New phenylamide or pyridylamide derivatives and using them as gpbar1 agonists

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new phenylamide or pyridylamide derivatives of formula

or their acceptable salts, wherein A1 is CR12 or N; A2 is CR13 or N; R1 and R2 are independently specified in hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup; R12 and R13 are independently specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino group and C1-7-alkylsulphanyl; R3 is specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, cyano group, C3-7-cycloalkyl, five-merous heteroaryl and phenyl; R4 is specified in methyl and ethyl; or R3 and R4 together represent -X-(CR14R15)n- and form a part of the ring, wherein X is specified in -CR16R17-, O, S, C=O; R14 and R15 are independently specified in hydrogen or C1-7-alkyl; R16 and R17 are independently specified in hydrogen, C1-7-alkoxycarbonyl, heterocyclyl substituted by two groups specified in a halogen, or R16 and R17 together with an atom C, which they are attached to, form =CH2 group; or X is specified in a group NR18; R14 and R15 are hydrogen; R18 is specified in hydrogen, C1-7-alkyl, halogen-C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarbonyloxy-C1-7-alkyl, phenyl, wherein phenyl is unsubstituted, phenylcarbonyl, wherein phenyl is substituted by C1-7-alkoxycarbonyl, and phenylsulphonyl, wherein phenyl is substituted by carboxyl-C1-7-alkyl, or R18 and R14 together represent -(CH2)3- and form a part of the ring, or R18 together with R14 and R15 represent -CH=CH-CH= and form a part of the ring; and n has the value of 1, 2 or 3; B1 represents N or CR19 and B2 represents N or CR20, provided no more than one of B1 and B2 represents N; and R19 and R20 are independently specified in a group consisting of hydrogen and halogen-C1-7-alkyl; R5 and R6 are independently specified in a group consisting of hydrogen, halogen and cyano group; and one-three, provided R4 represents methyl or ethyl, two of the residues R7, R8, R9, R10 and R11 are specified in C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxygroup, cyano group, C1-7-alkoxycarbonyl, hydroxy-C3-7-alkynyl, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkynyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl-carbonyl, wherein phenyl is unsubstituted, phenyl-C1-7-alkyl, wherein phenyl is substituted by 1-2 groups specified in a halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-alkynyl, wherein phenyl is substituted by 2 groups specified in halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidine carbonyl-C1-7-alkyl, wherein pyrrolidinyl is substituted by carboxyl, and the other R7, R8, R9, R10 and R11 represent hydrogen; the term 'heteroaryl' means an aromatic 5-merous ring containing one or two atoms specified in nitrogen or oxygen; the term 'heterocyclyl' means a saturated 4-merous ring, which can contain one atom specified in nitrogen or oxygen. Besides, the invention refers to a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new compounds possessing the GPBAR1 agonist activity.

21 cl, 1 tbl, 190 ex

 

The invention relates to new phenylamine or pyridylamine derived from receiving them, containing their pharmaceutical compositions and their use as pharmaceuticals.

In particular, the present invention relates to compounds of the formula:

where

And1represents CR12or N;

And2represents CR13or N;

R1and R2independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography and C1-7-alkoxygroup;

R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography, C1-7-alkoxygroup, amino, and C1-7alkylsulfanyl;

R3selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, ceanography,3-7-cycloalkyl, N-heterocyclyl, five-membered heteroaryl and phenyl;

R4selected from the group consisting of methyl, ethyl, isopropyl, diformate, trifloromethyl, cyclopropyl and oxetanyl; or

R3and R4together are-X-(CR14R15)nand form part of a ring; where

X is selected from the group consisting of CR16R17-, O, S, C=O and NR18;

R14and R15independently from each other is and is selected from hydrogen or C 1-7-alkyl;

R16and R17independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, C1-7-alkoxycarbonyl, unsubstituted heterocyclyl and heterocyclyl substituted by one or two groups selected from C1-7-alkyl or halogen,

or R16and R17together with the C atom to which they are attached, form cyclopropyl or oxetanyl ring, or together form the group =CH2or =CF2;

R18selected from the group consisting of hydrogen, C1-7-alkyl, halogen-(C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heterocyclyl-C1-7-alkyl, heteroaryl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarboxylic-C1-7-alkyl, phenyl, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl, phenylcarbinol, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl, and phenylsulfonyl, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl,

or R18and R14together represent -(CH2)3and form part of the ring, or R18together with PA is th R 14and R15represent-CH=CH-CH= and form part of a ring;

and n is 1, 2 or 3;

B1represents N or CR19and B2represents N or CR20provided that not more than one of B1and B2represents N; and

R19and R20independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup and cyanopropyl;

R5and R6independently from each other selected from the group consisting of hydrogen, halogen, C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkyl, halogen-(C1-7-alkoxygroup and cyanopropyl;

and at least one, or when R4represents methyl or ethyl, at least two of R7, R8, R9, R10and R11selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup, ceanography, carboxyl, C1-7-alkoxycarbonyl, hydroxy-C1-7-alkyl, hydroxy-C3-7-alkenyl, hydroxy-C3-7-quinil, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, carboxyl-C2-7-quinil, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C2-7alkenyl is, C1-7-alkoxycarbonyl-C2-7-quinil, carboxyl-C1-7-alkylaminocarbonyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenylcarbinol, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenyl-C1-7-alkyl, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenyl-C2-7-quinil, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidinyl-carbonyl-C1-7-alkyl, where pyrrolidinyl replaced by carboxyla,

and other R7, R8, R9, R10and R11represent hydrogen;

or its formats whitesky acceptable salts.

The compounds of formula I possess pharmaceutical activity, in particular they are modulators or ligands receptor GPBAR1. More specifically, the compounds are powerful GPBAR1 agonists.

Diabetes is a growing threat to human health. For example, in the United States at the present time, presumably 16 million people suffer from diabetes. Type II diabetes, also known as non-insulin-dependent diabetes, accounts for about 90-95% of cases of diabetes, leading to the destruction of 193,000 people in the U.S. each year. Type II diabetes is the seventh cause of death. In Western countries, type II diabetes currently affects 6% of the adult population, and the global incidence of the disease is assumed to grow at 6% per year. Although there are some inherited traits that can determine the predisposition of specific patients to the development of type II diabetes, the driving force behind the increase in the present cases is increasing sedentary lifestyle, diet and obesity, prevailing at present in developed countries. About 80% of patients with type II diabetes have significant excess weight. There is an increasing number of young people who develop the disease. The type II diabetes is now recognized around the world as one of the main health hazards h the rights in the XXI century.

Type II diabetes is manifested as the inability to adequately regulate glucose levels in the blood, and may be characterized by impaired insulin secretion or insulin resistance. Namely, patients with type II diabetes have too little insulin, or inefficient use of insulin. Insulin resistance refers to the inability of the body tissues to react to endogenous insulin. Insulin resistance develops due to many factors, including genetics, obesity, age, and the presence of high glucose levels over a long period of time. Type II diabetes, sometimes referred to as Mature diabetes can develop at any age, but most often becomes apparent when the age of majority. However, cases of type II diabetes in children is increasing. In patients with diabetes levels glucose accumulate in the blood and urine, causing excessive urination, thirst, hunger, and problems with fat and protein metabolism. If left untreated, diabetes can cause life-threatening complications, including blindness, kidney failure and heart disease.

Type II diabetes currently treated in several levels. The first level of treatment includes long-term diet and/or exercise, alone or in combination with therapeutic agents. Such agents can include in the Ulin or pharmaceutical means, which reduce the levels of glucose in the blood. About 49% of patients with type II diabetes require oral medications, 40% require insulin injections or a combination of insulin injections and oral medications, and 10% use diet and exercise separately.

Subsequent therapy include substances that contribute to the development of insulin, such as sulfonylureas, which increase the production of insulin from pancreatic 13-cells; the substance that lowers glucose levels, such as Metformin, which reduces the production of glucose by the liver; activators activated peroxymonosulfate receptor γ (PPARγ), such as preparations of thiazolidinediones, which increase the action of insulin; inhibitors of α-glucosidase, which affect the production of glucose in the intestine. However, there is a shortage of currently available treatment methods. For example, sulfonylureas and insulin injections may be associated with hypoglycemic events and increasing weight. In addition, patients over time often lose their sensitivity to sulfonylureas. Metformin and inhibitors of α-glucosidase often lead to gastrointestinal problems, and PPARγ agonists cause weight gain and swelling.

Bile acids (BA) are amphipatic molecules that are synthesized in the liver is C cholesterol, and stored in the gallbladder before secretion into the duodenum and intestines, and play an important role in the solubility and absorption of dietary fats and lipidosterolic vitamins. About 99% VA absorbed again by passive diffusion and active transport in the terminal ileum and transported back to the liver via the portal vein (enterohepatic circulation). In the liver, VA reduce their own biosynthesis of cholesterol by activating farnesoid X receptor alpha (FXRα) and small heterodimeric partner (SHP), leading to transcriptional suppression of cholesterol 7α-hydroxylase, the rate-limiting the speed stages of the biosynthesis VA from cholesterol.

GPBAR1, in the prior art known as TGR5, M-BAR or BG37, recently identified as the receptor-associated G-protein (GPCR)that are sensitive to SOCIETY (article Kawamata, etc., J. Biol. Chem., 2003, 275, SS.9435-9440; Maruyama and others, Biochem. Biophys. Res. Commun., 2002, 298, SS.714-719). GPBAR1 is a C(alpha)-associated GPCR, and stimulated by ligand binding causes activation of adenylylcyclase, which leads to increased intracellular camp and increased activation and subsequent signaling pathways. The receptor of a man reveals 86, 90, 82, and 83% amino acid identity with the receptor of the ox, rabbit, rat and mouse, respectively. GPBAR1 enough is expressed in the intestinal tract, monocytes and macrophages, lung, sat since, the placenta (article Kawamata, etc., J. Biol. Chem., 2003, 278, SS.9435-9440). VA induce the internalization of the receptor, intracellular production of camp and activation of extracellular signal-regulated kinase in GPBAR1-expressing NECK and Cho cells.

It was found that GPBAR1 enough is expressed in monocytes/macrophages of human and rabbit (article Kawamata, etc., J. Biol. Chem., 2003, 275, SS.9435-9440), and VA treatment inhibits LPS-induced production of cytokines in alveolar macrophages rabbit and TPR-1 human cells expressing GPBAR1. These data suggest that bile acids can inhibit the function of macrophages through activation of GPBAR1. In the liver functional GPBAR1 was detected in the plasma membranes of cells Kapfer, mediaready inhibition of LPS-induced expression of cytokines (article Keitel, Biochem. Biophys. Res. Commun., 2008, 372, SS.78-84) and sinusoidal endothelial cells, where salts of bile acids cause an increase of intracellular camp and activation and increased expression of endothelial synthase nitric oxide (NO) (article Keitel, Hepatology, 2007, 45, SS.695-704). In addition, GPBAR1 defined in cholangiocyte rat liver (article Keitel, Biochem. Biophys. Res. Commun., 2008, 372, SS.78-84). Hydrophobic bile acids, such as turritecava acid, increase camp in cholangiocyte, assuming GPBAR1 can modulate running the secretion and flow of bile. In the end, agony what you GPBAR1 can run protective, and meditatively mechanism in cholestatic liver.

GPBAR1 is expressed in putting enteroendocrine human cell lines (NCI-H716) and mouse (STC-1 and GLUTag) (article Maruyama and others, Biochem. Biophys. Res. Commun., 2002, 298, SS.714-719). Stimulation of GPBAR1 VA stimulates the production of camp in cells NCI-N. The intracellular increase of camp suggest that VA can induce the secretion of like peptide-1 (GLP-1). Indeed, activation of GPBAR1 VA promotiom GLP-1 secretion in STC-1 cells (article Katsuma and others, Biochem. Biophys. Res. Commun., 2005, 329, SS.386-390). Specificity to the receptor was demonstrated by experiments with RNA, which show that reduced expression of GPBAR1 leads to a weakening of the secretion of GLP-1. There is full proof that GPBAR1 - mediated release of GLP-1 is transferred in vivo. In selected vascular parkandannounce the colon of the rat, VA, as was shown to trigger the secretion of GLP-1 (article Plaisancie etc., J. Endocrin., 1995, 145, SS.521-526). In humans, the introduction to the colon of desoxycholate showed a noticeable increase levels of GLP-1 in plasma and secreted together PYY (article Adrian, etc.. Gut, 1993, 34, SS.1219-1224).

GLP-1 is a peptide, the secretory of enteroendocrine L-cells, and as shown, stimulates the release of insulin glucosidation way people (article Kreymann, etc., Lancet, 1987, 2, SS.1300-1304), and IP is the study on experimental animals showed this produced a hormone necessary for normal glucose homeostasis. In addition, GLP-1 may have some positive effects on diabetes and obesity, including 1) increased distribution of glucose, 2) suppressing the production of glucose, 3) reduction of gastric emptying, 4) reduction of food intake and 5) reduction in weight. Recently, extensive research has focused on the use of GLP-1 to treat conditions and disorders, such as diabetes, stress, obesity, appetite control and satiety, Alzheimer's disease, inflammation and diseases of the Central nervous system (see, for example, articles Bojanowska, etc., Med. Sci. Monit., 2005, 8, cc. RA271-8; Perry et al., Current Alzheimer's Res., 2005, 3, cc.377-385; Meier et al., Diabetes Metab. Res. Rev., 2005, 2, cc.91-117). However, the use of the peptide in clinical treatment is limited by the difficulty of introducing and stability in vivo. Therefore, low molecular weight compounds that are mimetics of action of GLP-1 directly, or increases the secretion of GLP-1 may be useful for treatment of the above-described various conditions or disorders, namely diabetes.

In addition, activation of GPBAR1 may be beneficial for the treatment of obesity and metabolic syndrome. Mice were given a high-fat diet (HFD)containing 0.5% of halyevoy acid, providing a reduction in weight compared with the control HFD separately and independently by the consumption of food(article Watanabe and others, Nature, 2006. 439, cc.484-489). These actions do not depend on FXR-alpha, and probably lead to binding VA with GPBAR1. Offer GPBAR1 - mediated mechanism leads to the subsequent induction of camp-dependent activation of the enzyme thyroid hormone type 2 (D2), which converts inactive TK in active T4, resulting in stimulation of the receptor for thyroid hormone and promotion of consumption. Mouse without D2 gene resistant to caused halyevoy acid weight loss. In rodents and humans most thermogene important tissue (brown fat and skeletal muscle) is specific bound by this mechanism due to the fact that they jointly Express D2 and GPBAR1. BA-GPBAR1-camp-D2 signal path, therefore, is a key mechanism proper homeostasis of energy, which may be associated with improved metabolic control.

Therefore, the present invention is the provision of a selective agonists GPBAR1 direct action. Such agonists are useful as therapeutically active substances, especially for the treatment and/or prevention of diseases that are associated with activation of GPBAR1.

The new compounds of the present invention superior to the compounds known from the prior art because they are low molecular weight compounds, and they are all connected and selectively activate GPBAR1 effectively. It is assumed that they have a high therapeutic potential compared to the compounds known from the prior art, and can be useful for the treatment of diabetes, obesity, metabolic syndrome, hypercholesterolemia, dyslipidemia and a wide range of acute and chronic inflammatory diseases.

Unless otherwise stated, the following definitions are provided to illustrate and define the meaning and scope of various terms used to describe the invention.

The term "halogen" denotes fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine are preferred, and fluorine and chlorine are preferable.

The term "alkyl", alone or in combination with other groups, denotes a branched or linear monovalent saturated aliphatic hydrocarbon radical containing from one to twenty carbon atoms, preferably from one to sixteen carbon atoms, more preferably one to ten carbon atoms. The term "C1-10-alkyl" means a branched or linear monovalent saturated aliphatic hydrocarbon radical containing from one to ten carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 1,1,3,3-TETRAMETHYLBUTYL and the like. Lower alkyl is, major group, as described below, are also preferred alkyl groups.

The term "lower alkyl" or "C1-7-alkyl", alone or in combination, denotes a linear or branched alkyl group containing from 1 to 7 carbon atoms, preferably a linear or branched alkyl group containing from 1 to 6 carbon atoms, and particularly preferably a linear or branched alkyl group containing from 1 to 4 carbon atoms. Examples of linear and branched C1-7alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric of Penteli, isomeric sexily and isomeric Gately, preferably methyl and ethyl and most preferably methyl.

The term "lower alkenyl" or "C2-7alkenyl" denotes a linear or branched hydrocarbon residue containing olefinic bond and from 2 to 7, preferably from 3 to 6, particularly preferably 3 or 4 carbon atoms. Examples alkenyl groups are ethynyl, 1-propenyl, 2-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and Isobutanol. A preferred example is 2-propenyl (allyl).

The term "lower quinil" or "C2-7-quinil" denotes a linear or branched hydrocarbon residue comprising a triple bond and from 3 to 7, preferably from 3 to 6, especially predpochtite is the super 3 or 4 carbon atoms. Preferred alkenylamine groups are atenil and 1-PROPYNYL (-C≡C-CH2).

The term "cycloalkyl" or "C3-7-cycloalkyl" denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Especially preferred is cyclopropyl.

The term "lower cycloalkenyl" or "C3-7-Cycloalkyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where one of the hydrogen atoms of the lower alkyl groups substituted by cycloalkyl. Preferred lower cycloalkylcarbonyl groups are-CH2-cyclopropyl or-CH2-cyclobutyl.

The term "lower alkoxygroup" or "C1-7-alkoxygroup" refers to the group-O-R, where R is a lower alkyl, and the term "lower alkyl" has the above meaning. Examples of the lower alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan and tert-butoxypropan, preferably the methoxy group and ethoxypropan.

The term "lower alkylsulfonyl" or "C1-7-alkylsulfonyl" denotes the group-S-R, where R is a lower alkyl, and the term "lower alkyl" has the above meaning. Examples of the lower alkyls levonline groups are methylsulfonyl (-SCH 3or ethylsulfanyl (-SC2H5),

The term "lower halogenated" or "halogen-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. Although the preferred halogenated lower alkyl groups are trifluoromethyl, deformity, triptorelin, 2,2-dottorati, vermeil and chloromethyl, trifluoromethyl or deformity are particularly preferred.

The term "lower halogenlampe" or "halogen-C1-7-alkoxygroup" denotes lowest alkoxygroup as defined above, where at least one of the hydrogen atoms of the lower alkoxygroup substituted by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. Although the preferred halogenated lower alkoxygroup are tripterocarpa, dipterocarp, formicoxenus and chlorethoxyfos, tripterocarpa is especially preferred.

The term "lower hydroxyalkyl" or "hydroxy-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl group substituted by a hydroxy-group. Predpochtitelney hydroxyalkyl groups are hydroxymethyl or hydroxyethyl.

The term "lower hydroxyalkyl" or "hydroxy-C3-7alkenyl" indicates the lowest alkeneamine group as defined above, but containing at least 3 carbon atoms, where at least one of the hydrogen atoms of the lower alkenylphenol group substituted by a hydroxy-group. Preferred lower hydroxyalkyl group is hydroxyethyl.

The term "lower hydroxyalkyl" or "hydroxy-C3-7-quinil" indicates the lowest alkyline group as defined above, but containing at least 3 carbon atoms, where at least one hydrogen atom of the lower alkenylphenol group substituted by a hydroxy-group. Preferred lower hydroxyalkyloxy group is-C≡C-CH2HE.

"Amino" denotes the group-NH2. The term "C1-7-alkylamino" denotes the group-other, where R represents lower alkyl and the term "lower alkyl" has the above value.

The term "carboxyl" denotes the group-COOH.

The term "lower carboxylate" or "carboxyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where one of the hydrogen atoms of the lower alkyl groups substituted by carboxyla. Preferred lower carboxyaniline groups are-CH2-COOH or-CH2-CH2-COOH.

The term "lower carboxylphenyl" or "to roxil-C 2-7alkenyl" indicates the lowest alkeneamine group as defined above where one of the hydrogen atoms of the lower alkenylphenol group substituted by carboxyla. Preferred lower carboxylterminal group is-CH=CH-CH2-COOH.

The term "lower carboxylating" or "carboxyl-C2-7-quinil" indicates the lowest alkylamino group as defined above where one of the hydrogen atoms of the lower alkenylphenol group substituted by carboxyla. Preferred lower carboxyaniline group is-C≡C-CH2-COOH.

The term "aminocarbonyl" refers to a group-CO-NH2.

The term "lower carboxymethylaminomethyl" or "carboxyl-C1-7-alkylaminocarbonyl" means aminocarbonyl as defined above, where one of the hydrogen atoms of the amino group substituted carboxyl-C1-7-alkyl. Preferred lower carboxymethylaminomethyl group is-CO-NH-CH2-COOH.

The term "lower carboxymethylaminomethyl" or "carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl" denotes a lower alkyl group where one of the hydrogen atoms of the lower alkyl groups substituted "carboxyl-C1-7-alkylaminocarbonyl" as defined above. Preferred lower carboxymethylaminomethyl group is-CH2-CO-NH-CH2-COOH.

The terminology is "carboxyl-C 1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl" denotes a lower alkyl group where one of the hydrogen atoms of the lower alkyl groups substituted "carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl, for example a group of formula-CH2-CO-NR-CH2-COOH, where R represents lower alkyl.

"Lower alkoxycarbonyl" or "C1-7-alkoxycarbonyl" refers to a group-CO-OR, where R represents lower alkyl and the term "lower alkyl" has the above meaning. Preferred lower alkoxycarbonyl groups are methoxycarbonyl or etoxycarbonyl.

The term "lower alkoxycarbonyl" or "C1-7-alkoxycarbonyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where one of the hydrogen atoms of the lower alkyl group substituted With1-7-alkoxycarbonyl. Preferred lower alkoxycarbonylmethyl groups are-CH2SOON3and CH2-CH2SOON3.

The term "lower alkoxycarbonylmethyl" or "C1-7-alkoxycarbonyl-C2-7alkenyl" indicates the lowest alkenylphenol group as defined above where one of the hydrogen atoms of the lower alkenylphenol group substituted With1-7-alkoxycarbonyl. Preferred lower alkoxycarbonylmethyl group is-CH-CH-CH2WITH the CH 3.

The term "lower alkoxycarbonyl" or "C1-7-alkoxycarbonyl-C2-7-quinil" indicates the lowest alkylamino group as defined above where one of the hydrogen atoms of the lower alkenylphenol group substituted With1-7-alkoxycarbonyl. Preferred lower alkoxycarbonylmethyl group is-C=C-CH2SOON3.

The term "lower alkoxycarbonylmethyl" or "C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl" means aminocarbonyl as defined above, where one of the hydrogen atoms of the amino group substituted With 1.7-alkoxycarbonyl-C1-7-alkyl. Preferred lower carboxymethylaminomethyl group is-CO-NH-CH2-COOCH3.

The term "lower alkoxycarbonylmethyl" or "C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl-C1-7-alkyl" denotes a lower alkyl group where one of the hydrogen atoms of the lower alkyl group substituted With1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl" as defined above. Preferred lower alkoxycarbonylmethyl group is-CH2-CO-NH-CH2SOON3.

The term "C1-7-alkoxycarbonyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl" denotes a lower alkyl group, where the in of the hydrogen atoms of the lower alkyl group substituted With 1-7-alkoxycarbonyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl". The preferred group is-CH2-CO-NCH3-CH2SOON3.

The term "C1-7-alkylaryl" refers to a group-CO-R, where R is a lower alkyl as defined above.

The term "C1-7-alkylcarboxylic" refers to the group-O-CO-R, where R is a lower alkyl as defined above.

The term "lower alkylcarboxylic" or "C1-7-alkylcarboxylic-C1-7-alkyl" refers to lower alkyl groups as defined above, where one of the hydrogen atoms of the lower alkyl group substituted With1-7-alkylcarboxylic. Preferred lower alkylcarboxylic group is-CH2-CH2-O-CO-CH3.

The term "phenylcarbinol" refers to a group-CO-R', where R' represents phenyl.

The term "phenylsulfonyl" denotes the group-SO2-R', where R' represents phenyl.

The term "lower phenylalkyl or phenyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl group substituted phenyl group. The phenyl group may be further substituted. Preferred lower phenylalkylamine groups are benzyl or phenethyl.

The term "phenyl lower linil or phenyl-C 2-7-quinil" indicates the lowest alkylamino group as defined above where one of the hydrogen atoms of the lower alkenylphenol group substituted phenyl group. The phenyl group may be further substituted. Preferred lower phenylalkylamines group is phenylethynyl.

The term "pyrrolidinylcarbonyl" refers to a group:

.

The term "heterocyclyl" generally refers to a saturated or partially unsaturated 3-, 4-, 5-, 6- or 7-membered ring which may contain one, two or three atoms selected from nitrogen, oxygen and/or sulfur. Examples heterocyclyl rings include azirines, azetidine, oxetane, piperidinyl, piperazinil, azepine, pyrrolidinyl, pyrazolidine, imidazoline, imidazolidine, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidine, morpholine, thiazolidine, isothiazolinones, thiadiazolidine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran and thiomorpholine. Preferred heterocyclyl group is oxetanyl.

The term "lower geterotsiklicheskikh" or "heterocyclyl-C1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted heterocyclyl group, as defined above.

"N-heterocyclyl" means 3-, 4-, 5- 6- or 7-membered saturated heterocyclic ring, containing a nitrogen atom ("N"), and optionally containing another heteroatom selected from nitrogen, oxygen or sulfur. Preferably N-heterocyclyl ring linked through the nitrogen atom with a carbon atom attached to the ring. Preferred N-heterocyclyl ring selected from the group consisting of azirine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolinone, piperidinyl, piperazinil, morpholinyl, thiomorpholine and azepane.

The term "heteroaryl" generally refers to an aromatic 5 - or 6-membered ring which comprises one, two or three atoms selected from nitrogen, oxygen and/or sulfur, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 2-oxo-1,2-dihydropyridine, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl. The term "heteroaryl" also refers to bicyclic aromatic groups containing two 5 - or 6-membered ring in which one or both rings can contain one, two or three atoms selected from nitrogen, oxygen or sulfur, such as chinoline, ethenolysis, cinnoline, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, honokalani, benzothiazolyl, benzotriazolyl, indolyl and indazoles. Preferred heteroaryl group is a furyl.

T is pmin "low heteroaromatic" or "heteroaryl-C 1-7-alkyl" refers to lower alkyl groups as defined above, where at least one of the hydrogen atoms of the lower alkyl groups substituted heteroaryl group as defined above.

The term "five-membered N-heteroaryl" refers to an aromatic 5-membered ring that includes at least one nitrogen atom and may optionally include 1-3 atoms selected from nitrogen, oxygen and/or sulfur. Preferred five-membered heteroaryl ring selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl and thiazolyl. Preferably, five-membered heteroaryl ring is connected by a nitrogen atom with a carbon atom attached to the ring. Most preferably, five-membered heteroaryl group is pyrrolyl.

The compounds of formula I can form pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Salts are, for example acid additive salts of compounds of formula I with physiologically compatible mineral acids such as hydrochloric acid, sulfuric acid, with Mista acid or phosphoric acid; or with organic acids, such as methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, malonic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid or salicylic acid. In addition, pharmaceutically acceptable salts can be obtained by adding an inorganic base or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, primenenie resin and the like. The compound of the formula I can also be present in the form zwitterions. Particularly preferred pharmaceutically acceptable salts joint the formula I are cleaners containing hydrochloride salt.

The compounds of formula I can also be solvated, for example, gidratirovana. Solvation can be carried out during the production method, or may be, for example, due to the hygroscopic properties of the initially anhydrous compound of formula I (hydration). The term "pharmaceutically acceptable salt" also includes a physiologically acceptable solvate.

"Isomers are compounds that have the same molecular formula, but differ in the nature or sequence of links of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other, are called "diastereoisomer"and stereoisomers that are nenalogovye mirror images are called "enantiomers", or sometimes optical isomers. The carbon atom associated with four different substituents, is called a "chiral center".

