Derivatives of tetrahydrocarbazoles, method of obtaining them and pharmaceutical compositions containing them

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

 

X-receptors of the liver (LXR - abbr. from the English. Liver-X-Receptor) are members of the superfamily, found in the nucleus of the cell receptors of hormones. X-receptors of the liver are activated by endogenous oxysterols and regulate the transcription of genes controlling various stages of metabolic reactions.

Described two subtypes of receptors, LXRα and LXRβ (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc. Natl. Acad. Sci. USA. 1994, 91:10809-13). LXRα is expressed ubiquitously, whereas LXRβ is preferably expressed metabolizing cholesterol tissues, such as liver, adipose tissue, intestine and macrophages. X-receptors of the liver modulate a number of physiological responses, including the regulation of cholesterol absorption, cholesterol excretion (synthesis of bile acids) and the transport of cholesterol through the plasma lipoproteins from peripheral tissues to the liver. X-receptors of the liver is also involved in glucose metabolism, cholesterol metabolism in the brain, cell differentiation and inflammation.

Currently, approximately half of all patients with coronary artery disease has a low concentration of plasma cholesterol, high density lipoprotein (HDL-cholesterol). Paramount high density lipoprotein (HDL) in combating atherosclerosis was first demonstrated 25 years ago called the d, what stimulated the study of genetic factors and environmental factors that affect the level of HDL cholesterol (Miller N. E., Lipids 1978,13:914-9). The protective function of HDL is a consequence of their role in the process of determining the reverse transport of cholesterol. HDL associated with the removal of cholesterol from the cells of peripheral tissues, including foam cell macrophages in atherosclerotic lesions of arterial walls. HDL bring your cholesterol in the liver and metabolized Sterol bodies for conversion into bile acids and removal from the body with feces. Studies have shown that the rate of cholesterol HDL allows you to predict the risk of coronary artery disease regardless of the level of cholesterol low-density lipoprotein (LDL) (Gordon et al., Am. J. Med. 1977, 62:707-14).

Currently estimated comparative age indicators Americans aged 20 years and older found that among people whose cholesterol, HDL cholesterol less than 35 mg/DL, 16% of men and 5.7% were women. A significant increase of HDL-cholesterol at the present time is achieved by the intake of Niacin in the composition of different compositions. However, significant unwanted side effects limit therapeutic possibilities of this method.

It is estimated that more than 90% of the 14 million patients diagnosed with dia is no type-2 notes are overweight or obese and a significant proportion of patients with type 2 diabetes is characterized different from the norm concentrations of lipoproteins. Studies have shown that the excess of the total cholesterol > 240 mg/DL is 37% of male diabetics and 44% in women-diabetics. Indicators of LDL cholesterol>160 mg/DL typical for 31% and 44%, respectively, and ratios of HDL-cholesterol < 35 mg/DL typical for 28% and 11% of male diabetics and women-diabetics, respectively. Diabetes is a disease in which decreases the patient's ability to control glucose in the blood due to partial disturbance reactions to the effects of insulin. Type 2 diabetes (T2D) is also called non-insulin-dependent diabetes mellitus (NIDDM), and it is shown that in developed countries the disease is concerned about 80-90% of the total number of patients with diabetes. When type 2 diabetes pancreatic islets of Langerhans continue to produce insulin. However, target organs to the effects of insulin, mainly the muscles, liver and adipose tissue, have considerable resistance to stimulation by insulin. The body continues to compensate for the production nefiziologichnoe high amounts of insulin, which ultimately decreases at later stages of the disease, as a result of damage and depletion of producing insulin in the pancreas. Thus, type 2 diabetes is cardiovasculare-the metabolic syndrome is, associated with many disease symptoms, including insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.

The main directions of treatment of dyslipidemia and diabetes currently, in General, include a diet low in fat and low in glucose, exercise, and weight loss. However, resistance to disease can be weakened and as a consequence with the progression of the disease becomes necessary treatment for a variety of deficits metabolism with the use of agents that modulates lipid levels, for example, using such agents as statins and fibrates in the case of dyslipidemia and hypoglycemic drugs such as sulfonylureas, Metformin or insulin sensitizers (agents that increase insulin sensitivity) class thiazolidinedione (TZD) PPARγ agonists, in the case of insulin resistance. Recent research has established that the modulators X receptor liver may represent compounds that enhance therapeutic potential, and as such modulators X receptors of the liver can improve the lipid profile and increase the cholesterol content of HDL (Lund et al. Arterioscler. Thromb. Vase. Biol. 2003, 23:1169-77). It is also known that X receptors of the liver is controlled from the OK of cholesterol from foam cells are macrophages of atherosclerotic plaques, moreover, as shown, agonists X receptors of the liver can counteract the development of atherosclerosis (Joseph, Tontonoz, Curr. Opin. Pharmacol. 2003, 3:192-7). Thus, modulators X receptors of the liver can be effective in the treatment of atherosclerotic diseases that lead to cardiovascular disease and fatal attacks and heart disease. Recent studies also confirmed that also manifests itself independently of the influence of X-receptors of the liver in insulin resistance, in addition to protection from atherosclerosis (Cao et aL, J Biol Chem. 2003, 278:1131-6). Thus, modulators X-receptors of the liver have a significant therapeutic effect on the increase in the concentration of HDL, as well as a therapeutic effect against atherosclerosis, in combination with an additional effect against diabetes, compared with currently known therapeutic agents.

The present invention relates to new modulators X-receptors of the liver, to obtain these compounds and their use as medicines. In particular, the present invention relates to compounds of formula (I):

where

n means an integer from 0 to 3;

R1independently selected from the group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, triptoreline, OR 11, piperidinyl, pyrrolidinyl and-N(R11)(R11), where R11independently selected from lower alkyl and N,

X1X2X3and X4independently selected from nitrogen or carbon, provided that not more than two of X1X2X3and X4can mean nitrogen, and in the case when two of X1X2X3and X4mean nitrogen, n is 0, 1 or 2;

k is the integer 0 or 1;

R2represents N;

R3represents H, alkyl or halogen;

R4represents aryl, heteroaryl, alkylaryl or alkylglycerol, each of which is optionally substituted by one to five substituents which are independently selected from the group consisting of halogen, alkyl, -OR41the bottom quinil and NR42R43where R41represents lower alkyl or-H,

R42and R43independently from each other represent hydrogen or alkyl, or NR R represents piperidinyl or pyrrolidinyl, or R4represents alkyl;

R5selected from the group consisting of:

moreover, the mentioned aryl and heteroaryl can be optionally substituted in one or more positions of one or more to cover the firs, independently selected from the group consisting of H, halogen, lower alkyl group and (CH2)vR53where

R51selected from the group consisting of H, alkyl, lower alkenyl and alkylaryl, and the specified alkylaryl optionally substituted in one or more positions of one or more lower alkyl, -CN, halogen, -COOR54and-CH2OR54where R54represents an alkyl or-H;

R52represents lower alkyl or-H;

R53represents H, alkyl, cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2, -CH2OR55or-CONR55R56where R55independently selected from the group consisting of alkyl, -N, -C(O)aryl, -C(O)alkyl or-C(O)heteroaryl, and R56selected from the group consisting of H, alkyl, C(O)CF3-C(O)aryl, -C(O)alkyl, -C(O)heteroaryl, alkylaryl and alkylglycerol, and where specified aryl, heteroaryl, alkylaryl and alkylglycerols are optionally substituted at one or more positions by one or more alkyl, -CN, halogen, -COOR57and the group-CH2OR57where R57represents lower alkyl or-H, or R55and R56together with the atom to which they are attached, form a ring system;

or R53represents aryl, which may be optionally substituted with edusim radical: benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbarnoyl, lower allylcarbamate, di-(lower alkyl)-carbarnoyl,

m means an integer from 0 to 2;

v denotes an integer from 0 to 4;

and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

As found, the new compounds according to the present invention are associated and selectively activate the receptors of hepatic LXRα or LXRβ or jointly activate LXRα and LXRβ. Thus, the cholesterol absorption is reduced, cholesterol, increases HDL and the inflammatory atherosclerosis decreases. Since the modulators X-receptors of the liver have a varied impact on the combined dyslipidemia and cholesterol homeostasis, the new compounds according to the present invention have enhanced therapeutic potential compared to the compounds known from the prior art. These compounds can be used for the treatment and prevention of diseases that are mediated by agonists of receptors LXRα and/or LXRβ. Such diseases include elevated levels of lipids and cholesterol levels, particularly low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic the systematic syndrome, dyslipidemia, Alzheimer's disease, sepsis (General purulent infection and inflammatory diseases, such as colitis, pancreatitis, cholestasis (bile stasis)/fibrosis of the liver, and diseases in which there is an inflammatory component, such as Alzheimer's disease or reduced/measurable improvement in cognitive function. The new compounds according to the present invention, furthermore, can be used to treat and prevent age-related macular degeneration of the retina.

The present invention also relates to pharmaceutical compositions comprising the compounds of formula I and a pharmaceutically acceptable carrier and/or excipient. In addition, the present invention relates to the use of such compounds as therapeutically active compounds and to the use of such compounds to obtain drugs for the treatment or prevention of diseases which are mediated by agonists of receptors LXRα and/or LXRβ. In addition, the present invention relates to methods of preparing compounds of formula I. In addition, the present invention relates to a method for prophylaxis or therapeutic treatment of diseases mediated by agonists of receptors LXRα and/or LXRβ, such as elevated lipids and cholesterol, in particular low the level of HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis (General purulent infection, and inflammatory diseases such as colitis, pancreatitis, cholestasis (bile stasis)/fibrosis of the liver, and diseases in which there is an inflammatory component, such as Alzheimer's disease or reduced/measurable improvement in cognitive function, this method includes the introduction of the compounds of formula I to a human or animal.

More specifically, the present invention relates to compounds of formula (I):

where

n means an integer from 0 to 3;

R1independently selected from the group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, triptoreline, -OR11, piperidinyl, pyrrolidinyl and-N(R11)(R11), where R11independently selected from lower alkyl and N,

X1X2X3and X4independently selected from nitrogen or carbon, provided that not more than two of X1X2X3and X4can mean nitrogen, and in the case when two of X1X2X3and X4mean nitrogen, n is 0, 1 or 2;

k is the integer 0 or 1;

R2not only is em a N;

R3represents H, alkyl or halogen;

R4represents aryl, heteroaryl, alkylaryl or alkylglycerol, each of which is optionally substituted by one to five substituents which are independently selected from the group consisting of halogen, alkyl, -OR41the bottom quinil and NR42R43where R41represents lower alkyl or-H,

R42and R43independently from each other represent hydrogen or alkyl, or

NR42R43is piperidinyl or pyrrolidinyl, or R4represents alkyl;

R5selected from the group consisting of:

moreover, the mentioned aryl and heteroaryl optionally substituted in one or more positions by one or more substituents independently selected from the group consisting of H, halogen, lower alkyl and (CH2)vR53where

R51selected from the group consisting of H, alkyl, lower alkenyl and alkylaryl, and the specified alkylaryl optionally substituted in one or more positions of one or more lower alkyl, -CN, halogen, -COOR54and-CH2OR54where R represents an alkyl or-H;

R52represents lower alkyl or-H;

R53PR is dstanley a N, alkyl, cycloalkyl, -COOR, -N(R55)(R56), -CH2HE, -CN, CF3, -CONH2, -CH2OR55or-CONR55R56where R55independently selected from the group consisting of alkyl, -N, -C(O)aryl, -C(O)alkyl or-C(O)heteroaryl, and R56selected from the group consisting of H, alkyl, C(O)CF3-C(O)aryl, -C(O)alkyl, -C(O)heteroaryl, alkylaryl and alkylglycerol, and where specified aryl, heteroaryl, alkylaryl and alkylglycerols are optionally substituted at one or more positions by one or more alkyl group,- CN, halogen, a group

-COOR57and-CH2OR57where R57represents lower alkyl or-H, or R55and R56together with the atom to which they are attached, form a ring system;

or R53represents aryl, which may be optionally substituted radical benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbarnoyl, lower allylcarbamate, di-(lower alkyl)carbarnoyl,

m means an integer from 0 to 2;

v denotes an integer from 0 to 4;

and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

Preferred compounds of formula (I)as defined above are such compounds where

n means an integer from 0 to 3;

R1independently selected from a group is s, consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, triptoreline, -OR11and-N(R11)(R11), where R11independently selected from lower alkyl and N;

X1X2X3and X4independently selected from nitrogen or carbon, provided that not more than two of X1X2X3and X4can mean nitrogen, and in the case when two of X1X2X3and X4mean nitrogen, n is 0, 1 or 2;

k is the integer 0 or 1;

R2represents N;

R3represents H, alkyl or halogen;

R4represents aryl, heteroaryl, alkylaryl or alkylglycerol, each of which is optionally substituted by one to five substituents which are independently selected from the group consisting of halogen, alkyl and-OR41where R41represents lower alkyl or-H, or R4represents alkyl;

R5selected from the group consisting of:

moreover, the mentioned aryl and heteroaryl optionally substituted in one or more positions by one or more substituents independently selected from the group consisting of H, halogen, lower alkyl and (CH2)vR53where

R51selected from a group is s, consisting of H, alkyl, allyl and alkylaryl, specified alkylaryl optionally substituted in one or more positions of one or more lower alkyl, a group-CN, halogen, a group-COOR54and the group-CH2OR54where R54represents an alkyl or-H;

R52represents lower alkyl or-H;

R53represents H, alkyl, cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, -CONH2, -CH2OR55or-CONR55R56where R55independently selected from the group consisting of alkyl, -N, -C(O)aryl, -C(O)alkyl or-C(O)heteroaryl, and R56selected from the group consisting of H, alkyl, -C(O)aryl, -C(O)alkyl, -C(O)heteroaryl, alkylaryl and alkylglycerol, and where specified aryl, heteroaryl, alkylaryl and alkylglycerols are optionally substituted at one or more positions by one or more alkyl group,- CN, halogen, a group-COOR57and the group-CH2OR57where R57represents lower alkyl or-H, or R55and R56together with the atom to which they are attached, form a ring system;

m means an integer from 0 to 2;

v denotes an integer from 0 to 4;

and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

Unless otherwise indicated, to establish the value and volume of razlichimie, used in the text of this application, and to illustrate the possible cases of use of such terms should use the following definitions.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine are preferred.

The term "alkyl", alone or in combination with other groups, refers to a linear or branched, 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 group lower alkyl, such as described below, are also preferred alkyl groups.

The term "lower alkyl", alone or in combination with other groups, refers to a linear or branched, monovalent alkyl, the radical containing from one to six carbon atoms, preferably from one to four carbon atoms. The value of this additional term can be exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

The term "lower alkenyl", separately or in combination, means linear or branched hydrocarbon radical comprising olefinic bond and from 2 to 8, before occhialino from 2 to 6, particularly preferably from 2 to 4 carbon atoms. Examples alkenyl groups are ethynyl, 1-propenyl, 2-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-but-2-enyl and Isobutanol.

The term "lower quinil", alone or in combination with other groups, means a linear or branched hydrocarbon residue comprising a triple bond and up to 7, preferably up to 4, carbon atoms, for example 2-PROPYNYL or ethinyl.

The term "cycloalkyl" refers to a monovalent carbocyclic to radical containing from 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, such radicals as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "aryl" refers, or aromatic monocyclic system containing six carbon atoms, or aromatic bicyclic system containing 10 carbon atoms. For example, the term aryl includes phenyl or naftalina ring system, preferably the phenyl group. The term "alkylaryl" refers to an aryl group that is attached through an alkyl group, such as benzyl.

The term "heteroaryl" refers to an aromatic 5 - or 6-membered ring system which may comprise 1-4 heteroatoms selected from nitrogen, oxygen and/or sulfur, for example, such as furyl, pyridyl, pyridazinyl, pirimidine, pyrazinyl, thienyl, isooxazolyl, oxazolyl, imidazolyl or pyrrolyl. The term "heteroaryl also includes heteroaryl, as defined above, is condensed (mated) with one or more other cycle, representing heterocyclyl, aryl, or heteroaryl, for example benzothiazolyl. The term "alkylglycerol" refers to a heteroaryl group that is attached through an alkyl group.

The term "pharmaceutically acceptable salt" includes salts of compounds of formula (I) with inorganic or organic acids, such as chloromethane acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid (butanedioate), tartaric acid, methanesulfonate acid, n-toluensulfonate acid and the like, which are non-toxic in relation to living organisms. Preferred salts are phosphates, citrates, fumarate, formate, hydrochloride, hydrobromide and salt methanesulfonic acid.

The term "pharmaceutically acceptable esters" includes esters of compounds of formula (I), in which the hydroxy-group converted into the corresponding ester groups with inorganic or organic acids, such as nitric acid is, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid (butanedioate), tartaric acid, methanesulfonate acid, p-toluensulfonate acid and the like, which are non-toxic in relation to living organisms.

Preferred are the compounds of formula (I), where each of X1X2X3and X4is the carbon. Also preferred compounds of formula (I), where X1means nitrogen, and each of X2X3and X4is the carbon.

In accordance with another embodiment of the present invention preferred are such compounds of formula (I), where n is 1, X2represents a carbon, and R1directly attached to X2- carbon. Compounds where R is selected from the group consisting of halogen, preferably Cl, cyano, nitro, SO2Me, lower alkyl and N(Me)2are more preferable. Another preferred implementation of the present invention refers to those compounds, where R1selected from the group consisting of halogen, cyano, nitro, SO2Me, lower alkyl, N(Me)2, NHMe and piperidinyl.

Also preferred are such compounds of formula (I), where R1represents a halogen. Especially predpochtite the flaxes such compounds of formula (I), where R1represents Cl.

In addition, preferred compounds of formula (I), where n means 2. In accordance with another embodiment of the present invention preferred compounds of formula (I), where n is 2 and each R1represents a halogen. More preferably X2represents a carbon, and one of the two groups R1directly attached to X2-carbon.

In accordance with another embodiment of the present invention preferred compounds of formula (I), where k denotes 0 or 1, more preferably, where k is 0. Connection, where k means 0 and where k is 1, separately constitute preferred embodiments of the present invention.

In accordance with another preferred embodiment of the present invention R3in the formula (I) represents H, halogen or methyl. Preferably R3represents F or methyl. Deputy F and methyl individually constitute preferred embodiments of the present invention.

Another preferred embodiment of the invention relates to compounds as defined above, where R4represents aryl or heteroaryl, each of which is optionally substituted by one to five substituents which are independently researched the performance is chosen from the group consisting of halogen, alkyl, -OR41the bottom quinil and NR42R43where R41represents lower alkyl or-H, R42and R43independently from each other represent hydrogen or alkyl, or NR42R43is piperidinyl or pyrrolidinyl, or R4represents a lower alkyl

Compounds as defined above, where R4selected from the group consisting of naphthyl, pyridinyl, methyl, phenyl or mono - or disubstituted phenyl, where the Deputy had phenyl represents halogen, N(lower alkyl)2or or41and where R41is the same as defined above, are also preferred.

Are also preferred such compounds of formula (I), where R4represents aryl, heteroaryl or lower alkyl.

Also preferred are such compounds of formula (I), where R4selected from the group consisting of naphthyl, pyridinyl, methyl, phenyl or mono - or disubstituted phenyl, where the Deputy had phenyl is halogeno or or41and where R41represents a lower alkyl or hydrogen.

Preferred such compounds according to the present invention, where

R4represents aryl or heteroaryl, which is optionally substituted in one or more positions by lower alkyl. In private the tee, preferred such compounds, where R4selected from the group consisting of phenyl; mono - or disubstituted phenyl, where one or more substituents represent halogeno or or41; naphthyl; pyridinyl or methyl. Especially preferred compounds of formula (I), where R4represents phenyl or mono - or disubstituted phenyl, where the specified one or more substituents are halogen, more preferably R4represents phenyl, 4-chlorophenyl, 3-forfinal or 3,4-differenl. Another preferred implementation of the present invention relates to compounds as described above, where R4represents phenyl, 3-bromophenyl or 3-dimethylaminophenyl.

In accordance with other preferred compounds of formula (I) according to the present invention R5selected from the group consisting of

the specified heteroaryl optionally substituted in one or more positions by one or more substituents independently selected from the group consisting of H, halogen, lower alkyl and (CH2)vR53where R51selected from the group consisting of H, alkyl and alkylaryl, specified alkylaryl optionally substituted in one or more positions on the him or more lower alkyl, -CN, halogen, -COOR54and-CH2OR54where R54represents an alkyl or-H; and R52represents lower alkyl or-H;

R53represents H, alkyl, cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, -CONH2, -CH2OR55or-CONR55R56where R55independently selected from the group consisting of alkyl,-N, -C(O)aryl, -C(O)alkyl or-C(O)heteroaryl, and R56selected from the group consisting of H, alkyl, -C(O)aryl, -C(O)alkyl, -C(O)heteroaryl, alkylaryl and alkylglycerol, and where specified aryl, heteroaryl, alkylaryl and alkylglycerols are optionally substituted at one or more positions by one or more alkyl group,- CN, halogen, a group-COOR and group-CH2OR57where R57represents lower alkyl or-H, or R55and R56together with the atom to which they are attached, form a ring system;

m means an integer from 0 to 2; and

v denotes an integer from 0 to 4. In accordance with a preferred embodiment of the present invention m is 0.

In accordance with other preferred compounds R is chosen from the group consisting of:

where R51selected from the group consisting of H; alkyl; alkylaryl, neobythites is but mono - or disubstituted by one or more lower alkyl, the group-CN, halogen or a group-COOR54where R54represents an alkyl or-H; and R52represents a lower alkyl or N, and where m has the values listed above.

Alternatively, preferred compounds of formula (I), where R5selected from the group consisting of:

the specified heteroaryl optionally substituted in one or more positions by one or more substituents independently selected from the group consisting of H, halogen, lower alkyl and (CH2)vR53where m, v and R53are as described above. More preferably heteroaryl selected from the group consisting of:

where v and R53are as above, R58independently selected from H, halogen and lower alkyl, D represents O or S, and D represents O, S or NR58and where in the case when the specified connection contains two groups (CH2)vR53these groups can be optionally connected with other atoms to which they are attached with the formation of the ring system.

According to an alternative preferred variant implementation of the present invention preferred are such compounds of formula (I), where R5selected from the group consisting of pursuing what about:

where aryl is chosen from the group consisting of:

and where R53so, as stated above,

X5X6X7and X8selected from carbon and nitrogen, provided that no more than two of X5X6X7and X8that can mean N, and where m and v are as described above. Preferably m is 0. Preferably the aryl is a phenyl substituted by a group -(CH2)vR53where R53and v are as described above.

The preferred compounds as defined above are such compounds where R5is heteroaryl selected from the group consisting of oxadiazolyl, oxazolyl and benzothiazolyl, specified heteroaryl optionally substituted lower alkyl, lower alkoxycarbonyl or phenyl, the said phenyl optionally substituted by a carboxy group, a lower alkylcarboxylic, carbamoyl or group di(lower alkyl)carbarnoyl. More preferred are such compounds in which R5represents 5-methyl-(1,3,4)oxadiazol-2-yl, 5-(methyl ether 4-benzoic acid)-(1,3,4)oxadiazol-2-yl, 5-(4-benzoic acid)-(1,3,4)oxadiazol-2-yl, 5-(4-benzamide)-(1,3,4)oxadiazol-2-yl, 5-(4-dimethylbenzamide)-(1,3,4)oxadiazol-2-yl, 4-(methyl ether of carbon is th acid)oxazo-2-yl or benzothiazol-2-yl.

Preferred compounds of formula (I) are the compounds of formula (Ia):

where R1, R2, R3, R4, R5, n, k, X1X2X3and X4are as described above. Preferably R3represents halogen or alkyl.

In addition, preferred compounds of formula (I) are the compounds of formula (Ib):

in which R1, R2, R3, R4, R5, n, k, X1X2X3and X4are as described above. Preferably R represents halogen or alkyl.

Especially preferred compounds of formula (I)in which m takes the value of zero.

Preferred compounds of General formula (I) are compounds that are selected from the following group of compounds:

methyl ether benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid;

methyl ether benzazolyl-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-CT the azole-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(6-nitro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(6-cyano-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)propionic acid;

(RS,SR)-2-benzazolyl-2-(2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid methyl ester;

methyl ester of (RS,SR)-2-benzazolyl-2-(6-methanesulfonyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(8-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro - 1H-carbazole-2-yl)forexpros acids;

methyl ester of (RS,SR)benzosulfimide-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid;

methyl ester of (RS,SR)benzazolyl-(6-cyano-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(2-chloro-6,7,8,9-tetrahydro-1H-pyrido[3,2-b]indol-7-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(6-bromo-5-fluoro-2,3,4,9-tetrahed is about - 1H-carbazole-2-yl)forexpros acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(7-bromo-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(7-cyano-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(7-methyl-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)propionic acid;

methyl ester of (RS,SR)benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(7-bromo-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(5-chloro-1,2,3,8-tetrahydro-4,8-disallowment[a]inden-2-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(7-bromo-6-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(7-bromo-8-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acids;

methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(naphthalene-1-sulfonyl)propionic acid;

methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(naphthalene-2-sulfonyl)propionic acid;

methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(3,4-dichlorobenzenesulfonyl)impregnated the new acid;

methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(toluene-3-sulfonyl)propionic acid;

methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(3-methoxybenzenesulfonyl)propionic acid;

methyl ester of (RS,SR)-2-(2-chlorobenzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro - 1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(2-methoxybenzenesulfonyl)propionic acid;

methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(4-permentantly)propionic acid;

methyl ester of (RS,SR)-2-(3-chlorobenzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(4-permentantly)acetic acid;

methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(6-chloro-2,3,4,9-tetrahydro - 1H-carbazole-2-yl)forexpros acids;

methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(3-permentantly)acetic acid;

methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-(3,4-differentiality)forexpros acids;

methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(pyridine-3-sulfonyl)acetic acid;

methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-methoxybenzenesulfonyl)acetic acid;

milovy ether (RS,SR)-(3-chlorobenzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;

(RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(pyridine-2-sulfonyl)acetic acid methyl ester;

methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-permentantly)acetic acid;

methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-(3,4-differentiality)forexpros acids;

methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(pyridine-3-sulfonyl)acetic acid;

methyl ester of (RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-(pyridine-2-sulfonyl)propionic acid;

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

(RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)ftorotana acid;

(RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole;

(RS,SR)-2-benzazolyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile;

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile;

(RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forcecontrol;

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide;

(RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-N-methylacetamide;

(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-toranzo sulfonyl)-N-methylacetamide;

(RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-2-(3-permentantly)-N-methylacetamide;

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N,N-dimethylacetamide;

(RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-M,N-dimethylacetamide;

(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide;

(RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide;

(RS,SR)-2-benzazolyl-N-benzyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide;

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(4-cyano-benzyl)-2-fluoro-N-methylacetamide;

(RS,SR)-2-benzazolyl-N-(4-bromobenzyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide;

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(3,5-diferensial)-2-fluoro-N-methylacetamide;

methyl ester of (RS,SR)-4-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid;

methyl ester of (RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]methylamino}methyl)benzoic acid;

(RS,SR-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(2-cyano-benzyl)-2-fluoro-N-methylacetamide;

(RS,SR)-N-allyl-2-benzazolyl-2-(-chloro-2,3,4,9-tetrahydro-1 H-carbazole-2-yl)-2-fluoro-N-methylacetamide;

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(3-cyano-benzyl)-2-fluoro-N-methylacetamide;

(RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]methylamino}methyl)benzoic acid;

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-(3-hydroxymethylene)-1H-methylacetamide;

(RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(S)-2-[(R)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(R)-2-[(S)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-[1-benzazolyl-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-(benzosulfimide-[1,3,4]oxadiazol-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-6-chloro-2,3,4,9-tetrahydro-1H-carbazole;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}dimethylamine;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent-[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}dimethylamine;

(RS,SR)-2-[b is zolsulphonate-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

methyl ester of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent-[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent-[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methanol;

(RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid;

amide(RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine;

(RS,SR)-7-chloro-2-[(3-chlorobenzenesulfonyl)fluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-7-chloro-2-[(3-chlorobenzenesulfonyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent-[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}dimethylamine;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent-[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}diethylamine;/p>

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent-[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}diethylamine;

(RS,SR)-2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent-[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}ndimethylacetamide;

(RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}benzamide;

methyl ester of (RS,SR)-2-benzazolyl-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)-2-benzazolyl-2-(6-dimethylamino-2,3,4,9-tetrahydro - 1H-carbazole-2-yl)propionic acid;

methyl ester (6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)methanesulfonate acids;

methyl ester of (RS,SR)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acids;

methyl ester of (RS,SR)-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid,

and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

Other preferred compounds of General formula (I) are compounds that are selected from the following group of compounds:

methyl ether (3-bromomethylphenyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)acetic acid;

mate the new ester of (RS,SR)-2-(3-brabanthallen)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid;

methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-(3-pyrrolidin-1-eventality)propionic acid;

(RS,SR) 2-[1 -(3-brabanthallen)-1 -(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-[(3-brabanthallen)fluoro-(5-methyl-[l,3,4]oxidiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR) 2-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-brabanthallen)-vermeil]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR) {3-[(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methanesulfonyl]phenyl}dimethylamine;

(RS,SR)-7-chloro-2-[(3-ethinyl-benzazolyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-[5-(4-benzyloxybenzyl)-[l,3,4]oxidiazol-2-yl-(3-brabanthallen)formetal]-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indole;

(RS,SR)-7-chloro-2-[(3-ethylbenzonitrile)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole;

methyl ester of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid;

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid;

(RS,SR) (4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]acadias the l-2-yl}-phenyl)methanol;

(RS,SR) 2-{benzosulfimide-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]-methyl}-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR) 4-{5-[(benzazolyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid;

(RS,SR) 4-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-ylmethyl}benzoic acid;

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol-2-yl)formetal]- [1,3,4] oxadiazol-2-yl}benzamide;

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}-N-methylbenzamide;

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}-N,N-dimethylbenzamide;

(RS,SR)-2-[-benzosulfimide-(5-methyl-[l,3,4]oxidiazol-2-yl)methyl]-7-bromo-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-[-benzosulfimide-(5-methyl-[l,3,4]oxidiazol-2-yl)methyl]-7-piperidine-1-yl-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-N-{2-[-benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl}-N-methylamine;

2-[benzosulfimide-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-benzazolyl--(-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methyl-N-(3-methyl-but-2-enyl)ndimethylacetamide;

(RS,SR)-5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carbonitrile;

(RS,SR)-{5-[-benzazolyl-(-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine;

methyl ester of (RS,SR)-4-[({5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]benzoic acid;

methyl ester of (RS,SR)-3-[({5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]benzoic acid;

(RS,SR)-{4-[({5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]phenyl}methanol;

(RS,SR)-2-(benzosulfimide-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-N-{5-[(S)benzazolyl-((R)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-2,2,2-triptorelin;

2-[benzosulfimide-(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

methyl ester of (RS,SR)-2-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]oxazol-4-carboxylic acid;

2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-[-benzazolyl-(4,5-dimethyloxazole-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]Indo is;

and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

Especially preferred compounds of General formula (I) are compounds that are selected from the following group of compounds:

methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;

methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acids;

methyl ester of (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)propionic acid;

methyl ester of (RS,SR)benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)forexpros acids;

methyl ester of (RS,SR)benzazolyl-(7-bromo-8-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acids;

methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acids;

methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-permentantly)acetic acid;

methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-(3,4-differentiality)forexpros acids;

(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide;

(RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]ind the l;

(S)-2-[(R)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(R)-2-[(S)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4] oxadiazol-2-yl}dimethylamine;

(RS,SR)-2- [benzosulfimide-(3-methyl- [1,2,4] oxadiazol-5-yl)methyl] -7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine;

and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

Other particularly preferred compounds of General formula (I) are compounds that are selected from the following group of compounds:

(RS,SR)-2-[(3-brabanthallen)fluoro-(5-methyl-[1,3,4] oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;

(RS,SR){3-[(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methanesulfonyl]phenyl}dimethylamine;

methyl ester of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal] -[1,3,4] oxadiazol-2-yl}benzoic acid;

(RS,SR) 4-{5-[(3-brombenzola who yl)-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid;

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzamide;

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}-N,N-dimethylbenzamide;

methyl ester of (RS,SR)-2-[-benzazolyl-(-7-chloro-l,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]oxazol-4-carboxylic acid;

2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indole;

and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

The compounds of formula (I) can contain one or more asymmetric centers and may be in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, in the form of optically pure diastereomers, mixtures of diastereoisomers, of diastereomeric racemates or mixtures of diastereomeric racemates. Optically active forms may be obtained, for example, by separation of racemates by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or suenami).

