Heterocyclic aryl sulphones, suitable for treating disorders responsive to 5ht6 receptor modulation

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

 

The level of technology

The present invention relates to new heterocyclic compounds. These compounds possess valuable therapeutic properties and are suitable, in particular, for treating diseases that respond to modulation of the serotonin receptor 5HT6.

Serotonin (5-hydroxytryptamine, 5HT), monoamine neurotransmitter and local hormone, is produced by hydroxylation and decarboxylation of tryptophan. The highest concentration is formed in enterochromaffin cells of the gastrointestinal tract, the remainder is mainly in platelets and Central nervous system (CNS). NT involved in a large number of physiological and pathophysiological processes. At the periphery it causes a reduction of the number of smooth muscle and causes endothelium-dependent vasodilatation. In the CNS, it is believed that he is involved in a wide range of functions, including appetite control, mood, anxiety, hallucinations, sleep, vomiting and pain sensitivity.

Neurons that secrete NT, referred to as serotonergic. Function NT is mediated through its interaction with specific (serotonergic) neurons. So far, it identified seven types of receptors NT: 5HT1(with subtypes of 5HT1A, 5HT1B, 5HT1D, 5HT 1Eand 5HT1F), 5HT2(with subtypes of 5HT2A, 5HT2Band 5HT1C), 5HT3, 5HT4, 5HT5(with subtypes of 5HT1Aand 5HT1B), 5HT6and 5HT7. Most of these receptors interfaced to G-proteins that affect the activity of either adenylate cyclase or phospholipase Cγ. Human 5HT6receptors positively coupled with adenylate cyclase. They are common on the limbic, veins and cortical areas of the brain and demonstrate a high affinity for the antipsychotic agents.

The modulation of 5HT6receptors suitable substances, as expected, corrects some disorders, including cognitive dysfunction, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease age-related cognitive decline and mild cognitive disturbance, attention deficit disorder/hyperactivity disorder, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive-compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including breach of circadian rhythm), eating disorders such as anorexia and bulimia, some the gastrointestinal disorders, such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal cord trauma, head trauma or head injury such as hydrocephalus, drug addiction and obesity.

Another neurotransmitter involved in the Central nervous system is dopamine. Disorders of the dopaminergic transmitting system lead to diseases of the Central nervous system, which include, for example, schizophrenia, depression and Parkinson's disease. These diseases and others are treated with drugs that interact with dopamine receptors.

Dopamine receptors are divided into two families. On the one hand, there is a group of D2including D2D3and D4receptors, and, on the other hand, group D1including D1and D5the receptors. While D1and D2receptors are widely distributed, D3receptors expressed regioselective. Thus, these receptors are preferentially found in the limbic system and the projected areas of the mesolimbic dopamine system, especially in the adjacent nucleus, but also in other areas, such as olive. Due to its relatively regioselective expression of receptors D3considered as a target, with few side effect the points, and it is assumed that while the electoral D3the ligand has the properties of a known antipsychotic drugs, it will not have their neurological side effects, mediated by the dopamine receptor D2(P.Sokoloff et al., Localization and Function of the D3Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P.Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics, Nature, 347, 146 (1990)).

Compounds with affinity for the dopamine D3receptor, have been described in the prior art in various sources, for example in WO 95/04713, WO 96/23760, WO 97/45503, WO 99/58499 and in unpublished international patent application PCT/EP 2005/011106.

Compounds with affinity to 5HT6receptor, has also been described in the prototypes, for example in WO 2005/037830, WO 2005/026125, WO 00/05225 and WO 98/27081. However, their affinity and selectivity towards 5HT6receptor or their pharmacological profile is not satisfactory.

The purpose of this invention is to provide compounds that have high affinity and selectivity against 5HT6receptor and, optionally, a high affinity and selectivity (in particular, for the D2) in relation to the dopamine receptor D3thus allowing to treat disorders associated with or susceptible to 5HT6the receptors. Connection obladaushi the affinity to both receptors, expected to be suitable for the treatment of disorders associated with or susceptible to both 5HT6receptor and D3receptor, thereby allowing you to treat more than one manifestation of the relevant disorder.

These connections will also have good pharmacological profile, for example a good ratio of concentrations in brain and plasma, good bioavailability, and good metabolic stability or reduced inhibition of mitochondrial respiration.

The invention

The invention is based on the objective of compounds that act as 5HT6receptor ligands. The task unexpectedly is achieved by compounds of the formula I

where

n is 0, 1 or 2;

G represents CH2or CHR3;

R1represents H, C1-C6-alkyl, C1-C6-alkyl, substituted C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, fluorinated C1-C6-alkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6alkenyl, fluorinated C3-C6alkenyl, formyl, acetyl, propionyl or benzyl;

R2, R3and R4independently of one another represent H, methyl, f is ormetal, deformity or trifluoromethyl;

A represents 1,4-phenylene or 1,3-phenylene, which is optionally substituted one, two, three or four substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4-alkoxy;

E represents NR5or CH2where R5represents N or C1-C3-alkyl;

Ar represents a radical of the formula A, B, C, D, E, F or G

where

Rarepresents halogen, hydroxyl, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C6-alkyl, C2-C6alkenyl, fluorinated C2-C6alkenyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, phenylsulfonyl, pyridylsulfonyl, benzyloxy, phenoxy, f the Nile, where phenyl and peredelnyj radical in the five last mentioned radicals may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, CN, nitro, C1-C6-alkylsulphonyl, fluorinated C1-C6-alkylsulphonyl, C1-C6-alkylcarboxylic, fluorinated C1-C6-alkylcarboxylic, carboxy, NH-C(O)-NR6R7, NR6R7, NR6R7-C1-C6-alkylene, O-NR6R7where R6and R7independently of one another represent H, C1-C4-alkyl, fluorinated C1-C4-alkyl or C1-C4-alkoxy or may form, together with N 4-, 5 - or 6-membered saturated or unsaturated ring, R9-CO-NR6-C1-C6-alkylen, where R6defined above and R9represents a C1-C4-alkyl or phenyl, where the phenyl radical may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, CH2-pyridyl, where peredelnyj radical may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, or represents nasy the military or unsaturated aromatic or non-aromatic 3-7 membered heterocyclic ring, contains as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S and/or 1, 2 or 3 containing a heteroatom group selected from NR8where R8represents H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylsulphonyl or fluorinated C1-C4-alkylsulphonyl, SO, SO2and CO, and where the heterocyclic ring may carry 1, 2 or 3 substituent selected from hydroxy, halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, NR6R7-C1-C6-alkylene, where R6and R7defined above, carboxyl and C1-C4-allyloxycarbonyl;

Rband Rcindependently of one another represent H, a halogen, CH3, OCH3CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2CH2CF3or OCH2CF3;

Rddefined as Ra;

Rerepresents H or defined as Ra;

Rfdefined as Ra;

k is 0, 1, 2 or 3; and

j is 0, 1, 2, 3 or 4;

provided that Rais not F, CH2F CHF 2, CF3or OCF3if A represents 1,4-phenylene, Ar is a radical of formula (A) and Rband Rcrepresent H or halogen;

with the exception of compounds where R1represents propyl, G is a CH2, n is 1, A represents 1,4-phenylene, E is NH, Ar is a radical of formula (F) and Rdrepresents halogen, C1-C6-alkyl, C2-C6alkenyl or 5-membered heteroaromatic ring;

and their physiologically acceptable acid additive salt.

The present invention thus relates to compounds of General formula I and to their physiologically acceptable acid additive salts.

In a particular embodiment of the compounds of formula I, Ar is a radical of formula (A), (B), (C), (D) or (E)where the substituents have the following meanings:

Rarepresents halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C6-alkyl, C2-C6alkenyl, fluorinated C2-C6alkenyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, ferroban the th C 1-C6-alkoxy, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, phenylsulfonyl, benzyloxy, phenoxy, where the phenyl radical in the three last mentioned radicals may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, CN, nitro, C1-C6-alkylsulphonyl, fluorinated C1-C6-alkylsulphonyl, C1-C6-alkylcarboxylic, fluorinated C1-C6-alkylcarboxylic, carboxy, NH-C(O)-NR6R7, NR6R7, NR6R7-C1-C6-alkylene, O-NR6R7where R6and R7independently of one another represent H, C1-C4-alkyl, fluorinated C1-C4-alkyl or C1-C4-alkoxy or may form, together with N 4-, 5 - or 6-membered saturated or unsaturated ring, or represents a saturated or unsaturated 3-7 membered heterocyclic ring comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S and/or 1, 2 or 3 containing a heteroatom group selected from NR8where R8presented EET a N, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylsulphonyl or fluorinated C1-C4-alkylsulphonyl, SO, SO2and CO, and where the heterocyclic ring may carry 1, 2 or 3 substituent selected from hydroxy, halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl and C1-C6-alkoxy; and

Rband Rcindependently of one another represent H, a halogen, CH3, OCH3, CHF2, OCHF2, CF3or OCF3;

provided that Rais not F, CH2F, CHF2, CF3or OCF3if A is a 1,4-phenylene and Rband Rcrepresent H or halogen;

and their physiologically acceptable acid additive salt.

The present invention also relates to a pharmaceutical composition that contains at least one compound of the formula I and/or at least one physiologically acceptable acid additive salt of formula I, and together with the corresponding physiologically acceptable carriers and/or auxiliary substances.

The present invention also relates to a method for treating disorders that respond to the effects of antagonists 5HT6receptor or agonists 5HT6specified the method includes introducing an effective amount, hence, is her least one of the compounds of formula I

where

n is 0, 1 or 2;

G represents CH2or CHR3;

R1represents H, C1-C6-alkyl, C1-C6-alkyl, substituted C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, fluorinated C1-C6-alkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6alkenyl, fluorinated C3-C6alkenyl, formyl, acetyl, propionyl or benzyl;

R2, R3and R4independently of one another represent H, methyl, vermeil, deformity or trifluoromethyl;

A represents 1,4-phenylene or 1,3-phenylene, which is optionally substituted one, two, three or four substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4-alkoxy;

E represents NR5or CH2where R5represents N or C1-C3-alkyl;

Ar represents a radical of the formula A, B, C, D, E, F or G

where

Rarepresents halogen, hydroxy, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-and what coxi-C 1-C6-alkyl, C2-C6alkenyl, fluorinated C2-C6alkenyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, phenylsulfonyl, pyridylsulfonyl, benzyloxy, phenoxy, phenyl, where phenyl and peredelnyj radical in the five last mentioned radicals may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, CN, nitro, C1-C6-alkylsulphonyl, fluorinated C1-C6-alkylsulphonyl, C1-C6-alkylcarboxylic, fluorinated C1-C6-alkylcarboxylic, carboxy, NH-C(O)-NR6R7, NR6R7, NR6R7-C1-C6-alkylene, O-NR6R7where R6and R7independently of one another represent H, C1-C4-alkyl, fluorinated C1-C4-alkyl or C1-C4-alkoxy, or can about razvivat together with N 4-, 5 - or 6-membered saturated or unsaturated ring, R9-CO-NR6-C1-C6-alkylen, where R6defined above and R9represents a C1-C4-alkyl or phenyl, where the phenyl radical may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, CH2-pyridyl, where peredelnyj radical may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, or represents a saturated or unsaturated aromatic or non-aromatic 3-7 membered heterocyclic ring comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S and/or 1, 2 or 3 containing a heteroatom group selected from NR8where R8represents H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylsulphonyl or fluorinated C1-C4-alkylsulphonyl, SO, SO2and CO, and where the heterocyclic ring may carry 1, 2 or 3 substituent selected from hydroxy, halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio, fluorinated C1-C -alkylthio, NR6R7-C1-C6-alkylene, where R6and R7defined above, carboxyl and C1-C4-allyloxycarbonyl;

Rband Rcindependently of one another represent H, a halogen, CH3, OCH3CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2CH2CF3or OCH2CF3;

Rddefined as Ra;

Rerepresents H or defined as Ra;

Rfdefined as Ra;

k is 0, 1, 2 or 3; and

j is 0, 1, 2, 3 or 4;

and/or at least one physiologically acceptable acid additive salt of formula I to a subject in need of it.

The present invention also relates to the use of compounds as defined for the above method and/or its physiologically acceptable acid salt additive, to obtain a pharmaceutical composition for treating a medical disorder susceptible to treatment with ligand 5HT6the receptor.

In a specific embodiment, the compound used in accordance with the invention or the method according to the invention, defined above, but with the above conditions.

In a particular embodiment of the use and method according invented the Yu in the compounds of formula I, Ar is a radical of formula (A), (B), (C), (D) or (E)where the substituents have the following meanings:

R1represents H, C1-C6-alkyl, C1-C6-alkyl, substituted C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, fluorinated C1-C6-alkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6alkenyl, fluorinated C3-C6alkenyl, formyl, acetyl or propionyl;

Rarepresents halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C6-alkyl, C2-C6alkenyl, fluorinated C2-C6alkenyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, phenylsulfonyl, benzyloxy, phenoxy, where the phenyl radical in the three last mentioned radicals may be unsubstituted or may carry 1 to 3 substituents, selected the C 1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, CN, nitro, C1-C6-alkylsulphonyl, fluorinated C1-C6-alkylsulphonyl, C1-C6-alkylcarboxylic, fluorinated C1-C6-alkylcarboxylic, carboxy, NH-C(O)-NR6R7, NR6R7, NR6R7-C1-C6-alkylene, O-NR6R7where R6and R7independently of one another represent H, C1-C4-alkyl, fluorinated C1-C4-alkyl or C1-C4-alkoxy or may form, together with N 4-, 5 - or 6-membered saturated or unsaturated ring, or represents a saturated or unsaturated 3-7 membered heterocyclic ring comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S and/or 1, 2 or 3 containing a heteroatom group selected from NR8where R8represents H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylsulphonyl or fluorinated C1-C4-alkylsulphonyl, SO, SO2and CO, and where the heterocyclic ring may carry 1, 2 or 3 substituent selected from hydroxy, halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl and C1-C6-alkoxy; and

Rband Rcindependently from each other represent Cobain, halogen, CH3, OCH3, CHF2, OCHF2, CF3or OCF3;

provided that Rais not F, CH2F, CHF2, CF3or OCF3if A is a 1,4-phenylene and Rband Rcrepresent H or halogen.

Detailed description of the invention

Further comments are made regarding the preferred aspects of the invention, for example, the preferred values of the variables of the compounds I, preferred compounds I and the preferred embodiments of the method or use according to this invention, applicable in each case, to themselves or their combinations.

Diseases that are sensitive to the effects of antagonists or agonists 5HT6receptors include, in particular, disorders and diseases of the Central nervous system, in particular cognitive dysfunction, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease age-related cognitive decline and mild cognitive disturbance, attention deficit disorder/hyperactivity disorder, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, bipolar disorder, anxiety and obsessive-compulsive disorders, motion or motorsierrista, such as Parkinson's disease and epilepsy, migraine, sleep disorders (including breach of circadian rhythm), eating disorders such as anorexia and bulimia, certain gastrointestinal disorders such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal cord trauma, head trauma or head injury such as hydrocephalus, drug addiction and obesity.

In accordance with the invention, at least one compound of General formula I having values originally mentioned, is used to treat the above symptoms. The compounds of formula I of this structure may exist in different spatial locations, for example if they possess one or more centers of asymmetry, polyamidine rings or double bonds, or as different tautomers, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, however, preferred appropriate especially pure enantiomers, diastereomers and tautomers of compounds of formula I and/or their salts.

In particular, the carbon atom of the ring containing the nitrogen carrying A group can have (S)- or (R)-configuration. However, (S)-configuration is preferred.

Moreover, the radical A mo is et to be in CIS - or TRANS-position is obtained to any one of the substituents R 2, R3or R4(if at least one of them represents hydrogen). However, the TRANS-position is obtained is preferred.

Similarly, it is possible to apply physiologically acceptable salts of the compounds of formula I, especially an acid additive salts with physiologically acceptable acids. Examples of suitable physiologically acceptable organic and inorganic acids are hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, C1-C4-alkylsulfonate acid, such as methanesulfonate acid, aromatic sulfonic acid, such as benzolsulfonat acid and toluensulfonate acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic and benzoic acid. Other usable acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basel and Stuttgart, 1966.

Organic residues referred to in the above definitions represent variables, similar to the term "halogen" are General terms for individual definitions of individual group members. The prefix Cn-Cmrepresents in each case, the possible number of carbon atoms in the group.

The term "halogen" means, in each case fluorine, bromine, chlorine or iodine, the particular fluorine, chlorine or bromine.

C1-C4alkyl represents an alkyl group with straight or branched chain, having from 1 to 4 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, ISO-propyl, n-butyl, 2-butyl, ISO-butyl ortert-butyl. C1-C2alkyl represents methyl or ethyl, C1-C3alkyl represents, in addition, n-propyl or isopropyl.

C1-C6alkyl represents an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms. Examples include C1-C4alkyl as mentioned above and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

Fluorinated C1-C6alkyl represents an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms (= fluorinated C1-C4alkyl), in particular from 1 to 3 carbon atoms (= fluorinated C1-C3alkyl), where at least one, e.g. 1, 2, 3, 4 and the and all hydrogen atoms replaced by fluorine atom, for example, as in permatile, deformative, trifluoromethyl, (R)-1-veratile, (S)-1-veratile, 2-veratile, 1,1-deperately, 2,2-deperately, 2,2,2-triptoreline, 1,1,2,2-tetraborate, (R)-1-forprofile, (S)-1-forprofile, 2-forprofile, 3-forprofile, 1,1-deferrable, 2,2-deferrable, 3,3-deferrable, 3,3,3-triptocaine, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, (R)-2,2-debtor-1-methylethyl, (S)-2,2-debtor-1-methylethyl, (R)-1,2-debtor-1-methylethyl, (S)-1,2-debtor-1-methylethyl, (R)-2,2,2-Cryptor-1-methylethyl, (S)-2,2,2-Cryptor-1-methylethyl, 2-fluoro-1-(permitil)ethyl, 1-(deformity)-2,2-deperately, 1-(trifluoromethyl)-2,2,2-triptoreline, 1-(trifluoromethyl)-1,2,2,2-tetraborate, (R)-1-terbutyl, (S)-1-terbutyl, 2-terbutyl, 3-terbutyl, 4-terbutyl, 1,1-deverbative, 2,2-deverbative, 3,3-deverbative, 4,4-deverbative, 4,4,4-triptoreline and the like.

Branched C3-C6alkyl is an alkyl having 3-6 carbon atoms, at least one of which is a secondary or tertiary carbon atom. Examples are isopropyl,tert-butyl, 2-butyl, isobutyl, 2-pentyl, 2-hexyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1-methyl-1-ethylpropyl.

Fluorinated branched C3-C6alkyl is an alkyl having 3-6 carbon atoms, at least one secondary or tertiary carbon atom, where IU is greater least one, for example, 1, 2, 3, 4 or all of the hydrogen atoms replaced by fluorine atom.

C1-C6alkoxy is an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms (= C1-C4alkoxy), which is connected with the rest of the molecule through an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, out-butoxy,tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3 methylbutoxy, 2,2-DIMETHYLPROPANE, 1 ethylpropoxy, hexyloxy, 1,1-DIMETHYLPROPANE, 1,2-DIMETHYLPROPANE, 1 methylpentylamino, 2-methylpentylamino, 3 methylpentane, 4-methylpentane, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,2-dimethylbutylamino, 2,3-dimethylbutylamino, 3,3-dimethylbutylamino, 1 ethylbutyrate, 2-ethylbutylamine, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.

Fluorinated C1-C6alkoxy represents alkoxygroup straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms (= fluorinated C1-C4alkoxy), where at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms replaced by fluorine atoms, for example, as in formatosi, deformedarse, triptoreline, (R)-1-floratone, (S)-1-floratone, 2-floratone, 1,1-diflorasone,2,2-diflorasone, 2,2,2-triptoreline, 1,1,2,2-tetrafluoroethoxy, (R)-1-forproperty, (S)-1-forproperty, (R)-2-forproperty, (S)-2-forproperty, 3 forproperty, 1,1-diffiplomacy, 2,2-diffiplomacy, 3,3-diffiplomacy, 3,3,3-cryptocracy, (R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy, (R)-2,2-debtor-1 methylethoxy, (S)-2,2-debtor-1 methylethoxy, (R)-1,2-debtor-1 methylethoxy, (S)-1,2-debtor-1 methylethoxy, (R)-2,2,2-Cryptor-1 methylethoxy, (S)-2,2,2-Cryptor-1 methylethoxy, 2-fluoro-1-(permitil)ethoxy, 1-(deformity)-2,2-diflorasone, (R)-1-forbooks, (S)-1-forbooks, 2-forbooks, 3 forbooks, 4-forbooks, 1,1-diperbaiki, 2,2-diperbaiki, 3,3-diperbaiki, 4,4-diperbaiki, 4,4,4-triptoreline and the like.

C1-C6hydroxyalkyl represents an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms (= C1-C4hydroxyalkyl), in particular from 1 to 3 carbon atoms (= C1-C3hydroxyalkyl), where one of the hydrogen atoms substituted by a hydroxy-group, such as 2-hydroxyethyl or 3-hydroxypropyl.

C1-C6-alkoxy-C1-C6-alkyl represents an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms, particularly from 1 to 3 carbon atoms, where one of the hydrogen atoms substituted C1-C6-alkoxygroup, is for example, as methoxymethyl, 2-methoxyethyl, ethoxymethyl, 3-methoxypropyl, 3-ethoxypropane and the like.

C1-C6-alkoxy-C1-C6-alkoxy is an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms, particularly from 1 to 3 carbon atoms, where one of the hydrogen atoms substituted C1-C6-alkoxygroup, for example, as a 2-methoxyethoxy, ethoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane and the like.

C1-C6-alkylsulphonyl represents an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms (= C1-C4alkylsulphonyl), in particular from 1 to 3 carbon atoms (= fluorinated C1-C3alkylsulphonyl), where one of the hydrogen atoms is substituted by a carbonyl group (CO), for example, as in the acetyl and propionyl.

Fluorinated C1-C6-alkylsulphonyl represents an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms (= fluorinated C1-C4alkylsulphonyl), in particular from 1 to 3 carbon atoms (= fluorinated C1-C3alkylsulphonyl), where one of the hydrogen atoms is substituted by a carbonyl group (CO) and where at least one of ostasis the hydrogen atoms, for example, 1, 2, 3 or 4 hydrogen atoms replaced by fluorine atom, for example, as TRIFLUOROACETYL and 3,3,3-triptocaine.

C1-C6-alkylcarboxylic represents an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms (= C1-C4alkylcarboxylic), in particular from 1 to 3 carbon atoms (= C1-C4alkylcarboxylic), where one of the hydrogen atoms replaced by carbylamines (CO-NH-), for example, as acetamido (acetylamino) (CH3CONH -), propionamide (CH3CH2CONH-).

Fluorinated C1-C6-alkylcarboxylic represents an alkyl group with straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms (= fluorinated C1-C4alkylcarboxylic), in particular from 1 to 3 carbon atoms (= fluorinated C1-C4alkylcarboxylic), where one of the hydrogen atoms replaced by carbylamines (CO-NH-) and where at least one of the remaining hydrogen atoms, e.g. 1, 2, 3 or 4 hydrogen atoms replaced by fluorine atom, for example, as in triptorelin and 3,3,3-triphosphopyridine.

C1-C6alkylthio (also defined as C1-C6-alkylsulfanyl) (or C1-C6-alkylsulfonyl or C1-C6-alkylsulfonyl, according to the government) refers to alkyl groups of straight or branched chain, having from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms, which are connected with the rest of the molecule via a sulfur atom (or S(O)O in case of alkylsulfonyl or S(O)2O in case alkylsulfonyl, respectively, at any bond in the alkyl group. Examples for C1-C4-alkylthio include methylthio, ethylthio, propylthio, isopropylthio and n-butylthio. Examples for C1-C4-alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl and n-butylsulfonyl. Examples for C1-C4-alkylsulfonyl include methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl and n-butylsulfonyl.

Fluorinated C1-C6alkylthio (also defined as fluorinated C1-C6-alkylsulfanyl) is allylthiourea straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms, where at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms replaced by fluorine atoms. Fluorinated C1-C6alkylsulfonyl is alkylsulfonyl group with a straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms, where at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms replaced by fluorine atoms. Fluorinated C1-C6alkylsulfonyl is the Oh alkylsulfonyl group with a straight or branched chain, having from 1 to 6, especially from 1 to 4 carbon atoms, where at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms replaced by fluorine atoms.

C3-C6cycloalkyl represents a cycloaliphatic radical having from 3 to 6 atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl radical may be unsubstituted or may have 1, 2, 3 or 4 C1-C4alkyl radicals, preferably methyl radicals. One alkyl radical preferably located in the 1-position cycloalkyl radical, for example, as in 1-methylcyclopropyl or 1-methylcyclobutene.

Fluorinated C3-C6cycloalkyl represents a cycloaliphatic radical having from 3 to 6 atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, where at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms replaced by fluorine atoms, for example, as in 1-ferricopiapite, 2-ferricopiapite, (S)- and (R)-2,2-divorcecare, 1,2-divorcecare, 2,3-divorcecare, panafcortelone, 1-forceclosure, 2-forceclosure, 3-forceclosure, 2,2-diversilobum, 3,3-diversilobum, 1,2-diversilobum, 1,3-diversilobum, 2,3-diversilobum, 2,4-diversilobum or 1,2,2-triptoreline.

C2-C6alkenyl is abiotically unsaturated hydrocarbon radical, having 2, 3, 4, 5 or 6 C atoms, for example vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl (2-methylprop-2-EN-1-yl) and the like. C3-C6alkenyl represents, in particular, allyl, 1-methylprop-2-EN-1-yl, 2-butene-1-yl, 3-butene-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-EN-1-yl or 2-aterproof-2-EN-1-yl.

Fluorinated C2-C6alkenyl is a separate unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 C atoms, where at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms replaced by fluorine atoms, for example, as in 1-pervenire, 2-pervenire, 2,2-pervenire, 3,3,3-forproposal, 1,1-debtor-2-propenyl, 1-fluoro-2-propenyl and the like.

C1-C6-alkylen is a hydrocarbon bridging group having 1, 2, 3, 4, 5 or 6 carbon atoms such as methylene, ethylene, 1,2 - and 1,3-propylene, 1,4-butylene and the like.

Examples having 5 or 6-member heteroaromatic radicals include 2-, 3 - or 4-pyridyl, 2-, 4 - or 5-pyrimidinyl, pyrazinyl, 3 - or 4-pyridazinyl, 2 - or 3-thienyl, 2 - or 3-furyl, 2 - or 3-pyrrolyl, 2-, 3 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 3 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-imidazolyl, 2 - or 5-[1,3,4]oxadiazolyl, 4 - or 5-[1,2,3]oxadiazolyl, 3 - or 5-[1,2,4]oxadiazolyl, 2 - or 5-[1,3,4]thiadiazolyl, 2 - or 5-[1,3,4]tiava is alil, 4 - or 5-[1,2,3]thiadiazolyl, 3 - or 5-[1,2,4]thiadiazolyl, 1H-, 2Hor 3H-1,2,3-triazole-4-yl, 2H-triazole-3-yl, 1H-, 2Hor 4H-1,2,4-triazolyl and 1Hor 2H-tetrazolyl, which may be unsubstituted or which may carry 1, 2 or 3 of the above-mentioned radicals Ra.

Examples of the phenyl rings, condensed with a saturated or unsaturated 5 or 6 member carbocyclic or heterocyclic ring include indenyl, indanyl, naphthyl, 1,2 - or 2,3-dihydronaphtho, tetralin, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazyl, indolyl, indazoles, benzimidazoles, benzoxadiazole, benzoxadiazole, benzothiadiazole, benzoxazines, dihydroisoxazole, chinoline, ethenolysis, tetrahydroisoquinoline, bromanil, bromanil and the like, which may be unsubstituted or which may carry 1, 2 or 3 of the above-mentioned radicals Ra. Specified condensed system can be connected with the remainder of the molecule (more precisely sulfonyloxy group) through the carbon atoms of the phenyl residue or through the atoms (C - or N-atoms) ring fused with a phenyl.

Examples of saturated or unsaturated 3-7 membered heterocyclic rings (as radicals Rainclude saturated or unsaturated aromatic or non-aromatic heterocyclic ring. Examples of such clicks the zoom, include, in addition to defined above, 5 - or 6-membered heteroaromatic radicals, ezyrider, diaziridines, oxiranyl, azetidine, athetini, di - and tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, oxopyrrolidin, pyrazolines, pyrazolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, oxo-oxazolidinyl, isoxazolyl, isoxazolidine, piperidine, piperazinil, morpholinyl, thiomorpholine, Osotimehin, diocletianopolis and the like.

If R6and R7form together with the N 4-, 5 - or 6-membered ring, examples for the specified type of radical include, in addition to defined above, 5 - or 6-membered heteroaromatic radical containing at least one N atom as a ring member, azetidine, athetini, pyrrolidyl, pyrrolidinyl, pyrazolyl, pyrazolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, piperidine, piperazinil, morpholinyl and the like.

In the compounds of the formula I n preferably has a value of 0 or 1; that is, the nitrogen-containing ring is azetidinol group or pyrrolidinyl group; and, in particular, n has a value of 1, which means that in a particularly preferred embodiment of the nitrogen-containing ring is pyrrolidinyl ring.

Preferably, the radical R1selected from H, C1-C4-alkyl is, C1-C4of alkyl, substituted C3-C6-cycloalkyl or hydroxy, fluorinated C1-C4-alkyl, C2-C4-alkenyl and benzyl. More preferably is selected from H, propyl, cyclopropylmethyl, fluorinated ethyl, e.g. 2-veratile, fluorinated propyl, e.g. 3-forprofile, hydroxypropyl, for example 3-hydroxypropyl, propionyl, allyl and benzyl. More preferably, R1selected from H, propyl, ethyl, methyl, cyclopropylmethyl, 2-veratile, 3-forprofile, 3-hydroxypropyl, allyl and benzyl. Even more preferably, R1selected from H, propyl, cyclopropylmethyl, 2-veratile, 3-forprofile, 3-hydroxypropyl, allyl or benzyl. In a particularly preferred embodiment, R1represents N, n-propyl or allyl, in particular H or n-propyl, in particular H.

Preferably, R2, R3and R4represent N, CH3or CH2F and more preferably H.

If the group A is substituted, preferred substituents selected from halogen, especially fluorine, methyl, diformate, trifloromethyl, methoxy, deformedarse, triptoreline. More preferred substituents selected from halogen, in particular fluorine and methoxy. Specifically, the Deputy represents methoxy. Examples include 2-FPO is -1,4-phenylene, 3-fluoro-1,4-phenylene, 2-fluoro-1,3-phenylene, 4-fluoro-1,3-phenylene, 2-methoxy-1,4-phenylene, 3-methoxy-1,4-phenylene, 2-methoxy-1,3-phenylene and 3-methoxy-1,3-phenylene. In a particular embodiment, But is an unsubstituted 1,4-phenylene or unsubstituted 1,3-phenylene. More specifically, a represents a 1,3-peridinin, in particular unsubstituted 1,3-peridinin.

Group E preferably represents NR5more preferably NH or NCH3in particular NH.

In one of preferred embodiments of the invention Ar is a radical of formula (A), (B), (C), (D) or (E). Especially preferred is the radical (A). Among peredelnyh radicals (B)-(E) are preferred radicals (C) and (E).

In these Ar the radicals (A)-(E) Rapreferably selected from the group consisting of halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C6-alkyl, C2-C6-alkenyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkoxy, fluorinated C1-C6-alkoxy, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfonyl, phenylsulfonyl, benzyloxy, phenoxy, CN, nitro, acetyl, TRIFLUOROACETYL, acetamido, carbon and, NH-C(O)-NH2, NR6R7, NR6R7-C1-C6-alkylene, O-NR6R7where R6and R7independently of one another represent H, C1-C4-alkyl, fluorinated C1-C4-alkyl or C1-C4-alkoxy and a saturated or unsaturated aromatic or non-aromatic 3-7 membered heterocyclic ring comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S and/or 1, 2 or 3 containing a heteroatom group selected from NR8where R8defined above and preferably represents H or C1-C4-alkyl, such as methyl, SO, SO2and CO, and where the 3-7-membered heterocyclic ring may carry 1, 2 or 3 substituent selected from hydroxy, halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl and C1-C6-alkoxy.

Preferably, a saturated or unsaturated aromatic or non-aromatic 3-7 membered heterocyclic ring selected from azetidin-1-yl, 2-methylaziridinyl, 3-methoxyacridine, 3-hydroxyazetidine, 3-porazitelnie, 2,2-diversecity-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2 - and 3-ftorpirimidinu-1-yl, 2,2-debtorprovidian-1-yl, 3,3-debtorprovidian-1-yl, 2 - and 3-methylpyrrolidine-1-yl 1 methylpyrrolidine-2-yl, 2,2-dimethylpiperidin-1-yl, 3,3-dimethylpyrrole the Jn-1-yl, 2-oxo-pyrrolidin-1-yl, 2 - and 3-triftormetilfullerenov-1-yl, 2-oxo-oxazolidin-1-yl, piperidine-1-yl, 2-methylpiperidin-1-yl, 2-foreperiod-1-yl, 2,2-deformability-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-yl, 1-methylpyrrole-3-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, 5-propylthiophene-2-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, 1-methylpyrazole-4-yl, 4-perperson-1 ILA, imidazol-1-yl, imidazol-2-yl, 1-Mei-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2-methylthiazole-4-yl, 2-methylthiazole-5-yl, [1,2,3]triazole-1-sludge, [1,2,4]triazole-1-yl, [1,2,3]triazole-2-yl, [1,2,4]triazole-3-yl, [1,2,4]triazole-4-yl, 4-methyl-[1,2,4]triazole-3-yl, 2-methyl-[1,2,3]triazole-4-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, [1,2,4]-oxadiazol-5-yl, [1,2,3]-oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl, 5-methyl-[1,2,4]-oxadiazol-3-yl, [1,2,3]thiadiazole-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl, furazan-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4 ILA, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl and 2-methylpyrimidin-4-yl.

More preferably, a saturated or unsaturated 3-7 membered hetero is clichesque the ring selected from nitrogen-containing rings, such as azetidin-1-yl, 2-methylaziridinyl, 3-methoxyacetyl, 3-hydroxyazetidine, 3-foreseeing, 2,2-diversecity-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2 - and 3-ftorpirimidinu-1-yl, 2,2-debtorprovidian-1-yl, 3,3-debtorprovidian-1-yl, 2 - and 3-methylpyrrolidine-1-yl, 1-methylpyrrolidine-2-yl, 2,2-dimethylpyrimidin-1-yl, 3,3-dimethylpiperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2 - and 3-triftormetilfullerenov-1-yl, 2-oxo-oxazolidin-1-yl, piperidine-1-yl, 2-methylpiperidin-1-yl, 2-foreperiod-1-yl, 2,2-deformability-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-yl, 1-methylpyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, 1-methylpyrazole-4-yl, 4-perperson-1-yl, imidazol-1-yl, imidazol-2-yl, 1-Mei-2-Il, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2-methylthiazole-4-yl, 2-methylthiazole-5-yl, [1,2,3]triazole-1-yl, [1,2,4]triazole-1-yl, [1,2,3]triazole-2-yl, [1,2,4]triazole-3-yl, [1,2,4]triazole-4-yl, 4-methyl-[1,2,4]triazole-3-yl, 2-methyl-[1,2,3]triazole-4-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, [1,2,4]-oxadiazol-5-yl, [1,2,3]-oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl, 5-methyl-[1,2,4]-oxadiazol-3-yl, [1,2,3]thiadiazole-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-the l 1-methyltetrazol-5-yl, furazan-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl and 2-methylpyrimidin-4-yl.

Even more preferably, a saturated or unsaturated 3-7 membered heterocyclic ring selected from nitrogen-containing rings, which are connected with phenyl or pyridinium ring group Ar through their nitrogen atom, such as azetidin-1-yl, 2-methylaziridine-1-yl, 3-methoxyisatin-1-yl, 3-hydroxyazetidine-1-yl, 3-torasemide-1-yl, 2,2-diversecity-1-yl, pyrrolidin-1-yl, 2 - and 3-ftorpirimidinu-1-yl, 2,2-debtorprovidian-1-yl, 3,3-debtorprovidian-1-yl, 2 - and 3-methylpyrrolidine-1-yl, 2,2-dimethylpiperidin-1-yl, 3,3-dimethylpiperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2 - and 3-triftormetilfullerenov-1-yl, 2-oxo-oxazolidin-1-yl, piperidine-1-yl, 2-methylpiperidin-1-yl, 2-foreperiod-1-yl, 2,2-deformability-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, pyrrol-1-yl, pyrazole-1-yl, 4-perperson-1-yl, imidazol-1-yl, [1,2,3]triazole-1-yl, [1,2,4]triazole-1-yl, [1,2,3]triazole-2-yl, [1,2,4]triazole-3-yl, [1,2,4]triazole-4-yl, 4-methyl-[1,2,4]triazole-3-yl, 2-methyl-[1,2,3]triazole-4-yl, tetrazol-1-yl and tetrazol-2-yl.

In the alternative even more preferred embodiment, a saturated or unsaturated 3-7 membered heterocyclic ring selected from 5 - or 6-membered, preferably 5-membered, satsadaram heteroaromatic rings, linked via a carbon atom, such as pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-yl, 1-methylpyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, 1-methylpyrazole-4-yl, imidazol-2-yl, 1-Mei-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2-methylthiazole-4-yl, 2-methylthiazole-5-yl, [1,2,3]triazole-2-yl, [1,2,4]triazole-3-yl, [1,2,4]triazole-4-yl, 4-methyl-[1,2,4]triazole-3-yl, 2-methyl-[1,2,3]triazole-4-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, [1,2,4]-oxadiazol-5-yl, [1,2,3]-oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl, 5-methyl-[1,2,4]-oxadiazol-3-yl, [1,2,3]thiadiazole-4-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl furazan-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl and 2-methylpyrimidin-4-yl.

Heterocyclic ring is unsubstituted or substituted by one Deputy, which is preferably selected from halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy and fluorinated C1-C4-alkoxy, in particular halogen, especially fluorine, C1-C4-alkyl, in particular methyl and fluorinated C1-C4-alkyl, in particular fluorinated methyl.

In the preferred embodiment Raselected from the group consisting of halogen, C1-C6-is Lila, C1-C6-hydroxyalkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, C2-C4-alkenyl, fluorinated C2-C4-alkenyl, NR6R7, ONR6R7C1-C6-alkylene-NR6R7where R6and R7independently of one another represent H, C1-C4-alkyl or C1-C4-alkoxy, ureido (NHCONH2), C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, acetyl, carboxyl, hydroxy, cyano, nitro, benzoxa, methylsulfanyl, pharmacysulfacet, deformational, trifloromethyl, methylsulphonyl and one of the above-mentioned saturated or unsaturated 3-7 membered heterocyclic ring, in particular azetidin-1-yl, 2-methylaziridinyl, 3-methoxyacetyl, 3-hydroxyazetidine, 3-foreseeing, 2,2-diversecity-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2 - and 3-ftorpirimidinu-1-yl, 2,2-debtorprovidian-1-yl, 3,3-debtorprovidian-1-yl, 2 - and 3-methylpyrrolidine-1-yl, 1-methylpyrrolidine-2-yl, 2,2-dimethylpiperidin-1-yl, 3,3-dimethylpiperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2 - and 3-triftormetilfullerenov-1-yl, 2-oxo-oxazolidin-1-yl, piperidine-1-yl, 2-methylpiperidin-1-yl, 2-foreperiod-1-yl, 2,2-deformability-1-yl, n is perazin-1-yl, 4-methylpiperazin-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-yl, 1-methylpyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, 1-methylpyrazole-4-yl, 4-perperson-1-yl, imidazol-1-yl, imidazol-2-yl, 1-Mei-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2-methylthiazole-4-yl, 2-methylthiazole-5-yl, [1,2,3]triazole-1-yl, [1,2,4]triazole-1-yl, [1,2,3]triazole-2-yl, [1,2,4]triazole-3-yl, [1,2,4]triazole-4-yl, 4-methyl-[1,2,4]triazole-3-yl, 2-methyl-[1,2,3]triazole-4-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, [1,2,4]-oxadiazol-5-yl, [1,2,3]-oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl, 5-methyl-[1,2,4]-oxadiazol-3-yl, [1,2,3]thiadiazole-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl, furazan-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl and 2-methylpyrimidin-4-yl.

In a more preferred embodiment Raselected from the group consisting of halogen, C1-C6-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, OCF3, OCHF2, OCH2F, 2 floratone, 2,2-diflorasone, 2,2,2-triptoreline, 1,1,2,2-tetrafluoroethoxy, 1,1,2,2,2-pentaverate, C2-C4-alkenyl, C3-C6-cycloalkyl, fluorinated C -C6-cycloalkyl, ureido, acetyl, acetylamino, carboxyl, hydroxy, cyano, nitro, benzoxa, cryptomelane, methylsulfonyl, azetidin-1-yl, 2-methylaziridinyl, 3-methoxyacridine, 3-hydroxyazetidine, 3-porazitelnie, 2,2-diversecity-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2 - and 3-ftorpirimidinu-1-yl, 2,2-debtorprovidian-1-yl, 3,3-debtorprovidian-1-yl, 2- and 3 methylpyrrolidine-1-yl, 1-methylpyrrolidine-2-yl, 2,2-dimethylpiperidin-1-yl, 3,3-dimethylpiperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2 - and 3-triftormetilfullerenov-1-yl, 2-oxo-oxazolidin-1-yl, piperidine-1-yl, 2-methylpiperidin-1-yl, 2-foreperiod-1-yl, 2,2-deformability-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-yl, 1-methylpyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, 1-methylpyrazole-4-yl, 4-perperson-1-yl, imidazol-1-yl, imidazol-2-yl, 1-Mei-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2-methylthiazole-4-yl, 2-methylthiazole-5-yl, [1,2,3]triazole-1-yl, [1,2,4]triazole-1-yl, [1,2,3]triazole-2-yl, [1,2,4]triazole-3-yl, [1,2,4]triazole-4-yl, 4-methyl-[1,2,4]triazole-3-yl, 2-methyl-[1,2,3]triazole-4-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]-oxadiazol-5-yl, [1,2,3]-oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl, 5-methyl-[1,2,4]-oxadiazol-3-yl, [1,2,3]thiadiazole-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl, furazan-3-yl pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl and 2-methylpyrimidin-4-yl.

In an alternative preferred embodiment Rahas the formula Ra'

where

Y represents N, CH or CF,

Ra1and Ra2independently from each other selected from C1-C2-alkyl, in particular methyl, fluorinated C1-C2-alkyl, in particular formatie, diformate or trifloromethyl, provided that Y having a value of CH or CF one of the radicals Ra1or Ra2may also be hydrogen or fluorine, or

Ra1and Ra2form a radical (CH2)mwhere 1 or 2 hydrogen atoms may be replaced by fluorine, and where m has the value 2, 3 or 4, in particular CH2-CH2, CHF-CH2, CF2-CH2CH2-CH2-CH2, CHF-CH2-CH2, CF2-CH2-CH2CH2-CHF-CH2CH2-CF2-CH2.

In the case when Ra1and Ra2differ from each other, a radical of the above-mentioned formula Ra'may be, or (R)-or (S)-configuration is the Y-balance.