In more detail, the present invention relates to compounds of the formula:

where

And1represents CR12or N;

And2represents CR13or N;

R1and R2independently from each other selected from the group consisting of hydrogen, C1-7 -alkyl, halogen, ceanography and C1-7-alkoxygroup;

R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography, C1-7-alkoxygroup, amino, and C1-7alkylsulfanyl;

R3selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, ceanography,3-7-picoalgae, N-heterocyclyl, five-membered heteroaryl and phenyl;

R4selected from the group consisting of methyl, ethyl, isopropyl, diformate, trifloromethyl, cyclopropyl and oxetanyl; or

R3and R4together are-X-(CR14R15)nand form part of a ring; where

X is selected from the group consisting of CR16R17-, O, S, C=O and NR18;

R14and R15independently from each other selected from hydrogen or C1-7-alkyl;

R16and R17independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, C1-7-alkoxycarbonyl, unsubstituted heterocyclyl and heterocyclyl substituted by one or two groups selected from C1-7-alkyl or halogen,

or R16and R17together with the atom to which they are attached, form cyclopropyl or oxetanyl ring, or together form =CH2or =CF3group;

R1 selected from the group consisting of hydrogen, C1-7-alkyl, halogen-(C1-7-alkyl, C3-7-picoalgae,3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heterocyclyl-C1-7-alkyl, heteroaryl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarboxylic-C1-7-alkyl, phenyl, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl, phenylcarbinol, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl, and phenylsulfonyl, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl,

or R18and R14together represent -(CH2)3and form part of the ring, or R18together with a pair of R14and R15represent-CH=CH-CH= and form part of a ring;

and n is 1, 2 or 3;

B1represents N or CR19and B2represents N or CR20provided that not more than one of B1and B2represents N; and

R19and R20independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-Alcock is gruppy and cyanopropyl;

R5and R6independently from each other selected from the group consisting of hydrogen, halogen, C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkyl, halogen-(C1-7-alkoxygroup and cyanopropyl;

and at least one, or when R4represents methyl or ethyl, at least two of R7, R8, R9, R10and R11selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup, ceanography, carboxyl, C1-7-alkoxycarbonyl, hydroxy-C1-7-alkyl, hydroxy-C3-7-alkenyl, hydroxy-C3-7-quinil, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, carboxyl-C2-7-quinil, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-quinil, carboxyl-C1-7-alkylaminocarbonyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl, where phenyl is unsubstituted what does substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenylcarbinol, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenyl-C1-7-alkyl, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenyl-C2-7-quinil, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidinylcarbonyl-C1-7-alkyl, where pyrrolidinyl replaced by carboxyla,

and other R7, R8, R9, R10and R11represent hydrogen;

or their pharmaceutically acceptable salts.

Preferred compounds of formula I in accordance with the present invention are compounds where a is a CR12and2represents CR13or where a1represents CR12and2represents N, or where a1represents N and2represents CR13and R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography, C1-7"and what of maxigrip, the amino and C1-7alkylsulfanyl.

Especially preferred are the compounds of formula I in accordance with the present invention, where a1represents CR12and2represents CR13where R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography,1-7-alkoxygroup, amino, and C1-7alkylsulfanyl. They are compounds of the formula:

.

Also preferred are the compounds of formula I, where a represents N and2represents CR12or where a1represents CR13and2represents N, and R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography, C1-7-alkoxygroup, amino, and C1-7alkylsulfanyl.

Especially preferred are the compounds of formula I, where a1represents CR13and2represents N, and R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography, C1-7-alkoxygroup, amino, and C1-7alkylsulfanyl.

In addition, preferred are soedineniya I, where R1and R2independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography and C1-7-alkoxygroup, more preferably from the group consisting of hydrogen, C1-7of alkyl and halogen.

Also preferred compounds of formula I, where R3and R4together are-X-(CR14R15)nand form part of a ring; where

X is selected from the group consisting of CR16R17-, O, S, C=O and NR18;

R14and R15independently from each other selected from hydrogen or C1-7-alkyl;

R16and R17independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, C1-7-alkoxycarbonyl, unsubstituted heterocyclyl and heterocyclyl substituted by one or two groups selected from C1-7-alkyl or halogen,

or R16and R17together with the atom to which they are attached, form cyclopropyl or oxetanyl ring, or together form the group =CH2or =CF3;

R18selected from the group consisting of hydrogen, C1-7-alkyl, halogen-(C1-7-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heterocyclyl-C1-7-alkyl, heteroaryl, heteroaryl - C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-aldoxycarb the Il-From 1-7-alkyl, C1-7-alkylcarboxylic-C1-7-alkyl, phenyl, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl, phenylcarbinol, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl, and phenylsulfonyl, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl,

or R18and R14together represent -(CH2)3and form part of the ring, or R18together with a pair of R14and R15represent-CH=CH-CH= and form part of a ring;

and n is 1, 2 or 3.

In this group of compounds of formula I are especially preferred are compounds where X is selected from the group consisting of CR16R17-, O, S, C=O and NR18; R14and R15independently from each other selected from hydrogen or C1-7-alkyl; R16and R17independently from each other selected from hydrogen or C1-7-alkyl, or together with the atom to which they are attached, form cyclopropyl or oxetanyl ring, or together form the group =CH2or =CF3; R18selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl and pyridyl, and n is 1, 2 or 3.

In addition, particularly preferred and are the compounds of formula I, where X represents-CH2-, R14and R15independently from each other selected from hydrogen or methyl, and n denotes 2. Even more preferred are compounds where R14and R15represent hydrogen. They are compounds of the formula:

.

Also especially preferred are compounds of formula I, where X represents Oh, R14and R15represent hydrogen and n is 2. These compounds have the formula:

.

In addition, especially preferred are the compounds of formula I, where R14and R15represent hydrogen, n is 2 and X represents NR18and R18selected from the group consisting of hydrogen, C1-7-alkyl, halogen-C1-7-alkyl, C3-7-cycloalkyl,3-7-iclooly-C1-7-alkyl, heterocyclyl, heterocyclyl-C1-7-alkyl, heteroaryl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarboxylic-C1-7-alkyl, phenyl, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl, phenylcarbinol, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxide what anilam, and phenylsulfonyl, where phenyl is unsubstituted or substituted carboxyl-C1-7-alkyl or C1-7-alkoxycarbonyl. They are compounds of the formula:

.

Also included in the invention the compounds of formula I, where R18and R14together represent -(CH2)3and form part of the ring. These compounds have the formula:

.

In addition, in the present invention includes compounds of formula I, where R18together with a pair of R14and R15represent-CH=CH-CH= and form part of the ring. These compounds have the formula:

Another group of preferred compounds of formula I includes compounds where R3selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, ceanography,3-7-cycloalkyl, N-heterocyclyl, five-membered heteroaryl ring and phenyl; and R4selected from the group consisting of methyl, ethyl, isopropyl, diformate, trifloromethyl, cyclopropyl and oxetanyl. Especially preferred are the compounds of formula I, where R4represents methyl or ethyl. Preferably, R3selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, ceanography, cyclopropyl pyrrolyl and phenyl.

Also preferred are the compounds of formula I, where In1represents N and2represents CR20and R20selected from the group consisting of hydrogen, C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup and ceanography. These compounds have the formula:

Also preferred are the compounds of formula I of the present invention, where In1represents CR19and2represents N, and R is selected from the group consisting of hydrogen, C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup and ceanography. These compounds have the formula:

Preferred are also the compounds of formula I, where In1represents CR19and2represents CR20and R19and R20independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup and ceanography. These compounds have the formula:

.

R5and R6independently from each other selected from the group consisting of hydrogen, halogen, C-7 -alkyl, C1-7-alkoxygroup and halogen-C1-7-alkoxygroup. Preferred are the compounds of formula I, where R5and R6independently from each other represent hydrogen or halogen.

Compounds of the present invention also include compounds where at least one, or when R4represents methyl or ethyl, at least two of R7, R8, R9, R10and R11selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup, ceanography, carboxyl, C1-7-alkoxycarbonyl, hydroxy-C1-7-alkyl, hydroxy-C3-7-alkenyl, hydroxy-C3-7-quinil, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, carboxyl-C2-7-quinil, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-quinil, carboxyl-C1-7-alkylaminocarbonyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl - C1-7-alkyl-(C1-7-alkylamine is)-carbonyl-C 1-7-alkyl, phenyl, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenylcarbinol, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenyl-C1-7-alkyl, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenyl-C2-7-quinil, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidinylcarbonyl-C1-7-alkyl, where pyrrolidinyl replaced by carboxyla, and other R7, R8, R9, R10and R11represent hydrogen.

More preferably, at least two of R7, R8, R9, R10and R11selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup, ceanography, carboxyl, C1-7-alkoxycarbonyl, hydroxy-C1-7-alkyl, hydroxy-C3-7-alkenyl, hydroxy-C3-7-quinil, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, carboxyl-C2-7-quinil, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-quinil, carboxyl-C1-7-alkylaminocarbonyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenylcarbinol, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenyl-C1-7-alkyl, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, phenyl-C2-7-quinil, where phenyl is unsubstituted or substituted by 1-3 groups selected from halogen, C1-7-alkoxygroup, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidinylcarbonyl-C1-7-alkyl, where pyrrolidinyl replaced by carboxyla, and other R , R8, R9, R10and R11represent hydrogen.

Especially preferred are the compounds of formula I, where R7and R10represent halogen. Most preferably, R7and R10represent halogen, and R8, R9and R11represent hydrogen.

Also preferred are compounds of the formula:

where

And1represents CR12or N;

And2represents CR13or N;

R1and R2independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography and C1-7-alkoxygroup;

R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, ceanography and C1-7-alkoxygroup;

R3selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, ceanography, N-heterocyclyl, five-membered heteroaryl and phenyl;

R4selected from the group consisting of methyl, ethyl, isopropyl, diformate, trifloromethyl, cyclopropyl and oxetanyl; or

R3and R4together are-X-(CR14R15)nand form part of a ring; where

X is selected from the group consisting of CR16R17-, O, S, C=O and NR 18;

R14and R15independently from each other selected from hydrogen or C1-7-alkyl,

R16and R17independently from each other selected from hydrogen or C1-7-alkyl, or together with the C atom to which they are attached, form cyclopropyl or oxetanyl ring, or together form the group =CH2or =CF2,

R18selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl and pyridyl,

and n is 1, 2 or 3;

B1represents N or CR19and B2represents N or CR20provided that not more than one of B1and B2represents N; and

R19and R20independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7-alkoxygroup and cyanopropyl;

R5and R6independently from each other selected from the group consisting of hydrogen, halogen, C1-7-alkyl, C1-7-alkoxygroup and halogen-C1-7-alkoxygroup,

and at least one, or when R4represents methyl or ethyl, at least two of R7, R8, R9, R10and R11selected from the group consisting of C1-7of alkyl, halogen, halogen-C1-7-alkyl, C1-7-alkoxygroup, halogen-C1-7

and other R7, R8, R9, R10and R11represent hydrogen;

or their pharmaceutically acceptable salts.

Examples of preferred compounds of formula I are the following compounds:

(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-triptoreline)pyridine-3-yl]metano,

[2-(2-chlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

(6-methyl-3,4-dihydro-2H-quinoline-1-yl)-[2-(3-triptoreline)pyridine-3-yl]metano,

[2-(3-chlorophenoxy)pyridine-3-yl]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3,4-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

3-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)pyridine-2-yloxy]benzonitrile,

(3,4-dihydro-2H-quinoline-1-yl)-(2-m-collectibility-3-yl)methanon,

[2-(3-chloro-4-methylphenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chloro-4-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(5-chloro-2-methylphenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,3-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chloro-5-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

(3,4-dihydro-2H-quinoline-1-yl)-[2-(2,4,5-trichlorophenoxy)pyridine-3-yl]metano,

[2-(3-benzoylperoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-is)methanon,

(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-triftormetilfosfinov)pyridine-3-yl]metano,

[2-(3,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-pertenece)pyridine-3-yl]metano,

(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-isopropylphenoxy)pyridine-3-yl]metano,

(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-ethylenoxy)pyridine-3-yl]metano,

(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-iodinase)pyridine-3-yl]metano,

[2-(3-chloro-2-fluoro-5-triptoreline)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-bromophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-divergence)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[5-chloro-2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[5-chloro-2-(2,5-divergence)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)-6-triptorelin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

2-(2,5-dichlorophenoxy)-N-ethyl-N-phenyldiamine,

(7-chloro-3,4-dihydro-2H-quinoline-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

[2-(2,5-dichlorophen the XI)pyridine-3-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

2-(2,5-dichlorophenoxy)-N-methyl-N-phenyldiamine,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]thiazin-4-yl)methanon,

N-(2-chlorophenyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-methyl-N-o-callincoming,

2-(2,5-dichlorophenoxy)-N-(2-methoxyphenyl)-N-nicotine amide,

N-biphenyl-2-yl-2-(2,5-dichlorophenoxy)-N-nicotine amide,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

2-(2,5-dichlorophenoxy)-N-(2-ethylphenyl)-N-nicotine amide,

N-(3-chloropyridin-2-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

N-(4-chloropyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2-methoxypyridine-3-yl)-N-nicotine amide,

N-(3-chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

N-(5-chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

N-(2-chloro-6-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2,6-dimetilfenil)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2-methoxy-6-were)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(5-fluoro-2-methoxyphenyl)-N-nicotine amide,

N-(5-chloro-2-methox is phenyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

N-(4-chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2,3-dimetilfenil)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2,4-dimetilfenil)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2-methoxy-5-were)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2,6-acid)-N-nicotine amide,

N-(6-chloro-4-methylpyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

N-(2-cyanophenyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2-forfinal)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2,6-differenl)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-methyl-N-(2-pyrrol-1-ylphenyl)nicotinamide,

2-(2,5-dichlorophenoxy)-N-(2,4-differenl)-N-nicotine amide,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(8-fluoro-6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

N-(2-chloro-4-methylpyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(8-methoxy-3,4-dihydro-2H-quinoline-1-yl)methanon,

(6-chloro-3,4-dihydro-2H-quinoline-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,8-debtor-2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-phenyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,/p>

2-(2,5-dichlorophenoxy)-N-(4-methoxypyridine-3-yl)-N-nicotine amide,

[2-(2,4-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chloro-4-pertenece)pyridine-3-yl]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chloro-4-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-[1,5]naphthiridine-1-yl)methanon,

[2-(3-chloro-4-pertenece)pyridine-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,

1-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-1,2,3,4-tetrahydrobenzo[b]azepin-5-he,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

2-(2,5-dichlorophenoxy)-N-ethyl-5-fluoro-N-phenyldiamine,

[2-(3-chlorophenoxy)-5-herperidin-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chloro-4-pertenece)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chloro-4-pertenece)-5-herperidin-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(3-chloro-4-pertenece)-5-herperidin-3-yl]-(8-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,5-is chlorphenoxy)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

3-(2,5-dichlorophenoxy)-N-methyl-N-o-tolylenediamine,

N-(2-chlorophenyl)-3-(2,5-dichlorophenoxy)-N-methylethanolamine,

3-(2,5-dichlorophenoxy)-N-(2-methoxyphenyl)-N-methylethanolamine,

[3-(2,4-dichlorophenoxy)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,4-dichlorophenoxy)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,4-dichlorophenoxy)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

3-(2,4-dichlorophenoxy)-N-methyl-N-o-tolylenediamine,

N-(2-chlorophenyl)-3-(2,4-dichlorophenoxy)-N-methylethanolamine,

3-(2,4-dichlorophenoxy)-N-(2-methoxyphenyl)-N-methylethanolamine,

3-(2,4-dichlorophenoxy)-N-(2-methoxypyridine-3-yl)-N-methylethanolamine,

[3-(3-chloro-4-pertenece)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(3-chloro-4-pertenece)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(3-chloro-4-pertenece)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

3-(3-chloro-4-pertenece)-N-methyl-N-o-tolylenediamine,

3-(3-chloro-4-pertenece)-N-(2-chlorophenyl)-N-methylethanolamine,

3-(3-chloro-4-pertenece)-N-(2-methoxyphenyl)-N-methylethanolamine,

3-(3-chloro-4-pertenece)-N-(2-methoxypyridine-3-yl)-N-methylethanolamine,

[2-(2,5-dichlorophenoxy)phenyl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)phenyl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)f the Nile]-(2-methyl-2,3-dihydroindol-1-yl)methanon,

[2-(2,5-dichlorophenoxy)-5-forfinal]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)-5-forfinal]-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)-5-forfinal]-(8-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)-5-forfinal]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)-5-forfinal]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,

2-(2,5-dichlorophenoxy)-5-fluoro-N-methyl-N-phenylbenzene,

4-(2,5-dichlorophenoxy)-3-(3,4-dihydro-2H-quinoline-1-carbonyl)benzonitrile,

[2-(2,5-dichlorophenoxy)phenyl]-(8-fluoro-6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)phenyl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

or their pharmaceutically acceptable salts.

Other preferred compounds of formula I are the following compounds:

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-methyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-isopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

(4-cyclobutyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-oxetan-3-yl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

1-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]2,3-dihydro-1H-quinoline-4-one,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-methylene-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-[4-(3,3-debtor-azetidin-1-yl)-3,4-dihydro-2H-quinoline-1-yl]metano,

N-(2-cyclopropylethyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-methyl-N-(2-methylsulfinylphenyl)nicotinamide,

2-(2,5-dichlorophenoxy)-N-methyl-N-[2-(2-methyl-2H-pyrazole-3-yl)phenyl]nicotinamide,

N-(2-AMINOPHENYL)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

2-(2,5-dichlorophenoxy)-N-(2,5-dichlorophenyl)-N-nicotine amide,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2,3,3 a,4-tetrahydro-1H-pyrrolo[1,2-a]cinoxacin-5-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-isobutyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

(4-cyclopropylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

(4-cyclobutylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

2-{4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}ethyl ester acetic acid,

ethyl ester {4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,

{4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,

3-(4-{4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-sulfonyl}phenyl)propionic acid,

(3,4-dihydro-2H-quinoline-1-yl)-[2-(2-fluoro-5-cryptomite is phenoxy)pyridine-3-yl]metano,

2-(2,5-dichlorophenoxy)-5-fluoro-N-(2-methoxypyridine-3-yl)-N-nicotine amide,

N-(2,6-dichloro-3-methoxyphenyl)-2-(2,5-dichlorophenoxy)-5-fluoro-N-nicotine amide,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon,

methyl ether of 1-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-1,2,3,4-tetrahydroquinolin-4-carboxylic acid,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(4H-pyrrolo[1,2-a]cinoxacin-5-yl)methanon,

(4-cyclobutyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]metano,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(4-furan-3-ylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

(4-cyclobutylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]metano,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-[4-(3,3,3-cryptochromes)-3,4-dihydro-2H-cinoxacin-1-yl]metano,

ethyl ester {4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,

{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,

ethyl ester 3-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}propionic acid,

3-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}-2-methylpropionate acid,

ethyl ester 4-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-genoxal the-1-yl}butane acid,

ethyl ester 5-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}pentanol acid,

methyl ester 6-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}hexanoic acid,

6-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}hexanoic acid,

methyl ester 4-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-carbonyl}benzoic acid,

[2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-{2-[2,5-dichloro-4-(3-hydroxyprop-1-inyl)phenoxy]pyridine-3-yl}mechanon,

[2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

methyl ester 5-{2,5-dichloro-4-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)pyridine-2-yloxy]phenyl}Penta-4-invoi acid,

methyl ester 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid,

2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid,

2-chloro-4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)benzoic acid,

4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)benzoylacetate,

4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)-3-methoxybenzoic acid,

3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}acrylic acid,

3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionic acid,

methyl ester of 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}but-3-ene acid,

4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}but-3-ANOVA acid,

4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}butane acid,

(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)acetic acid,

[(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)methylamino]acetic acid,

3-(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)propionic acid,

1-(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)pyrrolidine-2-carboxylic acid,

3-(4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}bucillamine)propionic who Isleta,

methyl ester of 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]benzoic acid,

methyl ester {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]benzoylamine}acetic acid,

(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)phenyl]metano,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

or their pharmaceutically acceptable salts.

Especially preferred compounds of formula I of the present invention are the following compounds:

[2-(3-chloro-4-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

2-(2,5-dichlorophenoxy)-N-ethyl-N-phenyldiamine,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(b-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]thiazin-4-yl)methanon,

2-(2,5-dichlorophenoxy)-N-methyl-N-o-callincoming,

2-(2,5-dichlorophenoxy)-N-(2-methoxyphenyl)-N-nicotine amide,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

N-(2-chloro-6-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,

2-(2,5-is chlorphenoxy)-N-(5-fluoro-2-methoxyphenyl)-N-nicotine amide,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,

3-(2,5-dichlorophenoxy)-N-methyl-N-o-tolylenediamine,

3-(2,5-dichlorophenoxy)-N-(2-methoxyphenyl)-N-methylethanolamine,

[2-(2,5-dichlorophenoxy)phenyl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-methyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

(4-cyclobutyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-oxetan-3-yl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-methylene-3,4-dihydro-2H-quinoline-1-yl)methanon,

2-(2,5-dichlorophenoxy)-N-methyl-N-(2-methylsulfinylphenyl)nicotinamide,

(4-cyclopropylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,

[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon,

(4-cyclobutyl-3,4-dihydro-2H-x is exalin-1-yl)-[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]metano,

ethyl ester {4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl} acetic acid,

[2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,

(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-{2-[2,5-dichloro-4-(3-hydroxyprop-1-inyl)phenoxy]pyridine-3-yl}mechanon,

4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)benzoic acid,

3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionic acid,

methyl ester of 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}but-3-ene acid,

(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)acetic acid,

[(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)methylamino]acetic acid,

3-(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)propionic acid,

1-(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)pyrrolidine-2-carboxylic acid,

3-(4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}bucillamine)propionic acid,

(4-Cyclops the saw-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)phenyl]metano,

[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

or their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of compounds of formula I are also available separately are the preferred compounds of the present invention.

The compounds of formula I can contain one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric of racemates or mixtures diastereoisomeric racemate. Optically active forms may be obtained, for example, the splitting of the racemate, an asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluent). The present invention includes all these forms.

It is clear that from compounds of General formula I of the present invention can be obtained derivative functional groups with obtaining derivatives, which are capable of transforming back to the original compound in vivo. Physiologically acceptable and metabolically labile derivatives, which are able to give the parent compound of General formula I in vivo, are also included in the scope of the present invention.

Another embodiment of the present invention is SPO is about producing compounds of formula I as defined above, which includes:

a) the reaction of the carboxylic acid of the formula II:

,

where1In2and R5-R11are as defined above, with an amine of the formula III:

,

where a1And2and R1-R4are as defined above, in the presence of a condensing reagent in the basic conditions of obtaining the compounds of formula I:

,

where a1And2In1In2and R1-R11are as defined above, and optionally conversion of the compounds obtained into pharmaceutically acceptable salt;

or, alternatively,

b) condensation of the compounds of formula IV:

,

where a1And2In1In2and R1-R6are as defined above, and Hal denotes a halogen atom or sulfonate, with a phenol of the formula V:

,

where R7-R11are as defined above, in the presence of a source of copper (I), to obtain the compounds of formula I:

,

where a1And2In1In2and R1-R11are as defined above, and optionally conversion of the compounds obtained into pharmaceutically acceptable salt.

Approaching what they condensing agents are, for example, N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexaflurophosphate (HATU), 1-hydroxy-1,2,3-benzotriazol (NOVT), 2-chloro-1-methylpyridine iodide or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexaflurophosphate (THIEF). "Basic conditions" means the presence of a base, such as diisopropylethylamine, triethylamine, N-methylmorpholine or 4-(dimethylamino)pyridine. The reaction is carried out in a stable rastvoritele, such as, for example, N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), dichloromethane or dioxane, at temperatures from 0°C to 100°C, where heating may be achieved by conventional heating or microwave radiation.

The source of copper (I) refers to a salt of copper (I), such as copper bromide (I) or copper iodide (I) or complexes of copper (I), which are generally more soluble in organic solvents, such as hexaphosphate tetrakis(acetonitrile)copper (I). Additionally, the condensation can be carried out in the presence of metallic copper powder. The condensation is preferably carried out under heating or under microwave irradiation (usually at a temperature of from 100 to 200°C. or at the boiling point will dissolve the La) in an aprotic solvent, such as N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), N-organic (NMP), sulfolane, ethylene glycol, acetonitrile or THF, or mixtures thereof. Optional is also present tertiary amine, such as triethylamine, N-ethyldiethanolamine (base Chenega) or pyridine.

The present invention also relates to compounds of formula I as defined above, obtained in accordance with the method as defined above.

In more detail, the compounds of formula I in accordance with the present invention can be obtained by the methods and techniques described above. Conventional methods of producing compounds of the formula I is depicted in figure 1.

Scheme 1

Mediated by copper(aryl)-O condensation halogenoalkanes acids of the General structure 1 with phenols 2 (classic reaction of Ullmann and Goldberg and its variants; review, see: S. V. Ley and A. W. Thomas, Angew. Chem. Int. Ed., 2003, 42, SS.5400-5449) at room or elevated temperatures results in diarylamino 3 (scheme 1, stage a), where X is typically a halogen, such as iodine, bromine or chlorine (reaction Cana-Evans-Lam X may also be a derivative airborne acid). To increase the speed of transformation can be used for heating, conventional heating or microwave radiation, using a suitable device for MICR is a new radiation. In addition, the reaction may be conducted in the presence or absence of a solvent (typically an aprotic polar solvent, such as DMF (N,N-dimethylformamide), DMAc (dimethylacetamide), NMP (N-organic, ethylene glycol, acetonitrile or THF, or a mixture thereof; and sometimes also less polar solvent, such as toluene, may be appropriate) and in the presence or absence of a tertiary amine base, such as triethylamine, N-ethyldiethanolamine (base Chenega) or pyridine and in the presence or absence of a source of copper(I), such as bromide copper(I) or copper iodide(I). In some cases, the reaction may be conducted in the presence of complexes of copper (I) with a higher solubility, such as hexaphosphate tetrakis(acetonitrile)copper(I) (for example, US 06/0287297 A1 (Johnson & Johnson)). This reaction can be carried out in the presence or absence of metallic copper (e.g. copper nanopowder(0)). Alternatively, mediated by copper condensation reaction With(aryl)-O can be carried out in basic conditions using a2CO3Cs2CO3, CON, NaOCH3Cotret-Bu or NaH (reaction of nucleophilic aromatic substitution), where X is a suitable leaving group such as chlorine, bromine, iodine, SO2alkyl, SO2foralkyl, SO2aryl, mesilate (methanesulfonate) or triplet (triftorbyenzola). Source the materials of the General structure 1 (for example, 2-chloronicotinic acid, 2-bromonicotinate acid or 3-bromoisonicotinic acid) are known compounds and are commercially available or can be obtained in numerous ways using conventional reaction methods known from the prior art. For example, the carboxylic acid group in Allah 1 can be obtained from the appropriate benzonitrile or from the corresponding esters of carboxylic acids using standard reaction conditions known for transformations of this type skilled in the art, such as hydrolysis, catalyzed by acid (e.g., H2SO4, HCl) or by mixing with the hydroxides of alkali metals (for example, LiOH, NaOH, KOH), in a solvent mixture, usually containing THF and water, optionally in the presence of alcohols, such as methanol or ethanol), when conventional heating or heating by microwave radiation. These reactions can be carried out in a wide temperature range from room temperature to the boiling temperature of the solvent. The phenols of formula 2 are known compounds and are commercially available, or can be obtained by multiple methods, using conventional reaction techniques known to a person skilled in the technical field.

Amide condensation of intermediate compounds is s kilowog ether 3 with optional substituted cycloalkyl/arylamine 4 (commercially available or obtained by means described in the prior art, or by known methods) leads to the production of the target structures of the General structure (I) (scheme 1, stage b). Amide condensation of this type are widely described in the prior art (for example, article Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2-thedition, Richard C. Larock, John Wiley & Sons, New York, NY. 1999), and can be implemented using a condensing reagent such as, for example, N,N-carbonyldiimidazole (CDI), N,N-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexaflurophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (NOVT), O-benzotriazol-1-yl-N,N,N,N-tetramethylurea tetrafluoroborate (TBTU) or 2-chloro-1-methylpyridine iodide (reagent of Mukoyama; E. Bald, K. Saigo, and T. Mukaiyama, Chem. Lett., 1975, 4, SS.1163-1166) in a suitable solvent, such as, for example, N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), dichloromethane or dioxane, optionally in the presence of a base (e.g. triethylamine, diisopropylethylamine or 4-(dimethylamino)pyridine). Alternatively, the target structure (I) can be obtained by transformation of intermediate compound 3 in their anhydrides acid treatment, for example, thionyl chloride without solvent, or optionally in a solvent such as, for example, dichloromethane, and the reaction of carboxylic acids with amines 4 in the walking solvent, such as, for example, dichloromethane or DMF (N,N-dimethylformamide) and bases, such as, for example, triethylamine, N-ethyldiethanolamine (base Chenega), pyridinedicarboxylate or 4-(dimethylamino)pyridine, and these reactions are carried out in a wide temperature range from room temperature to the boiling point of the used solvent. When aniline 4 represents a primary amine, which leads to alkylation of amides (e.g., methylation) amide linkages, it can be carried out by reaction with alkylhalogenide (for example, methyliodide or bromide) in the presence of a base such as sodium hydride, in a suitable solvent, such as DMF (N,N-dimethylformamide), THF or mixtures thereof, at temperatures from CT to elevated temperatures (scheme 1, stage C).