The compounds of formula (I), pharmaceutically acceptable salts of compounds of formula (I) and pharmaceutically acceptable esters of compounds of formula (I) individually represent preferred options the imp is the link of the present invention. Especially preferred are the compounds of formula (I).

It should be noted that compounds of General formula (I) according to the present invention can be modified to obtain this derivative functional groups that are able to reverse the transformation in vivo to the parent compound.

The present invention also relates to a method for producing compounds of formula (I)as described above, this method involves reacting the compounds of formula (II):

in which R2, R3, R4, R5and k have the meanings given above, with a compound of formula III:

in which R1n, X1X2X3and X4have the meanings given above, and optional conversion of the compounds of formula I in a pharmaceutically acceptable salt and/or pharmaceutically acceptable ester.

The interaction of the compounds of formula (II) with a hydrazine of formula (III) can be performed using methods known from the prior art, and thus, as shown in the following scheme 1. For example, in the case when substituted arylhydrazines interacts with the compound of the formula (II), when conducting a modified synthesis of indoles Fisher can be used pure acetic acid at the temperature of the re from room temperature up to 40°C, if k is 1, and from room temperature to 75°C, if k is 0. Alternatively, when the interaction of literaryheroine reaction can be carried out at 120°C in a sealed tube.

In accordance with another embodiment of the invention, in the case where the compounds of formula (I) contain a group R, which is a tertiary amide group, compounds of formula I can be obtained using methods known from the prior art, and thus, as shown in scheme 5 and scheme 6, below.

In addition, the present invention relates to compounds of formula (I)as defined above, which get in the manner specified above.

As described above, the compounds of formula (I) according to the present invention can be used as medicines for the treatment and/or prevention of diseases which are mediated by agonists of receptors LXRα and/or LXRβ. Examples of such diseases are elevated lipids and cholesterol levels, particularly low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis (General purulent infection), inflammatory diseases such as colitis, punk is eatit, cholestasis (bile stasis)/fibrosis of the liver, and diseases in which there is an inflammatory component, such as Alzheimer's disease or reduced/measurable improvement in cognitive function. The use of compounds of formula (I) for the treatment of atherosclerosis, low HDL cholesterol, non-insulin-dependent diabetes mellitus and metabolic syndrome is preferred. The compounds of formula (I) may also be used for the treatment and prevention of age-related macular degeneration of the retina.

The present invention also relates to pharmaceutical compositions comprising a compound of formula (I)as defined above, and a pharmaceutically acceptable carrier and/or excipient.

In addition, the present invention relates to compounds as defined above, intended for use as therapeutically active substances, particularly as therapeutically active compounds for the treatment and/or prevention of diseases which are mediated by agonists of receptors LXRα and/or LXRβ. Preferred examples of such diseases are atherosclerosis, elevated lipids and cholesterol levels, particularly low HDL cholesterol, high LDL cholesterol, non-insulin-dependent diabetes mellitus, metabolic syndrome, dyslipidemia, bolezn is Alzheimer's disease, sepsis (General purulent infection and inflammatory diseases.

In accordance with another variant of the present invention relates to a method of treatment and/or prevention of diseases which are mediated by agonists of receptors LXRα and/or LXRβ, such as atherosclerosis, elevated lipids and cholesterol levels, particularly low HDL cholesterol, high LDL cholesterol, non-insulin-dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis (General purulent infection and/or inflammatory disease, the method includes the introduction of the compounds of formula (I) human or animal.

Also preferred is a method of treatment and/or prevention of diseases which are mediated by agonists of receptors LXRα and/or LXRβ, this method includes the introduction of compounds as defined above, a person or an animal, in particular, in the case when the disease is chosen from the group consisting of the following: elevated levels of lipids and cholesterol levels, particularly low HDL cholesterol and/or high LDL cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis (General purulent infection), inflammatory diseases, including colitis,pancreatitis, cholestasis (bile stasis)/fibrosis of the liver, and diseases in which there is an inflammatory component, such as Alzheimer's disease or reduced/measurable improvement in cognitive function.

In addition, the present invention relates to the use of the compounds defined above, for the treatment and/or prevention of diseases which are mediated by agonists of receptors LXRα and/or LXRβ, such as atherosclerosis, elevated lipids and cholesterol levels, particularly low HDL cholesterol, high LDL cholesterol, non-insulin-dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis (General purulent infection and/or inflammatory diseases.

In addition, the present invention relates to the use of compounds defined above, to obtain drugs for the treatment and/or prevention of diseases which are mediated by agonists of receptors LXRα and/or LXRβ, such as atherosclerosis, elevated lipids and cholesterol levels, particularly low HDL cholesterol, high LDL cholesterol, non-insulin-dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis (General purulent infection and/or inflammatory diseases.

The compounds of formula (I) can be half the modern ways, below, the methods described in the examples or by analogous methods. Suitable conditions for carrying out the individual stages of the reactions known to the person skilled in the art. Source materials are either commercially available or can be obtained using methods similar to that shown below or in the examples or by methods known from the prior art. If not stated otherwise, all of the substituents mentioned in schemes 1, 2A, 2B, 3, 4, 5, and 6, are as described above. Deputy R2means hydrogen and therefore not always specified.

The compounds of formula I can be obtained in accordance with the following reaction scheme 1:

Scheme 1

in which R1, R2, R3, R4X, k and n have the meanings specified above. R means hydrogen and therefore is not indicated in the formula (I).

Join Michael derivative sulfonyl 2 to cyclic 2-may 1, at room temperature in the Meon containing 10-20% NaOMe, or THF, or acetonitrile in the presence of bases, such as2CO3or Cs2CO3leads to the corresponding 3-substituted cyclic ketone 3 (stage a). Alkylation of compound 3 can be performed using NaH in DMF at 0°C, followed doba the population of the electrophile R 3-X (such as Me, N-forbindelseshastighed)to give the compound 4 in the form of a racemic mixture of diastereomers (stage b). Two diastereoisomer (RS,SR) and (RR,SS) can be separated at this stage column chromatography on silica gel. A modified synthesis of indole derivatives Fisher used to produce the compounds of formula (I). The interaction of ketone 3 or 4 arylhydrazines (replaced by arylhydrazines) in pure acetic acid at a temperature from room temperature up to 40°C for k=1, and at temperatures from room temperature up to 75°C for k=0, and at approximately 120°C. in a sealed tube for heteroeroticism leads to the production of the compounds of formula (I) (stage b).

Functional groups present in the radicals R1and R4may be at this stage of the synthesis transformed into other functional groups using conventional techniques, generally known from the prior art. Typical examples are the replacement of the Deputy iodo - or bromo - amino group with the conditions of condensation Buchwald (Buchwald) or substitution Deputy iodo - or bromo - 1-quinil in the conditions of the condensation Sonogashira (Sonogashira). Such alkyline fragments can then be modified in the alkyl fragments by hydrogenation. Functional groups present in the radical R5can be TA is received in the other group with the receipt of this group, listed

R1and R4or turning alkoxycarbonyl group into a carboxyl group by hydrolysis in the presence of LiOH or NaOH, carboxyl group aminocarbonyl group using primary or secondary amine agent and the condensation of peptides, such as EDCI, turning alkoxycarbonyl group in the hydroxyalkyl residue through recovery using LiAlH4or turning hydroxyalkyl residue in the fragment of simple ester by alkylation. If necessary, the nitrogen tetrahydrocarbazole, 1,2,3,3A,4,8b-tetrahydrocyclopent[b]indoles and related heterocycles can be RE-or Z-protected before carrying out these transformations.

To obtain sulfanilamidnyh 2, necessary for carrying out the joining Michael indicated in scheme 1, can be used following 2 different methods of synthesis. In figure 2A shows the synthesis sulfanilamidnyh, which begins with the alkylation of thiol 1 with the use of the electrophile of formula 2 in the presence of a base, while receiving sulfides 3. The preferred base is either a2CO3using acetone as a solvent or NaH in DMF (stage a). Sulfides 3 further oxidized to the corresponding sulfanilic derivative 4 using the-W or oxone (peroxymonosulfate potassium) in the Meon at room temperature over night, or using mjpbk in CHCl3or CH2Cl2at room temperature (stage b).

Scheme 2A

Scheme 2B

An alternative method of obtaining derivatives of sulfones shown in scheme 2B. Sodium salt sulfinol acid 5, which is either commercially available or can be obtained from the appropriate sulfinol acids and bases, can be processed by electrophile 6 with getting this sulfonic derivatives of 4 (see Y.Nagao, S.Yamada, E. Fujita, Tet. Lett. 1983, 2291-2294).

In the case when it is necessary to obtain the compounds of formula I, in which sulfonylurea derivatives have R substituted [1,3,4]oxadiazolyl fragment may be used in the method shown in scheme 3. The addition of hydrazine hydrate is added to the complex ether 1 (thus obtained, as shown in figure 2A, for R5=X-CH2-(CH2)mCO2Me) in the Meon at room temperature leads to the production of hydrazide 2 (stage a). Hydrazide 2 acelerou acetic anhydride in acetic acid to obtain the intermediate compounds of formula 3 (stage b), which is subjected to cyclization using POCl3in acetonitrile, thus obtaining the compound 4 (stage b). Alternatively, oxadiazol 4 can be obtained by treatment of the hydrazide 2 POCl2in PR is the absence of a carboxylic acid R 53-(CH2)v-COOH boiling under reflux (method g). An additional method of obtaining derivatives 4 is in the handling of hydrazide 2 triethylorthoformate using POCl3.

Scheme 3

Getting sulfanilic derivatives with substituted [1,2,4]oxadiazolyl fragment shown in figure 4 below (compound 5). Processing nitrile derivatives 1 hydroxylaminopurine and NaOMe in Meon at room temperature leads to the production of amino-hydroxyimino derivatives 2 (stage a), which transform in oxadiazole 4 through interaction with the compound 3, using one of the following methods (stage b).

Method A. After processing connections 2 using NaH in THF at room temperature add ester 3, and then the reaction mixture was stirred at 60°C for 2 hours.

Method B. alternatively, the handle 2 at room temperature in THF using 3 (X=Cl) for 2 hours. After evaporation of the solvent the resulting mixture was refluxed in dioxane overnight in the presence of molecular sieves.

The resulting sulfides 4 oxidizes to sulfanilic derivatives of formula 5 using mjpbk at room temperature in CHCl3(stage b).

Scheme 4

Obtaining compounds of General formula (I)in which R is a tertiary amide group shown in scheme 5. Esters of type 1 (obtained using the techniques described above) turn in the secondary amides 2 by reaction with a primary amine and KCN in a sealed tube (stage a). The BOC-protection (Vos)2Oh, DMAP, Et3N, CH2Cl2at room temperature leads to the formation of compounds 3 (stage b), which alkylate through deprotonation using NaH in THF and through subsequent processing by a number of electrophiles. The removal of the protective group using TFU CH2Cl2results target compounds 4 (stage b).

Scheme 5

The following tests are used to determine the activity of compounds of the formula (I) and their salts.

Functional groups present in R4or R53may be, if appropriate or necessary, converted into other functional groups at the appropriate stage of the synthesis by the usual methods known from the prior art. Typical examples are the transformation of alkoxycarbonyl group into a carboxyl group by hydrolysis in the presence of LiOH, the transformation of the carboxyl group in aminocarbonyl group ispolzovaniya or secondary amine agent and the condensation of peptides, for example, such as EDCI, replacing Deputy iodo - or bromo - amino group under conditions of condensation Buchwald (Buchwald) or substitution Deputy iodo - or bromo-1-alkenylphenol group under the conditions of condensation Sonogashira (Sonogashira). If necessary, the nitrogen tetrahydrocarbazole, 1,2,3,3A,4,8b-tetrahedrite-Penta[b]indoles and related heterocycles can be RE - or Z-protected before carrying out the transformation.

General information

Basic information about the used analysis methods, see: J. S. Nichols et al. "Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain". Anal Biochem. 1998,257: 112-119.

Construct expressing vectors mammal for expression of full-length receptors human LXRα and LXRβ. Construct expressing bacterial vectors for the production of glutathione-s-transferase (GST). from the English. glutathione-s-transferase), merged with the domains of the ligand binding (LBD). from the English. ligand binding domain) receptors LXRα person (amino acids from 164 to 447) and LXRβ person (amino acids from 155 to 460). For this part of the sequences encoding the LBD domains, amplified from full-length clones by polymerase chain reaction (PCR) and then subcloning in plasmid vectors. The structure of the final clones confirmed by sequencing (sequencing) DNA (Willy et A1., Genes Dev. 1995, :1033-45; Song et A1., Proc Nail Acad Sci USA, 1994, 91:10809-13).

The induction, expression and purification of the fused protein GST-LBD carried out using cells of the strain E. coli BL21 (pLysS) according to standard techniques (see: Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel et al).

Research associate with the use of radioactive ligands

Binding to receptors LXRα and LXRβ are examined in buffer consisting of 50 mm HEPES, pH 7.4, 10 mm NaCl, 5 mm MgCl2. When each of the reactions carried out in the wells of 96-hole tablet, 500 ng of GST-LXRα-LBD or 700 ng GST-LXRβ-LBD fused protein is associated with 80 μg or 40 μg SPA beads (Pharmacia Amersham), respectively, at final volume of 50 µl, with shaking. The resulting suspension is incubated for 1 hour at room temperature and centrifuged for 2 minutes at 1300 x g. The supernatant containing unbound protein is removed and the resulting semi-dry residue remaining in the tube after centrifugation, containing beads, the surface of which there are receptors resuspended in 50 μl of buffer. Add the radioactive ligand (e.g., (N-(2,2,2-triptorelin)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)-phenyl]benzosulfimide, 100,000 disintegrations per minute)and the reaction mixture incubated at room temperature for 1 hour in the presence of test compounds, followed by measurement of the scintillation. All studies St. the statements performed in 96-well tablets and the amount of bound ligand is measured using a scintillation counter Packard TopCount", system OptiPlates ("Packard"). Curves dose-response build for the concentration range from 10-10M to 10-4M

Cells baby hamster kidney (KSS-21 ATSS CCL10) are grown in DMEM (modified Dulbecco Wednesday Needle)containing 10% FBS at 37°C in an atmosphere of 95% O2: 5% CO2. Cells were seeded in 6-hole tablets with density, component 10 cells/well, and then periodically transfection or full-LXRα or full-LXRβ-expressing plasmids plus plasmid reporter expressing the luciferase controlled LXR-responsive elements. Transfection complete with reagent " Fugene 6" (firm Roche Molecular Biochemicals) in accordance with the proposed firm methodology. 6 hours after transfection, the cells are harvested by treatment with trypsin and seeded in 96-well tablets with a density of 10 cells/well. 24 hours required for attachment of cells, the medium removed and replaced with 100 μl of medium containing no phenol red but containing test compounds or reference ligand (final concentration of DMSO is 0.1%). After incubation of the cells with the compounds for 24 hours, 50 μl of supernatant is removed and added to 50 μl of luciferase reagent "Luciferase Constant-Light" (firm Roche Molecular Biochemicals") in order to lyse the cells and initiate the luciferase reactions is. The amount of luminescence as a characteristic luciferase activity determined using counter Packard TopCount". Activation of transcription in the presence of test compounds is expressed through the rate of change of luminescence compared to cells that were incubated without the addition of compounds. Values EU50calculated using XLfit (ID Business Solutions Ltd., UK).

Compounds according to formula (I), display activity according to at least one of the above studies (EU50or IC50) at a concentration of from 0.1 nm to 100 μm, preferably from 0.1 nm to 1 micron (μm means micromolar).

For example, the following compounds are characterized by the following values IC50according to the research link:

td align="left"> 0,090
ConnectionBindingBinding
Methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acidLXR-alpha IC50[µmol/l] 1,600LXR-beta IC50[µmol/l] 0,270
Methyl ester of (RS,SR)benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)forexpros acid0,050
(RS,SR) {3-[(7-Chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methanesulfonyl]phenyl}dimethylamine0,0430,006

The compounds of formula I and/or pharmaceutically acceptable salts and/or pharmaceutically acceptable esters can be used as medicines, for example in the form of pharmaceutical preparations for enteral, parenteral or local administration. They can also be entered, for example, orally, such as tablets, coated 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 injectable solutions or solutions for injection, or topically, for example in the form of ointments, creams or oils. Oral administration is preferred.

Obtaining pharmaceutical preparations can be carried out using methods known to experts in this field, through the introduction of compounds of the formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically important compounds, in dosage form intended for administration, together with eligible and, non-toxic, inert, therapeutically compatible solid or liquid substances-carriers and, if desired, with conventional pharmaceutical auxiliary substances.

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

As pharmaceutical excipients should be considered a conventional stabilizers, preservatives, wetting and emulsifying agents, agents for improving the consistency, agents for improving taste and smell, salts for regulating the osmotic pressure, buffer substances, soljubilizatory tinted substances and antioxidants.

The dosage of the compounds of formula I can vary within wide limits depending on the disease, which is subject to control, age and specific condition of the patient and the route of administration and, of course, must be adjusted to the individual requirements in each particular case. For adult patients a daily dosage of approximately 1 to 1000 mg, in particular, consider the dosage is about 1 to 100 mg depending on the severity of symptoms and specific pharmacokinetic profile connection, you can enter in the form of dosage units of one or several times a day, such as from 1 to 3 unit dosage forms.

Convenient to use, if the pharmaceutical preparations contain approximately 1-500 mg, preferably 1-100 mg, of the compounds of formula I./p>

The following examples serve to further illustrate the present invention. However, these examples should not in any way be considered as limiting the scope of the present invention, which is defined by the formula of the present invention.

Examples

Abbreviations and symbols:

BOC=tert-butyloxycarbonyl, CH2Cl2=dichloromethane, CCl4=tetrachloride, mjpbk=m-chloroperbenzoic acid, CuI=copper iodide, DMAP=4-dimethylaminopyridine, DMF=dimethylformamide, EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EtOAc=ethyl acetate; EtOH=ethanol, Et2O=diethyl simple ester, Et3N=triethylamine, EQ.=equivalent, the basis of Chenega=iPr2NEt=N-ethyldiethanolamine, LiAlH4=alumoweld lithium Meon=methanol, NaH=sodium hydride, NaOtBu=tert-butyl sodium, N-BS=N-bromosuccinimide, CT=room temperature, THF=tetrahydrofuran, NaHCO3=sodium bicarbonate, NH4Cl=chloride of ammonium, TFU=triperoxonane acid, NaOH=sodium hydroxide.

General remarks

All reactions carried out in an argon atmosphere.

Example 1

Methyl ether benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid

1.1 To mix a solution of 9 g (0,042 mol) methylphenylsulfonyl-acetate in 90 ml Meon at 0°C, and 1.56 ml (0,008 mol, 0.2 EQ.) add a solution of sodium methoxide (5.4 M in the Meon). After 15 minutes before ablaut of 4.04 g (0.02 mol) 2-cyclohexen-1-it. The reaction mixture is allowed to warm to room temperature for 4 hours, diluted with saturated aqueous NH4Cl and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of heptane/EtOAc to 1:1 ratio to receive 11,50 g (yield 88%) of methyl ester benzazolyl-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 311 (MN+).

1.2 To 5 g (0,016 mol) methyl ester benzazolyl-(3-Exotica-hexyl)acetic acid in glacial acetic acid (30 ml) is added 3,17 g (0.018 mol, 1.1 EQ.) 4-chlorpheniramineydrocodone and then the reaction mixture was stirred at 40°C for 2 hours. Add an aqueous solution of NaHCO3to achieve pH 7 and then the resulting mixture was extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel, followed by rubbing with Et2O obtain 4.3 g (yield 64%) of methyl ester benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid in the form of a racemic mixture of diastereomers, light brown crystalline substance, mass spectrum: 418 (MN+).

P is the iMER 2

Methyl ether benzazolyl-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid

In accordance with the methodology, which is similar to the technique of example 1.2, from methyl ester benzazolyl-(3-oxocyclohexyl)-acetic acid and (4-forfinal)hydrazinecarboxamide get methyl ether benzazolyl-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid in the form of a racemic mixture of diastereomers, light yellow solid, mass spectrum: 402 (MN+).

Example 3

Methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

3.1

To a stirred solution of 2 g methyl ester (6,44 mmol) benzazolyl-(3-oxocyclohexyl)acetic acid in 40 ml of DMF at 0°C is added 283 mg (7,09 mmol, 1.1 EQ.) NaH (60%). The reaction mixture is stirred at this temperature for one hour and then add to 1.37 g (to 9.66 mmol, 1.5 EQ.) under the conditions. After 2 hours at room temperature the reaction mixture was poured into water and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. Two of the resulting diastereoisomer shared by column chromatography on silica gel using a mixture of heptane/EtOAc to 2:1 ratio, while receiving 0,79 g (yield 38%) of methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexa who yl)propionic acid as a white solid, mass spectrum: 325 (MN+) and 0.71 g (yield 34%) of methyl ester of (RR,SS)-2-benzazolyl-2-(3-oxocyclohexyl)-propionic acid as a white solid, mass spectrum: 325 (MN+).

3.2

To 0.14 g (0.43 mmol) of methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid in glacial acetic acid (3 ml) was added 88 mg (0.47 mmol, 1.1 EQ.) (4-chlorophenyl)hydrazinecarboxamide, after which the reaction mixture is stirred at 40°C during the night. Add an aqueous solution of NaHCO3to achieve pH 7 and then the resulting mixture was extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of heptane/EtOAc 2:1, followed by rubbing with Et2O obtain 187 mg (yield 65%) of methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as a white solid, mass spectrum: 432 (MN+).

Enantiomers share preparative chiral GHUR. Column: hiralal HELL (chiralpak AD), solvent: 20%isopropanol/heptane

Example 4

Methyl ester of (RS,SR)-2-benzazolyl-2-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 3.2, methyl ester (RS,S)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid and (4-forfinal)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as white solid substance mass spectrum: 416 (MN+).

Example 5

Methyl ester of (RS,SR)-2-benzazolyl-2-(6-methyl-2,3,4,9-tetrahydro - 1H-carbazole-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid and (4-were)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as a white solid, mass spectrum: 412 (MN+).

Example 6

Methyl ester of (RS,SR)-2-benzazolyl-2-(6-nitro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid and (4-nitro-phenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(6-nitro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as light yellow solid, mass spectrum: 460 (MNH4+).

Example 7

Methyl ester of (RS,SR)-2-benzazolyl-2-(6-cyano-2,3,4,9-tetrahydro - 1H-carbazole-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid and (4-C is anafanil)hydrazine hydrochloride receive the methyl ester of (RS,SR)-2-benzazolyl-2-(6-cyano-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as a pale yellow solid, mass spectrum: 423 (MN+).

Example 8

Methyl ester of (RS,SR)-2-benzazolyl-2-(2-chloro-6,7,8,9-tetrahydro-1H-pyrido[3,2-b]indol-7-yl)propionic acid

8.1

To 0.5 g (3.9 mmol) of 6-chloropyridin-3-ylamine in 6 ml of 12 M model HC1 at -20°C. add a solution of 0.36 g (5.2 mmol, 1.3 EQ.) sodium nitrite dissolved in 2 ml of N2O. the Reaction mixture is stirred for 15 minutes and then add 4.4 g (of 19.5 mmol, 5 EQ.) the chloride dihydrate tin, dissolved in 2 ml of 12 M HCl. The reaction mixture is allowed to warm to 4°C for 4 minutes and then the white precipitate was separated by filtration, washed using Et2O, obtaining thus 0.35 g (yield 62%) (6-chloropyridin-3-yl)hydrazinecarboxamide in the form of a white solid, mass spectrum: 144 (MN+).

8.2

In a sealed tube 50 mg (0.15 mmol) of methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid in 4 ml of glacial acetic acid is treated using 27 mg (0.18 mmol, 1.2 equiv.) (6-chloropyridin-3-yl)hydrazinecarboxamide, then stirred at 115°C for 3 hours. Add an aqueous solution of NaHCO3to achieve pH 7, after which the resulting mixture was extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of heptane/EtOAc to 1:1 ratio with subsequent p is erased with Et 2O obtain 52 mg (yield 76%) of methyl ester of (RS,SR)-2-benzazolyl-2-(2-chloro-6,7,8,9-tetrahydro-1H-pyrido[3,2-b]indol-7-yl)propionic acid as a white solid, mass spectrum: 433 (MN+).

Example 9

Methyl ester of (RS,SR)-2-benzazolyl-2-(2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid and phenylhydrazine receive the methyl ester of (RS,SR-2-benzazolyl-2-(2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as light yellow solid, mass spectrum: 398 (MN+).

Example 10

Methyl ester of (RS,SR)-2-benzazolyl-2-(b-methanesulfonyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid and (4-methanesulfonyl)hydrazine-hydrochloride receive the methyl ester of (RS,SR)-2-benzazolyl-2-(6-methanesulfonyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as light yellow solid, mass spectrum: 476 (MN+).

Example 11

Methyl ester of (RS,SR)-2-benzazolyl-2-(8-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

In the accordance with the methodology which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid and (2-forfinal)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(8-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as light yellow solid, mass spectrum: 416 (MN+).

Example 12

Methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid

12.1

To mix a solution of 10 g (to 0.032 mol) of methyl ether benzazolyl-(3-oxocyclohexyl)acetic acid in 110 ml of DMF at 0°C is added 1.42 g (0.035 mol, 1.1 EQ.) NaH (60%). The reaction mixture is stirred at this temperature for one hour and then add 15,71 g (0,048 mol, 1.5 EQ.) N-forbindelseshastighed. After 2 hours at room temperature the reaction mixture was poured into water and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. Two of the resulting diastereoisomer shared by column chromatography on silica gel using a mixture of heptane/EtOAc to 2:1 ratio, while receiving a 3.06 g (yield 27%) of methyl ester of (RS,SR)benzosulfimide-(3-oxocyclohexyl)acetic acid as a white solid, mass spectrum: 329 (MN+) and 3.2 g (yield 28%) of methyl ester of (RR,SS)- benzo is sulfonato-(3-oxocyclohexyl)acetic acid as a white solid, mass spectrum: 329 (MN+).