Examples of preferred radicals of the formula Ra'include isopropyl, (R)-1-foretel, (S)-1-foretel, 2-foretel, 1,1-dottorati, 2,2-dottorati, 2,2,2-triptorelin, (R)-1-forproper, (S)-1-forprofit, 2-forproper, 3-forproper, 1,1-direcror, 2,2-direcror, 3,3-direcror, 3,3,3-cryptochromes, cyclopropyl, cyclobutyl, 1-forciblepoppy, (S)- and (R)-2,2-diversicolor and 2-forciblepoppy.

Among the radicals of the formula Ra'preferred are those which contain 1, 2, 3 or 4, in particular 1, 2 or 3 fluorine atom.

Rband Rcindependently of one another represent H, a halogen, CH3, OCH3CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2CH2CF3or OCH2CF3. If both Rband Rcother than H, it is preferred that one of Rband Rcselected from a halogen and the other is selected from halogen, CH3, OCH3CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2CH2CF3and OCH2CF3in particular, CH3, OCH3CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3CH2CH2F and OCH2CH2F.

Preferred examples of the La Ar, where Ar represents a radical of formula (A), (B), (C), (D) or (E), in particular, are the following: 3-were 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl, 3-second-butylphenyl, 3-isobutylphenyl, 3-tert-butylphenyl, 3-(1,1-dimethylpropyl)phenyl, 3-vinylbenzyl, 3-isopropylphenyl, 3-forfinal, 3-chlorophenyl, 3-bromophenyl, 3-iopener, 3-(permitil)phenyl, 3-(deformity)phenyl, 3-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 3-(1-foradil)phenyl, 3-((S)-1-foradil)phenyl, 3-((R)-1-foradil)phenyl, 3-(2-foradil)phenyl, 3-(1,1-dottorati)phenyl, 3-(2,2-dottorati)phenyl, 3-(2,2,2-triptorelin)phenyl, 3-(3-forproper)phenyl, 3-(2-forproper)phenyl, 3-((S)-2-forproper)phenyl, 3-((R)-2-forproper)phenyl, 3-(3,3-deferror)phenyl, 3-(3,3,3-cryptochromes)phenyl, 3-(1-fluoro-1-methylethyl)phenyl, 3-(2-fluoro-1-methylethyl)phenyl, 3-((S)-2-fluoro-1-methylethyl)phenyl, 3-((R)-2-fluoro-1-methylethyl)phenyl, 3-(2,2-debtor-1-methylethyl)phenyl, 3-((S)-2,2-debtor-1-methylethyl)phenyl, 3-((R)-2,2-debtor-1-methylethyl)phenyl, 3-(2,2,2-Cryptor-1-methylethyl)phenyl, 3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl, 3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl, 3-(2-fluoro-1-permethylated)phenyl, 3-(1-deformity-2,2-dottorati)phenyl, 3-(1,1-dimethyl-2-foradil)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 3-isopropoxyphenyl, 3-butoxyphenyl, 3-(formatosi)phenyl, 3-(deformedarse)phenyl, 3-(triptoreline)phenyl, 3-(2-floratone)phenyl, 3-(2,2-diflorasone)phenyl, 3-(2,2,2-triptoreline)phenyl, 3-(1,1,2,2-titrator the toxi)phenyl, 3-cyclopropylethyl, 3-cyclobutenyl, 3-cyclopentenyl, 3-(2,2-diversicolor)phenyl, 3,4-differenl, 3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 4-bromo-3-forfinal, 3-bromo-2-forfinal, 2-bromo-3-forfinal, 3-chloro-4-forfinal, 3-bromo-2,5-differenl, 4-bromo-2,5-differenl, 5-bromo-2,4-differenl, 3-bromo-2,4-differenl, 4-chloro-3-(trifluoromethyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 4-bromo-3-(trifluoromethyl)phenyl, 3-bromo-5-(trifluoromethyl)phenyl, 2-bromo-5-(trifluoromethyl)phenyl, 5-bromo-2-methoxyphenyl, 3-bromo-4-methoxyphenyl, 3-bromo-4-(triptoreline)phenyl, 3,5-dibromo-4-(2-floratone)phenyl, 2-fluoro-3-isopropylphenyl, 4-fluoro-3-isopropylphenyl, 3-(1-hydroxy-1-methylethyl)phenyl, 3-(2-hydroxy-2-methylpropyl " phenyl, 3-acetylphenyl, 3-acetylaminophenol, 3-carboxyphenyl, 3-cyanophenyl, 3-nitrophenyl, 3-hydroxyphenyl, 3-(O-benzyl)phenyl, 3-(2-methoxyethoxy)phenyl, 3-(CH2-N(CH3)2)phenyl, 3-(NH-CO-NH2)phenyl, 3-(methylsulfanyl)phenyl, 3-(pharmacysulfacet)phenyl, 3-(deformational)phenyl, 3-(trifloromethyl)phenyl, 3-(methylsulphonyl)phenyl, 3-(N-methoxy-N-methylamino)phenyl, 3-(methoxyamino)phenyl, 3-(ethoxyline)phenyl, 3-(N-methylenedioxy)phenyl, 3-(N,N-dimethylaminoethoxy)phenyl, 3-cyanophenyl, 2,5-dimetilfenil, 2,5-di-(trifluoromethyl)phenyl, 3,5-di(trifluoromethyl)phenyl, 2,5-acid, 2-methoxy-5-methyl is Anil, 2-methoxy-5-(trifluoromethyl)phenyl, 3-(azetidin-1-yl)phenyl, 3-(2-methylaziridine-1-yl)phenyl, 3-((S)-2-methylaziridine-1-yl)phenyl, 3-((R)-2-methylaziridine-1-yl)phenyl, 3-(3-torasemide-1-yl)phenyl, 3-(2,2-diversecity-1-yl)phenyl, 3-(3-methoxyisatin-1-yl)phenyl, 3-(3-hydroxyazetidine-1-yl)phenyl, 3-(pyrrolidin-1-yl)phenyl, 3-(pyrrolidin-2-yl)phenyl, 3-((S)-pyrrolidin-2-yl)phenyl, 3-((R)-pyrrolidin-2-yl)phenyl, 3-(pyrrolidin-3-yl)phenyl, 3-((S)-pyrrolidin-3-yl)phenyl, 3-((R)-pyrrolidin-3-yl)phenyl, 3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl, 5-(pyrrolidin-1-yl)-2-methoxyphenyl, 3-(pyrrolidin-1-yl)-4-methoxyphenyl, 5-(pyrrolidin-1-yl)-2,4-differenl, 3-(pyrrolidin-1-yl)-2,4-differenl, 3-(2-ftorpirimidinu-1-yl)phenyl, 3-((S)-2-ftorpirimidinu-1-yl)phenyl, 3-((R)-2-ftorpirimidinu-1-yl)phenyl, 3-(3-ftorpirimidinu-1-yl)phenyl, 3-((S)-3-ftorpirimidinu-1-yl)phenyl, 3-((R)-3-ftorpirimidinu-1-yl)phenyl, 3-(2,2-debtorprovidian-1-yl)phenyl, 3-(3,3-debtorprovidian-1-yl)phenyl, 3-(2-methylpyrrolidine-1-yl)phenyl, 3-((S)-2-methylpyrrolidine-1-yl)phenyl, 3-((R)-2-methylpyrrolidine-1-yl)phenyl, 3-(3-methylpyrrolidine-1-yl)phenyl, 3-((S)-3-methylpyrrolidine-1-yl)phenyl, 3-((R)-3-methylpyrrolidine-1-yl)phenyl, 3-(1 methylpyrrolidine-2-yl)phenyl, 3-((S)-1-methylpyrrolidine-2-yl)phenyl, 3-((R)-1-methylpyrrolidine-2-yl)phenyl, 3-(1-methylpyrrolidine-3-yl)phenyl, 3-((S)-1-methylpyrrolidine-3-yl)phenyl, 3-((R)-1-methylpyrrolidine-3-yl)phenyl, 3-(2,2-dimethylpyrimidin-1-yl)phenyl, 3-(3,3-dimethylpiperidin-1-yl)phenyl, 3-(2-trifloromethyl Raiden-1-yl)phenyl, 3-((S)-2-triftormetilfullerenov-1-yl)phenyl, 3-((R)-2-triftormetilfullerenov-1-yl)phenyl, 3-(3-triftormetilfullerenov-1-yl)phenyl, 3-((S)-3-triftormetilfullerenov-1-yl)phenyl, 3-((R)-3-triftormetilfullerenov-1-yl)phenyl, 3-(2-oxopyrrolidin-1-yl)phenyl, 3-(2-oxo-oxazolidin-3-yl)phenyl, 3-(piperidine-1-yl)phenyl, 3-(2-methylpiperidin-1-yl)phenyl, 3-((S)-2-methylpiperidin-1-yl)phenyl, 3-((R)-2-methylpiperidin-1-yl)phenyl, 3-(2-foreperiod-1-yl)phenyl, 3-((S)-2-foreperiod-1-yl)phenyl, 3-((R)-2-foreperiod-1-yl)phenyl, 3-(2,2-deformability-1-yl)phenyl, 3-(piperazine-1-yl)phenyl, 3-(4-methylpiperazin-1-yl)phenyl, 3-(morpholine-4-yl)phenyl, 3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl, 5-(morpholine-4-yl)-2-methoxyphenyl, 3-(morpholine-4-yl)-4-methoxyphenyl, 5-(morpholine-4-yl)-2,4-differenl, 3-(morpholine-4-yl)-2,4-differenl, 3-(thiomorpholine-4-yl)phenyl, 3-(1-Osotimehin-4-yl)phenyl, 3-(1,1-diocletianopolis-4-yl)phenyl, 3-(pyrrol-1-yl)phenyl, 3-(pyrrol-2-yl)phenyl, 3-(pyrrol-3-yl)phenyl, 3-(1-methylpyrrole-2-yl)phenyl, 3-(1-methylpyrrole-3-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(furan-3-yl)phenyl, 3-(thiophene-2-yl)phenyl, 3-(thiophene-3-yl)phenyl, 3-(5-properties-2-yl)phenyl, 3-(pyrazole-1-yl)phenyl, 3-(pyrazole-3-yl)phenyl, 3-(pyrazole-4-yl)phenyl, 3-(1-methyl-1H-pyrazole-4-yl)phenyl, 3-(1-ethyl-1H-pyrazole-4-yl)phenyl, 3-(1-methyl-1H-pyrazole-5-yl)phenyl, 3-(4-perperson-1-yl)phenyl, 3-(1H-imidazol-2-yl)phenyl, 3-(imidazol-1-yl)phenyl, 3-(1-Mei-2-yl)phenyl, 3-(oxazol-2-yl)phenyl, 3-(oxazol-4-yl)phenyl, 3-(oxazol-yl)phenyl, 4-fluoro-3-(oxazol-4-yl)phenyl, 3-(isoxazol-3-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(isoxazol-5-yl)phenyl, 3-(thiazol-2-yl)phenyl, 3-(thiazol-4-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(2-methylthiazole-4-yl)phenyl, 3-(2-methylthiazole-5-yl)phenyl, 3-([1,2,3]-triazole-1-yl)phenyl, 3-([1,2,4]-triazole-1-yl)phenyl, 3-([1,2,3]-triazole-2-yl)phenyl, 3-(4H-[1,2,4]-triazole-3-yl)phenyl, 3-([1,2,4]-triazole-4-yl)phenyl, 3-(2H-[1,2,3]-triazole-4-yl)phenyl, 3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl, 3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl, 3-([1,3,4]-oxadiazol-2-yl)phenyl, 3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl, 3-([1,2,4]-oxadiazol-3-yl)phenyl, 3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl, 3-([1,2,4]-oxadiazol-5-yl)phenyl, 3-([1,2,3]-oxadiazol-4-yl)phenyl, 3-([1,2,3]-oxadiazol-5-yl)phenyl, 3-([1,2,3]-thiadiazole-4-yl)phenyl, 3-(1H-tetrazol-5-yl)phenyl, 3-(tetrazol-1-yl)phenyl, 3-(2-methyl-2H-tetrazol-5-yl)phenyl, 3-(1-methyl-1H-tetrazol-5-yl)phenyl, 3-furazan-3-yl-phenyl, 3-(pyrid-2-yl)phenyl, 3-(pyrid-3-yl)phenyl, 3-(pyrid-4-yl)phenyl, 3-(pyrimidine-2-yl)phenyl, 3-(pyrimidine-4-yl)phenyl, 3-(2-methylpyrimidin-4-yl)phenyl, 3-(pyrimidine-5-yl)phenyl, 5-bromopyridin-3-yl, 3-bromo-2-chloropyridin-5-yl, 4-methylpyridin-2-yl, 6-methylpyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(pyrrolidin-1-yl)pyridine-3-yl, 3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl and 3-(morpholine-4-yl)-2-chloropyridin-5-yl.

In an alternative preferred embodiment Ar is a group of formula (F) or (G), (F) is especially PR is doctitle.

In the compounds of formula I where Ar is a radical (F), Rdpreferably selected from halogen, hydroxyl, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylsulfonyl, fluorinated C1-C4-alkylsulfonyl, phenylsulfonyl, pyridylsulfonyl, phenyl, where phenyl and peredelnyj radical in the three last mentioned radicals may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, R9-CO-NR6-C1-C2-alkylene, CH2-pyridyl where peredelnyj radical may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, and a saturated, partially unsaturated or aromatic 5 - or 6-membered heterocyclic ring comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S and/or 1, 2 or 3 containing a heteroatom group selected from NR8where R8represents H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylsulphonyl or fluorinated C1-C4-alkylaryl, and where the heterocyclic ring may carry 1, 2 or 3 substituent selected from hydroxy, halogen, C 1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, NR6R7-C1-C6-alkylene, carboxyl and C1-C4-allyloxycarbonyl, where R6, R7and R9defined above.

More preferably, Rdselected from halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylsulfonyl, fluorinated C1-C4-alkylsulfonyl, phenylsulfonyl, where the phenyl radical may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, and 5 - or 6-membered heteroaromatic ring comprising as ring members one nitrogen atom or one group NR8where R8represents N or C1-C4-alkyl, and optionally one or two additional heteroatoms selected from N, O, and S, where the heteroaromatic ring may carry 1, 2 or 3 substituent selected from halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio and fluorinated C1-C6-alkylthio.

the even more preferably, Rdselected from halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl, phenylsulfonyl, where the phenyl radical may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, and 5 - or 6-membered heteroaromatic ring comprising as ring members one nitrogen atom or one group NR8where R8represents N or C1-C4-alkyl, and optionally one or two additional heteroatoms selected from N, O, and S, where the heteroaromatic ring may carry 1, 2 or 3 substituent selected from halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio and fluorinated C1-C6-alkylthio.

5-membered heteroaromatic radical may be linked via a ring carbon atom or ring nitrogen atom.

5 - or 6-membered heteroaromatic radical preferably selected from oxazolyl, isoxazolyl, thiazolyl, isothiazoline, oxadiazolyl, thiadiazolyl, pyridyl and pyrimidyl. In the case where the heteroaromatic radical is substituted, it preferably carries one Deputy, which is preferably selected from halogen, C1-C6/sub> -alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, C1-C6-alkylthio and fluorinated C1-C6-alkylthio and more preferably from F, CH3CH2F, CHF2, CF3, OCH3, OCH2F, OCHF2, OCF3, SCH3, SCH2F, SCHF2and SCF3.

k preferably has the value 0, 1 or 2, more preferably 0 or 1, especially 1.

Thienyl radical (F) can be associated with sulfonyloxy group SO2through its 2 - or 3-position, 2-position (= atom adjacent to the atom's ring (S=1-position)) is preferred. If thienyl radical carries one radical Rdspecified radical preferably attached at the 4 - or 5-position, more preferably in the 5-position (relative to the 2 - or 3-position of the atom ring associated with sulfonyloxy group). If thienyl radical carries two radicals Rdthese radicals preferably attached at the 4 - or 5-position.

Particularly preferred Ar radicals of the formula (F) is selected from the Tien-2-yl, Tien-3-yl, 3-chlortan-2-yl, 4-chlortan-2-yl, 5-chlortan-2-yl, 3-Bratan-2-yl, 4-Bratan-2-yl, 5-Bratan-2-yl, 4,5-dichlorotin-2-yl, 4,5-libration-2-yl, 4-bromo-5-chlortan-2-yl, 3-bromo-5-chlortan-2-yl, 5-methyltin-2-yl, 5-utilties-2-yl, 5-properties-2-yl, 5-t is ivermectin-2-yl, 5-penalties-2-yl, 5-(pyrid-2-yl)Tien-2-yl, 5-(phenylsulfonyl)Tien-2-yl, 4-(phenylsulfonyl)Tien-2-yl, 5-(pyrid-2-ylsulphonyl)Tien-2-yl, 5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl, 5-(benzoylamino)Tien-2-yl, 5-((4-chlorbenzoyl)aminomethyl)Tien-2-yl, 5-(acetamidomethyl)Tien-2-yl, 5-(pyrazole-1-yl)Tien-2-yl, 5-(pyrazole-3-yl)Tien-2-yl, 5-(pyrazole-4-yl)Tien-2-yl, 5-(pyrazole-5-yl)Tien-2-yl, 5-(4-perperson-1-yl)Tien-2-yl, 5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl, 5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl, 5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl, 5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl, 5-(isoxazol-3-yl)Tien-2-yl, 5-(isoxazol-4-yl)Tien-2-yl, 5-(isoxazol-5-yl)Tien-2-yl, 5-(5-cryptometrics-3-yl)Tien-2-yl, 5-(oxazol-2-yl)Tien-2-yl, 5-(oxazol-4-yl)Tien-2-yl, 5-(oxazol-5-yl)Tien-2-yl, 5-(2-methoxazole-4-yl)Tien-2-yl, 5-(2-methoxazole-5-yl)Tien-2-yl, 5-(isothiazol-3-yl)Tien-2-yl, 5-(isothiazol-4-yl)Tien-2-yl, 5-(isothiazol-5-yl)Tien-2-yl, 5-(5-triftoratsetata-3-yl)Tien-2-yl, 5-(thiazol-2-yl)Tien-2-yl, 5-(thiazol-4-yl)Tien-2-yl, 5-(thiazol-5-yl)Tien-2-yl, 5-(2-methylthiazole-4-yl)Tien-2-yl, 5-(2-methylthiazole-5-yl)Tien-2-yl, 5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl, 5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl, 5-(pyrimidine-2-yl)Tien-2-yl, 5-(pyrimidine-4-yl)Tien-2-yl, 5-(pyrimidine-5-yl)Tien-2-yl, 5-(2-methylthiopyrimidin-4-yl)Tien-2-yl, 5-([1,3]-dioxolane-2-yl)Tien-2-yl,3-([1,3]-dioxolane-2-yl)Tien-2-yl, 5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl, 5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl, 2-chlortan-3-yl, 4-chlortan-3-yl, 5-chlortan-3-yl, 2-Bratan-3-yl, 4-Bratan-3-yl, 5-Bratan-3-yl, 2,5-dichlorotin-3-yl, 2,5-libration-3-yl, 2,4,5-tripartie-3-yl, 4-bromo-2,5-dichlorotin-3-yl, 2-chloro-5-methylsulfonate-3-yl, 2,5-dietitian-3-yl, 4-hydroxicut-3-yl, 2-venitien-3-yl, 4-phenyl-5-(trifluoromethyl)Tien-3-yl and 2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl.

In the compounds of formula I where Ar is a radical (G), Repreferably selected from H, halogen, C1-C4-alkyl and fluorinated C1-C4-alkyl, more preferably from halogen, C1-C4-alkyl and fluorinated C1-C4-alkyl and more preferably from C1-C4-alkyl, in particular CH3.

Rfpreferably selected from halogen, C1-C4-alkyl and fluorinated C1-C4-alkyl, more preferably from halogen, in particular chlorine.

j preferably has a value of 0 or 1, especially 1. In the case when j is 1, Rfpreferably attached at the 4 - or especially 5-position (relative to the 3-position Re).

In the compounds of formula I where Ar is a radical (G), n typically has a value of 0.

In particular, the pre is respectful Ar radicals of the formula (G) is selected from benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 3-methylbenzo[b]thiophene-2-yl, 5-methylbenzo[b]thiophene-2-yl, 5-fluoro-3-methylbenzo[b]thiophene-2-yl, 5-chloro-3-methylbenzo[b]thiophene-2-yl and 5-bromo-3-methylbenzo[b]thiophene-2-Il.

In one of the preferred embodiments And represents a 1,3-phenylene. In this case, the radicals R1, R2, R3, R4E and Ar with its variable Ra, Rb, RcRd, Reand Rfhave the abovementioned General or preferred values.

In an alternative preferred embodiment A represents a 1,4-phenylene. In this case, the radicals R1, R2, R3, R4E and Ar with its variable Ra, Rb, Rc, Rd, Reand Rfhave the abovementioned General or preferred meanings. However, Rain this case, preferably selected from the group consisting of C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C6-alkyl, C2-C6-alkenyl, fluorinated C2-C6-alkenyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, C1-C6-alkylthio, fluorinated C1-C6-alkylthio, C1-C6-alkylsulfonyl, fluorinated who CSOs C 1-C6-alkylsulfonyl, C1-C6-alkylsulfonyl, fluorinated C1-C6-alkylsulfonyl, phenylsulfonyl, benzyloxy, phenoxy, where the phenyl radical in the three last mentioned radicals may be unsubstituted or may carry 1 to 3 substituents selected from C1-C4-alkyl, fluorinated C1-C4-alkyl and halogen, CN, nitro, C1-C6-alkylsulphonyl, fluorinated C1-C6-alkylsulphonyl, C1-C6-alkylcarboxylic, fluorinated C1-C6-alkylcarboxylic, carboxy, NH-C(O)-NR6R7, NR6R7, NR6R7-C1-C6-alkylene, O-NR6R7where R6and R7independently of one another represent H, C1-C4-alkyl, fluorinated C1-C4-alkyl or C1-C4-alkoxy or may form, together with N 4-, 5 - or 6-membered saturated or unsaturated ring, or represents a saturated or unsaturated 3-7 membered heterocyclic ring comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S and/or 1, 2 or 3 containing a heteroatom group selected from NR8where R8defined above, SO, SO2and CO, and where the heterocyclic ring may carry 1, 2 or 3 substituent selected from hydroxy, halogen, C1-C6-al the sludge, fluorinated C1-C6-alkyl and C1-C6-alkoxy. More preferably, Rain this case, selected from the group consisting of C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, C2-C4-alkenyl, fluorinated C2-C4-alkenyl, NR6R7, ONR6R7C1-C6-alkylene-NR6R7where R6and R7independently of one another represent H, C1-C4-alkyl or C1-C4-alkoxy, ureido (NHCONH2), C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, acetyl, carboxyl, hydroxy, cyano, nitro, benzoxa, methylsulfanyl, pharmacysulfacet, deformational, trifloromethyl, methylsulphonyl and one of the above-mentioned saturated or unsaturated 3-7 membered heterocyclic ring, in particular azetidin-1-yl, 2-methylaziridinyl, 3-methoxyacetyl, 3-hydroxyazetidine, 3-foreseeing, 2,2-diversecity-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2 - and 3-ftorpirimidinu-1-yl, 2,2-debtorprovidian-1-yl, 3,3-debtorprovidian-1-yl, 2 - and 3-methylpyrrolidine-1-yl, 1-methylpyrrolidine-2-yl, 2,2-dimethylpiperidin-1-yl, 3,3-dimethylpiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2 - and 3-triftormetilfullerenov-1-yl, 2-occaecat the one-1-yl, piperidine-1-yl, 2-methylpiperidin-1-yl, 3-(2-foreperiod-1-yl)phenyl, 3-((S)-2-foreperiod-1-yl)phenyl, 3-((R)-2-foreperiod-1-yl)phenyl, 3-(2,2-deformability-1-yl)phenyl, piperazine-1-yl, 4-methylpiperazin-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-yl, 1-methylpyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, 1-methylpyrazole-4-yl, 4-perperson-1-yl, imidazol-1-yl, imidazol-2-yl, 1-Mei-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2-methylthiazole-4-yl, 2-methylthiazole-5-yl, [1,2,3]triazole-1-yl, [1,2,4]triazole-1-yl, [1,2,3]triazole-2-yl, [1,2,4]triazole-3-yl, [1,2,4]triazole-4-yl, 4-methyl-[1,2,4]triazole-3-yl, 2-methyl-[1,2,3]triazole-4-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, [1,2,4]-oxadiazol-5-yl, [1,2,3]-oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl, 5-methyl-[1,2,4]-oxadiazol-3-yl, [1,2,3]thiadiazole-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl, furazan-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl and 2-methylpyrimidin-4-yl.

Even more preferably, Rain this case, selected from the group consisting of C1-C6-alkyl, C1-C4-alkoxy, C2-C4-alkenyl, C3-C6-cycloalkyl, ftorirovannogo the C 3-C6-cycloalkyl, ureido, acetyl, acetylamino, carboxyl, hydroxy, cyano, nitro, benzoxa, cryptomelane, methylsulfonyl, azetidin-1-yl, 2-methylaziridinyl, 3-methoxyacridine, 3-hydroxyazetidine, 3-porazitelnie, 2,2-diversecity-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2 - and 3-ftorpirimidinu-1-yl, 2,2-debtorprovidian-1-yl, 3,3-debtorprovidian-1-yl, 2- and 3 methylpyrrolidine-1-yl, 1-methylpyrrolidine-2-yl, 2,2-dimethylpiperidin-1-yl, 3,3-dimethylpiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2 - and 3-triftormetilfullerenov-1-yl, 2-oxoacridine-1-yl, piperidine-1-yl, 2-methylpiperidin-1-yl, 3-(2-foreperiod-1-yl)phenyl, 3-((S)-2-foreperiod-1-yl)phenyl, 3-((R)-2-foreperiod-1-yl)phenyl, 3-(2,2-deformability-1-yl)phenyl, piperazine-1-yl, 4-methylpiperazin-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrole-2-silt, 1-methylpyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, 1-methylpyrazole-4-yl, 4-perperson-1-yl, imidazol-1-yl, imidazol-2-yl, 1-Mei-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, the thiazole-2-yl, thiazol-4-yl, thiazol-5-yl, 2-methylthiazole-4-yl, 2-methylthiazole-5-yl, [1,2,3]triazole-1-yl, [1,2,4]triazole-1-yl, [1,2,3]triazole-2-yl, [1,2,4]triazole-3-yl, [1,2,4]triaz the l-4-yl, 4-methyl-[1,2,4]triazole-3-yl, 2-methyl-[1,2,3]triazole-4-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, [1,2,4]-oxadiazol-5-yl, [1,2,3]-oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl, 5-methyl-[1,2,4]-oxadiazol-3-yl, [1,2,3]thiadiazole-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl, 1-methyltetrazol-5-yl, furazan-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 4-methylpyridin-2-yl, 6-methylpyridin-2-yl, 5-bromopyridin-2-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl and 2-methylpyrimidin-4-yl.

In this case, that is, if A represents 1,4-phenylene, preferred examples of Ar, in particular, are the following: 3-were 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl, 3-second-butylphenyl, 3-isobutylphenyl, 3-tert-butylphenyl, 3-(1,1-dimethylpropyl)phenyl, 3-vinylbenzyl, 3-isopropylphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 3-isopropoxyphenyl, 3-butoxyphenyl, 3-cyclopropylethyl, 3-cyclobutenyl, 3-cyclopentenyl, 3-(2,2-diversicolor)phenyl, 3-(1-hydroxy-1-methylethyl)phenyl, 3-(2-hydroxy-2-methylpropyl " phenyl, 3-(cyanophenyl), 2,5-dimetilfenil, 2,5-di(trifluoromethyl)phenyl, 3,5-di(trifluoromethyl)phenyl, 2,5-acid, 2-methoxy-5-were, 2-methoxy-5-(trifluoromethyl)phenyl, 3-acetylphenyl, 3-acetylaminophenol, 3-carboxyphenyl, 3-cyanophenyl, 3-nitrophenyl, 3-hydroxyphenyl, 3-(O-benzyl)phenyl, 3-(2-methoxyethoxy)phenyl, 3-(C 2-N(CH3)2)phenyl, 3-(NH-CO-NH2)phenyl, 3-(methylsulfanyl)phenyl, 3-(pharmacysulfacet)phenyl, 3-(deformational)phenyl, 3-(trifloromethyl)phenyl, 3-(methylsulphonyl)phenyl, 3-(N-methoxy-N-methylamino)phenyl, 3-(methoxyamino)phenyl, 3-(ethoxyline)phenyl, 3-(N-methylenedioxy)phenyl, 3-(N,N-dimethylaminoethoxy)phenyl, 3-(azetidin-1-yl)phenyl, 3-(2-methylaziridine-1-yl)phenyl, 3-((S)-2-methylaziridine-1-yl)phenyl, 3-((R)-2-methylaziridine-1-yl)phenyl, 3-(3-torasemide-1-yl)phenyl, 3-(2,2-diversecity-1-yl)phenyl, 3-(3-methoxyisatin-1-yl)phenyl, 3-(3-hydroxyazetidine-1-yl)phenyl, 3-(pyrrolidin-1-yl)phenyl, 3-(pyrrolidin-2-yl)phenyl, 3-((S)-pyrrolidin-2-yl)phenyl, 3-((R)-pyrrolidin-2-yl)phenyl, 3-(pyrrolidin-3-yl)phenyl, 3-((S)-pyrrolidin-3-yl)phenyl, 3-((R)-pyrrolidin-3-yl)phenyl, 3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl, 5-(pyrrolidin-1-yl)-2-methoxyphenyl, 3-(pyrrolidin-1-yl)-4-methoxyphenyl, 5-(pyrrolidin-1-yl)-2,4-differenl, 3-(pyrrolidin-1-yl)-2,4-differenl, 3-(2-ftorpirimidinu-1-yl)phenyl, 3-((S)-2-ftorpirimidinu-1-yl)phenyl, 3-((R)-2-ftorpirimidinu-1-yl)phenyl, 3-(3-ftorpirimidinu-1-yl)phenyl, 3-((S)-3-ftorpirimidinu-1-yl)phenyl, 3-((R)-3-ftorpirimidinu-1-yl)phenyl, 3-(2,2-debtorprovidian-1-yl)phenyl, 3-(3,3-debtorprovidian-1-yl)phenyl, 3-(2-methylpyrrolidine-1-yl)phenyl, 3-((S)-2-methylpyrrolidine-1-yl)phenyl, 3-((R)-2-methylpyrrolidine-1-yl)phenyl, 3-(3-methylpyrrolidine-1-yl)phenyl, 3-((S)-3-methylpyrrolidine-1-yl)phenyl, 3-((R)-3-methylpyrrolidine the-1-yl)phenyl, 3-(1-methylpyrrolidine-2-yl)phenyl, 3-((S)-1-methylpyrrolidine-2-yl)phenyl, 3-((R)-1-methylpyrrolidine-2-yl)phenyl, 3-(1-methylpyrrolidine-3-yl)phenyl, 3-((S)-1-methylpyrrolidine-3-yl)phenyl, 3-((R)-1-methylpyrrolidine-3-yl)phenyl, 3-(2,2-dimethylpyrimidin-1-yl)phenyl, 3-(3,3-dimethylpiperidin-1-yl)phenyl, 3-(2-triftormetilfullerenov-1-yl)phenyl, 3-((S)-2-triftormetilfullerenov-1-yl)phenyl, 3-((R)-2-triftormetilfullerenov-1-yl)phenyl, 3-(3-triftormetilfullerenov-1-yl)phenyl, 3-((S)-3-triftormetilfullerenov-1-yl)phenyl, 3-((R)-3-triftormetilfullerenov-1-yl)phenyl, 3-(2-oxopyrrolidin-1-yl)phenyl, 3-(2-oxoacridine-3-yl)phenyl, 3-(piperidine-1-yl)phenyl, 3-(2-methylpiperidin-1-yl)phenyl, 3-((S)-2-methylpiperidin-1-yl)phenyl, 3-((R)-2-methylpiperidin-1-yl)phenyl, 3-(2-foreperiod-1-yl)phenyl, 3-((S)-2-foreperiod-1-yl)phenyl, 3-((R)-2-foreperiod-1-yl)phenyl, 3-(2,2-deformability-1-yl)phenyl, 3-(piperazine-1-yl)phenyl, 3-(4-methylpiperazin-1-yl)phenyl, 3-(morpholine-4-yl)phenyl, 3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl, 5-(morpholine-4-yl)-2-methoxyphenyl, 3-(morpholine-4-yl)-4-methoxyphenyl, 5-(morpholine-4-yl)-2,4-differenl, 3-(morpholine-4-yl)-2,4-differenl, 3-(thiomorpholine-4-yl)phenyl, 3-(1-Osotimehin-4-yl)phenyl, 3-(1,1-diocletianopolis-4-yl)phenyl, 3-(pyrrol-1-yl)phenyl, 3-(pyrrol-2-yl)phenyl, 3-(pyrrol-3-yl)phenyl, 3-(1-methylpyrrole-2-yl)phenyl, 3-(1-methylpyrrole-3-yl)phenyl, 3-(furan-2-yl)phenyl, 3-(furan-3-yl)phenyl, 3-(thiophene-2-yl)phenyl, 3-(thiophene-3-yl)phenyl, 3-(5-properties-2-yl)phenyl, 3-pyrazole-1-yl)phenyl, 3-(pyrazole-3-yl)phenyl, 3-(pyrazole-4-yl)phenyl, 3-(1-methyl-1H-pyrazole-4-yl)phenyl, 3-(1-ethyl-1H-pyrazole-4-yl)phenyl, 3-(1-methyl-1H-pyrazole-5-yl)phenyl, 3-(4-perperson-1-yl)phenyl, 3-(1H-imidazol-2-yl)phenyl, 3-(imidazol-1-yl)phenyl, 3-(1-Mei-2-yl)phenyl, 3-(oxazol-2-yl)phenyl, 3-(oxazol-4-yl)phenyl, 3-(oxazol-5-yl)phenyl, 4-fluoro-3-(oxazol-4-yl)phenyl, 3-(isoxazol-3-yl)phenyl, 3-(isoxazol-4-yl)phenyl, 3-(isoxazol-5-yl)phenyl, 3-(thiazol-2-yl)phenyl, 3-(thiazol-4-yl)phenyl, 3-(thiazol-5-yl)phenyl, 3-(2-methylthiazole-4-yl)phenyl, 3-(2-methylthiazole-5-yl)phenyl, 3-([1,2,3]-triazole-1-yl)phenyl, 3-([1,2,4]-triazole-1-yl)phenyl, 3-([1,2,3]-triazole-2-yl)phenyl, 3-(4H-[1,2,4]-triazole-3-yl)phenyl, 3-([1,2,4]-triazole-4-yl)phenyl, 3-(2H-[1,2,3]-triazole-4-yl)phenyl, 3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl, 3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl, 3-([1,3,4]-oxadiazol-2-yl)phenyl, 3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl, 3-([1,2,4]-oxadiazol-3-yl)phenyl, 3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl, 3-([1,2,4]-oxadiazol-5-yl)phenyl, 3-([1,2,3]-oxadiazol-4-yl)phenyl, 3-([1,2,3]-oxadiazol-5-yl)phenyl, 3-([1,2,3]-thiadiazole-4-yl)phenyl, 3-(1H-tetrazol-5-yl)phenyl, 3-(tetrazol-1-yl)phenyl, 3-(2-methyl-2H-tetrazol-5-yl)phenyl, 3-(1-methyl-1H-tetrazol-5-yl)phenyl, 3-furazan-3-yl-phenyl, 3-(pyrid-2-yl)phenyl, 3-(pyrid-3-yl)phenyl, 3-(pyrid-4-yl)phenyl, 3-(pyrimidine-2-yl)phenyl, 3-(pyrimidine-4-yl)phenyl, 3-(2-methylpyrimidin-4-yl)phenyl, 3-(pyrimidine-5-yl)phenyl, 5-bromopyridin-3-yl, 3-bromo-2-chloropyridin-5-yl, 4-methylpyridin-2-Il, 6-methylpyridin-2-yl, 4-(trifluoromethyl)p is ridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(pyrrolidin-1-yl)pyridine-3-yl, 3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl and 3-(morpholine-4-yl)-2-chloropyridin-5-yl.

Particularly preferred compounds of formula I are those which have the formula I.A, I.b, I.c, I.d, I.e, I.f, I.g, I.h, I.i, I.k, I.l, I.m, I.n, I.o, I.P. Pavlova, I.q, I.r, I.s and I.t, where R1and Ar are as defined above values. The preferred values of R1and Ar are those defined above.

Examples of preferred compounds which are represented by the formulas I.q, I.r, I.s and I.t are listed in the following tables 1 to:

Table 1

The compounds of formula I.q, in which R4represents methyl and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 2

The compounds of formula I.q, in which R4is vermeil and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 3

The compounds of formula I.q, in which R4is deformity and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 4

Soy is inane formula I.q, in which R4represents trifluoromethyl and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 5

The compounds of formula I.r, in which R4represents methyl and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 6

The compounds of formula I.r, in which R4is vermeil and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 7

The compounds of formula I.r, in which R4is deformity and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 8

The compounds of formula I.r, in which R4represents trifluoromethyl and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 9

The compounds of formula I.s, in which R3represents methyl and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 10

The compounds of formula I.s, in which R3is vermeil and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 11

The compounds of formula I.s, in the which R 3is deformity and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 12

The compounds of formula I.r, in which R3represents trifluoromethyl and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 13

The compounds of formula I.t, in which R3represents methyl and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 14

The compounds of formula I.t, in which R3is vermeil and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 15

The compounds of formula I.t, in which R3is deformity and the combination of R1and Ar for compound corresponds in each case to one row in table A

Table 16

The compounds of formula I.t, in which R3represents trifluoromethyl and the combination of R1and Ar for compound corresponds in each case to one row in table A

Examples of preferred compounds which are represented by the formula I.A, I.b, I.c, I.d, I.e, I.f, I.g, I.h, I.i, I.k, I.l, I.m, I.n, I.o, I.P. Pavlova, I.q, I.r, I.s and I.t represent individual compounds listed above, where the variables Ar and R1have meaning to the Oia, the data in one row of table A.