Target structures of formula I can also be obtained by using the inverse of the reaction sequence, namely, first, the formation of amide linkages between arylcarbamoyl acids 1 and cycloalkyl/arylamine 4 (scheme 2, step a), followed mediated by copper(aryl)-O condensation of intermediate 5 with phenols 2 (scheme 2, step b). Then get the target structure (I), which further alkiliruyutza to the secondary amide (scheme 2, step C). When the amino group is a target group, option strategies, preveden the th scheme 1, is a special interest. On the contrary, the strategy illustrated in figure 2, allows you to change the phenolic part of the structure quickly and in parallel.

Scheme 2

As described above, the compounds of formula I of the present invention can be used as an intermediate means for the treatment of diseases that are associated with the modulation of GPBAR1 activity.

Since the compounds of formula I of the present invention are agonists of the receptor GPBAR1, the compounds are useful for reducing the level of glucose, lipids and insulin resistance in patients with diabetes and patients without diabetes who have poor glucose tolerance or who are predisposed to diabetes. The compounds of formula I are also useful to facilitate hyperinsulinemia, which often occurs in patients with diabetes or pre-emergence diabetes by modulating increase the level of glucose in serum, which is often found in these patients. The compounds of formula I are also useful for reducing the risks associated with metabolic syndrome, to reduce the risk of atherosclerosis or stop the spread of atherosclerosis and reduce the risk of angina, claudication, heart attack, stroke, and coronary arterial disease. Supporting hyperglycemia under control is, the compounds are useful for stopping or prevention of vascular restenosis and diabetic retinopathy.

The compounds of formula I of the present invention is useful to improve or restore β-cell function, so that they can be useful for the treatment of type 1 diabetes or stop or prevent patients with type 2 diabetes requiring insulin therapy. Connections can be used to reduce appetite and body weight in obese patients, and therefore, can be useful to reduce the risk of co-morbidities associated with obesity such as hypertension, atherosclerosis, diabetes, and dyslipidemia. By increasing the levels of active GLP-1 in vivo, the compounds are useful for the treatment of neurological disorders such as Alzheimer's disease, multiple sclerosis and schizophrenia.

So, the expression ' diseases which are associated with the modulation of GPBAR1 activity" refers to diseases such as metabolic, cardiovascular and inflammatory diseases, for example diabetes, especially type 2 diabetes or gestational diabetes, impaired uptake of glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglyceridemia, dyslipidemia is or hyperlipidemia, lipid abnormalities such as low HDL cholesterol or high LDL cholesterol, high blood pressure, angina, coronary arterial disease, atherosclerosis, cardiac hypertrophy, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, disease, Irritable bowel (IBS), allergic diseases, fatty liver, liver fibrosis, cirrhosis, cholestasis of the liver, kidney fibrosis, anorexia nervosa, bulimia nervosa and neurological disorders such as Alzheimer's disease, multiple sclerosis, schizophrenia and impaired cognitive ability.

In a preferred embodiment, the expression 'diseases which are associated with the modulation of GPBAR1 activity'refers to diabetes, especially type II diabetes, impaired absorption of glucose, impaired glucose tolerance, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia and dyslipidemia. More preferably, the expression 'diseases which are associated with the modulation of GPBAR1 activity'refers to diabetes, preferably type II diabetes, and hyperglycemia.

The present invention also relates to pharmaceutical compositions containing the compound, as defined above, and a pharmaceutically acceptable carrier and/or adjuvant. More specifically, the invention con is seeking to pharmaceutical compositions, useful for treating diseases that are associated with the modulation of GPBAR1 activity.

In addition, the present invention relates to compounds of formula I as defined above for use as therapeutically active substances, especially as therapeutically active substances for the treatment of diseases that are associated with the modulation of GPBAR1 activity. Especially preferred are the compounds of formula I for use for the treatment of diabetes, preferably type II diabetes, or hyperglycemia.

In another embodiment, the present invention relates to a method of treating diseases that are associated with the modulation of GPBAR1 activity, which includes the introduction of a therapeutically active amount of the compounds of formula I to a human or animal. A method of treatment of diabetes, preferably type II diabetes, or hyperglycemia, is preferred.

The present invention also relates to the use of compounds of the formula I as defined above for the treatment of diseases that are associated with the modulation of GPBAR1 activity.

In addition, the present invention relates to the use of compounds of the formula I as defined above for the manufacture of drugs for the treatment of diseases that are associated with the modulation of GPBAR1 activity. The use of compounds of the formula I as defined what about the above for the manufacture of medicines for diabetes, preferably type II diabetes, or hyperglycemia, is preferred.

Also described combination therapy with one or more compounds of the formula I or compositions of the present invention or their pharmaceutically acceptable salts, in combination with one or more other pharmaceutically active compounds independently selected from the group consisting of the following substances:

(a) gamma agonists activated proliferation peroxisome receptor (PPAR) of the person (for example, preparations of thiazolidinediones and glitazone, for example, rosiglitazone, troglitazone, piaglitazone, englitazone, balaglitazone and netoglitazone),

(b) biguanides, such as Metformin, Metformin hydrochloride, buformin, phenformin,

(c) inhibitors dipeptidylpeptidase IV (DPP-4), such as sitagliptin, sitagliptin phosphate, saxagliptin, vildagliptin, alogliptin, Carmelites, linagliptin, sitagliptin, saxagliptin and SYR-322,

(d) incretin, such as agonists of the receptor of like peptide-1 (GLP-1) (for example, exenatide (Byetta™), NN2211 (liraglutide), amide GLP-1(7-36) and its analogues, GLP-1(7-37) and its analogues, AVE-0010 (ZP-10), R1583 (taspoglutide), GSK-716155 (albiglutide, GSK/Human Genome Sciences), BRX-0585 (Pfizer/Biorexis) and CJC-1134-PC (basis 4:RS PAZ™) or glucosideuronic insulinotropic peptide (GIP),

(e) insulin or insulin analogs, such as LysPro insulin or inhalated SOS is ava, containing insulin,

(f) sulfonylureas such as tolazamide, hlorpropamid, glipizide, glimepiride, gliburid, glibenclamide, tolbutamide, acetohexamide or glipizide,

(g) inhibitors of α-glucosidase, such as miglitol, acarbose, epalrestat or voglibose,

(h) inhibitors of cholesterol biosynthesis, such as inhibitors of HMG COA reductase, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, tseriwastatina, Faustin, nicastrin and mevastatin, or inhibitors salanova epoxidase, for example, terbinafine,

(i) agents that increase the level of HDL in the plasma, such as inhibitors SETR, for example, anacetrapib, torcetrapib and dalcetrapib, or agonists, PPAR alpha, for example, gemfibrozil, clofibrate, fenofibrate and bezafibrat,

(j) dual PPAR alpha/gamma agonists, such as muraglitazar, naveglitazar, aleglitazar, tesaglitazar, pioglitazon, farglitazar and JT-501,

(k) substances that contribute to the accumulation of bile acids, for example, anion exchange resin, or Quaternary amines (e.g., cholestyramine or colestipol), or inhibitors of bile acid Transporter in the small intestine (BATi);

(l) nicotinebuy alcohol, nicotinic acid, Niacinamide or its salt,

(m) inhibitors of cholesterol absorption, such as ezetimibe, or inhibitors of acyl-coenzyme a:cholesterol O-acyltransferase (AST), such as AVAS the MIB,

(n) are selective modulators of the estrogen receptor, such as raloxifene or tamoxifen) or LXR agonists alpha or beta antagonists or partial agonists (such as 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, T or GW3965);

(a) inhibitors of protein microsomal triglyceride transfer (MTP), A2-antagonists and imidazolines (for example, midaglizole, Salida, deriglidole, idazoxan, efaroxan, flyproxy),

(b) substances, contributing to the generation of insulin, such as linogliride, nateglinide, Repaglinide, mitiglinide hydrate or meglitinide);

(q) inhibitors of SGLT-2 (for example, dapagliflozin, sergliflozin and AVE 2268),

(s) glucokinase activators such as the compounds described, for example, in international patent application WO 00/58293 A1;

(t) inhibitors patientinitiated-1B (PTP-1B),

(u) antagonists glucagonoma receptor,

(v) agents, anti-obesity, such as fenfluramine, dexfenfluramin phenteramin, sibutramine, orlistat, antagonists of neuropeptide Y1 or Y5, agonists, neuropeptide Y2, agonists, MC4R (melanocortin receptor 4), antagonists of cannabinoid receptor 1 (CB-1)/inverse agonists and agonists B3-adrenergic receptor (e.g., GW-320659), agonist of growth factor nerve (e.g., axokine), agonists of growth hormone (e.g., AOD-9604), an inhibitor of 5-HT (serotonin) perezagua/transport (e.g. the measures Prozac), inhibitors of perezagua DA (dopamine) (for example, bupropion), 5-HT, NA and blockers perezagua DA, steroid plant extracts (for example, P57), agonists, CCK-a (cholecystokinin-A)antagonist GHSR1a (receptor, releasing growth factor)/inverse agonists, ghrelin antibodies, MCH1R antagonists (melaninconcentrating hormone 1R) (e.g., SNAP 7941), agonist/antagonists MCH2R (melaninconcentrating hormone 2R), inverse agonists or antagonists NC (histamine receptor 3), aginity H1 (histamine receptor 1), inhibitors of FAS (fatty acid synthase)inhibitors ACC-2 (acetyl-COA carboxylase-1), inhibitors of DGAT-2 (diacylglycerides 2), inhibitors of DGAT-1 (diacylglycerides 1), CRF agonists (corticotropinreleasing factor)antagonists Galanina, activators UCP-1 (unbound protein-1), 2 or 3, leptin or derivatives of leptin, opioid antagonists, antagonists of orexin, BRS3 agonist, the agonist of GLP-1 (like peptide-1), agonists of IL-6, agonists a-MSH antagonist AgRP, BRS3 agonist (bumbasirevic receptor subtype 3)agonists 5-NTV antagonists O.G. ROMs, CNTF (ciliary neurotrophic factor or derived CNTF), NN2211, topiramate, glucocorticoid antagonist, the agonist of the basis 4, agonists of 5-HT2C(serotonin receptor 2C) (for example, lorcaserin), inhibitors of PDE (phosphodiesterase)inhibitors of transport girn the x acids, inhibitors of transport in primary forms, inhibitors of glucose transport,

(w) anti-inflammatory agents, such as inhibitors of cyclicality-2 (SOH-2) (for example, rofecoksib and celecoxib); glucocorticoids, azulfidine, thrombin inhibitors (eg, heparin, argatroban, melagatran, dabigatran) and platelet aggregation inhibitors (e.g., antagonists of glycoprotein IIb/IIIa fibrinogenesis receptor or aspirin), and

(y) antihypertensive agents such as beta-blockers (e.g., receptor antagonists angiotensin II, such as losartan, eprosartan, irbesartan, tasosartan, telmisartan or valsartan; angiotensin converting enzyme inhibitors such as enalapril, captopril, cilazapril, ramipril, zofenopril, lisinopril and fosinopril; blockers, calcium channel, such as nifedipine and diltiazam, and endothelial antagonists.

Such other pharmaceutically active compounds can be administered in usually the quantity used, therefore, simultaneously or sequentially with the compound of the formula I or its pharmaceutically acceptable salt. In the treatment of patients with type 2 diabetes, insulin resistance, obesity, metabolic syndrome, neurological disorders and comorbid conditions that accompany these diseases usually do a few pharmacist is logically active compounds. The compounds of formula I of the present invention typically can be administered to a patient already taking one or more medications for these conditions. When the compound of formula I is used simultaneously with one or more other pharmaceutically active compounds, pharmaceutical composition in unit dosage form containing such other pharmaceutically active compound and the compound of formula I is preferred. Thus, the invention also relates to pharmaceutical compositions containing a compound of formula I in combination with one or more other pharmaceutically active compounds, as defined above. When used in combination with one or more other active ingredients, a compound of formula I of the present invention and other pharmaceutically active compounds can be administered in lower doses than individual use. These pharmaceutical compositions are also included in the present invention.

However, combination therapy also includes therapies in which the compound of formula I and one or more other pharmaceutically active compounds are administered in various dosage forms, but the overlapping scheme. The present invention also relates to a method of treatment of disease is s, that are associated with the modulation of GPBAR1 activity, which includes the introduction of a therapeutically active amount of the compounds of formula I in combination with one or more other pharmaceutically active compounds in human or animal.

The following test was carried out to determine the activity of compounds of the formula I:

cDNA of the receptor GPBAR1 human (Genbank: NM_170699 except for the weak C:G mutations at position 339 from the start codon) amplified polymerase chain reaction (PCR) from cDNA of man, and was built in pCineo (Promega) by standard methods (Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel and others). The final clone was verified by analysis of DNA sequences. The plasmids were transferrable in Cho cells, an excellent activity digidrofolatreduktazy (CHO-dhfr-), using lipofectamine plus (Invitrogen). Clones were isolated with limited dilution, and identified the activities in the analysis of camp, using lithocholic acid as the agonist. The cloned cell line, which showed the highest activity increases camp, were selected and identified as giving equally good response up to 20 passages.

Analysis of camp

Cells Cho-dhfr (minus)expressing the receptor GPBAR1 man planted for 17-24 hours before the experiment in the amount of 50,000 cells per well in a black 96-well p is ancheta with clear bottom (Corning Costar # 3904) in DMEM (Invitrogen No. 31331), additive 1x HT with 10% serum embryo calf, and incubated in 5% CO2and 37°C in a humidified incubator. Environment for the growth was replaced by bicarbonate buffer Krebs Ringer with 1 mm IBMX, and incubated at 30°C for 30 min. Compounds were added in a final volume analysis, 100 μl, and incubated for 30 min at 30°C. the assay was stopped by adding 50 µl lisanova reagent (Tris, NaCl, and 1.5% Triton X100, 2.5% of NP40, 10% NaN3) and 50 μl of the solutions to determine (20 μm mAb AEA-camp 1:1, and 48 μm ruthenium-2-AHA-camp), and was shaken for 2 h at room temperature. Temporary energy transfer was measured using counter TRF (Evotec Technologies GmbH, Hamburg, Germany)equipped with a ND:YAG laser as excitation source. The tablet was measured twice with excitation at 355 nm and at emission with the stop 100 and the output is not 100, the total processing time of 10 s at 730 (frequency 30 nm) or 645 nm (frequency 75 nm), respectively. The measured signal at 730 nm was correlated with ruthenium layer, direct excitation of Alexa and the control buffer.

The FRET signal was calculated as follows: FRET=T730-Alexa730-R(T-V) with P=Ru730-B730/Ru645-B645, where T is a test hole, measured at 730 nm, T is a test hole, measured at 645 nm, V and W represent the buffer controls at 730 nm and 645 nm, respectively. The content of camp was determined by standard functions the th curve, constructed from 10 μm to 0.13 nm camp.

Values EU50were determined using the primary analysis activity (ID Business Solution Limited). Values EU50for a wide range of bile acids obtained from this analysis were consistent with values published in the scientific literature. Specificity GPBAR1 tested in retransferring Cho cells by the same analysis as described above.

Compounds in accordance with formula I have activity in the above assay (EU50) is preferably from 0.5 nm to 10 μm, more preferably from 0.5 nm to 2 μm, more preferably from 0.5 nm to 1 μm, and most preferably from 0.5 nm to 100 nm.

For example, the following compounds showed the following values EU50for the man in the functional analysis of camp, described above:

ExampleEU50for man [µm]ExampleEU50for man [µm]
10,39694of) 0.157
20,989950,028
3 0,192960,328
41,398970,028
50,649980,217
60,996990,388
70,5751001,055
80,6441010,150
91,014 registered1020,703
100,0531030,299
110,1531040,173
121,152105was 0.138
130,1491060,425
140,236107to 0.662
151,6921080,122
161,9231090,562
170,1761100,029

ExampleEU50for man [µm]ExampleEU50For man [µm]
180,322111is 0.102
19of 0.6251121,714
200,4731130,149
210,3451140,946
220,6511150,920
230,2321161,160
240,0101170,572
250,1281180,771
260,1061190,165
270,1451201,654
281,9761210,231
290,1441220,062
300,4361230,002
31was 0.1381240,607
320,0701250,004
330,203 1260,010
340,0581270,014
350,2831280,918
36is 0.1351290,024
370,0281301,829
380,0571310,321
390,029132of 0.066
400,1031331,974
410,0331341,652
420,0201350,473
430,4961360,246
44 0,0441370,201
450,0921380,035
460,9051390,926
471,2471400,259
48of 0.0661410,324
490,1731420,307
500,6311430,745
510,0591440,286
520,1161450,029
530,3211461,967
540,0351470,015
550,6411481,964
561,3931490,155
570,3851500,058
580,7581511,071
591,5541520,689
601,551153of 0.565
611,9791540,053
620,8201550,788
630,1701560,841

ExampleEU50for man [µm]ExampleEU50for a person [who kms]
640,1551571,676
650,3571580,384
660,5181590,395
671,6911600,724
680,8371610.104 g
690,5661621,164
700,5611630,054
710,436164being 0.036
720,1631650,340
730,4181660,148
741,532 1670,211
751,5771681,436
761,956169to 0.127
770,7651700,069
780,128171is 0.102
79to 0.1271720,132
800,6301730,047
810,0781740,029
821,2671750,843
830,0131760,114
84China 0,6861770,063
85 0,2311780,096
860,0961790,041
870,0751800,071
880,9501810,091
890,0071820,181
900,0191830,341
910,0151840,022
920,0071850,092
930,057

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, parenteral or local administration. They can be entered, e.g. the, orally, for example in the form of tablets, oblachennyh tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or suspensions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.

Obtaining pharmaceutical drugs can be performed in a manner known to the person skilled in the art by introducing described compounds of formula I and their pharmaceutically acceptable salts, optionally in combination with other therapeutically active substances in herbal form for injection together with suitable, non-toxic, inert, therapeutically compatible solid or liquid materials of the carrier, and if necessary, useful pharmaceutical adjuvants.

Suitable materials media are not only inorganic materials media, but also organic materials media. So, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as materials of media tablets, coated tablets, dragées and hard gelatin capsules. Suitable materials of medium to soft W is latinovich capsules are for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient carriers, however, may not be required for soft gelatin capsules). Suitable materials of the carrier for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Appropriate media materials for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable materials media for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable materials media for local products are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose

Conventional stabilizers, preservatives, moisturizing and emulsifying agents that improve the consistency of agents that improve the smell of agents, salts for regulating the osmotic pressure, buffer substances, soljubilizatory, dyes and masking agents and antioxidants are used as pharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limits depending on the controlled Zabol the tion, age and individual condition of the patient and the route of administration, and, of course, be adjusted in accordance with the individual requirements in each particular case. For adult patients suitable daily dosage of from about 1 to 1000 mg, especially from about 1 to 300 mg, depending on the severity of the disease and pre-defined pharmacokinetic profile of the compound may be injected in one or more daily unit doses, for example, 1-3 metered units.

The pharmaceutical preparations normally contain about 1-500 mg, preferably 1-100 mg of the compounds of formula I.

The following examples serve to further illustrate the present invention. However, they are in no way intended to limit its scope.

Examples

Abbreviations:

CAS RN = register number in chemical abstracts. Celite® = filtration material, DMAc = dimethylacetamide, DMAP = 4-dimethylaminopyridine, DMF = N,N-dimethylformamide, DMSO = dimethylsulfoxide, EI = electron impact, h = hour, HATU = hexaphosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide, HCl = hydrogen chloride, HPLC = high performance liquid chromatography; ICP = positive ion flow (the way), ISN=negative ion flow (method), min = minutes, LiOH = lithium hydroxide, MgSO4= magnesium sulfate, MPLC = liquid the chromatography medium pressure, MS = mass spectrum, NaHCO3= sodium bicarbonate, NaOH = sodium hydroxide, Na2SO4= sodium sulfate, NH4Cl = chloride of ammonium, NMR = nuclear magnetic resonance, KOH = potassium hydroxide, P = protective group, R = any group, CT = room temperature, SiO2= silica gel, THF = tetrahydrofuran, X = halogen.

Example 1

(3,4-Dihydro-2H-quinoline-1-yl)-[2-(3-triptoreline)pyridine-3-yl]metano

Stage 1: 2-(3-Triptoreline)nicotinic acid

To a solution of 2-chloronicotinic acid (1.0 g, 6.35 mmole, 1.0 equiv.; [CAS RN 2942-59-8]) and 3-triptoreline (1,03 g, 6.35 mmole, 1.0 equiv.; [CAS RN 98-17-9]) in anhydrous DMF (5 ml) was added potassium carbonate (1.75 g, 12,69 mmole, 2.0 equiv.; [CAS RN 584-08-7]), copper iodide (I) (0.12 g, of 0.64 mmole, 0.1 equiv.; [CAS RN 7681-65-4]) and copper nanopowder (0) with an average particle size of 100 nm (0.12 g, 1,90 mmole, 0.3 equiv.; [CAS RN 7440-50-8]). The reaction mixture was heated under microwave irradiation at 140°C for 30 minutes the Solvent was evaporated under reduced pressure and the crude reaction product was transferred into water (25 ml) and was filtered. The value of pH was brought to 4 by adding acetic acid and the resulting white precipitate was filtered off, washed with small amount of cold water and dried in high vacuum with the receipt of 0.53 g (28%) specified in the connection header.1H NMR (300 MHz, DMSO): δ 7,26-7,30 m, 1H), 7,43-to 7.50 (m, 2H), EUR 7.57-7,66 (m, 2H), compared to 8.26-8,29 (m, 2H).19F NMR (282 MHz, DMSO): δ -61,0. MS (ISN): 282,1 [M-H]-.

Stage 2:

To a solution of 2-(3-triptoreline)nicotinic acid (200 mg, of 0.71 mmole, 1.0 equiv.) in anhydrous DMF (3 ml) was added 1,2,3,4-tetrahydroquinolin (113 mg, 107 μl, of 0.85 mmole, 1.2 equiv.; [CAS RN 635-46-1]), N-ethyldiethanolamine (457 mg, 617 μl, of 3.53 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (322 mg, of 0.85 mmole, 1.2 equiv.; [CAS RN 148893-10-1]). The reaction mixture was heated under microwave irradiation at 100°C for 5 min to Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler pumps, two Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and Rooms UVD 340S UV detector), elwira gradient acetonitrile/water, resulted in the receipt of 157 mg (56%) specified in the connection header. MS (ISP): 399,2 [M+H]+.

Example 2

[2-(2-Chlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(2-Chlorophenoxy)nicotinic acid

2-(2-Chlorophenoxy)nicotinic acid was obtained analogously to example 1, step 1, replacing 3-cryptomaterial 2-chlorophenol ([CAS RN 95-57-8]). MS (ISN): 248,1 [M-H]-.

Stage 2:

Specified in the title compound was obtained analogously to example 1, step 2, substituting 2-(3-triptoreline)nicotinic acid 2-(2-chloro what enocsi)nicotinic acid. MS (ISP): 365,1 [M+H]+.

Example 3

[2-(3-Chlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(3-Chlorophenoxy)nicotinic acid

2-(3-Chlorophenoxy)nicotinic acid was obtained analogously to example 1, step 1, replacing 3-cryptomaterial 3-chlorophenol ([CAS RN 108-43-0]).1H NMR (300 MHz, DMSO): δ 7,11 (d, J=9.0 Hz, 1H), 7,25-7,30 (m, 3H), 7,44 (t, J=7.5 Hz, 1H), 8,29-8,31 (m, 1H), 13,28 (br s, 1H). MS (ISN): 248.1 [M-H]-.

Stage 2:

Specified in the title compound was obtained analogously to example 1, step 2, substituting 2-(3-triptoreline)nicotinic acid 2-(3-chlorophenoxy)nicotinic acid. MS (ISP): 365,1 [M+H]+.

Example 4

(6-Methyl-3,4-dihydro-2H-quinoline-1-yl)-[2-(3-triptoreline)pyridine-3-yl]metano

Specified in the title compound was obtained from 2-(3-triptoreline)nicotinic acid analogously to example 1, step 2, substituting 1,2,3,4-tetrahydroquinolin 6-methyl-1,2,3,4-tetrahydroquinolin ([CAS RN 91-61-2]). MS (ISP): 413,2 [M+H]+.

Example 5

[2-(3-Chlorophenoxy)pyridine-3-yl-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 1, step 2, substituting 2-(3-triptoreline)nicotinic acid 2-(3-chlorophenoxy)nicotinic acid (example 3, step 1) and 1,2,3,4-tetrahydroquinolin 6 IU the Il-1,2,3,4-tetrahydroquinolin ([CAS RN 91-61-2]). MS (ISP): 379,1 [M+H]+.

Example 6

[2-(3,4-Dichlorophenoxy)pyridine-3-yl-(3.4-dihydro-2H-quinoline-yl)methanon

Stage 1: (2-Chloropyridin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon

To a solution of 2-chloronicotinic acid (1.0 g, 6.35 mmole, 1.0 equiv.; [CAS RN 2942-59-8]) in dichloromethane (40 ml) was added 1,2,3,4-tetrahydroquinolin (0,93 g to 0.88 ml, 6,98 mmole, 1.1 equiv.; [CAS RN 635-46-1]), triethylamine (1.28 g, 1.77 ml, 12,69 mmole, 2.0 equiv.; [CAS RN 121-44-8]) and iodide 2-chloro-1-methylpyridine (1,96 g, 6,98 mmole, 1.1 equiv.; [CAS RN 14338-32-0]). The reaction mixture was stirred at RT for 2 hours To the residue was added to feast upon. the solution of NaHCO3(100 ml)and the solution was extracted with dichloromethane (3×50 ml). The combined organic phases were dried Na2SO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate, getting 1.52 g (88%) indicated in the title compound as a pale yellow solid.1H NMR (400 MHz, CDCl3): δ 2,07 (quint, J=6.6 Hz, 2H), 2,86 (t, J=6.6 Hz, 2H), 3,90 (t, J=6.4 Hz, 2H), only 6.64 (br s, 1H), 6,93 (br t, J=4.0 Hz, 1H),? 7.04 baby mortality (br d, J=4.0 Hz, 1H), was 7.08 (t, J=7,6 Hz, 1H), 7,19 (d, J=7,6 Hz, 1H), 7,30 (s, 1H), 8,31 (d, J=7,6 Hz, 1H). MS (ISP): 273,1 [M+H]+.

Stage 2:

To a solution of (2-chloropyridin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanone (50 mg, of 0.18 mmole, 1.0 equiv.) and 3,4-dichlorophenol (29,9 mg of 0.18 mmole, 1.0 equiv.; [CAS RN 95-77-2]) in anhydrous DMF (1 ml) we use the and potassium carbonate (50,7 mg, 0.37 mmole, 2.0 equiv.; [CAS RN 584-08-7]), copper iodide(I) (3.5 mg, 0,018 mmole, 0.1 equiv.; [CAS RN 7681-65-4]) and copper nanopowder(0) with an average particle size of 100 nm (3.5 mg, by 0.055 mmole, 0.3 equiv.; [CAS RN 7440-50-8]). The reaction mixture was heated under microwave irradiation at 200°C for 30 minutes Cleaning preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215 pumps, two Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and Rooms UVD 340S UV detector), elwira gradient acetonitrile/water, resulted in the receipt of 2.2 mg (3%) specified in the connection header. MS (ISP): 399,2 [M+H]+.

Example 7

3-[3-(3,4-Dihydro-2H-quinoline-1-carbonyl)pyridine-2-yloxy]benzonitrile

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-hydroxybenzonitrile ([CAS RN 873-62-1]). MS (ISP): 356,1 [M+H]+.

Example 8

(3,4-Dihydro-2H-quinoline-1-yl)-(2-m-collectibility-3-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-METHYLPHENOL ([CAS RN 108-39-4]). MS (ISP): 345,4 [M+H]+.

Example 9

[2-(3-Chloro-4-methylphenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol is 3-chloro-4-METHYLPHENOL ([CAS RN 615-62-3]). MS (ISP): 379,3 [M+H]+.

Example 10

[2-(3-Chloro-4-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-chloro-4-terfenol ([CAS RN 2613-23-2]). MS (ISP): 383,3 [M+H]+.

Example 11

[2-(5-Chloro-2-methylphenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 5-chloro-2-METHYLPHENOL ([CAS RN 5306-98-9]). MS (ISP): 379,3 [M+H]+.

Example 12

[2-(2,3-Dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 2.3-dichlorphenol ([CAS RN 576-24-9]). MS (ISP): 399,2 [M+H]+.

Example 13

[2-(3-Chloro-5-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-chloro-5-terfenol ([CAS RN 202982-70-5]). MS (ISP): 383,3 [M+H]+.

Example 14

(3,4-Dihydro-2H-quinoline-1-yl)-[2-(2,4,5-trichlorophenoxy)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophe the ol on 2,4,5-trichlorophenol ([CAS RN 95-95-4]). MS (ISP): 435,1 [M+H]+.

Example 15

[2-(3-Benzoylperoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol (3-hydroxyphenyl)phenylmethane ([CAS RN 13020-57-0]). MS (ISP): 435,2 [M+H]+.

