, DMSO-d ₆ ), δ 13.23 (d, J = 6.6 Hz, 1H), 12.59 (s, 1H), 8.87 (d, J = 6, 8 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 7.86-7.79 (m, 3H), 7.58-7.42 (m, 3H), 3, 38 (m, 2H), 1.88 (m, 2H), 1.30 (s, 6H).

HPLC: retention time 2.40 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 348.2 m / z (MH ⁺ ).

Other examples

Example 1

General scheme

Specific example

163 ; (4-Aminomethyl-2'-ethoxybiphenyl-2-yl) 4-oxo-1,4-dihydroquinolin-3-carboxylic acid amide

{2'-ethoxy-2 - [(4-oxo-1,4-dihydroquinolin-3-carbonyl) amino] biphenyl-4-ylmethyl} carbamic acid tert-butyl ester ( 304 ) (40 mg, 0.078 mmol) is stirred in mixtures of CH ₂ Cl ₂ / TFA (3: 1, 20 ml) at room temperature for 1 hour. Volatiles are removed on a rotary evaporator. The crude product was purified by preparative HPLC to give (4-aminomethyl-2'-ethoxybiphenyl-2-yl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid amide ( 163 ) as a tan solid (14 mg, yield 43%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) 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), 8.26 (br s, 2H), 8.01 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 7, 75 (dt, J = 8.1 Hz, J = 1.2 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.47-7.37 (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), 4.09 (m, 2H), 4.04 (q, J = 6.9 Hz, 2H), 1.09 ( t, J = 6.9 Hz, 3H).

HPLC: retention time 1.71 min, 10-100% CH ₃ CN, gradient 5 min.

ESI-MS: 414.1 m / z (MH ⁺ ).

Another example

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

N- [3- (Aminomethyl) -4-tert-butylphenyl] -4-oxo-1H-quinoline-3-carboxamide ( 390 ) is synthesized according to the general scheme given above starting from tert-butyl ether [5 - [( 4-oxo-1H-quinolin-3-yl) carbonylamino] -2-tert-butylphenyl] methylamino formic acid ( 465 ).

HPLC: retention time 2.44 min, 10-99% CH ₃ CN, gradient 5 min.

ESI-MS: 350.3 m / z (M + H ⁺ ).

Example 2

General scheme

Specific example

3- (2- (4- (1-amino-2-methylpropan-2-yl) phenyl) acetyl) quinolin-4 (1H) -one

(2-Methyl-2- {4- [2-oxo-2- (4-oxo-1,4-dihydroquinolin-3-yl) ethyl] phenyl} propyl) carbamic acid tert-butyl ester (88) (0, 50 g, 1.15 mmol), TFA (5 ml) and CH ₂ Cl ₂ (5 ml) were combined and stirred at room temperature overnight. Then the reaction mixture is neutralized with 1N. NaOH solution. The precipitate was isolated by filtration to give the product 3- (2- (4- (1-amino-2-methylpropan-2-yl) phenyl) acetyl) quinolin-4 (1H) -one, as a brown solid (651 mg, yield 91%).

HPLC: retention time 2.26 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 336.5 m / z (M + H ⁺ ).

323 ; [2-Methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid methyl ester

Methyl chloroformate (0.012 g, 0.150 mmol) is added to a solution of 3- (2- (4- (1-amino-2-methylpropan-2-yl) phenyl) acetyl) quinolin-4 (1H) -one (0.025 g, 0.075 mmol ), TEM (0.150 mmol, 0.021 ml) and DMF (1 ml) and stirred at room temperature for 1 hour. Then piperidine (0.074 ml, 0.750 mmol) is added and the reaction mixture is stirred for the next 30 minutes. The reaction mixture was filtered and purified by preparative HPLC (10-99% CH ₃ CN / H ₂ O) to give the product, methyl ester [2-methyl-2- [4 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] propyl] amino formic acid ( 323 ).

^oneH-NMR (400 MHz, DMSO-d₆) δ 12.94 (br s, 1H), 12.44 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H) 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7 54 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.02 (t, J = 6.3 Hz, 1H), 3.50 (s, 3H), 3.17 (d, J = 6.2 Hz, 2H), 1.23 (s, 6H).

HPLC: retention time 2.93 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 394.0 m / z (MH ⁺ ).

The table below lists other examples of substances synthesized according to the above general scheme.

Product Chloroformate 119 ethyl chloroformate 416 propyl chloroformate 460 butyl chloroformate 251 isobutyl chloroformate 341 neopentyl chloroformate 28 2-methoxyethyl chloroformate 396 (tetrahydrofuran-3-yl) methyl chloroformate

Example 3

General scheme

Specific example

273-I ; N- (1-Aminotetralin-7-yl) -4-oxo-1H-quinoline-3-carboxamide

To a solution of [7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid ( 273 ) (250 mg, 0.6 mmol) in dichloromethane (2 ml) ) add TFA (2 ml). The reaction mixture was stirred at room temperature for 30 minutes. More dichloromethane (10 ml) was added to the reaction mixture, and the solution was washed with saturated NaHCO ₃ solution (5 ml). Thus, a precipitate begins to form in the organic layer, the combined organic layers are concentrated, obtaining N- (1-aminotetralin-7-yl) -4-oxo-1H-quinoline-3-carboxamide ( 273-I ) (185 mg, yield 93 %).

HPLC: retention time 1.94 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 334.5 m / z (MH ⁺ ).

159 ; [7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid methyl ester

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) methyl chloroformate (22 μl, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. LCMS analysis of the reaction mixture shows peaks corresponding to products of both mono- and bis-addition. Piperidine (2 ml) was added and the reaction mixture was stirred overnight, after which only the mono-addition product was detected. The resulting solution was filtered and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product, methyl ester [7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid ( 159 ) (27 mg, 35% yield).

HPLC: retention time 2.68 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 392.3 m / z (MH ⁺ ).

Another example

482 ; [7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid ethyl ester

The [7 - [(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid ethyl ester ( 482 ) is synthesized according to the general scheme given above from amine ( 273-I ) and ethyl chloroformate . Total yield (18%).

HPLC: retention time 2.84 min, 10-99% CH ₃ CN, analysis time 5 min.

ESI-MS: 406.5 m / z (MH ⁺ ).

The table below shows the characteristic data of the compounds according to the present invention obtained in accordance with the above examples.

table 2 Connection No. LC-MS M + 1 LC-RT min Connection No. LC-MS M + 1 LC-RT min Connection No. LC-MS M + 1 LC-RT min one 444.3 3.19 23 457.5 3.56 45 308.1 3.18 2 350.1 3.8 24 398.3 3.13 46 490.1 1.89 3 455.3 3.75 25 397.1 2,38 47 375.3 3.33 four 350,3 2.81 26 348.1 2,51 48 317.1 3.06 5 337.3 2.76 27 446.2 2,33 49 400.1 2.88 6 351.4 3 28 438.4 2.9 fifty 307.3 3.08 7 472.3 3.6 29th 307.1 3.32 51 521.5 3.79 8 307.1 1.21 thirty 379.1 2.62 52 354.1 3.02 9 344.1 2.43 31 278.9 3.03 53 266.1 1.99 10 334.2 2.2 32 338.2 3 54 323.3 2.97 eleven 408.1 2.91 33 303.9 2.83 55 366.3 2.6 12 383.1 2.63 34 397.1 4.19 56 335.4 3.18 13 346.3 3.48 35 362.2 2,53 57 403.1 2.86 fourteen 394.3 3.07 36 307.3 3.25 58 364.3 3.02 fifteen 296.3 2.68 37 303.9 2.98 59 412.1 3.31 16 307.3 3.38 38 380.3 3.33 60 422.2 3.53 17 338.3 3.74 39 480.5 3.82 61 293.1 3.05 eighteen 352.9 3.62 40 309.1 2.46 62 349.1 3.4 19 316.3 2.71 41 321.1 1.88 63 376.1 2.89 twenty 371.3 3.53 42 460.0 3.71 64 321.1 2,31 21 421.1 2.66 43 457.5 3.6 65 381.5 1.85 22 332,2 2.21 44 336.1 2.95 66 345.1 3.32 67 332.3 3.17 109 404.5 3.17 151 360.0 3 68 398.1 2.85 110 303.9 2.75 152 322.3 2,31 69 322.5 2,37 111 333.1 3 153 425.1 4,52 70 341.1 2.15 112 348.5 3.07 154 401.3 3.77 71 426.1 2.6 113 318.3 3.02 155 266.1 2.11 72 293.1 3.27 114 499.2 3.74 156 424.1 3.12 73 380.9 2,4 115 330.1 2.67 157 321.0 2.13 74 334.1 3.32 116 320,2 3.18 158 380.2 3.05 75 316.3 2.43 117 349.1 1.32 159 392.3 2.68 76 376.1 2.97 118 379.1 2.61 160 321.1 1.34 77 322.5 2.93 119 408.4 3.07 161 409.2 3.82 78 344.1 2,38 120 309.1 2.93 162 296.3 2.61 79 372.1 3.07 121 333.1 3.69 163 413.1 1.71 80 295.3 2.78 122 325.1 2.66 164 333.1 3.33 81 336.3 2.73 123 330.1 2.64 165 344.1 2.41 82 350,3 2.11 124 378.3 3.4 166 398.1 2.83 83 365.1 Z76 125 294.3 2.21 167 294.3 2.12 84 280.3 2.11 126 411.1 3.06 168 265.9 1.96 85 408.0 3.25 127 408.5 3.22 169 318 2.98 86 370.3 2.08 128 369.1 3.53 170 300,3 3.08 87 357.1 3,5 129 365.1 1.74 171 408.0 3.08 88 436.3 3.37 130 440.2 3.57 172 396.0 3.14 89 303.9 3,1 131 313.0 2,4 173 280.3 2.14 90 321.1 3.43 132 365.9 2.73 174 388.0 2,58 91 355.2 3.47 133 488.1 1.97 175 374.2 2.85 92 295.2 3.84 134 402.1 2.25 176 349.1 3.38