Table A
No.R1Ar
1cut3-were
2cut3-ethylphenyl
3cut3-propylphenyl
4cut3-isopropylphenyl
5cut3-second-butylphenyl
6cut3-tert-butylphenyl
7cut3-isobutylphenyl
8cut3-(1,1-dimethylpropyl)phenyl
9cut3-vinylphenol
10cut 3-isopropylphenyl
11cut3-forfinal
12cut3-chlorophenyl
13cut3-bromophenyl
14cut3-itfinal
15cut3-(permitil)phenyl
16cut3-(deformity)phenyl
17cut3-(trifluoromethyl)phenyl
18cut3,5-bis(trifluoromethyl)phenyl
19cut3-(1-foradil)phenyl
20cut3-((S)-1-foradil)phenyl
21cut3-((R)-1-foradil)phenyl
22 cut3-(2-foradil)phenyl

23cut3-(1,1-dottorati)phenyl
24cut3-(2,2-dottorati)phenyl
25cut3-(2,2,2-triptorelin)phenyl
26cut3-(3-forproper)phenyl
27cut3-(2-forproper)phenyl
28cut3-((S)-2-forproper)phenyl
29cut3-((R)-2-forproper)phenyl
30cut3-(3,3-deferror)phenyl
31cut3-(3,3,3-cryptochromes)phenyl
32cut3-(1-fluoro-1-methylethyl)phenyl
cut3-(2-fluoro-1-methylethyl)phenyl
34cut3-((S)-2-fluoro-1-methylethyl)phenyl
35cut3-((R)-2-fluoro-1-methylethyl)phenyl
36cut3-(2,2-debtor-1-methylethyl)phenyl
37cut3-((S)-2,2-debtor-1-methylethyl)phenyl
38cut3-((R)-2,2-debtor-1-methylethyl)phenyl
39cut3-(2,2,2-Cryptor-1-methylethyl)phenyl
40cut3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl
41cut3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
42cut3-(2-fluoro-1-permethylated)phenyl
43cut3-(1-gift rmeil-2,2-dottorati)phenyl
44cut3-(1,1-dimethyl-2-foradil)phenyl
45cut3-methoxyphenyl
46cut3-ethoxyphenyl
47cut3-propoxyphenyl
48cut3-isopropoxyphenyl
49cut3-butoxyphenyl
50cut3-(formatosi)phenyl
51cut3-(deformedarse)phenyl
52cut3-(triptoreline)phenyl

td align="center"> cut
53cut3-(2-floratone)phenyl
54cut3-(2,2-diflorasone)phenyl
55cut3-(2,2,2-triptoreline)phenyl
56cut3-(1,1,2,2-tetrafluoroethoxy)phenyl
57cut3-cyclopropylethanol
58cut3-cyclobutylmethyl
59cut3-cyclopentylphenol
60cut3-(2,2-diversicolor)phenyl
61cut3,4-differenl
62cut3-bromo-2-forfinal
63cut2-bromo-3-forfinal
64cut3-bromo-2,5-differenl
65cut5-bromo-2,4-differenl
663-bromo-2,4-differenl
67cut4-chloro-3-(trifluoromethyl)phenyl
68cut2-chloro-5-(trifluoromethyl)phenyl
69cut2-fluoro-5-(trifluoromethyl)phenyl
70cut4-fluoro-3-(trifluoromethyl)phenyl
71cut3-fluoro-5-(trifluoromethyl)phenyl
72cut4-bromo-3-(trifluoromethyl)phenyl
73cut3-bromo-5-(trifluoromethyl)phenyl
74cut2-bromo-5-(trifluoromethyl)phenyl
75cut5-bromo-2-methoxyphenyl
76cut3-bromo-4-methoxyphenyl
77 cut2-fluoro-3-isopropylphenyl
78cut4-fluoro-3-isopropylphenyl
79cut3-(1-hydroxy-1-methylethyl)phenyl
80cut3-(2-hydroxy-2-methylpropyl " phenyl
81cut3-acetylphenyl
82cut3-acetylaminophenol

83cut3-carboxyphenyl
84cut3-cyanophenyl
85cut3-nitrophenyl
86cut3-hydroxyphenyl
87cut3-(O-benzyl)phenyl
88p is filing 3-(2-methoxyethoxy)phenyl
89cut3-(CH2-N(CH3)2)phenyl
90cut3-(NH-CO-NH2)phenyl
91cut3-(methylsulfanyl)phenyl
92cut3-(pharmacysulfacet)phenyl
93cut3-(deformational)phenyl
94cut3-(trifloromethyl)phenyl
95cut3-(methylsulphonyl)phenyl
96cut3-(N-methoxy-N-methylamino)phenyl
97cut3-(methoxyamino)phenyl
98cut3-(ethoxyline)phenyl
99 cut3-(N-methylenedioxy)phenyl
100cut3-(N,N-dimethylaminoethoxy)phenyl
101cut3-(azetidin-1-yl)phenyl
102cut3-(2-methylaziridine-1-yl)phenyl
103cut3-((S)-2-methylaziridine-1-yl)phenyl
104cut3-((R)-2-methylaziridine-1-yl)phenyl
105cut3-(3-torasemide-1-yl)phenyl
106cut3-(2,2-diversecity-1-yl)phenyl
107cut3-(3-methoxyisatin-1-yl)phenyl
108cut3-(3-hydroxyazetidine-1-yl)phenyl
109cut3-(pyrrolidin-1-yl)phenyl
110cut3-(pyrrolidin-2-yl)phenyl
111cut3-((S)-pyrrolidin-2-yl)phenyl
112cut3-((R)-pyrrolidin-2-yl)phenyl

113cut3-(pyrrolidin-3-yl)phenyl
114cut3-((S)-pyrrolidin-3-yl)phenyl
115cut3-((R)-pyrrolidin-3-yl)phenyl
116cut3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl
117cut5-(pyrrolidin-1-yl)-2-methoxyphenyl
118cut3-(pyrrolidin-1-yl)-4-methoxyphenyl
119cut5-(pyrrolidin-1-yl)-2,4-differenl
120 cut3-(pyrrolidin-1-yl)-2,4-differenl
121cut3-(2-ftorpirimidinu-1-yl)phenyl
122cut3-((S)-2-ftorpirimidinu-1-yl)phenyl
123cut3-((R)-2-ftorpirimidinu-1-yl)phenyl
124cut3-(3-ftorpirimidinu-1-yl)phenyl
125cut3-((S)-3-ftorpirimidinu-1-yl)phenyl
126cut3-((R)-3-ftorpirimidinu-1-yl)phenyl
127cut3-(2,2-debtorprovidian-1-yl)phenyl
128cut3-(3,3-debtorprovidian-1-yl)phenyl
129cut3-(2-methylpyrrolidine-1-yl)phenyl
130cut3-((S)-2-methylpyrrole the DIN-1-yl)phenyl
131cut3-((R)-2-methylpyrrolidine-1-yl)phenyl
132cut3-(3-methylpyrrolidine-1-yl)phenyl
133cut3-((S)-3-methylpyrrolidine-1-yl)phenyl
134cut3-((R)-3-methylpyrrolidine-1-yl)phenyl
135cut3-(1-methylpyrrolidine-2-yl)phenyl
136cut3-((S)-1-methylpyrrolidine-2-yl)phenyl
137cut3-((R)-1-methylpyrrolidine-2-yl)phenyl
138cut3-(1-methylpyrrolidine-3-yl)phenyl
139cut3-((S)-1-methylpyrrolidine-3-yl)phenyl
140cut3-((R)-1-methylpyrrolidine-3-yl)phenyl
1413-(2,2-dimethylpiperidin-1-yl)phenyl
142cut3-(3,3-dimethylpiperidin-1-yl)phenyl

151
143cut3-(2-triftormetilfullerenov-1-yl)phenyl
144cut3-((S)-2-triftormetilfullerenov-1-yl)phenyl
145cut3-((R)-2-triftormetilfullerenov-1-yl)phenyl
146cut3-(3-triftormetilfullerenov-1-yl)phenyl
147cut3-((S)-3-triftormetilfullerenov-1-yl)phenyl
148cut3-((R)-3-triftormetilfullerenov-1-yl)phenyl
149cut3-(2-oxopyrrolidin-1-yl)phenyl
150cut3-(2-oxo-oxazolidin-3-yl)phenyl
cut3-(piperidine-1-yl)phenyl
152cut3-(2-methylpiperidin-1-yl)phenyl
153cut3-((S)-2-methylpiperidin-1-yl)phenyl
154cut3-((R)-2-methylpiperidin-1-yl)phenyl
155cut3-(2-foreperiod-1-yl)phenyl
156cut3-((S)-2-foreperiod-1-yl)phenyl
157cut3-((R)-2-foreperiod-1-yl)phenyl
158cut3-(2,2-deformability-1-yl)phenyl
159cut3-(piperazine-1-yl)phenyl
160cut3-(4-methylpiperazin-1-yl)phenyl
161cut3-(morpholine-4-and the)phenyl
162cut3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
163cut5-(morpholine-4-yl)-2-methoxyphenyl
164cut3-(morpholine-4-yl)-4-methoxyphenyl
165cut5-(morpholine-4-yl)-2,4-differenl
166cut3-(morpholine-4-yl)-2,4-differenl
167cut3-(thiomorpholine-4-yl)phenyl
168cut3-(1-Osotimehin-4-yl)phenyl
169cut3-(1,1-diocletianopolis-4-yl)phenyl
170cut3-(pyrrol-1-yl)phenyl
171cut3-(pyrrol-2-yl)phenyl
172cut 3-(pyrrol-3-yl)phenyl

173cut3-(1-methylpyrrole-2-yl)phenyl
174cut3-(1-methylpyrrole-3-yl)phenyl
175cut3-(furan-2-yl)phenyl
176cut3-(furan-3-yl)phenyl
177cut3-(thiophene-2-yl)phenyl
178cut3-(thiophene-3-yl)phenyl
179cut3-(5-properties-2-yl)phenyl
180cut3-(pyrazole-1-yl)phenyl
181cut3-(pyrazole-3-yl)phenyl
182cut3-(pyrazole-4-yl)phenyl
183cut 3-(4-perperson-1-yl)phenyl
184cut3-(1-methyl-1H-pyrazole-4-yl)phenyl
185cut3-(1-ethyl-1H-pyrazole-4-yl)phenyl
186cut3-(1-methyl-1H-pyrazole-5-yl)phenyl
187cut3-(1H-imidazol-2-yl)phenyl
188cut3-(imidazol-1-yl)phenyl
189cut3-(1-Mei-2-yl)phenyl
190cut3-(oxazol-2-yl)phenyl
191cut3-(oxazol-4-yl)phenyl
192cut3-(oxazol-5-yl)phenyl
193cut3-(isoxazol-3-yl)phenyl
194cut
195cut3-(isoxazol-5-yl)phenyl
196cut3-(thiazol-2-yl)phenyl
197cut3-(thiazol-4-yl)phenyl
198cut3-(thiazol-5-yl)phenyl
199cut3-(2-methylthiazole-4-yl)phenyl
200cut3-(2-methylthiazole-5-yl)phenyl
201cut3-([1,2,3]-triazole-1-yl)phenyl
202cut3-([1,2,4]-triazole-1-yl)phenyl

203cut3-([1,2,3]-triazole-2-yl)phenyl
204cut3-(4H-[1,2,4]-triazole-3-yl)phenyl
205cut 3-([1,2,4]-triazole-4-yl)phenyl
206cut3-(2H-[1,2,3]-triazole-4-yl)phenyl
207cut3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
208cut3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
209cut3-([1,3,4]-oxadiazol-2-yl)phenyl
210cut3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
211cut3-([1,2,4]-oxadiazol-3-yl)phenyl
212cut3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl
213cut3-([1,2,4]-oxadiazol-5-yl)phenyl
214cut3-([1,2,3]-oxadiazol-4-yl)phenyl
215cut3-([1,2,3]-oxadiazol-5-yl)phenyl
216/td> cut3-([1,2,3]-thiadiazole-4-yl)phenyl
217cut3-(1H-tetrazol-5-yl)phenyl
218cut3-(tetrazol-1-yl)phenyl
219cut3-(2-methyl-2H-tetrazol-5-yl)phenyl
220cut3-(1-methyl-1H-tetrazol-5-yl)phenyl
221cut3-furazan-3-ylphenyl
222cut3-(pyrid-2-yl)phenyl
223cut3-(pyrid-3-yl)phenyl
224cut3-(pyrid-4-yl)phenyl
225cut3-(pyrimidine-2-yl)phenyl
226cut3-(2-methylpyrimidin-4-yl)phenyl
227 cut3-(pyrimidine-4-yl)phenyl
228cut3-(pyrimidine-5-yl)phenyl
229cut5-bromopyridin-3-yl
230cut3-bromo-2-chloropyridin-5-yl
231cut4-methylpyridin-2-yl
232cut6-methylpyridin-2-yl

233cut4-(trifluoromethyl)pyridin-2-yl
234cut6-(trifluoromethyl)pyridin-2-yl
235cut5-(trifluoromethyl)pyridin-3-yl
236cut5-(pyrrolidin-1-yl)pyridine-3-yl
237cut3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl
238cut3-(morpholine-4-yl)-2-chloropyridin-5-yl
239cut2-(morpholine-4-yl)pyridin-5-yl
240cut2-phenoxypyridine-5-yl
241cut2,3-dichlorophenyl
242cut2,5-dichlorophenyl
243cut3,5-dichlorophenyl
244cut3-chloro-4-forfinal
245cut4-bromo-2,5-dichlorophenyl
246cut3-bromo-4-(triptoreline)phenyl
247cut3,5-dibromo-4-(2-floratone)phenyl
248cut2,5-dimetilfenil
249cut2,5-di-(trifluoromethyl)phenyl
250cut3,5-di-(trifluoromethyl)phenyl
251cut2,5-acid
252cut2-methoxy-5-were
253cut2-methoxy-5-(trifluoromethyl)phenyl
254cut4-fluoro-3-(oxazol-4-yl)phenyl
255cutTien-2-yl
256cutTien-3-yl
257cut3-chlortan-2-yl
258cut4-chlortan-2-yl
259cut5-chlortan-2-yl
260cut 3-Bratan-2-yl
261cut4-Bratan-2-yl
262cut5-Bratan-2-yl

263cut4,5-dichlorotin-2-yl
264cut4,5-libration-2-yl
265cut4-bromo-5-chlortan-2-yl
266cut3-bromo-5-chlortan-2-yl
267cut5-methyltin-2-yl
268cut5-utilties-2-yl
269cut5-properties-2-yl
270cut5-(trifluoromethyl)Tien-2-yl
271cut5-penalties-2-yl
272cut5-(pyrid-2-yl)Tien-2-yl
273cut5-(phenylsulfonyl)Tien-2-yl
274cut4-(phenylsulfonyl)Tien-2-yl
275cut5-(pyrid-2-ylsulphonyl)Tien-2-yl
276cut5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
277cut5-(benzoylamino)Tien-2-yl
278cut5-((4-chlorbenzoyl)aminomethyl)Tien-2-yl
279cut5-(acetamidomethyl)Tien-2-yl
280cut5-(pyrazole-1-yl)Tien-2-yl
281cut5-(pyrazole-3-yl)Tien-2-yl
282cut 5-(pyrazole-4-yl)Tien-2-yl
283cut5-(pyrazole-5-yl)Tien-2-yl
284cut5-(4-perperson-1-yl)Tien-2-yl
285cut5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl
286cut5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
287cut5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
288cut5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
289cut5-(isoxazol-3-yl)Tien-2-yl
290cut5-(isoxazol-4-yl)Tien-2-yl
291cut5-(isoxazol-5-yl)Tien-2-yl
292cut5-(5-three is timecritical-3-yl)Tien-2-yl

293cut5-(oxazol-2-yl)Tien-2-yl
294cut5-(oxazol-4-yl)Tien-2-yl
295cut5-(oxazol-5-yl)Tien-2-yl
296cut5-(2-methoxazole-4-yl)Tien-2-yl
297cut5-(2-methoxazole-5-yl)Tien-2-yl
298cut5-(isothiazol-3-yl)Tien-2-yl
299cut5-(isothiazol-4-yl)Tien-2-yl
300cut5-(isothiazol-5-yl)Tien-2-yl
301cut5-(5-triftoratsetata-3-yl)Tien-2-yl
302cut5-(thiazol-2-yl)Tien-2-yl
3035-(thiazol-4-yl)Tien-2-yl
304cut5-(thiazol-5-yl)Tien-2-yl
305cut5-(2-methylthiazole-4-yl)Tien-2-yl
306cut5-(2-methylthiazole-5-yl)Tien-2-yl
307cut5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl
308cut5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
309cut5-(pyrimidine-2-yl)Tien-2-yl
310cut5-(pyrimidine-4-yl)Tien-2-yl
311cut5-(pyrimidine-5-yl)Tien-2-yl
312cut5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
313cut5-([1,3]-dioxolane-2-yl)Tien-2-yl
314cut3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl
315cut5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl
316cut5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
317cut2-chlortan-3-yl
318cut4-chlortan-3-yl
319cut5-chlortan-3-yl
320cut2-Bratan-3-yl
321cut4-Bratan-3-yl
322cut5-Bratan-3-yl

323cut2,5-dichlorotin-3-yl
324cut25-libration-3-yl
325cut2,4,5-tripartie-3-yl
326cut4-bromo-2,5-dichlorotin-3-yl
327cut2-chloro-5-methylsulfonate-3-yl
328cut2,5-dietitian-3-yl
329cut4-hydroxicut-3-yl
330cut2-venitien-3-yl
331cut4-phenyl-5-(trifluoromethyl)Tien-3-yl
332cut2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl
333cutbenzo[b]thiophene-2-yl
334cutbenzo[b]thiophene-3-yl
335cut3 methylbenzo[b]tiof the h-2-yl
336cut5-methylbenzo[b]thiophene-2-yl
337cut5-fluoro-3-methylbenzo[b]thiophene-2-yl
338cut5-chloro-3-methylbenzo[b]thiophene-2-yl
339cut5-bromo-3-methylbenzo[b]thiophene-2-yl
340ethyl3-were
341ethyl3-ethylphenyl
342ethyl3-propylphenyl
343ethyl3-isopropylphenyl
344ethyl3-second-butylphenyl
345ethyl3-tert-butylphenyl
346ethyl3-isobutylphenyl
347 ethyl3-(1,1-dimethylpropyl)phenyl
348ethyl3-vinylphenol
349ethyl3-isopropylphenyl
350ethyl3-forfinal
351ethyl3-chlorophenyl
352ethyl3-bromophenyl

353ethyl3-itfinal
354ethyl3-(permitil)phenyl
355ethyl3-(deformity)phenyl
356ethyl3-(trifluoromethyl)phenyl
356ethyl3,5-bis(trifluoromethyl)phenyl
358ethyl3-(1-foradil)Fe is Il
359ethyl3-((S)-1-foradil)phenyl
360ethyl3-((R)-1-foradil)phenyl
361ethyl3-(2-foradil)phenyl
362ethyl3-(1,1-dottorati)phenyl
363ethyl3-(2,2-dottorati)phenyl
364ethyl3-(2,2,2-triptorelin)phenyl
365ethyl3-(3-forproper)phenyl
366ethyl3-(2-forproper)phenyl
367ethyl3-((S)-2-forproper)phenyl
368ethyl3-((R)-2-forproper)phenyl
369ethyl3-(3,3-deferror)phenyl
370 ethyl3-(3,3,3-cryptochromes)phenyl
371ethyl3-(1-fluoro-1-methylethyl)phenyl
372ethyl3-(2-fluoro-1-methylethyl)phenyl
373ethyl3-((S)-2-fluoro-1-methylethyl)phenyl
374ethyl3-((R)-2-fluoro-1-methylethyl)phenyl
375ethyl3-(2,2-debtor-1-methylethyl)phenyl
376ethyl3-((S)-2,2-debtor-1-methylethyl)phenyl
377ethyl3-((R)-2,2-debtor-1-methylethyl)phenyl
378ethyl3-(2,2,2-Cryptor-1-methylethyl)phenyl
379ethyl3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl
380ethyl3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
381ethyl3-(2-fluoro-1-permethylated)phenyl
382ethyl3-(1-deformity-2,2-dottorati)phenyl

383ethyl3-(1,1-dimethyl-2-foradil)phenyl
384ethyl3-methoxyphenyl
385ethyl3-ethoxyphenyl
386ethyl3-propoxyphenyl
387ethyl3-isopropoxyphenyl
388ethyl3-butoxyphenyl
389ethyl3-(formatosi)phenyl
390ethyl3-(deformedarse)phenyl
391ethyl3-(triptoreline)phenyl
392ethyl3-(2-floratone)phenyl
393ethyl3-(2,2-diflorasone)phenyl
394ethyl3-(2,2,2-triptoreline)phenyl
395ethyl3-(1,1,2,2-tetrafluoroethoxy)phenyl
396ethyl3-cyclopropylethanol
397ethyl3-cyclobutylmethyl
398ethyl3-cyclopentylphenol
399ethyl3-(2,2-diversicolor)phenyl
400ethyl3,4-differenl
401ethyl3-bromo-2-forfinal
402ethyl2-bromo-3-forfinal
403ethyl 3-bromo-2,5-differenl
404ethyl5-bromo-2,4-differenl
405ethyl3-bromo-2,4-differenl
406ethyl4-chloro-3-(trifluoromethyl)phenyl
407ethyl2-chloro-5-(trifluoromethyl)phenyl
408ethyl2-fluoro-5-(trifluoromethyl)phenyl
409ethyl4-fluoro-3-(trifluoromethyl)phenyl
410ethyl3-fluoro-5-(trifluoromethyl)phenyl
411ethyl4-bromo-3-(trifluoromethyl)phenyl
412ethyl3-bromo-5-(trifluoromethyl)phenyl

413ethyl2-bromo-5-(trifluoromethyl)phenyl
414 ethyl5-bromo-2-methoxyphenyl
415ethyl3-bromo-4-methoxyphenyl
416ethyl2-fluoro-3-isopropylphenyl
417ethyl4-fluoro-3-isopropylphenyl
418ethyl3-(1-hydroxy-1-methylethyl)phenyl
419ethyl3-(2-hydroxy-2-methylpropyl " phenyl
420ethyl3-acetylphenyl
421ethyl3-acetylaminophenol
422ethyl3-carboxyphenyl
423ethyl3-cyanophenyl
424ethyl3-nitrophenyl
425ethyl3-hydroxyphenyl
426ethyl3-(O-benzyl)phenyl
427ethyl3-(2-methoxyethoxy)phenyl
428ethyl3-(CH2-N(CH3)2)phenyl
429ethyl3-(NH-CO-NH2)phenyl
430ethyl3-(methylsulfanyl)phenyl
431ethyl3-(pharmacysulfacet)phenyl
432ethyl3-(deformational)phenyl
433ethyl3-(trifloromethyl)phenyl
434ethyl3-(methylsulphonyl)phenyl
435ethyl3-(N-methoxy-N-methylamino)phenyl
436ethyl3-(methoxyamino)phenyl
437/td> ethyl3-(ethoxyline)phenyl
438ethyl3-(N-methylenedioxy)phenyl
439ethyl3-(N,N-dimethylaminoethoxy)phenyl
440ethyl3-(azetidin-1-yl)phenyl
441ethyl3-(2-methylaziridine-1-yl)phenyl
442ethyl3-((S)-2-methylaziridine-1-yl)phenyl

443ethyl3-((R)-2-methylaziridine-1-yl)phenyl
444ethyl3-(3-torasemide-1-yl)phenyl
445ethyl3-(2,2-diversecity-1-yl)phenyl
446ethyl3-(3-methoxyisatin-1-yl)phenyl
447ethyl3-(3-GI is roxatidine-1-yl)phenyl
448ethyl3-(pyrrolidin-1-yl)phenyl
449ethyl3-(pyrrolidin-2-yl)phenyl
450ethyl3-((S)-pyrrolidin-2-yl)phenyl
451ethyl3-((R)-pyrrolidin-2-yl)phenyl
452ethyl3-(pyrrolidin-3-yl)phenyl
453ethyl3-((S)-pyrrolidin-3-yl)phenyl
454ethyl3-((R)-pyrrolidin-3-yl)phenyl
455ethyl3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl
456ethyl5-(pyrrolidin-1-yl)-2-methoxyphenyl
457ethyl3-(pyrrolidin-1-yl)-4-methoxyphenyl
458ethyl5-(pyrrolidin--yl)-2,4-differenl
459ethyl3-(pyrrolidin-1-yl)-2,4-differenl
460ethyl3-(2-ftorpirimidinu-1-yl)phenyl
461ethyl3-((S)-2-ftorpirimidinu-1-yl)phenyl
462ethyl3-((R)-2-ftorpirimidinu-1-yl)phenyl
463ethyl3-(3-ftorpirimidinu-1-yl)phenyl
464ethyl3-((S)-3-ftorpirimidinu-1-yl)phenyl
465ethyl3-((R)-3-ftorpirimidinu-1-yl)phenyl
466ethyl3-(2,2-debtorprovidian-1-yl)phenyl
467ethyl3-(3,3-debtorprovidian-1-yl)phenyl
468ethyl3-(2-methylpyrrolidine-1-yl)phenyl
469ethyl 3-((S)-2-methylpyrrolidine-1-yl)phenyl
470ethyl3-((R)-2-methylpyrrolidine-1-yl)phenyl
471ethyl3-(3-methylpyrrolidine-1-yl)phenyl
472ethyl3-((S)-3-methylpyrrolidine-1-yl)phenyl

473ethyl3-((R)-3-methylpyrrolidine-1-yl)phenyl
474ethyl3-(1-methylpyrrolidine-2-yl)phenyl
475ethyl3-((S)-1-methylpyrrolidine-2-yl)phenyl
476ethyl3-((R)-1-methylpyrrolidine-2-yl)phenyl
477ethyl3-(1-methylpyrrolidine-3-yl)phenyl
478ethyl3-((S)-1-methylpyrrolidine-3-yl)phenyl
479ethyl3-((R)-1-metier is lidin-3-yl)phenyl
480ethyl3-(2,2-dimethylpiperidin-1-yl)phenyl
481ethyl3-(3,3-dimethylpiperidin-1-yl)phenyl
482ethyl3-(2-triftormetilfullerenov-1-yl)phenyl
483ethyl3-((S)-2-triftormetilfullerenov-1-yl)phenyl
484ethyl3-((R)-2-triftormetilfullerenov-1-yl)phenyl
485ethyl3-(3-triftormetilfullerenov-1-yl)phenyl
486ethyl3-((S)-3-triftormetilfullerenov-1-yl)phenyl
487ethyl3-((R)-3-triftormetilfullerenov-1-yl)phenyl
488ethyl3-(2-oxopyrrolidin-1-yl)phenyl
489ethyl3-(2-oxo-oxazolidin-3-yl)phenyl
490ethyl3-(piperidine-1-yl)phenyl
491ethyl3-(2-methylpiperidin-1-yl)phenyl
492ethyl3-((S)-2-methylpiperidin-1-yl)phenyl
493ethyl3-((R)-2-methylpiperidin-1-yl)phenyl
494ethyl3-(2-foreperiod-1-yl)phenyl
495ethyl3-((S)-2-foreperiod-1-yl)phenyl
496ethyl3-((R)-2-foreperiod-1-yl)phenyl
497ethyl3-(2,2-deformability-1-yl)phenyl
498ethyl3-(piperazine-1-yl)phenyl
499ethyl3-(4-methylpiperazin-1-yl)phenyl
500ethyl3-(morpholine-4-yl)phenyl
501ethyl3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
502ethyl5-(morpholine-4-yl)-2-methoxyphenyl

503ethyl3-(morpholine-4-yl)-4-methoxyphenyl
504ethyl5-(morpholine-4-yl)-2,4-differenl
505ethyl3-(morpholine-4-yl)-2,4-differenl
506ethyl3-(thiomorpholine-4-yl)phenyl
507ethyl3-(1-Osotimehin-4-yl)phenyl
508ethyl3-(1,1-diocletianopolis-4-yl)phenyl
509ethyl3-(pyrrol-1-yl)phenyl
510ethyl3-(pyrrol-2-yl)phenyl
511ethyl 3-(pyrrol-3-yl)phenyl
512ethyl3-(1-methylpyrrole-2-yl)phenyl
513ethyl3-(1-methylpyrrole-3-yl)phenyl
514ethyl3-(furan-2-yl)phenyl
515ethyl3-(furan-3-yl)phenyl
516ethyl3-(thiophene-2-yl)phenyl
517ethyl3-(thiophene-3-yl)phenyl
518ethyl3-(5-properties-2-yl)phenyl
519ethyl3-(pyrazole-1-yl)phenyl
520ethyl3-(pyrazole-3-yl)phenyl
521ethyl3-(pyrazole-4-yl)phenyl
522ethyl3-(4-perperson-1-yl)phenyl
523/td> ethyl3-(1-methyl-1H-pyrazole-4-yl)phenyl
524ethyl3-(1-ethyl-1H-pyrazole-4-yl)phenyl
525ethyl3-(1-methyl-1H-pyrazole-5-yl)phenyl
526ethyl3-(1H-imidazol-2-yl)phenyl
527ethyl3-(imidazol-1-yl)phenyl
528ethyl3-(1-Mei-2-yl)phenyl
529ethyl3-(oxazol-2-yl)phenyl
530ethyl3-(oxazol-4-yl)phenyl
531ethyl3-(oxazol-5-yl)phenyl
532ethyl3-(isoxazol-3-yl)phenyl

533ethyl3-(isoxazol-4-yl)phenyl
534ethyl3-(isoxazol-5-yl)phenyl
535ethyl3-(thiazol-2-yl)phenyl
536ethyl3-(thiazol-4-yl)phenyl
537ethyl3-(thiazol-5-yl)phenyl
538ethyl3-(2-methylthiazole-4-yl)phenyl
539ethyl3-(2-methylthiazole-5-yl)phenyl
540ethyl3-([1,2,3]-triazole-1-yl)phenyl
541ethyl3-([1,2,4]-triazole-1-yl)phenyl
542ethyl3-([1,2,3]-triazole-2-yl)phenyl
543ethyl3-(4H-[1,2,4]-triazole-3-yl)phenyl
544ethyl3-([1,2,4]-triazole-4-yl)phenyl
545ethyl 3-(2H-[1,2,3]-triazole-4-yl)phenyl
546ethyl3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
547ethyl3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
548ethyl3-([1,3,4]-oxadiazol-2-yl)phenyl
549ethyl3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
550ethyl3-([1,2,4]-oxadiazol-3-yl)phenyl
551ethyl3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl
552ethyl3-([1,2,4]-oxadiazol-5-yl)phenyl
553ethyl3-([1,2,3]-oxadiazol-4-yl)phenyl
554ethyl3-([1,2,3]-oxadiazol-5-yl)phenyl
555ethyl3-([1,2,3]-thiadiazole-4-yl)phenyl
556ethyl3-(1H-tetrazol-5-yl)phenyl
557ethyl3-(tetrazol-1-yl)phenyl
558ethyl3-(2-methyl-2H-tetrazol-5-yl)phenyl
559ethyl3-(1-methyl-1H-tetrazol-5-yl)phenyl
560ethyl3-furazan-3-ylphenyl
561ethyl3-(pyrid-2-yl)phenyl
562ethyl3-(pyrid-3-yl)phenyl

td align="center"> ethyl
563ethyl3-(pyrid-4-yl)phenyl
564ethyl3-(pyrimidine-2-yl)phenyl
565ethyl3-(2-methylpyrimidin-4-yl)phenyl
566ethyl3-(pyrimidine-4-yl)phenyl
567ethyl3-(pyrimidine-5-yl)phenyl
568ethyl5-bromopyridin-3-yl
569ethyl3-bromo-2-chloropyridin-5-yl
570ethyl4-methylpyridin-2-yl
571ethyl6-methylpyridin-2-yl
572ethyl4-(trifluoromethyl)pyridin-2-yl
573ethyl6-(trifluoromethyl)pyridin-2-yl
574ethyl5-(trifluoromethyl)pyridin-3-yl
575ethyl5-(pyrrolidin-1-yl)pyridine-3-yl
576ethyl3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl
577ethyl3-(morpholine-4-yl)-2-chloropyridin-5-yl
5782-(morpholine-4-yl)pyridin-5-yl
579ethyl2-phenoxypyridine-5-yl
580ethyl2,3-dichlorophenyl
581ethyl2,5-dichlorophenyl
582ethyl3,5-dichlorophenyl
583ethyl3-chloro-4-forfinal
584ethyl4-bromo-2,5-dichlorophenyl
585ethyl3-bromo-4-(triptoreline)phenyl
586ethyl3,5-dibromo-4-(2-floratone)phenyl
587ethyl2,5-dimetilfenil
588ethyl2,5-di-(trifluoromethyl)phenyl
589ethyl3,5-di-(trifluoromethyl)Fe is Il
590ethyl2,5-acid
591ethyl2-methoxy-5-were
592ethyl2-methoxy-5-(trifluoromethyl)phenyl

593ethyl4-fluoro-3-(oxazol-4-yl)phenyl
594ethylTien-2-yl
595ethylTien-3-yl
596ethyl3-chlortan-2-yl
597ethyl4-chlortan-2-yl
598ethyl5-chlortan-2-yl
599ethyl3-Bratan-2-yl
600ethyl4-Bratan-2-yl
601 ethyl5-Bratan-2-yl
602ethyl4,5-dichlorotin-2-yl
603ethyl4,5-libration-2-yl
604ethyl4-bromo-5-chlortan-2-yl
605ethyl3-bromo-5-chlortan-2-yl
606ethyl5-methyltin-2-yl
607ethyl5-utilties-2-yl
608ethyl5-properties-2-yl
609ethyl5-triptorelin-2-yl
610ethyl5-penalties-2-yl
611ethyl5-(pyrid-2-yl)Tien-2-yl
612ethyl5-(phenylsulfonyl)Tien-2-yl
ethyl4-(phenylsulfonyl)Tien-2-yl
614ethyl5-(pyrid-2-ylsulphonyl)Tien-2-yl
615ethyl5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
616ethyl5-(benzoylamino)Tien-2-yl
617ethyl5-((4-chlorbenzoyl)aminomethyl)Tien-2-yl
618ethyl5-(acetamidomethyl)Tien-2-yl
619ethyl5-(pyrazole-1-yl)Tien-2-yl
620ethyl5-(pyrazole-3-yl)Tien-2-yl
621ethyl5-(pyrazole-4-yl)Tien-2-yl
622ethyl5-(pyrazole-5-yl)Tien-2-yl

623ethyl 5-(4-perperson-1-yl)Tien-2-yl
624ethyl5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl
625ethyl5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
626ethyl5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
627ethyl5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
628ethyl5-(isoxazol-3-yl)Tien-2-yl
629ethyl5-(isoxazol-4-yl)Tien-2-yl
630ethyl5-(isoxazol-5-yl)Tien-2-yl
631ethyl5-(5-cryptometrics-3-yl)Tien-2-yl
632ethyl5-(oxazol-2-yl)Tien-2-yl
633ethyl5-(oxazol-4 and is)Tien-2-yl
634ethyl5-(oxazol-5-yl)Tien-2-yl
635ethyl5-(2-methoxazole-4-yl)Tien-2-yl
636ethyl5-(2-methoxazole-5-yl)Tien-2-yl
637ethyl5-(isothiazol-3-yl)Tien-2-yl
638ethyl5-(isothiazol-4-yl)Tien-2-yl
639ethyl5-(isothiazol-5-yl)Tien-2-yl
640ethyl5-(5-triftoratsetata-3-yl)Tien-2-yl
641ethyl5-(thiazol-2-yl)Tien-2-yl
642ethyl5-(thiazol-4-yl)Tien-2-yl
643ethyl5-(thiazol-5-yl)Tien-2-yl
644ethyl5-(2-methylthiazole-4-yl)Tien-2-yl
645ethyl5-(2-methylthiazole-5-yl)Tien-2-yl
646ethyl5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl
647ethyl5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
648ethyl5-(pyrimidine-2-yl)Tien-2-yl
649ethyl5-(pyrimidine-4-yl)Tien-2-yl
650ethyl5-(pyrimidine-5-yl)Tien-2-yl
651ethyl5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
652ethyl5-([1,3]-dioxolane-2-yl)Tien-2-yl
653ethyl3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl

654ethyl5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl
655ethyl5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
656ethyl2-chlortan-3-yl
657ethyl4-chlortan-3-yl
658ethyl5-chlortan-3-yl
659ethyl2-Bratan-3-yl
660ethyl4-Bratan-3-yl
661ethyl5-Bratan-3-yl
662ethyl2,5-dichlorotin-3-yl
663ethyl2,5-libration-3-yl
664ethyl2,4,5-tripartie-3-yl
665ethyl4-bromo-2,5-dichlorotin-3-yl
666ethyl2-chloro-5-m is tranposition-3-yl
667ethyl2,5-dietitian-3-yl
668ethyl4-hydroxicut-3-yl
669ethyl2-venitien-3-yl
670ethyl4-phenyl-5-(trifluoromethyl)Tien-3-yl
671ethyl2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl
672ethylbenzo[b]thiophene-2-yl
673ethylbenzo[b]thiophene-3-yl
674ethyl3 methylbenzo[b]thiophene-2-yl
675ethyl5-methylbenzo[b]thiophene-2-yl
676ethyl5-fluoro-3-methylbenzo[b]thiophene-2-yl
677ethyl5-chloro-3-methylbenzo[b]thiophene-2-yl
678ethyl5-bromo-3-methylbenzo[b]thiophene-2-yl
679methyl3-were
680methyl3-ethylphenyl
681methyl3-propylphenyl
682methyl3-isopropylphenyl
683methyl3-second-butylphenyl

td align="center"> methyl
684methyl3-tert-butylphenyl
685methyl3-isobutylphenyl
686methyl3-(1,1-dimethylpropyl)phenyl
687methyl3-vinylphenol
688methyl3-isopropylphenyl
6893-forfinal
690methyl3-chlorophenyl
691methyl3-bromophenyl
692methyl3-itfinal
693methyl3-(permitil)phenyl
694methyl3-(deformity)phenyl
695methyl3-(trifluoromethyl)phenyl
696methyl3,5-bis(trifluoromethyl)phenyl
697methyl3-(1-foradil)phenyl
698methyl3-((S)-1-foradil)phenyl
699methyl3-((R)-1-foradil)phenyl
700methyl3-(2-foradil)phenyl
701 methyl3-(1,1-dottorati)phenyl
702methyl3-(2,2-dottorati)phenyl
703methyl3-(2,2,2-triptorelin)phenyl
704methyl3-(3-forproper)phenyl
705methyl3-(2-forproper)phenyl
706methyl3-((S)-2-forproper)phenyl
707methyl3-((R)-2-forproper)phenyl
708methyl3-(3,3-deferror)phenyl
709methyl3-(3,3,3-cryptochromes)phenyl
710methyl3-(1-fluoro-1-methylethyl)phenyl
711methyl3-(2-fluoro-1-methylethyl)phenyl
712 methyl3-((S)-2-fluoro-1-methylethyl)phenyl
713methyl3-((R)-2-fluoro-1-methylethyl)phenyl

3-(1,1-dimethyl-2-foradil)phenyl
714methyl3-(2,2-debtor-1-methylethyl)phenyl
715methyl3-((S)-2,2-debtor-1-methylethyl)phenyl
716methyl3-((R)-2,2-debtor-1-methylethyl)phenyl
717methyl3-(2,2,2-Cryptor-1-methylethyl)phenyl
718methyl3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl
719methyl3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
720methyl3-(2-fluoro-1-permethylated)phenyl
721methyl3-(1-deformity-2,2-dottorati)phenyl
722methyl
723methyl3-methoxyphenyl
724methyl3-ethoxyphenyl
725methyl3-propoxyphenyl
726methyl3-isopropoxyphenyl
727methyl3-butoxyphenyl
728methyl3-(formatosi)phenyl
729methyl3-(deformedarse)phenyl
730methyl3-(triptoreline)phenyl
731methyl3-(2-floratone)phenyl
732methyl3-(2,2-diflorasone)phenyl
733methyl3-(2,2,2-triptoreline)phenyl
734methyl3-(1,1,2,2-tetrafluoroethoxy)phenyl
735methyl3-cyclopropylethanol
736methyl3-cyclobutylmethyl
737methyl3-cyclopentylphenol
738methyl3-(2,2-diversicolor)phenyl
739methyl3,4-differenl
740methyl3-bromo-2-forfinal
741methyl2-bromo-3-forfinal
742methyl3-bromo-2,5-differenl
743methyl5-bromo-2,4-differenl

744methyl3-bromo-2,4-differenl
745methyl4-chloro-3-(trifluoromethyl)phenyl
746methyl2-chloro-5-(trifluoromethyl)phenyl
747methyl2-fluoro-5-(trifluoromethyl)phenyl
748methyl4-fluoro-3-(trifluoromethyl)phenyl
749methyl3-fluoro-5-(trifluoromethyl)phenyl
750methyl4-bromo-3-(trifluoromethyl)phenyl
751methyl3-bromo-5-(trifluoromethyl)phenyl
752methyl2-bromo-5-(trifluoromethyl)phenyl
753methyl5-bromo-2-methoxyphenyl
754methyl3-bromo-4-methoxyphenyl
755methyl2-fluoro-3-isopropylphenyl
756methyl4-fluoro-3-isopropylphenyl
757methyl3-(1-hydroxy-1-methylethyl)phenyl
758methyl3-(2-hydroxy-2-methylpropyl " phenyl
759methyl3-acetylphenyl
760methyl3-acetylaminophenol
761methyl3-carboxyphenyl
762methyl3-cyanophenyl
763methyl3-nitrophenyl
764methyl3-hydroxyphenyl
765methyl3-(O-benzyl)phenyl
766methyl3-(2-methoxyethoxy)phenyl
767methyl 3-(CH2-N(CH3)2)phenyl
768methyl3-(NH-CO-NH2)phenyl
769methyl3-(methylsulfanyl)phenyl
770methyl3-(pharmacysulfacet)phenyl
771methyl3-(deformational)phenyl
772methyl3-(trifloromethyl)phenyl
773methyl3-(methylsulphonyl)phenyl

789
774methyl3-(N-methoxy-N-methylamino)phenyl
775methyl3-(methoxyamino)phenyl
776methyl3-(ethoxyline)phenyl
777methyl3-(N-methylenedioxy)phenyl
778methyl3-(N,N-dimethylaminoethoxy)phenyl
779methyl3-(azetidin-1-yl)phenyl
780methyl3-(2-methylaziridine-1-yl)phenyl
781methyl3-((S)-2-methylaziridine-1-yl)phenyl
782methyl3-((R)-2-methylaziridine-1-yl)phenyl
783methyl3-(3-torasemide-1-yl)phenyl
784methyl3-(2,2-diversecity-1-yl)phenyl
785methyl3-(3-methoxyisatin-1-yl)phenyl
786methyl3-(3-hydroxyazetidine-1-yl)phenyl
787methyl3-(pyrrolidin-1-yl)phenyl
788methyl3-(pyrrolidin-2-yl)phenyl
methyl3-((S)-pyrrolidin-2-yl)phenyl
790methyl3-((R)-pyrrolidin-2-yl)phenyl
791methyl3-(pyrrolidin-3-yl)phenyl
792methyl3-((S)-pyrrolidin-3-yl)phenyl
793methyl3-((R)-pyrrolidin-3-yl)phenyl
794methyl3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl
795methyl5-(pyrrolidin-1-yl)-2-methoxyphenyl
796methyl3-(pyrrolidin-1-yl)-4-methoxyphenyl
797methyl5-(pyrrolidin-1-yl)-2,4-differenl
798methyl3-(pyrrolidin-1-yl)-2,4-differenl
799methyl3-(2-fererro the one-1-yl)phenyl
800methyl3-((S)-2-ftorpirimidinu-1-yl)phenyl
801methyl3-((R)-2-ftorpirimidinu-1-yl)phenyl
802methyl3-(3-ftorpirimidinu-1-yl)phenyl
803methyl3-((S)-3-ftorpirimidinu-1-yl)phenyl

810
804methyl3-((R)-3-ftorpirimidinu-1-yl)phenyl
805methyl3-(2,2-debtorprovidian-1-yl)phenyl
806methyl3-(3,3-debtorprovidian-1-yl)phenyl
807methyl3-(2-methylpyrrolidine-1-yl)phenyl
808methyl3-((S)-2-methylpyrrolidine-1-yl)phenyl
809methyl3-((R)-2-methylpyrrolidine-1-yl)phenyl
methyl3-(3-methylpyrrolidine-1-yl)phenyl
811methyl3-((S)-3-methylpyrrolidine-1-yl)phenyl
812methyl3-((R)-3-methylpyrrolidine-1-yl)phenyl
813methyl3-(1-methylpyrrolidine-2-yl)phenyl
814methyl3-((S)-1-methylpyrrolidine-2-yl)phenyl
815methyl3-((R)-1-methylpyrrolidine-2-yl)phenyl
816methyl3-(1-methylpyrrolidine-3-yl)phenyl
817methyl3-((S)-1-methylpyrrolidine-3-yl)phenyl
818methyl3-((R)-1-methylpyrrolidine-3-yl)phenyl
819methyl3-(2,2-dimethylpiperidin-1-yl)phenyl
820methyl 3-(3,3-dimethylpiperidin-1-yl)phenyl
821methyl3-(2-triftormetilfullerenov-1-yl)phenyl
822methyl3-((S)-2-triftormetilfullerenov-1-yl)phenyl
823methyl3-((R)-2-triftormetilfullerenov-1-yl)phenyl
824methyl3-(3-triftormetilfullerenov-1-yl)phenyl
825methyl3-((S)-3-triftormetilfullerenov-1-yl)phenyl
826methyl3-((R)-3-triftormetilfullerenov-1-yl)phenyl
827methyl3-(2-oxopyrrolidin-1-yl)phenyl
828methyl3-(2-oxo-oxazolidin-3-yl)phenyl
829methyl3-(piperidine-1-yl)phenyl
830methyl3-(2-methylpiperidin-1 and is)phenyl
831methyl3-((S)-2-methylpiperidin-1-yl)phenyl
832methyl3-((R)-2-methylpiperidin-1-yl)phenyl
833methyl3-(2-foreperiod-1-yl)phenyl

td align="center"> 3-(1-ethyl-1H-pyrazole-4-yl)phenyl
834methyl3-((S)-2-foreperiod-1-yl)phenyl
835methyl3-((R)-2-foreperiod-1-yl)phenyl
836methyl3-(2,2-deformability-1-yl)phenyl
837methyl3-(piperazine-1-yl)phenyl
838methyl3-(4-methylpiperazin-1-yl)phenyl
839methyl3-(morpholine-4-yl)phenyl
840methyl3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
methyl5-(morpholine-4-yl)-2-methoxyphenyl
842methyl3-(morpholine-4-yl)-4-methoxyphenyl
843methyl5-(morpholine-4-yl)-2,4-differenl
844methyl3-(morpholine-4-yl)-2,4-differenl
845methyl3-(thiomorpholine-4-yl)phenyl
846methyl3-(1-Osotimehin-4-yl)phenyl
847methyl3-(1,1-diocletianopolis-4-yl)phenyl
848methyl3-(pyrrol-1-yl)phenyl
849methyl3-(pyrrol-2-yl)phenyl
850methyl3-(pyrrol-3-yl)phenyl
851methyl3-(1-methylpyrrole-2-yl)phenyl
852methyl3-(1-methylpyrrole-3-yl)phenyl
853methyl3-(furan-2-yl)phenyl
854methyl3-(furan-3-yl)phenyl
855methyl3-(thiophene-2-yl)phenyl
856methyl3-(thiophene-3-yl)phenyl
857methyl3-(5-properties-2-yl)phenyl
858methyl3-(pyrazole-1-yl)phenyl
859methyl3-(pyrazole-3-yl)phenyl
860methyl3-(pyrazole-4-yl)phenyl
861methyl3-(4-perperson-1-yl)phenyl
862methyl3-(1-methyl-1H-pyrazole-4-yl)phenyl
863methyl