Example 16

(3,4-Dihydro-2H-quinoline-1-yl)-[2-(3-triftormetilfosfinov)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-cryptomaterial ([CAS RN 827-99-6]). MS (ISP): of 415.3 [M+H]+.

Example 17

[2-(3,5-Dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3.5-dichlorphenol ([CAS RN 591-35-5]). MS (ISP): 399,2 [M+H]+.

Example 18

(3,4-Dihydro-2H-quinoline-1-yl)-[2-(3-pertenece)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-terfenol ([CAS RN 372-20-3]). MS (ISP): 349,3 [M+H]+.

Example 19

(3,4-Dihydro-2H-quinoline-1-yl)-[2-(3-isopropylphenoxy)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichl rfinal 3-isopropylphenol ([CAS RN 618-45-1]). MS (ISP): 373,4 [M+H]+.

Example 20

(3,4-Dihydro-2H-quinoline-1-yl)-[2-(3-ethylenoxy)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-ethylphenol ([CAS RN 620-17-7]). MS (ISP): 359,2 [M+H]+.

Example 21

(3,4-Dihydro-2H-quinoline-1-yl)-[2-(3-iodinase)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-itfinal ([CAS RN 626-02-8]). MS (ISP): 457,1 [M+H]+.

Example 22

[2-(3-Chloro-2-fluoro-5-triptoreline)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-chloro-2-fluoro-5-triptoreline ([CAS RN 261763-12-6]). MS (ISP): 451,2 [M+H]+.

Example 23

[2-(3-Bromophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 3-bromophenol ([CAS RN 591-20-8]). MS (ISP): 409,2 [M+H]+.

Example 24

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 2, substituting 3,4-dichlorophenol 2.5-chlorphenol ([CAS RN 583-78-8]). MS (ISP): 399,2 [M+H]+.

Example 25

[2-(3-Chlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: (2-Chloro-5-herperidin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon

To a solution of 2-chloro-5-fornicating acid (0,60 g of 3.42 mmole, 1.0 equiv.; [CAS RN 38186-88-8]) in anhydrous DMF (5 ml) was added 1,2,3,4-tetrahydroquinolin (0.55 g, of 0.52 ml, 4,10 mmole, 1.2 equiv.; [CAS RN 635-46-1]), N-ethyldiethanolamine (2,21 g, 2.91 in ml, 17,09 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (1.56 g, 4,10 mmole, 1.2 equiv.; [CAS RN 148893-10-1]). The reaction mixture was heated under microwave irradiation at 100°C for 10 minutes To the residue was added to feast upon. a solution of NaHCO3(50 ml)and the solution was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried Na2SO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate, getting 0.51 g (52%) indicated in the title compound as a pale yellow solid. MS (ISP): 291,1 [M+H]+.

Stage 2:

To a solution of (2-chloro-5-herperidin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanone cases (53.2 mg, of 0.18 mmole, 1.0 equiv.) and 3-chlorophenol (23,5 mg of 0.18 mmole, 1.0 equiv.; [CAS RN 108-43-0]) in acetonitrile (1 ml) was added potassium carbonate (50,7 mg, 0.37 mmole, 2.0 equiv.; [CAS RN 584-08-7]), copper iodide (I) (3.5 mg, 0,018 mmole, 0.1 equiv.; [CAS RN 7681-65-4]) and copper nanopowder(0) with an average RA is the mayor of particles 100 nm (3.5 mg, by 0.055 mmole, 0.3 equiv.; [CAS RN 7440-50-8]). The reaction mixture was heated under microwave irradiation at 200°C for 90 minutes removing the solvent under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, h mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 4.3 mg (6%) specified in the connection header. MS (ISP): 383,2 [M+H]+.

Example 26

[2-(2,5-Divergence)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 25, step 2, substituting 3-chlorophenol 2.5-diferena ([CAS RN 2713-31-7]). MS (ISP): 385,3 [M+H]+.

Example 27

[5-Chloro-2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: (2.5-Dichloropyridine-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon

(2.5-Dichloropyridine-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon was obtained analogously to example 25, step 1, substituting 2-chloro-5-fornicating acid 2,5-dichloronicotinic acid ([CAS RN 59782-85-3]). MS (ISP): 307,2 [M+H]+.

Stage 2:

Specified in the title compound was obtained analogously to example 25, step 2, replacing (2-chloro-5-herperidin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanol (2,5-d is chloropyridin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon, and 3-chlorophenol 2.5-dichlorphenol ([CAS RN 583-78-8]). MS (ISP): 433,2 [M+H]+.

Example 28

[5-Chloro-2-(2,5-divergence)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 27, step 2 replacing 2,5-dichlorophenol 2.5-diferena ([CAS RN 2713-31-7]). MS (ISP): 401,3 [M+H]+.

Example 29

[2-(2,5-Dichlorophenoxy)-6-triptorelin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: (2-Chloro-6-triptorelin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon

(2-Chloro-6-triptorelin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon was obtained analogously to example 25, step 1, substituting 2-chloro-5-fornicating acid 2-chloro-6-triftormetilfosfinov acid ([CAS RN 280566-45-2]). MS (ISP): 341,1 [M+H]+.

Stage 2:

Specified in the title compound was obtained analogously to example 25, step 2, replacing (2-chloro-5-herperidin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon (2-chloro-6-triptorelin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon, and 3-chlorophenol 2.5-dichlorphenol ([CAS RN 583-78-8]). MS (ISP): 467,1 [M+H]+.

Example 30

[2-(3-Chlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

Specified in the title compound was obtained analogously to example 3, step 2, substituting 1,2,3,4-tetrahydroquinolin on 3,4-dihydro-2H-benzo[1,4]OK asin ([CAS RN 5735-53-5]). MS (ISP): 367,2 [M+H]+.

Example 31

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(2,5-Dichlorophenoxy)nicotinic acid

2-(2,5-Dichlorophenoxy)nicotinic acid was obtained analogously to example 1, step 1, replacing 3-cryptomaterial 2.5-dichlorphenol ([CAS RN 583-78-8]). MS (ISP): 284,0 [M+H]+.

Stage 2:

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (42,6 mg, 0.15 mmole, 1.0 equiv.) in anhydrous DMF (1 ml) was added 6-methyl-1,2,3,4-tetrahydroquinolin (26.5 mg, of 0.18 mmole, 1.2 equiv.; [CAS RN 91-61-2]), N-ethyldiethanolamine (97,0 mg, 131 μl, 0.75 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (68,4 mg of 0.18 mmole, 1.2 equiv.; [CAS RN 148893-10-1]). The reaction mixture was heated under microwave irradiation at 100°C for 10 minutes Remove the mixture of the solvent under reduced pressure and preparative purification (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and UV detector in Rooms UVD 340S) reverse phase, elwira gradient acetonitrile/water, resulted in the receipt of 30 mg (49%) specified in the connection header. MS (ISP): 413,2 [M+H]+.

Example 32

2-(2,5-Dichlorophenoxy)-N-ethyl-N-phenyldiamine

Specified in the title compound was obtained analogously to example 31, step 2, substituting 6-methyl-1,2,3,4-tetrahydro the quinoline to ethylvanillin ([CAS RN 103-69-5]). MS (ISP): 387,2 [M+H]+.

Example 33

(7-Chloro-3,4-dihydro-2H-quinoline-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (42,6 mg, 0.15 mmole, 1.0 equiv.; example 31, step 1) in anhydrous DMF (1.5 ml) were added hydrochloride is 7-chloro-1,2,3,4-tetrahydroquinoline (33,7 mg, 0,17 mmole, 1.1 equiv.; [CAS RN 90562-34-8]), triethylamine (30,4 mg, 42 μl, 0.3 mmole, 2.0 equiv.; [CAS RN 121-44-8]) and HATU (62,7 mg, 0,17 mmole, 1.1 equiv.; [CAS RN 148893-10-1]). The reaction mixture was heated under microwave irradiation at 110°C for 30 minutes Removing the mixture of the solvent under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 6 mg (10%) specified in the connection header. MS (ISP): 435,0 [M+H]+.

Example 34

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 33, replacing hydrochloride is 7-chloro-1,2,3,4-tetrahydroquinoline on the hydrochloride of 7-fluoro-1,2,3,4-tetrahydroquinoline (commercially available from Zannan Pharma Ltd). MS (ISP): 417,0 [M+H]+.

Example 35

2-(2,5-Dichlorophenoxy)-N-methyl-N-phenyldiamine the ID

Specified in the title compound was obtained analogously to example 33, replacing hydrochloride is 7-chloro-1,2,3,4-tetrahydroquinoline on methylphenylamine ([CAS RN 100-61-8]). MS (ISP): 373,0 [M+H]+.

Example 36

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (42,6 mg, 0.15 mmole, 1.0 equiv.; example 31, step 1) in dichloromethane (1.5 ml) was added 3,4-dihydro-2H-benzo[1,4]oxazin (22.9 mg, 0,17 mmole, 1.1 equiv.; [CAS RN 5735-53-5]), triethylamine (30,4 mg, 42 μl, 0.3 mmole, 2.0 equiv.; [CAS RN 121-44-8]) and iodide 2-chloro-1-methylpyridine (42.2 mg, 0,17 mmole, 1.1 equiv.; [CAS RN 14338-32-0]). The reaction mixture was stirred at RT over night. Remove the mixture of the solvent under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, has led to 11 mg (18%) specified in the connection header. MS (ISP): 401,0 [M+H]+.

Example 37

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (59,7 mg of 0.21 mmole, 1.0 equiv.; example 31, step 1) in dichloromethane (2 ml) to allali 6-fluoro-1,2,3,4-tetrahydroquinolin (34,9 mg, to 0.23 mmole, 1.1 equiv.; [CAS RN 59611-52-8]), triethylamine (42,5 mg, 59 μl, of 0.42 mmole, 2.0 equiv.; [CAS RN 121-44-8]) and iodide 2-chloro-1-methylpyridine (59,0 mg, 0,23 mmole, 1.1 equiv.; [CAS RN 14338-32-0]). The reaction mixture was stirred at 40°C during the night. Removal of solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, has led to 27 mg (31%) specified in the connection header. MS (ISP): 417,4 [M+H]+.

Example 38

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 37, substituting 6-fluoro-1,2,3,4-tetrahydroquinolin 6.7-debtor-1,2,3,4-tetrahydroquinolin ([CAS RN 953717-64-1]). MS (ISP): 435,1 [M+H]+.

Example 39

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]thiazin-4-yl)methanon

Specified in the title compound was obtained analogously to example 37, substituting 6-fluoro-1,2,3,4-tetrahydroquinolin on 3,4-dihydro-2H-benzo[1,4]thiazin ([CAS RN 3080-99-7]). MS (ISP): 417,1 [M+H]+.

Example 40

N-(2-Chlorophenyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the header of the group received analogously to example 37, substituting 6-fluoro-1,2,3,4-tetrahydroquinolin (2-chlorophenyl)methylamine ([CAS RN 932-32-1]). MS (ISP): 407,1 [M+H]+.

Example 41

2-(2,5-Dichlorophenoxy)-N-methyl-N-o-callincoming

Specified in the title compound was obtained analogously to example 37, substituting 6-fluoro-1,2,3,4-tetrahydroquinolin on methyl-o-tolylamino ([CAS RN 611-21-2]). MS (ISP): 387,1 [M+H]+.

Example 42

2-(2,5-Dichlorophenoxy)-N-(2-methoxyphenyl)-N-nicotine amide

Specified in the title compound was obtained analogously to example 37, substituting 6-fluoro-1,2,3,4-tetrahydroquinolin (2-methoxyphenyl)methylamine ([CAS RN 10541-78-3]). MS (ISP): 403,1 [M+H]+.

Example 43

N-Biphenyl-2-yl-2-('2.5 dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 37, substituting 6-fluoro-1,2,3,4-tetrahydroquinolin on the biphenyl-2-ylmethylamino ([CAS RN 14925-09-8]). MS (ISP): 448,9 [M+H]+.

Example 44

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 36, substituting 3,4-dihydro-2H-benzo[1,4]oxazin 6.8-debtor-1,2,3,4-tetrahydroquinolin ([CAS RN 926218-72-6]). MS (ISP): 434,9 [M+H]+.

Example 45

2-(2,5-Dichlorophenoxy)-N-(2-ethylphenyl)-N-nicotine amide

To a solution of 2-(2,5-di is lovenox)nicotinic acid (59,7 mg, of 0.21 mmole, 1.0 equiv.; example 31, step 1) in dichloromethane (2.0 ml) was added 2-ethylvanillin (27.9 mg, 0,23 mmole, 1.1 equiv.; [CAS RN 578-54-1]), triethylamine (42,5 mg, 59 μl, of 0.42 mmole, 2.0 equiv.; [CAS RN 121-44-8]) and iodide 2-chloro-1-methylpyridine (59,0 mg, 0,23 mmole, 1.1 equiv.; [CAS RN 14338-32-0]), and the reaction mixture was stirred at 40°C during the night. The solvent was removed on an evaporator under reduced pressure and the crude reaction mixture was dissolved in DMF (1 ml). To the solution was added sodium hydride (13,8 mg of 0.32 mmole, 1.5 equiv.; 55% free current powder moistened with oil; [CAS RN 7646-69-7]) and jodean (to 59.6 mg, 26 μl, of 0.42 mmole, 2.0 equiv.; [CAS RN 74-88-4]), and the reaction mixture was stirred at 35°C for 1 h Purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 6.9 mg (8%) specified in the connection header. MS (ISP): 401,2 [M+H]+.

Example 46

N-(3-Chloropyridin-2-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 3-chloropyridin-2-ylamine ([CAS RN 39620-04-7]). MS (ISP): 407,8 [M+H]+.

Example 47

N-(4-Chloropyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 4-chloropyridin-3-ylamine ([CAS RN 20511-15-3]). MS (ISP): 409,4 [M+H]+.

Example 48

2-(2,5-Dichlorophenoxy)-N-(2-methoxypyridine-3-yl)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2-methoxypyridine-3-ylamine ([CAS RN 20265-38-7]). MS (ISP): 403,6 [M+H]+.

Example 49

N-(3-Chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 3-chloro-2-methylphenylamine ([CAS RN 20265-38-7]). MS (ISP): 420,8 [M+H]+.

Example 50

N-(5-Chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 5-chloro-2-methylphenylamine ([CAS RN 95-79-4]). MS (ISP): 420,8 [M+H]+.

Example 51

N-(2-Chloro-6-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2-chloro-6-methylphenylamine ([CAS RN 87-63-8]). MS (ISP): 420,8 [M+H]+.

Example 52

2-(2,5-Dichlorophenoxy)-N-(2,6-dimetilfenil)-N-nicotine amide

Indicated the data in the title compound was obtained analogously to example 45, replacing 2-ethylvanillin 2.6-dimethylphenylamine ([CAS RN 87-62-7]). MS (ISP): 401,1 [M+H]+.

Example 53

2-(2,5-Dichlorophenoxy)-N-(2-methoxy-6-were)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2-methoxy-6-methylphenylamine ([CAS RN 50868-73-0]). MS (ISP): 417,1 [M+H]+.

Example 54

2-(2,5-Dichlorophenoxy)-N-(5-fluoro-2-methoxyphenyl)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 5-fluoro-2-methoxybenzylamine ([CAS RN 437-83-2]). MS (ISP): 420,9 [M+H]+.

Example 55

N-(5-Chloro-2-methoxyphenyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 5-chloro-2-methoxybenzylamine ([CAS RN 95-03-4]). MS (ISP): 436,8 [M+H]+.

Example 56

N-(4-Chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 4-chloro-2-methylphenylamine ([CAS RN 95-69-2]). MS (ISP): 420,9 [M+H]+.

Example 57

2-(2,5-Dichlorophenoxy)-N-(2,3-dimetilfenil)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, Zam the outermost 2-ethylvanillin 2.3-dimethylphenylamine ([CAS RN 87-59-2]). MS (ISP): 402,6 [M+H]+.

Example 58

2-(2,5-Dichlorophenoxy)-N-(2,4-dimetilfenil)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2,4-dimethylphenylamine ([CAS RN 95-68-1]). MS (ISP): 401,0 [M+H]+.

Example 59

2-(2,5-Dichlorophenoxy)-N-(2-methoxy-5-were)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2-methoxy-5-methylphenylamine ([CAS RN 120-71-8]). MS (ISP): 416,7 [M+H]+.

Example 60

2-(2,5-Dichlorophenoxy)-N-(2,6-acid)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2.6-dimethoxyaniline ([CAS RN 2734-70-5]). MS (ISP): 433,1 [M+H]+.

Example 61

N-(6-Chloro-4-methylpyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 6-chloro-4-methylpyridin-3-ylamine ([CAS RN 66909-38-4]). MS (ISP): 422,1 [M+H]+.

Example 62

N-(2-Cyanophenyl)-2-(2.5-dichlorophenoxy)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2-aminobenzonitrile ([CAS RN 1885-29-6]). MS (ISP): 398,1 M+H] +.

Example 63

2-(2,5-Dichlorophenoxy)-N-(2-forfinal)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2-forfinally ([CAS RN 348-54-9]). MS (ISP): to € 391.1 [M+H]+.

Example 64

2-(2,5-Dichlorophenoxy)-N-(2,6-differenl)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2.6-dipertanyakan ([CAS RN 5509-65-9]). MS (ISP): 409,1 [M+H]+.

Example 65

2-(2,5-Dichlorophenoxy)-N-methyl-N-(2-pyrrol-1-ylphenyl)nicotinamide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2-pyrrol-1-elfenlied ([CAS RN 6025-60-1]). MS (ISP): 438,2 [M+H]+.

Example 66

2-(2,5-Dichlorophenoxy)-N-(2,4-differenl)-N-nicotine amide

Specified in the title compound was obtained analogously to example 45, substituting 2-ethylvanillin 2,4-dipertanyakan ([CAS RN 367-25-9]). MS (ISP): 409,1 [M+H]+.

Example 67

[2-('2.5 Dichlorophenoxy)pyridine-3-yl]-(2-methyl-3.4-dihydro-2H-quinoline-1-yl)methanon

A solution of 2-(2,5-dichlorophenoxy)nicotinic acid (34,1 mg, 0.12 mmole, 1.0 equiv.; example 31, step 1) in thionyl chloride (492 mg, 300 ál, 4,14 mmole, 34,5 equiv.; [CAS RN 7719-09-7]) was heated at 100°C in those who tell the night. The reaction mixture was concentrated under reduced pressure, the remaining thionyl chloride was removed by azeotropic distillation with toluene, and the residue was dissolved in anhydrous DMF (1 ml). To this solution was added N-ethyldiethanolamine (155 mg, 204 μl, 1.20 mmole, of 10.0 equiv.; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydroquinolin (22,1 mg, 0.15 mmole, 1.25 equiv.; [CAS RN 1780-19-4]), and the reaction mixture was heated under microwave irradiation at 100°C for 15 minutes Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, a Sedex ELSD 75 svetorasseivateley and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 9 mg (18%) specified in the connection header. MS (ISP): 412,9 [M+H]+.

Example 68

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(8-fluoro-6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 36, substituting 3,4-dihydro-2H-benzo[1,4]oxazin 8-fluoro-6-methyl-1,2,3,4-tetrahydroquinolin ([CAS RN 954260-80-1]). MS (ISP): 431,2 [M+H]+.

Example 69

N-(2-Chloro-4-methylpyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (56.6 mg, 0.2 mmole, 1.0 equiv.; example 31 article is Diya 1) in anhydrous DMF (1 ml) was added 2-chloro-4-methylpyridin-3-ylamine (34,2 mg, 0.24 mmole, 1.2 equiv.; [CAS RN 133627-45-9]), N-ethyldiethanolamine (129,0 mg, 175 μl, 1.0 mmol, 5,0 equiv.; [CAS RN 7087-68-5]) and HATU (91,2 mg, 0.24 mmole, 1.2 equiv.; [CAS RN 148893-10-1]), and the reaction mixture was stirred at RT. After 18 h was added sodium hydride (13,0 mg, 0.3 mmole, 1.5 equiv.; 55% free current powder moistened with oil; [CAS RN 7646-69-7]) and jodean (56,8 mg, 25 ál, 0.4 mmole, 2.0 equiv.; [CAS RN 74-88-4]), and stirring continued at 40°C for 2 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 2.9 mg (3%) specified in the connection header. MS (ISP): 424,1 [M+H]+.

Example 70

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(8-methoxy-3,4-dihydro-2H-quinoline-1-yl)methanon

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (56.6 mg, 0.2 mmole, 1.0 equiv.; example 31, step 1) in anhydrous DMF (1 ml) was added 8-methoxy-1,2,3,4-tetrahydroquinolin (39,2 mg, 0.24 mmole, 1.2 equiv.; [CAS RN 53899-17-5]), N-ethyldiethanolamine (129,0 mg, 175 μl, 1.0 mmol, 5,0 equiv.; [CAS RN 7087-68-5]) and HATU (91,2 mg, 0.24 mmole, 1.2 equiv.; [CAS RN 148893-10-1]), and the reaction mixture was stirred at 50°C during the night. Removal of solvent mixture under reduced giving the situation and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 10.6 mg (12%) specified in the connection header. MS (ISP): 429,3 [M+H]+.

Example 71

(6-Chloro-3,4-dihydro-2H-quinoline-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 70, substituting 8-methoxy-1,2,3,4-tetrahydroquinolin 6-chloro-1,2,3,4-tetrahydroquinolin ([CAS RN 49716-18-9]). MS (ISP): 435,0 [M+H]+.

Example 72

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

Specified in the title compound was obtained analogously to example 70, substituting 8-methoxy-1,2,3,4-tetrahydroquinolin on the hydrochloride of 6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine ([CAS RN 105655-00-3]). MS (ISP): 419,3 [M+H]+.

Example 73

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(6,8-debtor-2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

Specified in the title compound was obtained analogously to example 70, substituting 8-methoxy-1,2,3,4-tetrahydroquinolin 6.8-debtor-3,4-dihydro-2H-benzo[1,4]oxazin ([CAS RN 939759-10-1]). MS (ISP): 437,0 [M+H]+.

Example 74

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(4-phenyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon

Stage 1: 1-Phenyl-1,2,3,4-tetrahydroquinoxalin

To a suspension of socialogical (3,99 g, 105.0 mmol, 5,0 equiv.) in THF (30 ml) was slowly added a solution of 1-phenyl-1,4-dihydroquinoxaline-2,3-dione (5,00 g, 21,0 mmol, 1.0 equiv.; obtained, as described in S.-K. Lin, Molecules, 1996, 7, SS.37-40) in THF (50 ml). After heating the reaction mixture to boiling under reflux for 16 h, the solution was added 1 M NaOH (100 ml). The reaction mixture was stirred for several minutes, was added MgSO4and then was filtered through celite. Extraction of the residue on the filter with ethyl acetate (3×100 ml) and evaporation of the solvent under reduced pressure yielded the crude reaction product, which was purified column chromatography on silica gel, elwira gradient heptane/ethyl acetate to obtain 3,23 g (73%) indicated in the title compound as an orange solid. MS (EI): 210,0 [M]+.

Stage 2:

Specified in the title compound was obtained analogously to example 70, substituting 8-methoxy-1,2,3,4-tetrahydroquinolin 1-phenyl-1,2,3,4-tetrahydroquinoxalin. MS (ISP): 476,0 [M+H]+.

Example 75

2-(2,5-Dichlorophenoxy)-N-(4-methoxypyridine-3-yl)-N-nicotine amide

Specified in the title compound was obtained analogously to example 69, substituting 2-chloro-4-methylpyridin-3-ylamine for 4-methoxypyridine-3-ylamine ([CAS RN 33631-0-3]). MS (ISP): 405,9 [M+H]+.

Example 76

[2-(2,4-Dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(2,4-Dichlorphenoxy)nicotinic acid To a solution of 2-chloronicotinic acid (2.15 g, 13,65 mmole, 1.0 equiv.; [CAS RN 2942-59-8]) and 2,4-dichlorphenol (2,22 g, 13,65 mmole, 1.0 equiv.; [CAS RN 120-83-2]) in toluene (40 ml) was added cesium carbonate (8,89 g, 27,29 mmole, 2.0 equiv.; [CAS RN 534-17-8]) and hexaphosphate tetrakis(acetonitrile)copper (I) (1,02 g, 2,73 mmole, 0.2 equiv.; [CAS RN 64443-05-6]). The reaction mixture was heated at the boil under reflux overnight. The solvent was evaporated under reduced pressure and the crude reaction product was transferred into water (100 ml), acidified to pH 1 by adding a solution of 1 M HCl, and was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried MgSO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient dichloromethane/methanol, getting 1,69 g (44%) indicated in the title compound in the form of a whitish solid.1H NMR (400 MHz, DMSO): δ 7,26 (dd, J=7,6 Hz, J=4,8 Hz, 1H), was 7.36 (d, J=8.7 Hz, 1H), 7,49 (dd, J=8.7 Hz, J=2.6 Hz, 1H), 7,76 (d, J=2.4 Hz, 1H), 8,25 (dd, J=4,8 Hz, J=2.2 Hz, 1H), 8.30 to (dd, J=7.5 Hz, J=2.2 Hz, 1H), 13,33 (s, 1H). MS (ISN): of 282.3 [M-H]-.

Stage 2:

Specified in the title compound was obtained analogously to example 37, substituting 2-(2,5-dichlorophenoxy)nicotine the second acid 2-(2,4-dichlorphenoxy)nicotinic acid, and 6-fluoro-1,2,3,4-tetrahydroquinolin on 1,2,3,4-tetrahydroquinolin ([CAS RN 635-46-1]). MS (ISP): 399,0 [M+H]+.

Example 77

[2-(3-Chloro-4-pertenece)pyridine-3-yl]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(3-Chloro-4-pertenece)nicotinic acid

2-(3-Chloro-4-pertenece)nicotinic acid was obtained analogously to example 1, step 1, replacing 3-cryptomaterial 3-chloro-4-terfenol ([CAS RN 2613-23-2]). MS (ISN): 265,9 [M-H]-.

Stage 2:

A solution of 2-(3-chloro-4-pertenece)nicotinic acid (32.1 mg, 0.12 mmole, 1.0 equiv.) in thionyl chloride (57 mg, 35 μl, 0.48 mmole, 4.0 equiv.; [CAS RN 7719-09-7]) was stirred at RT for 1 h the Reaction mixture was concentrated under reduced pressure, the remaining thionyl chloride was removed by azeotropic distillation with toluene, and the residue was dissolved in anhydrous DMF (1 ml). To this solution was added N-ethyldiethanolamine (77,6 mg, 102 μl, 0.60 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and 6-methyl-1,2,3,4-tetrahydroquinolin (21.2 mg, of 0.14 mmole, 1.2 equiv.; [CAS RN 91-61-2]), and the reaction mixture was heated under microwave irradiation at 140°C for 15 minutes Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira greentomatocars/water, resulted in the receipt of 3.7 mg (8%) specified in the connection header. MS (ISP): 397,0 [M+H]+.

Example 78

[2-(3-Chloro-4-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-[1,5]naphthiridine-1-yl)methanon

Specified in the title compound was obtained analogously to example 67, substituting 2-(2,5-dichlorophenoxy)nicotinic acid 2-(3-chloro-4-pertenece)nicotinic acid (example 77, step 1)and 2-methyl-1,2,3,4-tetrahydroquinolin on 1,2,3,4-tetrahydro-[1,5]naphthiridine ([CAS RN 13993-61-8]). MS (ISN): 383,9 [M+H]+.

Example 79

[2-(3-Chloro-4-pertenece)pyridine-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

To a solution of 2-(3-chloro-4-pertenece)nicotinic acid (32.1 mg, 0.12 mmole, 1.0 equiv.; example 77, step 1) in dichloromethane (1 ml) was added 6,7-debtor-1,2,3,4-tetrahydroquinolin (24,4 mg of 0.14 mmole, 1.2 equiv.; [CAS RN 953717-64-1]), tri-n-butylamine (of 111.2 mg, 143 μl, 0.60 mmole, of 5.0 equiv.; [CAS RN 102-82-9]) and iodide 2-chloro-1-methylpyridine cases (36.8 mg, of 0.14 mmole, 1.2 equiv.; [CAS RN 14338-32-0]), the Reaction mixture was heated under microwave irradiation at 60°C for 15 minutes Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient of acetonitril the/water, resulted in the receipt of 4.7 mg (9%) specified in the connection header. MS (ISP): 419,0 [M+H]+.

Example 80

[2-(2,5-Dichlorophenoxy)-5-herperidin-3-yl]-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(2,5-Dichlorophenoxy)-5-fornicative acid 2-(2,5-Dichlorophenoxy)-5-fornicating acid was obtained analogously to example 1, step 1, substituting 2-chloronicotinic acid 2-chloro-5-fornicating acid ([CAS RN 38186-88-8]), and 3-cryptomaterial 2.5-dichlorphenol ([CAS RN 583-78-8]).1H NMR (400 MHz, DMSO): δ 7,38 (dd, J=8,4 Hz, J=2.4 Hz, 1H), 7,51 (d, J=2.4 Hz, 1H), 7.62mm (d, J=8,4 Hz, 1H), 8,23 (dd, J=8,1 Hz, J=3.2 Hz, 1H), 8.34 per (d, J=3.2 Hz, 1H), 13,65 (s, 1H).19F NMR (376,5 MHz, DMSO): -134,6. MS (ISN): 302,0 [M-H]-.