12.2

To 1.70 g (5.2 mmol) of methyl ester of (RS,SR)benzosulfimide-(3-oxocyclohexyl)acetic acid in glacial acetic acid (20 ml)of 1.05 g (5,72 mmol, 1.1 EQ.) add (4-chlorophenyl)hydrazinehydrate and then the reaction mixture was stirred at 40°C during the night. Add an aqueous solution of NaHCO3to achieve pH 7, after which the resulting mixture was extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of heptane/EtOAc 2:1, followed by rubbing with Et3O obtain 1.56 g (yield 70%) of methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid in the form of a white solid, mass spectrum: 436 (MN+).

Enantiomers share preparative chiral GHUR. Column: hiralal HELL (chiralpak AD), solvent: 20%isopropanol/heptane

Example 13

Methyl ester of (RS,SR)benzosulfimide-(6-methyl-2,3,4,9-tetrahydro - 1H-carbazole-2-yl)acetic acid

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)benzosulfimide-(3-oxocyclohexyl)acetic acid and (4-were)hydrazinecarboxamide receive the methyl ester of (RS,SR)benzosulfimide-(6-methyl-2,3,4,9-is etrahydro-1H-carbazole-2-yl)acetic acid as a pale yellow solid, mass spectrum: 416 (MN+).

Example 14

Methyl ester of (RS,SR)benzazolyl-(6-cyano-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)benzosulfimide-(3-oxocyclohexyl)acetic acid and (4-cyanophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)benzazolyl-(6-cyano-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid as a pale yellow solid, mass spectrum: 427 (MN+).

Example 15

Methyl ester of (RS,SR)benzazolyl-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)benzosulfimide-(3-oxocyclohexyl)acetic acid and (4-bromophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)benzazolyl-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid in the form of a white solid, mass spectrum: 480; 482 (MN+).

Example 16

Methyl ester of (RS,SR)benzazolyl-(2-chloro-6,7,8,9-tetrahydro-1H-pyrido[3,2-b]indol-7-yl)forexpros acid

In accordance with the methodology, which is similar to the technique of example 8.2, methyl ester (RS,SR)benzosulfimide-(3-oxocyclohexyl)acetic acid and (6-chloropyridin-3-yl)hidras the n-hydrochloride (example 8.1) to obtain methyl ester of (RS,SR)benzazolyl-(2-chloro-6,7,8,9-tetrahydro-1H-pyrido[3,2-b]indol-7-yl)forexpros acid in the form of a white solid, mass spectrum: 437 (MN+).

Examples 17-18

Methyl ester of (RS,SR)benzazolyl-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid and

methyl ester of (RS,SR)benzazolyl-(6-bromo-5-fluoro-2,3,4,9-tetrahydro - 1H-carbazole-2-yl)forexpros acid

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)benzosulfimide-(3-oxocyclohexyl)acetic acid and (4-bromo-3-forfinal)hydrazine-hydrochloride receive the methyl ester of (RS,SR)benzazolyl-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid in the form of a white solid, mass spectrum: 515; 517 (MNH4+); (example 17) and methyl ester of (RS,SR)benzazolyl-(6-bromo-5-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid in the form of a white solid, mass spectrum: 515;

517 (MNH4+); (example 18). These two regioisomer get in the ratio of 1:1, and divide column chromatography on silica gel using a mixture of heptane/EtOAc to 2:1 ratio.

Example 19

Methyl ester of (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol-2-yl)propionic acid

19.1

To a stirred solution of 1.26 g (5.9 mmol) were-sulfonylamino in 20 ml of Meon at 0°C and 0.22 ml (1,17 mmol, 0.2 EQ.) add a solution of sodium methoxide (5.4 M in the Meon). Che is ez 15 minutes type of 0.53 g (6.5 mmol, 1.1 EQ.) cyclopent-2-Aenon. The reaction mixture is allowed to warm to room temperature for 4 hours, diluted with saturated aqueous NH4Cl and then extracted using EtOAc. The combined organic phases are dried over Na2SO4filter and parivuoteessa column chromatography on silica gel using a mixture of heptane/EtOAc to 1:1 ratio gain of 1.34 g (yield 77%) of methyl ester benzazolyl-(3-oxocyclopent)acetic acid in the form of a racemic mixture of diastereomers, a colorless oily substance mass spectrum: 297 (MN+).

19.2

To a stirred solution of 2.4 g (8.1 mmol) of methyl ether benzazolyl-(3-oxocyclopent)acetic acid in 15 ml of DMF at 0°C. add 389 mg (8.9 mmol, 1.1 EQ.) NaH (60%). The reaction mixture is stirred at this temperature for one hour and then add 1,72 g (12.1 mmol, 1.5 EQ.) under the conditions. After 2 hours at room temperature the reaction mixture was poured into water and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. Two of the resulting diastereoisomer shared by column chromatography on silica gel using a mixture of heptane/EtOAc (2:1 ratio to 2:1), receive 0,78 g (yield 31%) of methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclopent)propionic acid is a white solid substance, mass spectrum: 311 (MN+and of 0.53 g (yield 21%) of methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclopent)-propionic acid as a white solid, mass spectrum: 311 (MN+).

19.3

To 100 mg (0.32 mmol) of methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclopent)propionic acid in glacial acetic acid (3 ml), 63 mg (0.35 mmol, 1.1 EQ.) add (4-chlorophenyl)hydrazinehydrate and then the reaction mixture is heated at 70°C for approximately 5 hours. Until then, until the reaction is complete, the progress of the reaction is controlled according to GHWR and TLC. Add an aqueous solution of NaHCO3to achieve pH 7 and then the resulting mixture was extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of heptane/EtOAc to 1:1 ratio, followed by rubbing with Et2O receive 45 mg (yield 34%) of methyl ester of (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid as light yellow solid, mass spectrum: 418 (MN+).

Example 20

Methyl ester of (RS,SR)-2-benzazolyl-2-(7-bromo-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)-benzazolyl-2-(3-oxocyclopent)propionic acid and (4-bromophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(7-bromo-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid as light yellow solid, mass spectrum: 461; 463 (MN+).

Example 21

Methyl ester of (RS,SR)-2-benzazolyl-2-(7-cyano-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclopent)propionic acid and (4-cyanophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(7-cyano-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid as light brown solid, mass spectrum: 409 (MN+).

Example 22

Methyl ester of (RS,SR)-2-benzazolyl-2-(7-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclopent)propionic acid and (4-were)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(7-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid as a white solid, mass spectrum: 398 (MN+).

Example 23

Methyl ester of (RS,SR)benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid

23.1

To a stirred solution of 1.34 g (4.5 mmol) of methyl ether benzazolyl-(3-oxocyclopent)acetic acid in 15 ml of the MOF at 0°C add 199 mg (5.0 mmol, 1.1 EQ.) NaH (60%). The reaction mixture is stirred at this temperature for one hour and then added 2.14 g (of 6.75 mmol, 1.5 EQ.) N-forbindelseshastighed. After 2 hours at room temperature the reaction mixture was poured into water and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. Two of the resulting diastereoisomer shared by column chromatography on silica gel using a mixture of heptane/EtOAc (in a ratio of from 2:1 to 2:1), while receiving 0.40 g (yield 28%) of methyl ester of (RS,SR)benzosulfimide-(3-oxocyclopent)acetic acid as a white solid, mass spectrum: 332 (MNH4+) and 0.52 g (yield 37%) of methyl ester of (RR,SS)- benzosulfimide-(3-oxocyclopent)acetic acid as a white solid, mass spectrum: 332 (MNH4+).

23.2

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)benzosulfimide-(3-oxocyclopent)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid in the form of a white solid, mass spectrum: 439 (MNH4+).

Example 24

Methyl ester of (RS,SR)benzazolyl-(7-bromo-1,2,3,4-tetrahydrocyclopent[b] Indo is-2-yl)forexpros acid

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)benzosulfimide-(3-oxocyclopent)acetic acid and (4-bromophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)benzazolyl-(7-bromo-1,2,3,4-tetrahydrocyclopent-[b]indol-2-yl)forexpros acid in the form of a white solid, mass spectrum: 466; 468 (MN+).

Example 25

Methyl ester of (RS,SR)benzazolyl-(5-chloro-1,2,3,8-tetrahydro-4,8-disallowment[a]inden-2-yl)forexpros acid

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)benzosulfimide-(3-oxocyclopent)acetic acid and (6-chloropyridin-3-yl)hydrazine-hydrochloride receive the methyl ester of (RS,SR)benzazolyl-(5-chloro-1,2,3,8-tetrahydro-4,8-disallowment[a]inden-2-yl)forexpros acid in the form of a white solid, mass spectrum: 423 (MN+).

Examples 26-27

Methyl ester of (RS,SR)benzazolyl-(7-bromo-6-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid and methyl ester of (RS,SR)benzazolyl-(7-bromo-8-fluoro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)forexpros acid

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)benzosulfimide-(3-oxocyclopent)acetic acid and (4-bromo-3-f is arvanil)hydrazine-hydrochloride receive the methyl ester of (RS,SR)benzazolyl-(7-bromo-6-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid as a pale brown solid, mass spectrum: 484; 486 (MN+); (example 26) and methyl ester of (RS,SR)benzazolyl-(7-bromo-8-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid as a pale brown solid, mass spectrum: 484; 486 (MN+); (example 27). These two regioisomer get in the ratio of 1:1, and then divide column chromatography on silica gel using a mixture of heptane/EtOAc to 2:1 ratio.

Example 28

Methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(naphthalene-1-sulfonyl)propionic acid

28.1

To a stirred suspension of 3.1 g (0.019 mol) of naphthalene-1-thiol and 2.94 g (0,021 mol, 1.1 EQ.) To2CO3in 100 ml of propan-2-it, cooled at 0°C, add one dose of 3.15 g (0,029 mol, 1.5 EQ.) methyl ester Chloroacetic acid. The ice bath is removed, the reaction mixture was additionally stirred for 4 hours. The reaction mixture is filtered, the solvent evaporated and the resulting residue is transferred into a 100 ml Meon. Added 14.3 g (0,023 mol, 1.2 EQ.) oxone (peroxymonosulfate potassium), after which the reaction mixture is stirred over night at room temperature. Salt is filtered off, the solvent evaporated and the resulting residue is purified column chromatography on silica gel using a mixture of heptane/EtOAc (in a ratio of from 4:1 to 1:2), while receiving 2,78 g (yield 55%) IU the silt ether (naphthalene-1-sulfonyl)acetic acid as a pale yellow oily substance, mass spectrum: 265 (MN+).

28.2

To a stirred solution of 2.75 g (0,010 mol) methyl ether (naphthalene-1-sulfonyl)acetic acid in 100 ml Meon at room temperature add to 0.19 ml (to 0.011 mol, 1.1 EQ.) solution of sodium methoxide (5.4 M in the Meon). After 15 minutes add 1.1 g (to 0.011 mol, 1.1 EQ.) 2-cyclohexen-1-it. The reaction mixture was stirred at room temperature for 3 hours and then an additional 4 hours at 60°C, dilute aqueous solution of NH4Cl and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of heptane/EtOAc (in a ratio of from 4:1 to 1:2) to obtain 1.78 g (yield 48%) of methyl ester (naphthalene-1-sulfonyl)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light orange oily substance mass spectrum: 361 (MN+).

28.3

In accordance with the methodology, which is similar to the technique of example 3.1: 1,74 g (4.8 mmol) of methyl ether (naphthalene-1-sulfonyl)-(3-oxocyclohexyl)acetic acid are dissolved in 10 ml of DMF at 0°C. Add 232 mg (5.3 mmol, 1.1 EQ.) NaH (60%) and then the reaction mixture is stirred for 30 minutes before addition of 1.03 g (7.2 mmol, 1.5 EQ.) under the conditions. The reaction mixture was stirred overnight, poured into water and extra is irout, using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. Two of the resulting diastereoisomer shared by column chromatography on silica gel using a mixture of AcOEt/heptane 2:1, gain of 0.30 g (yield 17%) of methyl ester of (RS,SR)-2-(naphthalene-1-sulfonyl)-2-(3-oxocyclohexyl)-propionic acid as a white foam substance. Mass spectrum: 375 (MN+) and 0.42 g (yield 23%) of methyl ester of (RS,SR)-2-(naphthalene-1-sulfonyl)-2-(3-oxocyclohexyl)propionic acid as a white solid, mass spectrum: 375 (MN+).

28.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(naphthalene-1-sulfonyl)-2-(3-oxocyclohexyl)propionic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(naphthalene-1-sulfonyl)propionic acid as a brown solid, mass spectrum: 483 (MH+).

Example 29

Methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(naphthalene-2-sulfonyl)propionic acid

29.1

In accordance with the methodology, which is similar to the technique of example 28.1, naphthalene-2-thiol and methyl ester Chloroacetic acid get methyl ether (naphthalene-2-sulfonyl)acetic acid as white solid prophetic is STV, mass spectrum: 265 (MN+).

29.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (naphthalene-2-sulfonyl)acetic acid and cyclohexen-1-she gets methyl ether (naphthalene-2-sulfonyl)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light orange oily substance mass spectrum: 361 (MN+).

29.3

In accordance with the methodology, which is similar to the technique of example 28.3, methyl ester (naphthalene-2-sulfonyl)-(3-oxocyclohexyl)acetic acid and under the conditions get of the methyl ester of (RS,SR)-2-(naphthalene-2-sulfonyl)-2-(3-oxocyclohexyl)propionic acid as a white solid, mass spectrum: 375 (MN+).

29.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(naphthalene-2-sulfonyl)-2-(3-oxocyclohexyl)propionic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(naphthalene-2-sulfonyl)propionic acid as light yellow solid, mass spectrum: 483 (MN+).

Example 30

Methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(3,4-dichlorobenzenesulfonyl)propionic acid

30.1

In accordance with the methodology, which is similar to the method you is filling up example 28.1, from 3,4-dichlorobenzoyl and methyl ester Chloroacetic acid get methyl ether (3,4-dichlorobenzenesulfonyl)acetic acid as a white solid, mass spectrum: 284 (MN+).

30.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (3,4-dichlorobenzenesulfonyl)acetic acid and cyclohexen-1-she gets methyl ether (3,4-dichloro-benzazolyl)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light yellow solid, mass spectrum: 380 (MN+).

30.3

In accordance with the methodology, which is similar to the technique of example 28.3, methyl ester (3,4-dichlorobenzenesulfonyl)-(3-oxocyclohexyl)acetic acid and under the conditions get of the methyl ester of (RS,SR)-2-(3,4-dichlorobenzenesulfonyl)-2-(3-oxocyclohexyl)propionic acid as a white solid, mass spectrum: 394 (MN+).

30.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(3,4-dichlorobenzenesulfonyl)-2-(3-oxocyclohexyl)propionic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(3,4-dichlorobenzenesulfonyl)propionic acid as light brown solid, mass spectrum: 501 (MN+).

Example 31

Methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(toluene-3-sulfonyl)propionic acid

31.1

In accordance with the methodology, which is similar to the technique of example 28.1, methyl ester 3-methylbenzoyl and Chloroacetic acid get methyl ether (toluene-3-sulfonyl)acetic acid as colorless oily substance, mass spectrum: 229 (MN+).

31.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (toluene-3-sulfonyl)acetic acid and cyclohexen-1-she gets methyl ether (3-oxocyclohexyl)-(toluene-3-sulfonyl)acetic acid in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 325 (MN+).

31.3

In accordance with the methodology, which is similar to the technique of example 28.3, methyl ester (3-oxocyclohexyl)-(toluene-3-sulfonyl)acetic acid and under the conditions get of the methyl ester of (RS,SR)-2-(3-oxocyclohexyl)-(toluene-3-sulfonyl)propionic acid as a white solid, mass spectrum: 339 (MN+).

31.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(3-oxocyclohexyl)-(toluene-3-sulfonyl)propionic acid and (4-chlorophenyl)hydrazinecarboxamide methyl get the ether (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(toluene-3-sulfonyl)propionic acid as light brown solid, mass spectrum: 446 (MN+).

Example 32

Methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(3-methoxybenzenesulfonyl)propionic acid

32.1

In accordance with the methodology, which is similar to the technique of example 28.1, 3 methoxybenzoyl and methyl ester Chloroacetic acid get methyl ether (3-methoxybenzenesulfonyl)acetic acid as a pale brown oily substance, mass spectrum: 245 (MN+).

32.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (3-methoxybenzenesulfonyl)acetic acid and cyclohexen-1-she gets methyl ether (3-methoxybenzo-sulfonyl)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light orange oily substance mass spectrum: 341 (MN+).

32.3

In accordance with the methodology, which is similar to the technique of example 28.3, methyl ester (3-methoxybenzenesulfonyl)-(3-oxocyclohexyl)acetic acid and under the conditions get of the methyl ester of (RS,SR)-2-(3-methoxybenzenesulfonyl)-2-(3-oxocyclohexyl)propionic acid as colorless oily substance, the mass spectrum; 355 (MN+)).

32.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(3-methoxybenzo sulfonyl)-2-(3-oxocyclohexyl)propionic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(3-methoxybenzenesulfonyl)propionic acid as light brown solid, mass spectrum: 462 (MN+).

Example 33

Methyl ester of (RS,SR)-2-(2-chlorobenzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro - 177-carbazole-2-yl)propionic acid

33.1

In accordance with the methodology, which is similar to the technique of example 28.1, 2-chlorbenzoyl and methyl ester bromoxynil acid get methyl ether (2-chlorobenzenesulfonyl)acetic acid as a white solid, mass spectrum: 249 (MN+).

33.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (2-chlorobenzenesulfonyl)acetic acid and cyclohexen-1-she gets methyl ether (2-chlorobenzenesulfonyl)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, a colorless oily substance mass spectrum: 345 (MN+).

33.3

In accordance with the methodology, which is similar to the technique of example 28.3, methyl ester (2-chlorobenzenesulfonyl)-(3-oxocyclohexyl)acetic acid and under the conditions get of the methyl ester of (RS,SR)-2-(2-chlorobenzenesulfonyl)-2-(3-oxocyclohexyl)propionic acid as white crystals, mass spectrum: 359 (MN+).

33.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(2-chlorobenzenesulfonyl)-2-(3-oxocyclohexyl)propionic acid is you (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(2-chlorobenzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as light brown solid, mass spectrum: 467 (MN+).

Example 34

Methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(2-methoxybenzenesulfonyl)propionic acid

34.1

In accordance with the methodology, which is similar to the technique of example 28.1, 2-methoxybenzoyl and methyl ester Chloroacetic acid get methyl ether (2-methoxybenzenesulfonyl)acetic acid as white crystals, mass spectrum: 245 (MN+).

34.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (2-methoxybenzenesulfonyl)acetic acid and cyclohexen-1-she gets methyl ether (2-methoxy-benzazolyl)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 341 (MN+).

34.3

In accordance with the methodology, which is similar to the technique of example 28.3, methyl ester (2-methoxybenzenesulfonyl)-(3-oxocyclohexyl)acetic acid and under the conditions get of the methyl ester of (RS,SR)-2-(2-methoxybenzenesulfonyl)-2-(3-Exotica-hexyl)propionic acid as light yellow solid, mass spectrum: 355 (MN+).

34.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(2-methoxybenzenesulfonyl)-2-(3-oxacyclopropane acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(2-methoxybenzenesulfonyl)propionic acid as light brown solid, mass spectrum: 462 (MN+).

Example 35

Methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(4-permentantly)propionic acid

35.1

In accordance with the methodology, which is similar to the technique of example 28.1, methyl ester 4-fermentative and bromoxynil acid get methyl ester (4-permentantly)acetic acid as colorless oily substance, mass spectrum: 233 (MN+).

35.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (4-permentantly)acetic acid and cyclohexen-1-she gets methyl ester (4-permentantly)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, white crystals, mass spectrum: 329 (MN+).

35.3

In accordance with the methodology, which is similar to the technique of example 28.3, methyl ester (4-permentantly)-(3-oxocyclohexyl)acetic acid and under the conditions get of the methyl ester of (RS,SR)-2-(4-permentantly)-2-(3-oxocyclohexyl)propionic acid as light yellow solid, mass spectrum: 343 (MN+).

35.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(4-permentantly)-2-(3-oxocyclohexyl)propionic acid and (4-chloro who enyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(4-permentantly)propionic acid as a white solid, mass spectrum: 450 (MN+).

Example 36

Methyl ester of (RS,SR)-2-(3-chlorobenzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

36.1

In accordance with the methodology, which is similar to the technique of example 28.1, 3 chlorbenzoyl and methyl ester bromoxynil acid get methyl ether (3-chlorobenzenesulfonyl)acetic acid as colorless oily substance, mass spectrum: 249 (MN+).

36.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (3-chlorobenzenesulfonyl)acetic acid and cyclohexen-1-she gets methyl ether (3-chlorobenzenesulfonyl)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 345 (MN+).

36.3

In accordance with the methodology, which is similar to the technique of example 28.3, methyl ester (3-chlorobenzenesulfonyl)-(3-oxocyclohexyl)acetic acid and under the conditions get of the methyl ester of (RS,SR)-2-(3-chlorobenzenesulfonyl)-2-(3-oxocyclohexyl)propionic acid as a white solid, mass spectrum: 359 (MN+).

36.4

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-(3-chlorobenzenesulfonyl)-2-(3-oxocyclohexyl)propionic acid is you (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(3-chlorobenzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as a white solid, mass spectrum: 467 (MN+).

Example 37

Methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(4-permentantly)acetic acid

37.1

In accordance with the methodology, which is similar to the technique of example 12.1, methyl ester (4-permentantly)-(3-oxocyclohexyl)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)fluoro-(4-permentantly)-(3-oxocyclohexyl)acetic acid as colorless oily substance, mass spectrum: 347 (MN+).

37.2

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)fluoro-(4-permentantly)-(3-oxocyclohexyl)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(4-permentantly)acetic acid as a white solid, mass spectrum: 454 (MN+).

Example 38

Methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid

38.1

In accordance with the methodology, which is similar to the technique of example 12.1, methyl ester (3-chlorobenzenesulfonyl)-(3-oxocyclohexyl)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)- fluoro-(3-oxocyclohexyl)acetic acid in view of the white solids, mass spectrum: 363 (MN+).

38.2

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)-(3-chlorobenzenesulfonyl)- fluoro-(3-oxocyclohexyl)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid in the form of a white solid, mass spectrum: 471 (MN+).

Example 39

Methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(3-permentantly)acetic acid 39.1

In accordance with the methodology, which is similar to the technique of example 28.1, 3 fermentation and methyl ester Chloroacetic acid get methyl ether (3-permentantly)acetic acid as colorless oily substance, mass spectrum: 233 (MN+).

39.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (3-permentantly)acetic acid and cyclohexen-1-she gets methyl ether (3-permentantly)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 329 (MN+).

39.3

In accordance with the methodology, which is similar to the technique of example 12.1, methyl ester (3-forbindelserne the)-(3-oxocyclohexyl)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)fluoro-(3-permentantly)- (3-oxocyclohexyl)acetic acid as a white solid, mass spectrum: 347 (MN+).

39.4

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)fluoro-(3-permentantly)-(3-oxocyclohexyl)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(3-permentantly)acetic acid as a white solid, mass spectrum: 454 (MN+).

Example 40

Methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-(3,4-differentiality)forexpros acid

40.1

In accordance with the methodology, which is similar to the technique of example 28.1, from 3,4-diferential and methyl ester Chloroacetic acid get methyl ether (3,4-differentiality)acetic acid as colorless oily substance, mass spectrum: 251 (MN+).

40.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (3,4-differentiality)acetic acid and cyclohexen-1-she gets methyl ether (3,4-differenza-sulfonyl)-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 347 (MN+)).

40.3

In accordance with the methodology, which is similar to the technique of example 12.1, methyl ether,4-differentiality)-(3-oxocyclohexyl)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)-(3,4-differentiality)fluoro-(3-oxocyclohexyl)acetic acid as a white solid, mass spectrum: 365 (MN+).

40.4

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)-(3,4-differentiality)fluoro-(3-oxocyclohexyl)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-(3,4-differentiality)forexpros acid in the form of a white solid, mass spectrum: 472 (MN+).

Example 41

Methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(pyridine-3-sulfonyl)acetic acid

41.1

In accordance with the methodology, which is similar to the technique of example 28.1, from pyridine-3-thiol and methyl ester Chloroacetic acid get methyl ether (pyridine-3-sulfonyl)acetic acid as a yellow oily substance, mass spectrum: 216 (MN+).

41.2

In accordance with the methodology, which is similar to the technique of example 28.2, methyl ester (pyridine-3-sulfonyl)acetic acid and cyclohexen-1-she gets methyl ether (3-oxocyclohexyl)-(pyridine-3-sulfonyl)acetic acid in the form of a racemic mixture of diastereomers, yellow oily substance mass spectrum: 312 (MN+).

41.3

In accordance with the methodology, which is similar to the technique of example 12.1, methyl ester (3-oxocyclohexyl)-(pyridine-3-sulfon the l)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)fluoro-(3-oxocyclohexyl)-(pyridine-3-sulfonyl)acetic acid as white crystals, mass spectrum: 330 (MN+).

41.4

In accordance with the methodology, which is similar to the technique of example 12.2, methyl ester (RS,SR)fluoro-(3-oxocyclohexyl)-(pyridine-3-sulfonyl)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(pyridine-3-sulfonyl)acetic acid as a pale yellow solid, mass spectrum: 437 (MN+).

Example 42

Methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-methoxybenzenesulfonyl)acetic acid

42.1

In accordance with the methodology, which is similar to the technique of example 19.1, methyl ester (3-methoxybenzenesulfonyl)acetic acid and cyclopent-2-Aenon get methyl ether (3-methoxybenzo-sulfonyl)-(3-oxocyclopent)acetic acid in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 327 (MN+).

42.2

In accordance with the methodology, which is similar to the technique of example 23.1, methyl ester (3-methoxybenzenesulfonyl)-(3-oxocyclopent)acetic acid and N-torbenson-sulfonamide receive the methyl ester of (RS,SR)fluoro-(3-methoxy-benzazolyl)-(3-oxocyclopent)acetic acid as a white solid, mass spectrum: 345 (MN+).

42.3

In accordance with the methodology, which Ana is ogica the technique of example 23.2, of the methyl ester of (RS,SR)fluoro-(3-methoxybenzenesulfonyl)-(3-oxocyclopent)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)fluoro-(3-methoxybenzenesulfonyl)acetic acid as a white solid, mass spectrum: 452 (MH+).

Example 43

Methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid

43.1

In accordance with the methodology, which is similar to the technique of example 19.1, methyl ester (3-chlorobenzenesulfonyl)acetic acid and cyclopent-2-Aenon get methyl ether (3-chlorobenzenesulfonyl)-(3-oxocyclopent)acetic acid in the form of a racemic mixture of diastereomers, a colorless oily substance mass spectrum: 348 (MNH4+).

43.2

In accordance with the methodology, which is similar to the technique of example 23.1, methyl ester (3-chlorobenzenesulfonyl)-(3-oxocyclopent)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)fluoro-(3-oxocyclopent)acetic acid as a white solid, mass spectrum: 366 (MNH4+).

43.3

In accordance with the methodology, which is similar to the technique of example 23.2, methyl ester (RS,SR)-(3-chlorobenzenesulfonyl)fluoro-(3-OK is cyclopentyl)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid as a light brown solid substance mass spectrum: 457 (MN+).

Example 44

Methyl ester of (RS,SR)-7(-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(pyridine-2-sulfonyl)acetic acid

44.1

In accordance with the methodology, which is similar to the technique of example 28.1, from pyridine-2-thiol and methyl ester Chloroacetic acid get methyl ether (pyridine-2-sulfonyl)acetic acid as colorless oily substance, mass spectrum: 216 (MN+).

44.2

In accordance with the methodology, which is similar to the technique of example 19.1, methyl ester (pyridine-2-sulfonyl)acetic acid and cyclopent-2-Aenon get methyl ether (3-oxocyclopent)-(pyridine-2-sulfonyl)acetic acid in the form of a racemic mixture of diastereomers, a colorless oily substance mass spectrum: 298 (MN+).

44.3

In accordance with the methodology, which is similar to the technique of example 23.1, methyl ester (3-oxocyclopent)-(pyridine-2-sulfonyl)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)fluoro-(3-oxocyclopent)-(pyridine-2-sulfonyl)-acetic acid as a white solid, mass spectrum: 316 (MN+).

44.4

In accordance with the methodology, which is similar to the technique of example 23.2, methyl ester (RS,SR)fluoro-(3-oxocyclopent)-(pyridine-2-sulfonyl)acetic to the slots and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(pyridine-2-sulfonyl)acetic acid as a white solid, mass spectrum: 423 (MN+).