93 371.0 2.75 135 384.1 2.94 177 337.1 3,5 94 294.2 2.06 136 393.1 4.33 178 413.3 four 95 290.1 2.78 137 580.5 4.1 179 308.5 2,33 96 343.0 2.75 138 376.1 2.98 180 307.3 3.08 97 402.1 2.59 139 408.0 3.17 181 354.1 2.97 98 349.1 1.96 140 346.1 four 182 358.1 2.89 99 334.1 3.13 141 366.3 2.89 183 420.3 3.47 one hundred 303.9 2.63 142 321.3 3,58 184 372.3 2.66 101 322.5 2,35 143 355.2 3.45 185 414.1 2.96 102 443.1 3.97 144 281.3 2.49 186 372.3 3,59 103 411.2 3.85 145 376.2 2.98 187 346.3 2.9 104 318.0 2.94 146 306.3 2,51 188 376.2 2.95 105 322,2 2,4 147 376.3 3.27 189 370.9 3.38 106 350,3 2.86 148 415.5 2.79 190 392.0 3.09 107 420,2 3.37 149 349.1 1.45 191 316.3 2.1 108 448.2 3.77 150 430.0 3.29 192 280.3 2.13 193 326.3 3.02 235 308.4 2.12 277 358.1 2.89 194 290.1 2.98 236 333.1 3.35 278 408.1 3.09 195 280.3 2.14 237 410.3 2.96 279 386.1 2.88 196 434.5 3.38 238 489.4 2.78 280 316.3 2.06 197 334.1 3.15 239 379.0 2.62 281 293.1 3.22 198 283.1 3 240 370.9 3.65 282 307.1 1.22 199 354.1 2.96 241 316.3 2.61 283 370.1 3 200 335.5 2.49 242 348.3 3.08 284 305.3 2,57 201 303.9 3.08 243 363.0 2.44 285 376.1 2.88 202 404.0 3.19 244 358.1 3.48 286 319.1 3.35 203 394.3 3.42 245 425.1 3.69 287 411.2 4.15 204 349.3 3.32 246 292.9 3.2 288 413.3 3.8 205 455.5 3.74 247 432.1 3.23 289 297.3 3.25 206 386.1 3,5 248 336.3 2.46 290 382.1 3.19 207 390.3 2.71 249 365,0 2.54 291 371.0 3.57 208 429.7 3.89 250 352.3 2,53 292 391.1 3.69 209 294.1 2,39 251 436.2 3.38 293 330.3 3.05 210 385.2 3.72 252 368.9 3.17 294 303.9 2.67 211 351.3 3.53 253 424.1 3.25 295 334.3 2.26 212 360.9 2.45 254 340.1 3.08 296 365.3 3.6 213 408.0 3.3 255 526.5 3.89 297 358.3 3.26 214 358.1 2.7 256 306.1 2,4 298 379.1 1.91 215 265.3 3.07 257 297.3 3.28 299 320.3 2.18 216 305.3 2.27 258 306.3 2.05 300 348.2 2,4 217 305.3 2.41 259 360.3 3.46 301 346.3 2.26 218 413.2 3.98 260 336.3 2,33 302 370.1 2.28 219 266.9 2.48 261 368.1 3.08 303 362.2 2,51 220 409.0 3.35 262 352.3 2.7 304 513.2 3.66 221 379.1 2.68 263 372.9 3.69 305 370.1 2.98 222 324.3 3.27 264 353.1 3.42 306 384.1 3.11 223 386.1 3.14 265 354.9 3.4 307 374.0 3.05 224 466.3 3.08 266 405.3 4.05 308 304.1 2.71 225 393.1 2.75 267 357.1 3.43 309 316.3 2.83 226 306.1 3.6 268 400.3 6.01 310 320.1 3.73 227 381.1 2.24 269 393.0 2.75 311 344.9 3.43

228 371.1 2.84 270 329.3 3.02 312 400.1 2.86 229 311.1 2.93 271 336.5 2.75 313 358.1 2,8 230 318.1 2.81 272 524.1 1.87 314 335.1 3.52 231 471.3 3.41 273 434.5 3.17 315 293.1 2.9 232 363.1 2,57 274 493.5 3.46 316 378.5 2.84 233 348.5 2.75 275 427.1 3.93 317 333,2 2.91 234 372.3 3.2 276 414.3 2.81 318 522.1 1.8 319 373.3 3,59 361 400.1 2.91 403 423.1 4.45 320 360.1 3,5 362 355.5 3.46 404 440.3 2.87 321 453.5 3.12 363 388.1 2.92 405 299.3 3.16 322 349.3 3,7 364 330.3 2.68 406 547.3 3.74 323 394.0 2.93 365 307.1 2.6 407 371.3 3.8 324 320.1 3.81 366 408.1 3.09 408 295.3 2.9 325 321.3 3.22 367 408.0 3.14 409 335.1 1.82 326 418.0 2,5 368 338.2 2,33 410 432.1 3.41 327 424.2 3.2 369 358.1 3.29 411 299.1 3.17 328 307.1 2.76 370 299.1 3.03 412 376.2 2.93 329 396.3 3.72 371 365,0 3.27 413 357.1 3.37 330 299.3 3.02 372 362.1 2.66 414 305.3 2.11 331 308.3 2.25 373 305.3 3.38 415 351.5 3.44 332 288.0 2,5 374 350,3 3.01 416 422.4 3.23 333 379.1 2.61 375 319.3 3.4 417 396.0 2.67 334 531.3 3.26 376 382.3 3.48 418 308.3 2.23 335 322.3 2.41 377 340.2 3.08 419 322.3 2.48 336 321.5 3.52 378 310.3 2.07 420 379.1 3.2 337 407.5 3.37 379 389.0 2,53 421, 419.2 3.82 338 318.3 2.73 380 309.3 3.02 422 333.1 2.48 339 329.0 2.75 381 360,2 3.18 423 376.3 3.02 340 399.1 2.6 382 393.1 2.84 424 374.0 3.06 341 450,4 3.56 383 332.3 3.2 425 306.1 3.53 342 422.3 3.41 384 376.1 2.87 426 371.3 2.95 343 403.3 2.73 385 393.9 3.32 427 420.3 3.3 344 384.1 3.07 386 334.3 2,3 428 337.2 3.32 345 322,2 2.96 387 347.1 3.22 429 348.3 2.98 346 333.1 3.38 388 424.1 3.3 430 321.3 3.22 347 494.5 1.97 389 355.3 3.65 431 280.3 2.09 348 384.1 3.12 390 350,3 2.44 432 382.1 3.22 349 405.3 2.85 391 396.1 3.43 433 393.2 3.71 350 315.1 3.23 392 300,3 2.86 434 293.1 3.12 351 332.3 3.18 393 399.4 2.12 435 376.3 3.22 352 447.5 3.17 394 293.1 3.17 436 400.1 2.88 353 436.3 3.53 395 433.5 4.21 437 309.3 2.82 354 390.3 2,36 396 464.4 2.97 438 427.5 3.87 355 370.9 3.37 397 341.3 3.45 439 295.3 2,8 356 335.0 1.81 398 434.3 3,1 440 395.3 3.61 357 346.3 3.08 399 335.0 1.75 441 425.0 2.67 358 338.2 3.15 400 351.3 2.11 442 412.3 3.35 359 482.1 1.74 401 368.1 3.09 443 317.3 2.45 360 331.3 3.07 402 342.1 2.96 444 379.2 3.42 445 305.5 3.08 459 279.3 2.9 473 363.3 3.64 446 353.1 2.85 460 436.2 3.38 474 336.3 2,8

447 290.1 2.88 461 341.3 3.23 475 334 3 3.23 448 321.3 3,5 462 349.1 1.9 476 362.1 3.42 449 279.1 3.22 463 292.1 3.35 477 283.9 2,8 450 308.1 1.97 464 409.4 4.03 478 360.3 3.44 451 318.1 3.28 465 450.5 3.65 479 334.3 2.59 452 290.1 3.32 466 349.3 35 480 323.5 3.22 453 314.1 2.75 467 307.3 2.98 481 315.3 3 25 454 355.1 3,58 468 279.1 2.98 482 406.5 2.84 455 398.1 3.6 469 409.1 3.69 483 409 5 4.35 456 365.1 3.65 470 373.3 3.64 484 349.1 2.16 457 350,3 2.26 471 379.0 2.73 485 363.1 2.15 458 381.2 3.19 472 379.0 2.67

NMR data of the individual compounds are presented below in table 2-A.

Table 2-a Compound No. NMR data 2 ¹ H-NMR (300 MHz, CDCl ₃ ) δ 12.53 (s, 1H), 11.44 (br s, J = 6.0 Hz, 1H), 9.04 (d, J = 6.7 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.33-7.21 (m, 3H), 7.10 (d, J = 8.2 Hz, 1H), 3.79 (s, 3H), 1.36 (s, 9H) 5 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (br s, 1H), 12.41 (s, 1H), 8.88 (s, 1H), 8.34 (dd, J = 8.1 Hz, 1H), 7.82 (ddd, J = 8, 8, 1 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.64 (dd, J = 7, 2 Hz, 2H), 7.54 (ddd, J = 8, 8, 1 Hz, 1H), 7.35 (dd, J = 7.2 Hz, 2H), 4.66 (t, J = 5 Hz , 1H), 3.41 (d, J = 5 Hz, 2H), 1.23 (s, 6H) 8 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.86 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.54-7.47 (m, 1H), 7.38 (d, J = 8.5 Hz, 1H), 2.71 (q, J = 7.7 Hz, 2H), 1.30 (t, J = 7.4 Hz, 3H) 10 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (d, J = 6.4 Hz, 1H), 12.58 (s, 1H), 8.87 (d, J = 6.8 Hz , 1H), 8.33 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 7.89-7.77 (m, 3H), 7.56 (t, J = 8.1 Hz , 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 3.23 (m, 2H), 2.81 (m , 2H), 1.94 (m, 2H), 1.65 (m, 2H) 13 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.05 (br s, 1H), 12.68 (s, 1H), 8.89 (s, 1H), 8.35 (t, J = 2.5 Hz, 1H), 8.32 (d, J = 1.1 Hz, 1H), 7.85-7.76 (m, 3H), 7.58-7.54 (m, 2H), 1.47 (s, 9H) fourteen H-NMR (400 MHz, DMSO-d ₆ ) δ 1.32 (s, 9H), 3.64 (s, 3H), 7.36 (d, J = 8.4 Hz, 1H), 7.55 (m, 3H), 7.76 (d, J = 8.0 Hz, 1H), 7.83 (m, 1H), 8.33 (d, J = 7.0 Hz, 1H), 8.69 (s, 1H), 8.87 (d, J = 6.7 Hz, 1H), 12.45 (s, 1H), 12.97 (s, 1H)

27 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.20 (d, J = 6.7 Hz, 1H), 12.68 (s, 1H), 8.96-8.85 (m, 4H) 8.35 (d, J = 7.9 Hz, 1H), 7.91-7.77 (m, 3H), 7.64-7.54 (m, 3H), 6.82 (m, 1H ), 5.05 (s, 0.7H), 4.96 (s, 1.3H), 4.25 (t, J = 5.6 Hz, 1.3H), 4.00 (t, J = 5.7 Hz, 0.7H), 3.14 (s, 2H), 3.02 (s, 1H), 2.62 (t, J = 5.2 Hz, 2H), 2.54 (t, J = 5.4 Hz, 1H) 29th H-NMR (400 MHz, CDCl ₃ ) δ 9.09 (s, 1H), 8.62 (dd, J = 8.1, 1.5 Hz, 1H), 7.83-7.79 (m, 3H), 7.57 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.14 (t, J = 7.4 Hz, 2H) 5.05 (m, 1H); 1.69 (d, J = 6.6 Hz, 6H) 32 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (d, J = 6.6 Hz, 1H), 12.74 (s, 1H), 11.27 (s, 1H), 8.91 (d, J = 6.7 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.83 (t, J = 8.3 Hz , 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.38 (m , 1H), 6.40 (m, 1H) 33 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 12.47 (s, 1H), 11.08 (s, 1H), 8.90 (s, 1H), 8 , 35 (dd, J = 8.1, 1.1 Hz, 1H), 8.20 (t, J = 0.8 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H) , 7.76 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7 30 (t, J = 2.7 Hz, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 6.39 (m, 1H) 35 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (d, J = 6.7 Hz, 1H), 12.37 (s, 1H), 8.86 (d, J = 6.8 Hz , 1H), 8.33 (dd, J = 8.1, 1.3 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 8, 2 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.29 (m, 2H), 1.85 (m, 1H), 1.73-1.53 (m, 3H), 1.21 (s, 3H), 0.76 (t, J = 7.4 Hz, 3H) 43 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.77 (s, 1H), 11.94 (s, 1H), 9.56 (s, 1H), 8.81 (s, 1H), 8 11 (dd, J = 8.2, 1.1 Hz, 1H), 7.89 (s, 1H), 7.79-7.75 (m, 1H), 7.70 (d, J = 7 , 7 Hz, 1H), 7.49-7.45 (m, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.93-6 87 (m, 3H), 4.07 (q, J = 7.0 Hz, 2H), 1.38 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H) 47 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.24 (d, J = 6.9 Hz, 6H), 3.00 (m, 1H), 7.55 (m, 3H), 7.76 (d, J = 7.7 Hz, 1H), 7.83 (m, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 9.2 Hz , 1H), 8.89 (s, 1H), 12.65 (s, 1H), 12.95 (s, 1H) 56 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.81 (d, J = 6.7 Hz, 1H), 12.27 (s, 1H), 9.62 (s, 1H), 8.82 (d, J = 6.7 Hz, 1H), 8.32 (dd, J = 8.2, 1.3 Hz, 1H), 8.07 (s, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 6.58 (s, 1H), 2 , 62 (m, 4H), 1.71 (m, 4H) 58 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (d, J = 6.6 Hz, 1H), 12.39 (s, 1H), 8.86 (d, J = 6.8 Hz , 1H), 8.33 (d, J = 7.3 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H ), 7.54 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 8.7, 1.3 Hz , 1H), 6.91 (dd, J = 8.8, 2.5 Hz, 1H), 5.44 (br s, 2H)