Stage 2:

A solution of 2-(2,5-dichlorophenoxy)-5-fornicating acid (36,3 mg, 0.12 mmole, 1.0 equiv.) in thionyl chloride (492 mg, 300 ál, 4,14 mmole, 34,5 equiv.; [CAS RN 7719-09-7]) was heated at 100°C during the night. The reaction mixture was concentrated under reduced pressure, the remaining thionyl chloride was removed by azeotropic distillation with toluene, and the residue was dissolved in anhydrous DMF (1 ml). To this solution was added N-ethyldiethanolamine (155 mg, 204 μl, 1.20 mmole, of 10.0 equiv.; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydroquinolin (22,1 mg, 0.15 mmole, 1.25 equiv.; [CAS RN 1780-19-4]), and the reaction mixture was heated under microwave irradiation at 120°C for 15 minutes Remove solvent mixture when the pony is hinnon pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 11.5 mg (22%) specified in the connection header. MS (ISP): 430,8 [M+H]+.

Example 81

[2-(2,5-Dichlorophenoxy)-5-herperidin-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

Specified in the title compound was obtained analogously to example 80, step 2, substituting 2-methyl-1,2,3,4-tetrahydroquinolin on 3,4-dihydro-2H-benzo[1,4]oxazin ([CAS RN 5735-53-5]). MS (ISN): 419,3 [M+H]+.

Example 82

1-[2-(2,5-Dichlorophenoxy)-5-herperidin-3-carbonyl]-1,2,3,4-tetrahydrobenzo[b]azepin-5-he

Specified in the title compound was obtained analogously to example 80, step 2, substituting 2-methyl-1,2,3,4-tetrahydroquinolin on 1,2,3,4-tetrahydrobenzo[b]azepin-5-he ([CAS RN 1127-74-8]). MS (ISN): 444,7 [M+H]+.

Example 83

[2-(2,5-Dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 31, step 2, replacing 2-(2,5-dichlorophenoxy)nicotinic acid 2-(2,5-dichlorophenoxy)-5-fornicating acid (example 80, step 1), and 6-methyl-1,2,3,4-tetrahydroquinolin on 1,2,3,4-tetrahydroquinolin ([CAS RN 635-46-1]). MS (ISP): 417,0 [M+H]+.

Example 84

2-2,5-Dichlorophenoxy)-N-ethyl-5-fluoro-N-phenyldiamine

Specified in the title compound was obtained analogously to example 31, step 2, replacing 2-(2,5-dichlorophenoxy)nicotinic acid 2-(2,5-dichlorophenoxy)-5-fornicating acid (example 80, step 1), and 6-methyl-1,2,3,4-tetrahydroquinolin on ethylvanillin ([CAS RN 103-69-5]). MS (ISP): 405,0 [M+H]+.

Example 85

[2-(3-Chlorophenoxy)-5-herperidin-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(3-Chlorophenoxy)-5-fornicative acid

2-(3-Chlorophenoxy)-5-fornicating acid was obtained analogously to example 1, step 1, substituting 2-chloronicotinic acid 2-chloro-5-fornicating acid ([CAS RN 38186-88-8]), and 3-cryptomaterial 3-chlorophenol ([CAS RN 108-43-0]).1H NMR (400 MHz, DMSO): δ to 7.09 (dd, J=8,4 Hz, J=1.6 Hz, 1H), 7.24 to 7,25 (m, 2H), 7,44 (t, J=8,4 Hz, 1H), 8,19 (dd, J=8,1 Hz, J=3.2 Hz, 1H), of 8.37 (d, J=3.2 Hz, 1H), 13,60 (s, 1H).19F NMR (376,5 MHz, DMSO): -134,4. MS (ISN): 266,0 [M-H]-.

Stage 2:

Specified in the title compound was obtained analogously to example 79, substituting 2-(3-chloro-4-pertenece)nicotinic acid 2-(3-chlorophenoxy)-5-fornicating acid. MS (ISP): 419,3 [M+H]+.

Example 86

[2-(3-Chloro-4-pertenece)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(3-Chloro-4-pertenece)-5-fornicative acid

2-(3-Chloro-4-pertenece)-5-fornicating acid in which Uchali analogously to example 1, stage 1, replacing 2-chloronicotinic acid 2-chloro-5-fornicating acid ([CAS RN 38186-88-8]), and 3-cryptomaterial 3-chloro-4-terfenol ([CAS RN 2613-23-2]).1H NMR (400 MHz, DMSO): δ 7,16-7,19 (m, 1H), 7,44-of 7.48 (m, 2H), 8,19 (dd, J=8,1 Hz, J=3.2 Hz, 1H), 8,35 (d, J=3.2 Hz, 1H), 13,60 (s, 1H).19F NMR (376,5 MHz, DMSO): -121,6, -134,8. MS (ISN): 283,8 [M-H]-.

Stage 2:

Specified in the title compound was obtained analogously to example 31, step 2, replacing 2-(2,5-dichlorophenoxy)nicotinic acid 2-(3-chloro-4-pertenece)-5-fornicating acid, and 6-methyl-1,2,3,4-tetrahydroquinolin on 1,2,3,4-tetrahydroquinolin ([CAS RN 635-46-1]). MS (ISP): 401,0 [M+H]+.

Example 87

[2-(3-Chloro-4-pertenece)-5-herperidin-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 79, substituting 2-(3-chloro-4-pertenece)nicotinic acid 2-(3-chloro-4-pertenece)-5-fornicating acid (example 86, step 1). MS (ISP): 437,0 [M+H]+.

Example 88

[2-(3-Chloro-4-pertenece)-5-herperidin-3-yl]-(8-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

A solution of 2-(3-chloro-4-pertenece)-5-fornicating acid (to 34.3 mg, 0.12 mmole, 1.0 equiv.; example 86, step 1) in thionyl chloride (492 mg, 300 ál, 4,14 mmole, 34,5 equiv.; [CAS RN 7719-09-7]) was heated at 100°C during the night. The reaction mixture was concentrated under reduced pressure, the remaining is the action scene thionyl chloride was removed by azeotropic distillation with toluene, and the residue was dissolved in anhydrous DMF (1 ml). To this solution was added N-ethyldiethanolamine (155 mg, 204 μl, 1.20 mmole, of 10.0 equiv.; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydroquinolin (22,1 mg, 0.15 mmole, 1.25 equiv.; [CAS RN 1780-19-4]), and the reaction mixture was heated under microwave irradiation at 100°C for 20 minutes Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 10.6 mg (21%) specified in the connection header. MS (ISP): 414,9 [M+H]+.

Example 89

[3-(2,5-Dichlorophenoxy)pyridine-4-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: (3-Bromopyridin-4-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon

(3-Bromopyridin-4-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanon was obtained analogously to example 6, step 1, substituting 2-chloronicotinic acid 3-bromoisonicotinic acid ([CAS RN 13959-02-9]). MS (ISP): 319,1 [M+H]+.

Stage 2:

To a solution of (3-bromopyridin-4-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanone (41,2 mg of 0.13 mmole, 1.0 equiv.) and 2.5-dichlorphenol (21.2 mg, of 0.13 mmole, 1.0 equiv.; [CAS RN 583-78-8]) in DMAc (1 ml) was added potassium carbonate (35,9 mg of 0.26 mmole, 2.0 equiv.; [CAS RN 584-08-7]) and copper iodide (I) (5.0 mg, 0.026 mmole, 0.2 equivalent is.; [CAS RN 7681-65-4]). The reaction mixture was heated under microwave irradiation at 180°C for 8 hours Cleaning preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 5 mg (10%) specified in the connection header. MS (ISP): 399,1 [M+H]+.

Example 90

[3-(2,5-Dichlorophenoxy)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin on the hydrochloride of 7-fluoro-1,2,3,4-tetrahydroquinoline (commercially available from Zannan Pharma Ltd). Microwave heating in stage 2 was carried out at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 416,7 [M+H]+.

Example 91

[3-(2,5-Dichlorophenoxy)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin 6-fluoro-1,2,3,4-tetrahydroquinolin ([CAS RN 59611-52-8]). Microwave heating in stage 2 was carried out at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 416,8 [M+H]+.

Example 92

[3-(2,5-Dichlorophenoxy)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-x is the nolin-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin 6.8-debtor-1,2,3,4-tetrahydroquinolin ([CAS RN 926218-72-6]). Microwave heating in stage 2 was carried out at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 434,8 [M+H]+.

Example 93

3-(2,5-Dichlorophenoxy)-N-methyl-N-o-tolylenediamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin on methyl-o-tolylamino ([CAS RN 611-21-2]). Microwave heating in stage 2 was carried out at 180°C for 2 h, then at 150°C for 8 h MS (ISP): 387,2 [M+H]+.

Example 94

N-(2-Chlorophenyl)-3-(2,5-dichlorophenoxy)-N-methylethanolamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin (2-chlorophenyl)methylamine ([CAS RN 932-32-1]). Microwave heating in stage 2 was carried out at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 408,6 [M+H]+.

Example 95

3-(2,5-Dichlorophenoxy)-N-(2-methoxyphenyl)-N-methylethanolamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin (2-methoxyphenyl)methylamine ([CAS RN 10541-78-3]). Microwave Naga is evanie in stage 2 was carried out at 180°C for 11 h, then at 150°C for 1 h MS (ISP): 403,2 [M+H]+.

Example 96

[3-(2,4-Dichlorophenoxy)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin on the hydrochloride of 7-fluoro-1,2,3,4-tetrahydroquinoline (commercially available from Zannan Pharma Ltd). Stage 2 was carried out, replacing the 2,5-dichlorophenol 2,4-dichlorphenol ([CAS RN 120-83-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 416,8 [M+H]+.

Example 97

[3-(2,4-Dichlorophenoxy)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin 6-fluoro-1,2,3,4-tetrahydroquinolin ([CAS RN 59611-52-8]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 2,4-dichlorphenol ([CAS RN 120-83-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 416,7 [M+H]+.

Example 98

[3-(2,4-Dichlorophenoxy)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin 6.8-debtor-1,2,3,4-tetrahydroquinolin ([AS RN 926218-72-6]). Stage 2 was carried out, replacing the 2.5-d is chlorophenol 2,4-dichlorophenol ([AS RN 120-83-2]), and conducting microwave heating at 180°C for 1 h MS (ISP): 435,1 [M+H]+.

Example 99

3-(2,4-Dichlorophenoxy)-N-methyl-N-o-tolylenediamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin on methyl-o-tolylamino ([AS RN 611-21--2]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 2,4-dichlorphenol ([CAS RN 120-83-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 386,7 [M+H]+.

Example 100

N-(2-Chlorophenyl)-3-(2,4-dichlorophenoxy)-N-methylethanolamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin (2-chlorophenyl)methylamine ([CAS RN 932-32-1]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 2,4-dichlorphenol ([CAS RN 120-83-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 408,6 [M+H]+.

Example 101

3-(2,4-Dichlorophenoxy)-N-(2-methoxyphenyl)-N-methylethanolamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin (2-methoxyphenyl)methylamine ([CAS RN 10541-78-3]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 2,4-dichlorphenol ([CAS RN 120-83-2]), and performing microwave heating at 180°C in ECENA 2 h, then at 150°C for 8 h MS (ISP): 403,1 [M+H]+.

Example 102

3-(2,4-Dichlorophenoxy)-N-(2-methoxypyridine-3-yl)-N-methylethanolamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin 2-methoxypyridine-3-ylamine ([CAS RN 20265-38-7]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 2,4-dichlorphenol ([CAS RN 120-83-2J), and performing microwave heating at 180°C for 2 h, then at 150°C for 8 h MS (ISP): 403,8 [M+H]+.

Example 103

[3-(3-Chloro-4-pertenece)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin on the hydrochloride of 7-fluoro-1,2,3,4-tetrahydroquinoline (commercially available from Zannan Pharma Ltd). Stage 2 was carried out, replacing the 2,5-dichlorophenol 3-chloro-4-terfenol ([CAS RN 2613-23-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 400,7 [M+H]+.

Example 104

[3-(3-Chloro-4-pertenece)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin 6-fluoro-1,2,3,4-tetrahydroquinolin ([CAS RN 59611-52-8]). Stage 2 was carried out, replacing the 2,5-dichloro the enol 3-chloro-4-terfenol ([CAS RN 2613-23-2]), and conducting microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 400,7 [M+H]+.

Example 105

[3-(3-Chloro-4-pertenece)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin 6.8-debtor-1,2,3,4-tetrahydroquinolin ([CAS RN 926218-72-6]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 3-chloro-4-terfenol ([CAS RN 2613-23-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 418,7 [M+H]+.

Example 106

3-(3-Chloro-4-pertenece)-N-methyl-N-o-tolylenediamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin on methyl-o-tolylamino ([CAS RN 611-21-2]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 3-chloro-4-terfenol ([CAS RN 2613-23-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 370,8 [M+H]+.

Example 107

3-(3-Chloro-4-pertenece)-N-(2-chlorophenyl)-N-methylethanolamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin (2-chlorophenyl)methylamine ([CAS RN 932-32-1]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 3-chlorine is-4-terfenol ([CAS RN 2613-23-2]), and conducting microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 390,7 [M+H]+.

Example 108

3-(3-Chloro-4-pertenece)-N-(2-methoxyphenyl)-N-methylethanolamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin (2-methoxyphenyl)methylamine ([CAS RN 10541-78-3]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 3-chloro-4-terfenol ([CAS RN 2613-23-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 386,7 [M+H]+.

Example 109

3-(3-Chloro-4-pertenece)-N-(2-methoxypyridine-3-yl)-N-methylethanolamine

Specified in the title compound was obtained analogously to example 89, step 1, substituting 1,2,3,4-tetrahydroquinolin 2-methoxypyridine-3-ylamine ([CAS RN 20265-38-7]). Stage 2 was carried out, replacing the 2,5-dichlorophenol 3-chloro-4-terfenol ([CAS RN 2613-23-2]), and performing microwave heating at 180°C for 1 h, then at 150°C for 3 hours MS (ISP): 387,7 [M+H]+.

Example 110

[2-(2,5-Dichlorophenoxy)phenyl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(2,5-Dichlorophenoxy)benzoic acid

To a solution of 2-identies acid (3.0 g, 12,10 mmole, 1.0 equiv.; [CAS RN 88-67-5]) and 2,5-dichlorophenol (1.97 g, 12,10 mmole, 1.0 equiv.; [CAS RN 583-78-8]) in toluene (50 ml) was added to the carbonate cesium (7,88 g, 24,20 mmole, 2.0 equiv.; [CAS RN 534-17-8]) and hexaphosphate tetrakis(acetonitrile)copper (I) - (1.13 g, to 3.02 mmole, of 0.25 equiv.; [CAS RN 64443-05-6]). The reaction mixture was heated at the boil under reflux overnight. The solvent was evaporated under reduced pressure and the crude reaction product was transferred into water (100 ml), acidified to pH 1 by adding a solution of 1 M HCl and was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried MgSO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane (+1% acetic acid/acetate, getting 2,78 g (81%) indicated in the title compounds as white solids. MS (ISN): 281,1 [M-N]-.

Stage 2:

To a solution of 2-(2,5-dichlorophenoxy)benzoic acid (50.0 mg, 0,177 mmole, 1.0 equiv.) in anhydrous DMF (1 ml) was added N-ethyldiethanolamine (to 114.4 mg, 151 μl, of 0.89 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (80,8 mg of 0.21 mmole, 1.2 equiv.; [CAS RN 148893-10-1]). After stirring the reaction mixture at 50°C for 1 h, was added 1,2,3,4-tetrahydroquinolin (28,3 mg, 27 μl, of 0.21 mmole, 1.2 equiv.; [CAS RN 635-46-1]), and stirring continued at 50°C during the night. Removal of solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pump is mi Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 12.9 mg (18%) specified in the connection header. MS (ISP): 398,2 [M+H]+.

Example 111

[2-(2,5-Dichlorophenoxy)phenyl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 79 substituting 2-(3-chloro-4-pertenece)nicotinic acid 2-(2,5-dichlorophenoxy)benzoic acid (example 110, step 1). MS (ISP): of 434.1 [M+H]+.

Example 112

[2-(2,5-Dichlorophenoxy)phenyl]-(2-methyl-2,3-dihydroindol-1-yl)methanon

Specified in the title compound was obtained analogously to example 31, step 2, replacing 2-(2,5-dichlorophenoxy)nicotinic acid 2-(2,5-dichlorophenoxy)benzoic acid (example 110, step 1), and 6-methyl-1,2,3,4-tetrahydroquinolin 2-methyl-2,3-dihydro-1H-indole ([CAS RN 6872-06-6]). MS (ISP): 398,2 [M+H]+.

Example 113

[2-(2,5-Dichlorophenoxy)-5-forfinal]-(3,4-dihydro-2H-quinoline-1-yl)methanon

Stage 1: 2-(2,5-Dichlorophenoxy)-5-Formentera acid

2-(2,5-Dichlorophenoxy)-5-fermenting acid was obtained analogously to example 76, step 1, substituting 2-chloronicotinic acid 2-bromo-5-fermenting acid ([CAS RN 394-28-5]). MS (ISN): 299,0 [M-H]-.

Stage 2:

Specified in the title compound was obtained in the same what about the example 110, stage 2, replacing 2-(2,5-dichlorophenoxy)benzoic acid (example 110, step 1) 2-(2,5-dichlorophenoxy)-5-fermenting acid, and 6-fluoro-1,2,3,4-tetrahydroquinolin on 1,2,3,4-tetrahydroquinolin ([CAS RN 635-46-1]). MS (ISP): 416,1 [M+H]+.

Example 114

[2-(2,5-Dichlorophenoxy)-5-forfinal]-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

To a solution of 2-(2,5-dichlorophenoxy)-5-fermenting acid (36,1 mg, 0.12 mmole, 1.0 equiv.; example 113, step 1) in dichloromethane (1 ml) was added 2-methyl-1,2,3,4-tetrahydroquinolin (21.2 mg, of 0.14 mmole, 1.2 equiv.; [CAS RN 1780-19-4]), tri-n-butylamine (of 111.2 mg, 143 μl, 0.60 mmole, of 5.0 equiv.; [CAS RN 102-82-9]) and iodide 2-chloro-1-methylpyridine cases (36.8 mg, of 0.14 mmole, 1.2 equiv.; [CAS RN 14338-32-0]). The reaction mixture was heated at 40°C during the night. Removal of solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 7.8 mg (15%) specified in the connection header. MS (ISP): 430,1 [M+H]+.

Example 115

[2-(2,5-Dichlorophenoxy)-5-forfinal]-(8-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 114, substituting 2-methyl-1,2,3,4-tetrahydro the quinoline 8-methyl-1,2,3,4-tetrahydroquinolin ([CAS RN 52601-70-4]). MS (ISP): 430,0 [M+H]+.

Example 116

[2-(2,5-Dichlorophenoxy)-5-forfinal]-(6-methyl-3,4-dihydro-2H-quinoline-yl)methanon

Specified in the title compound was obtained analogously to example 114, substituting 2-methyl-1,2,3,4-tetrahydroquinolin 6-methyl-1,2,3,4-tetrahydroquinolin ([CAS RN 91-61-2]). MS (ISP): 430,1 [M+H]+.

Example 117

[2-(2,5-Dichlorophenoxy)-5-forfinal]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

Specified in the title compound was obtained analogously to example 114, substituting 2-methyl-1,2,3,4-tetrahydroquinolin on 3,4-dihydro-2H-benzo[1,4]oxazin ([CAS RN 5735-53-5]). MS (ISP): 418,0 [M+H}+.

Example 118

2-(2,5-Dichlorophenoxy)-5-fluoro-N-methyl-N-phenylbenzene

Specified in the title compound was obtained analogously to example 114, substituting 2-methyl-1,2,3,4-tetrahydroquinolin on methylphenylamine ([CAS RN 100-61-8]). MS (ISP): 390,0 [M+H]+.

Example 119

4-(2,5-Dichlorophenoxy)-3-(3,4-dihydro-2H-quinoline-1-carbonyl)benzonitrile

Stage 1: 4-Bromo-3-(3,4-dihydro-2H-quinoline-1-carbonyl)benzonitrile

To a solution of 2-bromo-5-cyanobenzoic acid (0.50 g, 2.12 mmole, 1.0 equiv.; [CAS RN 845616-12-8]) in dichloromethane (5 ml) was added 1,2,3,4-tetrahydroquinolin (0.35 g, 330 μl, of 2.66 mmole, 1.2 equiv.; [CAS RN 635-46-1]), N-ethyldiethanolamine (1,43 g of 1.88 ml, 11,06 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and iodide 2-chloro-1-metylene INIA (0.68 g, of 2.66 mmole, 1.2 equiv.; [CAS RN 14338-32-0]). The reaction mixture was stirred at RT over the weekend. To the residue was added to feast upon. the solution of NaHCO3(100 ml)and the solution was extracted with dichloromethane (3×50 ml). The combined organic phases were dried Na2SO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient toluene/acetone, receiving 0.35 g (46%) indicated in the title compound as a pale yellow solid. MS (ISP): 341,1 [M+H]+.

Stage 2:

To a solution of 4-bromo-3-(3,4-dihydro-2H-quinoline-1-carbonyl)benzonitrile (100 mg, of 0.44 mmole, 1.0 equiv.) and 2,4-dichlorphenol (72 mg, of 0.44 mmole, 1.0 equiv.; [CAS RN 120-83-2]) in toluene (1 ml) was added cesium carbonate (289 mg, of 0.89 mmole, 2.0 equiv.; [CAS RN 534-17-8]) and hexaphosphate tetrakis(acetonitrile)copper (I) - (41 mg, of 0.11 mmole, of 0.25 equiv.; [CAS RN 64443-05-6]). The reaction mixture was heated under microwave irradiation at 120°C for 3 hours the solvent under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 11.5 mg (6%) specified in the connection header. MS (ISP): 423,0 [M+H]+.

Example 120

[2-(2,5-Dichlorophenoxy)phenyl]-(8-f the PR-6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon

To a solution of 2-(2,5-dichlorophenoxy)benzoic acid (51,0 mg of 0.18 mmole, 1.0 equiv.; example 110, step 1) in dichloromethane (2 ml) was added 8-fluoro-6-methyl-1,2,3,4-tetrahydroquinolin (35,7 mg, 0.22 mmole, 1.2 equiv.; [CAS RN 954260-80-1]), triethylamine (36,5 mg, 50 μl, of 0.36 mmole, 2.0 equiv.; [CAS RN 121-44-8]) and iodide 2-chloro-1-methylpyridine (57,8 mg, 0.22 mmole, 1.2 equiv.; [CAS RN 14338-32-0]). The reaction mixture was stirred at RT for 2 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 20.7 mg (27%) specified in the connection header. MS (ISP): 430,2 [M+H]+.

Example 121

[2-(2,5-Dichlorophenoxy)phenyl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon

Specified in the title compound was obtained analogously to example 120, substituting 8-fluoro-6-methyl-1,2,3,4-tetrahydroquinolin 6.8-debtor-1,2,3,4-tetrahydroquinolin ([CAS RN 926218-72-6]). MS (ISP): 434,2 [M+H]+.

Example 122

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon

A solution of 2-(2,5-dichlorophenoxy)nicotinic acid (100 mg, 0.35 mmole, 1.0 equiv.; example 31, step 1) in thionyl the Ried im Innkreis (3.28 g, 2 ml, 27.6 mmole, 230 equiv.; [CAS RN 7719-09-7]) was heated at 100°C for 1 h, the Reaction mixture was concentrated under reduced pressure, the remaining thionyl chloride was removed by azeotropic distillation with toluene, and the residue was dissolved in anhydrous DMF (1 ml). To this solution was added N-ethyldiethanolamine (452 mg, 595 μl, 3.5 mmole, of 10.0 equiv.; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydroquinoxalin (56 mg, at 0.42 mmole, 1.2 equiv.; [CAS RN 3476-89-9]), and the reaction mixture was stirred at RT for 2 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 17.3 mg (12%) specified in the connection header. MS (ISP): 400,0 [M+H]+.

Example 123

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(4-methyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (42,6 mg, 0.15 mmole, 1.0 equiv.; example 31, step 1) in anhydrous DMF (1 ml) was added 1-methyl-1,2,3,4-tetrahydroquinoxalin (26,7 mg of 0.18 mmole, 1.2 equiv.; [CAS RN 36438-97-8]), N-ethyldiethanolamine (97 mg, 131 μl, 0.75 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (68 mg, of 0.18 mmole, 1.2 equiv.; [CAS RN 148893-10-1]). The reaction mixture was heated under microwave from the teaching at 100°C for 30 minutes Removal of solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 15.6 mg (25%) specified in the connection header. MS (ISP): 413,9 [M+H]+.

Example 124

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(4-isopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon

Specified in the title compound was obtained analogously to example 70, substituting 8-methoxy-1,2,3,4-tetrahydroquinolin on the oxalate of 1-isopropyl-1,2,3,4-tetrahydroquinoxaline (commercially available from Zannan Pharma Ltd). MS (ISP): 442,0 [M+H]+.

Example 125

(4-Cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano

Stage 1: Cyclopropyl-(2-nitrophenyl)amine

To cyclopropylamino (27,3 g, 33,1 ml of 0.48 mol, 2.25 equiv.; [CAS RN 765-30-0]) was added dropwise 2-ftorirovannom (30.0 g, of 0.21 mol, 1.0 equiv.; [CAS RN 1493-27-2]) for 1 h at 30°C, and stirring the reaction mixture kept at RT for 18 h, the Reaction mixture was extracted from the feast upon. solution of NaHCO3(500 ml) with ethyl acetate (3×300 ml)and the combined organic phases were dried MgSO4. Purification of column chromatography on when likehere, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira a mixture of heptane/ethyl acetate (9:1), resulted in obtaining 32,4 g (86%) indicated in the title compound as a yellow oil. MS (ISP): 178,0 [M+H]+.

Stage 2: Methyl ester of N-cyclopropyl-N-(2-nitrophenyl)assalamou acid

To a solution of cyclopropyl-(2-nitrophenyl)amine (32,0 g of 0.18 mol, 1.0 equiv.) in dichloromethane (320 ml) was slowly added triethylamine (18.2 g, 25,0 ml of 0.18 mol, 1.0 equiv.; [CAS RN 121-44-8]) and methylacetylene (22,0 g, 16.5 ml of 0.18 mol, 1.0 equiv.; [CAS RN 5781-53-3]) at 0°C. After addition the reaction mixture was stirred at RT for 72 h, the Reaction mixture was extracted from the feast upon. solution of NaHCO3(300 ml), dichloromethane (3×200 ml)and the combined organic phases were dried MgSO4. Purification of column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira a mixture of heptane/ethyl acetate (2:1), resulted in the receipt of 45.2 g (95%) indicated in the title compounds as white solids. MS (ISP): 265,1 [M+H]+.

Stage 3: 1-Cyclopropyl-4-hydroxy-1,4-dihydroquinoxaline-2,3-dione

To a solution of methyl ester of N-cyclopropyl-N-nitrophenyl)assalamou acid (45,0 g to 0.17 mol, 1.0 equiv.) in methanol (400 ml) was added palladium on coal (4.52 g, 0,0043 mole, of 0.025 equiv.; 10% Pd/C; [CAS RN 7440-05-3]), and the reaction mixture was stirred in hydrogen atmosphere (1.2 bar) at RT for 2 h, Reactio the ing the mixture was diluted with ethyl acetate (400 ml), was filtered through Celite, and the solvent mixture was removed at the evaporator under reduced pressure to get to 31.2 g (84%) indicated in the title compound as a pale yellow solid. MS (ISN): 219,1 [M+H]+.

Stage 4: 1-Cyclopropyl-1,4-dihydroquinoxaline-2,3-dione

To a solution of 1-cyclopropyl-4-hydroxy-1,4-dihydroquinoxaline-2,3-dione (31.0 g, of 0.14 mol, 1.0 equiv.) in DMF (250 ml) was added triphenylphosphine (55,9 g of 0.21 mol, 1.5 equiv.; [CAS RN 603-35-0]), and the reaction mixture was stirred at 135°C for 4 h, the Reaction mixture was cooled to 0°C, was added dichloromethane (400 ml). The suspension was stirred for 30 min, was filtered and washed with dichloromethane (200 ml), receiving of 23.8 g (83%) indicated in the title compounds as white solids. MS (ISN): 203,1 [M+H]+.