864methyl3-(1-methyl-1H-pyrazole-5-yl)phenyl
865methyl3-(1H-imidazol-2-yl)phenyl
866methyl3-(imidazol-1-yl)phenyl
867methyl3-(1-Mei-2-yl)phenyl
868methyl3-(oxazol-2-yl)phenyl
869methyl3-(oxazol-4-yl)phenyl
870methyl3-(oxazol-5-yl)phenyl
871methyl3-(isoxazol-3-yl)phenyl
872methyl3-(isoxazol-4-yl)phenyl
873methyl3-(isoxazol-5-yl)phenyl
874IU is Il 3-(thiazol-2-yl)phenyl
875methyl3-(thiazol-4-yl)phenyl
876methyl3-(thiazol-5-yl)phenyl
877methyl3-(2-methylthiazole-4-yl)phenyl
878methyl3-(2-methylthiazole-5-yl)phenyl
879methyl3-([1,2,3]-triazole-1-yl)phenyl
880methyl3-([1,2,4]-triazole-1-yl)phenyl
881methyl3-([1,2,3]-triazole-2-yl)phenyl
882methyl3-(4H-[1,2,4]-triazole-3-yl)phenyl
883methyl3-([1,2,4]-triazole-4-yl)phenyl
884methyl3-(2H-[1,2,3]-triazole-4-yl)phenyl
885methyl 3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
886methyl3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
887methyl3-([1,3,4]-oxadiazol-2-yl)phenyl
888methyl3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
889methyl3-([1,2,4]-oxadiazol-3-yl)phenyl
890methyl3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl
891methyl3-([1,2,4]-oxadiazol-5-yl)phenyl
892methyl3-([1,2,3]-oxadiazol-4-yl)phenyl
893methyl3-([1,2,3]-oxadiazol-5-yl)phenyl

894methyl3-([1,2,3]-thiadiazole-4-yl)phenyl
895methyl3-(1H-tetrazol-5-yl)F. the Nile
896methyl3-(tetrazol-1-yl)phenyl
897methyl3-(2-methyl-2H-tetrazol-5-yl)phenyl
898methyl3-(1-methyl-1H-tetrazol-5-yl)phenyl
899methyl3-furazan-3-ylphenyl
900methyl3-(pyrid-2-yl)phenyl
901methyl3-(pyrid-3-yl)phenyl
902methyl3-(pyrid-4-yl)phenyl
903methyl3-(pyrimidine-2-yl)phenyl
904methyl3-(2-methylpyrimidin-4-yl)phenyl
905methyl3-(pyrimidine-4-yl)phenyl
906methyl3-(pyrimidine-5-yl)phenyl
907methyl5-bromopyridin-3-yl
908methyl3-bromo-2-chloropyridin-5-yl
909methyl4-methylpyridin-2-yl
910methyl6-methylpyridin-2-yl
911methyl4-(trifluoromethyl)pyridin-2-yl
912methyl6-(trifluoromethyl)pyridin-2-yl
913methyl5-(trifluoromethyl)pyridin-3-yl
914methyl5-(pyrrolidin-1-yl)pyridine-3-yl
915methyl3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl
916methyl3-(morpholine-4-yl)-2-chloropyridin-5-yl
917methyl2-(morpholine-4-yl)pyridin-5-yl
918methyl2-phenoxypyridine-5-yl
919methyl2,3-dichlorophenyl
920methyl2,5-dichlorophenyl
921methyl3,5-dichlorophenyl
922methyl3-chloro-4-forfinal
923methyl4-bromo-2,5-dichlorophenyl

924methyl3-bromo-4-(triptoreline)phenyl
925methyl3,5-dibromo-4-(2-floratone)phenyl
926methyl2,5-dimetilfenil
927methyl2,5-di-(trifluoromethyl)phenyl
928methyl3,5-di-(trifluoromethyl)phenyl
methyl2,5-acid
930methyl2-methoxy-5-were
931methyl2-methoxy-5-(trifluoromethyl)phenyl
932methyl4-fluoro-3-(oxazol-4-yl)phenyl
933methylTien-2-yl
934methylTien-3-yl
935methyl3-chlortan-2-yl
936methyl4-chlortan-2-yl
937methyl5-chlortan-2-yl
938methyl3-Bratan-2-yl
939methyl4-Bratan-2-yl
940methyl5-Bratan-2-yl
941methyl4,5-dichlorotin-2-yl
942methyl4,5-libration-2-yl
943methyl4-bromo-5-chlortan-2-yl
944methyl3-bromo-5-chlortan-2-yl
945methyl5-methyltin-2-yl
946methyl5-utilties-2-yl
947methyl5-properties-2-yl
948methyl5-triptorelin-2-yl
949methyl5-penalties-2-yl
950methyl5-(pyrid-2-yl)Tien-2-yl
951methyl5-(phenylsulfonyl)Tien-2-yl
952methyl4-(Fe is ylsulphonyl)Tien-2-yl
953methyl5-(pyrid-2-ylsulphonyl)Tien-2-yl

methyl
954methyl5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
955methyl5-(benzoylamino)Tien-2-yl
956methyl5-((4-chlorbenzoyl)aminomethyl)Tien-2-yl
957methyl5-(acetamidomethyl)Tien-2-yl
958methyl5-(pyrazole-1-yl)Tien-2-yl
959methyl5-(pyrazole-3-yl)Tien-2-yl
960methyl5-(pyrazole-4-yl)Tien-2-yl
961methyl5-(pyrazole-5-yl)Tien-2-yl
962methyl5-(4-perperson-1-yl)Tien-2-yl
963methyl5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl
964methyl5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
965methyl5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
966methyl5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
967methyl5-(isoxazol-3-yl)Tien-2-yl
968methyl5-(isoxazol-4-yl)Tien-2-yl
969methyl5-(isoxazol-5-yl)Tien-2-yl
970methyl5-(5-cryptometrics-3-yl)Tien-2-yl
971methyl5-(oxazol-2-yl)Tien-2-yl
972methyl5-(oxazol-4-yl)Tien-2-yl
9735-(oxazol-5-yl)Tien-2-yl
974methyl5-(2-methoxazole-4-yl)Tien-2-yl
975methyl5-(2-methoxazole-5-yl)Tien-2-yl
976methyl5-(isothiazol-3-yl)Tien-2-yl
977methyl5-(isothiazol-4-yl)Tien-2-yl
978methyl5-(isothiazol-5-yl)Tien-2-yl
979methyl5-(5-triftoratsetata-3-yl)Tien-2-yl
980methyl5-(thiazol-2-yl)Tien-2-yl
981methyl5-(thiazol-4-yl)Tien-2-yl
982methyl5-(thiazol-5-yl)Tien-2-yl
983methyl5-(2-methylthiazole-4-yl)Tien-2-yl

984methyl5-(2-methylthiazole-5-yl)Tien-2-yl
985methyl5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl
986methyl5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
987methyl5-(pyrimidine-2-yl)Tien-2-yl
988methyl5-(pyrimidine-4-yl)Tien-2-yl
989methyl5-(pyrimidine-5-yl)Tien-2-yl
990methyl5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
991methyl5-([1,3]-dioxolane-2-yl)Tien-2-yl
992methyl3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl
993methyl5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl
994m is Teal 5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
995methyl2-chlortan-3-yl
996methyl4-chlortan-3-yl
997methyl5-chlortan-3-yl
998methyl2-Bratan-3-yl
999methyl4-Bratan-3-yl
1000methyl5-Bratan-3-yl
1001methyl2,5-dichlorotin-3-yl
1002methyl2,5-libration-3-yl
1003methyl2,4,5-tripartie-3-yl
1004methyl4-bromo-2,5-dichlorotin-3-yl
1005methyl2-chloro-5-methylsulfonate-3-the l
1006methyl2,5-dietitian-3-yl
1007methyl4-hydroxicut-3-yl
1008methyl2-venitien-3-yl
1009methyl4-phenyl-5-(trifluoromethyl)Tien-3-yl
1010methyl2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl
1011methylbenzo[b]thiophene-2-yl
1012methylbenzo[b]thiophene-3-yl
1013methyl3 methylbenzo[b]thiophene-2-yl

3-forfinal
1014methyl5-methylbenzo[b]thiophene-2-yl
1015methyl5-fluoro-3-methylbenzo[b]thiophene-2-yl
1016util 5-chloro-3-methylbenzo[b]thiophene-2-yl
1017methyl5-bromo-3-methylbenzo[b]thiophene-2-yl
1018H3-were
1019H3-ethylphenyl
1020H3-propylphenyl
1021H3-isopropylphenyl
1022H3-second-butylphenyl
1023H3-tert-butylphenyl
1024H3-isobutylphenyl
1025H3-(1,1-dimethylpropyl)phenyl
1026H3-vinylphenol
1027H3-isopropylphenyl
1028H
1029H3-chlorophenyl
1030H3-bromophenyl
1031H3-itfinal
1032H3-(permitil)phenyl
1033H3-(deformity)phenyl
1034H3-(trifluoromethyl)phenyl
1035H3,5-bis(trifluoromethyl)phenyl
1036H3-(1-foradil)phenyl
1037H3-((S)-1-foradil)phenyl
1038H3-((R)-1-foradil)phenyl
1039H3-(2-foradil)phenyl
1040H3-(1,1-dottorati)phenyl
1041H3-(2,2-dottorati)phenyl
1042H3-(2,2,2-triptorelin)phenyl
1043H3-(3-forproper)phenyl

1044H3-(2-forproper)phenyl
1045H3-((S)-2-forproper)phenyl
1046H3-((R)-2-forproper)phenyl
1047H3-(3,3-deferror)phenyl
1048H3-(3,3,3-cryptochromes)phenyl
1049H3-(1-fluoro-1-methylethyl)phenyl
1050H3-(2-fluoro-1-methylethyl)phenyl
1051H3-((S)-2-fluoro-1-methylethyl)phenyl
1052H3-((R)-2-fluoro-1-methylethyl)phenyl
1053H3-(2,2-debtor-1-methylethyl)phenyl
1054H3-((S)-2,2-debtor-1-methylethyl)phenyl
1055H3-((R)-2,2-debtor-1-methylethyl)phenyl
1056H3-(2,2,2-Cryptor-1-methylethyl)phenyl
1057H3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl
1058H3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
1059H3-(2-fluoro-1-permethylated)phenyl
1060H3-(1-deformity-2,2-dottorati)phenyl
1061H3-(1,1-dimethyl-2-foradil)phenyl
1062H3-methoxyphenyl
H3-ethoxyphenyl
1064H3-propoxyphenyl
1065H3-isopropoxyphenyl
1066H3-butoxyphenyl
1067H3-(formatosi)phenyl
1068H3-(deformedarse)phenyl
1069H3-(triptoreline)phenyl
1070H3-(2-floratone)phenyl
1071H3-(2,2-diflorasone)phenyl
1072H3-(2,2,2-triptoreline)phenyl
1073H3-(1,1,2,2-tetrafluoroethoxy)phenyl

2-fluoro-5-(trifluoromethyl)phenyl
1074H 3-cyclopropylethanol
1075H3-cyclobutylmethyl
1076H3-cyclopentylphenol
1077H3-(2,2-diversicolor)phenyl
1078H3,4-differenl
1079H3-bromo-2-forfinal
1080H2-bromo-3-forfinal
1081H3-bromo-2,5-differenl
1082H5-bromo-2,4-differenl
1083H3-bromo-2,4-differenl
1084H4-chloro-3-(trifluoromethyl)phenyl
1085H2-chloro-5-(trifluoromethyl)phenyl
1086H
1087H4-fluoro-3-(trifluoromethyl)phenyl
1088H3-fluoro-5-(trifluoromethyl)phenyl
1089H4-bromo-3-(trifluoromethyl)phenyl
1090H3-bromo-5-(trifluoromethyl)phenyl
1091H2-bromo-5-(trifluoromethyl)phenyl
1092H5-bromo-2-methoxyphenyl
1093H3-bromo-4-methoxyphenyl
1094H2-fluoro-3-isopropylphenyl
1095H4-fluoro-3-isopropylphenyl
1096H3-(1-hydroxy-1-methylethyl)phenyl
1097H3-(2-hydroxy-2-methylpropyl " phenyl
1098H3-acetylphenyl
1099H3-acetylaminophenol
1100H3-carboxyphenyl
1101H3-cyanophenyl
1102H3-nitrophenyl
1103H3-hydroxyphenyl

tr> H
1104H3-(O-benzyl)phenyl
1105H3-(2-methoxyethoxy)phenyl
1106H3-(CH2-N(CH3)2)phenyl
1107H3-(NH-CO-NH2)phenyl
1108H3-(methylsulfanyl)phenyl
1109H 3-(pharmacysulfacet)phenyl
1110H3-(deformational)phenyl
1111H3-(trifloromethyl)phenyl
1112H3-(methylsulphonyl)phenyl
1113H3-(N-methoxy-N-methylamino)phenyl
1114H3-(methoxyamino)phenyl
1115H3-(ethoxyline)phenyl
1116H3-(N-methylenedioxy)phenyl
1117H3-(N,N-dimethylaminoethoxy)phenyl
1118H3-(azetidin-1-yl)phenyl
1119H3-(2-methylaziridine-1-yl)phenyl
1120H3-((S)-2-methylaziridine-1-yl)phenyl
1121H3-((R)-2-methylaziridine-1-yl)phenyl
1122H3-(3-torasemide-1-yl)phenyl
1123H3-(2,2-diversecity-1-yl)phenyl
1124H3-(3-methoxyisatin-1-yl)phenyl
1125H3-(3-hydroxyazetidine-1-yl)phenyl
1126H3-(pyrrolidin-1-yl)phenyl
1127H3-(pyrrolidin-2-yl)phenyl
1128H3-((S)-pyrrolidin-2-yl)phenyl
1129H3-((R)-pyrrolidin-2-yl)phenyl
1130H3-(pyrrolidin-3-yl)phenyl
1131H3-((S)-pyrrolidin-3-yl)phenyl
11323-((R)-pyrrolidin-3-yl)phenyl
1133H3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl

1134H5-(pyrrolidin-1-yl)-2-methoxyphenyl
1135H3-(pyrrolidin-1-yl)-4-methoxyphenyl
1136H5-(pyrrolidin-1-yl)-2,4-differenl
1137H3-(pyrrolidin-1-yl)-2,4-differenl
1138H3-(2-ftorpirimidinu-1-yl)phenyl
1139H3-((S)-2-ftorpirimidinu-1-yl)phenyl
1140H3-((R)-2-ftorpirimidinu-1-yl)phenyl
1141H3-(3-ftorpirimidinu-1-yl)phenyl
1142H3-((S)-3-forperiod the-1-yl)phenyl
1143H3-((R)-3-ftorpirimidinu-1-yl)phenyl
1144H3-(2,2-debtorprovidian-1-yl)phenyl
1145H3-(3,3-debtorprovidian-1-yl)phenyl
1146H3-(2-methylpyrrolidine-1-yl)phenyl
1147H3-((S)-2-methylpyrrolidine-1-yl)phenyl
1148H3-((R)-2-methylpyrrolidine-1-yl)phenyl
1149H3-(3-methylpyrrolidine-1-yl)phenyl
1150H3-((S)-3-methylpyrrolidine-1-yl)phenyl
1151H3-((R)-3-methylpyrrolidine-1-yl)phenyl
1152H3-(1-methylpyrrolidine-2-yl)phenyl
1153H3-((S)-1-metile Raiden-2-yl)phenyl
1154H3-((R)-1-methylpyrrolidine-2-yl)phenyl
1155H3-(1-methylpyrrolidine-3-yl)phenyl
1156H3-((S)-1-methylpyrrolidine-3-yl)phenyl
1157H3-((R)-1-methylpyrrolidine-3-yl)phenyl
1158H3-(2,2-dimethylpiperidin-1-yl)phenyl
1159H3-(3,3-dimethylpiperidin-1-yl)phenyl
1160H3-(2-triftormetilfullerenov-1-yl)phenyl
1161H3-((S)-2-triftormetilfullerenov-1-yl)phenyl
1162H3-((R)-2-triftormetilfullerenov-1-yl)phenyl
1163H3-(3-triftormetilfullerenov-1-yl)phenyl

1164H3-((S)-3-triftormetilfullerenov-1-yl)phenyl
1165H3-((R)-3-triftormetilfullerenov-1-yl)phenyl
1166H3-(2-oxopyrrolidin-1-yl)phenyl
1167H3-(2-oxo-oxazolidin-3-yl)phenyl
1168H3-(piperidine-1-yl)phenyl
1169H3-(2-methylpiperidin-1-yl)phenyl
1170H3-((S)-2-methylpiperidin-1-yl)phenyl
1171H3-((R)-2-methylpiperidin-1-yl)phenyl
1172H3-(2-foreperiod-1-yl)phenyl
1173H3-((S)-2-foreperiod-1-yl)phenyl
1174H3-((R)-2-foreperiod-1-yl)phenyl
1175H3-(2,2-deformability-1-yl)phenyl
1176H3-(piperazine-1-yl)phenyl
1177H3-(4-methylpiperazin-1-yl)phenyl
1178H3-(morpholine-4-yl)phenyl
1179H3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
1180H5-(morpholine-4-yl)-2-methoxyphenyl
1181H3-(morpholine-4-yl)-4-methoxyphenyl
1182H5-(morpholine-4-yl)-2,4-differenl
1183H3-(morpholine-4-yl)-2,4-differenl
1184H3-(thiomorpholine-4-yl)phenyl
1185H3-(1-Osotimehin-4-yl)phenyl
1186 H3-(1,1-diocletianopolis-4-yl)phenyl
1187H3-(pyrrol-1-yl)phenyl
1188H3-(pyrrol-2-yl)phenyl
1189H3-(pyrrol-3-yl)phenyl
1190H3-(1-methylpyrrole-2-yl)phenyl
1191H3-(1-methylpyrrole-3-yl)phenyl
1192H3-(furan-2-yl)phenyl
1193H3-(furan-3-yl)phenyl

1194H3-(thiophene-2-yl)phenyl
1195H3-(thiophene-3-yl)phenyl
1196H3-(5-properties-2-yl)phenyl
1197H3-(feast of the evils-1-yl)phenyl
1198H3-(pyrazole-3-yl)phenyl
1199H3-(pyrazole-4-yl)phenyl
1200H3-(4-perperson-1-yl)phenyl
1201H3-(1-methyl-1H-pyrazole-4-yl)phenyl
1202H3-(1-ethyl-1H-pyrazole-4-yl)phenyl
1203H3-(1-methyl-1H-pyrazole-5-yl)phenyl
1204H3-(1H-imidazol-2-yl)phenyl
1205H3-(imidazol-1-yl)phenyl
1206H3-(1-Mei-2-yl)phenyl
1207H3-(oxazol-2-yl)phenyl
1208H3-(oxazol-4-yl)phenyl
1209H 3-(oxazol-5-yl)phenyl
1210H3-(isoxazol-3-yl)phenyl
1211H3-(isoxazol-4-yl)phenyl
1212H3-(isoxazol-5-yl)phenyl
1213H3-(thiazol-2-yl)phenyl
1214H3-(thiazol-4-yl)phenyl
1215H3-(thiazol-5-yl)phenyl
1216H3-(2-methylthiazole-4-yl)phenyl
1217H3-(2-methylthiazole-5-yl)phenyl
1218H3-([1,2,3]-triazole-1-yl)phenyl
1219H3-([1,2,4]-triazole-1-yl)phenyl
1220H3-([1,2,3]-triazole-2-yl)phenyl
1221 H3-(4H-[1,2,4]-triazole-3-yl)phenyl
1222H3-([1,2,4]-triazole-4-yl)phenyl
1223H3-(2H-[1,2,3]-triazole-4-yl)phenyl

1224H3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
1225H3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
1226H3-([1,3,4]-oxadiazol-2-yl)phenyl
1227H3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
1228H3-([1,2,4]-oxadiazol-3-yl)phenyl
1229H3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl
1230H3-([1,2,4]-oxadiazol-5-yl)phenyl
1231H3-([1,2,3], Accadia the ol-4-yl)phenyl
1232H3-([1,2,3]-oxadiazol-5-yl)phenyl
1233H3-([1,2,3]-thiadiazole-4-yl)phenyl
1234H3-(1H-tetrazol-5-yl)phenyl
1235H3-(tetrazol-1-yl)phenyl
1236H3-(2-methyl-2H-tetrazol-5-yl)phenyl
1237H3-(1-methyl-1H-tetrazol-5-yl)phenyl
1238H3-furazan-3-ylphenyl
1239H3-(pyrid-2-yl)phenyl
1240H3-(pyrid-3-yl)phenyl
1241H3-(pyrid-4-yl)phenyl
1242H3-(pyrimidine-2-yl)phenyl
1243H 3-(2-methylpyrimidin-4-yl)phenyl
1244H3-(pyrimidine-4-yl)phenyl
1245H3-(pyrimidine-5-yl)phenyl
1246H5-bromopyridin-3-yl
1247H3-bromo-2-chloropyridin-5-yl
1248H4-methylpyridin-2-yl
1249H6-methylpyridin-2-yl
1250H4-(trifluoromethyl)pyridin-2-yl
1251H6-(trifluoromethyl)pyridin-2-yl
1252H5-(trifluoromethyl)pyridin-3-yl
1253H5-(pyrrolidin-1-yl)pyridine-3-yl

1254H3-(Pirro is one-1-yl)-2-chloropyridin-5-yl
1255H3-(morpholine-4-yl)-2-chloropyridin-5-yl
1256H2-(morpholine-4-yl)pyridin-5-yl
1257H2-phenoxypyridine-5-yl
1258H2,3-dichlorophenyl
1259H2,5-dichlorophenyl
1260H3,5-dichlorophenyl
1261H3-chloro-4-forfinal
1262H4-bromo-2,5-dichlorophenyl
1263H3-bromo-4-(triptoreline)phenyl
1264H3,5-dibromo-4-(2-floratone)phenyl
1265H2,5-dimetilfenil
1266H 2,5-di-(trifluoromethyl)phenyl
1267H3,5-di-(trifluoromethyl)phenyl
1268H2,5-acid
1269H2-methoxy-5-were
1270H2-methoxy-5-(trifluoromethyl)phenyl
1271H4-fluoro-3-(oxazol-4-yl)phenyl
1272HTien-2-yl
1273HTien-3-yl
1274H3-chlortan-2-yl
1275H4-chlortan-2-yl
1276H5-chlortan-2-yl
1277H3-Bratan-2-yl
1278H4-Bratia the-2-yl
1279H5-Bratan-2-yl
1280H4,5-dichlorotin-2-yl
1281H4,5-libration-2-yl
1282H4-bromo-5-chlortan-2-yl
1283H3-bromo-5-chlortan-2-yl

1284H5-methyltin-2-yl
1285H5-utilties-2-yl
1286H5-properties-2-yl
1287H5-triptorelin-2-yl
1288H5-penalties-2-yl
1289H5-(pyrid-2-yl)Tien-2-yl
1290H 5-(phenylsulfonyl)Tien-2-yl
1291H4-(phenylsulfonyl)Tien-2-yl
1292H5-(pyrid-2-ylsulphonyl)Tien-2-yl
1293H5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
1294H5-(benzoylamino)Tien-2-yl
1295H5-((4-chlorbenzoyl)aminomethyl)Tien-2-yl
1296H5-(acetamidomethyl)Tien-2-yl
1297H5-(pyrazole-1-yl)Tien-2-yl
1298H5-(pyrazole-3-yl)Tien-2-yl
1299H5-(pyrazole-4-yl)Tien-2-yl
1300H5-(pyrazole-5-yl)Tien-2-yl
1301H5-(4-ftrp razol-1-yl)Tien-2-yl
1302H5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl
1303H5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
1304H5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
1305H5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
1306H5-(isoxazol-3-yl)Tien-2-yl
1307H5-(isoxazol-4-yl)Tien-2-yl
1308H5-(isoxazol-5-yl)Tien-2-yl
1309H5-(5-cryptometrics-3-yl)Tien-2-yl
1310H5-(oxazol-2-yl)Tien-2-yl
1311H5-(oxazol-4-yl)Tien-2-yl
1312 H5-(oxazol-5-yl)Tien-2-yl
1313H5-(2-methoxazole-4-yl)Tien-2-yl
1314H5-(2-methoxazole-5-yl)Tien-2-yl

1315H5-(isothiazol-3-yl)Tien-2-yl
1316H5-(isothiazol-4-yl)Tien-2-yl
1317H5-(isothiazol-5-yl)Tien-2-yl
1318H5-(5-triftoratsetata-3-yl)Tien-2-yl
1319H5-(thiazol-2-yl)Tien-2-yl
1320H5-(thiazol-4-yl)Tien-2-yl
1321H5-(thiazol-5-yl)Tien-2-yl
1322H5-(2-methylthiazole-4-yl)Tien-2-yl
1323 H5-(2-methylthiazole-5-yl)Tien-2-yl
1324H5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl
1325H5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
1326H5-(pyrimidine-2-yl)Tien-2-yl
1327H5-(pyrimidine-4-yl)Tien-2-yl
1328H5-(pyrimidine-5-yl)Tien-2-yl
1329H5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
1330H5-([1,3]-dioxolane-2-yl)Tien-2-yl
1331H3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl
1332H5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl
1333H5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
1334H2-chlortan-3-yl
1335H4-chlortan-3-yl
1336H5-chlortan-3-yl
1337H2-Bratan-3-yl
1338H4-Bratan-3-yl
1339H5-Bratan-3-yl
1340H2,5-dichlorotin-3-yl
1341H2,5-libration-3-yl
1342H2,4,5-tripartie-3-yl
1343H4-bromo-2,5-dichlorotin-3-yl
1344H2-chloro-5-methylsulfonate-3-yl

1345H2,5-dietitian-3-the l
1346H4-hydroxicut-3-yl
1347H2-venitien-3-yl
1348H4-phenyl-5-(trifluoromethyl)Tien-3-yl
1349H2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl
1350Hbenzo[b]thiophene-2-yl
1351Hbenzo[b]thiophene-3-yl
1352H3 methylbenzo[b]thiophene-2-yl
1353H5-methylbenzo[b]thiophene-2-yl
1354H5-fluoro-3-methylbenzo[b]thiophene-2-yl
1355H5-chloro-3-methylbenzo[b]thiophene-2-yl
1356H5-bromo-3-methylbenzo[b]thiophene-2-yl
13573-forproper3-were
13583-forproper3-ethylphenyl
13593-forproper3-propylphenyl
13603-forproper3-isopropylphenyl
13613-forproper3-second-butylphenyl
13623-forproper3-tert-butylphenyl
13633-forproper3-isobutylphenyl
13643-forproper3-(1,1-dimethylpropyl)phenyl
13653-forproper3-vinylphenol
13663-forproper3-isopropylphenyl
13673-forproper3-forfinal
1368 3-forproper3-chlorophenyl
13693-forproper3-bromophenyl
13703-forproper3-itfinal
13713-forproper3-(permitil)phenyl
13723-forproper3-(deformity)phenyl
13733-forproper3-(trifluoromethyl)phenyl
13743-forproper3,5-bis(trifluoromethyl)phenyl

1379
13753-forproper3-(1-foradil)phenyl
13763-forproper3-((S)-1-foradil)phenyl
13773-forproper3-((R)-1-foradil)phenyl
13783-forproper3-(2-foradil)phenyl
3-forproper3-(1,1-dottorati)phenyl
13803-forproper3-(2,2-dottorati)phenyl
13813-forproper3-(2,2,2-triptorelin)phenyl
13823-forproper3-(3-forproper)phenyl
13833-forproper3-(2-forproper)phenyl
13843-forproper3-((S)-2-forproper)phenyl
13853-forproper3-((R)-2-forproper)phenyl
13863-forproper3-(3,3-deferror)phenyl
13873-forproper3-(3,3,3-cryptochromes)phenyl
13883-forproper3-(1-fluoro-1-methylethyl)phenyl
13893-forproper3(2-fluoro-1-methylethyl)phenyl
13903-forproper3-((S)-2-fluoro-1-methylethyl)phenyl
13913-forproper3-((R)-2-fluoro-1-methylethyl)phenyl
13923-forproper3-(2,2-debtor-1-methylethyl)phenyl
13933-forproper3-((S)-2,2-debtor-1-methylethyl)phenyl
13943-forproper3-((R)-2,2-debtor-1-methylethyl)phenyl
13953-forproper3-(2,2,2-Cryptor-1-methylethyl)phenyl
13963-forproper3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl
13973-forproper3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
13983-forproper3-(2-fluoro-1-permethylated)phenyl
13993-forproper3-(1-deformity-2,2-deflorate is)phenyl
14003-forproper3-(1,1-dimethyl-2-foradil)phenyl
14013-forproper3-methoxyphenyl
14023-forproper3-ethoxyphenyl
14033-forproper3-propoxyphenyl
14043-forproper3-isopropoxyphenyl

14053-forproper3-butoxyphenyl
14063-forproper3-(formatosi)phenyl
14073-forproper3-(deformedarse)phenyl
14083-forproper3-(triptoreline)phenyl
14093-forproper3-(2-floratone)phenyl
1410 3-forproper3-(2,2-diflorasone)phenyl
14113-forproper3-(2,2,2-triptoreline)phenyl
14123-forproper3-(1,1,2,2-tetrafluoroethoxy)phenyl
14133-forproper3-cyclopropylethanol
14143-forproper3-cyclobutylmethyl
14153-forproper3-cyclopentylphenol
14163-forproper3-(2,2-diversicolor)phenyl
14173-forproper3,4-differenl
14183-forproper3-bromo-2-forfinal
14193-forproper2-bromo-3-forfinal
14203-forproper3-bromo-2,5-differenl
14213-forproper5-bromo-2,4-differenl
14223-forproper3-bromo-2,4-differenl
14233-forproper4-chloro-3-(trifluoromethyl)phenyl
14243-forproper2-chloro-5-(trifluoromethyl)phenyl
14253-forproper2-fluoro-5-(trifluoromethyl)phenyl
14263-forproper4-fluoro-3-(trifluoromethyl)phenyl
14273-forproper3-fluoro-5-(trifluoromethyl)phenyl
14283-forproper4-bromo-3-(trifluoromethyl)phenyl
14293-forproper3-bromo-5-(trifluoromethyl)phenyl
14303-forproper2-bromo-5-(trifluoromethyl)phenyl
14313-fluoro who robil 5-bromo-2-methoxyphenyl
14323-forproper3-bromo-4-methoxyphenyl
14333-forproper2-fluoro-3-isopropylphenyl
14343-forproper4-fluoro-3-isopropylphenyl

14353-forproper3-(1-hydroxy-1-methylethyl)phenyl
14363-forproper3-(2-hydroxy-2-methylpropyl " phenyl
14373-forproper3-acetylphenyl
14383-forproper3-acetylaminophenol
14393-forproper3-carboxyphenyl
14403-forproper3-cyanophenyl
14413-forproper3-nitrophe the Il
14423-forproper3-hydroxyphenyl
14433-forproper3-(O-benzyl)phenyl
14443-forproper3-(2-methoxyethoxy)phenyl
14453-forproper3-(CH2-N(CH3)2)phenyl
14463-forproper3-(NH-CO-NH2)phenyl
14473-forproper3-(methylsulfanyl)phenyl
14483-forproper3-(pharmacysulfacet)phenyl
14493-forproper3-(deformational)phenyl
14503-forproper3-(trifloromethyl)phenyl
14513-forproper3-(methylsulphonyl)phenyl
1452 3-forproper3-(N-methoxy-N-methylamino)phenyl
14533-forproper3-(methoxyamino)phenyl
14543-forproper3-(ethoxyline)phenyl
14553-forproper3-(N-methylenedioxy)phenyl
14563-forproper3-(N,N-dimethylaminoethoxy)phenyl
14573-forproper3-(azetidin-1-yl)phenyl
14583-forproper3-(2-methylaziridine-1-yl)phenyl
14593-forproper3-((S)-2-methylaziridine-1-yl)phenyl
14603-forproper3-((R)-2-methylaziridine-1-yl)phenyl
14613-forproper3-(3-torasemide-1-yl)phenyl
14623-forproper
14633-forproper3-(3-methoxyisatin-1-yl)phenyl
14643-forproper3-(3-hydroxyazetidine-1-yl)phenyl

14653-forproper3-(pyrrolidin-1-yl)phenyl
14663-forproper3-(pyrrolidin-2-yl)phenyl
14673-forproper3-((S)-pyrrolidin-2-yl)phenyl
14683-forproper3-((R)-pyrrolidin-2-yl)phenyl
14693-forproper3-(pyrrolidin-3-yl)phenyl
14703-forproper3-((S)-pyrrolidin-3-yl)phenyl
14713-forproper3-((R)-pyrrolidin-3-yl)phenyl
14723-forproper3-(pyrrolidin-1-yl-5-(trifluoromethyl)phenyl
14733-forproper5-(pyrrolidin-1-yl)-2-methoxyphenyl
14743-forproper3-(pyrrolidin-1-yl)-4-methoxyphenyl
14753-forproper5-(pyrrolidin-1-yl)-2,4-differenl
14763-forproper3-(pyrrolidin-1-yl)-2,4-differenl
14773-forproper3-(2-ftorpirimidinu-1-yl)phenyl
14783-forproper3-((S)-2-ftorpirimidinu-1-yl)phenyl
14793-forproper3-((R)-2-ftorpirimidinu-1-yl)phenyl
14803-forproper3-(3-ftorpirimidinu-1-yl)phenyl
14813-forproper3-((S)-3-ftorpirimidinu-1-yl)phenyl
14823-forproper3-((R)-3-forperiod the-1-yl)phenyl
14833-forproper3-(2,2-debtorprovidian-1-yl)phenyl
14843-forproper3-(3,3-debtorprovidian-1-yl)phenyl
14853-forproper3-(2-methylpyrrolidine-1-yl)phenyl
14863-forproper3-((S)-2-methylpyrrolidine-1-yl)phenyl
14873-forproper3-((R)-2-methylpyrrolidine-1-yl)phenyl
14883-forproper3-(3-methylpyrrolidine-1-yl)phenyl
14893-forproper3-((S)-3-methylpyrrolidine-1-yl)phenyl
14903-forproper3-((R)-3-methylpyrrolidine-1-yl)phenyl
14913-forproper3-(1-methylpyrrolidine-2-yl)phenyl
14923-forproper3-((S)-1-methylpyrrole the Jn-2-yl)phenyl
14933-forproper3-((R)-1-methylpyrrolidine-2-yl)phenyl
14943-forproper3-(1-methylpyrrolidine-3-yl)phenyl

14953-forproper3-((S)-1-methylpyrrolidine-3-yl)phenyl
14963-forproper3-((R)-1-methylpyrrolidine-3-yl)phenyl
14973-forproper3-(2,2-dimethylpiperidin-1-yl)phenyl
14983-forproper3-(3,3-dimethylpiperidin-1-yl)phenyl
14993-forproper3-(2-triftormetilfullerenov-1-yl)phenyl
15003-forproper3-((S)-2-triftormetilfullerenov-1-yl)phenyl
15013-forproper3-((R)-2-triftormetilfullerenov-1-yl)phenyl
1502 3-forproper3-(3-triftormetilfullerenov-1-yl)phenyl
15033-forproper3-((S)-3-triftormetilfullerenov-1-yl)phenyl
15043-forproper3-((R)-3-triftormetilfullerenov-1-yl)phenyl
15053-forproper3-(2-oxopyrrolidin-1-yl)phenyl
15063-forproper3-(2-oxo-oxazolidin-3-yl)phenyl
15073-forproper3-(piperidine-1-yl)phenyl
15083-forproper3-(2-methylpiperidin-1-yl)phenyl
15093-forproper3-((S)-2-methylpiperidin-1-yl)phenyl
15103-forproper3-((R)-2-methylpiperidin-1-yl)phenyl
15113-forproper3-(2-foreperiod-1-yl)phenyl
1512 3-forproper3-((S)-2-foreperiod-1-yl)phenyl
15133-forproper3-((R)-2-foreperiod-1-yl)phenyl
15143-forproper3-(2,2-deformability-1-yl)phenyl
15153-forproper3-(piperazine-1-yl)phenyl
15163-forproper3-(4-methylpiperazin-1-yl)phenyl
15173-forproper3-(morpholine-4-yl)phenyl
15183-forproper3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
15193-forproper5-(morpholine-4-yl)-2-methoxyphenyl
15203-forproper3-(morpholine-4-yl)-4-methoxyphenyl
15213-forproper5-(morpholine-4-yl)-2,4-differenl
15223-ftobr who drank 3-(morpholine-4-yl)-2,4-differenl
15233-forproper3-(thiomorpholine-4-yl)phenyl
15243-forproper3-(1-Osotimehin-4-yl)phenyl

15253-forproper3-(1,1-diocletianopolis-4-yl)phenyl
15263-forproper3-(pyrrol-1-yl)phenyl
15273-forproper3-(pyrrol-2-yl)phenyl
15283-forproper3-(pyrrol-3-yl)phenyl
15293-forproper3-(1-methylpyrrole-2-yl)phenyl
15303-forproper3-(1-methylpyrrole-3-yl)phenyl
15313-forproper3-(furan-2-yl)phenyl
15323-forproper 3-(furan-3-yl)phenyl
15333-forproper3-(thiophene-2-yl)phenyl
15343-forproper3-(thiophene-3-yl)phenyl
15353-forproper3-(5-properties-2-yl)phenyl
15363-forproper3-(pyrazole-1-yl)phenyl
15373-forproper3-(pyrazole-3-yl)phenyl
15383-forproper3-(pyrazole-4-yl)phenyl
15393-forproper3-(4-perperson-1-yl)phenyl
15403-forproper3-(1-methyl-1H-pyrazole-4-yl)phenyl
15413-forproper3-(1-ethyl-1H-pyrazole-4-yl)phenyl
15423-forproper3-(1-methyl-1H-pyrazole-5-yl)phenyl
1543 3-forproper3-(1H-imidazol-2-yl)phenyl
15443-forproper3-(imidazol-1-yl)phenyl
15453-forproper3-(1-Mei-2-yl)phenyl
15463-forproper3-(oxazol-2-yl)phenyl
15473-forproper3-(oxazol-4-yl)phenyl
15483-forproper3-(oxazol-5-yl)phenyl
15493-forproper3-(isoxazol-3-yl)phenyl
15503-forproper3-(isoxazol-4-yl)phenyl
15513-forproper3-(isoxazol-5-yl)phenyl
15523-forproper3-(thiazol-2-yl)phenyl
15533-forproper3-(thiazol-4-yl)phenyl
15543-forproper3-(thiazol-5-yl)phenyl

15553-forproper3-(2-methylthiazole-4-yl)phenyl
15563-forproper3-(2-methylthiazole-5-yl)phenyl
15573-forproper3-([1,2,3]-triazole-1-yl)phenyl
15583-forproper3-([1,2,4]-triazole-1-yl)phenyl
15593-forproper3-([1,2,3]-triazole-2-yl)phenyl
15603-forproper3-(4H-[1,2,4]-triazole-3-yl)phenyl
15613-forproper3-([1,2,4]-triazole-4-yl)phenyl
15623-forproper3-(2H-[1,2,3]-triazole-4-yl)phenyl
15633-forproper3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
15643-forproper3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
15653-forproper3-([1,3,4]-oxadiazol-2-yl)phenyl
15663-forproper3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
15673-forproper3-([1,2,4]-oxadiazol-3-yl)phenyl
15683-forproper3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl
15693-forproper3-([1,2,4]-oxadiazol-5-yl)phenyl
15703-forproper3-([1,2,3]-oxadiazol-4-yl)phenyl
15713-forproper3-([1,2,3]-oxadiazol-5-yl)phenyl
15723-forproper3-([1,2,3]-thiadiazole-4-yl)phenyl
15733-forproper3-(1H-tetrazol-5-yl)phenyl
1574 3-forproper3-(tetrazol-1-yl)phenyl
15753-forproper3-(2-methyl-2H-tetrazol-5-yl)phenyl
15763-forproper3-(1-methyl-1H-tetrazol-5-yl)phenyl
15773-forproper3-furazan-3-ylphenyl
15783-forproper3-(pyrid-2-yl)phenyl
15793-forproper3-(pyrid-3-yl)phenyl
15803-forproper3-(pyrid-4-yl)phenyl
15813-forproper3-(pyrimidine-2-yl)phenyl
15823-forproper3-(2-methylpyrimidin-4-yl)phenyl
15833-forproper3-(pyrimidine-4-yl)phenyl
15843-forproper3-(pyrimidine-5-yl)phenyl
/p>

15853-forproper5-bromopyridin-3-yl
15863-forproper3-bromo-2-chloropyridin-5-yl
15873-forproper4-methylpyridin-2-yl
15883-forproper6-methylpyridin-2-yl
15893-forproper4-(trifluoromethyl)pyridin-2-yl
15903-forproper6-(trifluoromethyl)pyridin-2-yl
15913-forproper5-(trifluoromethyl)pyridin-3-yl
15923-forproper5-(pyrrolidin-1-yl)pyridine-3-yl
15933-forproper3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl
15943-forproper3-(morpholine-4-yl)-2-chloropyridin-5-yl
15953-forproper2-(morpholine-4-yl)pyridin-5-yl
15963-forproper2-phenoxypyridine-5-yl
15973-forproper2,3-dichlorophenyl
15983-forproper2,5-dichlorophenyl
15993-forproper3,5-dichlorophenyl
16003-forproper3-chloro-4-forfinal
16013-forproper4-bromo-2,5-dichlorophenyl
16023-forproper3-bromo-4-(triptoreline)phenyl
16033-forproper3,5-dibromo-4-(2-floratone)phenyl
16043-forproper2,5-dimetilfenil
16053-forproper 2,5-di-(trifluoromethyl)phenyl
16063-forproper3,5-di-(trifluoromethyl)phenyl
16073-forproper2,5-acid
16083-forproper2-methoxy-5-were
16093-forproper2-methoxy-5-(trifluoromethyl)phenyl
16103-forproper4-fluoro-3-(oxazol-4-yl)phenyl
16113-forproperTien-2-yl
16123-forproperTien-3-yl
16133-forproper3-chlortan-2-yl
16143-forproper4-chlortan-2-yl

3-forproper
16153-forproper5-chlortan-2-yl
16163-Bratan-2-yl
16173-forproper4-Bratan-2-yl
16183-forproper5-Bratan-2-yl
16193-forproper4,5-dichlorotin-2-yl
16203-forproper4,5-libration-2-yl
16213-forproper4-bromo-5-chlortan-2-yl
16223-forproper3-bromo-5-chlortan-2-yl
16233-forproper5-methyltin-2-yl
16243-forproper5-utilties-2-yl
16253-forproper5-properties-2-yl
16263-forproper5-triptorelin-2-yl
16273-ftoc the filing 5-penalties-2-yl
16283-forproper5-(pyrid-2-yl)Tien-2-yl
16293-forproper5-(phenylsulfonyl)Tien-2-yl
16303-forproper4-(phenylsulfonyl)Tien-2-yl
16313-forproper5-(pyrid-2-ylsulphonyl)Tien-2-yl
16323-forproper5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
16333-forproper5-(benzoylamino)Tien-2-yl
16343-forproper5-((4-chlorbenzoyl)aminomethyl)Tien-2-yl
16353-forproper5-(acetamidomethyl)Tien-2-yl
16363-forproper5-(pyrazole-1-yl)Tien-2-yl
16373-forproper 5-(pyrazole-3-yl)Tien-2-yl
16383-forproper5-(pyrazole-4-yl)Tien-2-yl
16393-forproper5-(pyrazole-5-yl)Tien-2-yl
16403-forproper5-(4-perperson-1-yl)Tien-2-yl
16413-forproper5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl
16423-forproper5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
16433-forproper5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
16443-forproper5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
16453-forproper5-(isoxazol-3-yl)Tien-2-yl