Example 45

Methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-permentantly)acetic acid

45.1

In accordance with the methodology, which is similar to the technique of example 19.1, methyl ester (3-permentantly)acetic acid and cyclopent-2-northward get methyl ether (3-permentantly)-(3-oxocyclopent)acetic acid in the form of a racemic mixture of diastereomers, a colorless oily substance mass spectrum: 315 (MN+).

45.2

In accordance with the methodology, which is similar to the technique of example 23.1, methyl ester (3-permentantly)-(3-oxocyclopent)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)fluoro-(3-permentantly)-(3-oxocyclopent)acetic acid as a white solid, mass spectrum: 333 (MN+).

45.3

In accordance with the methodology, which is similar to the technique of example 23.2, methyl ester (RS,SR)fluoro-(3-permentantly)-(3-oxocyclopent)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(7-chloro-l, 2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-permentantly)acetic acid as a pale brown solid, mass spectrum: 440 (MN+).

Example 46

Methyl ester of (RS,SR)-(7-chlorine is -1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-(3,4-differentiality)forexpros acid

46.1

In accordance with the methodology, which is similar to the technique of example 19.1, methyl ester (3,4-differentiality)acetic acid and cyclopent-2-Aenon get methyl ether (3,4-debtor-endolsulfan)-(3-oxocyclopent)acetic acid in the form of a racemic mixture of diastereomers, a colorless oily substance mass spectrum: 333 (MN+).

46.2

In accordance with the methodology, which is similar to the technique of example 23.1, methyl ester (3,4-differentiality)-(3-oxocyclopent)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)-(3,4-differentiality)fluoro-(3-oxocyclopent)acetic acid as a white solid, mass spectrum: 351 (MN+).

46.3

In accordance with the methodology, which is similar to the technique of example 23.2, methyl ester (RS,SR)-(3,4-differentiality)fluoro-(3-oxocyclopent)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)-(3,4-differentiality)forexpros acid as a pale brown solid, mass spectrum: 458 (MN+).

Example 47

Methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(pyridine-3-sulfonyl)acetic acid

47.1

In accordance with the methodology, which analogues which on the technique to example 19.1, from methyl ester (pyridine-3-sulfonyl)acetic acid and cyclopent-2-Aenon get methyl ether (pyridine-3-sulfonyl)-(3-oxocyclopent)acetic acid in the form of a racemic mixture of diastereomers, yellow oily substance mass spectrum: 298 (MN+).

47.2

In accordance with the methodology, which is similar to the technique of example 23.1, methyl ester (pyridine-3-sulfonyl)-(3-oxocyclopent)acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR)fluoro-(3-oxocyclopent)-(pyridine-3-sulfonyl)acetic acid as white crystals, mass spectrum: 333 (MNH4+).

47.3

In accordance with the methodology, which is similar to the technique of example 23.2, methyl ester (RS,SR)fluoro-(3-oxocyclopent)-(pyridine-3-sulfonyl)acetic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(pyridine-3-sulfonyl)acetic acid as a pale brown solid, mass spectrum: 423 (MN+).

Example 48

Methyl ester of (RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-(pyridine-2-sulfonyl)propionic acid

48.1

In accordance with the methodology, which is similar to the technique of example 19.2, methyl ester (3-oxocyclopent)-(pyridine-2-sulfonyl)acetic acid (example 44.2) and m is triodide receive the methyl ester of (RS,SR)-2-(3-oxocyclopent)-2-(pyridine-2-sulfonyl)propionic acid as a white solid, mass spectrum: 312 (MN+).

48.2

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)-2-(3-oxocyclopent)-2-(pyridine-2-sulfonyl)propionic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-(7-chloro-l,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-(pyridine-2-sulfonyl)propionic acid as a white solid, mass spectrum: 419 (MN+).

Example 49

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

To 50 mg (0,115 mmol) of methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid (example 3) in 4 ml of a mixture of THF/Meon in the ratio of 1:1 add to 0.29 ml of 2 M NaOH solution (of 0.58 mmol, 5 EQ.). The reaction mixture was stirred at 60°C for 3 hours, acidified to pH 6 aqueous solution of NH4Cl and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using CH2Cl2/Meon in the ratio 3:1, obtain 40 mg (yield 82%) of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as a white solid, mass spectrum: 435 (MNH4+).

Example 50

(RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)ftorotana to the slot

In accordance with the methodology, which is similar to the technique of example 49, of the methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid get (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)florexpo acid as a white solid, mass spectrum: 420 (M-N)-.

Example 51

(RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole

51.1

Treated with 350 mg (0.81 mmol) of methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid (obtained according to example 3) in 10 ml THF at 0°C, using 39 mg (0.89 mmol, 1.1 EQ.) NaH (55% in mineral oil) and adding portions over 30 minutes. Add 0.10 ml (1,22 mmol, 1.5 EQ.) 1-chloro-2-methoxy-ethane and take a bath with ice. After 2 hours the reaction is stopped by adding to the reaction mixture of a saturated aqueous solution of NH4Cl, then extracted using EtOAc, and the organic phase is dried over Na2SO4. After evaporation of the solvent to obtain methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as a yellow solid, mass spectrum: 493 (MNH4+). Untreated substance use in the next stage without additional purification.

51.2

To 402 mg (0.84 mmol methyl ester (RS,SR)-2-benzazolyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid in 6 ml of THF added 1.0 ml (1.0 mmol, 1.2 EQ.) LiAlH4in THF at room temperature. After 30 minutes the reaction mixture was poured into water and extracted using EtOAc, dried over Na2SO4and after evaporation of the solvent receive (RS,SR)-2-benzazolyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propan-1-ol as a colorless oily substance, mass spectrum: 465 (MNH4+). Untreated substance use in the next stage without additional purification.

51.3

Handle 130 mg (0.29 mmol) of (RS,SR)-2-benzazolyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propan-1-ol in 5 ml of THF at 0°C, using 14 mg (0.32 mmol, 1.1 EQ.) NaH (55% in mineral oil)is added in portions during 30 minutes. Then add 30 μl (0.43 mmol, 1.5 EQ.) Me, after which the reaction mixture is stirred additionally for 2 hours, split between EtOAc and saturated aqueous NH4Cl. The organic phase is washed with saturated salt solution, dried over Na2SO4and evaporated. After column chromatography using a mixture of heptane/EtOAc in a ratio of 1:2 to obtain 96 mg (yield 72%) of (RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole in the form of a white solid, mass spectrum: 479 (MNH4+).

51.4

95 mg (0.20 mmol) of (RS,SR)-2-(1-benzazolyl-2-methoxy-1-mutilate is)-6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole dissolved in 8 ml of a mixture of Meon/THF in a ratio of 1:1 and add 5 drops of HCl (12 M). The temperature was raised to 55°C. and the resulting solution was stirred for 6 hours. By adding a 2 M solution of NaHCO3the solution is neutralized to pH 7 and then the resulting mixture was extracted using EtOAc. After column chromatography on silica gel using a mixture of heptane/EtOAc 2:1 get 11 mg (yield 13%) of (RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole in the form of a white solid, mass spectrum: 418 (MN+).

Example 52

(RS,SR)-2-benzazolyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile

52.1

To 9.4 g (0,052 mol) of benzosulfonazole in 200 ml DME at -50°C type of 7.8 ml (0,052 mol, 1 EQ.) TMEDA and 32.4 ml (0,052 ml, 1 EQ.) nBuLi (1.6 M in hexane) and continue stirring for 45 minutes. To the resulting white suspension add to 4.98 g (0,052 mol, 1 EQ.) cyclohex-2-Aenon and the temperature was raised to -10°C for 4 hours. The reaction mixture was poured into 180 ml of 1 M solution of model HC1, extracted using EtOAc and then the combined organic phases are dried over Na2SO4. After evaporation of the solvent and recrystallization from a mixture of AcOEt/Et2O get to 8.25 g (yield 57%) benzazolyl-(3-oxocyclohexyl)of acetonitrile in the form of a racemic mixture of diastereomers, white crystals, mass spectrum: 278 (MN+) (by analogy with: E.Hatzigrigoriou, L.Wartski, Synth. Comm., 1983, 14 (4), 319-25).

52.2

Treated with 4.0 g (0.014 mol) benzazolyl-(3-oxocyclohexyl)-acetonitrile in 40 ml of DMF, using 0,69 g (0,016 mol, 1.1 EQ.) NaH (55% in mineral oil) is added in portions during 30 minutes at 0°C. Then add of 3.07 g (0,022 mol, 1.5 EQ.) under the conditions, after which the bath with ice removed. After 2 hours the reaction mixture was poured into water and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of AcOEt/heptane 1; 1 get 4 g (yield 98%) 2-benzazolyl-2-(3-oxocyclohexyl)propionitrile in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 292 (MN+).

52.3

To 322 mg (1.10 mmol) of 2-benzazolyl-2-(3-oxocyclohexyl)-propionitrile in 10 ml of glacial acetic acid add 193 mg (1,21 mmol, 1.1 EQ.) (4-were)hydrazinecarboxamide and continue stirring at room temperature over night. Then add an aqueous solution of NaHCO3to achieve pH 7, after which the resulting product is extracted using EtOAc. The organic phase is dried over Na2SO4, filtered and evaporated. Two of the resulting diastereoisomer shared by column chromatography on silica gel using a mixture of AcOEt/heptane 1:4, then triturated with Et2 O. Obtain 158 mg (yield 38%) (RR,SS)-2-benzene-sulfonyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile and 123 mg (yield 29%) of (RS,SR)-2-benzazolyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile as a pale yellow solid, mass spectrum: 379 (MN+).

Example 53

(RS,SR)-2-benzazolyl-2-(6-chloro-23,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile

In accordance with the methodology, which is similar to the technique of example 53.3, 2-benzazolyl-2-(3-oxocyclohexyl)propionitrile and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile and (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile in the form of a white solid, mass spectrum: 397 (M-N)+.

Example 54

(RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forcecontrol

54.1

Process of 3.85 g (0.014 mol) benzazolyl-(3-oxocyclohexyl)-acetonitrile in 40 ml of DMF, using 0.68 g (0,016 mol, 1.1 EQ.) NaH (55% in mineral oil) adding portions over 30 minutes at 0°C. Then add to 4.81 g (0.015 mol, 1.1 EQ.) N-forbindelseshastighed and take a bath with ice. After 2 hours the reaction mixture was poured into water, extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated, while e is ω 4 g of crude oily substance, consisting of a mixture of racemic diastereomers benzosulfimide-(3-oxocyclohexyl)acetonitrile, which is used in the next stage without additional purification.

54.2

In accordance with the methodology, which is similar to the technique of example 52.3, benzosulfimide-(3-oxocyclohexyl)acetonitrile and (4-chlorophenyl)hydrazinecarboxamide receive (RR,SS)-benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forcecontrol and (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forcecontrol as a pale yellow solid, mass spectrum: 402 (M).

Example 55

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide

To 400 mg (0,92 mmol) of methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid (obtained according to example 12) in a closed test tube add 20 ml of methylamine (33 wt.%, solution in EtOH) and 13 mg (0.27 mmol, 0.3 EQ.) sodium cyanide. The reaction mixture was stirred at 90°C for 2 hours and then the solvent evaporated. After column chromatography on silica gel using EtOAc, obtain 340 mg (yield 86%) of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide in the form of a white solid, mass spectrum: 435 (MN+).

Example 56

(RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahedral the lo-Penta[b]indol-2-yl)-2-fluoro-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 55, of the methyl ester of (RS,SR)benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid (obtained according to example 23) get (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-N-methylacetamide in the form of a white solid, mass spectrum 438 (MNH4+).

Example 57

(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 55, of the methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(3-permentantly)acetic acid (obtained according to example 39) get (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N-methylacetamide in the form of a white solid mass spectrum: 470 (MNH4+).

Example 58

(RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-2-(3-permentantly)-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 55, of the methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)fluoro-(3-permentantly)acetic acid (obtained according to example 45) get (RS,SR')-2-(7-chloro-1, 2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-2-(3-permentantly)-N-m tileceramic in the form of a white solid, mass spectrum: 439 (MN+).

Example 59

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N,N-dimethylacetamide

59.1

To 950 mg (2,18 mmol) of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide (obtained according to example 56) in 10 ml of CH2Cl2at room temperature add to 0.60 ml (4,36 mmol, 2 EQ.) Et3N, 27 mg (0.22 mmol, 0.1 EQ.) DMAP and 571 mg (2,62 mmol, 1.2 EQ.) di-tert-butyl ether carboxylic acid. The reaction mixture was stirred at room temperature for 2 hours and then extracted using 1 M HCl solution. The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography receive 682 mg (yield 59%) of tert-butyl methyl ether (RS,SR)-2-(benzazolyl-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid as a white solid, mass spectrum: 552 (MNH4+).

59.2

Treated with 680 mg (1,27 mmol) tert-butyl ether (RS,SR)-2-(benzene-selfanimationsmolly)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid in 10 ml of DMF, using 83 mg (1,90 mmol, 1.5 EQ.) NaH (55% in mineral oil) adding portions over 30 minutes at 0°C. Then add 217 mg (of 1.52 mmol, 1.2 EQ.) under the conditions, and the reaction mixture was stirred an additional 30 minutes, then pour out the water and is extracted, using EtOAc. The crude substance was dissolved in 10 ml of CH2Cl2and then add 1 ml of TFU at room temperature. Add an aqueous solution of Na2CO3to achieve pH 7, after which the organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of heptane/EtOAc to 1:1 ratio to receive 420 mg (yield 65%) of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N,N-dimethylacetamide in the form of a white solid, mass spectrum: 449 (MH+).

Example 60

(RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)-2-fluoro-N,N-dimethylacetamide

In accordance with the methodology, which is similar to the technique of example 59, from (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)-2-fluoro-N-methylacetamide (obtained according to example

57) get (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)-2-fluoro-N,N-dimethylacetamide in the form of a white solid, mass spectrum: 452 (MNH4+).

Example 61

(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide

In accordance with the methodology, which is similar to the technique of example 59, from (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N-methyl is of etamide (obtained according to example 58) get (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide in the form of a white solid, mass spectrum: 467 (MN+).

Example 62

(RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide

In accordance with the methodology, which is similar to the technique of example 59, from (RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-(3-permentantly)-N-methylacetamide (obtained according to example

58) get (RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide in the form of a white solid, mass spectrum: 453 (MN+).

Example 63

(RS,SR)-2-benzazolyl-N-benzyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide

Treated with 60 mg (0,112 mmol) tert-butyl ether (RS,SR)-2-(pensacolanewsjournal.com)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid (obtained according to example 59.1) in 3 ml THF, using 7 mg (has 0.168 mmol, 1.5 EQ.) NaH (55% in mineral oil) at 0°C for 40 minutes. Added 38 mg (0,224 mmol, equ.) bromoethylene and then the reaction mixture was stirred over night at room temperature. The solvent is evaporated, the obtained residue is dissolved in 3 ml of CH2Cl2add 1 ml of TFU, after which the reaction mixture is stirred over night at room temperature. After evaporation of the solvent and purification of the obtained residue preparative GHUR (who elonka 18) to obtain 35 mg (yield 60%) of (RS,SR)-2-benzazolyl-N-benzyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide in the form of a white solid, mass spectrum: 525 (MN+).

Example 64

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(4-cyano-benzyl)-2-fluoro-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 63, from tert-butyl ether (RS,SR)-2-(benzazolyl-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydrocarbazol-9-carboxylic acid and 4-bromobutyronitrile get (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(4-cyanobenzyl)-2-fluoro-N-methylacetamide in the form of a white solid, mass-range: 551 (MN+).

Example 65

(RS,SR)-2-benzazolyl-N-(4-bromobenzyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 63, from tert-butyl ether (RS,SR)-2-(benzazolyl-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid and 1-bromo-4-bromomethylphenyl get (RS,SR)-2-benzazolyl-N-(4-bromobenzyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide in the form of a white solid, mass spectrum: 603; 605 (MN+).

Example 66

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(3,5-diferensial)-2-fluoro-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 63, from tert-butyl ether (RS,SR)-2-(benzols Lionel-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid and 1-bromomethyl-3,5-diferente get (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(3,5-diferensial)-2-fluoro-N-methylacetamide in the form of a light brown solid, mass spectrum: 561 (M).

Example 67

Methyl ester of (RS,SR)-4-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]methylamino}methyl)benzoic acid

In accordance with the methodology, which is similar to the technique of example 63, from tert-butyl ether (RS,SR)-2-(benzazolyl-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydrocarbazol-9-carboxylic acid and methyl ester 4-bromomethylphenyl acid get (RS,SR)-4-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid in the form of light brown solid, mass spectrum: 583 (M).

Example 68

Methyl ester of (RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid

In accordance with the methodology, which is similar to the technique of example 63, from tert-butyl ether (RS,SR)-2-(benzazolyl-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid and methyl ester 3-bromomethylphenyl acid get methyl ester of (RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid acid in the form of a white solid, mass spectrum: 583 (M).

Example 69

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-shall carbazol-2-yl)-N-(2-cyanobenzyl)-2-fluoro-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 63, from tert-butyl ether (RS,SR)-2-(benzazolyl-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydrocarbazol-9-carboxylic acid and 2-bromobutyronitrile get (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(2-cyano-benzyl)-2-fluoro-N-methylacetamide in the form of a white solid mass range: 550 (M).

Example 70

(RS,SR)-N-allyl-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 63, from tert-butyl ether (RS,SR)-2-(benzazolyl-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid and 3-bromopropene get (RS,SR)-N-allyl-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide in the form of a white solid, mass spectrum: 475 (MN+).

Example 71

(RS,SR)-2-benzazolyl-2-(b-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(3-cyano-benzyl)-2-fluoro-N-methylacetamide

In accordance with the methodology, which is similar to the technique of example 63, from tert-butyl ether (RS,SR)-2-(benzazolyl-pharmacycarisoprodol)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid and 3-bromobutyronitrile get (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N - (3-cyano-benzyl)-2-fluoro-N-methylacetamide in the form of a white solid substances mass spectrum: 550 (M).

Example 72

(RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid

To 88 mg (0,151 mmol) of methyl ester of (RS,SR)-3{[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}benzoic acid (obtained according to example 69) in 5 ml of a mixture of THF/Meon in the ratio of 1:1 add 1 ml of 1 M NaOH solution and then the reaction mixture was stirred over night at room temperature. Add an aqueous solution of NH4Cl to achieve pH 7, the product obtained is extracted using EtOAc, dried over Na2SO4, filtered and evaporated the solvent. After recrystallization from Et2O obtain 66 mg (yield 77%) of (RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid as a white solid, mass spectrum: 570 (MN+).

Example 73

(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-(3-hydroxymethylene)-N-methylacetamide

To 61 mg (0,107 mmol) of (RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-lH-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid (obtained according to example 73) in 3 ml THF at 0°C add 160 ál (0,107 mmol, 1 EQ.) NR3. Then add THF (1M in THF), after which the reaction mixture is stirred additionally is within 1 hour then divide between EtOAc and water. The organic layer is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using EtOAc/heptane 2:1 to obtain 50 mg (yield 84%) of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-(3-hydroxymethylene)-N-methylacetamide in the form of a white solid, mass spectrum: 555 (M).

Example 74

(RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

74.1

To a stirred solution of 5.0 g (is 0.023 mol) of methyl ether benzolsulfonate acid in 10 ml of Meon at room temperature add 3.50 g (0,070 mol, 3 EQ.) hydrazine hydrate is added. After one hour the solvent and excess hydrazine is removed under reduced pressure, thus obtaining 4,90 g (quantitative yield) of the hydrazide benzolsulfonate acid in the form of a colorless oily substance, mass spectrum: 232 (MNH4+).

74.2

To a stirred solution of 1.50 g (7.0 mmol) of hydrazide benzolsulfonate acid in 5 ml acetic acid is added 1.44 g (14.0 mmol, 2 EQ.) anhydride of acetic acid and then the resulting solution is refluxed for 1 hour. The reaction mixture is diluted with water, extracted using EtOAc, the organic phase is dried over Na2SO4shown that the comfort and evaporated, while receiving 1.40 g (yield 78%) of N-(2-benzolsulfonate)of acetic acid hydrazide in the form of a white solid, mass spectrum: 274 (MNH4+).

74.3

To a stirred solution of 1.40 g (5.5 mmol) of N'-(2-benzolsulfonate)of acetic acid hydrazide in 50 ml of acetonitrile add 1,02 g (6.5 mmol, 1.2 EQ.) of phosphorus oxychloride and then the resulting solution is refluxed for 3 hours. The reaction mixture is diluted with water, extracted using EtOAc, the organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using EtOAc receive from 0.90 g (yield 70%) 2-benzosulfimide-5-methyl-[1,3,4]oxadiazole in the form of a white solid, mass spectrum: 239 (MN+).

74.4

To 650 mg (2,73 mmol) 2-benzosulfimide-5-methyl-[1,3,4]oxadiazol in 35 ml Meon at 0°C. add 50 μl (0.27 mmol, 0.1 EQ.) solution of sodium methoxide (5.4 M in the Meon). After 15 minutes add 246 mg (3.0 mmol, 1.1 EQ.) cyclopent-2-Aenon. The reaction mixture was stirred at 0°C and allowed to warm to room temperature for 4 hours, diluted with saturated aqueous NH4Cl and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using EtOAc get mg (yield 86%) of 3-[benzazolyl-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-Cyclopentanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 321 (MN+).

74.5

Treated with 375 mg (1,17 mmol) 3-[benzazolyl-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone in 10 ml of DMF, using 52 mg (1,29 mmol, 1.1 EQ.) NaH (55% in mineral oil) in 30 minutes. Add 554 mg (1,75 mmol, 1.5 EQ.) N-forbindelseshastighed and after 2 hours the reaction mixture was diluted with saturated aqueous NH4Cl, then extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. Two of the resulting diastereoisomer shared by column chromatography on silica gel using EtOAc/heptane 2:1, while receiving 80 mg (yield 20%) of (RS,SR)-3-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone in the form of a colorless oily substance, mass spectrum: 339 (MN+) and 75 mg (yield 19%) of (RS,SR)-3-[benzene-sulfonato-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone as a white solid, mass spectrum: 339 (MN+).

74.6

In accordance with the methodology, which is similar to the technique of example 23.2, from 80 mg (0.23 mmol) of (RS,SR)-3-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone and 49 mg (0.26 mmol, 1.15 EQ.) (4-chlorophenyl)hydrazinecarboxamide obtain 38 mg (yield 36%) of (RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4] oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydric is openta[b] indole as a pale orange crystals, mass spectrum: 446 (MN+).

Enantiomers share preparative chiral GHUR. Column:

hiralal HELL (chiralpak AD), solvent: 20% isopropanol / heptane, get (S)-2-[(R)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole and (R)-2-[(S)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indole.

Example 75

(RS,SR)-2-[1-benzazolyl-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

75.1

Treated with 375 mg (1,17 mmol) 3-[benzazolyl-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone in 10 ml of DMF, using 52 mg (1,29 mmol, 1.1 EQ.) NaH (55% in mineral oil) in 30 minutes. Add 300 mg (2.32 mmol, 1.8 EQ.) under the conditions and within 2 hours the reaction mixture was diluted with saturated aqueous NH4Cl, then extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. Two of the resulting diastereoisomer shared by column chromatography on silica gel using a mixture of EtOAc/heptane 1:2, while receiving 95 mg (yield 24%) of (RS,SR)-3-[1-benzazolyl-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]Cyclopentanone as a white solid, mass spectrum: 335 (MN+) and 90 mg (23%) (RR,SS)-3-[1-benzazolyl-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]Cyclopentanone in the form of b the logo solids, mass spectrum: 335 (MN+).

75.2

In accordance with the methodology, which is similar to the technique of example 19.3, from 90 mg (0.27 mmol) of (RS,SR)-3-[1-benzazolyl-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]Cyclopentanone and 58 mg (0.33 mmol, 1.2 EQ.) (4-chlorophenyl)hydrazinecarboxamide obtain 35 mg (yield 30%) of (RS,SR)-2-[1-benzazolyl-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a pale yellow solid, mass spectrum: 442 (MN+).

Example 76

(RS,SR)-2-(benzosulfimide-[1,3,4]oxadiazol-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

76.1

To 1.73 g (8,07 mmol) hydrazide benzolsulfonate acid 20 ml triethylorthoformate and 1.26 g (8,07 mmol, 1 EQ.) oxychloride of phosphorus. The reaction mixture is stirred for 1 hour at room temperature and then concentrated under reduced pressure. After column chromatography on silica gel using EtOAc/hexane in a ratio of 2:1, obtain 930 mg (yield 52%) of 2-benzosulfimide-[1,3,4]oxadiazole in the form of a white solid, mass spectrum: 225 (MN+).

76.2

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-benzosulfimide-[1,3,4]oxadiazole and cyclopent-2-may receive 3-(benzazolyl-[1,3,4]oxadiazol-2-ylmethyl)-Cyclopentanone in the form of a racemic mixture of diastereomers. The obtained p is oduct directly used in the next stage without additional analyses.

76.3

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-(benzazolyl-[1,3,4]oxadiazol-2-ylmethyl)beclometasone and N-forbindelseshastighed get (RS,SR)-3-(benzosulfimide-[1,3,4]oxadiazol-2-yl)methyl)Cyclopentanone as a white solid, mass spectrum: 342 (MNH4+) and (RR,SS)-3-(benzosulfimide- [1,3,4] oxadiazol-2-yl)methyl)beclometason in the form of a white solid, mass spectrum: 342 (MNH4+).

76.4

In accordance with the methodology, which is similar to the technique of example 74.6, from (RS,SR)-3-(benzosulfimide-[1,3,4]oxadiazol-2-yl)methyl)Cyclopentanone and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-(benzosulfimide-[1,3,4] oxadiazol-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a pale yellow solid, mass spectrum: 449 (MNH4+).

Example 77

(RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

77.1

To 3.0 g (14.0 mmol) of hydrazide benzolsulfonate acid in 30 ml of phosphorus oxychloride added 1.47 g (17,0 mmol, 1.2 EQ.) cyclopropane-carboxylic acid and then refluxed for 2 hours. The reaction mixture is carefully poured on ice, extracted using EtOAc, filtered and evaporated. After column of HRO is ecografia on silica gel, using EtOAc/heptane 2:1, get 1,49 g (yield 41%) of 2-benzosulfimide-5-cyclopropyl-[1,3,4]oxadiazole in the form of a white solid, mass spectrum: 265 (MN+).

77.2

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-benzosulfimide-5-cyclopropyl-[1,3,4]oxadiazole and cyclopent-2-may receive 3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 347 (MN+).

77.3

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone and N-forbindelseshastighed get (RS,SR)-3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]Cyclopentanone as a white solid, mass spectrum: 365 (MN+) and (RR,SS)-3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]Cyclopentanone as a white solid, mass spectrum: 365 (MN+).

77.4

In accordance with the methodology, which is similar to the technique of example 74.6, from (RS,SR)- 3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]Cyclopentanone and (4-chlorophenyl)hydrazine-hydrochloride get (RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4] oxadiazol-2-yl)formetal]-7-chloro-1,2,3,4-Tetra is kotilaine[b] indole as a pale brown solid, mass spectrum: 472 (MN+).

Example 78

(RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-6-chloro-2,3,4,9-tetrahydro-1H-carbazole

78.1

To 2,47 g (9.3 mmol) of 2-benzosulfimide-5-cyclopropyl-[1,3,4]oxadiazol in 25 ml Meon at 0°C add 170 ál (0,93 mmol, 0.1 EQ.) solution of sodium methoxide (5.4 M in the Meon). After 15 minutes 895 mg (9.3 mmol, 1 EQ.) cyclohex-2-Aenon. The reaction mixture is stirred at a temperature of from 0°C. to room temperature for 4 hours, diluted with saturated aqueous NH4Cl and extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using EtOAc/heptane 2:1, obtain 1.48 g (yield 44%) of 3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)methyl]cyclohexanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 361 (MN+).

78.2

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)methyl]cyclohexanone and N-forbindelseshastighed get (RS,SR)-3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]cyclohexanone as a white solid, mass spectrum: 379 (MN+) and (RR,SS)-3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)shall tormentil]cyclohexanone as a white solid, mass spectrum: 379 (MN+).

78.3

In accordance with the methodology, which is similar to the technique of example 12.2, from (RS,SR)-3-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal] cyclohexanone and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-6-chloro-2,3,4,9-tetrahydro-1H-carbazole as a yellow solid, mass spectrum: 486 (MN+).

Example 79

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl} dimethylamine

79.1

To 3.0 g (14.0 mmol) of hydrazide benzolsulfonate acid in 100 ml of CHCl3add to 3.41 g (21,0 mmol, 1.5 EQ.) chloride dihlormetilen-dimethylammonio and are 3.90 ml (28,0 mmol, 2 EQ.) of triethylamine. The resulting solution was stirred at the boil under reflux for 1 hour, split between aqueous NaOH solution (0.5 M) and EtOAc. The combined organic phases are dried over Na2SO4, filtered, evaporated, after column chromatography on silica gel using CH2Cl2/Meon in the ratio of 100:1, gain of 0.59 g (yield 15%) (5-benzosulfimide-[1,3,4]oxadiazol-2-yl)-amine as a white solid, mass spectrum: 268 (MN+).