Stage 5: 1-Cyclopropyl-1,2,3,4-tetrahydroquinoxalin

To a stirred suspension of 1-cyclopropyl-1,4-dihydroquinoxaline-2,3-dione (10.0 g, 49,45 mmole, 1.0 equiv.) in THF (500 ml) was added dropwise a 1 M solution of the complex of borane-tetrahydrofuran (108,8 ml, 108,8 mmole, 2.2 equiv.; [CAS RN 14044-65-6]), and the reaction mixture was stirred at RT over night. The solvent was removed on an evaporator under reduced pressure and the crude reaction mixture was extracted from the feast upon. solution of NaHCO3(100 ml) with ethyl acetate (3×100 ml). The combined organic phases were dried Na2SO4and cleansed colonos the second chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate to obtain 4,2 g (49%) indicated in the title compound as a pale yellow solid. MS (ISP): 175,4 [M+H]+.

Step 6:

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (70 mg, 0.25 mmole, 1.0 equiv.; example 31, step 1) in anhydrous DMF (1.4 ml) was added N-ethyldiethanolamine (96 mg, 126 μl, of 0.74 mmole, 3.0 equiv.; [CAS RN 7087-68-5]) and HATU (112 mg, 0.30 mmole, 1.2 equiv.; [CAS RN 148893-10-1]), and the reaction mixture was stirred at RT. After 15 min was added 1-cyclopropyl-1,2,3,4-tetrahydroquinoxalin (52 mg, 0.30 mmole, 1.2 equiv.), and stirring at RT was continued during the night. Purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 38 mg (35%) specified in the connection header. MS (ISP): 440,1 [M+H]+.

Example 126

(4-Cyclobutyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano

To a solution of [2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (50 mg, 0.125 mmole, 1.0 equiv.; example 122) in cyclobutanone (469 mg, 0.5 ml, 6,69 mmole, 53,5 equiv.; [CAS RN 1191-95-3]) was added acetic acid (28 mg, 27 μl, 0.5 mmole, 4.0 equiv.;[CAS RN 64-19-7]), and the reaction mixture was stirred at RT. After 90 min was added cyanoborohydride sodium (15.7 mg, 0.25 mmole, 2.0 equiv.; [CAS RN 25895-60-7]), and stirring at RT was continued for 2 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 12.5 mg (22%) specified in the connection header. MS (ISP): 454,2 [M+H]+.

Example 127

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(4-oxetan-3-yl-3,4-dihydro-2H-cinoxacin-1-yl)methanon

Specified in the title compound was obtained analogously to example 126, replacing CYCLOBUTANE on oxetan-3-one ([CAS RN 6704-31-0]). MS (ISP): 456,2 [M+H]+.

Example 128

1-[2-(2,5-Dichlorophenoxy)pyridine-3-carbonyl]-2,3-dihydro-1H-quinoline-4-one

To a solution of [2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanone (100 mg, 0.25 mmole, 1.0 equiv.; example 24) in anhydrous 1,2-dichloroethane (2 ml) was added sodium hydrogen carbonate (11 mg, 0.125 mmole, 0.5 equiv.; [CAS RN 144-55-8]), tert-butylhydroperoxide (189 mg, 227 μl, 1.25 mmole, of 5.0 equiv, 5.5 M solution in decane; [CAS RN 75-91-2], TNR) and caprolactamate derode (1.7 mg, 0,0025 mmole, 0.01 equiv.; [CAS RN 138984-26-6]; the floor is built in accordance with article M. P. Doyle, L. J. Westrum, W. N. E. Wolthuis, M. M. See, W. R. Boone, V. Bagheri, M. M. Pearson, J. Am. Chem. Soc., 1993, 115, CC.958-964). The reaction mixture was stirred at RT over night. Removal of solvent mixture under reduced pressure and purification of column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate, then preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 59 mg (57%) indicated in the title compounds as white solids. MS (ISP): 413,1 [M+H]+.

Example 129

[2-(2,5-Dichlorphenoxy)pyridine-3-yl]-(4-methylene-3,4-dihydro-2H-quinoline-1-yl)methanon

Step 1: tert-Butyl ether 4-methylene-3,4-dihydro-2H-quinoline-1-carboxylic acid

The solution methyltriphenylphosphonium (1.92 g, 5,38 mmole, 1.1 equiv.; [CAS RN 1779-49-3]) and tert-butoxide potassium (0,60 g, 5,38 mmole, 1.1 equiv.; [CAS RN 865-47-4]) in toluene (20 ml) was heated at boiling under reflux. After 1 h was added tert-botilony ether 4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid (1,21 g, 4,89 mmole, 1.0 equiv.; [CAS RN 179898-00-1])dissolved in toluene (10 ml), and heating was continued for another one hour. The reaction mixture was extracted from ASUS. solution of NH4Cl (100 ml) with ethyl acetate (3×50 ml)and the combined organic phases were dried MgSO4. Purification of column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate resulted in the receipt of 0.87 g (73%) indicated in the title compounds as colorless oils. MS (ISP): 246,4 [M+H]+.

Stage 2:

A solution of tert-butyl methyl ether 4-methylene-3,4-dihydro-2H-quinoline-1-carboxylic acid (44,2 mg of 0.18 mmole, 1.2 equiv.) in 4 M HCl in dioxane (4 ml) was stirred at RT for 2 h the Solvent was removed under reduced pressure, and the crude product was dissolved in anhydrous DMF (1 ml). To this solution was added 2-(2,5-dichlorophenoxy)nicotinic acid (42,6 mg, 0.15 mmole, 1.0 equiv.; example 31, step 1), N-ethyldiethanolamine (97 mg, 131 μl, 0.75 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (68 mg, of 0.18 mmole, 1.2 equiv.; [CAS RN 148893-10-1]), and the reaction mixture was heated under microwave irradiation at 100°C for 30 min to Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 4.1 mg (7%) specified in the connection header. MS (ISP): 410,7 [M+H]+.

Example 130

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-[4-(3,3-diversecity-1-yl)-3,4-dihydro-2H-quinoline-1-yl]metano

To a suspension of 1 -[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-2,3-dihydro-1H-quinoline-4-it (50 mg, 0.12 mmole, 1.0 equiv.; example 128) in ethanol (1.2 ml) were added hydrochloride 3,3-diversityin (31 mg, 0.24 mmole, 2.0 equiv.; [CAS RN 288315-03-7]), acetic acid (27 mg, 26 μl, 0.48 mmole, 4.0 equiv.; [CAS RN 64-19-7]) and N-ethyldiethanolamine (31 mg, 42 μl, 0.24 mmole, 2.0 equiv.; [CAS RN 7087-68-5]). The reaction mixture was heated under microwave irradiation at 100°C for 10 minutes was Added triacetoxyborohydride sodium (33 mg, 0.16 mmole, 1.3 equiv.; [CAS RN 56553-60-7]), and heated at 100°C. was continued for 15 minutes, the Reaction mixture was extracted from the feast upon. solution of NaHCO3(50 ml) with ethyl acetate (3×50 ml)and the combined organic phases were dried MgSO4. Purification of column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate resulted in the receipt of 0.04 g (7%) indicated in the title compound as a pale yellow solid. MS (ISP): 490,0 [M+H]+.

Example 131

N-(2-Cyclopropylethyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (42,6 mg, 0.15 mmole, 1.0 equiv.; example 31, step 1) in anhydrous DMF (1 ml) was added N-utiliser is pelamin (97 mg, 128 μl, 0.75 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (67 mg, of 0.18 mmole, 1.2 equiv.; [CAS RN 148893-10-1]), and the reaction mixture was stirred at RT for 30 minutes After adding 2-cyclopropylalanine (24 mg, of 0.18 mmole, 1.2 equiv.; [CAS RN 3158-73-4]), the reaction mixture was heated under microwave irradiation at 100°C. After 30 min was added sodium hydride (8.6 mg, 0.2 mmole, 2.0 equiv.; 55% free flowing powder moistened with oil; [CAS RN 7646-69-7]) and jodean (28.4 mg, 12 μl, 0.2 mmole, 2.0 equiv.; [CAS RN 74-88-4]), and stirring the reaction mixture kept at RT for 2 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 12.6 mg (20%) specified in the connection header. MS (ISP): 412,9 [M+H]+.

Example 132

2-(2,5-Dichlorophenoxy)-N-methyl-N-(2-methylsulfinylphenyl)nicotinamide

Specified in the title compound was obtained analogously to example 131, replacing 2-cyclopropylamino 2-methylsulfinylphenyl ([CAS RN 2987-53-3]). MS (ISP): 418,9 [M+H]+.

Example 133

2-(2,5-Dichlorophenoxy)-N-methyl-N-[2-(2-methyl-2H-pyrazole-3-yl)phenyl]nicotinamide

A solution of 2-(2,5-dihl is Hinoki)nicotinic acid (28.4 mg, 0.1 mmole, 1.0 equiv.; example 31, step 1) in thionyl chloride (984 mg, 800 μl, 11.0 mmol, 110 equiv.; [CAS RN 7719-09-7]) was heated at 100°C for 1 h, the Reaction mixture was concentrated under reduced pressure, the remaining thionyl chloride was removed by azeotropic distillation with toluene, and the residue was dissolved in anhydrous DMF (1 ml). To this solution was added N-ethyldiethanolamine (129 mg, 170 μl, 1.0 mmol, 10.0 g equiv.; [CAS RN 7087-68-5]) and 2-(2H-pyrazole-3-yl)phenylamine (19 mg, 0.12 mmole, 1.2 equiv.; [CAS RN 111562-32-4]), and the reaction mixture was stirred at RT for 18 h To this solution was added sodium hydride (8.6 mg, 0.2 mmole, 2.0 equiv.; 55% free flowing powder moistened with oil; [CAS RN 7646-69-7]) and jodean (28.4 mg, 12 μl, 0.2 mmole, 2.0 equiv.; [CAS RN 74-88-4]), and stirring the reaction mixture at RT was continued for 2 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 1.0 mg (2%) specified in the connection header. MS (ISP): 453,1 [M+H]+.

Example 134

N-(2-AMINOPHENYL)-2-(2,5-dichlorophenoxy)-N-nicotine amide

To a solution of 2-(2,5-dichlorophenoxy)nicotinic acid (50 mg, of 0.18 mmole, 1.0 EQ the century; example 31, step 1) in anhydrous DMF (2 ml) was added N-ethyldiethanolamine (116 mg, 154 μl, of 0.90 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (82 mg, 0.22 mmole, 1.2 equiv.; [CAS RN 148893-10-1]), and the reaction mixture was stirred at RT for 30 minutes After adding N-methylbenzol-1,2-diamine (26.9 mg, 0.22 mmole, 1.2 equiv.; [CAS RN 4760-34-3]) stirring was continued at RT for 90 minutes removing the solvent under reduced pressure and purification of column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate, yielded 33 mg (47%) indicated in the title compounds as white solids. MS (ISP): 388,0 [M+H]+.

Example 135

2-(2,5-Dichlorophenoxy)-N-(2,5-dichlorophenyl)-N-nicotine amide

Specified in the title compound was obtained analogously to example 133, replacing 2-(2H-pyrazole-3-yl)phenylamine 2.5-dichlorophenylamino ([CAS RN 95-82-9]). MS (ISP): 443,1 [M+H]+.

Example 136

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(2,3,3 a,4-tetrahydro-1H-pyrrolo[1,2-a]cinoxacin-5-yl)methanon

To a solution of 4,5-dihydropyrrolo[1,2-a]finokalia (30,6 mg of 0.18 mmole, 1.2 equiv.; [CAS RN 56721-86-9]) in ethanol (5 ml) was added palladium on coal (3.2 mg, of 0.003 mmole, of 0.02 equiv.; 10% Pd/C; [CAS RN 7440-05-3]), and the reaction mixture was stirred in hydrogen atmosphere (3 bar) at RT for 4 h, the Reaction mixture was concentrate who has demonstrated under reduced pressure, was filtered through Celite, and the obtained residue was dissolved in anhydrous DMF (1 ml). To this solution was added N-ethyldiethanolamine (64 mg, 86 μl, of 0.50 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and 2-(2,5-dichlorophenoxy)nicotinergic (45,4 mg, 0.15 mmole, 1.0 equiv.; obtained in accordance with example 122), and the reaction mixture was stirred at RT over night. Removal of solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt to 21.4 mg (32%) specified in the connection header. MS (ISP): 440,1 [M+H]+.

Example 137

[2-(2,5-Dichlorophenoxy)pyridine-3-yl]-(4-isobutyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon

To a solution of [2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (24 mg, 0.06 to mmole, 1.0 equiv.; example 122) in anhydrous DMF (1 ml) was added 2-methylpropionamide (17.3 mg, 22 μl, 0.24 mmole, 4.0 equiv.; [CAS RN 78-84-2]), dichloride dibutyrate (1.8 mg, 0,006 mmole, 0.1 equiv.; [CAS RN 683-18-1]) and phenylsilane (13,0 mg, 15 μl, 0.12 mmole, 2.0 equiv.; [CAS RN 694-53-1]). The reaction mixture was heated under microwave irradiation at 150°C for 15 minutes Remove the mixture of solvents under reduced pressure the purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 10.3 mg (38%) indicated in the title compound as a pale yellow powder. MS (ISP): 456,4 [M+H]+.

Example 138

(4-Cyclopropylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 137, replacing 2-methylpropionamide on cyclopropanecarboxaldehyde ([CAS RN 1489-69-6]). MS (ISP): 454,0 [M+H]+.

Example 139

(4-Cyclobutylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano

Specified in the title compound was obtained analogously to example 137, replacing 2-methylpropionamide on cyclobutanecarbonitrile ([CAS RN 2987-17-9]). MS (ISP): 468,3 [M+H]+.

Example 140

2-{4-[2-(2,5-Dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}ethyl ester of acetic acid

To a solution of [2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (24 mg, 0.06 to mmole, 1.0 equiv.; example 122) in anhydrous DMF (1 ml) was added socialogical (2,3 mg to 0.06 mmole, 1.0 equiv.; [CAS RN 16853-85-3]), and the reaction mixture was stirred at RT. After 30 min we use the 2-bromatology ether acetic acid (12.0 mg, 8 μl, 0,072 mmole, 1.2 equiv.; [CAS RN 927-68-4]), and the reaction mixture was heated under microwave irradiation at 180°C for 60 minutes Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 8.9 mg (31%) indicated in the title compound in the form of light yellow powder. MS (ISP): 486,1 [M+H]+.

Example 141

Ethyl ester {4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid

To a solution of [2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (60 mg, 0.15 mmole, 1.0 equiv.; example 122) in anhydrous DMF (0.5 ml) was added N-ethyldiethanolamine (96 mg, 129 μl, 0.75 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and ethylbromoacetate (55,1 mg, 37 μl, of 0.33 mmole, 2.2 equiv.; [CAS RN 105-36-2]), and the reaction mixture was heated under microwave irradiation at 100°C for 2 hours the solvent under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetone is home to the thrill/water, resulted in the receipt of 42.7 mg (62%) indicated in the title compound as a pale yellow powder. MS (ISP): 486,1 [M+H]+.

Example 142

{4-[2-(2,5-Dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid

To a solution of [2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (30 mg, of 0.075 mmole, 1.0 equiv.; example 122) in anhydrous DMF (0.5 ml) was added N-ethyldiethanolamine (48 mg, 65 µl, the 0.375 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and ethylbromoacetate (27,6 mg, 19 μl, 0,165 mmole, 2.2 equiv.; [CAS RN 105-36-2]), and the reaction mixture was heated under microwave irradiation at 100°C. After 2 h was added 5 M aqueous sodium hydroxide solution (0.5 ml, 2.5 mmole, 33 equiv.; [CAS RN 1310-73-2]), and the reaction mixture was stirred at RT over night. Removal of the solvent under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 7.5 mg (22%) indicated in the title compound as a pale yellow powder. MS (ISP): 458,1 [M+H]+.

Example 143

3-(4-{4-[2-(2,5-Dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-sulfonyl}phenyl)propionic acid

Stage 1: Met Lowy ether 3-(4-{4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-sulfonyl}phenyl)propionic acid

To a solution of [2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (80 mg, 0.2 mmole, 1.0 equiv.; example 122) in anhydrous dichloromethane (2 ml) was added N-ethyldiethanolamine (51.3 mg, 69 μl, 0.4 mmole, 2.0 equiv.; [CAS RN 7087-68-5]) and methyl 3-(4-chlorosulfonyl)phenylpropionate (57,8 mg, 0.22 mmole, 1.1 equiv.; [CAS RN 374537-95-8]), and the reaction mixture was stirred at RT over night. Removal of the solvent under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 44 mg (35%) indicated in the title compound as a pale whitish powder. MS (ISP): 626,2 [M+H]+.

Stage 2:

To a suspension of methyl ester 3-(4-{4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-sulfonyl}phenyl)propionic acid (36 mg, 0,058 mmole, 1.0 equiv.) in ethanol (1 ml) was added 1 M sodium hydroxide solution (120 μl, 0.12 mmole, 2.0 equiv.; [CAS RN 1310-73-2]), and the reaction mixture was stirred at RT over night. Removal of the solvent under reduced pressure, and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 the UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 4.5 mg (13%) indicated in the title compound as a pale yellow powder. MS (ISP): 612,1 [M+H]+.

Example 144

(3,4-Dihydro-2H-quinoline-1-yl)-[2-(2-fluoro-5-triptoreline)pyridine-3-yl]metano

To a solution of (2-chloropyridin-3-yl)-(3,4-dihydro-2H-quinoline-1-yl)methanone (50 mg, of 0.18 mmole, 1.0 equiv.; example 6, step 1) and 2-fluoro-5-triptoreline (42,1 mg, 0,23 mmole, 1.3 equiv.; [CAS RN 141483-15-0]) in anhydrous toluene (0.5 ml) was added cesium carbonate (176 mg, 0.54 mmole, 3.0 equiv.; [CAS RN 534-17-8]) and hexaphosphate tetrakis(acetonitrile)copper (I) (20,1 mg, 0,054 mmole, 0.3 equiv.; [CAS RN 64443-05-6]). The reaction mixture was heated under microwave irradiation at 150°C for 1 h Purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 50 mg (67%) indicated in the title compound as a pale yellow solid. MS (ISP): 417,4 [M+H]+.

Example 145

2-(2,5-Dichlorophenoxy)-5-fluoro-N-(2-methoxypyridine-3-yl)-N-nicotine amide

To a solution of 2-(2,5-dichlorophenoxy)-5-fornicating acid (100 mg, of 0.33 mmole, 1.0 equiv.; example 80, step 1) in anhydrous DMF (1 ml) was added N-ethyldiethanolamine (213 mg, 282 μl, 1.65 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and HATU (151 mg, 0.40 mmole, 1.2 equiv.; [CAS RN 148893-10-1]), and the reaction mixture was stirred at RT. After 1 h was added 3-amino-2-methoxypyridine (49 mg, 0.40 mmole, 1.2 equiv.; [CAS RN 20265-38-7]), and stirring at RT was continued during the night. The reaction mixture was extracted from the feast upon. solution of NaHCO3(100 ml), dichloromethane (3×50 ml), the combined organic phases were dried MgSO4the solvent was removed on an evaporator under reduced pressure and the crude reaction mixture was dissolved in DMF (1.5 ml). To this solution was added sodium hydride (28,6 mg of 0.66 mmole, 2.0 equiv.; 55% free flowing powder moistened with oil; [CAS RN 7646-69-7]) and jodean (93,7 mg, 41 μl, of 0.66 mmole, 2.0 equiv.; [CAS RN 74-88-4]), and the reaction mixture was stirred at RT for 30 minutes Cleaning preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 28.5 mg (20%) specified in the connection header. MS (ISP): 422,0 [M+H]+.

Example 146

N-(2,6-Dichloro-3-methoxyphenyl)-2-(2,5-dichlorophenoxy)-5-fluoro-N-nicotine amide

Stage 1: 2-(2,5-Dichlorophenoxy)-5-fornicationem

To a solution of 2-(2,5-dichlorophenoxy)-5-fornicating acid (2.14 g, 7,08 IMO is I, 1.0 equiv.; example 80, step 1) in dichloromethane (15 ml) was added thionyl chloride (16.4 g, 10 ml, 138 mmol, 19,5 equiv.; [CAS RN 7719-09-7]), and the reaction mixture was heated at boiling reverse refrigerated within 2 hours the Reaction mixture was concentrated under reduced pressure, and the remaining thionyl chloride was removed by azeotropic distillation with toluene. The crude material was used in the next stage of the reaction without additional purification.

Stage 2:

To a solution of 2-(2,5-dichlorophenoxy)-5-fioricethydrochloride (76,6 mg, 0.24 mmole, 1.0 equiv.) in anhydrous DMF (1 ml) was added N-ethyldiethanolamine (155 mg, 205 μl, 1.2 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and 2,6-dichloro-3-methoxybenzylamine (50,7 mg, 0,264 mmole, 1.1 equiv.; [CAS RN 55285-43-3]), and the reaction mixture was stirred at RT over night. To this solution was added sodium hydride (20.6 mg, 0.48 mmole, 2.0 equiv.; 55% free flowing powder moistened with oil; [CAS RN 7646-69-7]) and jodean (68,2 mg, 29 μl, 0.48 mmole, 2.0 equiv.; [CAS RN 74-88-4]), and stirring the reaction mixture at RT was continued for 2 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 8.1 mg (7%) indicated in the title the connection information in the form of a whitish powder. MS (ISP): 490,9 [M+H]+.

Example 147

[2-(2,5-Dichlorophenoxy)-5-Herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon

Specified in the title compound was obtained analogously to example 146, step 2, substituting 2,6-dichloro-3-methoxybenzylamine on 1,2,3,4-tetrahydroquinoxalin ([CAS RN 3476-89-9]). MS (ISP): 418,3 [M+H]+.

Example 148

Methyl ether of 1-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-1,2,3,4-tetrahydroquinolin-4-carboxylic acid

To a solution of 2-(2,5-dichlorophenoxy)-5-fioricethydrochloride of 48.1 mg, 0.15 mmole, 1.0 equiv.; example 146, step 1) in anhydrous DMF (1 ml) was added N-ethyldiethanolamine (97 mg, 128 μl, 0.75 mmole, of 5.0 equiv.; [CAS RN 7087-68-5]) and methyl ester of 1,2,3,4-tetrahydroquinolin-4-carboxylic acid (31,6 mg, 0,165 mmole, 1.1 equiv.; [CAS RN 68066-85-3]), and the reaction mixture was stirred at RT for 2 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 9.1 mg (13%) indicated in the title compound as a pale yellow solid. MS (ISP): 475,1 [M+H]+.

Example 149

[2-(2,5-dichlorophenoxy)-5-fluoro-3-pyridyl]-(4H-Pirro is about[1,2- a] cinoxacin-5-yl)methanon

Specified in the title compound was obtained analogously to example 148, replacing the methyl ester of 1,2,3,4-tetrahydroquinolin-4-carboxylic acid 4,5-dihydropyrrolo[1,2-and]cinoxacin ([CAS RN 56721-86-9]). MS (ISP): 454,0 [M+H]+.

Example 150

(4-Cyclobutyl-3,4-dihydro-2-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]metano

To a solution of [2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (52,3 mg, 0.125 mmole, 1.0 equiv.; example 147) in methanol (0.5 ml) was added cyclobutanone (188 mg, 0.2 ml, 2.68 mmole, 21,4 equiv.; [CAS RN 1191-95-3]), acetic acid (28 mg, 27 μl, 0.5 mmole, 4.0 equiv.; [AS RN 64-19-7]), and the reaction mixture was stirred at RT. After 90 min was added cyanoborohydride sodium (15.7 mg, 0.25 mmole, 2.0 equiv.; [CAS RN 25895-60-7]), and stirring at RT was continued for 18 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 3.3 mg (6%) specified in the connection header. MS (ISP): 474,1 [M+H]+.

Example 151

[2-(2,5-Dichlorophenoxy)-5-herperidin-3-yl]-(4-furan-3-ylmethyl-3,4-dihydro-H-cinoxacin-1-yl)methanon

To a solution of [2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (25.1 mg, is 0.06 mmole, 1.0 equiv.; example 148) in anhydrous DMF (1 ml) was added furan-3-carbaldehyde (23.1 mg, 20 μl, 0.24 mmole, 4.0 equiv.; [CAS RN 498-60-2]), dichloride dibutyrate (1.8 mg, 0,006 mmole, 0.1 equiv.; [CAS RN 683-18-1]) and phenylsilane (13,0 mg, 15 μl, 0.12 mmole, 2.0 equiv.; [CAS RN 694-53-1]). The reaction mixture was heated under microwave irradiation at 150°C for 15 minutes Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 5.4 mg (18%) indicated in the title compound as a pale yellow solid. MS (ISP): 498,3 [M+H]+.

Example 152

(4-Cyclobutylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]metano

Specified in the title compound was obtained analogously to example 151, substituting furan-3-carbaldehyde to cyclobutanecarbonitrile ([CAS RN 2987-17-9]). MS (ISP): 486,3 [M+H]+.

Example 153

[2-(2,5-Dichlorophenoxy)-5-herperidin-3-yl]-[4-(3,3,3-cryptochromes)-3,4-dihydro-2H-cinoxacin-1-yl]metano

Specified in the title compound was obtained analogously to example 151, substituting furan-3-carbaldehyde on 3,3,3-cryptocraphically ([CAS RN 460-40-2]). MS (ISP): 486,3 [M+H]+.

Example 154

Ethyl ester {4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid

To [2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (200 mg, 0,478 mmole, 1.0 equiv.; example 147) was added a 50% solution of ethyl ester of Glyoxylic acid in toluene (1,03 g, 1 ml, 1,913 mmole, 4.0 equiv.; [CAS RN 924-44-7]), dichloride dibutyrate (14.6 mg, 0,048 mmole, 0.1 equiv.; [CAS RN 683-18-1]) and phenylsilane (to 103.8 mg, 118 μl, 0,956 mmole, 2.0 equiv.; [CAS RN 694-53-1]). The reaction mixture was heated under microwave irradiation at 100°C for 30 min to Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in obtaining 82,7 mg (34%) indicated in the title compound as a pale yellow solid. MS (ISP): 504,3 [M+H]+.

Example 155

{4-[2-(2,5-Dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid

It races the thief ethyl ester {4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid (82 mg, 0,163 mmole, 1.0 equiv.; example 154) in THF (1 ml) was added 5 M aqueous sodium hydroxide solution (0.5 ml, 2.5 mmole, 15 equiv.; [CAS RN 1310-73-2]), and the reaction mixture was heated under microwave irradiation at 120°C for 30 minutes the solvent under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 7.5 mg (10%) specified in the connection header in the form of light-yellow powder. MS (ISP): 476,0 [M+H]+.

Example 156

Ethyl ester 3-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}propionic acid

To a solution of [2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (25.1 mg, is 0.06 mmole, 1.0 equiv.; example 147) in anhydrous DMF (1 ml) was added socialogical (2,3 mg to 0.06 mmole, 1.0 equiv.; [CAS RN 16853-85-3]), and the reaction mixture was stirred at RT. After 30 min was added ethyl ester 3-bromopropionic acid (13,0 mg, 10 ál, 0,072 mmole, 1.2 equiv.; [CAS RN 539-74-2]), and the reaction mixture was heated under microwave irradiation at 150°C for 30 min to Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 2.4 mg (8%) indicated in the title compound as light brown oil. MS (ISP): 518,3 [M+H]+.

Example 157

3-{4-[2-(2,5-Dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}-2-methylpropionate acid

To a solution of [2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (25.1 mg, is 0.06 mmole, 1.0 equiv.; example 147) in a mixture of 1:1 THF and water (1 ml) was added methyl ether 2-methyl-3-oxopropanoic acid (27.9 mg, 0.24 mmole, 4.0 equiv.; [CAS RN 51673-64-4]), dichloride dibutyrate (1.8 mg, 0,006 mmole, 0.1 equiv.; [CAS RN 683-18-1]) and phenylsilane (13,0 mg, 15 μl, 0.12 mmole, 2.0 equiv.; [CAS RN 694-53-1]). The reaction mixture was heated under microwave irradiation at 150°C for 1.5 hours removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 2.2 mg (7%) indicated in the title compound as a pale yellow solid. MS (ISP): 504,0 [M+H]+ .

Example 158

Ethyl ester 4-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}butane acid

To a solution of [2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (50.2 mg, 0.12 mmole, 1.0 equiv.; example 147) in anhydrous DMF (1 ml) was added sodium hydride (10.3 mg, 0.24 mmole, 2.0 equiv.; 55% free flowing powder moistened with oil [CAS RN 7646-69-7]), and the reaction mixture was stirred at RT. After 1 h was added ethyl ester 4-bromoethanol acid (545 mg, 400 ál, 2,80 mmole, 23.3 equiv.; [CAS RN 2969-81-5]), and the stirring was continued under microwave heating at 120°C for 30 min to Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 5.5 mg (9%) indicated in the title compound as light-yellow oil. MS (ISP): 532,2 [M+H]+.