16463-forproper5-(isoxazol-4-yl)Tien-2-and the
16473-forproper5-(isoxazol-5-yl)Tien-2-yl
16483-forproper5-(5-cryptometrics-3-yl)Tien-2-yl
16493-forproper5-(oxazol-2-yl)Tien-2-yl
16503-forproper5-(oxazol-4-yl)Tien-2-yl
16513-forproper5-(oxazol-5-yl)Tien-2-yl
16523-forproper5-(2-methoxazole-4-yl)Tien-2-yl
16533-forproper5-(2-methoxazole-5-yl)Tien-2-yl
16543-forproper5-(isothiazol-3-yl)Tien-2-yl
16553-forproper5-(isothiazol-4-yl)Tien-2-yl
16563-forproper5-(isothiazol-5-yl)Tien-2-yl
1657/td> 3-forproper5-(5-triftoratsetata-3-yl)Tien-2-yl
16583-forproper5-(thiazol-2-yl)Tien-2-yl
16593-forproper5-(thiazol-4-yl)Tien-2-yl
16603-forproper5-(thiazol-5-yl)Tien-2-yl
16613-forproper5-(2-methylthiazole-4-yl)Tien-2-yl
16623-forproper5-(2-methylthiazole-5-yl)Tien-2-yl
16633-forproper5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl
16643-forproper5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
16653-forproper5-(pyrimidine-2-yl)Tien-2-yl
16663-forproper5-(pyrimidine-4-yl)Tien-2-yl
16673-FPO is propyl 5-(pyrimidine-5-yl)Tien-2-yl
16683-forproper5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
16693-forproper5-([1,3]-dioxolane-2-yl)Tien-2-yl
16703-forproper3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl
16713-forproper5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl
16723-forproper5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
16733-forproper2-chlortan-3-yl
16743-forproper4-chlortan-3-yl
16753-forproper5-chlortan-3-yl

3-forproper
16763-forproper2-Bratan-3-yl
16774-Bratan-3-yl
16783-forproper5-Bratan-3-yl
16793-forproper2,5-dichlorotin-3-yl
16803-forproper2,5-libration-3-yl
16813-forproper2,4,5-tripartie-3-yl
16823-forproper4-bromo-2,5-dichlorotin-3-yl
16833-forproper2-chloro-5-methylsulfonate-3-yl
16843-forproper2,5-dietitian-3-yl
16853-forproper4-hydroxicut-3-yl
16863-forproper2-venitien-3-yl
16873-forproper4-phenyl-5-(trifluoromethyl)Tien-3-yl
168 3-forproper2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl
16893-forproperbenzo[b]thiophene-2-yl
16903-forproperbenzo[b]thiophene-3-yl
16913-forproper3 methylbenzo[b]thiophene-2-yl
16923-forproper5-methylbenzo[b]thiophene-2-yl
16933-forproper5-fluoro-3-methylbenzo[b]thiophene-2-yl
16943-forproper5-chloro-3-methylbenzo[b]thiophene-2-yl
16953-forproper5-bromo-3-methylbenzo[b]thiophene-2-yl
16962-foradil3-were
16972-foradil3-ethylphenyl
16982-foradil 3-propylphenyl
16992-foradil3-isopropylphenyl
17002-foradil3-second-butylphenyl
17012-foradil3-tert-butylphenyl
17022-foradil3-isobutylphenyl
17032-foradil3-(1,1-dimethylpropyl)phenyl
17042-foradil3-vinylphenol
17052-foradil3-isopropylphenyl

17062-foradil3-forfinal
17072-foradil3-chlorophenyl
17082-foradil3-bromophenyl
17092-foradil 3-itfinal
17102-foradil3-(permitil)phenyl
17112-foradil3-(deformity)phenyl
17122-foradil3-(trifluoromethyl)phenyl
17132-foradil3,5-bis(trifluoromethyl)phenyl
17142-foradil3-(1-foradil)phenyl
17152-foradil3-((S)-1-foradil)phenyl
17162-foradil3-((R)-1-foradil)phenyl
17172-foradil3-(2-foradil)phenyl
17182-foradil3-(1,1-dottorati)phenyl
17192-foradil3-(2,2-dottorati)phenyl
17202-foradil3-(2,2-triptorelin)phenyl
17212-foradil3-(3-forproper)phenyl
17222-foradil3-(2-forproper)phenyl
17232-foradil3-((S)-2-forproper)phenyl
17242-foradil3-((R)-2-forproper)phenyl
17252-foradil3-(3,3-deferror)phenyl
17262-foradil3-(3,3,3-cryptochromes)phenyl
17272-foradil3-(1-fluoro-1-methylethyl)phenyl
17282-foradil3-(2-fluoro-1-methylethyl)phenyl
17292-foradil3-((S)-2-fluoro-1-methylethyl)phenyl
17302-foradil3-((R)-2-fluoro-1-methylethyl)phenyl
17312-foradil 3-(2,2-debtor-1-methylethyl)phenyl
17322-foradil3-((S)-2,2-debtor-1-methylethyl)phenyl
17332-foradil3-((R)-2,2-debtor-1-methylethyl)phenyl
17342-foradil3-(2,2,2-Cryptor-1-methylethyl)phenyl
17352-foradil3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl

17362-foradil3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
17372-foradil3-(2-fluoro-1-permethylated)phenyl
17382-foradil3-(1-deformity-2,2-dottorati)phenyl
17392-foradil3-(1,1-dimethyl-2-foradil)phenyl
17402-foradil3-methoxyphenyl
17412 Ferati the 3-ethoxyphenyl
17422-foradil3-propoxyphenyl
17432-foradil3-isopropoxyphenyl
17442-foradil3-butoxyphenyl
17452-foradil3-(formatosi)phenyl
17462-foradil3-(deformedarse)phenyl
17472-foradil3-(triptoreline)phenyl
17482-foradil3-(2-floratone)phenyl
17492-foradil3-(2,2-diflorasone)phenyl
17502-foradil3-(2,2,2-triptoreline)phenyl
17512-foradil3-(1,1,2,2-tetrafluoroethoxy)phenyl
17522-f is oratel 3-cyclopropylethanol
17532-foradil3-cyclobutylmethyl
17542-foradil3-cyclopentylphenol
17552-foradil3-(2,2-diversicolor)phenyl
17562-foradil3,4-differenl
17572-foradil3-bromo-2-forfinal
17582-foradil2-bromo-3-forfinal
17592-foradil3-bromo-2,5-differenl
17602-foradil5-bromo-2,4-differenl
17612-foradil3-bromo-2,4-differenl
17622-foradil4-chloro-3-(trifluoromethyl)phenyl
17632-fluoro what Teal 2-chloro-5-(trifluoromethyl)phenyl
17642-foradil2-fluoro-5-(trifluoromethyl)phenyl
17652-foradil4-fluoro-3-(trifluoromethyl)phenyl

17662-foradil3-fluoro-5-(trifluoromethyl)phenyl
17672-foradil4-bromo-3-(trifluoromethyl)phenyl
17682-foradil3-bromo-5-(trifluoromethyl)phenyl
17692-foradil2-bromo-5-(trifluoromethyl)phenyl
17702-foradil5-bromo-2-methoxyphenyl
17712-foradil3-bromo-4-methoxyphenyl
17722-foradil2-fluoro-3-isopropylphenyl
17732-foradil17742-foradil3-(1-hydroxy-1-methylethyl)phenyl
17752-foradil3-(2-hydroxy-2-methylpropyl " phenyl
17762-foradil3-acetylphenyl
17772-foradil3-acetylaminophenol
17782-foradil3-carboxyphenyl
17792-foradil3-cyanophenyl
17802-foradil3-nitrophenyl
17812-foradil3-hydroxyphenyl
17822-foradil3-(O-benzyl)phenyl
17832-foradil3-(2-methoxyethoxy)phenyl
17842-foradil3-(CH 2-N(CH3)2)phenyl
17852-foradil3-(NH-CO-NH2)phenyl
17862-foradil3-(methylsulfanyl)phenyl
17872-foradil3-(pharmacysulfacet)phenyl
17882-foradil3-(deformational)phenyl
17892-foradil3-(trifloromethyl)phenyl
17902-foradil3-(methylsulphonyl)phenyl
17912-foradil3-(N-methoxy-N-methylamino)phenyl
17922-foradil3-(methoxyamino)phenyl
17932-foradil3-(ethoxyline)phenyl
17942-foradil3-(N-methylenedioxy)phenyl
1795 2-foradil3-(N,N-dimethylaminoethoxy)phenyl

17962-foradil3-(azetidin-1-yl)phenyl
17972-foradil3-(2-methylaziridine-1-yl)phenyl
17982-foradil3-((S)-2-methylaziridine-1-yl)phenyl
17992-foradil3-((R)-2-methylaziridine-1-yl)phenyl
18002-foradil3-(3-torasemide-1-yl)phenyl
18012-foradil3-(2,2-diversecity-1-yl)phenyl
18022-foradil3-(3-methoxyisatin-1-yl)phenyl
18032-foradil3-(3-hydroxyazetidine-1-yl)phenyl
18042-foradil3-(pyrrolidin-1-yl)phenyl
18052-foradil3-(pyrrolidin-2-yl)phenyl
18062-foradil3-((S)-pyrrolidin-2-yl)phenyl
18072-foradil3-((R)-pyrrolidin-2-yl)phenyl
18082-foradil3-(pyrrolidin-3-yl)phenyl
18092-foradil3-((S)-pyrrolidin-3-yl)phenyl
18102-foradil3-((R)-pyrrolidin-3-yl)phenyl
18112-foradil3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl
18122-foradil5-(pyrrolidin-1-yl)-2-methoxyphenyl
18132-foradil3-(pyrrolidin-1-yl)-4-methoxyphenyl
18142-foradil5-(pyrrolidin-1-yl)-2,4-differenl
18152-fluoro what Teal 3-(pyrrolidin-1-yl)-2,4-differenl
18162-foradil3-(2-ftorpirimidinu-1-yl)phenyl
18172-foradil3-((S)-2-ftorpirimidinu-1-yl)phenyl
18182-foradil3-((R)-2-ftorpirimidinu-1-yl)phenyl
18192-foradil3-(3-ftorpirimidinu-1-yl)phenyl
18202-foradil3-((S)-3-ftorpirimidinu-1-yl)phenyl
18212-foradil3-((R)-3-ftorpirimidinu-1-yl)phenyl
18222-foradil3-(2,2-debtorprovidian-1-yl)phenyl
18232-foradil3-(3,3-debtorprovidian-1-yl)phenyl
18242-foradil3-(2-methylpyrrolidine-1-yl)phenyl
18252-foradil 3-((S)-2-methylpyrrolidine-1-yl)phenyl

18262-foradil3-((R)-2-methylpyrrolidine-1-yl)phenyl
18272-foradil3-(3-methylpyrrolidine-1-yl)phenyl
18282-foradil3-((S)-3-methylpyrrolidine-1-yl)phenyl
18292-foradil3-((R)-3-methylpyrrolidine-1-yl)phenyl
18302-foradil3-(1-methylpyrrolidine-2-yl)phenyl
18312-foradil3-((S)-1-methylpyrrolidine-2-yl)phenyl
18322-foradil3-((R)-1-methylpyrrolidine-2-yl)phenyl
18332-foradil3-(1-methylpyrrolidine-3-yl)phenyl
18342-foradil3-((S)-1-methylpyrrolidine-3-yl)phenyl
1835 2-foradil3-((R)-1-methylpyrrolidine-3-yl)phenyl
18362-foradil3-(2,2-dimethylpiperidin-1-yl)phenyl
18372-foradil3-(3,3-dimethylpiperidin-1-yl)phenyl
18382-foradil3-(2-triftormetilfullerenov-1-yl)phenyl
18392-foradil3-((S)-2-triftormetilfullerenov-1-yl)phenyl
18402-foradil3-((R)-2-triftormetilfullerenov-1-yl)phenyl
18412-foradil3-(3-triftormetilfullerenov-1-yl)phenyl
18422-foradil3-((S)-3-triftormetilfullerenov-1-yl)phenyl
18432-foradil3-((R)-3-triftormetilfullerenov-1-yl)phenyl
18442-foradil3-(2-oxopyrrolidin-1-yl)phenyl
18452-foradil3-(2-oxo-oxazolidin-3-yl)phenyl
18462-foradil3-(piperidine-1-yl)phenyl
18472-foradil3-(2-methylpiperidin-1-yl)phenyl
18482-foradil3-((S)-2-methylpiperidin-1-yl)phenyl
18492-foradil3-((R)-2-methylpiperidin-1-yl)phenyl
18502-foradil3-(2-foreperiod-1-yl)phenyl
18512-foradil3-((S)-2-foreperiod-1-yl)phenyl
18522-foradil3-((R)-2-foreperiod-1-yl)phenyl
18532-foradil3-(2,2-deformability-1-yl)phenyl
18542-foradil3-(piperazine-1-yl)phenyl
18552 ftora the Il 3-(4-methylpiperazin-1-yl)phenyl

18562-foradil3-(morpholine-4-yl)phenyl
18572-foradil3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
18582-foradil5-(morpholine-4-yl)-2-methoxyphenyl
18592-foradil3-(morpholine-4-yl)-4-methoxyphenyl
19602-foradil5-(morpholine-4-yl)-2,4-differenl
18612-foradil3-(morpholine-4-yl)-2,4-differenl
18622-foradil3-(thiomorpholine-4-yl)phenyl
18632-foradil3-(1-Osotimehin-4-yl)phenyl
18642-foradil3-(1,1-diocletianopolis-4-yl)phenyl
1865 2-foradil3-(pyrrol-1-yl)phenyl
18662-foradil3-(pyrrol-2-yl)phenyl
18672-foradil3-(pyrrol-3-yl)phenyl
18682-foradil3-(1-methylpyrrole-2-yl)phenyl
18692-foradil3-(1-methylpyrrole-3-yl)phenyl
18702-foradil3-(furan-2-yl)phenyl
18712-foradil3-(furan-3-yl)phenyl
18722-foradil3-(thiophene-2-yl)phenyl
18732-foradil3-(thiophene-3-yl)phenyl
18742-foradil3-(5-properties-2-yl)phenyl
18752-foradil3-(pyrazole-1-yl)phenyl
1876 2-foradil3-(pyrazole-3-yl)phenyl
18772-foradil3-(pyrazole-4-yl)phenyl
18782-foradil3-(4-perperson-1-yl)phenyl
18792-foradil3-(1-methyl-1H-pyrazole-4-yl)phenyl
18802-foradil3-(1-ethyl-1H-pyrazole-4-yl)phenyl
18812-foradil3-(1-methyl-1H-pyrazole-5-yl)phenyl
18822-foradil3-(1H-imidazol-2-yl)phenyl
18832-foradil3-(imidazol-1-yl)phenyl
18842-foradil3-(1-Mei-2-yl)phenyl
18852-foradil3-(oxazol-2-yl)phenyl

18862-foradil 3-(oxazol-4-yl)phenyl
18872-foradil3-(oxazol-5-yl)phenyl
18882-foradil3-(isoxazol-3-yl)phenyl
18892-foradil3-(isoxazol-4-yl)phenyl
18902-foradil3-(isoxazol-5-yl)phenyl
18912-foradil3-(thiazol-2-yl)phenyl
18922-foradil3-(thiazol-4-yl)phenyl
18932-foradil3-(thiazol-5-yl)phenyl
18942-foradil3-(2-methylthiazole-4-yl)phenyl
18952-foradil3-(2-methylthiazole-5-yl)phenyl
18962-foradil3-([1,2,3]-triazole-1-yl)phenyl
18972-foradil 3-([1,2,4]-triazole-1-yl)phenyl
18982-foradil3-([1,2,3]-triazole-2-yl)phenyl
18992-foradil3-(4H-[1,2,4]-triazole-3-yl)phenyl
19002-foradil3-([1,2,4]-triazole-4-yl)phenyl
19012-foradil3-(2H-[1,2,3]-triazole-4-yl)phenyl
19022-foradil3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
19032-foradil3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
19042-foradil3-([1,3,4]-oxadiazol-2-yl)phenyl
19052-foradil3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
19062-foradil3-([1,2,4]-oxadiazol-3-yl)phenyl
19072-foradil3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl
19082-foradil3-([1,2,4]-oxadiazol-5-yl)phenyl
19092-foradil3-([1,2,3]-oxadiazol-4-yl)phenyl
19102-foradil3-([1,2,3]-oxadiazol-5-yl)phenyl
19112-foradil3-([1,2,3]-thiadiazole-4-yl)phenyl
19122-foradil3-(1H-tetrazol-5-yl)phenyl
19132-foradil3-(tetrazol-1-yl)phenyl
19142-foradil3-(2-methyl-2H-tetrazol-5-yl)phenyl
19152-foradil3-(1-methyl-1H-tetrazol-5-yl)phenyl

19162-foradil3-furazan-3-ylphenyl
19172-foradil3-(pyrid-2-yl)phenyl
19182-foradil3-(pyrid-3-yl)phenyl
19192-foradil3-(pyrid-4-yl)phenyl
19202-foradil3-(pyrimidine-2-yl)phenyl
19212-foradil3-(2-methylpyrimidin-4-yl)phenyl
19222-foradil3-(pyrimidine-4-yl)phenyl
19232-foradil3-(pyrimidine-5-yl)phenyl
19242-foradil5-bromopyridin-3-yl
19252-foradil3-bromo-2-chloropyridin-5-yl
19262-foradil4-methylpyridin-2-yl
19272-foradil6-methylpyridin-2-yl
19282-foradil4-(trifluoromethyl)pyridin-2-yl
19292-foradil6-(trifluoromethyl)pyridin-2-yl
19302-foradil5-(trifluoromethyl)pyridin-3-yl
19312-foradil5-(pyrrolidin-1-yl)pyridine-3-yl
19322-foradil3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl
19332-foradil3-(morpholine-4-yl)-2-chloropyridin-5-yl
19342-foradil2-(morpholine-4-yl)pyridin-5-yl
19352-foradil2-phenoxypyridine-5-yl
19362-foradil2,3-dichlorophenyl
19372-foradil2,5-dichlorophenyl
19382-foradil3,5-dichlorophenyl
19392-foradil3-chloro-4-terphenyl
19402-foradil4-bromo-2,5-dichlorophenyl
19412-foradil3-bromo-4-(triptoreline)phenyl
19422-foradil3,5-dibromo-4-(2-floratone)phenyl
19432-foradil2,5-dimetilfenil
19442-foradil2,5-di-(trifluoromethyl)phenyl
19452-foradil3,5-di-(trifluoromethyl)phenyl

19462-foradil2,5-acid
19472-foradil2-methoxy-5-were
19482-foradil2-methoxy-5-(trifluoromethyl)phenyl
19492-foradil4-fluoro-3-(oxazol-4-yl)phenyl
19502-foradilTien-2-yl
19512-foradilTien-3-yl
19522-foradil3-chlortan-2-yl
19532-foradil4-chlortan-2-yl
19542-foradil5-chlortan-2-yl
19552-foradil3-Bratan-2-yl
19562-foradil4-Bratan-2-yl
19572-foradil5-Bratan-2-yl
19582-foradil4,5-dichlorotin-2-yl
19592-foradil4,5-libration-2-yl
19602-foradil4-bromo-5-chlortan-2-yl
19612-foradil 3-bromo-5-chlortan-2-yl
19622-foradil5-methyltin-2-yl
19632-foradil5-utilties-2-yl
19642-foradil5-properties-2-yl
19652-foradil5-triptorelin-2-yl
19662-foradil5-penalties-2-yl
19672-foradil5-(pyrid-2-yl)Tien-2-yl
19682-foradil5-(phenylsulfonyl)Tien-2-yl
19692-foradil4-(phenylsulfonyl)Tien-2-yl
19702-foradil5-(pyrid-2-ylsulphonyl)Tien-2-yl
19712-foradil5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
19722-f is oratel 5-(benzoylamino)Tien-2-yl
19732-foradil5-((4-chlorbenzoyl)aminomethyl)Tien-2-yl
19742-foradil5-(acetamidomethyl)Tien-2-yl
19752-foradil5-(pyrazole-1-yl)Tien-2-yl

td align="center"> 2-foradil
19762-foradil5-(pyrazole-3-yl)Tien-2-yl
19772-foradil5-(pyrazole-4-yl)Tien-2-yl
19782-foradil5-(pyrazole-5-yl)Tien-2-yl
19792-foradil5-(4-perperson-1-yl)Tien-2-yl
19802-foradil5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl
19812-foradil5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
1982/td> 2-foradil5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
19832-foradil5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
19842-foradil5-(isoxazol-3-yl)Tien-2-yl
19852-foradil5-(isoxazol-4-yl)Tien-2-yl
19862-foradil5-(isoxazol-5-yl)Tien-2-yl
19872-foradil5-(5-cryptometrics-3-yl)Tien-2-yl
19882-foradil5-(oxazol-2-yl)Tien-2-yl
19892-foradil5-(oxazol-4-yl)Tien-2-yl
19902-foradil5-(oxazol-5-yl)Tien-2-yl
19912-foradil5-(2-methoxazole-4-yl)Tien-2-yl
19925-(2-methoxazole-5-yl)Tien-2-yl
19932-foradil5-(isothiazol-3-yl)Tien-2-yl
19942-foradil5-(isothiazol-4-yl)Tien-2-yl
19952-foradil5-(isothiazol-5-yl)Tien-2-yl
19962-foradil5-(5-triftoratsetata-3-yl)Tien-2-yl
19972-foradil5-(thiazol-2-yl)Tien-2-yl
19982-foradil5-(thiazol-4-yl)Tien-2-yl
19992-foradil5-(thiazol-5-yl)Tien-2-yl
20002-foradil5-(2-methylthiazole-4-yl)Tien-2-yl
20012-foradil5-(2-methylthiazole-5-yl)Tien-2-yl
20022-foradil5-([1,2,3]-oxadiazol-4-the l)Tien-2-yl
20032-foradil5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
20042-foradil5-(pyrimidine-2-yl)Tien-2-yl
20052-foradil5-(pyrimidine-4-yl)Tien-2-yl
20062-foradil5-(pyrimidine-5-yl)Tien-2-yl

20072-foradil5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
20082-foradil5-([1,3]-dioxolane-2-yl)Tien-2-yl
20092-foradil3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl
20102-foradil5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl
20112-foradil5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
20122-f is oratel 2-chlortan-3-yl
20132-foradil4-chlortan-3-yl
20142-foradil5-chlortan-3-yl
20152-foradil2-Bratan-3-yl
20162-foradil4-Bratan-3-yl
20172-foradil5-Bratan-3-yl
20182-foradil2,5-dichlorotin-3-yl
20192-foradil2,5-libration-3-yl
20202-foradil2,4,5-tripartie-3-yl
20212-foradil4-bromo-2,5-dichlorotin-3-yl
20222-foradil2-chloro-5-methylsulfonate-3-yl
20232-foradil20242-foradil4-hydroxicut-3-yl
20252-foradil2-venitien-3-yl
20262-foradil4-phenyl-5-(trifluoromethyl)Tien-3-yl
20272-foradil2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl
20282-foradilbenzo[b]thiophene-2-yl
20292-foradilbenzo[b]thiophene-3-yl
20302-foradil3 methylbenzo[b]thiophene-2-yl
20312-foradil5-methylbenzo[b]thiophene-2-yl
20322-foradil5-fluoro-3-methylbenzo[b]thiophene-2-yl
20332-foradil5-chloro-3-methylbenzo[b]thiophene-2-yl
2034 2-foradil5-bromo-3-methylbenzo[b]thiophene-2-yl
2035cyclopropylmethyl3-were
2036cyclopropylmethyl3-ethylphenyl

2037cyclopropylmethyl3-propylphenyl
2038cyclopropylmethyl3-isopropylphenyl
2039cyclopropylmethyl3-second-butylphenyl
2040cyclopropylmethyl3-tert-butylphenyl
2041cyclopropylmethyl3-isobutylphenyl
2042cyclopropylmethyl3-(1,1-dimethylpropyl)phenyl
2043cyclopropylmethyl3-vinylphenol
2044cyclopropylmethyl 3-isopropylphenyl
2045cyclopropylmethyl3-forfinal
2046cyclopropylmethyl3-chlorophenyl
2047cyclopropylmethyl3-bromophenyl
2048cyclopropylmethyl3-itfinal
2049cyclopropylmethyl3-(permitil)phenyl
2050cyclopropylmethyl3-(deformity)phenyl
2051cyclopropylmethyl3-(trifluoromethyl)phenyl
2052cyclopropylmethyl3,5-bis(trifluoromethyl)phenyl
2053cyclopropylmethyl3-(1-foradil)phenyl
2054cyclopropylmethyl3-((S)-1-foradil)phenyl
2055 cyclopropylmethyl3-((R)-1-foradil)phenyl
2056cyclopropylmethyl3-(2-foradil)phenyl
2057cyclopropylmethyl3-(1,1-dottorati)phenyl
2058cyclopropylmethyl3-(2,2-dottorati)phenyl
2059cyclopropylmethyl3-(2,2,2-triptorelin)phenyl
2060cyclopropylmethyl3-(3-forproper)phenyl
2061cyclopropylmethyl3-(2-forproper)phenyl
2062cyclopropylmethyl3-((S)-2-forproper)phenyl
2063cyclopropylmethyl3-((R)-2-forproper)phenyl
2064cyclopropylmethyl3-(3,3-deferror)phenyl
2065cyclopropylmethyl 3-(3,3,3-cryptochromes)phenyl
2066cyclopropylmethyl3-(1-fluoro-1-methylethyl)phenyl

2067cyclopropylmethyl3-(2-fluoro-1-methylethyl)phenyl
2068cyclopropylmethyl3-((S)-2-fluoro-1-methylethyl)phenyl
2069cyclopropylmethyl3-((R)-2-fluoro-1-methylethyl)phenyl
2070cyclopropylmethyl3-(2,2-debtor-1-methylethyl)phenyl
2071cyclopropylmethyl3-((S)-2,2-debtor-1-methylethyl)phenyl
2072cyclopropylmethyl3-((R)-2,2-debtor-1-methylethyl)phenyl
2073cyclopropylmethyl3-(2,2,2-Cryptor-1-methylethyl)phenyl
2074cyclopropylmethyl3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl
2075cyclopropylmethyl3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
2076cyclopropylmethyl3-(2-fluoro-1-permethylated)phenyl
2077cyclopropylmethyl3-(1-deformity-2,2-dottorati)phenyl
2078cyclopropylmethyl3-(1,1-dimethyl-2-foradil)phenyl
2079cyclopropylmethyl3-methoxyphenyl
2080cyclopropylmethyl3-ethoxyphenyl
2081cyclopropylmethyl3-propoxyphenyl
2082cyclopropylmethyl3-isopropoxyphenyl
2083cyclopropylmethyl3-butoxyphenyl
2084cyclopropylmethyl3-(formatosi)phenyl
2085 cyclopropylmethyl3-(deformedarse)phenyl
2086cyclopropylmethyl3-(triptoreline)phenyl
2087cyclopropylmethyl3-(2-floratone)phenyl
2088cyclopropylmethyl3-(2,2-diflorasone)phenyl
2089cyclopropylmethyl3-(2,2,2-triptoreline)phenyl
2090cyclopropylmethyl3-(1,1,2,2-tetrafluoroethoxy)phenyl
2091cyclopropylmethyl3-cyclopropylethanol
2092cyclopropylmethyl3-cyclobutylmethyl
2093cyclopropylmethyl3-cyclopentylphenol
2094cyclopropylmethyl3-(2,2-diversicolor)phenyl
2095cyclopropa is methyl 3,4-differenl
2096cyclopropylmethyl3-bromo-2-forfinal

2097cyclopropylmethyl2-bromo-3-forfinal
2098cyclopropylmethyl3-bromo-2,5-differenl
2099cyclopropylmethyl5-bromo-2,4-differenl
2100cyclopropylmethyl3-bromo-2,4-differenl
2101cyclopropylmethyl4-chloro-3-(trifluoromethyl)phenyl
2102cyclopropylmethyl2-chloro-5-(trifluoromethyl)phenyl
2103cyclopropylmethyl2-fluoro-5-(trifluoromethyl)phenyl
2104cyclopropylmethyl4-fluoro-3-(trifluoromethyl)phenyl
2105 cyclopropylmethyl3-fluoro-5-(trifluoromethyl)phenyl
2106cyclopropylmethyl4-bromo-3-(trifluoromethyl)phenyl
2107cyclopropylmethyl3-bromo-5-(trifluoromethyl)phenyl
2108cyclopropylmethyl2-bromo-5-(trifluoromethyl)phenyl
2109cyclopropylmethyl5-bromo-2-methoxyphenyl
2110cyclopropylmethyl3-bromo-4-methoxyphenyl
2111cyclopropylmethyl2-fluoro-3-isopropylphenyl
2112cyclopropylmethyl4-fluoro-3-isopropylphenyl
2113cyclopropylmethyl3-(1-hydroxy-1-methylethyl)phenyl
2114cyclopropylmethyl3-(2-hydroxy-2-methylpropyl " phenyl
2115 cyclopropylmethyl3-acetylphenyl
2116cyclopropylmethyl3-acetylaminophenol
2117cyclopropylmethyl3-carboxyphenyl
2118cyclopropylmethyl3-cyanophenyl
2119cyclopropylmethyl3-nitrophenyl
2120cyclopropylmethyl3-hydroxyphenyl
2121cyclopropylmethyl3-(O-benzyl)phenyl
2122cyclopropylmethyl3-(2-methoxyethoxy)phenyl
2123cyclopropylmethyl3-(CH2-N(CH3)2)phenyl
2124cyclopropylmethyl3-(NH-CO-NH2)phenyl
2125cyclopropylmethyl3-(matilal panel)phenyl
2126cyclopropylmethyl3-(pharmacysulfacet)phenyl

2127cyclopropylmethyl3-(deformational)phenyl
2128cyclopropylmethyl3-(trifloromethyl)phenyl
2129cyclopropylmethyl3-(methylsulphonyl)phenyl
2130cyclopropylmethyl3-(N-methoxy-N-methylamino)phenyl
2131cyclopropylmethyl3-(methoxyamino)phenyl
2132cyclopropylmethyl3-(ethoxyline)phenyl
2133cyclopropylmethyl3-(N-methylenedioxy)phenyl
2134cyclopropylmethyl3-(N,N-dimethylaminoethoxy)phenyl
2135ecoproperty 3-(azetidin-1-yl)phenyl
2136cyclopropylmethyl3-(2-methylaziridine-1-yl)phenyl
2137cyclopropylmethyl3-((S)-2-methylaziridine-1-yl)phenyl
2138cyclopropylmethyl3-((R)-2-methylaziridine-1-yl)phenyl
2139cyclopropylmethyl3-(3-torasemide-1-yl)phenyl
2140cyclopropylmethyl3-(2,2-diversecity-1-yl)phenyl
2141cyclopropylmethyl3-(3-methoxyisatin-1-yl)phenyl
2142cyclopropylmethyl3-(3-hydroxyazetidine-1-yl)phenyl
2143cyclopropylmethyl3-(pyrrolidin-1-yl)phenyl
2144cyclopropylmethyl3-(pyrrolidin-2-yl)phenyl
21453-((S)-pyrrolidin-2-yl)phenyl
2146cyclopropylmethyl3-((R)-pyrrolidin-2-yl)phenyl
2147cyclopropylmethyl3-(pyrrolidin-3-yl)phenyl
2148cyclopropylmethyl3-((S)-pyrrolidin-3-yl)phenyl
2149cyclopropylmethyl3-((R)-pyrrolidin-3-yl)phenyl
2150cyclopropylmethyl3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl
2151cyclopropylmethyl5-(pyrrolidin-1-yl)-2-methoxyphenyl
2152cyclopropylmethyl3-(pyrrolidin-1-yl)-4-methoxyphenyl
2153cyclopropylmethyl5-(pyrrolidin-1-yl)-2,4-differenl
2154cyclopropylmethyl3-(pyrrolidin-1-yl)-2,4-differenl
2155cyclopropylmethyl3-(2-ftorpirimidinu-1-yl)phenyl
2156cyclopropylmethyl3-((S)-2-ftorpirimidinu-1-yl)phenyl

2157cyclopropylmethyl3-((R)-2-ftorpirimidinu-1-yl)phenyl
2158cyclopropylmethyl3-(3-ftorpirimidinu-1-yl)phenyl
2159cyclopropylmethyl3-((S)-3-ftorpirimidinu-1-yl)phenyl
2160cyclopropylmethyl3-((R)-3-ftorpirimidinu-1-yl)phenyl
2161cyclopropylmethyl3-(2,2-debtorprovidian-1-yl)phenyl
2162cyclopropylmethyl3-(3,3-debtorprovidian-1-yl)phenyl
2163cyclopropylmethyl3-(2-methylpyrrolidine-1-yl)phenyl
2164 cyclopropylmethyl3-((S)-2-methylpyrrolidine-1-yl)phenyl
2165cyclopropylmethyl3-((R)-2-methylpyrrolidine-1-yl)phenyl
2166cyclopropylmethyl3-(3-methylpyrrolidine-1-yl)phenyl
2167cyclopropylmethyl3-((S)-3-methylpyrrolidine-1-yl)phenyl
2168cyclopropylmethyl3-((R)-3-methylpyrrolidine-1-yl)phenyl
2169cyclopropylmethyl3-(1-methylpyrrolidine-2-yl)phenyl
2170cyclopropylmethyl3-((S)-1-methylpyrrolidine-2-yl)phenyl
2171cyclopropylmethyl3-((R)-1-methylpyrrolidine-2-yl)phenyl
2172cyclopropylmethyl3-(1-methylpyrrolidine-3-yl)phenyl
2173cyclopropylmethyl3-((S)-1-methylpyrrolidine-3 is)phenyl
2174cyclopropylmethyl3-((R)-1-methylpyrrolidine-3-yl)phenyl
2175cyclopropylmethyl3-(2,2-dimethylpiperidin-1-yl)phenyl
2176cyclopropylmethyl3-(3,3-dimethylpiperidin-1-yl)phenyl
2177cyclopropylmethyl3-(2-triftormetilfullerenov-1-yl)phenyl
2178cyclopropylmethyl3-((S)-2-triftormetilfullerenov-1-yl)phenyl
2179cyclopropylmethyl3-((R)-2-triftormetilfullerenov-1-yl)phenyl
2180cyclopropylmethyl3-(3-triftormetilfullerenov-1-yl)phenyl
2181cyclopropylmethyl3-((S)-3-triftormetilfullerenov-1-yl)phenyl
2182cyclopropylmethyl3-((R)-3-triftormetilfullerenov-1-yl)phenyl
2183cyclopropylmethyl3-(2-oxopyrrolidin-1-yl)phenyl
2184cyclopropylmethyl3-(2-oxo-oxazolidin-3-yl)phenyl
2185cyclopropylmethyl3-(piperidine-1-yl)phenyl
2186cyclopropylmethyl3-(2-methylpiperidin-1-yl)phenyl

2187cyclopropylmethyl3-((S)-2-methylpiperidin-1-yl)phenyl
2188cyclopropylmethyl3-((R)-2-methylpiperidin-1-yl)phenyl
2189cyclopropylmethyl3-(2-foreperiod-1-yl)phenyl
2190cyclopropylmethyl3-((S)-2-foreperiod-1-yl)phenyl
2191cyclopropylmethyl3-((R)-2-foreperiod-1-yl)phenyl
2192cycloprop lmutil 3-(2,2-deformability-1-yl)phenyl
2193cyclopropylmethyl3-(piperazine-1-yl)phenyl
2194cyclopropylmethyl3-(4-methylpiperazin-1-yl)phenyl
2195cyclopropylmethyl3-(morpholine-4-yl)phenyl
2196cyclopropylmethyl3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
2197cyclopropylmethyl5-(morpholine-4-yl)-2-methoxyphenyl
2198cyclopropylmethyl3-(morpholine-4-yl)-4-methoxyphenyl
2199cyclopropylmethyl5-(morpholine-4-yl)-2,4-differenl
2200cyclopropylmethyl3-(morpholine-4-yl)-2,4-differenl
2201cyclopropylmethyl3-(thiomorpholine-4-yl)phenyl
2202 cyclopropylmethyl3-(1-Osotimehin-4-yl)phenyl
2203cyclopropylmethyl3-(1,1-diocletianopolis-4-yl)phenyl
2204cyclopropylmethyl3-(pyrrol-1-yl)phenyl
2205cyclopropylmethyl3-(pyrrol-2-yl)phenyl
2206cyclopropylmethyl3-(pyrrol-3-yl)phenyl
2207cyclopropylmethyl3-(1-methylpyrrole-2-yl)phenyl
2208cyclopropylmethyl3-(1-methylpyrrole-3-yl)phenyl
2209cyclopropylmethyl3-(furan-2-yl)phenyl
2210cyclopropylmethyl3-(furan-3-yl)phenyl
2211cyclopropylmethyl3-(thiophene-2-yl)phenyl
2212cyclopropylmethyl 3-(thiophene-3-yl)phenyl
2213cyclopropylmethyl3-(5-properties-2-yl)phenyl
2214cyclopropylmethyl3-(pyrazole-1-yl)phenyl
2215cyclopropylmethyl3-(pyrazole-3-yl)phenyl
2216cyclopropylmethyl3-(pyrazole-4-yl)phenyl

cyclopropylmethyl
2217cyclopropylmethyl3-(4-perperson-1-yl)phenyl
2218cyclopropylmethyl3-(1-methyl-1H-pyrazole-4-yl)phenyl
2219cyclopropylmethyl3-(1-ethyl-1H-pyrazole-4-yl)phenyl
2220cyclopropylmethyl3-(1-methyl-1H-pyrazole-5-yl)phenyl
2221cyclopropylmethyl3-(1H-imidazol-2-yl)phenyl
22223-(imidazol-1-yl)phenyl
2223cyclopropylmethyl3-(1-Mei-2-yl)phenyl
2224cyclopropylmethyl3-(oxazol-2-yl)phenyl
2225cyclopropylmethyl3-(oxazol-4-yl)phenyl
2226cyclopropylmethyl3-(oxazol-5-yl)phenyl
2227cyclopropylmethyl3-(isoxazol-3-yl)phenyl
2228cyclopropylmethyl3-(isoxazol-4-yl)phenyl
2229cyclopropylmethyl3-(isoxazol-5-yl)phenyl
2230cyclopropylmethyl3-(thiazol-2-yl)phenyl
2231cyclopropylmethyl3-(thiazol-4-yl)phenyl
2232cyclopropylmethyl 3-(thiazol-5-yl)phenyl
2233cyclopropylmethyl3-(2-methylthiazole-4-yl)phenyl
2234cyclopropylmethyl3-(2-methylthiazole-5-yl)phenyl
2235cyclopropylmethyl3-([1,2,3]-triazole-1-yl)phenyl
2236cyclopropylmethyl3-([1,2,4]-triazole-1-yl)phenyl
2237cyclopropylmethyl3-([1,2,3]-triazole-2-yl)phenyl
2238cyclopropylmethyl3-(4H-[1,2,4]-triazole-3-yl)phenyl
2239cyclopropylmethyl3-([1,2,4]-triazole-4-yl)phenyl
2240cyclopropylmethyl3-(2H-[1,2,3]-triazole-4-yl)phenyl
2241cyclopropylmethyl3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
2242cyclopropylmethyl 3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
2243cyclopropylmethyl3-([1,3,4]-oxadiazol-2-yl)phenyl
2244cyclopropylmethyl3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
2245cyclopropylmethyl3-([1,2,4]-oxadiazol-3-yl)phenyl
2246cyclopropylmethyl3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl

2252
2247cyclopropylmethyl3-([1,2,4]-oxadiazol-5-yl)phenyl
2248cyclopropylmethyl3-([1,2,3]-oxadiazol-4-yl)phenyl
2249cyclopropylmethyl3-([1,2,3]-oxadiazol-5-yl)phenyl
2250cyclopropylmethyl3-([1,2,3]-thiadiazole-4-yl)phenyl
2251cyclopropylmethyl3-(1H-tetrazol-5-yl)phenyl
cyclopropylmethyl3-(tetrazol-1-yl)phenyl
2253cyclopropylmethyl3-(2-methyl-2H-tetrazol-5-yl)phenyl
2254cyclopropylmethyl3-(1-methyl-1H-tetrazol-5-yl)phenyl
2255cyclopropylmethyl3-furazan-3-ylphenyl
2256cyclopropylmethyl3-(pyrid-2-yl)phenyl
2257cyclopropylmethyl3-(pyrid-3-yl)phenyl
2258cyclopropylmethyl3-(pyrid-4-yl)phenyl
2259cyclopropylmethyl3-(pyrimidine-2-yl)phenyl
2260cyclopropylmethyl3-(2-methylpyrimidin-4-yl)phenyl
2261cyclopropylmethyl3-(pyrimidine-4-yl)phenyl
2262 cyclopropylmethyl3-(pyrimidine-5-yl)phenyl
2263cyclopropylmethyl5-bromopyridin-3-yl
2264cyclopropylmethyl3-bromo-2-chloropyridin-5-yl
2265cyclopropylmethyl4-methylpyridin-2-yl
2266cyclopropylmethyl6-methylpyridin-2-yl
2267cyclopropylmethyl4-(trifluoromethyl)pyridin-2-yl
2268cyclopropylmethyl6-(trifluoromethyl)pyridin-2-yl
2269cyclopropylmethyl5-(trifluoromethyl)iridin-3-yl
2270cyclopropylmethyl5-(pyrrolidin-1-yl)pyridine-3-yl
2271cyclopropylmethyl3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl
2272 cyclopropylmethyl3-(morpholine-4-yl)-2-chloropyridin-5-yl
2273cyclopropylmethyl2-(morpholine-4-yl)pyridin-5-yl
2274cyclopropylmethyl2-phenoxypyridine-5-yl
2275cyclopropylmethyl2,3-dichlorophenyl
2276cyclopropylmethyl2,5-dichlorophenyl

cyclopropylmethyl
2277cyclopropylmethyl3,5-dichlorophenyl
2278cyclopropylmethyl3-chloro-4-forfinal
2279cyclopropylmethyl4-bromo-2,5-dichlorophenyl
2280cyclopropylmethyl3-bromo-4-(triptoreline)phenyl
2281cyclopropylmethyl3,5-dibromo-4-(2-floratone)phenyl
2282cyclopropylmethyl2,5-dimetilfenil
2283cyclopropylmethyl2,5-di-(trifluoromethyl)phenyl
2284cyclopropylmethyl3,5-di-(trifluoromethyl)phenyl
2285cyclopropylmethyl2,5-acid
2286cyclopropylmethyl2-methoxy-5-were
2287cyclopropylmethyl2-methoxy-5-(trifluoromethyl)phenyl
2288cyclopropylmethyl4-fluoro-3-(oxazol-4-yl)phenyl
2289cyclopropylmethylTien-2-yl
2290cyclopropylmethylTien-3-yl
2291cyclopropylmethyl3-chlortan-2-yl
2292cyclopropylmethyl the 4-chlortan-2-yl
2293cyclopropylmethyl5-chlortan-2-yl
2294cyclopropylmethyl3-Bratan-2-yl
2295cyclopropylmethyl4-Bratan-2-yl
2296cyclopropylmethyl5-Bratan-2-yl
2297cyclopropylmethyl4,5-dichlorotin-2-yl
2298cyclopropylmethyl4,5-libration-2-yl
2299cyclopropylmethyl4-bromo-5-chlortan-2-yl
2300cyclopropylmethyl3-bromo-5-chlortan-2-yl
2301cyclopropylmethyl5-methyltin-2-yl
2302cyclopropylmethyl5-utilties-2-yl
23035-properties-2-yl
2304cyclopropylmethyl5-triptorelin-2-yl
2305cyclopropylmethyl5-penalties-2-yl
2306cyclopropylmethyl5-(pyrid-2-yl)Tien-2-yl