64 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 12.41 (s, 1H), 10.63 (s, 1H), 10.54 (s, 1H), 8 86 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7, 7 Hz, 1H), 7.69 (s, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H) 69 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.06 (d, J = 6.5 Hz, 1H), 12.51 (s, 1H), 8.88 (d, J = 6.6 Hz , 1H), 8.33 (dd, J = 8.1, 1.0 Hz, 1H), 7.85-7.74 (m, 3H), 7.55 (t, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 3.03 (septet, J = 6.8 Hz, 1H), 1.20 (d, J = 6.7 Hz, 6H) 76 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.84 (d, J = 6.6 Hz, 1H), 8.31 (d, J = 6.2 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.44-7.13 (m, 8H), 6.78 (d, J = 7.5 Hz, 1H), 77 H-NMR (400 MHz, DMSO-d ₆ ) δ 6.40 (m, 1H), 7.36 (t, J = 2.7 Hz, 1H), 7.43 (d, J = 11.8 Hz , 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.80 (m, 2H), 8.36 (d, J = 9.2 Hz, 1H), 8.65 (d , J = 6.8 Hz, 1H), 8.91 (s, 1H), 11.19 (s, 1H), 12.72 (s, 1H), 12.95 (s, 1H) 88 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (d, J = 6.6 Hz, 1H), 12.42 (s, 1H), 8.89 (d, J = 6.7 Hz , 1H), 8.33 (dd, J = 8.1, 1.2 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7, 8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 8.7 Hz , 2H), 6.67 (t, J = 6.3 Hz, 1H), 3.12 (d, J = 6.3 Hz, 2H), 1.35 (s, 9H), 1.22 (s , 6H) 90 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.98 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J = 8.2, 1.1 Hz, 1H ), 7.84-7.75 (m, 2H), 7.59 (dd, J = 7.8, 1.5 Hz, 1H), 7.55-7.51 (m, 1H), 7, 42 (dd, J = 7.9, 1.5 Hz, 1H), 7.26-7.21 (m, 1H), 7.19-7.14 (m, 1H), 1.43 (s, 9H) 96 H NMR (400 MHz, DMSO-d ₆ ) δ 12.58 (s, 1H), 11.11 (s, 1H), 8.89 (s, 1H), 8.35 (dd, J = 8.1 , 1.1 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.83-7.74 (m, 2H), 7.56-7.51 (m, 2H) , 7.30 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 8.5, 1.8 Hz, 1H), 4.03 (d, J = 0.5 Hz, 2H) 103 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.37 (s, 9H), 1.38 (s, 9H), 7.08 (s, 1H), 7.17 (s, 1H), 7 74 (m, 1H), 7.86 (m, 1H), 7.98 (dd, J = 9.2, 2.9 Hz, 1H), 8.90 (d, J = 6.7 Hz, 1H), 9.21 (s, 1H), 11.71 (s, 1H), 13.02 (d, J = 6.7 Hz, 1H) 104 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (d, J = 6.6 Hz, 1H), 12.41 (s, 1H), 10.88 (s, 1H), 8, 88 (d, J = 6.7 Hz, 1H), 8.36-8.34 (m, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.4, 1.9 Hz, 1H), 6.07-6.07 (m, 1H), 2.37 (s, 3H)

107 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.52 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H) , 7.81 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.57-7.51 (m, 3H), 7.15 ( d, J = 8.3 Hz, 1H), 4.51 (s, 2H), 3.56 (t, J = 5.7 Hz, 2H), 2.75 (t, J = 5.5 Hz, 2H), 1.44 (s, 9H) 109 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (br s, 1H), 12.45 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.88 (s, 1H), 7.82 (t, J = 8.4 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.43 (m, 1H), 7.31 (d, J = 8.5 Hz, 1H), 4.01 (m, 1H), 3.41 (m, 1H), 2.21 (s, 3H), 1.85 (m, 1H), 1.68-1.51 (m, 3H), 1.23 (s, 3H ), 0.71 (t, J = 7.4 Hz, 3H) 113 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (d, J = 6.6 Hz, 1H), 12.46 (s, 1H), 10.72 (d, J = 1.5 Hz, 1H), 8.89 (d, J = 6.7 Hz, 1H), 8.35 (dd, J = 8.1, 1.2 Hz, 1H), 8.13 (d, J = 1 5 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7 , 07-7.04 (m, 2H), 2.25 (d, J = 0.9 Hz, 3H) 114 ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 12.65 (d, J = 6.9 Hz, 1H), 11.60 (s, 1H), 9.33 (s, 1H), 8, 71 (d, J = 6.6 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.03 d, J = 7.8 Hz, 1H), 7.66 (t , J = 7.2 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.12 (m, 2H), 6.97 (m, 3H), 3.97 (m, 2H), 1.45 (s, 9H), 1.06 (t , J = 6.6 Hz, 3H), 126 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 12.33 (s, 1H), 9.49 (s, 1H), 8.88 (s, 1H), 8 35 (dd, J = 8.7, 0.5 Hz, 1H), 7.86-7.82 (m, 1H), 7.77 (d, J = 7.8 Hz, 7.58-7 54 (m, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.98 (dd, J = 8, 4, 2.2 Hz, 1H), 3.67 (s, 2H), 3.51-3.47 (m, 2H), 3.44-3.41 (m, 2H), 3.36 (s , 3H), 1.33 (s, 6H) 127 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (t, J = 7.0 Hz, 3H), 1.32 (s, 9H), 4.10 (q, J = 7.0 Hz , 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.54 (m, 3H), 7.76 (d, J = 7.9 Hz, 1H), 7.82 (m , 1H) 8.33 (d, J = 9.2 Hz, 1H), 8.64 (s, 1H), 8.87 (s, 1H), 12.45 (s, 1H), 12.99 ( s, 1H) 129 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.83 (s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.80 (m, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.55 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H), 3.76 (s, 3H, OMe), 2 62 (q, J = 7.5 Hz, 2H); 1.21 (t, J = 7.5 Hz, 3H) 131 ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 12.37 (s, 1H), 8.81 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7, 77 (m, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.09 (s, 1H), 6.74 (s, 1H), 6.32 (s, 1H), 5.47 (s, 2H) 135 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.86 (d, J = 6.6 Hz, 1H), 8.32 (d, J = 6.2 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.47-7.24 (m, 6H), 6.95-6.83 (m, 3H), 5.95 (s, 2H),

136 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.29 (s, 9H), 1.41 (s, 9H), 7.09 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.85 (t , J = 8.4 Hz, 1H), 8.36 (d, J = 9.5 Hz, 1H), 8.93 (d, J = 6.8 Hz, 1H), 9.26 (s, 1H ), 12.66 (s, 1H), 13.04 (d, J = 6.6 Hz, 1H) 141 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (d, J = 6.6 Hz, 1H), 12.42 (s, 1H), 8.87 (d, J = 6.8 Hz , 1H), 8.33 (dd, J = 8.1, 1.2 Hz, 1H), 7.85-7.75 (m, 3H), 7.55 (t, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.2, 2.2 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H) 143 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (d, J = 6.8 Hz, 1H), 12.56 (s, 1H), 9.44 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.34 (dd, J = 8.2, 1.3 Hz, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7 83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.00 (d, J = 13.3 Hz, 1H), 1.34 (s, 9H) 150 ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 8.86 (d, J = 6.9 Hz, 1H), 8.63 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.82-7.71 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.52 (td, J = 1.2 Hz, 1H), 157 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.91 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.46 (d , J = 8.5 Hz, 1H), 7.16 (d, J = 6.0 Hz, 1H), 3.08 (s, 3H, NMe), 2.94 (q, J = 7.4 Hz , 2H), 1.36 (t, J = 7.4 Hz, 3H), 161 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 12.41 (s, 1H), 8.88 (s, 1H), 8.33 (dd, J = 8, 2, 1.2 Hz, 1H), 7.84-7.80 (m, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.44 (s, 1H), 7.19 (s, 2H), 4.13 (t, J = 4.6 Hz, 2H), 3.79 (t, J = 4.6 Hz, 2H), 3.54 (q, J = 7.0 Hz, 2H), 1.36 (s, 9H), 1.15 (t, J = 7.0 Hz, 3H) 163 ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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), 8.26 (br s, 2H), 8.08 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 7, 75 (m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.24 (d, J = 0.9 Hz, 1H ), 7.15 (dd, J = 7.5 Hz, J = 1.8 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.02 (dt, J = 7 5 Hz, J = 0.9 Hz, 1H), 4.07 (m, 4H), 1.094 (t, J = 6.9 Hz, 3H), 167 H-NMR (400 MHz, DMSO-d ₆ ) δ 2.03 (s, 3H), 4.91 (s, 2H), 6.95 (m, 3H), 7.53 (m, 1H), 7 75 (d, J = 8.2 Hz, 1H), 7.81 (m, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.84 (s, 1H), 12 , 20 (s, 1H), 12.90 (s, 1H)