Example 159

Ethyl ester 5-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}pentanol acid

Specified in the title compound was obtained analogously to example 158, substituting the ethyl ester of 4-bromobutyronitrile on the ethyl ester of 5-bromopentanoate acid ([CAS RN 14660-52-7]). MS (ISP): 546,3 [M+H]+.

Example 160

Methyl ester 6-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}hexanoic acid

Specified in the title compound was obtained analogously to example 151, substituting furan-3-carbaldehyde on the methyl ester of tolualdehyde adipic acid ([CAS RN 6654-36-0]). MS (ISP): 546,3 [M+H]+.

Example 161

6-{4-[2-(2,5-Dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}hexanoic acid

Specified in the title compound was obtained analogously to example 157, replacing the methyl ester of 2-methyl-3-oxopropanoic acid methyl ester tolualdehyde adipic acid ([CAS RN 6654-36-0]). MS (ISP): 532,2 [M+H]+.

Example 162

Methyl ester 4-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-carbonyl}benzoic acid

To a solution of [2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanone (52,3 mg, 0.125 mmole, 1.0 equiv.; example 147) in anhydrous DMF (1 ml) was added N-ethyldiethanolamine (65 mg, 85 μl, 0.5 mmole, 4.0 equiv.; [CAS RN 7087-68-5]) and methyl ester of 4-chlororesorcinol acid (29,8 mg, 0.15 mmole, 1.2 equiv.; [CAS RN 7377-26-6]). The reaction mixture was heated under microwave irradiation at 120°C for 15 minutes Remove solvent mixture when the pony is hinnon pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 7.8 mg (11%) indicated in the title compound as a white powder. MS (ISP): 580,0 [M+H]+.

Example 163

[2-(4-Bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon

Stage 1: 2-(4-Bromo-2,5-dichlorophenoxy)nicotinic acid

To a solution of 2-chloronicotinic acid (100 mg, of 0.64 mmole, 1.0 equiv.; [CAS RN 2942-59-8]) and 4-bromo-2,5-dichlorophenol (184 mg, from 0.76 mmole, 1.2 equiv.; [CAS RN 1940-42-7]) in toluene (1 ml) was added cesium carbonate (517 mg, 1.59 mmole, 2.5 equiv.; [CAS RN 534-17-8]) and hexaphosphate tetrakis(acetonitrile)copper (I) - (47 mg, of 0.13 mmole, 0.2 equiv.; [CAS RN 64443-05-6]). The reaction mixture was heated under microwave irradiation at 140°C for 1 h the Solvent was evaporated under reduced pressure and the crude reaction product was transferred into water (100 ml), acidified to pH 1 by adding a solution of 1 M HCl and was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried MgSO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient dichloromethane/methanol, receiving 170 mg (73%) indicated in the title compound in the form Belov is also solid. 1H NMR (400 MHz, DMSO): δ 7,21 (dd, J=7,6 Hz, J=4,8 Hz, 1H), 7,42 (s, 1H), 7,76 (s, 1H), 8,29 (dd, J=4,8 Hz, J=1.9 Hz, 1H), and 8.50 (dd, J=7.7 Hz, J=2.0 Hz, 1H). MS (ISN): 362,0 [M-H]-.

Stage 2:

To a solution of 2-(4-bromo-2,5-dichlorophenoxy)nicotinic acid (50 mg, of 0.14 mmole, 1.0 equiv.) in anhydrous dichloromethane (1.5 ml) was added N-ethyldiethanolamine (36 mg, 47 μl, of 0.28 mmole, 2.0 equiv.; [CAS RN 7087-68-5]) and HATU (68 mg, of 0.18 mmole, 1.3 equiv.; [CAS RN 148893-10-1]), and the reaction mixture was stirred at RT. After 10 min was added 1-cyclopropyl-1,2,3,4-tetrahydroquinoxalin (29 mg, 0.17-mmole, 1.2 equiv.; example 125, step 5), and stirring at RT was continued during the night. To the reaction mixture was added to feast upon. the solution of NaHCO3(20 ml)and the solution was extracted with dichloromethane (3×20 ml). The combined organic phases were dried Na2SO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate, receiving 45 mg (63%) indicated in the title compound in the form of a whitish powder. MS (ISP): 520,3 [M+H]+.

Example 164

(4-Cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-{2-[2,5-dichloro-4-(3-hydroxyprop-1-inyl)phenoxy]pyridine-3-yl}metano

To a degassed suspension of [2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanone (100 mg, 0,19 mmole, 1.0 equiv.; example 163) in triethylamine (0.8 ml) in the atmosphere is ore AG was added 2-propyne-1-ol (216 mg, 220 μl, 3.85 mmole, 20 equiv.; [CAS RN 107-19-7]), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmole, 0.1 equiv.; [CAS RN 14221-01-3]) and copper iodide (I) (3.7 mg, 0.02 mmole, 0.1 equiv.; [CAS RN 7681-65-4]). The reaction mixture was heated under microwave irradiation at 100°C for 1 h removing the solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 49 mg (52%) indicated in the title compound in the form of a whitish powder. MS (ISP): 494,3 [M+H]+.

Example 165

[2-(4-Bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon

To a solution of 2-(4-bromo-2,5-dichlorophenoxy)nicotinic acid (50 mg, of 0.14 mmole, 1.0 equiv.; example 163, step 1) in anhydrous dichloromethane (1.5 ml) was added N-ethyldiethanolamine (152 mg, 200 ál, of 1.18 mmole, 8.4 equiv.; [CAS RN 7087-68-5]) and 2-chloro-1-methylpyridinium (42 mg, 0.17-mmole, 1.2 equiv.; [CAS RN 14338-32-0]), and the reaction mixture was stirred at RT. After 1 h was added 1,2,3,4-tetrahydroquinolin (22 mg, 21 μl, 0,17 mmole, 1.2 equiv.; [CAS RN 635-46-1]), and stirring at RT was continued during the night. Removal of solvent mixture under reduced pressure and purification preparative HPLC reverse what asoi (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, has led to 41 mg (61%) indicated in the title compound as a white powder. MS (ISP): of 476.9 [M+H]+.

Example 166

Methyl ester 5-{2,5-dichloro-4-[3-(3,4-Dihydro-2H-quinoline-1-carbonyl)pyridine-2-yloxy]phenyl}Penta-4-invoi acid

To a degassed suspension of [2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanone (50 mg, 0.10 mmole, 1.0 equiv.; example 165) in THF (2 ml) in an atmosphere of Ar was added methyl ether the Penta-4-invoi acid (34 mg, 0.30 mmole, 3 equiv.; [CAS RN 21565-82-2]), chloroform adduct and Tris(dibenzylideneacetone)diplegia(0) (1 mg, 0.001 mmole, 0.01 equiv.; [CAS RN 52522-40-4]), copper iodide(I) (0.2 mg, 0.001 mmole, 0.01 equiv.; [CAS RN 7681-65-4]) and triethylamine (20 mg, 28 μl, 0.20 per mmole, 2.0 equiv.; [CAS RN 121-44-8]). The reaction mixture was stirred at 60°C for the weekend. Removal of solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 3 mg (6%) specified in the connection header in the form of velo-brown oil. MS (ISP): 509,1 [M+H]+.

Example 167

Methyl ester 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid

Stage 1: Methyl ether of 2-chloro-4-trimethylsilylmethylamine acid

To a degassed solution of methyl ester 4-bromo-2-chlorbenzoyl acid (3.0 g, 12.0 mmol, 1.0 equiv.; [CAS RN 185312-82-7]) in triethylamine (24.3 g, and 33.5 ml, to 240.5 mmole, 20.0 equiv.; [CAS RN 121-44-8]) in the atmosphere of AG was added amenitieseven (1.24 g, of 1.78 ml, 12,63 mmole, 1.05 equiv.; [CAS RN 1066-54-2]), tetrakis(triphenylphosphine)palladium(0) (0,70 g, 0.60 mmole, of 0.05 equiv.; [CAS RN 14221-01-3]) and copper iodide(I) (0,23 g, 1.20 mmole, 0.1 equiv.; [CAS RN 7681-65-4]), and the reaction mixture was heated at 70°C for 18 hours the Crude reaction mixture was filtered through Celite®was added to feast upon. NaCl solution (50 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried Na2SO4and the product was used in the next stage without additional purification. Output: 4.52 g (99%) indicated in the title compound with a purity of about 70% in the form of a slightly brown oil. MS (ISN): 267,0 [M+H]+.

Stage 2: Methyl ether of 2-chloro-4-ethynylbenzene acid

To a solution of methyl ester of 2-chloro-4-trimethylsilylmethylamine acid (4.52 g, 12.0 mmol, 1.0 equiv.; 70% purity) in THF (50 ml) was added 1 M solution of fluoride is of tributylamine in THF (14.4 ml, 14,40 mmole, 1.20 equiv.; [CAS RN 429-41-4]), and the reaction mixture was stirred at RT over night. The crude reaction mixture was extracted with a feast upon. a solution of NH4Cl (50 ml), ethyl acetate (3×50 ml)and the combined organic phases were dried Na2SO4. Purification of the crude reaction product column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira a mixture of dichloromethane/methanol (4:1), resulted in the receipt of 1.12 g (48%) indicated in the title compound as a slightly orange solid. MS (ISN): 195,1 [M+H]+.

Stage 3:

To a degassed suspension of [2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanone (100 mg, 0,19 mmole, 1.0 equiv.; example 163) in triethylamine (0.73 g, 1.0 ml, 7,21 mmole, 38,0 equiv.; [CAS RN 121-44-8]) in the atmosphere of Ar was added methyl ether 2-chloro-4-ethynylbenzene acid (120 mg, of 0.62 mmole, 3.2 equiv.), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02 mmole, 0.1 equiv.; [CAS RN 14221-01-3]) and copper iodide(I) (3.7 mg, 0.02 mmole, 0.1 equiv.; [CAS RN 7681-65-4]). The reaction mixture was heated under microwave irradiation at 100°C for 40 minutes Remove solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340), and elwira gradient acetonitrile/water, resulted in the receipt of 40 mg (33%) indicated in the title compound as light brown powder. MS (ISP): 634,2 [M+H]+.

Example 168

2-Chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid

To a solution of methyl ester of 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid (150 mg, 0.24 mmole, 1.0 equiv.; example 167) in a mixture of 2:2:1 THF, methanol and water (2 ml) was added lithium hydroxide (11.4 mg, of 0.47 mmole, 2.0 equiv.; [CAS RN 1310-65-2]), and the reaction mixture was stirred at RT over night. The crude reaction product was transferred into water (50 ml), acidified to pH 1 by adding a solution of 1 M HCl and was extracted with ethyl acetate (3×40 ml). The combined organic phases were dried MgSO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient dichloromethane/methanol to obtain 110 mg (75%) indicated in the title compound as a light brown solid. MS (ISN): 616,1 [M-N]-.

Example 169

2-Chloro-4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-carbonyl)pyridine-2-yloxy]phenyl} ethyl)benzoic acid

To a suspension of 2-chloro-4-{25-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid (100 mg, 0.16 mmole, 1.0 equiv.; example 168) in ethanol (1.5 ml) was added palladium on coal (3.2 mg, of 0.003 mmole, of 0.02 equiv.; 10% Pd/C; [CAS RN 7440-05-3]), and the reaction mixture was stirred in hydrogen atmosphere (3 bar) at RT over night. Removal of solvent mixture under reduced pressure, filtered through Celite and lyophilization from dioxane resulted in the receipt of 100 mg (96%) indicated in the title compound in the form of a whitish solid. MS (ISP): 620,3 [M-N]-.

Example 170

4-(2-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)benzoic acid

Stage 1: Methyl ester of 4-{2,5-dichloro-4-G3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid

Specified in the title compound was obtained analogously to example 167, step 3, substituting methyl ester 2-chloro-4-ethynylbenzene acid methyl ester 4-ethynylbenzene acid ([CAS RN 3034-86-4]). MS (ISP): 598,2 [M+H]+.

Stage 2: Methyl ester of 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid

Specified in the title compound was obtained analogously to example 169, replacing 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid methyl ester 4-{2,5-dichloro-4-[3-(4-cycloprop is l-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid. MS (ISP): 602,2 [M+H]+.

Stage 3:

Specified in the title compound was obtained analogously to example 168, substituting methyl ester 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid methyl ester 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2L-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid. MS (ISP): 588,2 [M+H]+.

Example 171

4-(2-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)-3-methoxybenzoic acid

Specified in the title compound was obtained analogously to example 170, stage 1-3, substituting methyl ester 4-ethynylbenzene acid methyl ester 4-ethinyl-3-methoxybenzoic acid (obtained analogously to example 167, stage 1-2, substituting methyl ester 4-bromo-2-chlorbenzoyl acid methyl ester 4-bromo-3-methoxybenzoic acid ([CAS RN 17100-63-9])). MS(ISP): 616,3 [M-N]-.

Example 172

3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}-acrylic acid

Stage 1: Ethyl ester of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}acrylic acid

To a degassed solution of [2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-henok the'alene-1-yl)methanone (500 mg, 0.96 mmole, 1.0 equiv.; example 163) propionitrile (10 ml) in an atmosphere of Ar was added N-ethyldiethanolamine (373 mg, 491 μl, 2,89 mmole, 3.0 equiv.; [CAS RN 7087-68-5]), acrylate (0,58 g, 0.63 ml, 5.78 mmole, of 6.0 equiv.; [CAS RN 140-88-5]), palladium(II) acetate (22 mg, 0.10 mmole, 0.1 equiv.; [CAS RN 3375-31-3]) and tri-o-tolylphosphino (59 mg, 0,19 mmole, 0.2 equiv.; [CAS RN 6163-58-2]). The reaction mixture was heated at 95°C during the night. The crude reaction mixture was filtered through Celite®was added to feast upon. NaCl solution (50 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried Na2SO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate, receiving 320 mg (62%) indicated in the title compound as a yellow foam. MS (ISN): 538,3 [M+H]+.

Stage 2:

To a solution of ethyl ester of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}acrylic acid (74 mg, of 0.14 mmole, 1.0 equiv.) in a mixture of 1:1 THF and water (2 ml) was added sodium hydroxide (11 mg, of 0.28 mmole, 2.0 equiv.; [CAS RN 1310-73-2]), and the reaction mixture was heated under microwave irradiation at 100°C for 10 min the Crude reaction product was transferred into water (50 ml), acidified to pH 1 by adding a solution of 1 M HCl and was extracted with ethyl acetate (3×40 ml). The combined organic phases were dried MgSO4and p is oduct was purified preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, getting 21 mg (30%) indicated in the title compound as a yellow viscous oil. MS (ISP): 509,9 [M+H]+.

Example 173

3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionic acid

To a suspension of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}acrylic acid (36 mg, 0.07 mmole, 1.0 equiv.; example 172) in ethanol (1.5 ml) was added palladium on coal (1.5 mg, 0.001 mmole, of 0.02 equiv.; 10% Pd/C; [CAS RN 7440-05-3]), and the reaction mixture was stirred in hydrogen atmosphere (3 bar) at RT over night. Removal of solvent mixture under reduced pressure, filtered through Celite® and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 12 mg (33%) indicated in the title compound as a slightly yellow viscous oil. MS (ISP): 513,8 [M+H]+.

Example 174

Methyl ester of 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-idoxifene}but-3-ene acid

Specified in the title compound was obtained analogously to example 172, step 1, replacing the acrylate to methyl ether but-3-ene acid ([CAS RN 3724-55-8]). MS (ISP): 538,3 [M+H]+.

Example 175

4-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}but-3-ANOVA acid

Specified in the title compound was obtained analogously to example 172, step 2, substituting the ethyl ester of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}acrylic acid methyl ester 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}but-3-ene acid (example 174). MS (ISP): 524,5 [M+H]+.

Example 176

4-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxyl}butane acid

Specified in the title compound was obtained analogously to example 173 substituting 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}acrylic acid 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}but-3-envoy acid (example 175). MS (ISP): 526,3 [M+H]+.

Example 177

(3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)acetic acid is acid

To a solution of 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionic acid (50 mg, 0,098 mmole, 1.0 equiv.; example 173) in anhydrous DMF (1 ml) was added HATU (44,5 mg, 0.12 mmole, 1.2 equiv.; [CAS RN 148893-10-1]) and N-ethyldiethanolamine (25 mg, 33 μl, of 0.20 mmole, 2.0 equiv.; [CAS RN 7087-68-5]). After stirring the reaction mixture for 10 min was added glycine (8,1 mg of 0.11 mmole, 1.1 equiv.; [CAS RN 56-40-6]), and stirring continued at RT overnight. Removal of solvent mixture under reduced pressure and purification preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 9 mg (16%) indicated in the title compound as a pale yellow oil. MS (ISP): 569,2 [M+H]+.

Example 178

[(3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)methylamino]acetic acid

Specified in the title compound was obtained analogously to example 177 by replacing glycine at sarcosin ([CAS RN 107-97-1]). MS (ISP): 583,0 [M+H]+.

Example 179

3-(3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)is Rodionova acid

Specified in the title compound was obtained analogously to example 177 by replacing glycine, β-alanine ([CAS RN 107-95-9]). MS (ISP): 583,2 [M+H]+.

Example 180

1-(3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)pyrrolidine-2-carboxylic acid

Specified in the title compound was obtained analogously to example 177 by replacing glycine at DL-Proline ([CAS RN 609-36-9]). MS (ISP): 607,3 [M+H]+.

Example 181

3-(4-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}bucillamine)propionic acid

Specified in the title compound was obtained analogously to example 179, substituting 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionic acid 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}butane acid (example 176). MS (ISP): 597,3 [M+H]+.

Example 182

Methyl ester of 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]benzoic acid

To a solution of [2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanone (100 mg, 0,19 mmole, 1.0 equiv.; example 163) in 1:1-mixture of methanol and ethyl acetate (4 ml) was added chloride 11'-bis(diphenylphosphino)ferienparadies(II) (10.1 mg, a 0.012 mmole, 0,064 equiv.; [CAS RN 95464-05-4]), and the reaction mixture was stirred in an atmosphere of carbon monoxide (70 bar) at 100°C for 20 hours the Crude reaction mixture was filtered through Celite® and purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate, to obtain 50 mg (52%) indicated in the title compound in the form of a whitish solid. MS (ISN): 498,3 [M+H]+.

Example 183

Methyl ester {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-eloxal}acetic acid

Step 1: 2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]benzoic acid

To a solution of methyl ester of 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]benzoic acid (50 mg, 0.10 mmole, 1.0 equiv.; example 182) in a mixture of 2:2:1 THF, methanol and water (2 ml) was added lithium hydroxide (4.8 mg, of 0.20 mmole, 2.0 equiv.; [CAS RN 1310-65-2]), and the reaction mixture was stirred at RT over night. The crude reaction product was transferred into water (50 ml), acidified to pH 1 by adding a solution of 1 M HCl and was extracted with ethyl acetate (3×40 ml). The combined organic phases were dried MgSO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companin, Isco Inc.), elwira gradient heptane/ethyl acetate to obtain 40 mg (82%) indicated in the title compound as a pale yellow solid. MS (ISN): 482,0 [M-N]-.

Stage 2:

To a solution of 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]benzoic acid (38 mg, 0.079 in mmole, 1.0 equiv.) in dichloromethane (1.5 ml) was added HATU (38,8 mg, 0.10 mmole, 1.3 equiv.; [CAS RN 148893-10-1]) and triethylamine (16 mg, 22 μl, 0.16 mmole, 2.0 equiv.; [CAS RN 121-44-8]). After stirring the reaction mixture for 15 min was added the hydrochloride of the methyl ester of glycine (12,8 mg, 0.10 mmole, 1.3 equiv.; [CAS RN 5680-79-5]), and stirring continued at RT for 4 h the Crude reaction product was transferred to feast upon. the solution of NaHCO3(50 ml) and was extracted with dichloromethane (3×40 ml). The combined organic phases were dried MgSO4and the product was purified column chromatography on silica gel, using a MPLC system (CombiFlash Companion, Isco Inc.), elwira gradient heptane/ethyl acetate to obtain 43 mg (99%) indicated in the title compound as light yellow viscous oil. MS (ISN): 555,3 [M+H]+.

Example 184

(4-Cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)phenyl]metano

Specified in the title compound was obtained analogously to example 110, step 2, substituting 1,2,3,4-tetrahydroquinolin 1-cyclopropyl-1,2,3,4-tetrahydrothieno the saline (example 125, stage 1-5). MS (ISP): 439,1 [M+H]+.

Example 185

[3-(2,5-Dichlorophenoxy)pyridine-4-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

Stage 1: (3-Bromopyridin-4-yl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon

Specified in the title compound was obtained analogously to example 6, step 1, substituting 2-chloronicotinic acid 3-bromoisonicotinic acid [CAS RN 13959-02-9]), and 1,2,3,4-tetrahydroquinolin on 3,4-dihydro-2H-benzo[1,4]oxazin ([CAS RN 5735-53-5]). MS (ISP): 319,0 [M+H]+.

Stage 2:

To a solution of (3-bromopyridin-4-yl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanone (80 mg, 0.25 mmole, 1.0 equiv.) and 2.5-dichlorphenol (49 mg, 0.30 mmole, 1.2 equiv.; [CAS RN 583-78-8]) in anhydrous toluene (1.5 ml) was added cesium carbonate (204 mg, to 0.63 mmole, 2.5 equiv.; [CAS RN 534-17-8]) and hexaphosphate tetrakis(acetonitrile)copper (I) (18.7 mg, 0,050 mmole, 0.2 equiv.; [CAS RN 64443-05-6]). The reaction mixture was heated under microwave irradiation at 160°C for 2 hours Cleaning preparative HPLC reverse phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with autosamplers Gilson Liquid Handler 215, two pumps Rainin Dynamax® SD-300, svetorasseivateley Sedex ELSD 75 and UV detector in Rooms UVD 340S), elwira gradient acetonitrile/water, resulted in the receipt of 17 mg (17%) indicated in the title compound as a light brown solid. MS (ISP): 400,9 [M+H]+.

Example

Film-coated tablets containing the following the respective ingredients, can be obtained in the usual way:

IngredientsPills
Engine:
The compound of the formula I10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Water lactose60,0 mg70.0 mg
Povidone K12.5 mg15,0 mg
Nitroglicerine starch12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(Kernel weight)120,0 mg350,0 mg
Film coating:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient was sieved and mixed with microcrystalline cellulose, and the mixture was granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with Nitroglycerinum starch and magnesium stearate and pressed to obtain cores 120 or 350 mg, respectively. Cores were covered with aq. a solution/suspension of the above film coating.

Example B

Capsules containing the following ingredients can be obtained in the usual way:

IngredientsOn capsule
The compound of the formula I25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc 5.0 mg

Components are sieved and mixed and filling capsules of size 2.

The example In

Injectable solutions may have the following composition:

The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidto pH 5.0
Water for injection solutionsto 1.0 ml

The active ingredient was dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH value was brought to 5.0 by addition of acetic acid. The volume was made up to 1.0 ml by adding the remaining amount of water. The solution was filtered, filled into vessels, using the right equipment, and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be obtained in the usual way:

The contents of the capsules
The compound of the formula I5.0 mg
Yellow wax8.0 mg
Gadirov the soy oil 8.0 mg
Partially gidrirovannoe vegetable oil34,0 mg
Soybean oil110,0 mg
The weight of the contents of the capsules165,0 mg
Gelatin capsule

The contents of the capsules
Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry)
Titanium dioxide0.4 mg
Iron oxide yellow1.1 mg

The active ingredient was dissolved in warm melt the other ingredients, and the mixture was filled in soft gelatin capsules of suitable size. Filled soft gelatin capsules were processed in accordance with conventional techniques.

Example D

The sachet containing the following ingredients can be obtained in the usual way:

With the Association of the formula I 50.0 mg
Lactose, fine powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
The sodium carboxymethyl cellulose14,0 mg
Polyvinylpyrrolidone K10.0 mg
Magnesium stearate10.0 mg
Odorants1.0 mg

The active ingredient was mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and fragrances, and filled capsules.

1. The compounds of formula:

where
A1represents CR12or N;
A2represents CR13or N;
R1and R2independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup;
R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino, and C1-7alkylsulfanyl;
R3 selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, ceanography, C3-7-cycloalkyl, five-membered heteroaryl and phenyl;
R4selected from the group consisting of methyl and ethyl; or
R3and R4together are-X-(CR14R15)nand form part of a ring; where
X is selected from the group consisting of CR16R17-, O, S, C=O;
R14and R15independently from each other selected from hydrogen or C1-7-alkyl;
R16and R17independently from each other selected from the group consisting of hydrogen, C1-7-alkoxycarbonyl, heterocyclyl, substituted with two groups selected from halogen,
or R16and R17together with the C atom to which they are attached, form =CH2group; or
X is selected from the group NR18;
R14and R15represent hydrogen;
R18selected from the group consisting of hydrogen, C1-7-alkyl, halogen-(C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarboxylic-C1-7-alkyl, phenyl, where phenyl is unsubstituted, phenylcarbinol, where phenyl substituted C1-7-alkoxycarbonyl, and phenylsulfonyl, where phenyl for whom Eden carboxyl-C 1-7-alkyl,
or R18and R14together represent -(CH2)3and form part of the ring, or R18together with a pair of R14and R15represent-CH=CH-CH= and form part of a ring;
and n is 1, 2 or 3;
B1represents N or CR19and B2represents N or CR20provided that not more than one of B1and B2represents N; and
R19and R20independently from each other selected from the group consisting of hydrogen and halogen-C1-7-alkyl;
R5and R6independently from each other selected from the group consisting of hydrogen, halogen and cyanopropyl;
and one to three, or, when R4represents methyl or ethyl, two of the residues R7, R8, R9, R10and R11selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-(C1-7-alkoxygroup, ceanography, C1-7-alkoxycarbonyl, hydroxy-C3-7-quinil, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-quinil, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, Fenrir the onila, where phenyl is unsubstituted, phenyl-C1-7-alkyl, where phenyl is substituted by 1-2 groups selected from halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-quinil, where phenyl is substituted by 2 groups selected from halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidinylcarbonyl-C1-7-alkyl, where pyrrolidinyl replaced by carboxyla,
and the remaining R7, R8, R9, R10and R11represent hydrogen;
where
the term "heteroaryl" refers to an aromatic 5-membered ring that includes one or two atoms selected from nitrogen or oxygen,
the term "heterocyclyl" denotes a saturated 4-membered ring which may include one atom selected from nitrogen or oxygen,
or their pharmaceutically acceptable salts.

2. The compounds of formula I on p. 1, where A1represents CR12and A2represents CR13and where R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino, and C1-7alkylsulfanyl.

3. The compounds of formula I on p. 1, where A1represents N and A2represents CR13or where A1represents CR12and A2represents N, where R12and R13independently from each other selected from the gr is PPI, consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino, and C1-7alkylsulfanyl.

4. The compounds of formula I on p. 1, where R1and R2independently from each other selected from the group consisting of hydrogen, C1-7of alkyl and halogen.

5. The compounds of formula I on p. 1, where R3and R4together are-X-(CR14R15)nand form part of a ring; where
X is selected from the group consisting of CR16R17-, O, S, C=O;
R14and R15independently from each other selected from hydrogen or C1-7-alkyl;
R16and R17independently from each other selected from the group consisting of hydrogen, C1-7-alkoxycarbonyl, heterocyclyl, substituted with two groups selected from halogen,
or R16and R17together with the C atom to which they are attached, form =CH2group;
X is selected from the group NR18;
R14and R15represent hydrogen;
R18selected from the group consisting of hydrogen, C1-7-alkyl, halogen-(C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarboxylic-C1-7-alkyl, phenyl, where phenyl is unsubstituted, phenylcarbinol where FeNi is substituted C 1-7-alkoxycarbonyl, and phenylsulfonyl, where phenyl substituted carboxyl-C1-7-alkyl,
or R18and R14together represent -(CH2)3and form part of the ring, or R18together with a pair of R14and R15represent-CH=CH-CH= and form part of a ring;
and n is 1, 2 or 3.

6. The compounds of formula I on p. 5, where X represents-CH2-, R14and R15independently from each other selected from hydrogen or methyl and n is 2.

7. The compounds of formula I on p. 5, where R18selected from the group consisting of hydrogen, C1-7-alkyl, halogen-(C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarboxylic-C1-7-alkyl, phenyl, where phenyl is unsubstituted, phenylcarbinol, where phenyl substituted C1-7-alkoxycarbonyl, and phenylsulfonyl, where phenyl substituted carboxyl-C1-7-alkyl.

8. The compounds of formula I on p. 1, where R3selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, ceanography, C3-7-cycloalkyl, five-membered heteroaryl ring or phenyl, and R4selected from the group consisting of methyl and ethyl.