2332
2307cyclopropylmethyl5-(phenylsulfonyl)Tien-2-yl
2308cyclopropylmethyl4-(phenylsulfonyl)Tien-2-yl
2309cyclopropylmethyl5-(pyrid-2-ylsulphonyl)Tien-2-yl
2310cyclopropylmethyl5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
2311cyclopropylmethyl5-(benzoylamino)Tien-2-yl
2312cyclopropylmethyl5-((4-chlorbenzoyl)AMI the said;") Tien-2-yl
2313cyclopropylmethyl5-(acetamidomethyl)Tien-2-yl
2314cyclopropylmethyl5-(pyrazole-1-yl)Tien-2-yl
2315cyclopropylmethyl5-(pyrazole-3-yl)Tien-2-yl
2316cyclopropylmethyl5-(pyrazole-4-yl)Tien-2-yl
2317cyclopropylmethyl5-(pyrazole-5-yl)Tien-2-yl
2318cyclopropylmethyl5-(4-perperson-1-yl)Tien-2-yl
2319cyclopropylmethyl5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl
2320cyclopropylmethyl5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
2321cyclopropylmethyl5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
2322 cyclopropylmethyl5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
2323cyclopropylmethyl5-(isoxazol-3-yl)Tien-2-yl
2324cyclopropylmethyl5-(isoxazol-4-yl)Tien-2-yl
2325cyclopropylmethyl5-(isoxazol-5-yl)Tien-2-yl
2326cyclopropylmethyl5-(5-cryptometrics-3-yl)Tien-2-yl
2327cyclopropylmethyl5-(oxazol-2-yl)Tien-2-yl
2328cyclopropylmethyl5-(oxazol-4-yl)Tien-2-yl
2329cyclopropylmethyl5-(oxazol-5-yl)Tien-2-yl
2330cyclopropylmethyl5-(2-methoxazole-4-yl)Tien-2-yl
2331cyclopropylmethyl5-(2-methoxazole-5-yl)Tien-2-yl
cyclopropylmethyl5-(isothiazol-3-yl)Tien-2-yl
2333cyclopropylmethyl5-(isothiazol-4-yl)Tien-2-yl
2334cyclopropylmethyl5-(isothiazol-5-yl)Tien-2-yl
2335cyclopropylmethyl5-(5-triftoratsetata-3-yl)Tien-2-yl
2336cyclopropylmethyl5-(thiazol-2-yl)Tien-2-yl

2337cyclopropylmethyl5-(thiazol-4-yl)Tien-2-yl
2338cyclopropylmethyl5-(thiazol-5-yl)Tien-2-yl
2339cyclopropylmethyl5-(2-methylthiazole-4-yl)Tien-2-yl
2340cyclopropylmethyl5-(2-methylthiazole-5-yl)Tien-2-yl
2341cyclopropylmethyl 5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl
2342cyclopropylmethyl5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
2343cyclopropylmethyl5-(pyrimidine-2-yl)Tien-2-yl
2344cyclopropylmethyl5-(pyrimidine-4-yl)Tien-2-yl
2345cyclopropylmethyl5-(pyrimidine-5-yl)Tien-2-yl
2346cyclopropylmethyl5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
2347cyclopropylmethyl5-([1,3]-dioxolane-2-yl)Tien-2-yl
2348cyclopropylmethyl3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl
2349cyclopropylmethyl5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl
2350cyclopropylmethyl5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
2351cyclopropylmethyl2-chlortan-3-yl
2352cyclopropylmethyl4-chlortan-3-yl
2353cyclopropylmethyl5-chlortan-3-yl
2354cyclopropylmethyl2-Bratan-3-yl
2355cyclopropylmethyl4-Bratan-3-yl
2356cyclopropylmethyl5-Bratan-3-yl
2357cyclopropylmethyl2,5-dichlorotin-3-yl
2358cyclopropylmethyl2,5-libration-3-yl
2359cyclopropylmethyl2,4,5-tripartie-3-yl
2360cyclopropylmethyl4-bromo-2,5-dichlorotin-3-yl
2361cyclopropylmethyl2 the PRS-5-methylsulfonate-3-yl
2362cyclopropylmethyl2,5-dietitian-3-yl
2363cyclopropylmethyl4-hydroxicut-3-yl
2364cyclopropylmethyl2-venitien-3-yl
2365cyclopropylmethyl4-phenyl-5-(trifluoromethyl)Tien-3-yl
2366cyclopropylmethyl2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl

2367cyclopropylmethylbenzo[b]thiophene-2-yl
2368cyclopropylmethylbenzo[b]thiophene-3-yl
2369cyclopropylmethyl3 methylbenzo[b]thiophene-2-yl
2370cyclopropylmethyl5-methylbenzo[b]thiophene-2-yl
2371cyclopropylmethyl 5-fluoro-3-methylbenzo[b]thiophene-2-yl
2372cyclopropylmethyl5-chloro-3-methylbenzo[b]thiophene-2-yl
2373cyclopropylmethyl5-bromo-3-methylbenzo[b]thiophene-2-yl
2374allyl3-were
2375allyl3-ethylphenyl
2376allyl3-propylphenyl
2377allyl3-isopropylphenyl
2378allyl3-second-butylphenyl
2379allyl3-tert-butylphenyl
2380allyl3-isobutylphenyl
2381allyl3-(1,1-dimethylpropyl)phenyl
2382allyl 3-vinylphenol
2383allyl3-isopropylphenyl
2384allyl3-forfinal
2385allyl3-chlorophenyl
2386allyl3-bromophenyl
2387allyl3-itfinal
2388allyl3-(permitil)phenyl
2389allyl3-(deformity)phenyl
2390allyl3-(trifluoromethyl)phenyl
2391allyl3,5-bis(trifluoromethyl)phenyl
2392allyl3-(1-foradil)phenyl
2393allyl3-((S)-1-foradil)phenyl
2394all the l 3-((R)-1-foradil)phenyl
2395allyl3-(2-foradil)phenyl
2396allyl3-(1,1-dottorati)phenyl

2416
2397allyl3-(2,2-dottorati)phenyl
2398allyl3-(2,2,2-triptorelin)phenyl
2399allyl3-(3-forproper)phenyl
2400allyl3-(2-forproper)phenyl
2401allyl3-((S)-2-forproper)phenyl
2402allyl3-((R)-2-forproper)phenyl
2403allyl3-(3,3-deferror)phenyl
2404allyl3-(3,3,3-cryptochromes)phenyl
2405 allyl3-(1-fluoro-1-methylethyl)phenyl
2406allyl3-(2-fluoro-1-methylethyl)phenyl
2407allyl3-((S)-2-fluoro-1-methylethyl)phenyl
2408allyl3-((R)-2-fluoro-1-methylethyl)phenyl
2409allyl3-(2,2-debtor-1-methylethyl)phenyl
2410allyl3-((S)-2,2-debtor-1-methylethyl)phenyl
2411allyl3-((R)-2,2-debtor-1-methylethyl)phenyl
2412allyl3-(2,2,2-Cryptor-1-methylethyl)phenyl
2413allyl3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl
2414allyl3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
2415allyl3-(2-fluoro-1-permethylated)phenyl
allyl3-(1-deformity-2,2-dottorati)phenyl
2417allyl3-(1,1-dimethyl-2-foradil)phenyl
2418allyl3-methoxyphenyl
2419allyl3-ethoxyphenyl
2420allyl3-propoxyphenyl
2421allyl3-isopropoxyphenyl
2422allyl3-butoxyphenyl
2423allyl3-(formatosi)phenyl
2424allyl3-(deformedarse)phenyl
2425allyl3-(triptoreline)phenyl
2426allyl3-(2-floratone)phenyl

2427allyl3-(2,2-diflorasone)phenyl
2428allyl3-(2,2,2-triptoreline)phenyl
2429allyl3-(1,1,2,2-tetrafluoroethoxy)phenyl
2430allyl3-cyclopropylethanol
2431allyl3-cyclobutylmethyl
2432allyl3-cyclopentylphenol
2433allyl3-(2,2-diversicolor)phenyl
2434allyl3,4-differenl
2435allyl3-bromo-2-forfinal
2436allyl2-bromo-3-forfinal
2437allyl3-bromo-2,5-differenl
2438al is Il 5-bromo-2,4-differenl
2439allyl3-bromo-2,4-differenl
2440allyl4-chloro-3-(trifluoromethyl)phenyl
2441allyl2-chloro-5-(trifluoromethyl)phenyl
2442allyl2-fluoro-5-(trifluoromethyl)phenyl
2443allyl4-fluoro-3-(trifluoromethyl)phenyl
2444allyl3-fluoro-5-(trifluoromethyl)phenyl
2445allyl4-bromo-3-(trifluoromethyl)phenyl
2446allyl3-bromo-5-(trifluoromethyl)phenyl
2447allyl2-bromo-5-(trifluoromethyl)phenyl
2448allyl5-bromo-2-methoxyphenyl
2449 allyl3-bromo-4-methoxyphenyl
2450allyl2-fluoro-3-isopropylphenyl
2451allyl4-fluoro-3-isopropylphenyl
2452allyl3-(1-hydroxy-1-methylethyl)phenyl
2453allyl3-(2-hydroxy-2-methylpropyl " phenyl
2454allyl3-acetylphenyl
2455allyl3-acetylaminophenol
2456allyl3-carboxyphenyl

2457allyl3-cyanophenyl
2458allyl3-nitrophenyl
2459allyl3-hydroxyphenyl
2460 allyl3-(O-benzyl)phenyl
2461allyl3-(2-methoxyethoxy)phenyl
2462allyl3-(CH2-N(CH3)2)phenyl
2463allyl3-(NH-CO-NH2)phenyl
2464allyl3-(methylsulfanyl)phenyl
2465allyl3-(pharmacysulfacet)phenyl
2466allyl3-(deformational)phenyl
2467allyl3-(trifloromethyl)phenyl
2468allyl3-(methylsulphonyl)phenyl
2469allyl3-(N-methoxy-N-methylamino)phenyl
2470allyl3-(methoxyamino)phenyl
2471 allyl3-(ethoxyline)phenyl
2472allyl3-(N-methylenedioxy)phenyl
2473allyl3-(N,N-dimethylaminoethoxy)phenyl
2474allyl3-(azetidin-1-yl)phenyl
2475allyl3-(2-methylaziridine-1-yl)phenyl
2476allyl3-((S)-2-methylaziridine-1-yl)phenyl
2477allyl3-((R)-2-methylaziridine-1-yl)phenyl
2478allyl3-(3-torasemide-1-yl)phenyl
2479allyl3-(2,2-diversecity-1-yl)phenyl
2480allyl3-(3-methoxyisatin-1-yl)phenyl
2481allyl3-(3-hydroxyazetidine-1-yl)phenyl
2482 allyl3-(pyrrolidin-1-yl)phenyl
2483allyl3-(pyrrolidin-2-yl)phenyl
2484allyl3-((S)-pyrrolidin-2-yl)phenyl
2485allyl3-((R)-pyrrolidin-2-yl)phenyl
2486allyl3-(pyrrolidin-3-yl)phenyl

2487allyl3-((S)-pyrrolidin-3-yl)phenyl
2488allyl3-((R)-pyrrolidin-3-yl)phenyl
2489allyl3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl
2490allyl5-(pyrrolidin-1-yl)-2-methoxyphenyl
2491allyl3-(pyrrolidin-1-yl)-4-methoxyphenyl
2492allyl 5-(pyrrolidin-1-yl)-2,4-differenl
2493allyl3-(pyrrolidin-1-yl)-2,4-differenl
2494allyl3-(2-ftorpirimidinu-1-yl)phenyl
2495allyl3-((S)-2-ftorpirimidinu-1-yl)phenyl
2496allyl3-((R)-2-ftorpirimidinu-1-yl)phenyl
2497allyl3-(3-ftorpirimidinu-1-yl)phenyl
2498allyl3-((S)-3-ftorpirimidinu-1-yl)phenyl
2499allyl3-((R)-3-ftorpirimidinu-1-yl)phenyl
2500allyl3-(2,2-debtorprovidian-1-yl)phenyl
2501allyl3-(3,3-debtorprovidian-1-yl)phenyl
2502allyl3-(2-methylpyrrolidine-1-yl)phenyl
2503allyl3-((S)-2-methylpyrrolidine-1-yl)phenyl
2504allyl3-((R)-2-methylpyrrolidine-1-yl)phenyl
2505allyl3-(3-methylpyrrolidine-1-yl)phenyl
2506allyl3-((S)-3-methylpyrrolidine-1-yl)phenyl
2507allyl3-((R)-3-methylpyrrolidine-1-yl)phenyl
2508allyl3-(1-methylpyrrolidine-2-yl)phenyl
2509allyl3-((S)-1-methylpyrrolidine-2-yl)phenyl
2510allyl3-((R)-1-methylpyrrolidine-2-yl)phenyl
2511allyl3-(1-methylpyrrolidine-3-yl)phenyl
2512allyl3-((S)-1-methylpyrrolidine-3-yl)phenyl
2513allyl 3-((R)-1-methylpyrrolidine-3-yl)phenyl
2514allyl3-(2,2-dimethylpiperidin-1-yl)phenyl
2515allyl3-(3,3-dimethylpiperidin-1-yl)phenyl
2516allyl3-(2-triftormetilfullerenov-1-yl)phenyl

2517allyl3-((S)-2-triftormetilfullerenov-1-yl)phenyl
2518allyl3-((R)-2-triftormetilfullerenov-1-yl)phenyl
2519allyl3-(3-triftormetilfullerenov-1-yl)phenyl
2520allyl3-((S)-3-triftormetilfullerenov-1-yl)phenyl
2521allyl3-((R)-3-triftormetilfullerenov-1-yl)phenyl
2522allyl3-(2-oxopyrrolidin-1-yl)phenyl
2523 allyl3-(2-oxo-oxazolidin-3-yl)phenyl
2524allyl3-(piperidine-1-yl)phenyl
2525allyl3-(2-methylpiperidin-1-yl)phenyl
2526allyl3-((S)-2-methylpiperidin-1-yl)phenyl
2527allyl3-((R)-2-methylpiperidin-1-yl)phenyl
2528allyl3-(2-foreperiod-1-yl)phenyl
2529allyl3-((S)-2-foreperiod-1-yl)phenyl
2530allyl3-((R)-2-foreperiod-1-yl)phenyl
2531allyl3-(2,2-deformability-1-yl)phenyl
2532allyl3-(piperazine-1-yl)phenyl
2533allyl3-(4-methylpiperazin-1-yl)phenyl
2534allyl3-(morpholine-4-yl)phenyl
2535allyl3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
2536allyl5-(morpholine-4-yl)-2-methoxyphenyl
2537allyl3-(morpholine-4-yl)-4-methoxyphenyl
2538allyl5-(morpholine-4-yl)-2,4-differenl
2539allyl3-(morpholine-4-yl)-2,4-differenl
2540allyl3-(thiomorpholine-4-yl)phenyl
2541allyl3-(1-Osotimehin-4-yl)phenyl
2542allyl3-(1,1-diocletianopolis-4-yl)phenyl
2543allyl3-(pyrrol-1-yl)phenyl
2544allyl3-(pyrrol-2-yl)Hairdryer is l
2545allyl3-(pyrrol-3-yl)phenyl
2546allyl3-(1-methylpyrrole-2-yl)phenyl

2547allyl3-(1-methylpyrrole-3-yl)phenyl
2548allyl3-(furan-2-yl)phenyl
2549allyl3-(furan-3-yl)phenyl
2550allyl3-(thiophene-2-yl)phenyl
2551allyl3-(thiophene-3-yl)phenyl
2552allyl3-(5-properties-2-yl)phenyl
2553allyl3-(pyrazole-1-yl)phenyl
2554allyl3-(pyrazole-3-yl)phenyl
2555allyl3-(pyrazole-4-and the)phenyl
2556allyl3-(4-perperson-1-yl)phenyl
2557allyl3-(1-methyl-1H-pyrazole-4-yl)phenyl
2558allyl3-(1-ethyl-1H-pyrazole-4-yl)phenyl
2559allyl3-(1-methyl-1H-pyrazole-5-yl)phenyl
2560allyl3-(1H-imidazol-2-yl)phenyl
2561allyl3-(imidazol-1-yl)phenyl
2562allyl3-(1-Mei-2-yl)phenyl
2563allyl3-(oxazol-2-yl)phenyl
2564allyl3-(oxazol-4-yl)phenyl
2565allyl3-(oxazol-5-yl)phenyl
2566allyl3-(isoxazol-3-yl)phenyl
2567allyl3-(isoxazol-4-yl)phenyl
2568allyl3-(isoxazol-5-yl)phenyl
2569allyl3-(thiazol-2-yl)phenyl
2570allyl3-(thiazol-4-yl)phenyl
2571allyl3-(thiazol-5-yl)phenyl
2572allyl3-(2-methylthiazole-4-yl)phenyl
2573allyl3-(2-methylthiazole-5-yl)phenyl
2574allyl3-([1,2,3]-triazole-1-yl)phenyl
2575allyl3-([1,2,4]-triazole-1-yl)phenyl
2576allyl3-([1,2,3]-triazole-2-yl)phenyl

2577allyl3-4H-[1,2,4]-triazole-3-yl)phenyl
2578allyl3-([1,2,4]-triazole-4-yl)phenyl
2579allyl3-(2H-[1,2,3]-triazole-4-yl)phenyl
2580allyl3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
2581allyl3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
2582allyl3-([1,3,4]-oxadiazol-2-yl)phenyl
2583allyl3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
2584allyl3-([1,2,4]-oxadiazol-3-yl)phenyl
2585allyl3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl
2586allyl3-([1,2,4]-oxadiazol-5-yl)phenyl
2587allyl3-([1,2,3]-oxadiazol-4-yl)phenyl
2588allyl 3-([1,2,3]-oxadiazol-5-yl)phenyl
2589allyl3-([1,2,3]-thiadiazole-4-yl)phenyl
2590allyl3-(1H-tetrazol-5-yl)phenyl
2591allyl3-(tetrazol-1-yl)phenyl
2592allyl3-(2-methyl-2H-tetrazol-5-yl)phenyl
2593allyl3-(1-methyl-1H-tetrazol-5-yl)phenyl
2594allyl3-furazan-3-ylphenyl
2595allyl3-(pyrid-2-yl)phenyl
2596allyl3-(pyrid-3-yl)phenyl
2597allyl3-(pyrid-4-yl)phenyl
2598allyl3-(pyrimidine-2-yl)phenyl
2599allyl 3-(2-methylpyrimidin-4-yl)phenyl
2600allyl3-(pyrimidine-4-yl)phenyl
2601allyl3-(pyrimidine-5-yl)phenyl
2602allyl5-bromopyridin-3-yl
2603allyl3-bromo-2-chloropyridin-5-yl
2604allyl4-methylpyridin-2-yl
2605allyl6-methylpyridin-2-yl
2606allyl4-(trifluoromethyl)pyridin-2-yl

td align="center"> 2,5-dimetilfenil
2607allyl6-(trifluoromethyl)pyridin-2-yl
2608allyl5-(trifluoromethyl)pyridin-3-yl
2609allyl5-(pyrrolidin-1-yl)pyridine-3-yl
2610 allyl3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl
2611allyl3-(morpholine-4-yl)-2-chloropyridin-5-yl
2612allyl2-(morpholine-4-yl)pyridin-5-yl
2613allyl2-phenoxypyridine-5-yl
2614allyl2,3-dichlorophenyl
2615allyl2,5-dichlorophenyl
2616allyl3,5-dichlorophenyl
2617allyl3-chloro-4-forfinal
2618allyl4-bromo-2,5-dichlorophenyl
2619allyl3-bromo-4-(triptoreline)phenyl
2620allyl3,5-dibromo-4-(2-floratone)phenyl
2621allyl
2622allyl2,5-di-(trifluoromethyl)phenyl
2623allyl3,5-di-(trifluoromethyl)phenyl
2624allyl2,5-acid
2625allyl2-methoxy-5-were
2626allyl2-methoxy-5-(trifluoromethyl)phenyl
2627allyl4-fluoro-3-(oxazol-4-yl)phenyl
2628allylTien-2-yl
2629allylTien-3-yl
2630allyl3-chlortan-2-yl
2631allyl4-chlortan-2-yl
2632allyl5-chlortan-2-yl
2633 allyl3-Bratan-2-yl
2634allyl4-Bratan-2-yl
2635allyl5-Bratan-2-yl
2636allyl4,5-dichlorotin-2-yl

2637allyl4,5-libration-2-yl
2638allyl4-bromo-5-chlortan-2-yl
2639allyl3-bromo-5-chlortan-2-yl
2640allyl5-methyltin-2-yl
2641allyl5-utilties-2-yl
2642allyl5-properties-2-yl
2643allyl5-triptorelin-2-yl
2644allyl 5-penalties-2-yl
2645allyl5-(pyrid-2-yl)Tien-2-yl
2646allyl5-(phenylsulfonyl)Tien-2-yl
2647allyl4-(phenylsulfonyl)Tien-2-yl
2648allyl5-(pyrid-2-ylsulphonyl)Tien-2-yl
2649allyl5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
2650allyl5-(benzoylamino)Tien-2-yl
2651allyl5-((4-chlorbenzoyl)aminomethyl)Tien-2-yl
2652allyl5-(acetamidomethyl)Tien-2-yl
2653allyl5-(pyrazole-1-yl)Tien-2-yl
2654allyl5-(pyrazole-3-yl)Tien-2-yl
2655 allyl5-(pyrazole-4-yl)Tien-2-yl
2656allyl5-(pyrazole-5-yl)Tien-2-yl
2657allyl5-(4-perperson-1-yl)Tien-2-yl
2658allyl5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl
2659allyl5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
2660allyl5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
2661allyl5-(4-aminomethyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
2662allyl5-(isoxazol-3-yl)Tien-2-yl
2663allyl5-(isoxazol-4-yl)Tien-2-yl
2664allyl5-(isoxazol-5-yl)Tien-2-yl
2665allyl 5-(5-cryptometrics-3-yl)Tien-2-yl
2666allyl5-(oxazol-2-yl)Tien-2-yl
2667allyl5-(oxazol-4-yl)Tien-2-yl

2668allyl5-(oxazol-5-yl)Tien-2-yl
2669allyl5-(2-methoxazole-4-yl)Tien-2-yl
2670allyl5-(2-methoxazole-5-yl)Tien-2-yl
2671allyl5-(isothiazol-3-yl)Tien-2-yl
2672allyl5-(isothiazol-4-yl)Tien-2-yl
2673allyl5-(isothiazol-5-yl)Tien-2-yl
2674allyl5-(5-triftoratsetata-3-yl)Tien-2-yl
2675allyl5-(thiazol-2-yl)Tien-2-yl
2676allyl5-(thiazol-4-yl)Tien-2-yl
2677allyl5-(thiazol-5-yl)Tien-2-yl
2678allyl5-(2-methylthiazole-4-yl)Tien-2-yl
2679allyl5-(2-methylthiazole-5-yl)Tien-2-yl
2680allyl5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl
2681allyl5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
2682allyl5-(pyrimidine-2-yl)Tien-2-yl
2683allyl5-(pyrimidine-4-yl)Tien-2-yl
2684allyl5-(pyrimidine-5-yl)Tien-2-yl
2685allyl5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
2686allyl5-([1,3]-dioxolane-2-yl)Tien-2-yl
2687allyl3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl
2688allyl5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl
2689allyl5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
2690allyl2-chlortan-3-yl
2691allyl4-chlortan-3-yl
2692allyl5-chlortan-3-yl
2693allyl2-Bratan-3-yl
2694allyl4-Bratan-3-yl
2695allyl5-Bratan-3-yl
2696allyl2,5-dichlorotin-3-yl
2697allyl2,5-libration-3-yl

2698allyl2,4,5-tripartie-3-yl2699allyl4-bromo-2,5-dichlorotin-3-yl2700allyl2-chloro-5-methylsulfonate-3-yl2701allyl2,5-dietitian-3-yl2702allyl4-hydroxicut-3-yl2703allyl2-venitien-3-yl2704allyl4-phenyl-5-(trifluoromethyl)Tien-3-yl2705allyl2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl2706allylbenzo[b]thiophene-2-yl2707allylbenzo[b]thiophene-3-yl2708allyl3 methylbenzo[b]thiophene-2-yl 2709allyl5-methylbenzo[b]thiophene-2-yl2710allyl5-fluoro-3-methylbenzo[b]thiophene-2-yl2711allyl5-chloro-3-methylbenzo[b]thiophene-2-yl2712allyl5-bromo-3-methylbenzo[b]thiophene-2-yl2713benzil3-were2714benzil3-ethylphenyl2715benzil3-propylphenyl2716benzil3-isopropylphenyl2717benzil3-second-butylphenyl2718benzil3-tert-butylphenyl2719benzil3-isobutylphenyl2720 benzil3-(1,1-dimethylpropyl)phenyl2721benzil3-vinylphenol2722benzil3-isopropylphenyl2723benzil3-forfinal2724benzil3-chlorophenyl2725benzil3-bromophenyl2726benzil3-itfinal2727benzil3-(permitil)phenyl

2728benzil3-(deformity)phenyl
2729benzil3-(trifluoromethyl)phenyl
2730benzil3,5-bis(trifluoromethyl)phenyl
2731benzil 3-(1-foradil)phenyl
2732benzil3-((S)-1-foradil)phenyl
2733benzil3-((R)-1-foradil)phenyl
2734benzil3-(2-foradil)phenyl
2735benzil3-(1,1-dottorati)phenyl
2736benzil3-(2,2-dottorati)phenyl
2737benzil3-(2,2,2-triptorelin)phenyl
2738benzil3-(3-forproper)phenyl
2739benzil3-(2-forproper)phenyl
2740benzil3-((S)-2-forproper)phenyl
2741benzil3-((R)-2-forproper)phenyl
2742benzil3-(3,3-deferror)phenyl
2743benzil3-(3,3,3-cryptochromes)phenyl
2744benzil3-(1-fluoro-1-methylethyl)phenyl
2745benzil3-(2-fluoro-1-methylethyl)phenyl
2746benzil3-((S)-2-fluoro-1-methylethyl)phenyl
2747benzil3-((R)-2-fluoro-1-methylethyl)phenyl
2748benzil3-(2,2-debtor-1-methylethyl)phenyl
2749benzil3-((S)-2,2-debtor-1-methylethyl)phenyl
2750benzil3-((R)-2,2-debtor-1-methylethyl)phenyl
2751benzil3-(2,2,2-Cryptor-1-methylethyl)phenyl
2752benzil3-((S)-2,2,2-Cryptor-1-methylethyl)phenyl
2753benzil 3-((R)-2,2,2-Cryptor-1-methylethyl)phenyl
2754benzil3-(2-fluoro-1-permethylated)phenyl
2755benzil3-(1-deformity-2,2-dottorati)phenyl
2756benzil3-(1,1-dimethyl-2-foradil)phenyl
2757benzil3-methoxyphenyl

2758benzil3-ethoxyphenyl
2759benzil3-propoxyphenyl
2760benzil3-isopropoxyphenyl
2761benzil3-butoxyphenyl
2762benzil3-(formatosi)phenyl
2763benzil3-(deformedarse)phenyl
2764 benzil3-(triptoreline)phenyl
2765benzil3-(2-floratone)phenyl
2766benzil3-(2,2-diflorasone)phenyl
2767benzil3-(2,2,2-triptoreline)phenyl
2768benzil3-(1,1,2,2-tetrafluoroethoxy)phenyl
2769benzil3-cyclopropylethanol
2770benzil3-cyclobutylmethyl
2771benzil3-cyclopentylphenol
2772benzil3-(2,2-diversicolor)phenyl
2773benzil3,4-differenl
2774benzil3-bromo-2-forfinal
2775benzil 2-bromo-3-forfinal
2776benzil3-bromo-2,5-differenl
2777benzil5-bromo-2,4-differenl
2778benzil3-bromo-2,4-differenl
2779benzil4-chloro-3-(trifluoromethyl)phenyl
2780benzil2-chloro-5-(trifluoromethyl)phenyl
2781benzil2-fluoro-5-(trifluoromethyl)phenyl
2782benzil4-fluoro-3-(trifluoromethyl)phenyl
2783benzil3-fluoro-5-(trifluoromethyl)phenyl
2784benzil4-bromo-3-(trifluoromethyl)phenyl
2785benzil3-bromo-5-(trifluoromethyl)phenyl
2786benzil 2-bromo-5-(trifluoromethyl)phenyl
2787benzil5-bromo-2-methoxyphenyl

2788benzil3-bromo-4-methoxyphenyl
2789benzil2-fluoro-3-isopropylphenyl
2790benzil4-fluoro-3-isopropylphenyl
2791benzil3-(1-hydroxy-1-methylethyl)phenyl
2792benzil3-(2-hydroxy-2-methylpropyl " phenyl
2793benzil3-acetylphenyl
2794benzil3-acetylaminophenol
2795benzil3-carboxyphenyl
2796benzil3-cyanophenyl
2797 3-nitrophenyl
2798benzil3-hydroxyphenyl
2799benzil3-(O-benzyl)phenyl
2800benzil3-(2-methoxyethoxy)phenyl
2801benzil3-(CH2-N(CH3)2)phenyl
2802benzil3-(NH-CO-NH2)phenyl
2803benzil3-(methylsulfanyl)phenyl
2804benzil3-(pharmacysulfacet)phenyl
2805benzil3-(deformational)phenyl
2806benzil3-(trifloromethyl)phenyl
2807benzil3-(methylsulphonyl)phenyl
2808Ben is Il 3-(N-methoxy-N-methylamino)phenyl
2809benzil3-(methoxyamino)phenyl
2810benzil3-(ethoxyline)phenyl
2811benzil3-(N-methylenedioxy)phenyl
2812benzil3-(N,N-dimethylaminoethoxy)phenyl
2813benzil3-(azetidin-1-yl)phenyl
2814benzil3-(2-methylaziridine-1-yl)phenyl
2815benzil3-((S)-2-methylaziridine-1-yl)phenyl
2816benzil3-((R)-2-methylaziridine-1-yl)phenyl
2817benzil3-(3-torasemide-1-yl)phenyl

2840
2818benzil3-(2,2-deforested the n-1-yl)phenyl
2819benzil3-(3-methoxyisatin-1-yl)phenyl
2820benzil3-(3-hydroxyazetidine-1-yl)phenyl
2821benzil3-(pyrrolidin-1-yl)phenyl
2822benzil3-(pyrrolidin-2-yl)phenyl
2823benzil3-((S)-pyrrolidin-2-yl)phenyl
2824benzil3-((R)-pyrrolidin-2-yl)phenyl
2825benzil3-(pyrrolidin-3-yl)phenyl
2826benzil3-((S)-pyrrolidin-3-yl)phenyl
2827benzil3-((R)-pyrrolidin-3-yl)phenyl
2828benzil3-(pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl
2829benzil 5-(pyrrolidin-1-yl)-2-methoxyphenyl
2830benzil3-(pyrrolidin-1-yl)-4-methoxyphenyl
2831benzil5-(pyrrolidin-1-yl)-2,4-differenl
2832benzil3-(pyrrolidin-1-yl)-2,4-differenl
2833benzil3-(2-ftorpirimidinu-1-yl)phenyl
2834benzil3-((S)-2-ftorpirimidinu-1-yl)phenyl
2835benzil3-((R)-2-ftorpirimidinu-1-yl)phenyl
2836benzil3-(3-ftorpirimidinu-1-yl)phenyl
2837benzil3-((S)-3-ftorpirimidinu-1-yl)phenyl
2838benzil3-((R)-3-ftorpirimidinu-1-yl)phenyl
2839benzil3-(2,2-debtorprovidian-1-yl)phenyl
benzil3-(3,3-debtorprovidian-1-yl)phenyl
2841benzil3-(2-methylpyrrolidine-1-yl)phenyl
2842benzil3-((S)-2-methylpyrrolidine-1-yl)phenyl
2843benzil3-((R)-2-methylpyrrolidine-1-yl)phenyl
2844benzil3-(3-methylpyrrolidine-1-yl)phenyl
2845benzil3-((S)-3-methylpyrrolidine-1-yl)phenyl
2846benzil3-((R)-3-methylpyrrolidine-1-yl)phenyl
2847benzil3-(1-methylpyrrolidine-2-yl)phenyl

2848benzil3-((S)-1-methylpyrrolidine-2-yl)phenyl
2849benzil3-((R)-1-methylpyrrolidine-2-yl)phenyl
2850benzil3-(1-methylpyrrolidine-3-yl)phenyl
2851benzil3-((S)-1-methylpyrrolidine-3-yl)phenyl
2852benzil3-((R)-1-methylpyrrolidine-3-yl)phenyl
2853benzil3-(2,2-dimethylpiperidin-1-yl)phenyl
2854benzil3-(3,3-dimethylpiperidin-1-yl)phenyl
2855benzil3-(2-triftormetilfullerenov-1-yl)phenyl
2856benzil3-((S)-2-triftormetilfullerenov-1-yl)phenyl
2857benzil3-((R)-2-triftormetilfullerenov-1-yl)phenyl
2858benzil3-(3-triftormetilfullerenov-1-yl)phenyl
2859benzil3-((S)-3-triftormetilfullerenov-1-yl)phenyl
benzil3-((R)-3-triftormetilfullerenov-1-yl)phenyl
2861benzil3-(2-oxopyrrolidin-1-yl)phenyl
2862benzil3-(2-oxo-oxazolidin-3-yl)phenyl
2863benzil3-(piperidine-1-yl)phenyl
2864benzil3-(2-methylpiperidin-1-yl)phenyl
2865benzil3-((S)-2-methylpiperidin-1-yl)phenyl
2866benzil3-((R)-2-methylpiperidin-1-yl)phenyl
2867benzil3-(2-foreperiod-1-yl)phenyl
2868benzil3-((S)-2-foreperiod-1-yl)phenyl
2869benzil3-((R)-2-foreperiod-1-yl)phenyl
2870benzil 3-(2,2-deformability-1-yl)phenyl
2871benzil3-(piperazine-1-yl)phenyl
2872benzil3-(4-methylpiperazin-1-yl)phenyl
2873benzil3-(morpholine-4-yl)phenyl
2874benzil3-(morpholine-4-yl)-5-(trifluoromethyl)phenyl
2875benzil5-(morpholine-4-yl)-2-methoxyphenyl
2876benzil3-(morpholine-4-yl)-4-methoxyphenyl
2877benzil5-(morpholine-4-yl)-2,4-differenl

2878benzil3-(morpholine-4-yl)-2,4-differenl
2879benzil3-(thiomorpholine-4-yl)phenyl
2880benzil3-(1-oxathiolane the Jn-4-yl)phenyl
2881benzil3-(1,1-diocletianopolis-4-yl)phenyl
2882benzil3-(pyrrol-1-yl)phenyl
2883benzil3-(pyrrol-2-yl)phenyl
2884benzil3-(pyrrol-3-yl)phenyl
2885benzil3-(1-methylpyrrole-2-yl)phenyl
2886benzil3-(1-methylpyrrole-3-yl)phenyl
2887benzil3-(furan-2-yl)phenyl
2888benzil3-(furan-3-yl)phenyl
2889benzil3-(thiophene-2-yl)phenyl
2890benzil3-(thiophene-3-yl)phenyl
2891benzil3-(5-properties-2-yl)phenyl
2892benzil3-(pyrazole-1-yl)phenyl
2893benzil3-(pyrazole-3-yl)phenyl
2894benzil3-(pyrazole-4-yl)phenyl
2895benzil3-(4-perperson-1-yl)phenyl
2896benzil3-(1-methyl-1H-pyrazole-4-yl)phenyl
2897benzil3-(1-ethyl-1H-pyrazole-4-yl)phenyl
2898benzil3-(1-methyl-1H-pyrazole-5-yl)phenyl
2899benzil3-(1H-imidazol-2-yl)phenyl
2900benzil3-(imidazol-1-yl)phenyl
2901benzil3-(1-Mei-2-yl)phenyl
2902benzil3-(oxazol-2-yl)phenyl
2903benzil3-(oxazol-4-yl)phenyl
2904benzil3-(oxazol-5-yl)phenyl
2905benzil3-(isoxazol-3-yl)phenyl
2906benzil3-(isoxazol-4-yl)phenyl
2907benzil3-(isoxazol-5-yl)phenyl

2908benzil3-(thiazol-2-yl)phenyl
2909benzil3-(thiazol-4-yl)phenyl
2910benzil3-(thiazol-5-yl)phenyl
2911benzil3-(2-methylthiazole-4-yl)phenyl
2912benzil3-(2-methylthiazole-5-yl)phenyl
2913benzil3-([1,2,3]-triazole-1-yl)phenyl
2914benzil3-([1,2,4]-triazole-1-yl)phenyl
2915benzil3-([1,2,3]-triazole-2-yl)phenyl
2916benzil3-(4H-[1,2,4]-triazole-3-yl)phenyl
2917benzil3-([1,2,4]-triazole-4-yl)phenyl
2918benzil3-(2H-[1,2,3]-triazole-4-yl)phenyl
2919benzil3-(4-methyl-4H-[1,2,4]-triazole-3-yl)phenyl
2920benzil3-(2-methyl-2H-[1,2,3]-triazole-4-yl)phenyl
2921benzil3-([1,3,4]-oxadiazol-2-yl)phenyl
2922benzil3-(5-methyl-[1,3,4]-oxadiazol-2-yl)phenyl
2923benzil3-([1,2,4]-oxadiazol-3-yl)phenyl
2924benzil 3-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl
2925benzil3-([1,2,4]-oxadiazol-5-yl)phenyl
2926benzil3-([1,2,3]-oxadiazol-4-yl)phenyl
2927benzil3-([1,2,3]-oxadiazol-5-yl)phenyl
2928benzil3-([1,2,3]-thiadiazole-4-yl)phenyl
2929benzil3-(1H-tetrazol-5-yl)phenyl
2930benzil3-(tetrazol-1-yl)phenyl
2931benzil3-(2-methyl-2H-tetrazol-5-yl)phenyl
2932benzil3-(1-methyl-1H-tetrazol-5-yl)phenyl
2933benzil3-furazan-3-ylphenyl
2934benzil3-(pyrid-2-yl)phenyl
2935benzyl/td> 3-(pyrid-3-yl)phenyl
2936benzil3-(pyrid-4-yl)phenyl
2937benzil3-(pyrimidine-2-yl)phenyl

benzil
2938benzil3-(2-methylpyrimidin-4-yl)phenyl
2939benzil3-(pyrimidine-4-yl)phenyl
2940benzil3-(pyrimidine-5-yl)phenyl
2941benzil5-bromopyridin-3-yl
2942benzil3-bromo-2-chloropyridin-5-yl
2943benzil4-methylpyridin-2-yl
2944benzil6-methylpyridin-2-yl
2945benzil4-(trifluoromethyl)pyridin-2-yl
29466-(trifluoromethyl)pyridin-2-yl
2947benzil5-(trifluoromethyl)pyridin-3-yl
2948benzil5-(pyrrolidin-1-yl)pyridine-3-yl
2949benzil3-(pyrrolidin-1-yl)-2-chloropyridin-5-yl
2950benzil3-(morpholine-4-yl)-2-chloropyridin-5-yl
2951benzil2-(morpholine-4-yl)pyridin-5-yl
2952benzil2-phenoxypyridine-5-yl
2953benzil2,3-dichlorophenyl
2954benzil2,5-dichlorophenyl
2955benzil3,5-dichlorophenyl
2956benzil3-chloro-4-forfinal
2957 benzil4-bromo-2,5-dichlorophenyl
2958benzil3-bromo-4-(triptoreline)phenyl
2959benzil3,5-dibromo-4-(2-floratone)phenyl
2960benzil2,5-dimetilfenil
2961benzil2,5-di-(trifluoromethyl)phenyl
2962benzil3,5-di-(trifluoromethyl)phenyl
2963benzil2,5-acid
2964benzil2-methoxy-5-were
2965benzil2-methoxy-5-(trifluoromethyl)phenyl
2966benzil4-fluoro-3-(oxazol-4-yl)phenyl
2967benzilTien-2-yl

2968benzilTien-3-yl
2969benzil3-chlortan-2-yl
2970benzil4-chlortan-2-yl
2971benzil5-chlortan-2-yl
2972benzil3-Bratan-2-yl
2973benzil4-Bratan-2-yl
2974benzil5-Bratan-2-yl
2975benzil4,5-dichlorotin-2-yl
2976benzil4,5-libration-2-yl
2977benzil4-bromo-5-chlortan-2-yl
2978benzil3-bromo-5-chlortan-2-yl
2979benzil5-methyltin-2-yl
2980benzil5-utilties-2-yl
2981benzil5-properties-2-yl
2982benzil5-triptorelin-2-yl
2983benzil5-penalties-2-yl
2984benzil5-(pyrid-2-yl)Tien-2-yl
2985benzil5-(phenylsulfonyl)Tien-2-yl
2986benzil4-(phenylsulfonyl)Tien-2-yl
2987benzil5-(pyrid-2-ylsulphonyl)Tien-2-yl
2988benzil5-(3-chloro-5-triptorelin-2-ylsulphonyl)Tien-2-yl
2989benzil5-(benzoylamino)Tien-2-yl
2990benzil5-((4-chlorbenzoyl)is aminomethyl)Tien-2-yl
2991benzil5-(acetamidomethyl)Tien-2-yl
2992benzil5-(pyrazole-1-yl)Tien-2-yl
2993benzil5-(pyrazole-3-yl)Tien-2-yl
2994benzil5-(pyrazole-4-yl)Tien-2-yl
2995benzil5-(pyrazole-5-yl)Tien-2-yl
2996benzil5-(4-perperson-1-yl)Tien-2-yl
2997benzil5-(1-methyl-5-trifluoromethyl-(1H)-pyrazole-3-yl)Tien-2-yl

2998benzil5-(1-methyl-3-trifluoromethyl-(1H)-pyrazole-5-yl)Tien-2-yl
2999benzil5-(4-carboxy-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
3000benzil5-(4-amine is methyl-1-methyl-5-methylthio-(1H)-pyrazole-3-yl)Tien-2-yl
3001benzil5-(isoxazol-3-yl)Tien-2-yl
3002benzil5-(isoxazol-4-yl)Tien-2-yl
3003benzil5-(isoxazol-5-yl)Tien-2-yl
3004benzil5-(5-cryptometrics-3-yl)Tien-2-yl
3005benzil5-(oxazol-2-yl)Tien-2-yl
3006benzil5-(oxazol-4-yl)Tien-2-yl
3007benzil5-(oxazol-5-yl)Tien-2-yl
3008benzil5-(2-methoxazole-4-yl)Tien-2-yl
3009benzil5-(2-methoxazole-5-yl)Tien-2-yl
3010benzil5-(isothiazol-3-yl)Tien-2-yl
3011benzil 5-(isothiazol-4-yl)Tien-2-yl
3012benzil5-(isothiazol-5-yl)Tien-2-yl
3013benzil5-(5-triftoratsetata-3-yl)Tien-2-yl
3014benzil5-(thiazol-2-yl)Tien-2-yl
3015benzil5-(thiazol-4-yl)Tien-2-yl
3016benzil5-(thiazol-5-yl)Tien-2-yl
3017benzil5-(2-methylthiazole-4-yl)Tien-2-yl
3018benzil5-(2-methylthiazole-5-yl)Tien-2-yl
3019benzil5-([1,2,3]-oxadiazol-4-yl)Tien-2-yl
3020benzil5-([1,2,3]-thiadiazole-4-yl)Tien-2-yl
3021benzil5-(pyrimidine-2-yl)Tien-2-yl
3022 benzil5-(pyrimidine-4-yl)Tien-2-yl
3023benzil5-(pyrimidine-5-yl)Tien-2-yl
3024benzil5-(2-methylthiopyrimidin-4-yl)Tien-2-yl
3025benzil5-([1,3]-dioxolane-2-yl)Tien-2-yl
3026benzil3-([1,3]-dioxolane-2-yl)Tien-2-Illian-2-yl
3027benzil5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)Tien-2-yl

3028benzil5-[3-chloro-5-(trifluoromethyl)pyrid-2-ylsulphonyl]Tien-2-yl
3029benzil2-chlortan-3-yl
3030benzil4-chlortan-3-yl
3031benzil5-chlortan-3-yl
3032benzyl/td> 2-Bratan-3-yl
3033benzil4-Bratan-3-yl
3034benzil5-Bratan-3-yl
3035benzil2,5-dichlorotin-3-yl
3036benzil2,5-libration-3-yl
3037benzil2,4,5-tripartie-3-yl
3038benzil4-bromo-2,5-dichlorotin-3-yl
3039benzil2-chloro-5-methylsulfonate-3-yl
3040benzil2,5-dietitian-3-yl
3041benzil4-hydroxicut-3-yl
3042benzil2-venitien-3-yl
3043benzil4-phenyl-5-(trifluoromethyl)t is n-3-yl
3044benzil2-methoxycarbonyl-4-phenyl-5-(trifluoromethyl)Tien-3-yl
3045benzilbenzo[b]thiophene-2-yl
3046benzilbenzo[b]thiophene-3-yl
3047benzil3 methylbenzo[b]thiophene-2-yl
3048benzil5-methylbenzo[b]thiophene-2-yl
3049benzil5-fluoro-3-methylbenzo[b]thiophene-2-yl
3050benzil5-chloro-3-methylbenzo[b]thiophene-2-yl
3051benzil5-bromo-3-methylbenzo[b]thiophene-2-yl

The compounds of formula I of the present invention can be synthesized as described in synthetic routes A, B and C, below.