79.2

In accordance with the methodology, which is similar to the technique of example 74.4, from (5-benzosulfimide the l-[1,3,4]oxadiazol-2-yl)-dimethylamine and cyclopent-2-may receive 3-[benzazolyl-(5-dimethylamino-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, light yellow solid, mass spectrum: 350 (MN+).

79.3

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-[benzazolyl-(5-dimethylamino-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone and N-forbindelseshastighed get (RS,SR)-3-[benzazolyl-(5-dimethylamino-[1,3,4]oxadiazol-2-yl)formetal]-Cyclopentanone as a white solid, mass spectrum: 368 (MN+), and (RR,SS)-3-[benzazolyl-(5-dimethylamino-[1,3,4]oxadiazol-2-yl)formetal]Cyclopentanone as a white solid, mass spectrum: 368 (MN+).

79.4

In accordance with the methodology, which is similar to the technique of example 74.6, from (RS,SR)- 3-[benzazolyl-(5-dimethylamino-[1,3,4]oxadiazol-2-yl)formetal]Cyclopentanone (4-chlorophenyl)hydrazine-hydrochloride get (RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol-2-yl)formetal] - [1,3,4]oxadiazol-2-yl}dimethylamine as a white solid, mass range: 475 (MN+).

Example 80

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}dimethylamine; model HC1 salt

Dissolve 15 mg (0,031 mmol) of (RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}amine in 5 ml of a mixture of Et2O/EtOAc in a ratio of 3:1, bubbled in the solution model HC1 gas to about the adowanie white precipitate. The solvent is removed, the solid is dried in vacuum, to obtain 14 mg (yield 87%) of (RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}dimethylamine; HCl salt as a white solid, mass spectrum: 475 (MN+).

Example 81

(RS,SR)-2-[benzosulfimide-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

81.1

Treated with 10.8 g (0,098 mol) bentolila in 70 ml of DMF at 0°C, using or 4.31 g (to 0.108 mol, 1.1 EQ.) NaH (55% in mineral oil) in 40 minutes. Add 17,19 g (0,103 mol, of 1.05 equiv.) ethyl ether bromine-acetic acid and continue stirring over night. The reaction mixture is divided between the aqueous solution of NH4C1 and EtOAc, dried over Na2SO4, filtered and evaporated, thus obtaining of 15.4 g (yield 80%) of ethyl ether phenylsulfonylacetate acid in the form of a colorless oily substance, mass spectrum: 197 (MN+).

81.2

Process 565 mg (of 7.65 mmol, 1.5 EQ.) N-hydroxyazetidine in 50 ml of THF at room temperature, adding portions 306 mg (of 7.65 mmol, 1.5 EQ.) NaH within 30 minutes. Add 1.0 g (5.1 mmol) of ethyl ether phenylsulfonylacetate acid in THF solution and then continue stirring for 1 hour at 60°C. the Reaction mixture was diluted with saturated aqueous NH4Cl, extracted, IP is using EtOAc, filtered and evaporated. After column chromatography on silica gel using a mixture of EtOAc/heptane 1:1, obtain 480 mg (yield 46%) of 3-methyl-5-phenylsulfanyl-[1,2,4]oxadiazol in the form of a colorless oily substance.

81.3

To 450 mg (2.2 mmol) of 3-methyl-5-phenylsulfanyl-[1,2,4]oxadiazol in 50 ml l3at room temperature add 1,08 g (4.4 mmol, 2 EQ.) mjpbk and then stirred for 2 hours. The reaction mixture was washed with aqueous solution of NaHCO3and then the organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using EtOAc/heptane 1:1, obtain 385 mg (yield 74%) of 5-benzosulfimide-3-methyl-[1,2,4]oxadiazol in the form of a white solid, mass spectrum: 239 (MN+).

81.4

In accordance with the methodology, which is similar to the technique of example 74.4, from 5-benzosulfimide-3-methyl-[1,2,4]oxadiazole and cyclopent-2-may receive 3-[benzazolyl-(3-methyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 321 (MN+).

81.5

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-[benzazolyl-(3-methyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone and N-forbindelseshastighed get (RS,SR)-3-[benzolsulfonat is fluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone as a white solid, mass spectrum: 339 (MN+) and (RR,SS)-3-[benzosulfimide-(3-methyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone as a white solid, mass spectrum: 339 (MN+).

81.6

In accordance with the methodology, which is similar to the technique of example 74.6, from (RS,SR)-3-[benzosulfimide-(3-methyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-[benzosulfimide-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a pale brown solid, mass spectrum: 446 (MN+).

Example 82

(RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid methyl ester

82.1

To a stirred suspension of 10.0 g (0,117 mol) methyl ester nitrilases acid and 8,17 g (0,117 mol, 1 EQ.) hydroxylamine-hydrochloride in 250 ml of Meon at room temperature add to 21.8 ml (0,117 mol, 1 EQ.) solution of sodium methoxide (5.4 M in the Meon). Continue stirring for 3 hours and then the reaction mixture was filtered and concentrated in vacuo. The yellow rubbery substance is extracted several times using CH2Cl2and then the organic phase is filtered through dekalim and evaporated, thus obtaining 1.1 g (yield 8%) of the methyl ester aminohydrocinnamic acid in sideblog solids.

82.2

Mix 300 mg (2.54 mmol) of methyl ether aminohydrocinnamic acid and 428 mg (to 2.29 mmol, 0.9 EQ.) vinylsulfonylacetamido stirred in 10 ml of THF at room temperature for 1 hour. The solvent is evaporated, the obtained residue is dissolved in dioxane and the reaction mixture is refluxed overnight in the presence of molecular sieves. After filtration, concentration in vacuo and column chromatography on silica gel using a mixture of EtOAc/heptane 1:1 to obtain 310 mg (yield 49%) of the methyl ester 5-phenylsulfanyl-[1,2,4]oxadiazol-3-carboxylic acid as a pale yellow oily substance, mass spectrum: 268 (MNH4+).

82.3

In accordance with the methodology, which is similar to the technique of example 81.3, methyl ester 5-phenylsulfanyl-[1,2,4]oxadiazol-3-carboxylic acid get methyl ester 5-benzosulfimide-[1,2,4]oxadiazol-3-carboxylic acid as a white solid, mass spectrum: 283 (MN+).

82.4

In accordance with the methodology, which is similar to the technique of example 74,4, methyl ester 5-benzosulfimide-[1,2,4]oxadiazol-3-carboxylic acid and cyclopent-2-Aenon get methyl ester 5-[benzazolyl-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-carboxylic acid VI is e racemic mixture of diastereomers, colorless oily substance mass spectrum: 382 (MNH4+).

82.5

In accordance with the methodology, which is similar to the technique of example 74.5, from methyl ester 5-[benzazolyl-(3-Axapta-pentyl)methyl]-[1,2,4]oxadiazol-3-carboxylic acid and N-torbenson-sulfonamid receive the methyl ester of (RS,SR)-5-[benzosulfimide-(3-Exotica-pentyl)methyl]-[1,2,4]oxadiazol-3-carboxylic acid as a white solid, mass spectrum: 400 (MNH4+), and methyl ester of (RR,SS)-5-[benzosulfimide-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-carboxylic acid as a white solid, mass spectrum: 400(MNH4+).

82.6

In accordance with the methodology, which is similar to the technique of example 74.6, methyl ester (RS,SR)-5-[benzosulfimide-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-carboxylic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR')-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid as a pale orange solid substance mass spectrum: 490 (MN+).

Example 83

(RS,SR)- {5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methanol

To a mixed solution of 80 mg (0.16 mmol) of methyl ester of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-is tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid (obtained according to example 83) in 10 ml THF at room temperature add 180 ál (0,17 mmol, 1.1 EQ.) LiAlH4(1M in THF). After 1 hour the reaction mixture is divided between the aqueous solution of NH4Cl and EtOAc. The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of EtOAc/heptane 1:1, obtain 19 mg (yield 25%) of (RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-informatin]-[1,2,4]oxadiazol-3-yl}methanol as a pale yellow solid, mass spectrum: 462 (MN+).

Example 84

(RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid

To a stirred solution of 600 mg (1,22 mmol) of methyl ester of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid in 5 ml of a mixture of Meon/THF in a ratio of 1:1 add 980 mg (24.5 mmol, 20 EQ.) NaOH in the form of a solution in 3 ml of water. After 2 hours at room temperature, add aqueous NH4C1 solution to achieve pH 7, the product obtained is extracted using EtOAc, dried over Na2SO4, filtered and the solvent is then evaporated. After column chromatography on silica gel using a mixture of CH2Cl2/MeOH in a ratio of 8:2, obtain 300 mg (yield 52%) of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ka is oil acid as a white solid, mass spectrum: 430 (M-COOH).

Example 85

Amide (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid

To a mixed solution of 70 mg (0.14 mmol) of methyl ester of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid in 3 ml of EtOH add 0.5 ml of ammonium hydroxide solution (25% in water) and stirred over night. The reaction mixture was separated between EtOAc and water. The organic phase is dried over Na2SO4, filtered and evaporated. After recrystallization from Et2O receive 60 mg (yield 86%) of amide (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid as light orange crystals, mass spectrum: 475 (MN+).

Example 86

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine

86.1

In accordance with the methodology, which is similar to the technique of example 82.1, from dimethylaniline and hydroxylaminopurine get aminohydroxylation in the form of a light orange solid substance and directly use this substance in the next stage without carrying out purification and identification. In accordance with the methodology, which is similar to the determination of the e sample 82.2, from this is derived and ethyl ether phenylsulfonylacetate acid get dimethyl-(5-phenylsulfanyl-[1,2,4]oxadiazol-3-yl)amine as a colorless oily substance, mass spectrum: 236 (MN+).

86.2

In accordance with the methodology, which is similar to the technique of example 81.3, dimethyl-(5-phenylsulfanyl-[1,2,4]oxadiazol-3-yl)amine and mjpbk get (5-benzosulfimide-[1,2,4]oxadiazol-3-yl)-dimethylamine as a white solid, mass spectrum: 268 (MN+).

86.3

In accordance with the methodology, which is similar to the technique of example 74.4, from (5-benzosulfimide-[1,2,4]oxadiazol-3-yl)-dimethylamine and cyclopent-2-may receive 3-[benzazolyl-(3-dimethylamino-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, yellow solid, mass spectrum: 350 (MN+).

86.4

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-[benzazolyl-(3-dimethylamino-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone and N-forbindelseshastighed get (RS,SR)-3-[benzazolyl-(3-dimethylamino-[1,2,4]oxadiazol-5-yl)formetal]Cyclopentanone as a white solid, mass spectrum: 368 (MN+) and (RR,SS)- 3-[benzazolyl-(3-dimethylamino-[1,2,4]oxadiazol-5-yl)formetal]Cyclopentanone as a white solid, mass-Spa is Tr: 368 (MN +).

86.5

In accordance with the methodology, which is similar to the technique of example 74.6, from (RS,SR)-3-[benzazolyl-(3-dimethylamino-[1,2,4]oxadiazol-5-yl)formetal]Cyclopentanone and (4-chlorophenyl)hydrazine-hydrochloride get (RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine as a white solid, mass-range: 475 (MN+).

Example 87

(RS,SR)-7-chloro-2-[(3-chlorobenzenesulfonyl)fluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indol

87.1

In accordance with the methodology, which is similar to the technique of example 81.1, 4,34 g (0,030 mol) 3-chlorobenzoyl in 50 ml of DMF at 0°C is treated using 1,32 g (0,033 mol, 1.1 EQ.) NaH (55% in mineral oil), for 45 minutes. Add 4,82 g (0,032 g of 1.05 equiv.) ethyl ester bromoxynil acid and continue stirring for 2 hours. After extraction and purification obtain 5.9 g (yield 91%) of methyl ester of (3-chloro-phenylsulfanyl)-acetic acid as colorless oily substance.

87.2

In accordance with the methodology, which is similar to the technique of example 81, methyl ester (3-chlorophenylsulfonyl)acetic acid and N-hydroxyazetidine receive 5-(3-chlorophenylsulfonyl)-3-methyl-[1,2,4]oxadiazol in the form of a colorless oily substance, mass spectrum: 241 (MN ).

87.3

In accordance with the methodology, which is similar to the technique of example 81.3, from 5-(3-chlorophenylsulfonyl)-3-methyl-[1,2,4]oxadiazole and mjpbk receive 5-(3-chlorobenzenesulfonyl)-3-methyl-[1,2,4]oxadiazol in the form of a white solid, mass spectrum: 273 (MN+).

87.4

In accordance with the methodology, which is similar to the technique of example 81.4, from 5-(3-chlorobenzenesulfonyl)-3-methyl-[1,2,4]oxadiazole and cyclopent-2-may receive 3-[(3-chlorobenzenesulfonyl)-(3-methyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 355 (MH+).

87.5

In accordance with the methodology, which is similar to the technique of example 81.5, from 3-[(3-chlorobenzenesulfonyl)-(3-methyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone and N-forbindelseshastighed get (RS,SR)-3-[(3-chlorobenzenesulfonyl)fluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-Cyclopentanone as a white solid and (RS,SR)-3-[(3-chlorobenzene-sulfonyl)fluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone as a white solid.

87.6

In accordance with the methodology, which is similar to the technique of example 81.6, from (RS,SR)-3-[(3-chlorobenzenesulfonyl)fluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]beclometasone and (4-chlorophenyl)hydrazine-hydrochloride get (RS,SR)-7-chloro-2-[(3-chlorbenzoyl is of IMT fluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole as a white solid, mass spectrum: 480 (MN+).

Example 88

(RS,SR)-7-chloro-2-[(3-chlorobenzenesulfonyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indol

88.1

In accordance with the methodology, which is similar to the technique of example 81.3, methyl ester (3-chlorophenylsulfonyl)acetic acid and mjpbk get methyl ether (3-chlorophenylsulfonyl)acetic acid as colorless oily substance, mass spectrum: 256 (MNH4+).

88.2

In accordance with the methodology, which is similar to the technique of example 74.1, methyl ester (3-chlorophenylsulfonyl)acetic acid and hydrazine hydrate is added receive hydrazide (3-chlorophenylsulfonyl)acetic acid as a white solid, mass spectrum: 249 (MN+).

88.3

In accordance with the methodology, which is similar to the technique of example 74.2, hydrazide (3-chlorophenylsulfonyl)acetic acid and acetic anhydride get N-(2-benzolsulfonate)acetic acid hydrazide as a white solid, mass spectrum: 291 (MN+).

88.4

In accordance with the methodology, which is similar to the technique of example 74.3, from N-(2-benzolsulfonate)hydrazide acetic acid of phosphorus oxychloride get 2-(3-chlorobenzenesulfonyl)-5-methyl-[1,3,4]oxadiazol in the form of a viscous oily substance, mass-Spa is Tr: 273 (MN +).

88.5

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-(3-chlorobenzenesulfonyl)-5-methyl-[1,3,4]oxadiazole and cyclopent-2-may receive 3-[(3-chlorobenzenesulfonyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 355 (MN+).

88.6

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-[(3-chlorobenzenesulfonyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone and N-forbindelseshastighed get (RS,SR)-3-[(3-chlorobenzenesulfonyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-Cyclopentanone as a white solid, mass spectrum: 373 (MN+), and (RS,SR)-3-[(3-chlorobenzenesulfonyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone as a white solid, mass spectrum: 373 (MN+).

88.7

In accordance with the methodology, which is similar to the technique of example 74.6, from (RS,SR)-3-[(3-chlorobenzenesulfonyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone and (4-chlorophenyl)hydrazine-hydrochloride get (RS,SR)-7-chloro-2-[(3-chlorobenzenesulfonyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole in the form of a light brown solid, mass spectrum: 480 (MN4).

Example 89

(RS,SR)-2-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent the[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione

89.1

Handle 32 g (0,217 mol) isoindole-1,3-dione in 160 ml of DMF, using of 11.75 g (0,294 mol, of 1.35 EQ.) NaH (60% in mineral oil)for 45 minutes at 0°C. Add 22,17 g (0,294 mol, of 1.35 EQ.) chloroacetonitrile and then the reaction mixture was stirred over night. Then the reaction mixture is poured into 1.5 liters of water, after which the precipitate is collected by filtration, washed using Et2O, and dried in a high vacuum, thus obtaining the 36.1 g (yield 89%) of (1,3-dioxo-1,3-dihydroindol-2-yl)acetonitrile as a white solid, mass spectrum: 187 (MN+).

89.2

To a mixture of 35.4 g (0,190 mol) (1,3-dioxo-1,3-dihydro-isoindole-2-yl)acetonitrile and 14,78 g (0,213 mol, of 1.12 EQ.) hydroxylaminopurine in 100 ml of DMF is added dropwise of 38.7 ml (0,209 mol, 1.1 EQ.) solution of sodium methoxide (5.4 M in the Meon) at room temperature. After 2 hours the reaction mixture is poured into 1 l of cold water and then the precipitate is collected by filtration and dried in high vacuum. So get of 37.7 g (yield 90%) of 2-(l,3-dioxo-l,3-dihydro-isoindole-2-yl)-N-hydroxyazetidine in the form of a white solid, mass spectrum: 220 (MN+).

89.3

To 10 g (0.046 mol) of 2-(1,3-dioxo-1,3-dihydroindol-2-yl)-N-hydroxy-acetamidine dissolved in 500 ml DMF, added 1.84 g (0.046 mol, 1 EQ.) magnesium oxide. After 15 minutes, add 8.5 g (0.046 mol, 1 EQ.) phenylsulfonylacetate lorida, then the temperature was raised to 105°C. and the resulting solution stirred overnight. The reaction mixture is divided between the aqueous solution of NH4C1 and EtOAc, dried over Na2SO4. After column chromatography on silica gel using a mixture of EtOAc/heptane 1:1, obtain 8.7 g (yield 55%) of 2-(5-phenylsulfanyl-[1,2,4]oxadiazol-3-ylmethyl)isoindole-1,3-dione as a pale yellow solid, mass spectrum: 352 (MN+).

89.4

In accordance with the methodology, which is similar to the technique of example 81.3, from 2-(5-phenylsulfanyl-[1,2,4]oxadiazol-3-ylmethyl)isoindole-1,3-dione get 2-(5-benzosulfimide-[1,2,4]oxadiazol-3-ylmethyl)isoindole-1,3-dione as a white solid, mass spectrum: 384 (MN+).

89.5

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-(5-benzosulfimide-[1,2,4]oxadiazol-3-ylmethyl)isoindole-1,3-dione and cyclopent-2-may get 2-{5-[benzene-sulfonyl-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 452 (MH+).

89.6

In accordance with the methodology, which is similar to the technique of example 74.5, from 2-{5-[benzazolyl-(3-oxocyclopent)methyl]-[1,2,4] oxadiazol-3-ylmethyl} isoindole-1,3-dione and N-forbindelserne is and get 2- {5-[benzosulfimide-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 484 (MN+).

89.7

To 1,90 g (to 3.92 mmol) 2-{5-[benzosulfimide-(3-oxocyclopent)methyl] - [1,2,4] oxadiazol-3-ylmethyl} isoindole-1,3-dione (mixture of diastereoisomers) in 50 ml of glacial acetic acid is added 870 mg (4,70 mmol, 1.2 EQ.) (4-chlorophenyl)hydrazinecarboxamide. The reaction mixture is heated from 50 to 75°C for 2 hours. The solvent is removed in vacuum and add an aqueous solution of NaHCO3to achieve pH 7, after which the resulting product is extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of EtOAc/heptane 1:2, obtain 530 mg (yield 23%) (RR,SS)-2-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione as a pale yellow solid, mass spectrum: 608 (MNH4+), and 417 mg (yield 18%) of (RS,SR)-2-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione as a pale yellow solid, mass spectrum: 608 (MNH4).

Example 90

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine

To a stirred suspension of 420 mg (0.71 mmol) of (RS,SR)-2-{5-[benzazolyl-(7-chloro-,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione in 50 ml of EtOH added 0.10 ml (2,13 mmol, 3 EQ.) hydrazine hydrate is added. The reaction mixture is heated to 80°C for 3 hours, then divide between EtOAc and water solution model HC1 (1 BC). The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of CH2Cl2/Meon in the ratio 95:5, to obtain 210 mg (yield 64%) of (RS,SR)-{5-[benzene-sulfonyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl} methylamine, light brown solid, mass spectrum: 461 (MN+).

Example 91

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl } dimethylamine

To a stirred solution of 41 mg (0,089 mmol) of (RS,SR)-C-{5-[benzene-sulfonyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine in the Meon (5 ml) is added 0,07 ml solution of formaldehyde in water (36%, 0.89 mmol, 10 equiv.) 12 mg (0.18 mmol, 2 EQ.) and 1 drop of Asón. After one hour the reaction mixture is diluted with water and extracted using EtOAc. The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using EtOAc receive 9 mg (yield 21%) of (RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}amine as a white solid, massspectra: 489 (MN +).

Example 92

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}diethylamin

In accordance with the methodology, which is similar to the technique of example 91, from (RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl} methylamine get (RS,SR)- {5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-diethylamin in the form of a white solid, mass spectrum: 518 (MN+).

Example 93

(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-diethylamin;

HCl-salt

In accordance with the methodology, which is similar to the technique of example 80, from (RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol-2-yl)formetal] -[1,2,4] oxadiazol-3-ylmethyl} -diethylamino get (RS,SR)- {5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-diethylamin; HCl salt as a white solid, mass spectrum: 518 (MN+).

Example 94

(RS,SR)-2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol

94.1

A solution of 35 g (to 0.263 mol) of 2-methylbenzoxazolium in CCl4(300 ml) is treated using 47 g (to 0.263, 1 EQ.) N-BS and 1 g of benzoyl peroxide. The floor is obtained mixture is refluxed (100°C) during the night, then cooled. Succinimide filtered and the resulting mixture evaporated to dryness. After column chromatography gain of 9.2 g (yield 17%) of 2-bromomethylbiphenyl in the form of a light yellow oily substance, mass spectrum: 210, 212 (MN+). (N. Uno, M. Kurokawa, Y. Masuda, Chem. Pharm. Bull., 1981, 29, 2359).

94.2

9.1 g (0,043 mol) of 2-bromomethylbiphenyl in CH3CN (300 ml) is added 7,39 g (0.045 mol, of 1.05 equiv.) sodium salt benzosulfimide acid and of 2.27 g (8.6 mmol, 0.2 EQ.) 18-crown-6. Continue stirring over night, the solvent is evaporated and after column chromatography gain of 8.1 g (yield 70%) of 2-benzensulfonamidelor in the form of a white solid, mass spectrum: 274 (N). (Y. Nagao, S. Yamada, E. Fujita, Tet. Lett., 1983, 24, 2291).

94.3

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-benzensulfonamidelor and cyclopent-2-may receive 3-(benzolsulfonate-2-ylmethyl)Cyclopentanone in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 356 (MN+).

94.4

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-(benzolsulfonate-2-ylmethyl)of Cyclopentanone and N-forbindelseshastighed receive 3-(benzolsulfonate-2-informati)Cyclopentanone in the form of a racemic mixture of diastereoisomers, is aloe solid, mass spectrum: 374 (MN+).

94.5

In accordance with the methodology, which is similar to the technique of example 89.7, from 3-(benzolsulfonate-2-informati)-Cyclopentanone and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-Tetra-hydrocyclone[b] indole as a white solid, mass spectrum: 481 (MH+).

Enantiomers share preparative chiral GHUR. Column: hiralal HELL (chirapaq HELL (chiralpak AD)), solvent: 20% isopropanol/heptane.

Example 95

(RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}ndimethylacetamide

To a stirred solution of 57 mg (0,123 mmol) of (RS,SR)-C-{5-[benzene-sulfonyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine in 5 ml of THF, 20 ml (0,123 mmol, 1 EQ.) add the base Henige (Huenig) and 11.6 μl (0,123 mmol, 1 EQ.) acetic anhydride at 0°C. After 30 minutes the reaction is stopped by adding to the reaction mixture aqueous solution of NaHCO3and extracted using CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel get 30 mg (yield 48%) of (RS,SR)-N- {5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal] - [1,2,4]OK diazol-3-ylmethyl} ndimethylacetamide as a pale yellow solid, mass spectrum: 503 (MN+).

Example 96

(RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}benzamide

To a stirred solution of 44 mg (0,095 mmol) of (RS,SR)-C-{5-[benzene-sulfonyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4] oxadiazol-3-yl} methylamine in 5 ml of THF, add 19 ál (0,114 mmol, 1.2 EQ.) the base of Chenega (Huenig) and 11 μl (0,095 mmol, 1 EQ.) benzoyl-chloride at 0°C. After 2 hours the reaction is stopped by adding to the reaction mixture aqueous solution of NaHCO3and then extracted using CH3Cl3. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel using tO/heptane 1:1, obtain 28 mg (yield 51%) of (RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}benzamide as a white solid, mass spectrum: 565 (M).

Example 97

Methyl ester of (RS,SR)-2-benzazolyl-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclohexyl)propionic acid and (4-bromophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(6-b the OMO-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as a white solid, mass spectrum: 475 (M, 1 Br).

Example 98

Methyl ester of (RS,SR)-2-benzazolyl-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid

98.1

To 1.2 g (2,52 mmol) of methyl ester of (RS,SR)-2-benzazolyl-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid (obtained according to example 99) in 40 ml THF added 31 mg (0.25 mmol, 0.1 EQ.) DMAP and 660 mg (to 3.02 mmol, 1.2 EQ.) di-tire-butyl ether carboxylic acid at 0°C. the Reaction mixture was stirred at room temperature for 2 hours. Add EtOAc and an aqueous solution of NaHCO3, the phases are separated and the organic phase is extracted using a 1 M solution of KHSO4. The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography obtain 1.3 g (yield 90%) of tert-butyl methyl ether (RS,SR)-2-(-1-benzene-sulfonyl-1-methoxycarbonylethyl)-6-bromo-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid as a white solid, mass spectrum: 575 (M, 1 Br).

98.2

In an argon atmosphere in the flask 24 2 mg (0.03 mmol, of 0.05 EQ.) Tris(dibenzylideneacetone)diplodia, 16 mg (0.05 mmol, 0.1 EQ.) 2 (di-tert-butylphosphino)biphenyl and 85 mg (0.88 mmol, 1.7 EQ.) tert-butyl sodium, vacuum and re-filled with argon. Add 300 mg (0.52 mmol) of tert-butyl methyl ether (RS,SR)-2-(-1-benzazolyl-1-methoxycarbonylethyl)-6-bromo-1,2,3,4-tetrahydrocarbazol-9-Carbo the OIC acid in 15 ml of toluene, then the solution is added 1,95 ml 2M (3.9 mmol, 7.5 EQ.) dimethylamine in THF. The resulting solution was heated to 80°C. overnight in a sealed tube. The mixture is diluted using EtOAc, and add a saturated solution of Na2CO3. The inorganic layer is extracted using EtOAc. The combined organic phases are washed with saturated salt solution and dried over Na2SO4. After column chromatography obtain 68 mg (yield 24%) of tert-butyl methyl ether (RS,SR)-2-(1-benzazolyl-1-methoxycarbonylethyl)-6-dimethylamino-1,2,3,4-tetrahydrocarbazol-9-carboxylic acid as an orange oily substance, mass spectrum: 541 (MN+).

98.3

To 42 mg (9.3 mmol) of tert-butyl methyl ether (RS,SR)-2-(-1-benzazolyl-1-methoxycarbonylethyl)-6-dimethylamino-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid in 1 ml of CH2Cl2add 0.06 ml TFU at 0°C. the resulting solution was stirred at room temperature for 5 hours, add a solution of NaHCO3and the inorganic phase is extracted using CH2Cl2, washed with saturated salt solution and dried over Na2SO4. After column chromatography on aminopropiophenone silica gel "ISOLUTE Flash NH2" (Separtis)using EtOAc/heptane 2:1, followed by rubbing with a mixture of ether/heptane obtain 190 mg (yield 56%) of methyl ester of (R,SR)-2-benzazolyl-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid as a pale green amorphous substances, mass spectrum: 441 (MN+).

Example 99

Methyl ester (6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)methanesulfonyl-acetic acid

99.1

In accordance with the methodology, which is similar to the technique of example 1,1, from methylmethanesulfonamide and 2-cyclohexen-1-she gets methyl ether methanesulfonyl-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, orange amorphous substance, mass spectrum: 249 (MN+).

99.2

In accordance with the methodology, which is similar to the technique of example 1.2, from methyl ester methanesulfonyl-(3-oxocyclohexyl)acetic acid and (4-bromophenyl)hydrazinecarboxamide get methyl ester (6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)methanesulfonate acid in the form of a racemic mixture of diastereomers, light brown solid, mass spectrum: 400 (MH+, 1Br).

Example 100

Methyl ester of (RS,SR)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid

100.1

In accordance with the methodology, which is similar to the technique of example 3.1, of the racemic mixture of diastereomers of methyl ether methane sulfonyl-(3-oxocyclohexyl)acetic acid (obtained according to example 101.1) and under the conditions get of racemic mixture of diastereomers methyl ester 2-methanesulfonyl-2-(3-oxocyclohexa is)propionic acid as a colourless foam substance, mass spectrum: 263 (MN+).