169 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (d, J = 5.3 Hz, 1H), 12.51 (s, 1H), 8.89 (d, J = 6.3 Hz, 1H), 8.36 (dd, J = 8.1, 1.1 Hz, 1H), 8.06 (t, J = 0.7 Hz, 1H), 7.85-7.75 (m , 2H), 7.57-7.51 (m, 2H), 7.28 (d, J = 3.1 Hz, 1H), 7.24 (dd, J = 8.4, 1.8 Hz, 1H), 6.39 (dd, J = 3.1, 0.8 Hz, 1H), 3.78 (s, 3H) 178 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 8.89 (d, J = 6.8 Hz, 1H), 8.65 (dd, J = 8.1 , 1.6 Hz, 1H), 8.19 (dd, J = 8.2, 1.3 Hz, 1H), 7.80-7.71 (m, 2H), 7.48-7.44 ( m, 2H), 7.24-7.20 (m, 1H), 7.16-7.09 (m, 2H), 7.04-7.00 (m, 1H), 6.80 (dd, J = 8.0, 1.3 Hz, 1H), 6.69 (dd, J = 8.1, 1.4 Hz, 1H), 1.45 (s, 9H) 183 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.42 (s, 1H), 8.88 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H ), 8.06 (d, J = 2.1 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.38 (dd, J = 8.2, 2.1 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 3.66-3.63 (m, 2H), 2.70 (t, J = 6.5 Hz, 2H), 1.86-1.80 (m, 2H), 1.51 (s, 9H) 186 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (s, 1H), 12.47 (s, 1H), 10.72 (s, 1H), 8.89 (s, 1H), 8.35 (dd, J = 8.2, 1.1 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.82 (t, J = 8.2 Hz, 1H ), 7.76 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.05-7.02 (m, 2H), 3.19 (quintet, J = 8.2 Hz, 1H), 2.08 (m, 2H), 1.82-1.60 (m, 6H) 187 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 8.91 (s, 1H), 8.87-8.87 (m, 1H), 8.36 (dd , J = 8.2, 1.2 Hz, 1H), 7.85-7.75 (m, 3H), 7.64-7.53 (m, 3H), 6.71 (dd, J = 3 7, 0.5 Hz, 1H), 2.67 (s, 3H) 188 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 12.73 (d, J = 6.6 Hz, 1H), 11.39 (s, 1H), 8.85 (d, J = 6.7 Hz, 1H), 8.61 (s, 1H), 8.33 (d, J = 6.8 Hz, 1H), 8.23 (s, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.43 (m , 1H), 6.54 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) 204 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 12.37 (s, 1H), 8.87 (d, J = 1.2 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.2, 7.0 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7 54 (t, J = 7.5 Hz, 1H), 7.32-7.28 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 4.16 (t, J = 4.9 Hz, 2H), 1.78 (t, J = 4.9 Hz, 2H), 1.29 (s, 6H), 207 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (br s, 1H), 12.50 (s, 1H), 10.95 (s, 1H), 8.89 (s, 1H) 8.35 (dd, J = 8.2, 1.1 Hz, 1H), 8.17 (d, J = 1.5 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H) , 7.21 (d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.5, 1.8 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.72 (s, 2H), 1.20 (t, J = 7.1 Hz, 3H)

215 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J = 8, 1, 1.1 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.75 (m, 3H), 7.55 (t, J = 8.1 Hz, 1H) 7.37 (t, J = 7.9 Hz, 2H); 7.10 (t, J = 6.8 Hz, 1H) 220 H-NMR (400 MHz, DMSO -d ₆ ) δ 12.99 (d, J = 6.6 Hz, 1H), 12.07 (s, 1H), 8.93 (d, J = 6.8 Hz , 1H), 8.35 (d, J = 7.1 Hz, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.85-7.77 (m, 2H) 7.54 (td, J = 7.5, 1.2 Hz, 1H), 6.81 (s, 1H), 1.37 (d, J = 3.9 Hz, 9H), 1.32 ( d, J = 17.1 Hz, 9H) 225 ¹ H-NMR ( CD ₃ OD , 300 MHz) δ 8.79 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 7.75 (m, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.5 (m, 2H), 7.29 (d, J = 8.3 Hz, 1H), 4.21 (q, J = 7.2, 2H), 3.17 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H), 232 ¹ H-NMR ( CD ₃ OD , 300 MHz) δ 8.87 (s, 1H), 8.45 (d, J = 8.25, 1H), 8.27 (m, 1H), 7.83 ( t, J = 6.88, 1H), 7.67 (d, J = 8.25, 1H), 7.54 (t, J = 7.15, 1H), 7.39 (d, J = 6 05, 1H), 7.18 (d, J = 8.5, 1H), 2.77 (t, J = 6.87, 2H), 2.03 (s, 3H), 1.7 (q , 2H), 1.04 (t, J = 7.42, 3H) 233 ¹ H-NMR (400 MHz, DMSO -d ₆ ) δ 12.75 (d, J = 13.6 Hz, 1H), 8.87 (s, 1H), 8.32-8.28 (m, 2H ), 7.76-7.70 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.11 (t, J = 8.3 Hz, 2H), 3.10 (t, J = 7.7 Hz, 2H), 2.18 (s, 3H) 234 ¹ H-NMR (400 MHz, DMSO -d ₆ ) δ 12.49 (s, 1H), 11.50 (s, 1H), 8.90 (s, 1H), 8.36-8.34 (m , 2H), 7.97 (s, 1H), 7.85-7.81 (m, 1H), 7.77-7.75 (m, 1H), 7.56-7.50 (m, 2H ), 6.59-6.58 (m, 1H) 235 ¹ H-NMR (400 MHz, DMSO -d ₆ ) δ 13.09 (d, J = 6.5 Hz, 1H), 12.75 (s, 1H), 9.04 (s, 1H), 8, 92 (d, J = 6.8 Hz, 1H), 8.42 (d, J = 7.1 Hz, 1H), 8.34 (d, J = 6.9 Hz, 1H), 7.85 ( t, J = 8.4 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.63-7.56 (m, 2H), 3.15 (m, 1H), 1.29 (d, J = 6.9 Hz, 6H) 238 ¹ H-NMR (400 MHz, DMSO -d ₆ ) δ 12.93 (d, J = 6.4 Hz, 1H), 12.29 (s, 1H), 8.85 (d, J = 6.7 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 3.79 (m, 2H), 3.21- 2.96 (m, 4H), 1.91-1.76 (m, 4H), 1.52 (m, 2H), 1.43 (s, 9H) 242 H-NMR (400 MHz, DMSO -d ₆ ) δ 12.95 (d, J = 6.6 Hz, 1H), 12.65 (s, 1H), 8.87 (d, J = 6.8 Hz , 1H), 8.34 (dd, J = 8.1, 1.1 Hz, 1H), 8.17 (s, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7 76 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.37 (s, 1H), 5.60 (s, 2H)

243 ¹ H-NMR ( CD ₃ OD , 300 MHz) δ 8.87 (s, 1H), 8.45 (d, J = 8.25, 1H), 8.27 (m, 1H), 7.83 ( t, J = 6.88, 1H), 7.67 (d, J = 8.25, 1H), 7.54 (t, J = 7.15, 1H), 7.39 (d, J = 6 05, 1H), 7.18 (d, J = 8.5, 1H), 2.77 (t, J = 6.87, 2H), 2.03 (s, 3H), 1.7 (q , 2H), 1.04 (t, J = 7.42, 3H); NMR indicates the presence of a regioisomer 244 H-NMR (400 MHz, DMSO -d ₆ ) δ 12.89 (s, 1H), 12.42 (s, 1H), 10.63 (s, 1H), 8.88 (d, J = 6, 7 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.82 (t, J = 8.3 Hz , 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H ), 7.02 (dd, J = 8.4, 1.8 Hz, 1H), 2.69 (t, J = 5.3 Hz, 2H), 2.61 (t, J = 5.0 Hz , 2H), 1.82 (m, 4H) 248 H-NMR (400 MHz, DMSO -d ₆ ) 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), 8.33 (dd, J = 8.1, 1.3 Hz, 1H), 7.85-7.81 (m, 2H), 7.76 ( d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.2, 2.2 Hz, 1H), 7, 18 (d, J = 8.3 Hz, 1H), 2.18 (s, 3H), 2.08 (s, 3H) 259 H-NMR (400 MHz, DMSO -d ₆ ) δ 0.86 (t, J = 7.4 Hz, 3H), 1.29 (d, J = 6.9 Hz, 3H), 1.67 (m , 2H), 2.88 (m, 1H), 7.03 (m, 2H), 7.53 (m, 2H), 7.80 (m, 2H), 8.13 (s, 1H), 8 35 (d, J = 8.2 Hz, 1H), 8.89 (s, 1H), 10.75 (s, 1H), 12.45 (s, 1H), 12.84 (s, 1H) 260 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.23 (d, J = 6.6 Hz, 1H), 12.20 (s, 1H), 10.22 (br s, 2H), 8 88 (d, J = 6.8 Hz, 1H), 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) 261 ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 11.99 (s, 1H, NH), 8.76 (s, J = 6.6 Hz, 1H), 8.26 (d, J = 6 , 2 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.72-7.63 (m, 2H), 7.44-7.09 (m, 7H), 2 46 (s, 3H); 2.25 (s, 3H), 262 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 12.53 (s, 1H), 10.62 (s, 1H), 8.88 (s, 1H), 8.33 (dd, J = 8.2, 1.2 Hz, 1H), 7.85-7.75 (m, 2H), 7.57-7.50 (m, 2H), 7.34- 7.28 (m, 2H); 3.46 (s, 2H) 266 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (d, J = 6.6 Hz, 1H), 12.57 (s, 1H), 10.37 (s, 1H), 8.88 (d, J = 6.8 Hz, 1H), 8.34-8.32 (m, 1H), 7.99 (s, 1H), 7.85-7.81 (m, 1H), 7, 76 (d, J = 7.8 Hz, 1H), 7.56-7.52 (m, 1H), 7.38 (s, 1H), 1.37 (s, 9H) 268 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 12.62 (s, 1H), 8.91 (s, 1H), 8.34 (dd, J = 8, 1, 1.1 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.14 (dd, J = 8.8, 2.4 Hz, 1H), 7.84 ( t, J = 8.3 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.65-7.54 (m, 4H), 1.52 (s, 9H)

271 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.38 (s, 9H), 4.01 (s, 2H), 7.35 (s, 2H), 7.55 (m, 1H), 7 65 (s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.83 (m, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8 86 (d, J = 6.8 Hz, 1H), 12.49 (s, 1H), 13.13 (s, 1H) 272 ¹ H-NMR (Acetone-d ₆ , 300 MHz) δ 8.92 (d, J = 6.6 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.94 ( s, 1H), 7.79 (s, 1H), 7.77 (s, 2H), 7.53 (m, 1H), 7.36 (s, 1H), 3.94-3.88 (m , 5H), 3.64-3.59 (m, 3H), 3.30 (m, 4H), 274 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.21 (d, J = 6.6 Hz, 1H), 11.66 (s, 1H), 10.95 (s, 1H), 9.00 (d, J = 6.5 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.18 (dd, J = 8.7, 2.2 Hz, 1H), 7 97 (d, J = 8.8 Hz, 1H), 7.57 (m, 2H), 7.31 (t, J = 2.7 Hz, 1H), 6.40 (t, J = 2, 0 Hz, 1H), 3.19 (m, 4H), 1.67 (m, 4H), 1.46 (s, 9H) 275 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H), 9.47 (s, 1H), 9.20 (s, 1H), 8.43 (d, J = 7, 9 Hz, 1H), 7.79 (t, J = 2.0 Hz, 2H), 7.56 (m, 1H), 7.38-7.26 (m, 6H), 7.11 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.1 Hz, 1H), 5.85 (s, 2H), 1.35 (s, 9H) 282 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.90 (s, 1H), 8.51 (s, 1H), 8.44 (d, J = 7.9 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.42 (d , J = 7.9 Hz, 1H), 7.07 (d, J = 5.8 Hz, 1H), 2.93 (q, J = 7.4 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H), 283 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.82 (d, J = 6.6 Hz, 1H), 8.29 (d, J = 6.2 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.43-7.24 (m, 6H), 7.02 (m, 2H), 6.87-6.81 (dd, 2H), 3.76 (s , 3H), 287 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 13.28 (d, J = 6.6 Hz, 1H), 11.72 (d, J = 2.2 Hz , 1H), 9.42 (s, 1H), 8.87 (d, J = 6.9 Hz, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.67 (t , J = 8.2 Hz, 1H), 7.17 (dd, J = 8.3, 0.8 Hz, 1H), 7.01 (d, J = 13.7 Hz, 1H), 6.81 (dd, J = 8.1, 0.8 Hz, 1H), 2.10 (m, 2H), 1.63-1.34 (m, 8H), 1.26 (s, 3H) 288 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.16 (s, 1H), 12.85 (s, 1H), 8.98 (s, 1H), 8.43 (dd, J = 8, 1, 1.1 Hz, 1H), 8.34 (dd, J = 10.3, 3.1 Hz, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.86 ( d, J = 7.7 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.03 (dd, J = 10.7, 3.2 Hz, 1H), 4, 06 (s, 3H), 1.42 (s, 9H) 295 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.98 (m, 4H), 3.15 (m, 4H), 7.04 (m, 2H), 7.17 (d, J = 7, 8 Hz, 1H), 7.52 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.81 (m, 1H), 8.19 (dd, J = 7, 9, 1.4 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.88 (d, J = 6.7 Hz, 1H), 12.19 (s, 1H) 12.87 (s, 1H)