Scheme 1

In figure 1 A, Ar, G, n, R2and R4defined above. R' represents a or R1 1.

Path A

In the case of synthesis through the path a, aminosidine (II-1) interacts with a suitable derivative of sulfonic acid, which gives the sulfonamide (I-1) (E=NH). A suitable derivative of the sulfonic acid is, for example, sulphonylchloride Ar-SO2Cl. The sulfating reaction is preferably carried out in the presence of a base in accordance with standard techniques. In the reaction represented by the above scheme 1, the sulfonation is conducted under reaction conditions which are usual for receiving arylsulfonamides compounds or arylsulfonate esters, respectively, and which are described, for example, in J. March, Advanced Organic Chemistry, 3rdedition, John Wiley & Sons, New York, 1985, page 444ff in the prior art described there, European J. Org. Chem. 2002 (13), pp.2094-2108, Tetrahedron 2001, 57 (27), pp.5885-5895, Bioorganic and Medicinal Chemistry Letters, 2000, 10(8), pp.835-838 and Synthesis 2000 (1), pp.103-108. The reaction is usually carried out in an inert solvent, e.g. an ether, such as diethyl ether, diisopropyl ether, methyltert-butyl ether or tetrahydrofuran, hydrocarbons, such as dichloromethane, aliphatic or cycloaliphatic hydrocarbon, such as pentane, hexane or cyclohexane, or an aromatic hydrocarbon, such as toluene, xylene, cumene and the like, or mixtures of the aforementioned solvents. The reaction with Cl-SO2-Ar usually avodat in the presence of an auxiliary base. Suitable bases are inorganic bases such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate, and organic bases, such as trialkylamine, such as triethylamine, or pyridine compounds such as pyridine, lutidine and the like. The latter compound can at the same time to serve as solvents. The auxiliary base is usually used in at least equimolar quantities, based on the amine compound (II-1).

To the reaction sulfating the radical NH2can be turned into NR5'the group in which R5'matter other than hydrogen, which are specific to R5(not shown on diagram 1).

If the resulting sulfonamide (I'-1) R' does not represent the desired radical R1but its predecessor, the connection may be modified as described below to obtain the desired substituent R1. The predecessor is a radical, which can be easily removed and replaced by the desired group R1or which can be modified in a way that gives R1. The precursor may also be an N-protecting group.

If R' represents an allyl, allyl group can be split to get the connection, where R' represents hydrogen. Split the e allyl group is achieved, for example, by reacting the compound (I'-1) [R'=allyl] allisonallison agent such as mercaptobenzoic acid or 1,3-dimethylbarbituric acid, in the presence of catalytic amounts of palladium(0) compounds or palladium compounds, which are able to form a palladium(0) compound under reaction conditions, such as palladium dichloride, tetrakis(triphenylphosphine)palladium(0) or Tris(dibenzylideneacetone)diplegia(0), mostly in combination with phosphine ligands, such as triarylphosphine, such as triphenylphosphine, trialkylphosphines, such as tributylphosphine, and cycloalkylation such as tricyclohexylphosphine, and, in particular, with postingyektini ligands, such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 1,4-bis(diphenylphosphino)butane, using methods known from the prior art (in relation to the removal of N-allyl in the presence of mercaptobenzoic acid, see WO 94/24088; for removal in the presence of 1,3-dimethylbarbituric acid, see J. Am. Chem. Soc. 2001, 123 (28), pp.6801-6808 and J. Org. Chem. 2002, 67(11), pp.3718-3723). Alternatively, cleavage of the N-allyl can also be effective when interacting in the presence of rhodium compounds, such as Tris(triphenylphosphine)chloride(I)using methods known from the prior art (see J. Chem. Soc., Perkin Transaction I: Organic and Bio-Organic Chemistry 1999 (21), pp.3089-3104 and Terahedron Asymmetry 1997, 8(20), pp.3387-3391).

If R' is a benzyl, the Deputy may also be derived to obtain the compound (I'-1), where R' represents H. The reaction conditions for the cleavage known to the average expert. As a rule, the benzyl group is removed by means of the hydrogenation reaction in the presence of a suitable Pd catalyst such as Pd on coal or palladium hydroxide.

R' may also be a protecting group. The protective group can be removed to get at the output connection (I'-1), where R' represents H. Suitable protective groups are well known to the average expert and, for example, selected fromtert-butoxycarbonyl (boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Trt) and nitrobenzenesulfenyl (Nps). The preferred protecting group is boc. The protective group can be removed by known methods, such as processing protected amine acid, for example halogen acid, such as HCl or HBr, or triperoxonane acid or by hydrogenation, optionally in the presence of a Pd catalyst.

The compound obtained, where R' represents H, can then interact in a known manner, in the sense of alkylation, with a compound R1-X. In the specified connection R1represents a C1-C4-alkyl, C3-C6-recloak is l, C1-C4-halogenated, C1-C4-alkoxy-C1-C4-alkyl or C3-C6-cycloalkyl-C1-C4-alkyl and X represents nucleophile substitutable leaving group, for example halogen, trifenatate, alkylsulfonate, arylsulfonate, alkylsulfate and the like. Reaction conditions that are required for alkylation, sufficiently disclosed, for example, Bioorganic and Medicinal Chemistry Lett. 2002, 12(7), pp.2443-2446 and also 2002, 12(5), pp.1917-1919.

The alkylation can also be achieved, in the sense of a reductive amination, by reacting the compound (I'-1), where R'=H, with a suitable ketone or aldehyde in the presence of a recovery agent, for example in the presence of a borohydride such as sodium borohydride, cyanoborohydride sodium or triacetoxyborohydride sodium. Average person is familiar with the reaction conditions that are required for reductive amination, for example, Bioorganic and Medicinal Chemistry Lett. 2002, 12(5), pp.795-798 and 12(7), pp.1269-1273.

If R' represents hydrogen, the resulting sulfonamide (I'-1) may further interact with acylchlorides, to obtain the compound of formula I, where R1represents a C1-C3-alkylsulphonyl. Carbonyl group in these compounds can be recovered by DIBORANE to the teaching of the compounds of General formula I, where R1represents a C2-C4-alkyl. The carbonyl group may also be subjected to interaction with a fluorinating agent to obtain a compound of formula I, where R1represents a 1,1-diferuloyl. The acylation and recovery can be carried out in conventional ways, which are discussed in Jerry March, Advanced Organic Chemistry, 3rd ed. J. Wiley & Sons, New York, 1985, p.370 and 373 (acylation) and p.1099 f. and in the above prior art in the specified publication (in respect of acylation, see also Synth. Commun. 1986, 16, p.267, and recovery, see also J. Heterocycl. Chem. 1979, 16, p.1525).

Path B

In the case of synthesis through the path B poslednee the compound (II-2) interacts with the appropriate sulfonamide ArSO2Other5that gives the sulfonamide (I'-1). The reaction is generally carried out under conditions of activation, for example under microwave irradiation. Pd, in particular Pd(0) or Cu catalysts may also be used for binding (see, for example, Org. Lett. 2000, 2, 1101; J. Am. Chem. Soc. 2002, 124, 6043; Org. Lett. 2003, 5, 4373; Tetrahedron Lett. 2003, 44, 3385). Examples of suitable Pd(0) catalysts are tetrakis(triphenylphosphine)palladium(0) and Pd2(dba)3(Tris(dibenzylideneacetone)diplegia(0)), which is usually used in the presence of three(substituted)phosphine, such as triarylphosphine, such as triphenylphosphine, tricalifornia or Xanthos, three(cyclo)and is calphostin, such as Tris-n-butylphosphine, Tris(tert-butyl)phosphine or Tris(cyclohexylmethyl). This approach is particularly useful in cases when the corresponding sulphonylchloride not suitable.

Alternatively, bromide Deputy may be replaced by aminosubstituted, for example, by interacting with benzophenone or with bis(trimethylsilyl)amidon lithium in the presence of compounds of palladium(0), such as Tris(dibenzylideneacetone)dipalladium(0) in the presence of three(substituted)phosphine, such as triarylphosphine, such as triphenylphosphine or trailerforum, three(cyclo)alkylphosphine, such as Tris-n-butylphosphine, Tris(tert-butyl)phosphine or Tris(cyclohexyloxy), preferably in the presence of a base such as sodium hydride, in accordance with a method described in, for example, J. Org. Chem., 68 (2993), pp.8274-8276 or J. Org. Chem. 2000, 65, 2612. The resulting aminosilane can then be subjected to reaction sulfating through path A.

C

In the case of a synthesis through C the compound (II-3) interacts with mercaptoethane HS-Ar in the presence of a base such as sodium hydride or sodium alkoxide or alkali metal salt, thereby obtaining the output thioester compound. Thioester residue is then oxidized to sulfonic residue, for example, oxonol to polocaine output sulfon (I'-2).

Deputy Ar may vary or through the use of different sulphonylchloride, or by modification of the substituents of group Ar after the formation of the sulfonamida (I'-1) or sulfone (I'-2) by known methods. For example, bromine Deputy Ar group may be replaced by N-linked pyrrolidinyl group in accordance with the method described in Tetrahedron Asym. 1999, 10, 1831. The specified Pd-mediated coupling in General, applicable to all containing nitrogen heterocycles, such as azetidine, pyrazolidine, imidazolidine, piperidine, piperazinil, morpholinyl and the like. The reaction is also applicable to heterocyclic compounds containing one or more substituents, such as halogen, alkyl or fluorinated alkyl. Bromine Deputy Ar groups may also be replaced Isopropenyl group in accordance with the method of condensation on Still (Stille), where the bromine compound interacts with alkenylsilanes in the presence of a suitable Pd catalyst linking, for example, tetranitroaniline palladium(0) (see, for example, Tetrahedron, 2003, 59(34), 6545 and Bioorg. Med. Chem. 1999, 7(5), 665). Isopropylene group can then be converted into ISO-propyl group using known methods of hydrogenation.

The compounds of formula (II) (II-1, II-2 and II-3) can be synthesized as shown below.

1. The synthesis of the compounds is the second of the formulas (II-1)

Scheme 2

In scheme 2, A, G, n and R' are defined above.

The transformation of the acid (III) in its methyl ether (IV) is performed using conventional methods, for example, as described in Jerry March, Advanced Organic Chemistry, John Wiley, 3rdedition, page 348ff. For example, the acid is transformed into the corresponding acid chloride, for example, through its interaction with SOCl2. The acid chloride is then converted into ester via reaction with methanol.

Recovery stage (ii), respectively, is carried out in the usual conditions for the conversion of esters of carboxylic acids to alcohols. Suitable reaction conditions and the recovery agents are described, for example, in Jerry March, Advanced Organic Chemistry, John Wiley, 3rdedition, page 1093ff. Typical recovery agents are metal hydrides and hydride complexes. Examples of suitable metal hydrides include BH3, 9-BBN, AlH3and AlH(i-Bu)2(DIBAL-H), respectively, in the presence of complexing solvents such as tetrahydrofuran and diethyl ether. Hydride complexes are, for example, NaBH4, LiAlH4and LiAlH(OR)3where R represents a C1-C4-alkyl, such as methyl, ethyl, isobutyl ortert-butyl. The preferred recovery agent is LiAlH4. Restoring respectively carried out in complex solvents, such as simple EPE is s open-chain and cyclic ethers, for example, tetrahydrofuran, diethyl ether, DIPROPYLENE ether, diisopropyl ether, disutility ether and methylbutanoyl ether. The preferred solvent is tetrahydrofuran.

Under metilirovaniya (iii) an alcohol functionality make a better leaving group. Metilirovanie perform under normal conditions, for example, by reacting the alcohol with methanesulfonamide in the presence of a base. Suitable bases are, among others, bonds alkylamines, such as diethylamine, triethylamine and ethyldiethanolamine. At this stage other functionality, which represents a suitable leaving group, such as triptorelin, other alkyl sulphonates, arylsulfonate, for example tozilaty, alkyl sulphonates and such toilet, can be entered instead of methanesulfonyl group.

On the cyclization stage (iv), the compound (VI) or its derivative suitable interacts with the primary amine NH2R'. If the primary amine is a liquid, it can also be used as the solvent, making it unnecessary additional solvent. If Amin is viscous or solid, the reaction is mostly carried out in a suitable solvent.

The reaction in stage (v) is carried out under reaction conditions which are customary for reactions nitrovan is on the aromatic radical and described, for example, in Jerry March, Advanced Organic Chemistry, John Wiley, 3rdedition, page 468ff, Tetrahedron 1999, 55(33), pp.10243-10252, J. Med. Chem. 1997, 40(22), pp.3679-3686 and Synthetic Communications, 1993, 23(5), pp.591-599. For example, compound (VII) reacts with concentrated nitric acid or nitrate such as potassium nitrate or sodium, in the presence of concentrated sulfuric acid. The resulting product (VIII) may be in the form of different regioisomers (e.g., ortho, meta, or para), if a is a phenyl or a six-membered heteroaryl. In the case when A is a phenyl or a six-membered heteroaryl, para-nitrosoaniline generally prevails. However, a number of ortho-product can also be obtained, whereas the meta-product is not formed at all or only in negligible quantities. By separation of ortho - and para-products, the compounds of formula I, where a is a 1,4-linked phenyl, are available through the reaction path shown in scheme 2.

On stage (vi), the nitro-group in the compound of formula (VIII) to restore NH2group. Subsequently, NH2the group may be converted into-NR5'the group in which R5'matter other than hydrogen as defined for R5. Reaction conditions that are mandatory for the stage (vi)conform to the normal conditions for the recovery of aromatic nitrogroup is, which are widely described in the prior art (see, for example, J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons, New York, 1985, p.1183 and given the level of technology in the link). Recovery is achieved, for example, by reacting nitro compounds VII with metal, such as iron, zinc or tin in acidic reaction conditions, i.e. using the resulting hydrogen or using hydride complex such as lithium aluminum hydride or sodium borohydride, preferably in the presence of transition metal compounds of Nickel or cobalt, such as NiCl2(P(phenyl)3)2or CoCl2(see Ono et al. Chem. Ind. (London), 1983 p.480) or using NaBH2S3(see Lalancette et al. Can. J. Chem. 49, 1971, p.2990), with the existing ability to implement these restorations, depending on the given reagent, in substance or in a solvent or diluent. Alternatively, recovery may be carried out in the presence of hydrogen in the presence of a transition metal catalyst, for example, using hydrogen in the presence of catalysts based on platinum, palladium, Nickel, ruthenium or rhodium. The catalysts may contain a transition metal in atomic form or in the form of a complex compound of a salt or oxide of the transition metal with the possibility of modifying the activity to use the normal sahandy, for example organic fofi the new connection, such as triphenylphosphine, tricyclohexylphosphine or tri-n-butylphosphine or phosphites. The catalyst is usually used in amounts of 0.001 to 1 mol per mol of nitro compounds in the calculation of the metal in the catalyst. In a preferred embodiment, the recovery is effective when using tin chloride(II) by analogy with the methods described in Bioorganic and Medicinal Chemistry Letters, 2002, 12(15), pp.1917-1919 and J. Med. Chem. 2002, 45(21), pp.4679-4688. The reaction of the compound of formula VII with tin chloride(II) is preferably carried out in an inert organic solvent, preferably alcohol, such as methanol, ethanol, isopropanol or butanol.

For compounds where n is 1 and a is a phenylene (i.e. formula (I) represents N-(pyrrolidin-3-yl)phenylsulfonyl), the original compound (III) is, for example, commercially available (S) or (R) phenylethanol acid or its racemic mixture. On the basis of enantiomerically pure (S)- or (R)-compound (III) can be obtained pure (S)- or (R):

a) (S) isomer

At stage (i), commercially available (S)-phenylethanol acid (II-S) is transformed into methyl ester (III); restore it to the alcohol (IV), which interacts with methylsulfonylamino. Cyclization with a primary amine gives phenylpyrrolidine (VI). Phenyl group first nitrous, then the nitrogroup reset nalivajut to amino groups, which interacts with sulphonylchloride that gives the desired sulfanilamide (I'-S).

b) (R)-isomer

(R)-isomer can be obtained in a similar way on the basis of commercially available (R)-phenylethanol acid (III-R):

c) Isomeric mixture

Isomeric mixture of compounds of formulas I'-S I'-R can be obtained from the racemic compounds of formula III or a mixture of compounds of formula III-S and III-R.

Average expert it is clear that the synthesis described in scheme 2, is also suitable for producing compounds of the formula (II) and, therefore, for compounds of formula (I), where R2, R3and R4other than H, for example starting from an appropriately substituted compounds of formula (III). A similar approach to the synthesis of enantiomerically pure compounds of formula (I), which can be synthesized from the corresponding enantiomer (III).

2. The synthesis of compounds of the formula (II-2)

The compounds of formula (II-2) can be synthesized by performing on stage (v) of scheme 2 reaction of halogenation instead of nitration. Reactions halogenation of aryl and heteroaryl groups are widely known standard methods, for example, discussed in Jerry March, Advanced Organic Chemistry, John Wiley, 3rdedition page 476 ff.

3. The synthesis of compounds of the formula (II-3)

The synthesis of these compounds also is consistent with the standard reactionary ways and can be performed by monohalogenated methyl group methylsiloxanes aryl or heteroaryl compounds.

4. Synthesis of enantiomerically pure compounds of formula I

In addition to the method described in claim 1, enantiomerically pure compounds of formula (I) can also be obtained by applying standard methods of the division to the appropriate precursors. For example, the compound of formula VIII (see scheme 2 above) or the compounds of formula (II-2) or (II-3) (see scheme 1 above), where R' represents a suitable protective group such as benzyl, can interact with tartaric acid or its derivative (for example, diethyltartrate, dipropylamino, diisopropylamino etc), which gives two diastereomeric salt. They can be separated in the usual way, for example by extraction or chromatographic means or preferably by fractional crystallization. Thus, separated diastereomer salt is then converted into enantiomerically pure compounds of formula VIII, II-2 or II-3 by the interaction of salt with a suitable base, which gives the S - or R-enantiomeric compounds of formulas VIII, II-2 or II-3. Suitable bases are, for example, hydroxides of alkali metals such as potassium hydroxide and sodium hydroxide, hydroxides of alkaline earth metals, such as magnesium hydroxide and calcium hydroxide, carbonates of alkali metals such as sodium carbonate and potassium carbonate, alkaline earth carbonates m is the metal, such as magnesium carbonate and calcium carbonate, oxides of alkali metals such as sodium oxide and potassium oxide and oxides of alkaline earth metals, such as magnesium oxide and calcium oxide; organic bases, such as alcoholate such as sodium methylate, sodium ethylate ortert-butyl sodium, amines, such as dimethylamine, trimethylamine, diethylamine, triethylamine, dipropylamine, Tripropylamine, Diisopropylamine, diisopropylethylamine and the like, and nitrogen-containing basic heterocyclic compounds such as pyridine, picoline and lutidine.

5. Specific syntheses

5.1. The synthesis of compounds where n has a value of 1 (pyrrolidinylcarbonyl derivatives)

5.1.1

Scheme 3

In figure 3, A and R3defined above.

Pyrolidine ring is also available by using the [3+2] bipolar cycloaddition unstable the azomethine ylides to 1-alkynylaryl or heteroaryl derivative (IX) (for example, vinylbenzyl, R3=H). This technique is generally described in J. Org. Chem. 1987, 52, 235. Predecessor ilide, Amin N(CH2Rb)(CH2SiMe3)(CH2OCH3) (X), is commercially available or can be synthesized from the NH2(CH2Rb), Me3SiCH2Cl and HCHO in the presence of methanol.

1 Alkenyl-(hetero)aromatic compound(IX) can be synthesized, for example, by condensation on Style of halogenase, for example, bromine benzol with the corresponding alkenylsilanes, such as vinyl or isobutyltrimethoxysilane, in the presence of a suitable Pd catalyst condensation, such as tetranitroaniline palladium(0) (see, for example, Tetrahedron, 2003, 59(34), 6545 and Bioorg. Med. Chem. 1999, 7(5), 665). Choosing a special isomer upon Stille (e.g., CIS - or TRANS-isobutyltrimethoxysilane), the corresponding CIS - or TRANS-alkylpiperidines can be obtained selectively.

Alternative 1 alkenyl-(hetero)aromatic compound (IX) can be synthesized via the reaction Wittig (Wittig) arilaldegidov with the Wittig reagent, such as PPh3=CHR (R represents N or C1-C3-alkyl). Conditions for the Wittig reaction are well known to the average expert and, for example, discussed in Jerry March, Advanced Organic Chemistry, John Wiley, 3rdedition, page 845 ff.

Mainly 1-(hetero)alkanolamine compound (IX), in addition, contains a nitro-group or other halogen substituent (X=NO2or halogen). In this case, the subsequent reaction stage can be carried out, as described, via path A or B. If X=H, ring A may be first subjected to nitration as described in scheme 2, step (v), and then subjected to reaction scheme 2, step (vi), according to scheme 1, path A; or ring A mo is et to be galogenirovannami and then subjected to the techniques of path B.

The group CH2Rbpredecessor Amin mainly corresponds or the desired group R1the final compound I, or is an alternative tsepliaeva group, such as benzyl, which can be removed, which gives N-unsubstituted pyrrolidine. The latter can subsequently be functionalized as described above (see path A).

Synthesis of heteroarylboronic, for example, described in Chem. Pharm. Bull., 1985, 33, 2762-66; J. Heterocyclic Chemistry, 1996, 1995-2005; J. Heterocyclic Chemistry, 2001, 38, 1039-1044; Tetrahedron Letters, 1992, 33, 44, 6607-10; Heterocycles, 1998, 48, 12, 2535-2541 for a is peredilenim. Synthesis of vinylsubstituted of thiophene and thiazole, for example, described in Bioorg. Med. Chem. 1999, 7(5), 665.

5.1.2

Scheme 4

Phenylpyrrolidine can also be obtained using [3+2] bipolar cycloaddition unstable the azomethine ylides to 1-alkenylbenzene (XII) (see, for example, Tetrahedron 1996, 52, 59). Received pyrrolin (XIII) or the final product (I') then hydronaut to the appropriate pyrrolidine (XI). If the hydrogenation is carried out in a chiral environment, for example using chiral catalysts can be obtained enantiomerically pure phenylpyrrolidine connection. Chiral hydrogenation catalysts are well known to the average expert.

Subsequent transformation into the desired sulfonamide can be carried out as described is ANO via path A or B.

5.1.3

Alternatively, heteroarylboronic compounds may be derived from a heteroaryl halides, which are subjected to a Pd-mediated cross-linking tsinkorganicheskih pyrrolidinium connection. This method is described in further detail below through the path F. In this alternative also heteroaryl halide mainly contains the nitrogroup. In this case, the transformation into the desired sulfonamides can be carried out as described by path A. alternatively, a heteroaryl halide contains a halogen atom. In this case, the transformation into the desired sulfonamides can be achieved, as described through the path B.

5.1.4

The compounds of formula I where n is 1, G represents CH2And represents a 1,3-linked, Allen or heteroaryl and E is NH, can be obtained in a similar way in comparison with obtaining 1,4-linked compounds of the 3-aminoaryl or heteroarylboronic, which interacts with a suitable sulphonylchloride. Mainly, the N-atom of the pyrolidine ring protects using based on urethane protective group, such carbomethoxy (-COOCH3), benzyloxycarbonyl (cbz) andtert-butyloxycarbonyl (boc). This group can be replaced by the desired substituent R1by processing and connections acid, such as hydrochloric acid, thus removing acid group and then entering the desired Deputy, as described through path A.

3-aminoaryl or heteroarylboronic can be obtained through the reaction by Heck (Heck), where protected pyrrolin interacts with 1-iodine-3-nitrobenzene or the corresponding pyridine (2-iodine-4-nitropyridine or 3-iodine-5-nitropyridine) in a typical reaction conditions for Hake. Catalytic hydrogenation pyrrolinone double bond and the restoration of the nitro group in accordance with the methodology described in scheme 2, provides at the output the desired product.

N-protected pyrrolin can be obtained by reacting commercially available pyrroline with the desired protective group, for example with chlorotoluron, benzylchloride, Cbz-anhydride or Boc-anhydride.

Pyrrolin can be synthesized by the exchange reaction of N-protected diallylamine in the presence of a catalyst of the currency, for example the catalyst of Grubbs (Grubbs).

5.2. Synthesis of N-(azetidin-3-yl)sulfonamides

The compounds of formula I, where n has a value of 0 (azetidinone connection), can be synthesized as follows.

Scheme 5

Figure 5 Ar and R1defined above. X and Y independently from each other represent CH or N.

On the basis of 1-benzhydrylamine-3-ol mediated Pd removal protection the s with amine (Tetrahedron 2002, 58, 9865-9870), the formation of carbamate and subsequent halogenoalkane provide intermediate compounds, which are input Zn (Tetrahedron 1987, 43, 2203-2212; J. Org. Chem. 1988, 53, 2390-2392). The thus obtained tsinkorganicheskih residues can interact with the appropriate 2-halogen-necrocomicon (Synlett 1998, 4, 379-380; J. Am. Chem. Soc. 2003, 125, 12527-12530), which gives nitroimidazolidin the core. If you use 2-halogen-halogen ring, it is also possible to establish a direct link between arylacetylenes and appropriate sulfonamide (Org. Lett. 2000, 2, 1101-1104; J. Am. Chem. Soc. 2002, 124, 6043-6048; Org. Lett. 2003, 5, 4373-4376; Tetrahedron Lett. 2003, 44, 3385-3386). The amine can be recovered by cleavage of the carbamate (for example, using triperoxonane acid in the case of Boc carbamate) and subsequently transformed into the amide by using a reaction with a suitable acylchlorides. The nitro-group can be restored to the amine via the acid chloride of tin or catalytic hydrogenation (for example, Pd-C) and then converted to the desired sulfonamide via reaction with a suitable sulphonylchloride in the presence of a base, such as pyridine. The final restoration of Amida through hydroporinae makes the final connection.

Undoubtedly, the reaction also apply to compounds where (hetero)aromatic ring associated with azetidinone group represents and Audi 5-membered heterocyclic radical, for example, thienyl.

5.3. Synthesis of N-(piperidine-3-yl)sulfonamides

In addition, the above-described synthesis (paths A, B and C), compounds of formula I, where n is set to 2 and E is NR5(piperidine-3-ralfinamide)can be made from commercially available 3-aryl-or 3-heteroarylboronic. These starting compounds can then be converted into aminosilane or halogenated derivative and then be subjected to the synthesis of path A or B.

The average specialist easy it will be understood that the compounds of formula I can also be obtained from structural analogs of compounds by functional group interconversion. In particular N-linked radicals Racan be introduced into compounds of the formula I by reacting the corresponding halogen compounds, i.e. the compounds of formula I, which instead of Racontains halogen atom, particularly a bromine atom, or iodine, with a primary or secondary amine in the presence of a base, preferably in the presence of palladium catalyst according to the reaction Wuhan-Hartwig (Buchwald-Hartwig).

Unless otherwise specified, the above reaction is in General carried out in a solvent at temperature ranges between room temperature and the boiling point of the used solvent. Alternatively, the activation energy, which is trebuetsya for the reaction, can be introduced into the reaction mixture using microvalue radiation, that is, what was, had a value, in particular, in the case of reactions catalyzed by transition metals (in relation to reactions using microvalue radiation, see Tetrahedron 2001, 57, p.9199 ff. p.9225 ff., and also in a General way, "Microwaves in Organic Synthesis", André Loupy (Ed.), Wiley-VCH 2002.

Sulphonylchloride Cl-SO2-Ar are either commercially available or can be obtained in accordance with standard synthetic methods. Sulphonylchloride containing fluorinated radical Racan be obtained by using different ways of synthesis, for example, by reacting a suitable hydroxy or ekspressionista (for example, compounds Cl-SO2Ar bearing hydroxy or oxazolidinyl radical) with fluorination reagents, such DAST TRIFLUORIDE(diethylaminoethyl), morpholine-DAST, deoxofluor TRIFLUORIDE(bis(2-methoxyethyl)uminosity), the reagent Ishikawa (Ishikawa) (N,N-diethyl-(1,1,2,3,3,3-hexaferrites)amine; Journal of Fluorine Chemistry, 1989, 43, 371-377). More traditionally, the hydroxy-group of the aromatic compound, which contains replacement radical, but not chlorosulfonyl group into a leaving group, which is then replaced by fluoride ion (J. Org. Chem., 1994, 59, 2898-22901; Tetrahedron Letters, 1998, 7305-6; J. Org. Chem., 1998, 63, 9587-9589, Synthesis, 1987, 920-21)). Subsequent direct chlorosulfonylisocyanate holdem is Sultonova acid (Heterocycles, 2001, 55, 9, 1789-1803; J. Org. Chem., 2000, 65, 1399-1406) or 2-stage synthesis for obtaining first derivatives of sulfonic acids, which are then converted into sulphonylchloride using, for example, chlorosulfonic acid, pentachloride phosphorus (Eur. J. Med. Chem., 2002, 36, 809-828) and the like, provides a desired sulphonylchloride (Tetrahedron Letters, 1991, 33, 50, 7787-7788)). Sulphonylchloride can also be obtained by diazotization of the appropriate predecessor Amin Ar-NH2with sodium nitrite in acidic conditions and reaction with sulfur dioxide in acetic acid (scheme (iii); J. Org. Chem., 1960, 25, 1824-26); by oxidation of suitable heteroallyl HS-Ar or heteroarylboronic C6H5-CH2-S-Ar chlorine (Synthesis, 1998, 36-38; J. Am. Chem. Soc., 1950, 74, 4890-92) directly with the relevant sulphonylchloride. Further it is known to the average expert or can be obtained in the usual way.

Acid additive salts of compounds of the formula I get the usual manner by mixing the free base with the appropriate acid, if required, in a solution of an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyltert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone or ester, such as ethyl acetate.

Compounds according to the invention fo the mules I possess unexpectedly high affinity for 5HT 6the receptors. The compounds of formula I in which A is 1,3-phenylene, 2,4-peredilenim or 3.5-peredilenim and, in particular, 1,3-phenylene, are, moreover, highly selective ligands dopamine 5HT6receptors, which due to their low affinity for other receptors, such as the D1receptors, D5receptors, D4receptors, α1-adrenergic and/or α2-adrenergic receptors, muscarinic receptors, histamine receptors, opiate receptors and, in particular, the dopamine D2receptors, cause fewer side effects than other, less selective ligands 5HT6. The compounds of formula I in which a is 1,4-phenylene, show a high affinity to 5HT6receptors and, optionally, also to the dopamine D3the receptors. Because of their low affinity for other receptors, such as the D1receptors, D5receptors, D4receptors, α1-adrenergic and/or α2-adrenergic receptors, muscarinic receptors, histamine receptors, opiate receptors and, in particular, the dopamine D2receptors, cause fewer side effects than other, less selective compounds such as classical neuroleptics, which are antagonists of D2receptors.

The compound of the invention may be an agonist of dopamine receptors 5HT6cocktail recipes. is s, including partial agonistic activity, or an antagonist of dopamine receptors 5HT6receptors, including inverse agonistic activity.

The high affinity of the compounds according to this invention to 5HT6receptors is reflected in the very low binding constant of the receptor in vitro (Ki(5HT6values), which are typically less than 50 nm (nmol/l), preferably less than 10 nm and in particular less than 5 nm. The displacement of3H-LSD may, for example, be used in studies of the binding of the receptor to determine the affinity of binding to 5-HT6receptors and [125I]-iodometric to determine the affinity of binding to dopamine D3the receptors.

The selectivity of D3/D2compounds according to this invention, which also have a high affinity for the dopamine D3receptors, i.e. the ratio of Ki(D2)/Ki(D3) binding constant of the receptor, is, as a rule, at least 25, preferably at least 50, even better at least 100. The displacement of [3H]SCH23390 and [125I]spiperone can be used, for example, for studies of binding receptors D1D2and D4.

Due to their profile linking these compounds can be used to treat diseases that are perceived is Mcely to ligands 5HT 6receptor and, optionally, to the ligands of the dopamine D3receptors (or sensitive to treatment with ligands 5HT6receptors, and optionally, the ligands of the dopamine D3receptors, i.e. they are effective in treating those medical disorders or diseases in which exerting influence on (modulating) 5HT6receptors and optional on (modulating) the dopamine D3receptors, leads to clinical improvement or cure of the disease. Examples of these diseases are disorders or diseases of the Central nervous system.

Under disorders or diseases of the Central nervous system understand the significant disorders that affect the spinal cord and, in particular, the brain. For the purposes of this invention, the term "disorder" refers to disorders and/or anomalies, which are generally regarded as pathological conditions or operation and which can manifest itself in the form of private signs, symptoms and/or disorders. While the treatment according to this invention can be directed to a specific disorder, i.e. anomalies or pathological conditions, it is also possible for several anomalies that may have a causal connection with each other, to be sobran the mi system, i.e. syndromes that can be treated in accordance with the present invention.

Disorders that may be treated in accordance with the present invention are, in particular, disorders susceptible to modulation of 5HT6the receptors. They include cognitive dysfunction, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive disturbance, attention deficit disorder/hyperactivity disorder, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive-compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including breach of circadian rhythm), eating disorders such as anorexia and bulimia, some gastrointestinal disorders such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal injury, head injury or head injury such as hydrocephalus, drug addiction and obesity.

Addictive diseases include mental disorders and behavior disorders that are caused by the abuse of the substance, such as medicines or drugs, and other addictive disorders, such as addiction to games (unclassified impulse control disorders). Examples of addictive substances are opioids (e.g. morphine, heroin and codeine), cocaine; nicotine; alcohol; substances that interact with the complex GABA/chloride channel, sedatives, sleeping pills, and tranquilizers, such as benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylendioxy-N-methylamphetamine (ecstasy), amphetamine and amphetamine-like substances such as methylphenidate and other stimulants, including caffeine. Dependence-producing substances, which are particularly subject to review are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.

Regarding the treatment of addictive diseases, particular preference is given to those compounds according to this invention according to formula I which do not have any psychotropic effects. It can also be observed in the test using rats that after the introduction of compounds that can be used according to this invention, reduces the self-introduction of psychotropic substances, such as cocaine.

The compounds of formula I with high affinity to 5HT6R is the receptors, as to the dopamine D3receptors, can be successfully used in the treatment of disorders, preferably disorders of the Central nervous system, sensitive to dopaminergic and serotonergic effects. While 5HT6the more receptors are associated with cognitive functions, dopamine D3receptors associated with productive symptoms, such as mania, hallucination, confused thinking, confused speech, confused, agitated or catatonic behavior, and negative symptoms, such as loss of sensation, impaired speech, loss of motivation, apathy, lack of attention and care from the society. Thus, the compounds of formula I with high affinity to 5HT6receptors, and dopamine D3receptors, can be successfully used in the treatment of disorders such as Alzheimer's disease and, in particular, schizophrenia, which is characterized by impaired cognitive functions, as well as productive and negative symptoms.

According to another aspect of the present invention the compounds according to this invention is suitable for treatment of disorders, the causes of which can at least partially be explained by the abnormal activity of 5HT6receptors.

According to another aspect of the present invention, the treatment is directed, in particular, on those resstr Ista, which can be influenced through appropriate medical treatment by linking preferably introduced exogenous binding agents (ligands) with 5HT6the receptors.

Diseases that can be treated by the compounds according to this invention, often characterized by a progressive development, i.e. the above state change over time; as a rule, the severity increases and pathological conditions can be combined with each other or other pathological conditions can develop in addition to those that already exist.

Compounds according to this invention can be used to treat a large number of signs, symptoms and/or dysfunctions that are associated with disorders of the Central nervous system and, in particular, the above conditions. These signs, symptoms and/or dysfunctions include, for example, violated the relation to reality, the lack of understanding and ability to comply with the usual social norms or needs that arise in life, changes in temperament, changes in personal motives such as hunger, sleep, thirst and so on, and mood disorders the ability to observe and generalize, personality changes, in particular, emotional lability, hallucinations, disorders of ego, confusion, ambivalence, autism, on the personalization and false sensations, delusional ideas, speech, chanting, no joint reflex movements, mincing gait, bent torso, and limbs, tremor, paucity of facial expression, monotonous speech, depression, fatigue, difficulties with spontaneity and decisiveness, depleted the capacity of associations, anxiety, nervous agitate, stuttering, social phobia, panic disorder, withdrawal symptoms in combination with addiction, manic syndromes, state of excitement and confusion, dysphoria, dyskinetic syndromes and ticks, for example, Huntington's chorea and the syndrome of Gilles de La Tourette's syndrome vertigo such as peripheral positional, rotational and oscillatory vertigo, melancholia, hysteria, hypochondria, etc.

In the understanding of the invention, the treatment also includes preventive treatment (prophylaxis), in particular the prevention of the recurrence or phase prevention as well as treatment of acute or chronic signs, symptoms and/or dysfunctions. Treatment may be aimed symptomatically, for example, in the form of suppression of symptoms. It can be done within a short period, to be focused on the medium term or maybe long-term treatment, for example, in the context of supportive therapy.

Compounds of the present invention is preferably suitable for the treatment of tablevariable nervous system, more preferably for the treatment of cognitive dysfunction and, in particular, for the treatment of cognitive dysfunction associated with schizophrenia or Alzheimer's disease.

In the context of treatment application in accordance with this invention the desired compounds includes way. In this method, an effective amount of one or more compounds, as a rule, prepared in accordance with the pharmaceutical and veterinary practice, is administered to the subject being treated, preferably a mammal, in particular humans, livestock or domestic animal. Shows whether this treatment and how it should be done, depends on the individual case and is subject to medical assessment (diagnostic), which takes into account the signs, symptoms and/or dysfunctions that are present, the risk of development of specific signs, symptoms and/or dysfunctions and other factors.

Typically, the treatment is carried out by single or repeated daily injection, where individual treatment is appropriate joint or alternating administration with other active compounds or preparations containing the active compound, so that the daily dose was preferably from about 0.1 to 1000 mg/kg of body weight in the case of oral administration or from OK is lo 0.1 to 100 mg/kg of body weight in the case of parenteral administration.

This invention also relates to the production of pharmaceutical compositions for the treatment of an individual, preferably a mammal, in particular humans, livestock, or domestic animals. Thus, the ligands are usually introduced in the form of pharmaceutical compositions that include pharmaceutically acceptable excipient with at least one compound according to this invention and, where appropriate, other active compounds. These compositions can, for example, be administered orally, rectally, percutaneously, subcutaneously, intravenously, intramuscularly, or intranasally.

Examples of suitable pharmaceutical preparations are solid dosage forms such as powders, granules, tablets, in particular tablets, film-coated, plates, bags, a wafer coated with sugar pills, capsules such as hard capsules and soft gelatin capsules, suppositories or vaginal dosage forms, semi-solid dosage forms such as ointments, creams, hydrogels, pastes or patches, and liquid dosage forms such as solutions, emulsions, particularly emulsions of the oil-in-water, suspensions, such as lotions, preparations for injection and drugs for infusion, and eye drops and ear drops. Implantable releasing the drug device can also use the taken for introduction of the inhibitors according to this invention. In addition, it is also possible to use liposomes and microspheres.

In the production of compositions of the compounds according to this invention, if necessary, is mixed or diluted with one or more fillers. Excipients can be solid, semi-solid or liquid substances, which serve as fillers, carriers or medium for the active connection.

Suitable fillers are listed in the medical literature. In addition, the preparations may contain pharmaceutically suitable carriers or conventional excipients, such as lubricants, wetting agents; emulsifying and suspendresume agents; preservatives; antioxidants; funds from irritation; chelating agents; additional shell; the stabilizers of emulsions; film-forming means; glioblastoma means; masking the smell of agents; taste correctors; gum; hydrocolloids; solvents; a means of improving solubility; neutralizing agents; accelerators diffusion; pigments; Quaternary ammonium compounds; perejivayuschie agents; raw materials for ointments, creams and oils; silicone derivatives; disintegrators; stabilizers; sterilizers; basics suppositories; excipients for tablets, such as binders, fillers, lubricants, disintegrant or shell; the propellant is; drying agents; giving opacity agents; thickeners; waxes; plasticizers and light mineral oil. Preparation, therefore, is based on the knowledge of experts, as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4thedition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

It was also found that disorder susceptible to dopaminergic and serotonergic effects, can also be treated by combined application of ligand dopamine D3receptor and ligand 5HT6the receptors. This combination unexpectedly showed no side effects.

Accordingly, a further aspect of the invention relates to pharmaceutical compositions containing at least one compound with affinity for the dopamine D3receptors and at least one compound that has affinity to 5HT6receptors, and optionally at least one physiologically acceptable carrier and/or excipient.

This invention also relates to the use of at least one compound that has affinity for the dopamine D3receptors, together with at least one compound that has affinity to 5HT6the receptor or a pharmaceutical composition as described is use for the preparation of drugs for the treatment of diseases of the Central nervous system.

Compounds for use according to this invention or the above composition having affinity for the dopamine D3receptors, preferably does not have or does have a negligible activity against 5HT6receptors and Vice versa. Preferably, compounds having affinity for the dopamine D3the receptors have a binding constant of the Kiwith the dopamine D3receptors at the level of about 150 nm and a compound having an affinity for 5HT6the receptor has a binding constant of the Kito 5HT6receptors at the level of about 150 nm. More preferably, the compound with affinity for the dopamine D3receptors, has a selectivity for D3dopamine receptors compared with 5HT6receptors Ki(5HT6)/Ki(D3), at least 10; more preferably, at least 25; and in particular at least 50; and a compound having an affinity for 5HT6dopamine receptors, is selective for 5HT6receptors compared with the dopamine D3receptors Ki(D3)/Ki(5HT6), at least 10, more preferably at least 25, and in particular at least 50.