9. The compounds of formula I on p. 1 where B 1represents N and B2represents CR20and R is selected from the group consisting of hydrogen and halogen-C1-7-alkyl.

10. The compounds of formula I on p. 1, where B1represents CR19and B2represents N, and R19selected from the group consisting of hydrogen and halogen-C1-7-alkyl.

11. The compounds of formula I on p. 1, where B1represents CR19and B2represents CR20and R19and R20independently from each other selected from the group consisting of hydrogen and halogen-C1-7-alkyl.

12. The compounds of formula I on p. 1, where R5and R6independently from each other represent hydrogen or halogen.

13. The compounds of formula I on p. 1, where two or three R7, R8, R9, R10and R11selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-(C1-7-alkoxygroup, ceanography, C1-7-alkoxycarbonyl, hydroxy-C3-7-quinil, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-quinil, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-is Lila, phenylcarbinol, where phenyl is unsubstituted, phenyl-C1-7-alkyl, where phenyl is substituted by 1-2 groups selected from halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-quinil, where phenyl is substituted by 2 groups selected from halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidinylcarbonyl-C1-7-alkyl, where pyrrolidinyl replaced by carboxyla, and the remaining residues R7, R8, R9, R10and R11represent hydrogen.

14. The compounds of formula I on p. 1, where R7and R10represent halogen.

15. The compounds of formula I on p. 1, where
A1represents CR12or N;
A2represents CR13or N;
R1and R2independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup;
R12and R13independently from each other selected from the group consisting of hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup;
R3selected from the group consisting of hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, ceanography, five-membered heteroaryl ring or phenyl;
R4selected from the group consisting of methyl, ethyl; or
R3and R4together are-X-(CR14CR15)nand form part of a ring; where
X is selected from g is uppy, consisting of CR16R17-, O, S, C=O;
R14and R15independently from each other selected from hydrogen or C1-7-alkyl,
R16and R17independently from each other selected from hydrogen, or together with the C atom to which they are attached, form =CH2group,
X is selected from the group NR18;
R14and R15represent hydrogen;
R18selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl,
and n is 1, 2 or 3;
B1represents N or CR19and B2represents N or CR20provided that not more than one of B1and B2represents N; and
R19and R20independently from each other selected from the group consisting of hydrogen and halogen-C1-7-alkyl;
R5and R6independently from each other selected from the group consisting of hydrogen and halogen,
and one to three or, when R4represents methyl or ethyl, two of the residues R7, R8, R9, R10and R11selected from the group consisting of C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-(C1-7-alkoxygroup, ceanography and phenylcarbinol,
and other residues R7, R8, R9, R10and R11represent hydrogen;
or their pharmaceutically acceptable salts.

16. The compounds of formula I according to the .1, selected from the group consisting of the following compounds:
(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-triptoreline)pyridine-3-yl]metano,
[2-(2-chlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
(6-methyl-3,4-dihydro-2H-quinoline-1-yl)-[2-(3-triptoreline)pyridine-3-yl]metano,
[2-(3-chlorophenoxy)pyridine-3-yl]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3,4-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
3-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)pyridine-2-yloxy]benzonitrile,
(3,4-dihydro-2H-quinoline-1-yl)-(2-m-collectibility-3-yl)methanon,
[2-(3-chloro-4-methylphenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chloro-4-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(5-chloro-2-methylphenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,3-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chloro-5-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
(3,4-dihydro-2H-quinoline-1-yl)-[2-(2,4,5-trichlorophenoxy)pyridine-3-yl]metano,
[2-(3-benzoylperoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-triftormetilfosfinov)pyridine-3-yl]metano,
[2-(3,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-pertenece)pyridine-3-yl]metano,
(3,4-di is Idro-2H-quinoline-1-yl)-[2-(3-isopropylphenoxy)pyridine-3-yl]metano,
(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-ethylenoxy)pyridine-3-yl]metano,
(3,4-dihydro-2H-quinoline-1-yl)-[2-(3-iodinase)pyridine-3-yl]metano,
[2-(3-chloro-2-fluoro-5-triptoreline)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-bromophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-divergence)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[5-chloro-2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[5-chloro-2-(2,5-divergence)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)-6-triptorelin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
2-(2,5-dichlorophenoxy)-N-ethyl-N-phenyldiamine,
(7-chloro-3,4-dihydro-2H-quinoline-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
2-(2,5-dichlorophenoxy)-N-methyl-N-phenyldiamine,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,7-debtor-3,4-dihydro-2H-x is the nolin-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]thiazin-4-yl)methanon,
N-(2-chlorophenyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-methyl-N-o-callincoming,
2-(2,5-dichlorophenoxy)-N-(2-methoxyphenyl)-N-nicotine amide,
N-biphenyl-2-yl-2-(2,5-dichlorophenoxy)-N-nicotine amide,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
2-(2,5-dichlorophenoxy)-N-(2-ethylphenyl)-N-nicotine amide,
N-(3-chloropyridin-2-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
N-(4-chloropyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2-methoxypyridine-3-yl)-N-nicotine amide,
N-(3-chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
N-(5-chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
N-(2-chloro-6-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2,6-dimetilfenil)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2-methoxy-6-were)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(5-fluoro-2-methoxyphenyl)-N-nicotine amide,
N-(5-chloro-2-methoxyphenyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
N-(4-chloro-2-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2,3-dimetilfenil)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2,4-dimetilfenil)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2-methoxy-5-were)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2,6-acid)-N-methyl shall nicotinamid,
N-(6-chloro-4-methylpyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
N-(2-cyanophenyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2-forfinal)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(2,6-differenl)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-methyl-N-(2-pyrrol-1-ylphenyl)nicotinamide,
2-(2,5-dichlorophenoxy)-N-(2,4-differenl)-N-nicotine amide,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(8-fluoro-6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
N-(2-chloro-4-methylpyridin-3-yl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(8-methoxy-3,4-dihydro-2H-quinoline-1-yl)methanon,
(6-chloro-3,4-dihydro-2H-quinoline-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6-fluoro-2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,8-debtor-2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-phenyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
2-(2,5-dichlorophenoxy)-N-(4-methoxypyridine-3-yl)-N-nicotine amide,
[2-(2,4-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chloro-4-pertenece)pyridine-3-yl]-(6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chloro-4-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-[1,5]naphthiridine-1-yl)methanon,
[2-(3-chloro-4-pertenece)pyridine-3-yl]-(6,7-debtor-3,4-dihydro-2H-chinolin-yl)methanon,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,
1-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-1,2,3,4-tetrahydrobenzo[b]azepin-5-he,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-IO)methanon,
2-(2,5-dichlorophenoxy)-N-ethyl-5-fluoro-N-phenyldiamine,
[2-(3-chlorophenoxy)-5-herperidin-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chloro-4-pertenece)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chloro-4-pertenece)-5-herperidin-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(3-chloro-4-pertenece)-5-herperidin-3-yl]-(8-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
3-(2,5-dichlorophenoxy)-N-methyl-N-o-tolylenediamine,
N-(2-chlorophenyl)-3-(2,5-dichlorophenoxy)-N-methylethanolamine,
3-(2,5-dichlorophenoxy)-N-(2-methoxyphenyl)-N-methylethanolamine,
[3-(2,4-dichlorophenoxy)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,4-dichlorophenoxy)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,4-Dich is orphenochs)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-Hanalei-1-yl)methanon,
3-(2,4-dichlorophenoxy)-N-methyl-N-o-tolylenediamine,
N-(2-chlorophenyl)-3-(2,4-dichlorophenoxy)-N-methylethanolamine,
3-(2,4-dichlorophenoxy)-N-(2-methoxyphenyl)-N-methylethanolamine,
3-(2,4-dichlorophenoxy)-N-(2-methoxypyridine-3-yl)-N-methylethanolamine,
[3-(3-chloro-4-pertenece)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(3-chloro-4-pertenece)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(3-chloro-4-pertenece)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
3-(3-chloro-4-pertenece)-N-methyl-N-o-tolylenediamine,
3-(3-chloro-4-pertenece)-N-(2-chlorophenyl)-N-methylethanolamine,
3-(3-chloro-4-pertenece)-N-(2-methoxyphenyl)-N-methylethanolamine,
3-(3-chloro-4-pertenece)-N-(2-methoxypyridine-3-yl)-N-methylethanolamine,
[2-(2,5-dichlorophenoxy)phenyl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)phenyl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)phenyl]-(2-methyl-2,3-dihydroindol-1-yl)methanon,
[2-(2,5-dichlorophenoxy)-5-forfinal]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)-5-forfinal]-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)-5-forfinal]-(8-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)-5-forfinal]-(6-methyl-3,4-dihydro-2H-quinoline-1-IO)methanon,
[2-(2,5-dichlorophenoxy)-5-forfinal]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon,
2-(2,5-dichlorophenoxy)-5-fluoro-N-methyl-N-universalid,
4-(2,5-dichlorophenoxy)-3-(3,4-dihydro-2H-quinoline-1-carbonyl)benzonitrile,
[2-(2,5-dichlorophenoxy)phenyl]-(8-fluoro-6-methyl-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)phenyl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon
or their pharmaceutically acceptable salts.

17. The compounds of formula under item 1, selected from the group consisting of the following compounds:
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-methyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-isopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
(4-cyclobutyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-oxetan-3-yl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
1-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-2,3-dihydro-1H-quinoline-4-one,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-methylene-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-[4-(3,3-debtor-azetidin-1-yl)-3,4-dihydro-2H-quinoline-1-yl]metano,
N-(2-cyclopropylethyl)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-methyl-N-(2-methylsulfinylphenyl)nicotinamide,
2-(2,5-dichlorophenoxy)-N-methyl-N-[2-(2-methyl-2H-pyrazole-3-yl)phenyl]nicotinamide,
N-(2-AMINOPHENYL)-2-(2,5-dichlorophenoxy)-N-methylnicotinamide is,
2-(2,5-dichlorophenoxy)-N-(2,5-dichlorophenyl)-N-nicotine amide,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2,3,3 a,4-tetrahydro-1H-pyrrolo[1,2-a]cinoxacin-5-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-isobutyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
(4-cyclopropylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
(4-cyclobutylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
2-{4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}ethyl ester acetic acid,
ethyl ester {4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,
{4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,
3-(4-{4-[2-(2,5-dichlorophenoxy)pyridine-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-sulfonyl}phenyl)propionic acid,
(3,4-dihydro-2H-quinoline-1-yl)-[2-(2-fluoro-5-triptoreline)pyridine-3-yl]metano,
2-(2,5-dichlorophenoxy)-5-fluoro-N-(2-methoxypyridine-3-yl)-N-nicotine amide,
N-(2,6-dichloro-3-methoxyphenyl)-2-(2,5-dichlorophenoxy)-5-fluoro-N-nicotine amide,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon,
methyl ether of 1-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-1,2,3,4-tetrahydroquinolin-4-carboxylic acid,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(4H-pyrrolo[1,2-a]cinoxacin-5-yl)methanon,
(4-cyclobutyl-3,4-dihyd the on-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]metano,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(4-furan-3-ylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
(4-cyclobutylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]metano,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-[4-(3,3,3-cryptochromes)-3,4-dihydro-2H-cinoxacin-1-yl]metano,
ethyl ester {4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,
{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,
ethyl ester 3-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}propionic acid,
3-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}-2-methylpropionate acid,
ethyl ester 4-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}butane acid,
ethyl ester 5-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}pentanol acid,
methyl ester 6-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}hexanoic acid,
6-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}hexanoic acid,
methyl ester 4-{4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-carbonyl}benzoic acid,
[2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-is ihydro-2H-cinoxacin-1-yl)methanon,
(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-{2-[2,5-dichloro-4-(3-hydroxyprop-1-inyl)phenoxy]pyridine-3-yl}mechanon,
[2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
methyl ester 5-{2,5-dichloro-4-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)pyridine-2-yloxy]phenyl}Penta-4-invoi acid,
methyl ester 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid,
2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenylethynyl}benzoic acid,
2-chloro-4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)benzoic acid,
4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)benzoic acid,
4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)-3-methoxybenzoic acid,
3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}acrylic acid,
3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionic acid,
methyl ester of 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}but-3-ene acid,
4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]f the Nile}but-3-ANOVA acid,
4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}butane acid,
(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)acetic acid,
[(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)methylamino]acetic acid,
3-(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)propionic acid,
1-(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)pyrrolidine-2-carboxylic acid,
3-(4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}bucillamine)propionic acid,
methyl ester of 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]benzoic acid
methyl ester {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]benzoylamine}acetic acid,
(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)phenyl]metano,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon
or their pharmaceutically acceptable salts.

18. The compounds of formula I on p. 1, selected from the group consisting of the following compounds:
[2-(3-chloro-4-pertenece)pyridine-3-yl]-(3,4-dihydro-2H-hee is Olin-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
2-(2,5-dichlorophenoxy)-N-ethyl-N-phenyldiamine,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,7-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(2,3-dihydrobenzo[1,4]thiazin-4-yl)methanon,
2-(2,5-dichlorophenoxy)-N-methyl-N-o-callincoming,
2-(2,5-dichlorophenoxy)-N-(2-methoxyphenyl)-N-nicotine amide,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
N-(2-chloro-6-were)-2-(2,5-dichlorophenoxy)-N-nicotine amide,
2-(2,5-dichlorophenoxy)-N-(5-fluoro-2-methoxyphenyl)-N-nicotine amide,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(7-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)methanon,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(6,8-debtor-3,4-dihydro-2H-quinoline-1-yl)methanon,
3-(2,5-dichlorophenoxy)-N-methyl-N-o-tolylenediamine,
3-(2,5-dichlorophenoxy)-N-(2-methoxyphenyl)-N-methylethanolamine,
[2-(2,5-dichlorophenoxy)phenyl]-(3,4-dihydro-2H-quinoline-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(3,4-dihydro-2H-cinoxacin--yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-methyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
(4-cyclobutyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-oxetan-3-yl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
[2-(2,5-dichlorophenoxy)pyridine-3-yl]-(4-methylene-3,4-dihydro-2H-quinoline-1-yl)methanon,
2-(2,5-dichlorophenoxy)-N-methyl-N-(2-methylsulfinylphenyl)nicotinamide,
(4-cyclopropylmethyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)pyridine-3-yl]metano,
[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]-(3,4-dihydro-2H-cinoxacin-1-yl)methanon,
(4-cyclobutyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)-5-herperidin-3-yl]metano,
ethyl ester {4-[2-(2,5-dichlorophenoxy)-5-herperidin-3-carbonyl]-3,4-dihydro-2H-cinoxacin-1-yl}acetic acid,
[2-(4-bromo-2,5-dichlorophenoxy)pyridine-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)methanon,
(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-{2-[2,5-dichloro-4-(3-hydroxyprop-1-inyl)phenoxy]pyridine-3-yl}mechanon,
4-(2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}ethyl)benzoic acid,
3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionic acid,
methyl ester of 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-digitron-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}but-3-ene acid,
(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)acetic acid,
[(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)methylamino]acetic acid,
3-(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionamide)propionic acid,
1-(3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}propionyl)pyrrolidine-2-carboxylic acid,
3-(4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-carbonyl)pyridine-2-yloxy]phenyl}bucillamine)propionic acid,
(4-cyclopropyl-3,4-dihydro-2H-cinoxacin-1-yl)-[2-(2,5-dichlorophenoxy)phenyl]metano,
[3-(2,5-dichlorophenoxy)pyridine-4-yl]-(2,3-dihydrobenzo[1,4]oxazin-4-yl)methanon
or their pharmaceutically acceptable salts.

19. Pharmaceutical composition having activity as GPBAR1 agonist containing a compound of formula I under item 1 and a pharmaceutically acceptable carrier and/or adjuvant.

20. The compounds of formula I on p. 1, intended for use as therapeutically active substances which possess activity as agonists GPBAR1.

21. The compounds of formula I on p. 1, intended for use as therapeutically active substances for the treatment of diseases which are associated the with the modulation of GPBAR1 activity.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrazolopyridine derivatives of formula (I), a pharmaceutical composition based thereon, use for treating and/or preventing disorders or conditions associated with nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and an intermediate of formula (VIII). In general formula (I) G1 denotes H; G2 is selected from H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted phenyl; optionally substituted C1-C6-alkylaryl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted-C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G3 is selected from -(CH2)n-R1 and -(CH2)p-R5; G4 is selected from H; optionally substituted acyl; optionally substituted acylamino; optionally substituted acyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G5 dentes H.

EFFECT: high effectiveness of compounds.

15 cl, 2 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention refers to new phenoxymethyl compounds of formula (I) or its pharmaceutically acceptable salts, wherein: HET represents a heterocyclic ring having formula A29 or A31, wherein the far left part is connected to the group X of formula (I); X represents substituted phenyl or optionally substituted pyridinyl, wherein the substitutes are specified in C1-C4alkoxy and cyano; Z represents imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo[1,2-b]pyridazin-6-yl each of which can be substituted, wherein the substitutes are specified in C1-C4alkyl and a halogen atom; and each R2 are independently specified in C1-C4 alkyl inhibiting at least one phosphodiesterase 10, as well as to pharmaceutical compositions containing these compounds, and methods of treating various CNS disorders.

EFFECT: preparing the new compounds.

23 cl, 2 tbl, 732 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,2,3,4-tetrahydropyrido[4,3-b]indole-containing phenothiazines of general formula 1 as inhibitors of cholinestrerases and blockers of serotonin receptors 5-HT6, a pharmaceutical preparation on their base, in particular for treatment of neurodegenerative diseases. In general formula 1, in which R1=H, (C1-C6) alkyl; R2, R3, R4, R5=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, R6, R7=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, NH2, NHAlkyl, NAlkyl2; A=CH2CH2, CH=CHCH2, CH2CH2CH2, CH2CH[(C1-C6)alkyl]C(O), CH2CH2C(O)NHCH2CH2; CH2CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2, CH2CH(OH)CH2, CH2CH(OH)CH2NHCH2CH2, CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2, CH2CHFCH2NHCH2CH2, CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

EFFECT: increased efficiency of the application of compounds.

6 cl, 1 dwg, 1 tbl, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (I)

,

in which R1 stands for a phenyl group, optionally substituted with one or several halogen atoms; R2 stands for hydrogen or a halogen atom or a cyanogroup; group -C(=O)Y, in which Y stands for a hydrogen atom or the group -NH2 or -OR3; group -C(=S)NH2; group -C(=NH)NH-OH; group -CH2OH or -CH2F; group -CH=N-OH; group -CH=CH2 or -C≡C-Ra; group (II) or (III); and Ra stands for the hydrogen atom or the (C1-C4)alkyl group; R3 stands for thehydrogen atom or the (C1-C4)alkyl group; and R4 stands for -NH2, (C1-C4)alkyl, (C1-C4)fluoroalkyl or (C3-C7)cycloalkyl group. The invention also relates to methods of obtaining compounds of formula (I), a medical preparation, a pharmaceutical composition, intermediate compounds for obtaining the formula (I) compound and the application of the formula (I) compound and intermediate compounds.

EFFECT: claimed compounds have anti-cancer activity.

21 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phenothiazine-containing 1,2,3,4-tetrahydropyrido[4,3-b]indole derivatives of general formula 1 and hydrochlorides thereof as an agent for reducing uncontrolled protein aggregation in the nervous system, methods for production thereof, a pharmacological agent based thereon and a method of reducing uncontrolled protein aggregation in the nervous system. In general formula 1: R1=H, (C1-C6)alkyl; R2, R3, R4, R5=H, F, O, Br, (C1-C6)alkyl, (C1-C6)alkoxy, R6, R7= H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy, NH2, NHAlkyl, NAlkyl2, A=CH2CH2, CH=CHCH2, CH2CH2CH2, CH2CH[(C1-C6)alkyl]C(O), CH2CH2C(O)NHCH2CH2); CH2CH[((C1-C6)alkyl]C(O)N[(C1-C6))alkyl]CH2CH2), CH2CH(OH)CH2, CH2CH(OH)CH2NHCH2CH2, CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2, CH2CHFCH2NHCH2CH2, CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

EFFECT: improved properties of derivatives.

9 cl, 2 tbl, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel indolizine derivatives of formula , to their pharmaceutically acceptable salts or prodrugs, which represent C1-6alkyl ethers, where values U, R1, R2, R3 are given in item one of the formula.

EFFECT: compounds possess an inhibiting activity with respect to xanthine oxidase, which makes it possible to use them in a pharmaceutical composition for the prevention or treatment of a disease, selected from the group, consisting of hyperurecemia, gout nodule, gout arthritis with hyperurecemia of the renal disorder and urine concrements.

18 cl, 17 tbl, 76 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts specified in a group consisting of phosphate salt, hydrochloride salt, sulphate salt, mesylate salt, maleate salt or malate salt. Also, the invention refers to a method for preparing the above salts, using them and a pharmaceutical composition on the basis of the above salts.

EFFECT: there are prepared new pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts effective in treating diabetes.

5 cl, 3 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted pyrazino-quinolines of formula: , wherein the values R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, X and Y are presented in clause one of the patent claim, and to their pharmaceutically acceptable salts.

EFFECT: compounds can be used for treating cancer.

14 cl, 24 dwg, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, in particular to method of obtaining 3-hetaryl-1,5,3-dithiazepinanes of general formula (1) , where ; ; ; ; ; ; ; ; , consisting in the following: N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine is subjected to interaction with hetarylamine [2-pyridinamine, 3-pyridinamine, 5-bromo-2-pyridinamine, 5-methyl-2-pyridinamine, 4-pyridinylmethylamine, 5-nitro-1,3-thiazol-2-amine, 6-nitro-1,3-benzothiazol-2-amine, 2-91h-indol-3-yl)-1-ethanamone, 5-methyl-1H-pyrazol-3-amine] in presence of catalyst CuCl2 in molar ratio N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:hetarylamine: CuCl2=10:10:(0.3-0.7) at temperature 55-65°C and atmospheric pressure in chloroform as solvent for 50-80 minutes.

EFFECT: elaborated is method of obtaining 3-hetaryl-1,5,3-dithiazepinanes, which can be applied as biologically active substances.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (1), in which Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; R1 and R2 denote an unsubstituted -C1-8-aliphatic; R3 denotes an unsubstituted -C6-16-aryl; R4 denotes -H or -C(=O)R0, where R0 denotes -C1-8-aliphatic, unsubstituted or mono- or polysubstituted with substitutes independently selected from a group consisting of -F, -Cl, -Br, -I and -CN; Q denotes unsubstituted -C1-8-aliphatic-heteroaryl; X denotes =O, =CR6R7 or =N-R6, wherein R5 denotes -NH2, -NH-(unsubstituted-C1-8-aliphatic) or -N-(unsubstituted-C1-8-aliphatic)2, if X denotes =O, or R5 and R6 together form a 5-member ring in which the remaining ring atoms independently denote C, N, S or O, wherein the 5-member ring denotes 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, oxazolyl or thiazolyl, in each case unsubstituted or monosubstituted with unsubstituted C1-C8aliphatic or =O, or unsubstituted tetrazolyl, if X denotes =N-R6, or R5 and R6 together form unsubstituted phenyl, and R7 denotes -H, if X denotes =CR6R7, where "aliphatic" in each case represents a branched or straight, saturated hydrocarbon residue; "aryl" in each case independently denotes a carboxylic ring system containing at least one aromatic ring which does not contain heteroatoms, where the aryl may be optionally condensed with other saturated, (partially) unsaturated or aromatic ring systems; "heteroaryl" denotes indolyl; in the form of a separate stereoisomer or a mixture thereof, in the form of free compounds and/or physiologically compatible salts thereof. The compound of formula

is used to obtain a medicinal agent having affinity for the µ-opioid receptor and the ORL1-receptor, and for treating pain.

EFFECT: substituted cyclohexyldiamines, having affinity for the µ-opioid receptor and the ORL1-receptor.

7 cl, 1 tbl, 29 ex

FIELD: medicine.

SUBSTANCE: invention refers to a new agent representing rhodanine derivatives of formula (I), wherein X=N or CH for treating malignant diseases of varying sites.

EFFECT: agent is antiproloferative and antimetastatic action for treating malignant diseases.

3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula R1-NH-X-Y-Z (I), wherein R1 represents alkylcarbonyl; X represents a bivalent residue of thiazol; Z is described by formula A-B-D-E (II), wherein A represents a bivalent residue of benzene optionally substituted by 1 or 2 halogen atoms, or a bivalent residue of thiophen optionally substituted by a lower alkyl; B represents - (CH2)1-NR2-CO-, wherein R2 represents hydrogen, l is equal to an integer from 1 to 6, - (CH2)m-O-CO- or - (CH2)m-S-CO- (wherein m is equal to an integer from 0 to 6); D represents -NR3-, wherein R3 represents hydrogen; E represents amino; Y is described by formula J-L-M (III), wherein J represents a bond, a lower alkylene, -(CH2)n-O0-, -(CH2)n-CO- (wherein n is equal to an integer from 0 to 6); L represents a bond, -O-, -NH-; M represents a bond, a lower alkylene. Also, the invention refers to a pharmaceutical composition containing the above compounds and possessing vascular adhesive protein 1 (VAP-1) inhibitory activity, a VAP-1 inhibitor, a pharmaceutical agent, to using the compounds of formula (I) and pharmaceutical agent for preventing and treating a VAP-1 related disease, to a method of inhibiting VAP-1, and to a method of preventing or treating the VAP-1 related disease.

EFFECT: compounds of formula (I) as the VAP-1 inhibitors.

14 cl, 2 ex, 2 tbl, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to indolyl-substituted derivatives of thiadiazinones prepared from oxamic acid thiohydrazide of general formula: , wherein R represents H; R1 represents pyridinyl; phenyl substituted by alkyl C1-C5, Hal, CF3; R2 represents H; alkyl C1-C5; -CH2COOR4; benzyl substituted by Hal, OR4; benzoyl substituted by Hal, OR4, while R4 represents unsubstituted alkyl C1-C4.

EFFECT: there are prepared new compound which can find application in medicine for developing the therapeutic agent possessing pathogenic bacteria inhibitory activity.

2 cl, 2 dwg, 2 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

Amide compound // 2479576

FIELD: chemistry.

SUBSTANCE: compounds exhibit antagonistic activity towards the EP4 receptor, which enables use thereof as an active ingredient in a pharmaceutical composition for treating chronic kidney disease or diabetic nephropathy.

EFFECT: high efficiency of the compounds.

27 cl, 228 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method of producing α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes of general formula (1):

n=1-8, which involves reaction of α,ω-alkanediamines of general formula H2N-CH2-(CH2)n-NH2, where n=1-8, with tert-N-butyl-1,5,3-dithiazepinane in chloroform in the presence of a SmCl3·6H2O catalyst with molar ratio α,ω-alkanediamine:tert-N-butyl-1,5,3-dithiazepinane:SmCl3·6H2O = 10:20:(0.3-0.7) at room temperature (about 20°C) for 2.5-3.5 hours.

EFFECT: method of obtaining novel α,ω-bis-(1,5,3-dithiazepinan-3-yl)-alkanes which can be used as antibacterial, antifungual and antiviral agents, as biologically active complexing agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media (from light industry to oil industry).

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (1), in which Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; R1 and R2 denote an unsubstituted -C1-8-aliphatic; R3 denotes an unsubstituted -C6-16-aryl; R4 denotes -H or -C(=O)R0, where R0 denotes -C1-8-aliphatic, unsubstituted or mono- or polysubstituted with substitutes independently selected from a group consisting of -F, -Cl, -Br, -I and -CN; Q denotes unsubstituted -C1-8-aliphatic-heteroaryl; X denotes =O, =CR6R7 or =N-R6, wherein R5 denotes -NH2, -NH-(unsubstituted-C1-8-aliphatic) or -N-(unsubstituted-C1-8-aliphatic)2, if X denotes =O, or R5 and R6 together form a 5-member ring in which the remaining ring atoms independently denote C, N, S or O, wherein the 5-member ring denotes 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, oxazolyl or thiazolyl, in each case unsubstituted or monosubstituted with unsubstituted C1-C8aliphatic or =O, or unsubstituted tetrazolyl, if X denotes =N-R6, or R5 and R6 together form unsubstituted phenyl, and R7 denotes -H, if X denotes =CR6R7, where "aliphatic" in each case represents a branched or straight, saturated hydrocarbon residue; "aryl" in each case independently denotes a carboxylic ring system containing at least one aromatic ring which does not contain heteroatoms, where the aryl may be optionally condensed with other saturated, (partially) unsaturated or aromatic ring systems; "heteroaryl" denotes indolyl; in the form of a separate stereoisomer or a mixture thereof, in the form of free compounds and/or physiologically compatible salts thereof. The compound of formula

is used to obtain a medicinal agent having affinity for the µ-opioid receptor and the ORL1-receptor, and for treating pain.

EFFECT: substituted cyclohexyldiamines, having affinity for the µ-opioid receptor and the ORL1-receptor.

7 cl, 1 tbl, 29 ex

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