100.2

In accordance with the methodology, which is similar to the technique of example 1.2, from the racemic mixture of diastereomers methyl ester 2-methanesulfonyl-2-(3-oxocyclohexyl)propionic acid and (4-bromophenyl)hydrazinecarboxamide get the following 2 racemic diastereoisomer, which can be divided column chromatography to obtain this methyl ester (RS,SR)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid mass spectrum: 414 (MH,1 Br), and methyl ester (RR,SS)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid mass spectrum: 414 (MH+, 1Br).

Example 101

Methyl ester of (RS,SR)-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid

101.1

In accordance with the methodology, which is similar to the technique of example 98.1, methyl ester (RS,SR)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid (obtained according to example 102.2) receive tert-butyl ether (RS,SR)-6-bromo-2-(1-methanesulfonyl-1-methoxycarbonylethyl)-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid as a white solid, mass spectrum: 531 (M+NH4+, 1Br).

101.2

In accordance with the methodology, which is similar to the technique of example 98.2, from tert-butyl ether (RS,SR)-6-brough the o-2-(1-methanesulfonyl-1-methoxycarbonylethyl)-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid get tert-butyl ether (RS,SR)-6-dimethylamino-2-(1-methanesulfonyl-1-methoxycarbonylethyl)-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid in the form of a light yellow solid, mass spectrum: 479 (MN+).

101.3

In accordance with the methodology, which is similar to the technique of example 98.3, from tert-butyl ether (RS,SR)-6-dimethylamino-2-(1-methanesulfonyl-1-methoxycarbonylethyl)-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid to obtain methyl ester of (RS,SR)-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid as a pale green foam substance, mass spectrum: 378 (M).

Example 102

Methyl ether (3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)acetic acid

102.1

A solution of 8.0 g (42 mmol) of 3-bromothiophene process using 7,1 g (47 mmol) of methylpropanoate and potassium carbonate. The resulting suspension is stirred while boiling under reflux for 24 hours, cooled to room temperature and neutralized with a saturated aqueous solution of NH4Cl. Add diethyl simple ether, the phases are separated and the aqueous phase is twice extracted with diethyl simple ether. The combined organic phases are dried over Na2SO4, filtered and evaporated, thus obtaining a 12.1 g (yield 99%) of methyl ester of (3-bromopinacolone)-acetic acid as a pale yellow oily substance, mass spectrum: 279 (MNH4+, 1Br).

102.2

A solution of methyl ester of 6.0 g (2 mmol) (3-bromophenyl-sulfonyl)acetic acid in 50 ml of dichloroethane is treated, using 6.2 g (25 mmol) 3-chloroperbenzoic acid. After 30 minutes stirring addition of 6.2 g (25 mmol) 3-chloroperbenzoic acid, the resulting suspension is stirred over night at room temperature and then treated with 0.5 M aqueous solution of sodium thiosulfate. The phases are separated, then the aqueous phase is twice extracted with diethyl ether. The combined organic phases are washed with approximately 1 M aqueous solution of NaHCO3, dried over Na2SO4, filtered and evaporated, thus obtaining 6.3 g (yield 93%) of methyl ester of (3-bromomethylphenyl)acetic acid as colorless oily substance, mass spectrum: 312 (MNH4+, IBr).

102.3

In accordance with the methodology, which is similar to the technique of example 74.4, from methyl ester (3-brabanthallen)acetic acid and cyclopent-2-northward get methyl ether (3-brabanthallen)-(3-oxocyclopent)acetic acid in the form of a racemic mixture of diastereomers, colorless rubbery substance, mass spectrum: 394 (MNH4, IBr).

102.4

In accordance with the methodology, which is similar to the technique of example 1.2, from methyl ester (3-brabanthallen)-(3-oxocyclopent)acetic acid (racemic mixture of diastereomers) and (4-chlorophenyl)hydrazinecarboxamide get methyl ether (3-br benzolsulfonat)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)acetic acid in the form of a racemic mixture of diastereomers, orange solid, mass spectrum: 484 (MH, 1 Br).

Example 103

Methyl ester of (RS,SR)-2-(3-brabanthallen)-2-((7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid

103.1

In accordance with the methodology, which is similar to the technique of example 3.1, but excluding stage of separation of the diastereomers of methyl ester (3-brabanthallen)-(3-oxocyclopent)acetic acid (racemic mixture of diastereomers) and iodomethane receive the methyl ester of 2-(3-brabanthallen)-2-(3-oxocyclopent)propionic acid in the form of a racemic mixture of diastereomers, a colorless oily substance mass spectrum: 408 (MNH4+, 1 Br).

103.2

In accordance with the methodology, which is similar to the technique of example 3.2, from the methyl ester of 2-(3-brabanthallen)-2-(3-oxocyclopent)propionic acid (racemic mixture of diastereomers) and (4-chlorophenyl)hydrazine hydrochloride get methyl ether (3-brabanthallen)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid in the form of a racemic mixture of diastereomers. The diastereomers separated by chromatography on silica gel using a mixture of heptane/EUAs thus the methyl ester of (RS,SR)-2-(3-brabanthallen)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid as a brown solid substances is a, mass spectrum:

498 (MN, 1 Br) and methyl ester of (RR, SS)-2-(3-brabanthallen)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid as an orange solid, mass spectrum: 498 (MH, 1 Br).

Example 104

Methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-(3-pyrrolidin-1-eventality)propionic acid

A solution of 40 mg (0.08 mmol) of methyl ester of (RS,SR)-2-(3-brabanthallen)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid (example 103) in toluene is treated with 13 mg (0.13 mmol) of NaOtBu, 2 mg (0,007 mmol) of 2-(di-tert-butylphosphino)biphenyl, 0,03 ml (0.4 mmol) of pyrrolidine and 4 mg (0,004 mmol) of Tris(dibenzylideneacetone)diplodia. The resulting suspension is stirred at 80°C for 4 hours, treated with a dilute aqueous solution of NaHCO3and twice extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated, while receiving 14 mg (yield 35%) of methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)-2-(3-pyrrolidin-1-eventality)propionic acid as light brown solid, mass spectrum: 488 (MN+).

Example 105

(RS,SR) 2-[1-(3-brabanthallen)-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

105.1

In accordance with the methodology, which is similar to techniques who run the examples 74.1-74.3, of the methyl ester (3-brabanthallen)acetic acid to obtain 2-(3-bromobenzonitrile)-5-methyl-[1,3,4]oxadiazol in the form of a light yellow oily substance. Mass spectrum: 319 (MN, 1 Br).

105.2

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-(3-bromobenzonitrile)-5-methyl-[1,3,4]oxadiazole and cyclopent-2-may receive 3-[(3-brabanthallen)-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 400 (MN, 1 Br).

105.3

In accordance with the methodology, which is similar to the technique of example 103.1, from 3-[(3-brabanthallen)-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone (racemic mixture of diastereomers) and iodomethane receive 3-[1-(3-brabanthallen)-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]Cyclopentanone in the form of a racemic mixture of diastereomers, yellow oily substance mass spectrum: 414 (MH, 1 Br).

105.4

In accordance with the methodology, which is similar to the technique of example 103.2, from 3-[1-(3-brabanthallen)-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]Cyclopentanone (racemic mixture of diastereomers) and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR) 2-[1-(3-Brabanthal-sulfonyl)-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indole in the form of a dark brown rubber is similar substances, mass spectrum: 522 (MN+, 1 Br) and (RR, SS) 2-[1-(3-brabanthallen)-

1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indole in the form of a dark brown solid, mass spectrum: 522 (MH, 1 Br).

Example 106

(RS,SR)-2-[(3-brabanthallen)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

106.1

In accordance with the methodology, which is similar to the technique of example 12.1, 3-[(3-brabanthallen)-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone (racemic mixture of diastereomers) and N-forbindelseshastighed receive 3-[(3-brabanthallen)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 418 (MH, 1 Br).

106.2

In accordance with the methodology, which is similar to the technique of example 103.2, from 3-[(3-brabanthallen)fluoro-(5-methyl-[1,3,4]oxadiazol-

2-yl)methylene]Cyclopentanone (racemic mixture of diastereomers) and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-[(3-brabanthallen)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a brown rubbery substance, mass spectrum: 526 (MH, 1 Br) and (RR, SS)-2-[(3-brabanthallen)fluoride(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indole as a pale brown is solid substances, mass spectrum: 526 (MH, 1 Br).

Example 107

(RS,SR) 2-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-brabanthallen)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

107.1

In accordance with the methodology, which is similar to the technique of example 74.1, methyl ester 3-bromobenzaldehyde acid (example 102.2) and hydrazine hydrate is added receive hydrazide 3-bromobenzoyl-sulfonyloxy acid in the form of a colorless oily substance, mass spectrum: 294 (MN+, 1 Br).

107.2

In accordance with the methodology, which is similar to the technique of example 74.2, of hydrazide 3-bromobenzaldehyde acid and phenylacetylglutamine get /1/-[2-(3-brabanthallen)acetyl]hydrazide phenylacetic acid as a white solid, mass spectrum: 412 (MN+, 1 Br).

107.3

In accordance with the methodology, which is similar to the technique of example 74.3, by processing N-[2-(3-bromomethylphenyl)acetyl]-hydrazide phenylacetic acid with phosphorus oxychloride get 2-benzyl-5-(3-bromobenzonitrile)-[1,3,4]oxadiazol as an orange oily substance, mass spectrum: 394 (MH, 1 Br).

107.4

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-benzyl-5-(3-bromobenzonitrile)-[1,3,4]oxadiazole and cyclopent-2-may receive 3-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-b is abesalashvili)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, colorless rubbery substance, mass spectrum: 476 (MH, 1 Br).

107.5

In accordance with the methodology, which is similar to the technique of example 12.1, 3-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-brabanthallen)methylene]Cyclopentanone (racemic mixture of diastereomers) and N-forbindelseshastighed receive 3-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-brabanthallen)formetal]Cyclopentanone in the form of a racemic mixture of diastereomers, light yellow solid, mass spectrum: 494 (MH, 1 Br).

107.6

In accordance with the methodology, which is similar to the technique of example 103.2, from 3-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-brabanthallen)formetal]Cyclopentanone (racemic mixture of diastereomers) and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-brabanthallen)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a yellow solid mass spectrum: 602 (MN+, 1 Br), and (RR,SS)-2-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-brabanthallen)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a brown solid, mass spectrum: 602 (MN, 1 Br).

Example 108

(RS,SR) {3-[(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methanesulfonyl]phenyl}dimethylamine

In accordance with the methodology, which is similar to the technique of example 104, from (RS, SR)-2-[(3-Brom solarpanel)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole (example 106) and dimethylamine in THF receive (RS,SR) {3-[(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methanesulfonyl]phenyl}dimethylamine in the form of colorless rubbery substance, mass spectrum: 489 (MN+).

Example 109

(RS,SR)- 7-chloro-2-[(3-ethynylbenzoate)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indol

A solution of 76 mg (0.133 mmol) of (RS, SR)-2-[(3-brabanthallen)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indole (example 106) in 1.5 ml DMF is treated using 1 mg (0.005 mmol) CuI, 37 mg (0.29 mmol) of DIPEA, 17 mg (0.015 mmol) of tetrakis(triphenylphosphine)palladium and 71 mg (0,72 mmol) of amenitieseven obtained suspension stirred at 80°C for 4 hours. Add dilute aqueous NaOH solution, after which the resulting mixture was twice extracted with dichloromethane. The combined organic layers are dried over Na2SO4, filtered and evaporated. After chromatography on silica gel using a mixture of heptane/EtOAc (1:1 ratio) to obtain 33 mg (yield 48%) of (RS,SR)-7-chloro-2-[(3-ethinyl-benzazolyl)fluoro-(5-methyl- [1,3,4]oxadiazol-2-yl)methyl] -1,2,3,4-tetrahydrocyclopent[b]indole as a yellow solid, mass spectrum: 471 (MN+).

Example 110

(RS,SR)-2-[5-(4-benzyloxybenzyl)-[1,3,4]oxadiazol-2-yl-(3-brabanthallen)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

110.1

In accordance with the methodology, which is similar to the technique of example 74.2, of hydrazide 3-bromobenzonitrile ssnoi acid (example 107,1) and 4-benzyloxybenzaldehyde receive N-[2-(3-Brabanthal-sulfonyl)acetyl]hydrazide (4-benzyloxyphenyl)-acetic acid as a pale yellow solid, mass spectrum: 518 (MH, 1 Br).

110.2

In accordance with the methodology, which is similar to the technique of example 74.3, by treatment with N-[2-(3-brabanthallen)-acetyl]hydrazide (4-benzyloxyphenyl)acetic acid with phosphorus oxychloride get 2-(4-benzyloxybenzyl)-5-(3-bromobenzonitrile)-[1,3,4]oxadiazol as a pale yellow solid, mass spectrum: 500 (MN+, 1 Br).

110.3

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-(4-benzyloxybenzyl)-5-(3-bromobenzonitrile)-[1,3,4]oxadiazole and cyclopent-2-may receive 3-[[5-(4-benzyloxybenzyl)-[1,3,4]oxadiazol-2-yl]-(3-brabanthallen)methylene]Cyclopentanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 582 (MN+, 1 Br).

110.4

In accordance with the methodology, which is similar to the technique of example 12.1, 3-[[5-(4-benzyloxybenzyl)-[1,3,4]oxadiazol-2-yl]-(3-brabanthallen)methylene]Cyclopentanone (racemic mixture of diastereomers) and N-forbindelseshastighed receive 3-[[5-(4-benzyloxybenzyl)-[1,3,4]oxadiazol-2-yl]-(3-Brabanthal-sulfonyl)formetal]Cyclopentanone in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 600 (MN, 1 Br).

110.5

In accordance with the methodology, which is similar to the technique of example 103.2, 3-[[5-(4-benzyloxy who yl)-[1,3,4]oxadiazol-2-yl]-(3-brabanthallen)formetal]Cyclopentanone (racemic mixture of diastereomers) and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-[5-(4-benzyloxybenzyl)-[1,3,4]oxadiazol-2-yl-(3-brabanthallen)-vermeil]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole in the form of a brown solid, mass spectrum: 708 (MN+, 1 Br) and (RR, SS)-2-[5-(4-benzyloxybenzyl)-[1,3,4]oxadiazol-2-yl-(3-brabanthallen)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a yellow solid, mass spectrum: 708 (MN+, 1 Br).

Example 111

(RS,SR)-7-chloro-2-[(3-ethylbenzonitrile)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indol

A solution of 22 mg (0.05 mmol) of (RS,SR)-7-chloro-2-[(3-ethinyl-benzazolyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b] indole in 0.5 ml of methanol is treated with 1 mg of palladium on charcoal (10%) and stirred intensively in the atmosphere of H2(atmospheric pressure) for 5 hours. After filtration and evaporation of solvent to obtain 21 mg (yield 92%) of (RS,SR) 7-chloro-2-[(3-ethylbenzonitrile)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole as a yellow solid, mass spectrum: 475 (MN+).

Example 112

Methyl ester of (RS,SR) 4-{5-[(3-bromomethylphenyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid

112.1

In accordance with the methodology, which is similar to the technique of example 74.2, of hydrazide 3-bromobenzaldehyde acid (example 107,1) and methyl 4-chlorocarbonate receive the methyl ester of 4-{N-[2-(3-brabanthallen)are the Il]hydrazinecarboxamide}benzoic acid as a pale yellow solid, mass spectrum: 456 (MH, 1 Br).

112.2

In accordance with the methodology, which is similar to the technique of example 74.3, by treatment of methyl ester of 4-{N-[2-(3-brabanthallen)acetyl]hydrazinecarboxamide}benzoic acid with phosphorus oxychloride get methyl ester 4-[5-(3-Brabanthal-sulfonylated)-[1,3,4]oxadiazol-2-yl]benzoic acid as a pale yellow solid, mass spectrum: 438 (MH, 1 Br).

112.3

In accordance with the methodology, which is similar to the technique of example 74.4, from methyl ester 4-[5-(3-bromobenzonitrile)-[1,3,4]oxadiazol-2-yl]benzoic acid and cyclopent-2-may receive the methyl ester of 4-{5-[(3-brabanthallen)-(3-oxocyclopent)methyl]-[1,3,4]oxadiazol-2-yl}benzoic acid in the form of a racemic mixture of diastereomers, white solid, mass spectrum: 520 (MH, 1 Br).

112.4

In accordance with the methodology, which is similar to the technique of example 12.1, methyl ester 4-{5-[(3-brabanthallen)-(3-oxocyclopent)methyl]-[1,3,4]oxadiazol-2-yl}benzoic acid (racemic mixture of diastereomers) and N-forbindelseshastighed receive the methyl ester of 4-{5-[(3-brabanthallen)fluoro-(3-Exotica-pentyl)methyl]-[1,3,4]oxadiazol-2-yl}benzoic acid in the form of a racemic mixture of diastereomers, white solid substance mass spectrum: 538 (MH, 1 Br).

112.5

In accordance with metodiki, which is similar to the technique of example 103.2, methyl ester 4-{5-[(3-bromomethylphenyl)fluoro-(3-oxocyclopent)methyl]-[1,3,4]oxadiazol-2-yl}benzoic acid (racemic mixture of diastereomers) and (4-chlorophenyl)hydrazine receive the methyl ester of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid as a brown solid, mass spectrum: 646 (MN, 1 Br) and methyl ester of (RR, SS) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid as a pale brown solid, mass spectrum: 646 (MN+, 1 Br).

Example 113

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal] -[1,3,4] oxadiazol-2-yl}benzoic acid

A solution of 13 mg (0.02 mmol) of methyl ester of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid in a mixture in the ratio 1:1 of 0.5 ml of THF and 0.5 ml of 1 M aqueous LiOH solution was stirred at room temperature for one hour. Add the diluted aqueous solution of model HC1 and then the resulting mixture was twice extracted with dichloromethane. After drying the combined organic phases over Na2SO4, filtration and evaporation of the solvent obtained when listello 13 mg (quantitative yield) of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid as a yellow solid, mass spectrum: 632 (MH+, 1 Br).

Example 114

{RS, SR) (4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol-2-yl)formetal]- [1,3,4] oxadiazol-2-yl} -phenyl)methanol

A solution of 12 mg (0.02 mmol) of methyl ester of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]- [1,3,4] oxadiazol-2-yl }benzoic acid in 0.5 ml of THF is treated with 3 mg (0.08 mmol) of lithium aluminum hydride and stirred at room temperature for one hour. The resulting mixture is treated with a mixture of ice cubes and water and then twice extracted with dichloromethane. After drying the combined organic phases over Na2SO4, filtration and evaporation receive 10 mg (yield 86%) of (RS,SR) (4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}phenyl)methanol as a yellow solid, mass spectrum: 618 (MN, 1 Br).

Example 115

(RS,SR) 2-{benzosulfimide-[5-(4-iodobenzyl)-[1,3,4]oxadiazol-2-yl] methyl} - 7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol

115.1

A solution of 1 g (4.7 mmol) of hydrazide benzolsulfonate acid (example 74,1) in 4 ml of THF is treated 391 mg (4.7 mmol) IOpenRowset acid, 126 mg (0,93 mmol) of 1-hydroxybenzotriazole and 2.8 g (28 mmol) of N-methylmorpholine. The resulting mixture is stirred for 15 minutes at 0°C, treated using a 1.25 g (6.5 mmol) of EDCI, and peremeshivayte within 12 hours. The crude substance is treated with a dilute aqueous solution of NH4Cl and extracted twice using EtOAc. After drying the combined organic layers over Na2SO4, filtration and evaporation receive 2 g (yield 93%) of N'-[2-(4-iodo-phenyl)acetyl]hydrazide benzolsulfonate acid as a brown oily substance, mass spectrum: 266 (MN+).

115.2

In accordance with the methodology, which is similar to the technique of example 74.3, by treatment with N-[2-(benzazolyl)acetyl]hydrazide (4-iodophenyl)acetic acid with phosphorus oxychloride get 2-benzene-sulfanilyl-5-(4-iodobenzyl)-[1,3,4]oxadiazol as a pale yellow solid, mass spectrum: 441 (MN+).

115.3

In accordance with the methodology, which is similar to the technique of example 74,4, 2-benzosulfimide-5-(4-iodo-benzyl)-[1,3,4]oxadiazole and cyclopent-2-may get 3-{(benzazolyl)-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]methyl}Cyclopentanone in the form of a racemic mixture of diastereomers, light brown rubbery substance, mass spectrum: 523 (MN+).

115.4

In accordance with the methodology, which is similar to the technique of example 12.1, from 3-{(benzazolyl)-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]methyl}Cyclopentanone (racemic mixture of diastereomers) and N-forbindelseshastighed floor is given 3-{(3-brabanthallen)fluorine-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]-methyl}Cyclopentanone in the form of a racemic mixture of diastereomers, shared by chromatography on silica gel using a mixture of EtOAc/heptane 1:2, while receiving (RS,SR) 3-{(benzazolyl)fluorine-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]methyl}Cyclopentanone as a white solid, mass spectrum: 541 (MN+), and (RR, SS) 3-{(benzazolyl)fluorine-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]methyl}Cyclopentanone as a white solid. Mass spectrum: 541 (MN+).

115.5

In accordance with the methodology, which is similar to the technique of example 103.2, from (RS,SR) 3-{(benzazolyl)fluorine-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]-methyl}Cyclopentanone and (4-chlorophenyl)hydrazine-hydrochloride get (RS,SR) 2-{benzosulfimide-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]methyl}-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole, light yellow solid, mass spectrum: 648 (MN+).

Example 116

(RS,SR)4-{5-[(benzazolyl)-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid

A solution of 17 mg (0,027 mmol) of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid in 1 ml of methanol is treated with 1 mg of palladium on charcoal (10%) and intensively stirred for 2 hours in an atmosphere of H2(atmospheric pressure). After filtration and evaporation of solvent to obtain 14 mg (yield 94) (RS,SR) 4-{5-[(benzazolyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid as a white solid, mass spectrum: 553 (MN+).

Example 117

(RS,SR) 4- {5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-ylmethyl}benzoic acid

A solution of 66 mg (0.10 mmol) of (RS,SR) 2-{benzosulfimide-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]-methyl}-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indole (example 115) in 0.5 ml DMF and 0.5 ml of water is treated using 1 mg of NaI and 2 mg (0,009 mmol) of palladium acetate. Then the resulting mixture is stirred for 144 hours in the atmosphere (atmospheric pressure), treated with 2 M aqueous solution of model HC1 and extracted with dichloromethane. After drying the combined organic phases over Na2SO4after filtration and evaporation of the solvent receive 45 mg (yield 78%) of (RS,SR) 4-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-ylmethyl}benzoic acid as a pale brown solid, mass spectrum: 566 (MN+).

Example 118

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzamide

A solution of 63 mg (0.1 mmol) of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid (example 113) in 0.5 ml of DMF is treated, using 27 mg (0,511 mmol) NI-LtCl, 61 mg (0.6 mmol) N-methylmorpholine, 3 mg (0.02 mmol) of 1-hydroxybenzoic the Ola. The resulting mixture was stirred for 15 at 0°C and treated using 29 mg (0.15 mmol) of EDCI, and stirred at room temperature for 10 hours. Add a dilute aqueous solution of HCl, after which the resulting mixture was extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and the solvent evaporated, while receiving 60 mg of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzamide as a brown solid, mass spectrum: 630 (MN, 1 Br).

Example 119

(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl} -N-methylbenzamide

In accordance with the methodology, which is similar to the technique of example 118, from (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid (example 113) and methylaminopropane get (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b] indol-2-yl)formetal] -[1,3,4] oxadiazol-2-yl} -N-methylbenzamide in the form of a brown solid, mass spectrum: 643 (MN, 1 Br).

Example 120

[RS, SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}-N,N-dimethylbenzamide

In accordance with the methodology, to the which is similar to the technique of example 118, from (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid (example 113) and dimethylaminohydrolase get (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}-N,N-dimethylbenzamide in the form of a brown solid, mass spectrum: 657 (MN, 1 Br).

Example 121

(RS,SR)-2-[-benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-bromo-1,2,3,4-tetrahydrocyclopent[b]indol

In accordance with the methodology, which is similar to the technique of example 74.6, from (RS,SR)-3-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone (example 74.5) and (4-bromophenyl)hydrazinecarboxamide get (RS,SR)-2-[-benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-bromo-1,2,3,4-tetrahydrocyclopent[b]indole as a pale brown solid mass spectrum: 489 (M, 1 Br).

Example 122

(RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-piperidine-1-yl-1,2,3,4-tetrahydrocyclopent[b] indol

122.1

In accordance with the methodology, which is similar to the technique of example 98.1, from (RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-bromo-1,2,3,4-tetrahydrocyclopent[b]indole (obtained according to example 121) to obtain tert-butyl ether (RS,SR)-2-[-benzazolyl-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)IU is Il]-7-bromo-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid as a light brown foam substance, mass spectrum: 589 (M, 1 Br).

122.2

In accordance with the methodology, which is similar to the technique of example 98.2, from tert-butyl ether (RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-bromo-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid and piperidine receive tert-butyl ether (RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-piperidine-l-yl-2,3-dihydro-lH-cyclopent[b]indole-4-carboxylic acid as a pale orange foam substance, mass spectrum: 595 (MN+).

122.3

In accordance with the methodology, which is similar to the technique of example 98,3, from tert-butylate ether (RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-piperidine-1-yl-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid get (RS,SR)-2-[-benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-piperidine-1-yl-1,2,3,4-tetrahydrocyclopent[b]indole as a colorless semi-solid substances, mass spectrum: 494 (M).

Example 123

(RS,SR)-N-{2-[-benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl}-N-methylamine

123.1

In accordance with the methodology, which is similar to the technique of example 98.2, from tert-butyl ether (RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-bromo-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid (obtained soglasnoplanu 122.1) and methylamine receive tert-butyl ether (RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4] oxadiazol-2-yl)methyl]-7-methylamino-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic, mass spectrum: 541 (MN+).

123.2

In accordance with the methodology, which is similar to the technique of example 98.3, from tert-butyl ether (RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-methylamino-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid get (RS,SR)-N-{2-[benzene-sulfonato-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl}-N-methylamine in the form of a light yellow oily substance, mass spectrum: 441 (MN+).

Example 124

2-[Benzosulfimide-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

124.1

In accordance with the methodology, which is similar to the method implementation examples 74.2 and 74.3, hydrazide benzolsulfonate acid (obtained according to example 74.1) and TFU get 2-benzosulfimide-5-trifluoromethyl-[1,3,4]oxadiazol in the form of a pink crystalline substance, mass spectrum: 293 (MN+).

124.2

At 0°C 170 mg (0.5 mmol, 0.2 EQ.) Cs2CO3add to the mix a solution of 760 mg (2.6 mmol) of 2-benzosulfimide-5-trifluoromethyl-[1,3,4]oxadiazol in 30 ml of THF. After 45 minutes add 0,23 ml (2.9 mmol) of 2-cyclopenten-1-it. The reaction mixture was stirred at room temperature for 15 hours, diluted with saturated aqueous NH4Cl and extracted using EtOAc. The combined organic is the cue phase is dried over Na 2SO4, filtered and evaporated. After column chromatography on silica gel using a mixture of heptane/EtOAc to 1:1 ratio to receive 0,88 mg (yield 90%) of 3-[benzazolyl-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone as a colourless foam substances, 375 (MN+).

124.3

In accordance with the methodology, which is similar to the technique of example 12.1, from 3-[benzazolyl-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone at -20°C gain 3-[benzosulfimide-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone as a white solid, mass spectrum: 393 (MN+).

124.4

In accordance with the methodology, which is similar to the technique of example 74.6, from 3-[benzosulfimide-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)methylene]Cyclopentanone and (4-chlorophenyl)hydrazinecarboxamide receive a racemic mixture of diastereomers of 2-[benzosulfimide-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a brown oily substance, mass spectrum: 500 (MN, 1 CL).

Example 125

(RS,SR)-2-(1-Benzazolyl-2-methoxy-1-methylethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol

125.1

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)-2-benzazolyl-2-(3-oxocyclopent)propionic key is lots and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)propionic acid as a light brown solid.

125.2

Dissolved 130 mg (0.31 mmol) of methyl ester of (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid in 7 ml of CH2Cl2at room temperature. Add 90 ál (of 0.62 mmol, 2 equiv.) of triethylamine, 4 mg (0,031 mmol, 0.1 EQ.) DMAP and 81 mg (from 0.37 mmol, 1.2 equiv.) VOS2O. the Reaction mixture is stirred for 2 hours. The reaction is stopped by adding to the reaction mixture 10 ml of aqueous 1 M HCl solution. The organic layer is separated and then the aqueous layer was washed using CH2Cl3. The combined organic layers are dried over Na2SO4, filtered and evaporated to dryness, thus obtaining 152 mg (yield 94%) of tert-butyl methyl ether (RS,SR)-2-(1-benzazolyl-1-methoxycarbonylethyl)-7-chloro-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid as a white powder, M: 535 (MTN4+).