299 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.93-12.88 (m, 1H), 12.18 (s, 1H), 8.83 (d, J = 6.8 Hz, 1H) , 8.38-8.31 (m, 1H), 7.85-7.67 (m, 2H), 7.57-7.51 (m, 1H), 6.94 (s, 1H), 6 81-6.74 (m, 2H), 3.19-3.16 (m, 2H), 2.68-2.61 (m, 2H), 1.80-1.79 (m, 2H) 300 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.23 (d, J = 6.6 Hz, 1H), 12.59 (s, 1H), 8.87 (d, J = 6.8 Hz , 1H), 8.33 (d, J = 7.7 Hz, 1H), 7.86-7.79 (m, 3H), 7.58-7.42 (m, 3H), 3.38 ( m, 2H), 1.88 (m, 2H), 1.30 (s, 6H) 303 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (d, J = 6.5 Hz, 1H), 12.47 (s, 0.4H), 12.43 (s, 0.6H ), 8.87 (dd, J = 6.7, 2.3 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 8.2 Hz , 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.62-7.52 (m, 3H), 7.17 (d, J = 8.3 Hz, 1H), 4 66 (s, 0.8H), 4.60 (s, 1.2H), 3.66 (t, J = 5.9 Hz, 2H), 2.83 (t, J = 5.8 Hz, 1.2H), 2.72 (t, J = 5.9 Hz, 0.8H), 2.09 (m, 3H) 304 ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 8.07 (m, 1H), 7.72 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.45-7.31 (m, 3H), 7.15-6.95 (m, 5H) 4.17 (d, J = 6.0 Hz, 2H), 4.02 (q, J = 6.9 Hz, 2H), 1.40 (s, 9H), 1.09 (t, J = 6.9 Hz, 3H), 307 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.81 (d, J = 6.6 Hz, 1H), 8.30 (d, J = 6.2 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.44-7.26 (m, 9H), 6.79 (d, J = 7.5 Hz, 1H) 318 ¹ H-NMR (Acetone-d ₆ , 300 MHz) δ 8.92 (broad s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.05 (broad s, 1H ), 7.94 (br s, 1H), 7.78 (br s, 2H), 7.52 (m, 1H), 7.36 (br s, 1H), 3.97 (t, J = 7.2 Hz, 2H), 3.66 (t, J = 8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36-1.31 (m, 4H) 320 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 12.44 (s, 1H), 10.86 (s, 1H), 8.90 (s, 1H), 8 35 (dd, J = 8.2, 1.0 Hz, 1H), 8.12 (t, J = 0.8 Hz, 1H), 7.84-7.75 (m, 2H), 7, 56-7.52 (m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 6.99 (dd, J = 8.4, 1.9 Hz, 1H), 6.08 -6.07 (m, 1H), 1.35 (s, 9H) 321 H-NMR (400 MHz, DMSO-d ₆ ) δ 2.93 (m, 4H), 3.72 (m, 4H), 7.10 (m, 2H), 7.27 (d, J = 7, 8 Hz, 1H), 7.51 (m, 6H), 7.74 (d, J = 8.2 Hz, 1H), 7.81 (m, 1H), 8.40 (d, J = 8, 1 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.88 (d, J = 6.7 Hz, 1H), 12.69 (s, 1H), 12.86 (s, 1H) 323 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (br s, 1H), 12.44 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.02 (t, J = 6.3 Hz, 1H), 3.50 (s, 3H), 3.17 (d, J = 6.2 Hz, 2H), 1.23 (s, 6H)

334 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (br s, 1H), 12.46 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.89 (s, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.44 (m, 1H), 7.37 (d, J = 8.6 Hz, 1H), 3.85 (m, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.18-3.14 (m, 2H), 2.23 (s, 3H), 1.93 (t, J = 5 , 7 Hz, 2H), 1.79 (m, 2H), 1.53 (m, 2H), 1.43 (s, 9H) 337 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H), 9.35 (s, 1H), 8.22 (dd, J = 8.1, 1.1 Hz, 1H) 8.08 (s, 1H), 7.74-7.70 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.44-7.40 (m, 1H ), 7.23 (s, 1H), 3.31 (s, 3H), 1.37 (s, 9H), 1.36 (s, 9H) 351 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 12.34 (s, 1H), 10.96 (s, 1H), 8.91 (s, 1H), 8.48 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.84-7.76 (m, 2H), 7.53 (t, J = 7.4 Hz , 1H), 7.39 (s, 1H), 7.26 (t, J = 2.6 Hz, 1H), 6.34 (s, 1H), 2.89-2.84 (m, 2H) 1.29 (t, J = 7.4 Hz, 3H) 353 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.90 (s, 1H), 9.30 (s, 1H), 8.88 (s, 1H), 8.34 (dd, J = 8 , 2, 1.1 Hz, 1H), 7.84-7.71 (m, 3H), 7.55-7.50 (m, 1H), 7.28-7.26 (m, 1H), 7.20-7.17 (m, 1H), 1.47 (s, 9H), 1.38 (s, 9H) 356 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.89 (s, 1H), 8.59 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.42 (d , J = 8.5 Hz, 1H), 7.17 (d, J = 6.0 Hz, 1H), 3.09 (s, 3H, NMe), 2.91 (t, J = 7.4 Hz , 2H), 1.76 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H) 357 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (d, J = 6.6 Hz, 1H), 12.45 (s, 1H), 10.73 (d, J = 1.9 Hz , 1H), 8.89 (d, J = 6.7 Hz, 1H), 8.35 (dd, J = 8.1, 1.3 Hz, 1H), 8.13 (d, J = 1, 6 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.57-7.51 (m, 2H) , 7.06-7.02 (m, 2H), 3.12 (septet, J = 6.6 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H) 363 ¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.86 (d, J = 6.6 Hz, 1H), 8.24 (d, J = 6.2 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.43-7.16 (m, 5H), 7.02-6.92 (m, 2H), 6.83 (d, J = 7.9 Hz, 2H ), 3.87 (s, 3H) 368 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (d, J = 6.6 Hz, 1H), 12.36 (s, 1H), 8.86 (d, J = 6.7 Hz, 1H), 8.33 (dd, J = 8.1, 1.0 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7 , 8 Hz, 1H), 7.62 (s, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.25 (dd, J = 8.7, 2.2 Hz, 1H ), 7.01 (d, J = 8.8 Hz, 1H), 3.98 (t, J = 6.5 Hz, 2H), 1.78 (sextet, J = 6.9 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H) 375 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (d, J = 6.2 Hz, 1H), 12.35 (s, 1H), 8.86 (d, J = 6.7 Hz , 1H), 8.33 (d, J = 6.9 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H ), 7.54 (t, J = 8.1 Hz, 1H), 7.47-7.43 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 2.71 (m, 4H), 1.75 (m, 4H)

378 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.98 (d, J = 6.6 Hz, 1H), 12.39 (s, 1H), 8.86 (d, J = 6.7 Hz , 1H), 8.33 (dd, J = 8.1, 1.2 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.77 (d, J = 7, 7 Hz, 1H), 7.69 (s, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.8, 2.4 Hz, 1H) 7.06 (d, J = 8.8 Hz, 1H); 3.85 (s, 3H) 379 ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 12.79 (s, 1H), 10.30 (s, 1H), 8.85 (s, 1H), 8.32 (d, J = 7 8 Hz, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 6 , 9 Hz, 1H), 7.73 (s, 1H), 7.53 (t, J = 6.9 Hz, 1H), 2.09 (s, 3H) 381 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.78 (br s, 1H), 11.82 (s, 1H), 10.86 (s, 1H), 8.83 (s, 1H) 8.28 (dd, J = 8.1, 1.0 Hz, 1H), 7.75 (t, J = 8.3 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.49-7.43 (m, 3H), 7.23 (m, 1H), 6.32 (m, 1H), 1.39 (s, 9H) 382 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.83 (s, 1H), 8.40 (d, J = 7.4 Hz, 1H), 7.81-7.25 (m, 2H) 7.65 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.2, 1H), 7.24 (d, J = 8.3, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.17 (s, 3H), 1.60 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H), 383 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.27 (t, J = 7.5 Hz, 3H), 2.70 (q, J = 7.7 Hz, 2H), 7.05 (m , 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H ), 7.83 (t, J = 8.3 Hz, 1H), 8.13 (s, 1H), 8.35 (d, J = 6.9 Hz, 1H), 8.89 (d, J = 6.7 Hz, 1H), 10.73 (s, 1H), 12.46 (s, 1H), 12.91 (s, 1H) 386 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.18 (d, J = 6.8 Hz, 1H), 12.72 (s, 1H), 8.88 (d, J = 6.8 Hz , 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 7.86-7.79 (m, 2H), 7.58-7.50 ( m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 3.51 (s, 2H), 1.36 (s, 6H) 393 ¹ H-NMR (300 MHz, MeOH) δ 8.78 (s, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H ), 7.71 (t, J = 6.9, Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.39 (m, 3H), 7.18 (m, 2H), 7.06 (m, 2H), 4.02 (m, 2H), 1.13 (t, J = 6.9, Hz, 3H) 399 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.91 (s, 1H), 8.51 (s, 1H), 8.42 (d, J = 8.3 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.46 (d , J = 8.5 Hz, 1H), 7.24 (d, J = 6.0 Hz, 1H), 3.48 (m, 1H), 3.09 (s, 3H, NMe), 1.39 (d, J = 6.8 Hz, 6H) 412 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.81-12.79 (m, 2H), 10.96 (s, 1H), 8.87 (d, J = 6.7 Hz, 1H) , 8.35 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.83-7.73 (m, 3H), 7.53 ( t, J = 8.1 Hz, 1H), 7.36 (m, 1H), 6.52 (m, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.37 ( t, J = 7.1 Hz, 3H)

415 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 9.46 (s, 1H), 8.99 (s, 1H), 8.43-8.41 (m, 1H), 7.94-7.88 (m, 2H), 7.65-7.61 (m, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.10 (d , J = 8.4 Hz, 1H), 6.96 (dd, 1H), 4.08 (s, 3H), 1.35 (s, 9H) 420 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (br s, 1H), 12.51 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8, 1 Hz, 2H), 7.82 (ddd, J = 8, 8, 1 Hz, 1H), 7.75 (dd, J = 8, 1 Hz, 1H), 7.70 (d, J = 9 Hz, 2H), 7.54 (ddd, J = 8, 8, 1 Hz, 1H), 4.09 (q, J = 7 Hz, 2H), 1.51 (s, 6H), 1.13 (t, J = 7 Hz, 3H) 423 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (br s, 1H), 12.48 (s, 1H), 10.81 (d, J = 1.8 Hz, 1H), 8 89 (s, 1H), 8.35 (dd, J = 8.2, 1.1 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.56-7.48 (m, 2H), 7.11 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.5, 1.8 Hz, 1H), 3.62 (t, J = 7.3 Hz, 2H), 3.48 (q, J = 7 , 0 Hz, 2H), 2.91 (t, J = 7.3 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H) 425 ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 8.84 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.78-7.70 (m, 2H ), 7.61 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 2.85 (hex., J = 6.9 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H), 427 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.45 (s, 9H), 2.84 (t, J = 5.9 Hz, 2H), 3.69 (m, 2H), 4.54 (s, 1H), 6.94 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.55 (m, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.83 (m, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 9.2 Hz , 1H), 8.91 (s, 1H), 12.36 (s, 1H), 12.99 (s, 1H) 428 ¹ H-NMR (300 MHz, CD ₃ OD) δ 12.30 (s, 1H), 8.83 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 7.78 (see dt, J = 1.1, 7.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.53 (see t, J = 7.5 Hz, 1H), 7.21 (broad d, J = 0.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 2.1, 8 , 4 Hz, 1H), 1.38 (s, 9H) 429 H-NMR (400 MHz, DMSO-d ₆ ) δ 13.13 (d, J = 6.8 Hz, 1H), 12.63 (s, 1H), 8.86 (d, J = 6.8 Hz , 1H), 8.33 (d, J = 7.0 Hz, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H ), 7.56 (t, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.30 (s, 1H), 6.77 (s, 1H) 433 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.87 (br s, 1H), 11.82 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H) , 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.36 ( s, 9H) 438 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (d, J = 6.6 Hz, 1H), 12.08 (s, 1H), 8.90 (d, J = 6.8 Hz , 1H), 8.35-8.34 (m, 1H), 8.03 (s, 1H), 7.85-7.81 (m, 1H), 7.77-7.71 (m, 1H ), 7.58-7.44 (m, 2H), 1.46 (s, 9H), 1.42 (s, 9H)

441 ¹ H-NMR (Acetone-d ₆ , 300 MHz) δ 11.90 (br.s, 1H), 8.93 (br.s, 1H), 8.42 (d, J = 8.1 Hz, 1H ), 8.08 (s, 1H), 7.92 (s, 1H), 7.79 (m, 2H), 7.57 (m, 1H), 7.36 (s, 1H), 3.13 (s, 3H) 444 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.56 (s, 1H), 12.17 (broad d, J = 6 Hz, 1H), 8.89 (d, J = 6 Hz, 1H ), 8.42 (dd, J = 9, 2 Hz, 1H), 7.77 (d, J = 2 Hz, 1H), 7.68 (dd, J = 9, 2 Hz, 1H), 7, 60 (ddd, J = 9, 9, 2 Hz, 1H), 7.46-7.40 (m, 3H), 3.47 (s, 3H), 1.35 (s, 9H) 448 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (br s, 1H), 12.42 (s, 1H), 8.88 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 1.29 (s, 9H) 453 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (d, J = 6.5 Hz, 1H), 12.38 (s, 1H), 8.86 (d, J = 6.8 Hz , 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H ), 7.54 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.94 (dd, J = 8.6, 2.4 Hz, 1H) 458 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (d, J = 7.1 Hz, 1H), 12.39 (s, 1H), 8.88 (d, J = 6.8 Hz , 1H), 8.33 (d, J = 7.9 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H ), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.17 (s, 2H), 4.04 (t, J = 5.0 Hz, 2H ), 3.82 (t, J = 5.0 Hz, 2H), 1.36 (s, 9H) 461 ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 11.97 (s, 1H), 8.7 (s, 1H), 8.30 (d, J = 7.7 Hz, 1H), 8, 07 (d, J = 7.7 Hz, 1H), 7.726-7.699 (m, 2H), 7.446-7.357 (m, 6H), 7.236-7.178 (m, 2H); ¹³ C-NMR (DMSO-d ₆ , 75 MHz) δ 176.3, 163.7, 144.6, 139.6, 138.9, 136.3, 134.0, 133.4, 131.0, 129.8, 129.2, 128.4, 128.1, 126.4, 126.0, 125.6, 124.7, 123.6, 119.6, 111.2 463 ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 8.83 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.78-7.70 (m, 2H ), 7.61 (d, J = 7.8 Hz, 2H), 7.51 (t, 1H), 7.17 (d, J = 8.1 Hz, 2H), 2.57 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 1H), 0.92 (t, J = 7.8 Hz, 3H), 464 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.37 (s, 9H), 1.38 (s, 9H), 6.80 (dd, J = 8.1, 0.9 Hz, 1H ), 7.15 (m, 3H), 7.66 (t, J = 8.2 Hz, 1H), 8.87 (d, J = 6.9 Hz, 1H), 9.24 (s, 1H ), 11.07 (s, 1H), 13.23 (d, J = 6.5 Hz, 1H), 13.65 (s, 1H) 465 H-NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (d, J = 6.0 Hz, 1H), 12.40 (s, 1H), 8.87 (d, J = 6.8 Hz , 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.84-7.75 (m, 3H), 7.57-7.43 (m, 2H), 7.31 ( d, J = 8.6 Hz, 1H), 4.40 (d, J = 5.8 Hz, 2H), 1.44 (s, 9H), 1.38 (s, 9H)

471 ¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.87 (s, 1H), 8.44 (d, J = 8.25, 1H), 8.18 (m, 1H), 7.79 ( t, J = 6.88, 1H), 7.67 (d, J = 8.25, 1H), 7.54 (t, J = 7.15, 1H), 7.23 (d, J = 6 05, 1H), 7.16 (d, J = 8.5, 1H), 3.73 (s, 3H), 2.75 (t, J = 6.87, 2H), 1.7 (q , 2H), 1.03 (t, J = 7.42, 3H) 476 ¹ H-NMR (400 MHz, DMSO-d ₆ ) 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), 8.34 (d, J = 8.2 Hz, 1H), 8.16 (s, 1H), 7.85-7.75 (m, 2H ), 7.56-7.54 (m, 1H), 7.44 (s, 1H), 1.35 (s, 9H) 478 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.40 (s, 9H), 6.98 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.6 , 1.9 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 7 , 7 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 8.13 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 6.7 Hz, 1H), 10.74 (s, 1H), 12.44 (s, 1H), 12.91 (s, 1H) 484 ^oneH-NMR (300 MHz, DMSO-d₆) δ 12.90 (d, J = 6.3 Hz, 1H), 12.21 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.79 (visible. dt, J = 12, 8.0 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 6.9, 8.1 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.94 (s explicit direct doublet, 1H), 1H), 6.90 (d explicit direct doublet, J = 8.4 Hz, 1H), 2.81 (s, 3H); 1.34 (s, 9H) 485 ¹ H-NMR (300 MHz, CDCl ₃ ) δ 13.13 (br s, 1H), 12.78 (s, 1H), 8.91 (br s, 1H), 8.42 (br 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)

C) Tests for the detection and determination of ΔF508-CFTR corrective properties of compounds

I) Optical methods for determining the transmembrane potential for testing ΔF508-CFTR modulating properties of compounds

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

These voltage-sensitive tests are based on changing the resonant with fluorescence energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC ₂ (3) and the fluorescent phospholipid, CC2-DMPE, which is associated with the outer “leaf” of the cytoplasmic membrane and acts as a FRET donor. Changes in the transmembrane potential (V _m ) cause the redistribution of the negatively charged DiSBAC ₂ (3) in the cytoplasmic membrane and, accordingly, the amount of energy transferred from CC2-DMPE changes. Fluorescence emission changes are monitored using a VIPR ^™ II device, which is an integrated fluid manipulator and fluorescence detector designed for cell-based screening using 96- or 384-well microtiter plates.

Correction Connection Identification

To identify small molecules that correct the transport defect associated with ΔF508-CFTR, a test form with the only addition of a homozygous typing cell (HTS) was developed. Cells were incubated in serum-free medium for 16 hours at 37 ° C in the presence or absence (negative control) of the test compound. As a positive control, cells seeded in 384-well plates were incubated for 16 hours at 27 ° C. for “temperature correction” ΔF508-CFTR. Cells were then washed 3 times with Ringer-Krebs solution and loaded with voltage-sensitive dyes. To activate ΔF508-CFTR, 10 μM forskolin and a CFTR enhancer, genistein (20 μM) were added to each well together with a Cl ^- free medium. The outflow of Cl ^- , promoted by the addition of a Cl ^- free medium, in response to activation of ΔF508-CFTR and the achieved transmembrane depolarization was optionally controlled using FRET based voltage-sensitive dyes.

Identification of amplifier connections

To identify the ΔF508-CFTR amplifiers, a test type with the double addition of homozygous typing cells was developed. During the first addition, Cl ^- free medium with or without test compound was added to each well. After 22 seconds, to activate ΔF508-CFTR, a second supplement was added that did not contain Cl ^- medium, including 2-10 μM forskolin. The extracellular concentration of Cl ^- after both additions was 28 mM, which promoted the outflow of Cl ^- in response to activation of ΔF508-CFTR, and the achieved transmembrane depolarization was determined optically using FRET-based voltage-sensitive dyes.

Solutions

Solution for washing No. 1 (in mm): NaCl 160, KCl 4,5, CaCl ₂ 2, MgCl ₂ 1, HEPES 10, pH = 7.4, established using NaOH; Chloride-free flushing solution:

chloride salts in washing solution No. 1 are replaced by gluconate salts; CC2-DMPE: We prepared as a 10 mM stock solution in dimethylsulfoxide (DMSO) and stored at -20 ^{° C;} DiSBAC ₂ (3): prepared in the form of 10 mm stock solution and stored at a temperature of -20 ° C.

Cell culture

For optical measurements of the transmembrane potential, NIH3T3 murine fibroblasts stably expressing ΔF508-CFTR were used. Cells were kept at a temperature of 37 ° C in an atmosphere with 5% CO ₂ and humidity 90% in a Dulbecco-modified Eagle medium supplemented with 2 mM glutamine, 10% fetal calf serum, 1 X NEAA, β-ME, 1 X pen / strep and 25 mM HEPES, in cell culture flasks 175 cm ^{2 in area} . For all optical tests, cells were seeded at 30,000 per well in Matrigel-coated 384-well plates and cultured for 2 hours at 37 ° C before culturing at 27 ° C for 24 hours for amplification test. For corrective tests, cells were cultured at 27 ° C or 37 ° C with or without compounds for 16-24 hours.

C) Electrophysiological tests to determine the modulating ΔF508-CFTR properties of the compounds

1. Test in the Ussing camera

Ussing chamber experiments were performed using polarized epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators identified in optical tests. FRT ^ΔF508-CFTR- Epithelial cells cultured on Costar Snapweil cell culture inserts were placed in an Ussing chamber (Physiologic Instruments, Inc., San Diego, Canada) and the monolayers were continuously shorted using a potential clamp system (Voltage-clamp System; Departmen of Bioengineering, University of Iowa, IA, and Physiologic Instruments, Inc., San Diego, Canada). Transepithelial resistance was determined by applying a pulse of 2 mV. Under these conditions, the FRT-epithelium showed resistance of 4 KOhm / cm ² or more. The solutions were kept at a temperature of 27 ° C and air was bubbled through them. The electrode bias potential and fluid resistance were corrected using insert without cells. Under these conditions, the current reflects the flux of Cl ^- due to ΔF508-CFTR expressed in the apical membrane. I _SC in numerical value was achieved using the MP100A-CE interface and AcqKnowledge software (ν3.2.6; BIOPAC Systems, Santa Barbara, Canada).