125.3

Dissolve 152 mg (0.29 mmol) of tert-butyl methyl ether (RS,SR)-2-(l-benzazolyl-1-methoxycarbonylethyl)-7-chloro-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid in 3 ml of dry THF at room temperature. Add drop by drop of 0.32 ml (0.32 mmol, 1.1 EQ.) LiAlH4(1M in THF). The reaction mixture is stirred for 1 hour and 40 minutes. The reaction is stopped by adding to the reaction mixture, a saturated solution of NaHCO3. The organic phase is washed with saturated salt solution, dried the hell Na 2SO4filter and parivuoteessa column chromatography on silica gel (EtOAc/heptane 1:2) to obtain 50 mg (yield 35%) of tert-butyl methyl ether (RS,SR)-2-(1-benzazolyl-2-hydroxy-1-methylethyl)-7-chloro-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid as a white powder.

125.4

Dissolve 50 mg (0.1 mmol) of tert-butyl methyl ether (RS,SR)-2-(1-benzazolyl-2-hydroxy-1-methylethyl)-7-chloro-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid in 5 ml of dry THF at 0°C. Add 5 mg (0.11 mmol, 1.1 equiv.) NaH (55%) and then the reaction mixture is stirred for 20 minutes. Add 10 μl (0.15 mmol, 1.5 equiv.) under the conditions, and the reaction mixture is stirred for 1 hour at 0°C. the Reaction is stopped by adding to the reaction mixture, a saturated solution of NaHCO3. The organic phase is washed with saturated salt solution, dried over Na2SO4, filtered and evaporated to dryness, thus obtaining 52 mg (yield 100%) of tert-butyl methyl ether (RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-7-chloro-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid as a white powder.

125.5

Dissolve 52 mg (0.1 mmol) of tert-butyl methyl ether (RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-7-chloro-2,3-dihydro-1H-cyclopent[b]indole-4-carboxylic acid are dissolved in 4 ml of CH2Cl2at 0°C. Then added dropwise 1 ml of TFU and the temperature of the honey is i.i.d. increase to room, the reaction mixture is stirred for 20 minutes. The reaction is stopped by adding to the reaction mixture, a saturated solution of NaHCO3. The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel (EtOAc/heptane 1:2) to obtain 11 mg (yield 26%) of (RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole as a white powder, mass spectrum: 404 (MN+).

Example 126

(RS,SR) -2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methyl-N-(3-methylbut-2-enyl)ndimethylacetamide

126.1

In accordance with the methodology, which is similar to the technique of example 1.1, from the methyl ester of methylphenylsulfonyl and cyclohexen-1-she gets methyl ether benzazolyl-(3-oxocyclohexyl)acetic acid in the form of a racemic mixture of diastereomers, light yellow oily substance mass spectrum: 311 (MN+).

126.2

In accordance with the methodology, which is similar to the technique of example 74.5, from methyl ester benzazolyl-(3-oxocyclohexyl)-acetic acid and N-forbindelseshastighed receive the methyl ester of (RS,SR) benzosulfimide-(-3-oxocyclohexyl)acetic acid as a yellow oily substance, mass spectrum: 346 (MNH4+).

126.3

In accordance with the method of Kotor is similar to the technique of example 19.3, of the methyl ester of (RS,SR)benzosulfimide-(-3-oxocyclohexyl)acetic acid and 4-chlorpheniramineydrocodone receive the methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid as an orange solid.

126.4

In accordance with the methodology, which is similar to the technique of example 55, of the methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid and methylamine get (RS,SR) -2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide in the form of a white solid, mass spectrum: 435 (MN+).

126.5

Dissolve 0,924 g (0.002 mol) of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide in 20 ml of CH2Cl2at room temperature. Then add a 0.59 ml of triethylamine (0,004 mol, 2 equiv.) 26 mg DMAP (0.2 mmol, 0.1 EQ.) and 0,556 g VOS2O (0,003 mol, 1.2 EQ.). The reaction mixture is stirred for 2 hours and 30 minutes. The reaction is stopped by adding to the reaction mixture of a saturated aqueous solution of NH4Cl and then the resulting product is extracted using CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and evaporated. The crude substance is precipitated from diethyl ether. The solvent is removed, the remaining TV is Joe substance is dried in vacuum, while receiving 0,840 g (yield 74%) of tert-butyl methyl ether (RS,SR) -2-(pensacolanewsjournal.com)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid as a white solid, mass spectrum: 552 (MNH4+).

126.6

To a stirred solution of 60 mg (0.11 mmol) of tert-butyl methyl ether (RS,SR) -2-(pensacolanewsjournal.com)-6-chloro-1,2,3,4-tetrahydrocarbazol-9-carboxylic acid in 3 ml of THF added 7 mg of NaH (60% in mineral oil, 0,165 mmol, 1.5 EQ.) at 0°C. the Reaction mixture is stirred for 40 minutes and then add 52 μl (0.22 mmol, 2 EQ.) 1-bromo-3-methyl-but-2-ene (1 ml THF), after which the reaction mixture is stirred for 2 hours at 0°C, then overnight at room temperature. The solvent is evaporated. Add 1 ml of CH2Cl3and once dissolved, add 1 ml of TFU and 1 ml of CH2Cl2at room temperature. The reaction mixture was stirred over night. The solvent is then evaporated and after purification preparative GHUR receive 9 mg (yield 19%) of (RS,SR)-2-benzazolyl-2-(-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methyl-N-(3-methyl-but-2-enyl)ndimethylacetamide in the form of a white solid, mass spectrum: 503 (MN+).

Example 127

(RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carbonitril

127.1

Under the methodology, which is similar to the technique of example 82.1, methyl ester narisokonai acid and hydroxylamine-hydrochloride get methyl ether aminohydrocinnamic acid as a white solid.

127.2

In accordance with the methodology, which is similar to the technique of example 82.2, methyl ester aminohydrocinnamic acid and vinylsulfonylacetamido get methyl ester 5-phenylsulfanyl-[1,2,4]oxadiazol-3-carboxylic acid as a yellow oily substance, mass spectrum: 521 (MN+).

127.3

In accordance with the methodology, which is similar to the technique of example 81.3, methyl ester 5-phenylsulfanyl-[1,2,4]oxadiazol-3-carboxylic acid methyl ester and mjpbk get methyl ester 5-benzosulfimide-[1,2,4]oxadiazol-3-carboxylic acid as a white solid, mass spectrum: 282 (MN+).

127.4

In accordance with the methodology, which is similar to the technique of example 74.4, from methyl ester 5-benzosulfimide-[1,2,4]oxadiazol-3-carboxylic acid and cyclopent-2-Aenon get methyl ester 5-[benzazolyl-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-carboxylic acid in the form of a racemic mixture of diastereomers, a colorless oily substance mass spectrum: 382 (MNH4).

127.5

In accordance the with method, which is similar to the technique of example 74.5, from methyl ester 5-[benzazolyl-(3-Exotica-pentyl)methyl]-[1,2,4]oxadiazol-3-carboxylic acid and N-torbenson-sulfonamide receive the methyl ester of (RS,SR)-5-[benzosulfimide-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-carboxylic acid as a white solid, mass spectrum: 400 (MNH4) and methyl ester of (RR,SS)-5-[benzosulfimide-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-carboxylic acid as a white solid, mass spectrum: 400 (TNM4+).

127.6

In accordance with the methodology, which is similar to the technique of example 19.3, from the methyl ester of (RS,SR)-5-[benzosulfimide-(3-oxocyclopent)methyl]-[1,2,4]oxadiazol-3-carboxylic acid and (4-chlorophenyl)hydrazinecarboxamide receive the methyl ester of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid as a pale orange solid mass spectrum: 490 (MN+).

127.7

In accordance with the methodology, which is similar to the technique of example 85, of the methyl ester of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid and ammonium hydroxide solution (25% in water) receive amide (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]ndol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid, in the form of a yellow oily substance, mass spectrum: 475 (MN+).

127.8

To a stirred solution of 170 mg (0.35 mmol) of amide (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid in 2 ml of acetonitrile at room temperature, add 0.5 ml of phosphorus oxychloride. The dark brown solution is stirred for 1 hour and then the temperature was raised to 50°C. and stirred over night. After cooling to room temperature, add 0.5 ml of phosphorus oxychloride. The reaction mixture is stirred for 2 hours while boiling under reflux. The solvent was partially evaporated and the resulting oily substance was dissolved in EtOAc and washed with saturated solution of NaHCO3. The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel (EtOAc/heptane 1:1) to obtain 20 mg (yield 12%) of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carbonitrile as a light red solid, mass spectrum: 457 (MH+).

Example 128

(RS,SR)-{5-[benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine

128.1

To a stirred solution of 20.4 g (0,285 mol) of dimethylaniline 500 ml Meon at room is the temperature add 19,820 g (0,285 mol, 1 EQ.) hydroxylamine and then slowly add 52,82 ml (0,285 mol, 1 EQ.) of sodium methylate (exothermic reaction). The reaction mixture was stirred over night. The resulting mixture is filtered to remove salt, Meon evaporated and the mixture is diluted with chloroform. The precipitate is filtered off and the filtrate is evaporated to dryness, thus obtaining a 29.4 g (yield 95%) of 3-hydroxy-1,1-dimethylguanidine as an orange oily substance.

128.2

In accordance with the methodology, which is similar to the technique of example 81.1, fenistil and bromoethylamine of ester receive ethyl ester phenylsulfonylacetate acid in the form of a colorless oily substance, mass spectrum: 197 (MN+).

128.3

To a stirred suspension of 14 g (0,129 mol, 1.4 EQ.) 3-hydroxy-1,1-dimethylguanidine in 300 ml of dry THF at 0°C add portions 6,191 g (0,155 mol, 1.2 EQ.) NaH (60% in mineral oil). Received heavy suspension was stirred at room temperature for 1 hour and 30 minutes. Then slowly add 28,126 g (0,129 mol) of ethyl ether phenylsulfonylacetate acid. The reaction mixture was stirred at room temperature for 2 hours and then at 65°C for 1 hour. The reaction is stopped by adding to the reaction mixture of a saturated aqueous solution of NH4Cl and then the resulting product extragere is t, using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel (EtOAc/heptane in a ratio of from 1:9 to 1:2) get 19,370 g (yield 64%) dimethyl-(5-phenylsulfanyl-[1,2,4]oxadiazol-3-yl)amine as a colorless oily substance, mass spectrum: 236 (MN+).

128.4

In accordance with the methodology, which is similar to the technique of example 81.3, dimethyl-(5-phenylsulfanyl-[1,2,4]oxadiazol-3-yl)amine and mjpbk get (5-benzosulfimide-[1,2,4]oxadiazol-3-yl)-dimethylamine as a white solid, mass spectrum: 268 (MN+).

128.5

In accordance with the methodology, which is similar to the technique of example 74.4, from (5-benzosulfimide-[1,2,4]oxadiazol-3-yl)-amine and 2-cyclohexen-1-get it 3-[benzazolyl-(3-dimethyl-amino-[1,2,4]oxadiazol-5-yl)methyl]cyclohexanone in the form of a racemic mixture of diastereomers, light brown solid, mass spectrum: 364 (MNH4+).

128.6

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-[benzazolyl-(3-dimethylamino-[1,2,4]oxadiazol-5-yl)methyl]cyclohexanone and N-forbindelseshastighed receive (RR,SS)-3-[benzazolyl-(3-dimethylamino-[1,2,4] oxadiazol-5-yl)formetal]-cyclohexanone in the form of colorless melanosticta, mass spectrum: 382 (MN+) and (RS,SR)-3-[benzazolyl-(3-dimethylamino-[1,2,4]oxadiazol-5-yl)formetal]cyclohexanone in the form of a colorless oily substance, mass spectrum: 382 (MN+).

128.7

In accordance with the methodology, which is similar to the technique of example 19.3, from (RS,SR)- 3-[benzazolyl-(3-dimethylamino-[1,2,4]oxadiazol-5-yl)formetal]cyclohexanone and (4-chlorophenyl)hydrazine-hydrochloride get (RS,SR)- {5-[benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine as a pale yellow solid mass spectrum: 489 (MN+).

Example 129

Methyl ester of (RS,SR)-4-[({5-[-benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]benzoic acid

129.1

In accordance with the methodology, which is similar to the technique of example 89.7, from (RS,SR)-2-{5-[benzosulfimide-(3-oxocyclopent)-methyl]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione (example 89.6) and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2- {5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol-2-yl)formetal] -[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione as a pale yellow powder, mass spectrum: 608 (MNH4+).

129.2

To a suspension of 420 mg (0.7 mmol) of (RS,SR)-2-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadi the evil-3-ylmethyl}isoindole-1,3-dione in 50 ml of EtOH at room temperature, add 0.1 ml (2.1 mmol, 3 EQ.) hydrazine. The reaction mixture is heated at 80°C for 3 hours and 30 minutes. After cooling, the reaction stopped by the addition to the reaction mixture of 1 M HCl solution and then extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel (CH2Cl2/MeOH in a ratio of 95/5) to obtain 210 mg (yield 64%) of (RS,SR)-C-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine in the form of a light brown powder, mass spectrum: 461 (MN+).

129.3

To a stirred solution of 50 mg (0.1 mmol) of (RS,SR)-C-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine in 5 ml of Meon at 0°C. added 19 mg (0.1 mmol, 1 EQ.) methyl 4-formylbenzoate, 7 mg (0.1 mmol, equ.) cyanoborohydride sodium and one drop of acetic acid. The reaction mixture was stirred at 0°C for 20 minutes and then the temperature was raised to room. The reaction is stopped by adding to the reaction mixture of a saturated aqueous solution of NaHCO3. The reaction mixture was poured into water and extracted using EtOAc. The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel (heptane/EtOAc to 1:1 ratio) to receive 30 mg (Vyhod%) of methyl ester of (RS,SR)-4-[({5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}amino)methyl]benzoic acid as a pale yellow powder, mass spectrum: 609 (MN+).

Example 130

Methyl ester of (RS,SR)-3-[({5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]benzoic acid

In accordance with the methodology, which is similar to the technique of example 129.3, (OO')-C-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine and methyl-3-formylbenzoate receive the methyl ester of (RS,SR)-3-[({5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}amino)methyl]benzoic acid as a pale yellow powder, mass spectrum: 609 (MN+).

Example 131

(RS,SR)-{4-[({5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]phenyl}methanol

To a stirred solution of 27 mg (0.04 mmol) of methyl ester of(RS,SR)-4-[({5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]- [1,2,4] oxadiazol-3-ylmethyl} amino)methyl]benzoic acid (example 129.3) in 2 ml THF at 0°C. add 40 μl (0.04 mmol, 1 equiv.) of lithium aluminum hydride (1 M solution in THF). The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 30 minutes. The reaction is stopped by adding to the reaction mixture of a saturated aqueous solution of NaHCO3and then neojidannyy extracted, using EtOAc. The combined organic phases are dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel (heptane/EtOAc 2:8) receive 12 mg (yield 48%) of (RS,SR)- {4-[({5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b] indol-2-yl)formetal]-[1,2,4] oxadiazol-3-ylmethyl}-amino)methyl] phenyl} methanol as a pale yellow powder, mass spectrum: 581 (MN+).

Example 132

(RS,SR)-2-(benzosulfimide-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indol

132.1

To a stirred suspension of 2.5 g (0,010 mol) of the hydrobromide of 2-bromoethylamine in 10 ml of CH3CN at room temperature type of 1.78 ml (0,0105 mol, of 1.05 equiv.) the base of Chenega (Hunig). After complete dissolution of the salt type of 1.62 g (0,010 mol, 1 EQ.) benzosulfimide sodium 0.52 g (0.002 mol, 0.2 EQ.). The resulting mixture was stirred at room temperature for 48 hours and then the reaction stopped by the addition to the reaction mixture of water, after which the resulting product is extracted using EtOAc. The combined organic phases are dried over Na2SO4, filtered and dried in vacuum, to thereby obtain 1.86 g (yield 80%) of 2-benzosulfimide.

132.2

In accordance with the methodology, which is similar to the technique of example 74,4, 2-benzosulfimide and cyclopenten-2-get it 3(benzosulfimide-2-ylmethyl)Cyclopentanone in the form of a racemic mixture of diastereomers.

132.3

In accordance with the methodology, which is similar to the technique of example 19.3, from 3-(benzosulfimide-2-ylmethyl)of Cyclopentanone and (4-chlorophenyl)hydrazinecarboxamide receive (RR, SS)-2-(benzazolyl-pyridine-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole and (RS,SR)-2-(benzosulfimide-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydro-cyclopent[b] indole as a white solid, mass spectrum: 423 (MN+).

Example 133

(RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-2,2,2-triptorelin

133.1

In accordance with the methodology, which is similar to the technique of example 129.2, from (RS,SR)-2-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione (example 129.1) and hydrazine get (RS,SR)-C-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)vermeil]-[1,2,4]oxadiazol-3-yl}methylamine in the form of a light brown powder, mass spectrum: 461 (MN+).

133.2

To a stirred solution of 46 mg (0.1 mmol) of (RS,SR)-C-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine in 3 ml of CH2Cl2at room temperature, add 10 μl (0.1 mmol, 1 EQ.) triperoxonane acid and 80 μl of pyridine (1 mmol, 10 EQ.). Continue mixing in those who tell the night and then the reaction mixture is evaporated to dryness. After column chromatography on silica gel (mixture of heptane/EtOAc in a ratio of 6:4) receive 6 mg (yield 12%) of (RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-2,2,2-trifurcated in the form of light yellow powder, mass spectrum: 557 (MN+).

Example 134

2-[Benzosulfimide-(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

134.1

From N-hydroxybenzamide and chloroacetanilide [described in: Heterocycles, 26 (1), 163-73, 1987] get 5-chloromethyl-3-phenyl-[1,2,4]oxadiazol.

134.2

To a stirred solution of 525 mg (2.7 mmol) of 5-chloromethyl-3-phenyl-[1,2,4]oxadiazol in acetonitrile at room temperature add 465 mg (2.8 mmol, of 1.05 equiv.) benzosulfimide sodium and 143 mg (0.5 mmol, 0.2 EQ.) 18-crown-6. Continue stirring over night and then further added 50 mg (0.3 mmol, 0,12 EQ.) benzosulfimide sodium, after which the reaction mixture is additionally stirred for one hour. The solvent is evaporated and the resulting oily substance is transferred into EtOAc, washed with saturated solution of NaHCO3. The organic phase is dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel (mixture of heptane/EtOAc in a ratio of 8:2) receive 622 mg (yield 77%) of 5-benzosulfimide-3-phenyl-[1,2,4]oxadiazol in the form of a white solid is th substance, mass spectrum: 301 (MN+).

134.3

In accordance with the methodology, which is similar to the technique of example 74.4, from 5-benzosulfimide-3-phenyl-[1,2,4]oxadiazole and cyclopenten-2-get it 3-[benzazolyl-(3-phenyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereoisomers, white solid, mass spectrum: 400 (MNH4).

134.4

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-[benzazolyl-(3-phenyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone and N-forbindelseshastighed receive 3-[benzosulfimide-(3-phenyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone as not quite white viscous oily substance, mass spectrum: 401 (MN+).

134.5

In accordance with the methodology, which is similar to the technique of example 19.3, from 3-[benzosulfimide-(3-phenyl-[1,2,4]oxadiazol-5-yl)methylene]Cyclopentanone and (4-chlorophenyl)hydrazinecarboxamide get 2-[benzosulfimide-(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indole as a brown solid, mass spectrum: 508 (MH+).

Example 135

Methyl ester of (RS,SR)-2-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]oxazol-4-carboxylic acid

135.1

Mix 17,140 g (0,123 mol) of the hydrochloride of ethyl ether aminouksusnoy sour who you and 15,175 g (0,123 mol, 1 EQ.) hydrochloride ethyl ester acetamidoacrylate in solution in 300 ml of ice water. Add 200 ml of diethyl ether and then 16,97 g (0,123 mol, 1 EQ.) To2CO3. The reaction mixture is stirred for 10 minutes. The organic phase is separated and dried over Na2SO4, filtered and evaporated to dryness, thus obtaining 15,229 g (yield 72%) of ethyl ether (1-amoxicilian-amino)acetic acid as a pale yellow oily substance.

135.2

To a stirred suspension 3,222 g (36 mmol, of 1.05 equiv.) ethoxide potassium in 30 ml of diethyl ether and 5 ml of EtOH at 0°C. slowly add a solution 3,849 g (52 mmol, 1.5 EQ.) ethylformate and 6 g (35 mmol) of ethyl ether (1 ethoxymethyleneamino)acetic acid in 30 ml of diethyl ether and 5 ml of EtOH. The reaction mixture is stirred for one hour at 0°C. After adding 40 ml of diethyl ether, the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the obtained solid is washed with diethyl ether and dried under vacuum, thus obtaining 5 g (yield 60%) 2-etoxycarbonyl-2-(1-ethoxymethyleneamino)ethanolate potassium in the form of an orange solid.

135.3

Dissolve 5 g (25 mmol) 2-etoxycarbonyl-2-(1-ethoxymethyleneamino)ethanolate potassium fully in 15 ml of acetic acid at room temperature and then R is the target is heated to 110°C over night. After cooling, add 100 ml of EtOAc and the resulting solution was neutralized with saturated solution of NaHCO3. The organic phase is separated, dried over Na2SO4, filtered and evaporated. After column chromatography on silica gel (heptane/EtOAc in a ratio of 1:2) gain of 1.74 g (yield 45%) of ethyl ester of 2-methoxazole-4-carboxylic acid as a yellow oily substance, mass spectrum: 156 (MN+).

135.4

To a stirred solution of 1.74 g (11 mmol) of ethyl ester of 2-methoxazole-4-carboxylic acid in 15 ml of carbon tetrachloride at room temperature add 2,994 g (17 mmol, 1.5 EQ.) N-bromosuccinimide and 50 mg (0.2 mmol, 0.02 EQ.) of benzoyl peroxide. The reaction mixture was refluxed over night. The reaction mixture is filtered, the resulting filtrate is extracted using CH2Cl2and a solution of Na2S2O3. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness, thus obtaining 265 mg (yield 10%) ethyl ester 2-bromoethoxy-4-carboxylic acid as a yellow oily substance, mass spectrum: 235 (MN+).

135.5

In accordance with the methodology, which is similar to the technique of example 134.2, ethyl ester 2-bromoethoxy-4-carboxylic acid and benzosulfimide sodium get ethyl ester 2-baselslt the Il-methoxazole-4-carboxylic acid as a white solid, mass spectrum: 296 (MN+).

135.6

In accordance with the methodology, which is similar to the technique of example 74.4, from the ethyl ester of 2-benzensulfonamidelor-4-carboxylic acid and cyclopenten-2-it gets methyl ester 2-[benzazolyl-(3-oxocyclopent)methyl]oxazole-4-carboxylic acid in the form of a racemic mixture of diastereoisomers, in the form of a yellow oily substance, mass spectrum:

364 (MN+).

135.7

In accordance with the methodology, which is similar to the technique of example 74.5, from methyl ester 2-[benzazolyl-(3-oxocyclopent)methyl]oxazole-4-carboxylic acid and N-fluoro-benzosulfimide get methyl ester 2-[benzosulfimide-(3-oxocyclopent)methyl]oxazole-4-carboxylic acid in the form of a racemic mixture of diastereoisomers, white oily substance mass spectrum: 382 (MN+).

135.8

In accordance with the methodology, which is similar to the technique of example 19.3, from methyl ester 2-[benzosulfimide-(3-oxocyclopent)methyl]oxazole-4-carboxylic acid and (4-chlorophenyl)-hydrazinecarboxamide receive the methyl ester of (RS,SR)-2-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]oxazol-4-carboxylic acid as a brown oily substance, mass spectrum:

489 (MN+).

Example 136

2-(Benzolsulfonate the-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

136.1

In accordance with the methodology, which is similar to the technique of example 134.2, from 2-(methyl bromide)-1,3-benzothiazole and benzosulfimide sodium get 2-benzensulfonamidelor in the form of an orange crystalline substance, mass spectrum: 290 (MN+).

136.2

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-benzensulfonamidelor and cyclopenten-2-get it 3-(benzolsulfonate-2-ylmethyl)Cyclopentanone in the form of a racemic mixture of diastereoisomers, in the form of a white powder, mass spectrum:

372 (MN+).

136.3

In accordance with the methodology, which is similar to the technique of example 74.5, from 3-(benzolsulfonate-2-ylmethyl)of Cyclopentanone and N-forbindelseshastighed receive 3-(benzolsulfonate-2-informati)Cyclopentanone in the form of a racemic mixture of diastereoisomers, in the form of a yellow foam substance, mass spectrum: 390 (MN+).

136.4

In accordance with the methodology, which is similar to the technique of example 19.3, from 3-(benzolsulfonate-2-informati)-Cyclopentanone and hydrochloride (4-chlorophenyl)hydrazine get 2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole in the form of a racemic mixture of diastereoisomers, brown oily substance mass spectra is R: 497 (MN +).

Example 137

(RS,SR)-2-[benzazolyl-(4,5-dimethyloxazole-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol

137.1

In accordance with the methodology, which is similar to the technique of example 135.4, from trimethylhexanal get 2-bromomethyl-4,5-dimethyloxazole as a brown oily substance, mass spectrum: 190 (MN+).

137.2

In accordance with the methodology, which is similar to the technique of example 134.2, 2-bromomethyl-4,5-dimethyloxazole and benzosulfimide sodium get 2-benzosulfimide-4,5-dimethyloxazole in the form of a light yellow oily substance, mass spectrum: 364 (MN+).

137.3

In accordance with the methodology, which is similar to the technique of example 74.4, from 2-benzosulfimide-4,5-dimethyloxazole and cyclopenten-2-get it 3-[benzazolyl-(4,5-dimethyloxazole-2-yl)methylene]Cyclopentanone in the form of a racemic mixture of diastereoisomers, light yellow oily substance mass spectrum: 334 (MN+).

137.4

In accordance with the methodology, which is similar to the technique of example 19.3, from 3-[benzazolyl-(4,5-dimethyloxazole-2-yl)methylene]Cyclopentanone and (4-chlorophenyl)hydrazinecarboxamide get (RS,SR)-2-[benzazolyl-(4,5-dimethyloxazole-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b] indole as a pale yellow oily substance, mass spectrum: 441 (MN+ ).

Examples

Example

Tablets, film-coated, containing the following ingredients can be obtained in the conventional way:

IngredientsPills
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Lactose water60,0 mg70.0 mg
Povidone K12.5 mg15,0 mg
Sodium salt of starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(The mass of the nucleus)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 is sifted and mixed with microcrystalline cellulose, and then the resulting mixture granularit using a solution of polyvinylpyrrolidone in water. The obtained granules are mixed with the sodium salt starch glycolate and magnesium stearate, and then pressed while receiving core tablets weighing 120 or 350 mg, respectively. The core tablets are coated using an aqueous solution / suspension of the above components to obtain a film coating.

Example B

Capsules containing the following ingredients can be obtained in the conventional way:

25.0 mg
IngredientsOn capsule
The compound of formula (I)
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

Ingredients sifted, mixed and placed into capsules of size 2.

The example In

Prepare injectable solutions of the following composition:

The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidIn the quantity required to reach pH 5.0
Water for the preparation of solutions for injectionIn an amount necessary to bring to a volume of 1.0 ml

The active ingredient dissolved in a mixture of polyethylene glycol 400 and part of the specified quantity of water for injection. The pH value is brought to a magnitude of 5.0 by addition of acetic acid. The volume was adjusted to 1.0 ml by adding the rest of the water. The solution is filtered, filled them vials of appropriate volume and sterilized.