Correction Connection Identification

According to a specific protocol, a Cl concentration gradient was used ^, from the basolateral to the apical membrane. To achieve this gradient, normal Ringer solution was used in the case of the basolateral membrane, whereas apical NaCl was replaced with equimolar amount of sodium gluconate (setting pH = 7.4 with NaOH), yielding a large concentration gradient of Cl ^- through the epithelium. All experiments were carried out using intact monolayers. To fully activate ΔF508-CFTR, forskolin (10 μM) and PDE inhibitor, IBMX (100 μM) were used, followed by the addition of a CFTR enhancer, genistein (50 μM).

As was found in the case of other cell types, incubation at low temperatures of FRT cells stably expressing ΔF508-CFTR increases the functional density of CFTR in the cytoplasmic membrane. To determine the activity of corrective compounds, cells were incubated with 10 μM test compound for 24 hours at 37 ° C and then washed 3 times before registration. The cAMP and genistein I _SC mediated in the compound treated cells were normalized to the controls obtained at 27 ° C and 37 ° C and expressed as percent activity. Pre-incubation of the cells with the corrective compound significantly increased the mediated cAMP and genistein I _SC compared to the controls obtained at 37 ° C.

Identification of amplifier connections

According to a specific protocol, a Cl concentration gradient was used ^, from the basolateral to the apical membrane. To ensure this gradient, we used the usual Ringer's solution in the case of the basolateral membrane and nystatin (360 μg / ml) was added, while apical NaCl was replaced with an equimolar amount of sodium gluconate (setting pH = 7.4 using NaOH), obtaining a large concentration gradient Cl ^- through the epithelium. All experiments were carried out 30 minutes after the administration of nystatin. Forskalin (10 μM) and all test compounds were added on both sides of the cell culture insert. The efficacy of the proposed ΔF508-CFTR enhancers was compared with the efficacy of the known enhancer, genestein.

Solutions

Basolateral solution (in mm): NaCl (135), CaCl ₂ (1,2), MgCl ₂ (1,2), K ₂ HPO ₄ (2,4), KH ₂ PO ₄ (0,6), N-hydroxyethylpiperazine-N'-2- ethanesulfonic acid (HEPES) (10) and dextrose (10). The pH of the solution is 7.4, set using NaOH. Apical solution (in mm): the same as the basolateral solution, with the replacement of NaCl with sodium gluconate (135).

Cell culture

For experiments in the Ussing chamber regarding the putative ΔF508-CFTR modulators identified according to the authors optical tests, Fisher rat epithelial cells (FRT cells) expressing ΔF508-CFTR (FRT ^ΔF508-CFTR ) were used. Cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 ° C and in the presence of 5% CO ₂ in a Kuhn modified Gam medium supplemented with 5% fetal calf serum, 100 U / ml penicillin and 100 μm / ml streptomycin. Prior to use to characterize the enhancing activity of the compounds, cells were incubated at a temperature of 27 ° C for 16-48 hours before correction for ΔF508-CFTR. To determine the activity of corrective compounds, cells were incubated at a temperature of 27 ° C or 37 ° C with or without a compound for 24 hours.

2. Registration of the whole cell

The macroscopic current ΔF508-CFTR (I _ΔF508 ) in temperature-corrected and test compound NIH3T3 cells stably expressing ΔF508-CFTR was monitored using a perforated patch to record the whole cell. Briefly, patch clamp I _{ΔF508 was} performed at room temperature using an Axopatch 200D patch clamp amplifier (Axon Instruments Inc., Foster City, Canada). All recordings were carried out at a selected frequency of 10 kHz and using a low-pass filter at 1 kHz. The pipettes had a resistance of 5-6 MΩ when filled with an intracellular solution. Under these recording conditions, the calculated reversal potential for Cl ^- (E _Cl ) at room temperature was -28 mV. All registrations had a cutoff resistance> 20 GΩ and a serial resistance <15 MΩ. Pulse generation, data acquisition and analysis were performed using a personal computer equipped with a Digidata 1320 A / D interface together with Clampex 8 (Axon Instruments Inc.). The solution contained <250 μl of salt and was continuously perfused at a rate of 2 ml / min using a perfusion system in gravitational mode.

Correction Connection Identification

To determine the activity of correction compounds with respect to increasing the density of functional ΔF508-CFTR in the cytoplasmic membrane, the authors used the above methods of perforated “patch” registration to measure the current density after treatment with correction compounds for 24 hours. To fully activate ΔF508-CFTR, 10 μM forskolin and 20 μM genistein were added to the cells. Under the registration conditions according to the invention, the current density after incubation for 24 hours at 27 ° C was higher than the density observed after incubation for 24 hours at 37 ° C. These results are consistent with the known effects of low temperature incubation on the density ΔF508-CFTR in the cytoplasmic membrane. To determine the effects of correction compounds on CFTR current density, cells were incubated with 10 μM of the test compound for 24 hours at 37 ° C and the current density was compared with the controls obtained at 27 ° C and 37 ° C (% activity). Prior to registration, cells were washed 3 times with extracellular registration medium to remove any remaining test compound. Preincubation with 10 mM correction compounds significantly increases cAMP and genistein-dependent current compared to controls obtained at 37 ° C.

Identification of amplifier connections

The ability of ΔF508-CFTR amplifiers to increase the macroscopic ΔF508-CFTR Cl ^- current (I _ΔF508 ) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using perforated patch registration methods. The amplifiers identified in the optical tests caused a dose-dependent increase in I _ΔF508 with similar efficacy and efficacy observed in the case of optical tests. In all studied cells, the reversal potential before and during the application of the amplifier was about -30 mV, which is the calculated E _Cl (-28 mV).

Solutions

Intracellular solution (in mm): cesium aspartate (90), CsCl (50), MgCl ₂ (1), HEPES (10) and 240 μg / ml amphotericin-B (pH adjusted to 7.35 with CsOH). Extracellular solution (in mm): N-methyl-D-glucamine (NMDG) -Cl (150), MgCl ₂ (2), CaCl ₂ (2), HEPES (10) (pH adjusted to 7.35 with HCl).

Cell culture

NIH3T3 murine fibroblasts stably expressing ΔF508-CFTR were used for whole cell registrations. Cells were kept at a temperature of 37 ° C in an atmosphere with 5% CO ₂ and humidity 90% in a Dulbecco-modified Eagle medium supplemented with 2 mM glutamine, 10% fetal calf serum, 1 X NEAA, β-ME, 1 X pen / strep and 25 mM HEPES, in cell culture flasks 175 cm ^{2 in area} . To register whole cells, 2500-5000 cells were plated on poly-L-lysine-coated coverslips and cultured for 24-48 hours at 27 ° C before use to test the activity of amplifiers; and incubated with or without correction compound at a temperature of 37 ° C to determine the activity of the correctors.

3. Registration of one channel

The activity of one channel, temperature-corrected ΔF508-CFTR, stably expressed in NIH3T3 cells, and the activity of enhancer compounds were determined using a patch excised from the wrong side of the membrane. Briefly, the recording of the fixation of the activity potential of one channel was carried out at room temperature using an Axopatch 200B patch clamp amplifier (Axon Instruments Inc.). All recordings were carried out at a selected frequency of 10 kHz and using a low-pass filter at 400 Hz. The “patch” pipettes were made of Corning Kovar Sealing glass No. 7052 (World Precision Instruments, Inc., Sarasota, Finland) and they had a resistance of 5-8 MΩ when filled with an extracellular solution. ΔF508-CFTR was activated after excision by adding 1 mM Mg-ATP and 75 nM cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI). After stabilization of the activity of the patch channel, they were perfused using a gravity-mode microperfusion system. The inflow was placed next to the “patch”, achieving complete replacement of the solution within 1-2 seconds. To maintain ΔF508-CFTR activity during rapid perfusion, a nonspecific phosphatase inhibitor F ^- (10 mM NaF) was added to the washing solution. Under these recording conditions, channel activity was kept constant throughout the duration of the “patch” registration (up to 60 minutes). The currents caused by the movement of a positive charge from the intracellular solution to the extracellular solution (the movement of anions in the opposite direction) turned out to be positive currents. The pipette potential (V _p ) was maintained at 80 mV.

Channel activity was analyzed based on membrane “patches” containing ≤2 active channels. The maximum number of simultaneous openings determined the number of active channels during the experiment. To determine the amplitude of the current of one channel, the data recorded after 120 seconds of ΔF508-CFTR activity were filtered “autonomously” at 100 Hz and then used to plot the amplitude histograms for all points that were aligned by multi-Gaussian functions using the Bio-Patch Analysis software ( Bio-Logic Comp. France). The total microscopic current and the opening probability (P _o ) were determined after 120 seconds of channel activity. P _{o was} determined using the Bio-Patch software, or from the ratio P _o = I / i (N), where I = weak current, i = current amplitude of one channel and N = number of active channels in the patch.

Solutions

Extracellular solution (in mm): NMDG (150), aspartic acid (150), CaCl ₂ (5), MgCl ₂ (2) and HEPES (10) (pH adjusted to 7.35 using a TRIS base). Intracellular solution (in mm): NMDG-Cl (150), MgCl ₂ (2), EGTA (5), TES (10) and TRIS base (14) (pH adjusted to 7.35 with HCl).

Cell culture

For NIH3T3 murine fibroblasts excised from the membrane of patch clamp recordings. Cells were kept at a temperature of 37 ° C in an atmosphere with 5% CO ₂ and humidity 90% in a Dulbecco-modified Eagle medium supplemented with 2 mM glutamine, 10% fetal calf serum, 1 X NEAA, β-ME, 1 X pen / strep and 25 mM HEPES, in cell culture flasks 175 cm ^{2 in area} . To register one channel, 2500-5000 cells were plated on poly-L-lysine-coated coverslips and cultured for 24-48 hours at 27 ° C before use.

The compounds of the invention are useful as modulators of transporters of an ATP binding cassette. Table 3 below shows the EC50 and the relative effectiveness of some of the embodiments of table 1.

The following table presents the following values:

EC50: “+++” means <10 μM; “++” means from 10 μM to 25 μM; “+” Means from 25 μM to 60 μM.

% Efficiency: “+” means <25%; “++” means from 25% to 100%; “+++” means> 100%.

Table 3 Connection No. EC50 (μM) % Activity Connection No. EC50 (μM) % Activity Connection No. EC50 (μM) % Activity one +++ ++ 17 +++ ++ 34 +++ ++ 2 +++ ++ eighteen +++ ++ 35 +++ ++ 3 +++ ++ 19 ++ + 36 +++ ++ four +++ ++ twenty +++ ++ 37 +++ ++ 5 ++ ++ 21 + + 38 +++ ++ 6 +++ +++ 22 ++ ++ 39 ++ ++ 7 + + 23 +++ ++ 40 + + 8 +++ ++ 24 + + 41 +++ ++ 9 + + 25 ++ ++ 42 +++ ++ 10 +++ ++ 26 +++ ++ 43 +++ ++ eleven +++ ++ 28 ++ ++ 44 ++ ++ 12 +++ ++ 29th ++ ++ 46 ++ ++ 13 +++ ++ thirty +++ ++ 47 +++ ++ fourteen +++ ++ 31 +++ ++ 48 +++ ++

fifteen ++ ++ 32 +++ ++ 49 +++ ++ 16 +++ ++ 33 +++ ++ fifty +++ ++ 51 +++ ++ 95 ++ ++ 140 +++ ++ 52 +++ ++ 96 +++ ++ 141 ++ ++ 53 + + 97 +++ ++ 142 +++ ++ 54 + + 98 +++ ++ 143 +++ ++ 55 + + 99 +++ ++ 144 +++ ++ 56 +++ ++ one hundred + + 145 +++ ++ 57 ++ +++ 101 ++ 146 + + 58 +++ ++ 102 ++ ++ 147 +++ ++ 59 +++ +++ 103 +++ +++ 148 +++ ++ 60 +++ ++ 104 +++ ++ 149 ++ ++ 61 +++ ++ 105 ++ ++ 150 +++ ++ 62 +++ ++ 106 + + 151 +++ ++ 63 +++ ++ 107 ++ ++ 152 + + 64 + + 108 +++ ++ 153 +++ ++ 65 +++ ++ 109 ++ ++ 154 + + 66 ++ ++ 110 + + 155 + + 67 +++ ++ 111 +++ ++ 156 +++ ++ 68 +++ ++ 112 +++ ++ 157 +++ ++ 69 +++ ++ 113 +++ ++ 158 +++ ++ 70 ++ ++ 114 +++ ++ 159 ++ ++ 71 +++ ++ 115 +++ ++ 160 +++ ++ 72 +++ ++ 116 +++ ++ 161 +++ ++ 73 + + 117 +++ ++ 162 + + 74 + + 118 +++ ++ 163 ++ ++ 75 + + 119 +++ ++ 164 +++ ++ 76 +++ ++ 120 ++ ++ 165 + + 77 +++ ++ 122 + + 166 +++ ++ 78 + + 123 +++ ++ 167 ++ ++ 79 +++ ++ 124 +++ +++ 168 + + 80 +++ ++ 125 ++ ++ 169 ++ ++ 81 + + 126 +++ ++ 170 + + 82 +++ ++ 127 +++ ++ 171 +++ ++ 83 +++ ++ 128 + + 172 +++ ++ 84 + + 129 ++ ++ 173 + + 85 +++ ++ 130 +++ ++ 174 +++ ++ 86 ++ ++ 131 +++ ++ 175 ++ ++ 87 +++ ++ 132 + + 176 +++ ++ 88 +++ ++ 133 ++ ++ 177 +++ +++ 89 + + 134 +++ ++ 178 +++ ++ 90 +++ ++ 135 +++ +++ 179 + + 91 +++ ++ 136 +++ ++ 180 +++ ++ 92 +++ ++ 137 +++ ++ 181 +++ ++ 93 +++ ++ 138 +++ ++ 182 +++ ++ 94 +++ ++ 139 +++ ++ 183 +++ ++ 184 + + 228 +++ ++ 272 ++ ++ 185 + + 229 +++ ++ 273 +++ +++ 186 +++ ++ 230 ++ ++ 274 +++ ++ 187 +++ ++ 231 +++ ++ 275 ++ ++ 188 +++ ++ 232 ++ ++ 276 ++ ++

189 +++ ++ 233 ++ + 277 +++ +++ 190 +++ ++ 234 +++ ++ 278 +++ ++ 191 + + 235 +++ ++ 279 +++ ++ 192 + + 236 +++ ++ 280 + + 193 ++ ++ 237 +++ ++ 281 +++ ++ 194 + + 238 +++ ++ 282 +++ ++ 195 + + 239 +++ ++ 283 +++ +++ 196 +++ ++ 240 +++ ++ 284 ++ ++ 197 + + 241 ++ ++ 285 +++ ++ 198 +++ ++ 242 +++ ++ 286 +++ +++ 199 +++ ++ 243 ++ ++ 287 +++ ++ 200 ++ ++ 244 +++ ++ 288 +++ ++ 201 ++ + 245 +++ ++ 289 +++ ++ 202 +++ ++ 246 +++ ++ 290 +++ ++ 203 +++ ++ 247 +++ ++ 291 +++ ++ 204 +++ ++ 248 ++ ++ 292 +++ ++ 205 +++ ++ 249 ++ ++ 293 ++ +++ 206 +++ ++ 250 + + 294 ++ ++ 207 +++ ++ 251 +++ ++ 295 +++ ++ 208 +++ ++ 252 ++ ++ 296 ++ ++ 209 ++ ++ 253 +++ ++ 297 +++ ++ 210 ++ ++ 254 +++ ++ 298 +++ ++ 211 +++ ++ 255 +++ ++ 299 +++ ++ 212 + + 256 + + 300 +++ ++ 213 +++ ++ 257 +++ ++ 301 + + 214 ++ ++ 258 +++ ++ 302 ++ ++ 215 +++ ++ 259 +++ ++ 303 ++ ++ 216 + + 260 +++ ++ 304 +++ ++ 217 ++ ++ 261 +++ ++ 305 +++ +++ 218 +++ ++ 262 +++ ++ 306 +++ +++ 219 + + 263 +++ ++ 307 +++ ++ 220 +++ ++ 264 ++ ++ 308 ++ ++ 221 +++ ++ 265 +++ ++ 309 + + 222 ++ ++ 266 +++ ++ 310 +++ ++ 223 +++ ++ 267 +++ ++ 311 +++ ++ 224 +++ ++ 268 ++ ++ 312 +++ ++ 225 +++ ++ 269 +++ ++ 313 +++ ++ 226 +++ ++ 270 +++ ++ 314 +++ ++ 227 + + 271 +++ ++ 315 +++ ++ 316 ++ ++ 361 +++ +++ 405 +++ ++ 317 +++ ++ 362 +++ ++ 406 +++ ++ 318 ++ ++ 363 +++ +++ 407 +++ ++ 319 +++ ++ 364 +++ ++ 408 +++ ++ 320 +++ ++ 365 ++ ++ 409 +++ ++ 321 +++ ++ 366 +++ ++ 410 +++ +++ 322 +++ ++ 367 +++ ++ 411 +++ ++ 323 +++ ++ 368 +++ ++ 412 +++ ++ 324 +++ ++ 369 ++ + 413 +++ ++ 325 +++ ++ 370 +++ ++ 414 + + 326 ++ ++ 371 +++ ++ 415 +++ ++ 327 +++ ++ 372 +++ ++ 416 +++ ++

328 + + 373 +++ ++ 417 +++ ++ 329 ++ ++ 374 + + 418 ++ ++ 330 +++ ++ 375 +++ ++ 419 + + 331 + + 376 + + 420 +++ ++ 332 +++ ++ 377 ++ ++ 421 +++ ++ 333 +++ ++ 378 ++ ++ 423 +++ ++ 334 ++ ++ 379 ++ ++ 424 +++ ++ 335 + + 380 +++ ++ 425 +++ ++ 336 +++ ++ 381 +++ ++ 426 +++ ++ 337 +++ ++ 382 +++ ++ 427 +++ ++ 338 ++ ++ 383 +++ ++ 428 +++ ++ 339 +++ ++ 384 +++ ++ 429 +++ ++ 340 +++ ++ 385 +++ ++ 430 +++ ++ 341 +++ ++ 386 +++ ++ 431 ++ ++ 342 +++ ++ 387 +++ ++ 432 +++ ++ 343 ++ ++ 388 +++ ++ 433 +++ ++ 344 +++ ++ 389 +++ ++ 434 +++ ++ 345 +++ ++ 390 + + 435 +++ ++ 346 +++ ++ 391 +++ ++ 436 +++ ++ 347 ++ ++ 392 + + 437 + + 348 +++ ++ 393 +++ ++ 438 +++ ++ 350 +++ ++ 394 + + 439 +++ ++ 351 +++ ++ 395 +++ ++ 440 +++ ++ 352 +++ ++ 396 ++ ++ 441 +++ ++ 353 +++ ++ 397 +++ ++ 442 + + 354 +++ ++ 398 ++ ++ 443 + + 355 +++ ++ 399 +++ ++ 444 +++ ++ 356 +++ ++ 400 + + 445 +++ +++ 357 +++ ++ 401 +++ ++ 446 + + 358 +++ ++ 402 +++ + 447 ++ ++ 359 ++ ++ 403 +++ ++ 448 +++ ++ 360 +++ ++ 404 +++ ++ 449 +++ ++ 450 ++ ++ 462 +++ ++ 474 + + 451 +++ ++ 463 +++ ++ 476 +++ ++ 452 +++ ++ 464 +++ ++ 477 + + 453 +++ ++ 465 +++ ++ 478 +++ ++ 454 + + 466 +++ ++ 479 +++ ++ 455 +++ ++ 467 + + 480 + + 456 +++ ++ 468 + + 481 +++ ++ 457 + + 469 +++ ++ 482 ++ ++ 458 +++ ++ 470 +++ ++ 483 +++ ++ 459 +++ ++ 471 +++ ++ 484 +++ ++ 460 +++ ++ 472 +++ ++ 485 +++ ++ 461 +++ ++ 473 ++ ++

Claims (16)

1. A method of treating or alleviating the severity of a disease in a patient where the disease is selected from cystic fibrosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), dry eye disease, comprising administering to said patient an effective amount of N- (5-hydroxy-2, 4-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide having the chemical structure:

2. The method according to claim 1, where the disease is cystic fibrosis. 3. The method according to claim 1, where the disease is COPD. 4. The method according to claim 2, where the patient has a class III mutation, a class IV mutation, or a class V mutation of a cystic fibrosis transmembrane conductivity regulator (CFTR). 5. The method according to claim 4, where the patient has a class III mutation of the cystic fibrosis transmembrane conductivity regulator. 6. The method according to claim 4, where the patient has a mutation of the cystic fibrosis transmembrane conductivity regulator, which is a mutation of dysregulation, a mutation of the opening of the membrane channel, a mutation of an altered conductivity or a mutation of reduced synthesis. 7. The method according to claim 6, where the specified mutation is a mutation of the opening of the membrane channel. 8. The method according to claim 2, where the patient has a cystic fibrosis transmembrane conductivity regulator with a G551D mutation. 9. The method of claim 8, wherein the patient is homozygous for the G551D mutation. 10. The method of claim 8, wherein the patient is heterozygous for the G551D mutation. 11. The method according to claim 2, where the patient has a cystic fibrosis transmembrane conductivity regulator with ΔF508 mutation. 12. The method according to claim 11, where the patient is homozygous for the ΔF508 mutation. 13. The method of claim 11, wherein the patient is heterozygous for the ΔF508 mutation. 14. A method of treating or alleviating the severity of cystic fibrosis in a patient who exhibits residual CFTR activity, comprising the step of administering to said patient a pharmaceutical composition comprising N- (5-hydroxy-2,4-di-tert-butylphenyl) -4-oxo-1H -quinoline-3-carboxamide. 15. A method of treating or alleviating the severity of cystic fibrosis in a patient who exhibits residual CFTR activity, wherein said residual CFTR activity is induced or enhanced using a pharmacological method, comprising the step of administering to said patient a pharmaceutical composition containing N- (5-hydroxy-2,4 -di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide. 16. A method for treating or alleviating the severity of cystic fibrosis in a patient who exhibits residual CFTR activity, wherein said residual CFTR activity is increased using a pharmacological method, wherein said pharmacological method has the effect of increasing the amount of CFTR present on a cell surface, comprising the step of administering a pharmaceutical to said patient a composition comprising N- (5-hydroxy-2, 4-di-tert-butylphenyl) -4-oxo-1H-quinoline-3-carboxamide.