1. The compounds of formula (I)

in which
n means an integer from 0 to 3;
R 1independently selected from the group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, piperidinyl and-N(R11)(R11), where R11independently selected from lower alkyl and N,
X1X2X3and X4independently selected from nitrogen or carbon, provided that not more than two of X1X2X3and X4can mean nitrogen, and in the case when two of X1X2X3and X4mean nitrogen, n is 0, 1 or 2;
k is the integer 0 or 1;
R2represents H;
R3represents H, lower alkyl or halogen;
R4represents aryl, heteroaryl, lower alkylaryl or lower alkylether, each of which is optionally substituted by substituents in the amount of from one to five, which are independently selected from the group consisting of halogen, lower alkyl, -OR41the bottom quinil and NR42R43where R41represents lower alkyl, R42and R43independently from each other represent hydrogen or lower alkyl, or NR42R43is pyrrolidinyl, or R4represents lower alkyl;
R5selected from the group consisting of
;;
; ;
and
moreover, the mentioned aryl and heteroaryl are optionally substituted at one or more positions by one or more substituents independently selected from the group consisting of H, halogen, lower alkyl and (CH2)vR53where
R51selected from the group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl specified lower alkylaryl is optionally substituted in one or more positions of one or more lower alkyl, -CN, halogen, a group-COOR54and the group-CH2OR54where R54represents a lower alkyl or H;
R52represents lower alkyl or-H;
R53represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2or-CH2OR55where R55independently selected from the group consisting of lower alkyl, -H, -C(O)aryl, or-C(O)-lower alkyl, and R56selected from the group consisting of H, lower alkyl, -C(O)CF3-C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where specified, the aryl and lower alkylaryl are optionally substituted at one or more positions of one or more lower alkyl, halogen, a group-COOR57and the group-CH2OR57where R57predstavljaet a lower alkyl or-H, or R55and R56together with the atom to which they are attached, form a ring system;
or R53represents aryl, which may be optionally substituted benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl,
m means an integer from 0 to 2;
v denotes an integer from 0 to 4;
where the term "lower alkyl" alone or in combination with other groups, refers to a branched or linear monovalent alkyl, the radical containing from one to six carbon atoms, where the term "aryl" alone or in combination with other groups, refers to phenyl or naphthyl, and where the term "heteroaryl" refers to an aromatic 5 - or 6-membered ring, which can contain 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which may be condensed with a phenyl group;
and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

2. Compounds according to claim 1, where
n means an integer from 0 to 3;
R1independently selected from the group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11and-N(R11)(R11), where R11independently selected from lower alkyl and H;
X1X2X3and X4n is dependent selected from nitrogen and carbon, provided that not more than two of X1X2X3and X4can mean nitrogen, and in the case when two of X1X2X3and X4mean nitrogen, n is 0, 1 or 2;
k is the integer 0 or 1;
R2represents H;
R3represents H, lower alkyl or halogen;
R4represents aryl, heteroaryl, lower alkylaryl or lower alkylether, each of which is optionally substituted by substituents in the amount of from one to five, which are independently selected from the group consisting of halogen, lower alkyl and-OR41where R41represents lower alkyl, or R4represents lower alkyl;
R5selected from the group consisting of:
;;
;;
and
specified aryl and heteroaryl are optionally substituted at one or more positions by one or more substituents independently selected from the group consisting of H, halogen, lower alkyl and (CH2)vR53where
R51selected from the group consisting of H, lower alkyl, allyl and lower alkylaryl, and specified low alkylaryl is optionally substituted by the second at one or more positions of one or more lower alkyl, -CN, halogen, a group-COOR54and the group-CH2OR54where R54represents lower alkyl or-H;
R52represents lower alkyl or-H;
R53represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2HE, -CN, -CONH2or-CH2OR55where R55independently selected from the group consisting of lower alkyl, -H, -C(O)aryl, -C(O)-lower alkyl, and R56selected from the group consisting of H, lower alkyl, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where specified, the aryl and lower alkylaryl are optionally substituted at one or more positions of one or more lower alkyl, halogen, a group-COOR57and the group-CH2OR57where R57represents lower alkyl or-H, or R55and R56together with the atom to which they are attached, form a ring system;
m means an integer from 0 to 2;
v denotes an integer from 0 to 4;
and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

3. Compounds according to any one of claims 1 or 2, where each of X1X2X3and X4is the carbon.

4. Compounds according to any one of claims 1 or 2, where X1represents nitrogen, each of X2X3and X4represents the carbon is.

5. Compounds according to claim 1, where n is 1, X2represents a carbon, and R1directly attached to X2-carbon.

6. Compounds according to claim 5, where R1selected from the group consisting of halogen, cyano, nitro, SO2Me, lower alkyl, N(Me)2, NHMe and piperidinyl.

7. Compounds according to claim 6, where R1represents a halogen.

8. Compounds according to claim 7, where R1represents Cl.

9. Compounds according to any one of claims 1 to 2, where n means 2.

10. Compounds according to claim 9, where each R1represents a halogen.

11. Connection of claim 10, where X2means carbon, and one of the groups R1directly attached to X2-carbon.

12. Compounds according to claim 1, where k is 0.

13. Compounds according to claim 1, where R3represents H, halogen or methyl.

14. Compounds according to claim 1, where R3represents F or methyl.

15. Compounds according to claim 1, where R4represents aryl or heteroaryl, each of which is optionally substituted by substituents in the amount of from one to five, which are independently selected from the group consisting of halogen, lower alkyl,
-OR41the bottom quinil and NR42R43where R41represents lower alkyl, R42and R43independently from each other represent hydrogen or lower alkyl, or NR42R43the stand is made by pyrrolidinyl, or R4represents lower alkyl.

16. Compounds according to claim 1, where R4selected from the group consisting of naphthyl, pyridinyl, methyl, phenyl or mono - or disubstituted phenyl, where the Deputy had phenyl is halogen, N(lower alkyl)2or or41and where R41so, as stated in claim 1.

17. Compounds according to claim 1, where R4represents phenyl or mono - or disubstituted phenyl, where one or more of the substituents are a halogen.

18. Compounds according to claim 1, where R4represents phenyl, 4-chlorophenyl, 3-forfinal or 3,4-differenl.

19. Compounds according to claim 1, where R4represents phenyl, 3-bromophenyl or 3-dimethylaminophenyl.

20. Compounds according to claim 1, where R5choose from the group consisting of the following:
;;
;
and
moreover, the specified heteroaryl is optionally substituted in one or more positions of one or more Deputy independently selected from the group consisting of H, halogen, lower alkyl and (CH2)vR53where
R51selected from the group consisting of H, lower alkyl, allyl and lower alkylaryl specified lower alkylaryl optionally substituted in one or more of the provisions of the ne or more lower alkyl, the group-CN, halogen, a group-COOR54and the group-CH2OR54where R54represents lower alkyl or-H;
R52represents lower alkyl or-H;
R53represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, -CONH2or-CH2OR55where R55independently selected from the group consisting of lower alkyl, -H, -C(O)aryl, or-C(O)-lower alkyl, and R56selected from the group consisting of H, lower alkyl, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where specified, the aryl and lower alkylaryl are optionally substituted at one or more positions of one or more lower alkyl, halogen, a group-COOR57and the group-CH2OR57where R57represents lower alkyl or-H, or R55and R56together with the atom to which they are attached, form a ring system;
m means an integer from 0 to 2; and
v denotes an integer from 0 to 4.

21. Compounds according to claim 1, where m is 0.

22. Compounds according to item 21, where R5choose from the group consisting of the following:
;;
and;
where R51selected from the group consisting of H, lower alkyl, allyl, lower alkylaryl, neo is Astelin mono - or disubstituted by one or more lower alkyl, the group-CN, halogen or a group-COOR54where R54represents lower alkyl or-H; and R52represents a lower alkyl or N, and where m is as specified in claim 1.

23. Compounds according to item 21, where R5selected from the group consisting of

the specified heteroaryl is optionally substituted in one or more positions by one or more substituents independently selected from the group consisting of H, halogen, lower alkyl and (CH2)vR53and where m, v and R53are as indicated in claim 1.

24. Compounds according to item 23, where the specified heteroaryl selected from the group consisting of the following heteroaryl:
;;;;
;;
;;;
where v and R53are such as defined in claim 19, R58independently selected from H, halogen and lower alkyl, D1means O or S, and D2means O, S or NR58.

25. Compounds according to any one of claims 1 to 2, where R5selected from the group consisting of:

where aryl is:

where R53, m and v are the so is mi, as indicated in claim 1.

26. Connection A.25, where m is 0.

27. Compounds according to any one of claims 1 to 2, where R5is heteroaryl selected from the group consisting of oxadiazolyl, oxazolyl and benzothiazolyl, specified heteroaryl optionally substituted lower alkyl, lower alkoxycarbonyl or phenyl, the said phenyl optionally substituted by a carboxy group, a lower alkoxycarbonyl, carbamoyl or group di(lower alkyl)carbarnoyl.

28. Connection p, where R5represents 5-methyl-(1,3,4)oxadiazol-2-yl, 5-(methyl ether 4-benzoic acid)-(1,3,4)oxadiazol-2-yl, 5-(4-benzoic acid)-(1,3,4)oxadiazol-2-yl, 5-(4-benzamide)-(1,3,4)oxadiazol-2-yl, 5-(4-dimethylbenzamide)-(1,3,4)oxadiazol-2-yl, 4-(methyl ether carboxylic acid)oxazo-2-yl or benzothiazol-2-yl.

29. Compounds according to any one of claims 1 to 2, characterized by formula (Ia)

where R1, R2, R3, R4, R5, n, k, X1X2X3and X4are as specified in any one of claims 1 to 27.

30. Compounds according to any one of claims 1 to 2, characterized by formula (Ib)

in which R1, R2, R3, R4, R5, n, k, X1X2X3and X4are as specified in any one of claims 1 to 27.

31. Compounds according to any one of claims 1 to 2, selected from the group which ostoja of the following compounds:
methyl ether benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid;
methyl ether benzazolyl-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(6-nitro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(6-cyano-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(6-methanesulfonyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(8-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid;
methyl ester of (RS,SR)benzosulfimide-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)acetic acid;
methyl ether (RS,R)benzazolyl-(6-cyano-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid;
methyl ester of (RS,SR)benzazolyl-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid;
methyl ester of (RS,SR)benzazolyl-(2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-7-yl)forexpros acid;
methyl ester of (RS,SR)benzazolyl-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid;
methyl ester of (RS,SR)benzazolyl-(6-bromo-5-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(7-bromo-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(7-cyano-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(7-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid;
methyl ester of (RS,SR)benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;
methyl ester of (RS,SR)benzazolyl-(7-bromo-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;
methyl ester of (RS,SR)benzazolyl-(5-chloro-1,2,3,8-tetrahydro-4,8-diaza-cyclopent[a]inden-2-
Il)forexpros acid;
methyl ester of (RS,SR)benzazolyl-(7-bromo-6-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;
methyl ether (RSSR)benzazolyl-(7-bromo-8-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;
methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(naphthalene-1-sulfonyl)propionic acid;
methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(naphthalene-2-sulfonyl)propionic acid;
methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(3,4-dichlorobenzenesulfonyl)propionic acid;
methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(toluene-3-sulfonyl)propionic acid;
methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(3-methoxybenzenesulfonyl)propionic acid;
methyl ester of (RS,SR)-2-(2-chlorobenzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(2-methoxybenzenesulfonyl)propionic acid;
methyl ester of (RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-(4-permentantly)propionic acid;
methyl ester of (RS,SR)-2-(3-chlorobenzenesulfonyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(4-permentantly)acetic acid;
methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid;
methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(3-permentantly)acetic acid;
methyl ester of (RS,SR)-(6-chloro-2,3,4,-tetrahydro-1H-carbazole-2-yl)-(3,4-differentiality)forexpros acid;
methyl ester of (RS,SR)-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)fluoro-(pyridine-3-sulfonyl)acetic acid;
methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-methoxybenzenesulfonyl)acetic acid;
methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;
methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(pyridine-2-sulfonyl)acetic acid;
methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-permentantly)acetic acid;
methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-(3,4-differentiality)forexpros acid;
methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(pyridine-3-sulfonyl)acetic acid;
methyl ester of (RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-(pyridine-2-sulfonyl)propionic acid;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
(RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)ftorotana acid;
(RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole;
(RS,SR)-2-benzazolyl-2-(6-methyl-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionitrile;
(RS,SR)benzols lpanel-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forcecontrol;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide;
(RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)-2-fluoro-N-methylacetamide;
(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N-methylacetamide;
(RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-2-(3-permentantly)-N-methylacetamide;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N,N-dimethylacetamide;
(RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)-2-fluoro-N,N-dimethylacetamide;
(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide;
(RS,SR)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide;
(RS,SR)-2-benzazolyl-N-benzyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(4-cyano-benzyl)-2-fluoro-N-methylacetamide;
(RS,SR)-2-benzazolyl-N-(4-bromobenzyl)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(3,5-diferensial)-2-fluoro-N-methylacetamide;
methyl ester of (RS,SR)-4-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]methylamino}methyl)benzoic acid;
methyl EPE is (RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(2-cyano-benzyl)-2-fluoro-N-methylacetamide;
(RS,SR)-N-allyl-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-methylacetamide;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-N-(3-cyano-benzyl)-2-fluoro-N-methylacetamide;
(RS,SR)-3-({[2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-peracetyl]-methylamino}methyl)benzoic acid;
(RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-N-(3-hydroxymethylene)-N-methylacetamide;
(RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(S)-2-[(R)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(R)-2-[(S)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-[1-benzazolyl-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-(benzosulfimide-[1,3,4]oxadiazol-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-6-chloro-2,3,4,9-tetrahydro-1H-carbazole;
(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]ind the l-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}dimethylamine;
(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}dimethylamine;
(RS,SR)-2-[benzosulfimide-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
methyl ester of (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid;
(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methanol;
(RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid;
amide (RS,SR)-5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carboxylic acid;
(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine;
(RS,SR)-7-chloro-2-[(3-chlorobenzenesulfonyl)fluoro-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-7-chloro-2-[(3-chlorobenzenesulfonyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}isoindole-1,3-dione;
(RS,SR)-C-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}methylamine;
(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-is etrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}dimethylamine;
(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}diethylamine;
(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}diethylamine;
(RS,SR)-2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}ndimethylacetamide;
(RS,SR)-N-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}benzamide;
methyl ester of (RS,SR)-2-benzazolyl-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazole-2-yl)propionic acid;
methyl ester (6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)methanesulfonate acid
methyl ester of (RS,SR)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid;
methyl ester of (RS,SR)-2-(6-dimethylamino-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-methanesulfonylaminoethyl acid;
and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

32. The compound according to any one of claims 1 and 2, selected from the group consisting of the following compounds:
methyl ester of (RS,SR)-2-benzazolyl-2-(6-chloro-2,3,4,9-tet is ahydro-1H-carbazole-2-yl)propionic acid;
methyl ester of (RS,SR)benzazolyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)forexpros acid;
methyl ester of (RS,SR)-2-benzazolyl-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid;
methyl ester of (RS,SR)benzazolyl-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;
methyl ester of (RS,SR)benzazolyl-(7-bromo-8-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;
methyl ester of (RS,SR)-(3-chlorobenzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)forexpros acid;
methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(3-permentantly)acetic acid;
methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-(3,4-differentiality)forexpros acid;
(RS,SR)-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)-2-fluoro-2-(3-permentantly)-N,N-dimethylacetamide;
(RS,SR)-2-[benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(S)-2-[(R)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(R)-2-[(S)benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-[benzazolyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)formetal]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-{5-[benzazolyl-(7-x is the PR-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl} dimethylamine;
(RS,SR)-2-[benzosulfimide-(3-methyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-{5-[benzazolyl-(7-chloro-1,2,3,4-tetrahedrite-Penta[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine;
and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

33. Compounds according to any one of claims 1 and 2, selected from the group consisting of the following compounds:
methyl ether (3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)acetic acid;
methyl ester of (RS,SR)-2-(3-brabanthallen)-2-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)propionic acid;
methyl ester of (RS,SR)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)-2-(3-pyrrolidin-1-eventality)propionic acid;
(RS,SR) 2-[1-(3-brabanthallen)-1-(5-methyl-[1,3,4]oxadiazol-2-yl)ethyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-[(3-brabanthallen)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR) 2-[(5-benzyl-[1,3,4]oxadiazol-2-yl)-(3-brabanthallen)-vermeil]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR) {3-[(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methanesulfonyl]phenyl}dimethylamine;
(RS,SR)-7-chloro-2-[(3-ethinyl-benzazolyl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)2-[5-(4-benzyloxybenzyl)-[1,3,4]oxadiazol-2-yl-(3-brabanthallen)formetal]-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indole;
(RS,SR)-7-chloro-2-[(3-ethylbenzonitrile)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indole;
methyl ester of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid;
(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid;
(RS,SR) (4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}-phenyl)methanol;
(RS,SR) 2-{benzosulfimide-[5-(4-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]methyl}-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR) 4-{5-[(benzazolyl)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4] oxadiazol-2-yl}benzoic acid;
(RS,SR) 4-{5-[benzazolyl-(7-chloro-l,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-ylmethyl}benzoic acid;
(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzamide;
(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}-N-methylbenzamide;
(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}-N,N-dimethylbenzamide;
(RS,SR)-2-[-benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-bromo-1,2,3,-tetrahydrocyclopent[b]indole;
(RS,SR)-2-[-benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-piperidine-1-yl-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-N-{2-[-benzosulfimide-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl}-N-methylamine;
2-[benzosulfimide-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-(1-benzazolyl-2-methoxy-1-methylethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-benzazolyl-2-(-6-chloro-2,3,4,9-tetrahydro-lH-carbazole-2-yl)-2-fluoro-N-methyl-N-(3-methylbut-2-enyl)ndimethylacetamide;
(RS,SR)-5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-carbonitrile;
(RS,SR)-{5-[-benzazolyl-(-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-yl)formetal]-[1,2,4]oxadiazol-3-yl}dimethylamine;
methyl ester of (RS,SR)-4-[({5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]benzoic acid;
methyl ester of (RS,SR)-3-[({5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]benzoic acid;
(RS,SR)-{4-[({5-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-amino)methyl]phenyl}methanol;
(RS,SR)-2-(benzosulfimide-2-ylmethyl)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-N-{5-[(S)benzolamide the l-((R)-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]-[1,2,4]oxadiazol-3-ylmethyl}-2,2,2-triptorelin;
2-[benzosulfimide-(3-phenyl-[1,2,4]oxadiazol-5-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
methyl ester of (RS,SR)-2-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]oxazol-4-carboxylic acid;
2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR)-2-[-benzazolyl-(4,5-dimethyloxazole-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

34. Compounds according to any one of claims 1 to 2, selected from the group consisting of the following compounds:
(RS,SR)-2-[(3-brabanthallen)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methyl]-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
(RS,SR) {3-[(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)methanesulfonyl]phenyl}dimethylamine;
methyl ester of (RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid;
(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzoic acid;
(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]oxadiazol-2-yl}benzamide;
(RS,SR) 4-{5-[(3-brabanthallen)-(7-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-2-yl)formetal]-[1,3,4]Accadia the ol-2-yl}-N,N-dimethylbenzamide;
methyl ester of (RS,SR)-2-[-benzazolyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopent[b]indol-2-yl)formetal]oxazol-4-carboxylic acid;
2-(benzolsulfonate-2-informati)-7-chloro-1,2,3,4-tetrahydrocyclopent[b]indole;
and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

35. The method of obtaining the compounds of formula I according to any one of claims 1 to 34, including the stage of interaction of the compounds of formula (II)

in which R2, R3, R4, R5and k have the meanings specified in any one of claims 1 to 32, with a compound of formula III

in which R1n, X1X2X3and X4have the values listed in any one of claims 1 to 32, and optional conversion of the compounds of formula I in a pharmaceutically acceptable salt and/or a pharmaceutically acceptable ester.

36. Compounds according to any one of claims 1 to 34, obtained by reacting the compounds of formula (II)

in which R2, R3, R4, R5and k have the meanings specified in any one of claims 1 to 32, with a compound of formula III

in which R1n, X1X2X3and X4have the values listed in any one of claims 1 to 32, where the resulting compound of formula I optionally may be converted into its pharmaceutical is acceptable salt and/or a pharmaceutically acceptable ester.

37. Pharmaceutical compositions for the treatment of diseases selected from the group consisting of elevated lipids and cholesterol levels, particularly low HDL cholesterol and/or high LDL cholesterol levels, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases including colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases in which there is an inflammatory component, such as Alzheimer's disease and reduced/measurable improvement in cognitive function, comprising the compound according to any one of claims 1 and 2 as an active ingredient and pharmaceutically acceptable the carrier and/or excipient.

38. Compounds according to any one of paragraph and paragraphs 1 and 2, has a therapeutic activity against diseases selected from the group consisting of elevated lipids and cholesterol levels, particularly low HDL cholesterol and/or high LDL cholesterol levels, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, including colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases in which there is an inflammatory component, such as Bo is esgn Alzheimer's disease and reduced/measurable improvement in cognitive function.



 

Same patents:

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

where Xa represents 2 to 4 condensed cycloalkyl, aryl, heterocyclic rings containing 1 to 2 heteroatoms, chosen of N and O, and heteroaryl rings containing 1 to 4 heteroatoms, chosen of N, O or S where said rings can be additionally substituted. (Radical values R1-R4, R1, Y and n are specified in the patent claim), specific representatives of said compounds and a pharmaceutical composition containing them.

EFFECT: new compounds are effective in stimulation of endogenous development or release of growth hormone and can be used in treating obesity, osteoporosis and for increasing muscle bulk and muscle strength.

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel deazapurines of formula (I): and pharmaceutically acceptable salts thereof, where n = 0; R1 is H, -NH2, -NHCH3, -NH-Ac, -OH, F, -OCH3, -CN, -NH(C=O)OC2H5; R2 is H, -NRARB, -ORA, C1-20alkyl, C1-20halogenalkyl, C6-10aryl, where RA and RB each independently represents H, C1-20alkyl, where C6-10aryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of C1-20alkyl, C1-20alkoxy and C1-20thioalkyl; each R3 independently represents H, halogen, CN, C1-20alkyl, C1-20alkoxy, C1-20thioalkyl, a -G-RC group, where G is absent or represents CH2-, -(CH2)2-, -CH=CH-CH2-, -CH-CH-, -OC-, -O- or (C=O) and where RC is H, -NRF-RG , -ORF, -SRF, -S(=O)RF, -S(=O)2RF, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, tert-butyl dimethyl silyloxy, heterocycle, C6-10aryl, C5-14heteroaryl with one N atom as a heteroatom, where RF and RG each independently represents H, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-10aryl, 6-member heterocycle with one O atom as a heteroatom, where RF and RG together form a 3-, 4-, 5-, 6-, 7- or 8-member cycloalkyl, cycloalkenyl, where the said heterocycle relates to a non-aromatic 5-, 6-, 7-member ring or bi- or tri-cyclic group containing condensed 6-member rings with 1-2 heteroatoms independently selected from O, S, N; where each of the said alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of O, halogen, OH, -CN, C1-20halogenalkyl, -CH2CF3, C1-20alkyl, C1-20alkoxy, C3-6cycloalkyl, C6-10aryl, 5- or 6-member heterocycle with one or two N atoms as heteroatoms, NHRh, NRhRi, N-ORh, ORh, C(=O)Rh, S(=O)Rh, S(=O)2Rh, =CR4R5, =NR4, where Rh and Rj present C1-20alkyl, C6-10aryl, and each of R4, R5 independently represents H, OH, ORx or C1-6alkyl, where Rx is C1-6alkyl, where the said aryl can be independently further unsubstituted or substituted with one or more substitutes selected from a group consisting of halogen, C1-20alkyl or C1-20alkoxy.

EFFECT: compounds can inhibit cytokine induced expression of adhesion molecules with endothelial cells, which enables their use in pharmaceutical compositions.

54 cl

Organic compounds // 2379309

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (I) in free or salt form, where Q is a bond, R1 and R2 independently represent H or C1-C8alkyl, or R3 is C1-C8alkyl, R4 and R5 independently represent halogen, C1-C8alkyl, C1-C8haloalkyl, C3-C15carbocyclic group, nitro group, cyano-group, C1-C8alkylsulphonyl group, R6 is H or C1-C8alkyl; W is a group of formula (Wa1) or (Wa2), where A independently represents C or N, or W represents a group of formula (Wb); where Y independently represents C or N; and Z represents N, O or S, or W represents a group of formula (Wc), where Y independently represents C or N; and Z represents O or S; X represents -SO2-, -CH2-, -CH(C1-C8alkyl)- or a bond; m and n each independently represents an integer from 0 to 3; and p is 1, to a pharmaceutical composition with CRTh2 antagonist activity, as well as to use thereof as a medicinal agent and production method thereof.

EFFECT: new compounds which can be used in medicine are obtained and described.

10 cl, 153 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns compounds of general formula I or to their pharmaceutically acceptable salts, where X1 - CH; X2 - N or CH; Q1 represents ,

where X11 - CH or C-halogen; X12 - CH, C-halogen or C-CF3; X13 - CH; X14 - C-E11, and E11 represents C0-10alkyl or C0-10alkoxy; X15 - CH or N; X16 - N or N+ -0; G1 - phenyl or 5-6-members unsaturated ring containing one heteroatom N or S; R1 - C0-10alkyl, cycloC3-10alkyl or piperidinyl, any of which is optionally substituted with 1-2 independent substitutes G11, or R1 represents phenyl; G11 is chosen from: OR21 where R21 represents C0-10alkyl; -oxo; -cycloC3-8alkyl; -C0-10alkyl optionally substituted with group N(C0-10alkyl)(C0-10alkyl) wherein C0-10alkyl is optionally substituted with group N(C0-10alkyl)C(O)C0-10alkyl; group OR2221, where R2221 - C0-10alkyl; group N(C0-10alkyl)C(O)C0-10alkyl; group N(C0-10alkyl)SO2(C0-10alkyl); group -N(C0-10alkyl)C(O)N(C0-10alkyl)(C0-10alkyl); group -N(C0-10alkyl)C(=O)R3331, where R3331 - C1-10alkoxy C1-10alkyl or tetrahydrofuranyl; -N(R21)R31 where R21 and R31 independently represent C0-10alkyl optionally substituted with thiophenyl, morphlinyl, furanyl; cycloC3-8alkyl; C1-10alkoxyC1-10alkyl; tetrahydropyranyl; piperidylC0-10alkyl; or piperidyl optionally substituted with C0-10alkyl; or R21 and R31 optionally taken together with nitrogen atom whereto attached, form 3-10-members saturated ring optionally substituted with one or more independent substitutes G1111, and optionally including one or more heteroatoms different from nitrogen whereto R21 and R31 are attached; where G1111 - C0-10alkyl optionally substituted with group OR77 where R77 - C0-10alkyl, or G1111 represents C1-10alkoxyC1-10alkyl, pirimidinyl, pyrazinyl, imidazolylmethyl; C(O)N(R21)R31 where R21 and R31 independently represent C0-10alkyl; -C(O)O(C0-10alkyl); -C(O) C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or halogen; -heterocyclylC0-10alkyl where heterocyclyl represents 4-6-members saturated ring containing 1 or 2 heteroatoms, independently chosen from N, O or S optionally substituted with a substitute chosen from: 1) OR2221, where R2221 - pyrimidinyl or C0-10lkyl; 2) C(O)OR2221, where R2221 - C0-10alkyl or phenyl-C0-10alkyl; 3) C(O)C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or C1-10alkoxy C1-10alkyl; 4) C(O)N(C0-10alkyl)(C0-10alkyl); 5) S(O)2C0-10alkyl; 6) SO2N(C0-10alkyl)(C0-10alkyl); 7) -NR2221R3331, where R2221 and R3331 taken together with nitrogen atom whereto attached, form pyrrolidinyl; or G11 represents C, which taken together with carbon whereto attached, forms C=C double bond substituted with R5 and G111 where R5 and G111 are hydrogens. The invention also specifically concerns cys-3-[8-amino-1-(2-phenylquinoline-7-yl)-imidazo[1,5-α]pyrazine-3-yl]-1-methl-cyclobutanole or its pharmaceutically acceptable salt. The specified compounds and their pharmaceutically acceptable salts are applicable in treatment of conditions mediated by activity IGF-1R proteinkinase, particularly angiogenesis, vascular permeability, immune response, cell apoptosis, tumour growth or inflammation. The invention also concerns a pharmaceutical composition.

EFFECT: improved efficiency of the composition and method of treatment.

14 cl, 3 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrrolo[3,2-c]pyridine derivatives of formula (I) or their pharmaceutically acceptable salts in which R1 is hydrogen; straight or branched C1-C6alkyl group optionally substituted with one or more substitutes selected from a group consisting of C1-C5alkoxy, hydroxyl, C3-C7 cycloalkyl, C1-C3 alkylthiazolyl and 1,3-dioxolanyl; straight or branched C2-C6 alkenyl group; straight or branched C2-C6 alkynyl group; C3-C7cycloalkyl group; or benzyl group optionally substituted with one or more substitutes selected from a group consisting of halogen, C1-C3alkyl and C1-C3alkoxy, R2 is a straight or branched C1-C6 alkyl group, R3 is hydrogen; straight or branched C1-C6 alkyl group; straight or branched C2-C6alkenyl group; or a benzyl group optionally substituted with one or more halogens, and R4 is 1,2,3,4-tetrahydroisoquinolinyl group; a benzyloxy group optionally substituted with one or more halogens; or an amine group substituted with one or two substitutes selected from a group consisting of hydrogen, straight or branched C1-C5alkylcarbonyl, phenoxycarbonyl, benzyl, optionally substituted with one or more halogens, and benzoyl, optionally substituted with one or more halogens, as well as to method of producing said compounds and a pharmaceutical composition with inhibitory effect on a proton pump containing these compounds.

EFFECT: new compounds are obtained and described, which exhibit excellent inhibitory effect on a proton pump and can provide reversible inhibitory effect on a proton pump.

7 cl, 82 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-H-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazole[3,4-b]pyridine-5-carboxamide, which is a compound of formula or its pharmaceutically acceptable salt, as well as to a method of producing said compounds. The invention also relates to use of the said compound or its pharmaceutically acceptable salt as phosphodiesterase IV (PDE4) inhibitor, for example in treatment and/or prevention of inflammatory and/or allergic disease, cognitive impairment or depression in mammals. The invention particularly pertains to use of the compound or its pharmaceutically acceptable salt in treating and/or preventing atopic dermatitis in mammals, for example via external local administration to a mammal, for example a human being.

EFFECT: pharmaceutical compositions are also provided, which contain the said compound or its pharmaceutically acceptable salt, particularly suitable for external local administration.

35 cl, 1 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

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