Compounds with affinity for the dopamine D3the receptors are well known and described, for example, in the following publications: WO 2006/058753, WO 2006/040176, WO 2006/040177, WO 2006/040178, WO 2006/040179, WO 2006/0040180, WO 2006/008592, WO 2006/015842, WO 2005/058328, WO 2004/89905, WO 2004/108706, WO 2004/080981, WO 2004/069830, WO 01/72306, WO 00/67847, WO 00/42038, WO 99/09015, WO 99/02503, WO 97/25324, WO 96/002519, the contents of which are included in this description in its entirety by reference.

Preferred compounds having affinity for the dopamine D3receptors are antagonists of dopamine D3receptors.

Compounds with affinity to 5HT6the receptors are well known and described, for example, in the following publications: WO 2006/081322, WO 2005/040124, WO 2003/080580, WO 2002/032863, WO 00/05225, WO 98/27081 and S.-H. Zhao et al., Bioorganic and Medicinal Chemistry Letters 2007, the contents of which are included in this description in its entirety by reference.

Preferred compounds having affinity for the dopamine 5HT6receptors are antagonists of dopamine receptors 5HT6receptors.

Unexpectedly, the combination of compounds with affinity for the dopamine D3receptors and at least one compound that has affinity to 5HT6receptors, does not have any side effects. This can be proven through research (microdialysis studies described in the examples. In particular, the affinity of binding to one or the other receptor is not reduced.

In addition, it was found that the treatment of disorders which are susceptible to SS of energycheck, and serotonergic effects, may also be conducted by using compounds that have affinity to the dopamine D3receptors and 5HT6the receptors.

Thus, the invention also relates to the use of at least one compound that has affinity to both as the dopamine D3receptors and 5HT6the receptor for receiving drugs for the treatment of disorders of the Central nervous system, with the exception of compounds of the formula

where Ar is a substituted or unsubstituted aryl or heteroaryl ring;

Rather it represents a 3-7-membered substituted or unsubstituted cycloalkyl or heterocyclic ring;

Hc is a substituted or unsubstituted nitrogen-containing heterocyclic or heteroaryl ring;

Q is a C-K or N, where K represents H, lower alkyl, halogen or cyano;

Z represents O, S or NR, where R represents H or lower alkyl;

J represents a chain having from 0 to 8 units selected from unsubstituted or substituted methylene; NR8, O and S, where R8represents H or unsubstituted or substituted lower alkyl, cycloalkyl, heterocyclyl, aralkyl, heteroalkyl, aryl or heteroaryl.

Preferably, Obedinenie has antagonistic activity of combined dopamine D 3/5HT6.

The invention also relates to the use of at least one compound that is an antagonist of the dopamine D3receptor and has affinity for 5HT6the receptor for receiving drugs for the treatment of disorders of the Central nervous system.

Preferably, the compound has an antagonistic activity of 5HT6the receptor. Preferably, the compound has an antagonistic activity of combined dopamine D3/5HT6.

Compounds having these “mixed” affinity, are, for example, compounds described in WO 2006/040182.

Among the compounds of formula I described in WO 2006/040182, preferred are the compounds where

- R1represents H, n is 1, And represents an optionally substituted 1,4-phenylene, E is NH and Ar represents a phenyl containing the 4-position (relative to the 1-position of SO2group) Deputy Raand optionally 1 or 2 additional substituent Rawhere substituent Raconnected on 4-position preferably represents the radical Ra'and, in particular, selected from isopropyl or fluorinated isopropyl, such as 1-methyl-2-fluoro-1-ethyl, 1-methyl-2,2-debtor-1-ethyl or 1-methyl-2,2,2-Cryptor-1-ethyl; or

- R1the e represents H, and in particular, represents n-propyl, n is 0, And represents an optionally substituted 1,4-phenylene and Ar represents a phenyl containing 4-position (relative to the 1-position of SO2group) Deputy Raand optionally 1 or 2 additional substituent Ra; or

- R1does not represent H and, in particular, represents n-propyl, n is 1, And represents an optionally substituted 1,2-phenylene and Ar represents a phenyl containing at least one substituent Ra.

More preferred compounds are those described in the present description as the compounds of formula I, preference is given to those compounds, which are described in the present description as the preferred.

In particular, the compounds according to the invention, having a mixed activity, R1is not H. Preferably, R1selected from C1-C4-alkyl, in particular methyl, ethyl or in particular propyl, fluorinated C1-C4-alkyl, especially 3-forprofile or 2-forprofile, C3-C4-alkenyl, in particular allyl, cyclopropylmethyl or benzyl. Particularly preferably, R1is a drunk.

G preferably represents CH2and n has a value of preferably 1.

And p is ecstasy preferably a 1,4-phenylene, in particular unsubstituted 1,4-phenylene.

E preferably represents NH.

Ar preferably represents a group (A) or (F).

Rarepresents preferably a halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy or a 5 - or 6-membered unsaturated or saturated heterocyclic ring. Rband Rcpreferably selected from H, halogen and C1-C4-halogenoalkane.

Rdpreferably represents halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl or 5 - or 6-membered heteroaryl ring, which is unsubstituted or contains one Deputy, selected from C1-C4-alkyl and fluorinated C1-C4-alkyl. Preferred 6-membered heteroaryl ring containing one or two nitrogen atom (particularly preferred is pyridyl and pyrimidyl) and, in particular, one nitrogen atom. Preferred 5-membered heteroaryl ring containing one nitrogen atom and optionally one or two additional heteroatoms selected from N, O and S.

k preferably has a value of 0 or features 1.

The connection with “mixed” affinity to both, as the dopamine D3receptor and 5H 6receptor, preferably has a binding constant of the Kito the dopamine D3receptor up to 150 nm and 5HT6receptor up to 150 nm. More preferably, the compound with affinity for the dopamine D3receptors and 5HT6the receptor has a binding constant of the Kito the dopamine D3receptor up to 100 nm and 5HT6receptor up to 100 nm. Even more preferably, a compound with affinity for the dopamine D3receptors and 5HT6the receptor has a binding constant of the Kito the dopamine D3receptor up to 50 nm and 5HT6receptor up to 50 nm.

The violations that have both dopaminergic and serotonergic effects, are disorders that respond to modulation of the dopamine D3receptors and 5HT6the receptor. Violations, and dopaminergic and serotonergic effects are specific cognitive dysfunctions and specific cognitive dysfunctions associated with Alzheimer's disease and schizophrenia.

The following examples serve to explain the invention without its limitations.

Compounds characterized by or through proton NMR spectrum in d6-sulfoxide or d-chloroform, unless otherwise specified, 400 MHz or 500 MHz NMR instrument (Bruker AVANCE) or by mass with which ectromelia, in General, register via HPLC-MS in fast gradient on C18-material (way electrospray ionization (ESI)or melting temperature.

Spectral properties of nuclear magnetic resonance (NMR) refer to chemical shifts (δ)expressed in parts per million (ppm h/m). The relative area changes in1H NMR spectrum corresponds to the number of hydrogen atoms for the most functional type in the molecule. The nature of the shift in relation to the multiplicity is indicated as singlet (s), broadened singlet (users), doublet (d), broadened doublet (userd), triplet (t), broadened triplet (asirt), Quartet (q), quintet (Quint), and multiplet (m).

Examples:

I. the production of intermediate compounds

A. Getting sulphonylchloride

A.1 3-Bromo-4-triftormetilfullerenov

2.0 g of 1-bromo-2-(triptoreline)benzene (8.3 mmol) was dissolved in 30 ml of dichloromethane. At a temperature of 0-5°C is added dropwise 1.06 g chlorosulfonic acid (9,13 mmol)dissolved in 3 ml of dichloromethane. The reaction mixture is stirred for 30 minutes at room temperature. Add an additional amount to 5.5 equivalents of chlorosulfonic acid in dichloromethane, to bring the reaction to completion. Further standard processing and chromatography on silica gel in a mixture of n-heptane-dichloromethane (6:4) as eluent gives 2,19 g ukazannoj is in the connection header.

1H-NMR (CDCl3, 400 MHz): δ [h/million] of 8.3 (d, 1H), with 8.05 (DD, 1H), and 7.5 (DD, 1H).

b. Obtaining 3-(3-AMINOPHENYL)pyrrolidine

b.1 1-(Methoxycarbonyl)-3-(3-AMINOPHENYL)pyrrolidin

b.1.1. 1-(Methoxycarbonyl)pyrrolin

In a flask with a volume of 5 l equipped with a mechanical stirrer and thermocouple, load 500 g of powdery potassium carbonate, 2.5 l of dichloromethane and begin mixing. The resulting suspension is cooled to 0°C. Slowly load 300 g diallylamine. Is a slight exothermic reaction. Then in a separating funnel download 292,95 g methylcarbamate in 500 ml of CH2Cl2and the solution added slowly to the amine over a period of more than an hour. The reaction temperature kept lower than 10°C. Then the reaction mixture was allow to warm to room temperature over night. After filtering the reaction mixture through a thick layer of celite filter cake washed with dichloromethane. The dichloromethane solution is washed with water and dried over MgSO4. Concentration in vacuo gives the output product in the form of a yellow oil. Further purification is accomplished by vacuum distillation. At a pressure of approximately 10-12 mm Hg three fractions are collected in intervals of temperatures 50-61°C, 61-85°C and 85-90°C. the Second and third fractions identified by NMR for the presence of the desired N-protected dialium is on.

The N-carbomethoxyamino (400 g) is dissolved in 1.5 liters of dichloromethane, the solution is rinsed with nitrogen for 10 minutes by ozonation of nitrogen through the mixed solution. In a flask with a volume of 5 l equipped with a mechanical stirrer and a separating funnel, download the catalyst verification (Grubb's) (bis(tricyclohexylphosphine)stirolbutadienovyj (3 g, 3.9 mmol) under constant aeration. Add dichloromethane and the resulting dark colored solution was stirred at room temperature, barbotine nitrogen for 10 minutes. To the catalyst solution add a solution of N-carbomethoxyamino within 2 hours. After complete addition the solution was stirred at room temperature for 2.5 days. Then the reaction mixture was concentrated to obtain oil, which is then purified by vacuum distillation. The desired product is obtained in the form of a colorless transparent liquid, boiling at a temperature of approximately 90°C (10 mm Hg). The value of NMR is consistent with the expected structure.

1H-NMR (CDCl3): δ [h/million] 5,8-of 5.75 (m, 2H), 4,1 (m, 2H), 4,13 (m, 2H), and 3.72 (s, 3H).

b.1.2. 1-(Methoxycarbonyl)-3-(3-AMINOPHENYL)pyrrolidin

3-necked flask is rinsed with nitrogen for 10 minutes. In the flask is charged with palladium acetate and tri-o-tolylphosphino in a weak stream of nitrogen. Anhydrous dimethylformamide pre-rinsed with nitrogen by Barbati the Finance through him nitrogen for a few minutes and then load Pd(OAc) 2the catalyst and phosphine, continuing to blow through the flask nitrogen. Consistently in the flask is charged with diisopropylethylamine, pyrrolin obtained in example b.1.1, 1-iodine-3-nitrobenzene and silver carbonate(II). The reaction mixture is stirred and heated under nitrogen atmosphere to a temperature of 100°C for 6 hours. After about 9 hours the reaction is completed (TLC analysis). After cooling the reaction mixture to room temperature over night quenched with 10% sodium carbonate solution and three times extracted with MTBE (methyltert-butyl ether). The combined organic phases are dried over MgSO4and concentrate. The excess olefin is removed by vacuum distillation. The balance of dark colored dissolved in MTBE, loaded onto a column of silica gel and chromatographic a mixture of MTBE:heptane, gradient from 1:9 to 2:8.

Then 2,05 g lirovannomu pyrrolinone product suspended portions in 95 ml of methanol and hydronaut using 0.14 g of the catalyst of Wilkinson (RhCl(PPh3)3; 2% mol) at room temperature and 40 psi (1 psi = 0,069 bar) hydrogen pressure, to obtain a 1-(methoxycarbonyl)-3-(3-nitrophenyl)pyrrolidin.

The product is then subjected to acid treatment (HCl in methanol, TFA)to obtain the output specified in the header of the connection.

CI-MS: 221,2 [M+H]+

c. To obtain enantiomerically pure precursors

3-nitrostyryl interacts with 2.5 molar equivalents of benzyl methoxyethylmercury amine in dichloromethane in the presence of triperoxonane acid.

To 54 g of the hydrochloride of racemic 1-benzyl-3-(3-nitrophenyl)pyrrolidine (48 free base)dissolved in ethanol, was added 1 molar equivalent of L-tartaric acid. Fallen in sediment ttrat is isolated and recrystallized four times from methanol. Thus, refined salt out, dissolve and turn into a free pyrrolidin. Get 24,9 g (S)-1-benzyl-3-(3-nitrophenyl)pyrrolidine with >99%ee.

The combined filtrates of the above separation process concentrated, neutralized and subjected to the above processing, while using D-tartaric acid instead of L-shape. Get 17,5 g (R)-1-benzyl-3-(3-nitrophenyl)pyrrolidine with >99%ee.

II. Obtaining compounds of formula I

Example 1

3 Triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide and its hydrochloride

1.1. Dimethyl ether (S)-2-phenylethanol acid

5 g of (S)-2-phenylethanol acid (25,75 mmol) is dissolved in 50 ml of methanol. At a temperature of 4°C is added dropwise to 4.7 ml of thionyl chloride (64,37 mmol). The reaction mixture was stirred at room temperature for 2 hours, the solvents evaporated under reduced pressure. The rest of the OS is atok dissolved in diethyl ether, washed once with saturated aqueous NaHCO3re-extracted with diethyl ether and the combined organic layers are dried over magnesium sulfate, filtered and evaporated to dryness to obtain at the output of 5.8 g of the desired product.

ESI-MS: 223,1 [M+H]+

1.2. (S)-2-Phenylbutane-1,4-diol

of 2.54 g of sociallyengaged (66,95 mmol) is suspended under ice cooling in 25 ml of tetrahydrofuran. Slowly add 5.8 g of dimethyl ether (S)-2-phenylethanol acid (25,75 mmol)dissolved in 25 ml of tetrahydrofuran at a temperature of 5-10°C. Stirring is continued for 15 minutes and then added dropwise 15 ml of a mixture of tetrahydrofuran/water (1:1). The pH value of the suspension was adjusted to 3-4 with concentrated hydrochloric acid, filtered and the filter washed with dichloromethane. The filtrate is evaporated to dryness, transferred into diethyl ether, washed with saturated sodium hydrogen carbonate solution, re-extracted with diethyl ether and the combined organic layers are dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output of 4.2 g of diol.

ESI-MS: 189,1 [M+Na]+

1H-NMR (CDCl3): δ [h/million] 7,25 to 7.4 (m, 2H), 7,15-to 7.3 (m, 3H), 4,2-of 4.35 (m, 2H), 3,2 (m, 1H), 3,1 (m, 1H), to 2.1-2.3 (m, 3H).

1.3. (S)-4-methanesulfonate-3-privately ether methanesulfonate acid

4,19 g (S)-2-phenylbutane-1,4-what Iola (25,21 mmol) is dissolved in 50 ml of dichloromethane. Add 10,53 ml of triethylamine (75,6 mmol) and, under ice cooling, 5 ml of methanesulfonanilide (64,34 mmol). Stirring is continued for 15 minutes and then add 40 ml of water. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic layers are dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output of 8.37 g of the product.

1.4. (S)-3-Phenyl-1-propylpyrrolidine

2.0 g (S)-4-methanesulfonate-3-phenylbutyramide ether methanesulfonate acid (5.51 mmol) dissolved in 5 ml of n-Propylamine (60,82 mmol). The reaction mixture is stirred for 15 hours at room temperature, add diethyl ether, the organic phase is washed twice with water. The aqueous phase is re-extracted once with diethyl ether, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output of 1.09 g of product.

ESI-MS: 190,1 [M+H]+

1.5. (S)-3-(4-Nitrophenyl)-1-propylpyrrolidine

0.3 g (S)-3-Phenyl-1-propylpyrrolidine (1.48 mmol) dissolved in 2 ml of concentrated sulfuric acid in an argon atmosphere and ice cooling. Add small portions 165,16 mg of potassium nitrate (1,63 mmol). The reaction mixture is stirred for 15 minutes under ice cooling for 15 hours at room is based temperature and poured on crushed ice. The aqueous solution is alkalinized with 25% sodium hydroxide solution, extracted three times with diethyl ether, the aqueous phase is re-extracted once with diethyl ether, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output 0,326 g of a brownish oil. The second reaction network on the output of other 0,919 g of the desired product.

ESI-MS: 235,1 [M+H]+

1H-NMR (CDCl3): δ [h/million] of 8.15 (d, 2H), 7,45 (d, 2H), 3,4-3,5 (m, 1H), of 2.9-3.0 (m, 1H), 2,75 (m, 1H), 2,3-2,6 (m, 4H), 1,8-1,9 (m, 1H), 1,5-of 1.65 (m, 3H), of 0.95 (m, 3H).

1.6. (S)-3-(4-AMINOPHENYL)-1-propylpyrrolidine

0,907 g (S)-3-(4-Nitrophenyl)-1-propylpyrrolidine (3,59 mmol) was dissolved in 20 ml of methanol, add 7.0 g of tin dichloride (31,02 mmol) and the reaction mixture is stirred at the boiling temperature under reflux for one hour. The methanol evaporated, add 60 ml of 1 N sodium hydroxide solution and dichloromethane and the phases are separated after extensive mixing. The aqueous phase is extracted twice with dichloromethane, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output 0,744 g of crude amino compounds.

ESI-MS: 205,2 [M+H]+

1H-NMR (DMSO-d6): δ [h/million] of 6.9 (d, 2H), 6,45 (d, 2H), 4,7 (users, 2H), 3,1 (m, 1H), 2,85 (m, 1H), 2,65 (m, 1H), to 2.55 (m, 1H), 2,25-of 2.45 (m, 3H), 2,1 (who, 1H), 1,65 (m, 1H), 1,4-1,5 (m, 2H), 0,85 (m, 3H).

1.7. 3 Triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide and its hydrochloride

0.4 g (S)-3-(4-AMINOPHENYL)-1-propylpyrrolidine (a 1.96 mmol) and 0,455 g of commercially available 3-triftormetilfullerenov (to 1.86 mmol) dissolved in 15 ml of tetrahydrofuran. Type of 0.82 ml of triethylamine (by 5.87 mmol) and the reaction mixture is stirred for 15 hours at room temperature. The solvents are evaporated under reduced pressure, the residue is treated with water and the pH adjusted to an alkaline value by using sodium hydroxide solution. The aqueous layer was extracted three times with diethyl ether, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude product is purified by chromatography on silica gel with a mixture of ethyl acetate/methanol (2.5 to 3%) as eluent, which in turn yields 0,225 g of the pure product.

ESI-MS: 429,15 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] 7.7 (d, 1H), 7,55 (s, 1H), 7.5 (t, 1H), and 7.4 (d, 1H), 7,15 (d, 2H), 6,95 (d, 2H), 5,3 (users, 1H), 3,3 (m, 1H), 3,05 (m, 1H), 2,85 (m, 1H), 2,65 (m, 1H), 2,5 (m, 1H), 2,45 (m, 2H), 2,3 (m, 1H), 1.8 m (m, 1H), 1.55V (m, 2H), and 0.9 (t, 3H).

The specified product is dissolved in 15 ml diethyl ether and 1 ml of dichloromethane, add and 0.61 ml of 1 N HCl in diethyl ether and after the formation of the precipitate, the suspension is evaporated under reduced pressure to obtain the ihade 0,235 g of white precipitate.

Example 2

4-Bromo-3-fluoro-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

0,289 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide using commercially available 4-bromo-3-forbindelsesfaneblad.

ESI-MS: 441,0/443,0 [M+H]+

1H-NMR (CDCl3): δ [h/million] of 7.65 (m, 1H), 7.5 (m, 1H), and 7.4 (m, 1H), 7,15 (d, 2H), 7,0 (d, 2H), 3,3 (m, 1H), 3.0 a (m, 1H), 2,8 (m, 1H), 2,65 (m, 1H), 2,35-2,5 (m, 3H), 2,3 (m, 1H), 1.8 m (m, 1H), 1,5 (m, 2H)at 0.9 (m, 3H).

Example 3

4-Bromo-3,6-debtor-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

0,131 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide using commercially available 4-bromo-3,6-differentialalgebraic.

ESI-MS: 459,0/461,0 [M+H]+

1H-NMR (CDCl3): δ [h/million] of 7.55 (m, 1H), and 7.4 (m, 1H), 7,15 (d, 2H), 7,0 (d, 2H), 4,7 (very Sirs, 2H), 3,3 (m, 1H), 3.0 a (m, 1H), 2,85 (m, 1H), and 2.7 (m, 1H), 2,4-2,6 (m, 3H), of 2.25 (m, 1H), 1.8 m (m, 1H), 1.55V (m, 2H)to 0.85 (m, 3H).

Example 4

3-Trifluoromethyl-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

0.11 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)who enyl]benzosulfimide, using commercially available 3-triftoratsetilatsetonom.

ESI-MS: 427,2 [M+H]+

Example 5

Hydrochloride 3,4-debtor-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

ESI-MS: 381,2 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 11,25 (userd, 1H), 10,55 (m, 1H), a 7.85 (t, 1H), 7,65 (m, 2H), and 7.3 (d, 1H), 7,25 (d, 1H), and 7.1 (m, 2H), and 3.2 to 3.8 (m, 5H), 2,9-3,15 (m, 2H), 2,3 (m, 1H), 1,95 (m, 1H), 1,7 (m, 2H), 0,9 (t, 3H).

Example 6

N-(3-Pyrrolidin-3-ylphenyl)-3-triftormetilfullerenov

6.1. Methyl ester of 3-[3-(3-Triftormetilfullerenov)phenyl]pyrrolidin-1-carboxylic acid

The specified connection receive, following the synthesis technique similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide by reacting 1-(methoxycarbonyl)-3-(3-AMINOPHENYL)pyrrolidine, obtained as described in example b.1, with commercially available 3-cryptonetxdeviceinformation.

ESI-MS: 445,1 [M+H]+

6.2. N-(3-Pyrrolidin-3-ylphenyl)-3-triftormetilfullerenov

Methyl ester of 3-[3-(3-triftormetilfullerenov)phenyl]pyrrolidin-1-carboxylic acid (0,105 g; 0.24 mmol) was dissolved in 2.5 ml of ethanol and add 0.9 ml of concentrated HCl. The reaction mixture is heated in the system of microwave irradiation (CEM) at a temperature of 90-150°C for several hours is in, until you react the original product. The mixture was then concentrated in vacuo and the acid aqueous phase is extracted twice with diethyl ether. The pH value of the aqueous phase was adjusted to 9 with 1 N aqueous NaOH, extracted three times with diethyl ether and the combined organic layers dried over sodium sulfate, filtered and the solvent evaporated to dryness to obtain at the output 45 mg of product.

ESI-MS: 387,15 [M+H]+.

Example 7

N-((S)-3-Pyrrolidin-3-ylphenyl)-3-triftormetilfullerenov

7.1. (S)-1-Benzyl-3-(3-AMINOPHENYL)pyrrolidin

(S)-1-Benzyl-3-(3-nitrophenyl)pyrrolidine (1 g, 3.54 mmol) was dissolved in methanol, add 4.5 g of tin dichloride(II) (19,94 mmol) and the reaction mixture was stirred for 1.5 hours at boiling temperature under reflux. When the original product will enter into the reaction, the solvent was evaporated under reduced pressure and the residue is treated with a mixture of 1 N aqueous NaOH solution/ethyl acetate and filtered through celite. The phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic layers are dried over magnesium sulfate, filtered and evaporated to dryness to obtain at the output of 0.75 g of a yellowish oil.

7.2. N-[3-((S)-1-Benzylpyrrolidine-3-yl)phenyl]-3-triftormetilfullerenov

(S)-1-Benzyl-3-(3-AMINOPHENYL)pyrrolidine (0.4 g, of 1.59 mmol) and commercially on the affordable 3-triftormetilfullerenov (0.39 g, 1.5 mmol) dissolved in 30 ml of tetrahydrofuran. Add to 0.66 ml of triethylamine (3.75 mmol) and the mixture is stirred for 16 hours at room temperature. The solvent is evaporated under reduced pressure and the residue treated with a mixture of water/diethyl ether. After adjusting the pH of the aqueous phase to alkaline values using 1 N aqueous solution of NaOH, the aqueous layer was extracted with diethyl ether and the combined organic layers are dried over magnesium sulfate, filtered and evaporated. The product was then purified using chromatography on silica gel, using semi-automated chromatographic system Isco Companion to get the output 0,512 g of the desired compound.

ESI-MS: 477,1 [M+H]+

7.3. N-((S)-3-Pyrrolidin-3-ylphenyl)-3-triftormetilfullerenov

N-[3-((S)-1-Benzylpyrrolidine-3-yl)phenyl]-3-triftormetilfullerenov (0.5 g, 1.05 mmol) dissolved in glacial acetic acid and add 10% Pd on coal in nitrogen atmosphere. The reaction mixture was then hydronaut for 5 hours at 70°C. Then the catalyst was removed by filtration through celite. The filtrate is concentrated under reduced pressure. The residue is treated with water and the pH adjusted to alkaline values using 1 N aqueous solution of NaOH. The aqueous layer was extracted twice with ethyl acetate and once with dichloromethane, then the combined organic layers dried over Sul is an atom of magnesium, filtered and evaporated. The remaining white solid is ground to powder with 10 ml of diethyl ether and the precipitate is filtered and dried, to obtain at the output of 0.18 g specified in the connection header.

ESI-MS: 387,0 [M+H]+

1H-NMR (DMSO): δ [h/million] of 7.75 (d, 1H), 7,6 (m, 2H), 7.5 (d, 1H), 7,0 (t, 1H), 6,85 (s, 1H), 6,8 (d, 1H), 6,7 (d, 1H), 3,3 (m, 1H), 3,0-3,2 (m, 3H), and 2.7 (m, 1H), 2,1 (m, 1H), 1,7 (m, 1H).

Example 8

N-[4-Methoxy-3-(1-propylpyrrolidine-3-yl)phenyl]-3-triftormetilfullerenov

8.1. 1-[3-(2-Methoxyphenyl)pyrrolidin-1-yl]propane-1-he

Commercially available 3-(2-methoxyphenyl)pyrrolidin (1.64 g, a 9.25 mmol) was dissolved in 50 ml of tetrahydrofuran, add 1,873 g of triethylamine (18,51 mmol) and after cooling to a temperature of 0-5°C is added dropwise 1,325 g of anhydride propionic acid (10,18 mmol), dissolved in a certain amount of tetrahydrofuran. After stirring for 30 minutes the original product reacts, then add 2 ml of 7 N ammonia in methanol. After stirring at room temperature for 10 minutes, the solvents evaporated under reduced pressure, the residue treated with diethyl ether, washed once with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and the solvent evaporated again to obtain at the output of 2.2 g of the desired product.

ESI-MS: 234,1 [M+H]+

82. 1-[3-(2-Methoxy-5-nitrophenyl)pyrrolidin-1-yl]propane-1-he

1-[3-(2-Methoxyphenyl)pyrrolidin-1-yl]propane-1-he (0.7 g; 3 mmol) dissolved in 10 ml of nitromethane. In the temperature range from -5°C to -10°C add the mixture 0,290 g of nitric acid, 0.5 g water and 5,52 g of sulfuric acid within 25 minutes and the reaction mixture is stirred for another hour at low temperature and 16 hours at room temperature. Add ice, the pH value of the reaction mixture was adjusted to alkaline with 50% aqueous NaOH and the aqueous phase is extracted twice with diethyl ether. The organic layers are combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output of 0.85 g of the desired product as a mixture of isomers and a small amount dinitropropanol, which is used in the next stage without additional purification.

ESI-MS: 279,1 [M+H]+

8.3. 1-[3-(2-Methoxy-5-AMINOPHENYL)pyrrolidin-1-yl]propane-1-he

1-[3-(2-Methoxy-5-nitrophenyl)pyrrolidin-1-yl]propane-1-he (0,85 g; 3,05 mmol) is dissolved in 50 ml of methanol. Add the 3.65 g of tin dichloride (16,18 mmol) and the reaction mixture is stirred for 2 hours at the boil under reflux. When the original product is reacted, the solvent is evaporated under reduced pressure and the residue is treated with a mixture of 1 N aqueous NaOH solution/ethyl acetate, and f is trout. The phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic layers are dried over magnesium sulfate, filtered and evaporated to dryness to obtain at the output of 0.44 g of crude product, which is used in the next stage without additional purification.

ESI-MS: 249,1 [M+H]+

8.4. N-[4-Methoxy-3-(1-propenylboronic-3-yl)phenyl]-3-triftormetilfullerenov

1-[3-(2-Methoxy-5-AMINOPHENYL)pyrrolidin-1-yl]propane-1-he (0,44 g, 1.77 mmol) and commercially available 3-triftormetilfullerenov (to 0.23 g, 0.89 mmol) interact, as described above, to obtain at the output, after purification by chromatography on silica gel using ISCO instrument Companion, 0,198 g of the desired compound.

ESI-MS: 473,1 [M+H]+

8.5. N-[4-Methoxy-3-(1-propylpyrrolidine-3-yl)phenyl]-3-triftormetilfullerenov

N-[4-Methoxy-3-(1-propenylboronic-3-yl)phenyl]-3-triftormetilfullerenov (0,19 g, 0.4 mmol) dissolved in 15 ml of tetrahydrofuran and added dropwise 2 ml of 1 M brancherelaterede complex in tetrahydrofuran. The reaction mixture is heated to boiling point under reflux for 30 minutes, add 2 ml of 2 N aqueous hydrochloric acid and the mixture is heated at boiling temperature under reflux again for 3 hours. After stirring for 16 hours at room the Oh temperature, the solvent evaporated, the residue is treated with water and the pH adjusted to alkaline values using 1 N aqueous solution of NaOH. The aqueous layer was extracted twice with diethyl ether, the combined organic layers are dried over magnesium sulfate, filtered and the solvent evaporated. The crude product chromatografic on chromabond column using 0-5% of a mixture of dichloromethane/methanol as eluent, to obtain at the output 0,077 mg specified in the connection header.

ESI-MS: 459,1 [M+H]+

1H-NMR (CDCl3): δ [h/million] of 7.65 (d, 1H), and 7.5 (s, 1H), 7,45 (t, 1H), 7,35 (d, 1H), 6,95 (d, 1H), 6,85 (s, 1H), 6,7 (d, 1H), 6,5 (users, 1H), and 3.8 (s, 3H), 3,6 (m, 1H), 2,9 (m, 1H), 2,75 (m, 1H), 2,65 (m, 1H), 2,3-2,5 (several m, 3H), of 2.15 (m, 1H), 1,65 (m, 1H), 1,5 (m, 2H), and 0.9 (t, 3H).

Example 9

(3 Azetidin-3-ylphenyl)amide 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid

Following a methodology similar to that described to obtain compounds according to example 1.7,tert-butyl-3-(3-AMINOPHENYL)azetidin-1-carboxylate (100 mg, 0.40 mmol) associated with 5-chloro-3-methylbenzo[b]thiophene-2-sulphonylchloride (118 mg, 0.42 mmol), what givestert-butyl-3-(3-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide)phenyl)azetidin-1-carboxylate (140 mg, 71%).

ESI-MS: 437,0 [M+H]+

tert-Butyl-3-(3-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide)phenyl)azetidin-1-carboxylate (140 mg, 0.28 mmol) was stirred in formic acid (3 ml) at 0°C for 3 hours. The solution of concentri the comfort, dissolve in water, add concentrated HCl and the solution concentrated by lyophilization, which gives specified in the title compound (113 mg, 93%) as a white foam.

ESI-MS: 393,0 [M+H]+.

Compounds according to examples 10 and 32 receive the following similar methods.

Example 10

N-(3-Azetidin-3-ylphenyl)-3-(2-methylthiazole-4-yl)benzosulfimide

ESI-MS: 386,1 [M+H]+

Example 11

N-(4-Azetidin-3-ylphenyl)-3-triftoratsetilatsetonom

ESI-MS: 357,1 [M+H]+

Example 12

(3 Azetidin-3-ylphenyl)amide thiophene-2-sulfonic acid

ESI-MS: 294,9 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) is 3.82 (m, 2H), 3,92 (m, 1H), Android 4.04 (m, 2H), 6.87 in (d, 1H), 6,91 (d, 1H), 6,95 (s, 1H), 7,00 (t, 1H), 7,13 (t, 1H), 7,41 (d, 1H), 7,68 (d, 1H).

Example 13

N-(3-Azetidin-3-ylphenyl)for 3,5-bis-triftoratsetilatsetonom

ESI-MS: 425,0 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) 3,93 (m, 3H), 4,15 (m, 2H), of 6.71 (d, 1H), 6,78 (d, 1H), 6.87 in (s, 1H),? 7.04 baby mortality (t, 1H), 8,17 (s, 1H), to 8.20 (s, 1H).

Example 14

N-(3-Azetidin-3-ylphenyl)-2,5-dimethoxybenzenesulfonamide

ESI-MS: 349,0 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/mn) of 3.78 (m, 2H), 3,70 (m, 3H), 3,91 (m, 3H), 6,94 (t, 2H), 7,02 (s, 1H), to 7.09 (m, 1H), 7,11 (d, 1H), 7,17 (t, 1H), 7.23 percent (d, 1H).

Example 15

N-(3-Azetidin-3-ylphenyl)-3-forbindelsesfaneblad

ESI-MS: 306,9 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) 3,81 (m, 2H), 3,91 (m, 1H), Android 4.04 (m, 2H), 6.87 in (d, 1H), 6,94 with, 1H), 7,12 (t, 1H), was 7.36 (t, 1H), 7,47 (d, 1H), 7,49 (m, 1H), 7,56 (m, 1H).

Example 16

(3 Azetidin-3-ylphenyl)amide 2,5-dichlorothiophene-3-sulfonic acid

ESI-MS: 362,9 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) 3,93 (m, 3H), 4,14 (m, 2H), of 6.71 (d, 1H), for 6.81 (d, 1H), 6,85 (s, 1H), 7,06 (t, 1H), 7,10 (s, 1H).

Example 17

N-(3-Azetidin-3-ylphenyl)-3-chlorobenzenesulfonamide

ESI-MS: 322,9 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) 3,86 (m, 2H), 3,94 (m, 1H), 4,07 (m, 2H), 6.87 in (t, 2H), 6,94 (s, 1H), 7,13 (t, 1H), 7,52 (t, 1H), EUR 7.57 (d, 1H), 7,72 (m, 2H).

Example 18

N-(3-Azetidin-3-ylphenyl)for 3,5-dichlorobenzenesulfonate

ESI-MS: 356,9 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) 3,90 (m, 3H), 4,11 (m, 2H), 6,66 (d, 1H), 6,76 (d, 1H), PC 6.82 (s, 1H), 7,03 (t, 1H), 7.62mm (m, 2H).

Example 19

N-(3-Azetidin-3-ylphenyl)-3-methylbenzenesulfonamide

ESI-MS: 303,0 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) 2,31 (s, 3H), of 3.78 (m, 2H), 3,93 (m, 3H), 6,93 (d, 1H), of 6.96 (d, 1H), 7,00 (s, 1H), 7,17 (t, 1H), 7,38 (m, 2H), 7,54 (m, 1H), EUR 7.57 (s, 1H).

Example 20

N-(3-Azetidin-3-ylphenyl)-5-bromo-2-methoxybenzenesulfonamide

ESI-MS: 399,0 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/mn) of 3.78 (m, 2H), 3,85 (s, 3H), 3,91 (m, 3H), 6,95 (d, 1H), 6,97 (d, 1H), 7,02 (s, 1H), 7,13 (d, 1H), 7,18 (t, 1H), 7,71 (d, 1H), 7,80 (s, 1H).

Example 21

(3 Azetidin-3-ylphenyl)amide 5-benzosulfimide-2-sulfonic acid

ESI-MS: 435,0 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) 3,91 (m, 3H), 4,14 (m, 2H), 6,66 (d, 1H), 6,80 (s, 1H), for 6.81 (d, 1H), ,00 (d, 1H), 7,18 (t, 1H), 7,71 (d, 1H), 7,80 (s, 1H).

Example 22

N-(3-Azetidin-3-ylphenyl)-2-methoxy-5-methylbenzenesulfonamide

ESI-MS: 333,0 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/mn) of 1.78 (m, 3H), of 2.20 (s, 3H), 3,81 (m, 3H), 4,14 (m, 2H), 6.75 in (d, 1H), 6,80 (s, 1H), for 6.81 (d, 1H), 7,00 (d, 1H), 7,18 (t, 1H), 7,71 (d, 1H), 7,80 (s, 1H).

Example 23

(3 Azetidin-3-ylphenyl)amide 5-(2-methylsulfonylamino-4-yl)thiophene-2-sulfonic acid

ESI-MS: 417,1 [M-H]+

1H NMR (400 MHz, DMSO): δ (h/mn) of 3.85 (s, 3H), 3,91 (m, 3H), 4,10 (m, 2H), 6,70 (d, 1H), 6.89 in (m, 2H),? 7.04 baby mortality (d, 1H), was 7.36 (d, 1H), 7,58 (d, 1H), 7,83 (s, 1H), 8,58 (m, 1H).

Example 24

N-(3-Azetidin-3-ylphenyl)-3-cyanobenzenesulfonyl

ESI-MS: 313,9 [M+H]+

Example 25

N-(3-Azetidin-3-ylphenyl)-3-methoxybenzenesulfonamide

ESI-MS: 319,0 [M+H]+

Example 26

(4 Azetidin-3-ylphenyl)amide 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid

ESI-MS: to 393.3 [M+H]+

Example 27

N-(4-Azetidin-3-ylphenyl)-4-fluoro-3-oxazol-4-albenzaalbenza

ESI-MS: 374,1 [M+H]+

Example 28

N-(4-Azetidin-3-ylphenyl)-4-fluoro-3-oxazol-5-albenzaalbenza

ESI-MS: 374,1 [M+H]+

Example 29

N-(3-Azetidin-3-ylphenyl)-3-deformationsanalyse

ESI-MS: 355,1 [M+H]+

Example 30

N-(4-Azetidin-3-ylphenyl)-3-deformationsanalyse

ESI-MS: 355,1 [M+H]+

Example 31

N-(3-Asetic the n-3-ylphenyl)-3-triftoratsetilatsetonom

ESI-MS: 357,1 [M+H]+

Example 32

N-(3-Azetidin-3-ylphenyl)-3-triftormetilfullerenov

ESI-MS: 373,1 [M+H]+

Example 33

(4 Azetidin-3-ylphenyl)methylamide 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid

tert-Butyl-3-(4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide)phenyl)azetidin-1-carboxylate (216 mg, 0.44 mmol) stirred in THF (5 ml) and add NaH (25 mg, of 0.53 mmol). After stirring at room temperature for 15 minutes add methyliodide (0,028 ml, 0.44 mmol) and stirring is continued for 116 hours. The solution was concentrated in vacuo, dissolved in water (pH 11) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and concentrated, givingtert-butyl-3-(4-(5-chloro-N,3-dimethylbenzo[b]thiophene-2-sulfonamide)phenyl)azetidin-1-carboxylate (=original connection methylated amido-N) (185 mg, 83%).

ESI-MS: 508,1 [M+H]+

tert-Butyl-3-(4-(5-chloro-N,3-dimethylbenzo[b]thiophene-2-sulfonamide)phenyl)azetidin-1-carboxylate (185 mg, 0.36 mmol) was stirred in formic acid (3 ml) at 0°C for 3.5 hours. The solution is concentrated, dissolved in water, add concentrated HCl and the solution concentrated by lyophilization, which gives specified in the title compound (144 mg, 87%) as a white foam.

ESI-MS: 408,1 [M+H]+

Example 34

3-((S)-2,2-D is fluoro-1-methylethyl)-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

Following a methodology similar to that described to obtain compounds according to example 1.7, (S)-3-(4-AMINOPHENYL)-1-propylpyrrolidine associated with (S)-3-(1,1-ditropan-2-yl)benzene-1-sulphonylchloride that gives specified in the header of the connection.

ESI-MS: 424,1 [M+H]+

Connection examples 35 to 58 receive the following similar methods.

Example 35

[4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-isoxazol-5-althofen-2-sulfonic acid

ESI-MS: 418,1 [M+H]+

Example 36

[4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-isoxazol-3-althofen-2-sulfonic acid

ESI-MS: 418,1 [M+H]+

Example 37

[4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-oxazol-5-yl-thiophene-2-sulfonic acid

ESI-MS: 418,1 [M+H]+

Example 38

3-((S)-2-Methylpyrrolidine-1-yl)-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

ESI-MS: 428,1 [M+H]+

Example 39

[4-(1-propylamide-3-yl)phenyl]amide thiophene-2-sulfonic acid

Following a methodology similar to that described to obtain compounds according to example 1.7, 4-(1-propylamide-3-yl)aniline associated with thiophene-2-sulphonylchloride that gives specified in the header of the connection.

ESI-MS: 337,0 [M+H]+

1H NMR (400 MHz, DMSO): δ (h/m) to 0.88 (t, 3H), of 1.45 (m, 2H), 3,11 (m, 2H), 3,97 (m, 3H), 4,22 (m, 1H), 4,35 (m, 1H), 7,11 (m, 3H), 7,29 (m, 2H), 7,54 (m, 1H), to 7.84 (m, 1H).

Por what measures 40

2,5-Dichloro-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 400,8 [M+H]+

Example 41

N-[4-(1-Propylamide-3-yl)phenyl]-3-triftoratsetilatsetonom

ESI-MS: 400,8 [M+H]+

Example 42

N-[4-(1-Propylamide-3-yl)phenyl] - for 3,5-bis-triftoratsetilatsetonom

ESI-MS: 467,1 [M+H]+

Example 43

2,5-Dimethyl-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 359,1 [M+H]+

Example 44

3-Chloro-4-fluoro-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: of 383.0 [M+H]+

Example 45

3-Fluoro-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-ESI-MS: 349,0 [M+H]+349,1

Example 46

[4-(1-propylamide-3-yl)phenyl]amide 2,5-dichlorothiophene-3-sulfonic acid

ESI-MS: 404,9 [M+H]+

Example 47

[4-(1-propylamide-3-yl)phenyl]amide 5-chlorothiophene-2-sulfonic acid

ESI-MS: 370,9 [M+H]+

Example 48

3-Chloro-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 365,1 [M+H]+

Example 49

3,5-Dichloro-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 400,8 [M+H]+

Example 50

3-Methyl-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 345,1 [M+H]+

Example 51

2,3-Dichloro-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MC 400,8 [M+H] +

Example 52

3-Bromo-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 410,9 [M+H]+

Example 53

[4-(1-propylamide-3-yl)phenyl]amide 5-isoxazol-3-althofen-2-sulfonic acid

ESI-MS: 404.0 [M+H]+

Example 54

3,4-Debtor-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 367,0 [M+H]+

Example 55

3-Cyano-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 356,3 [M+H]+

Example 56

4-Fluoro-3-oxazol-4-yl-N-[4-(1-propylamide-3-yl)phenyl]benzosulfimide

ESI-MS: 416,1 [M+H]+

Example 57

4-Fluoro-3-oxazol-4-yl-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

ESI-MS: 430,1 [M+H]+

Example 58

4-Fluoro-3-oxazol-5-yl-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

ESI-MS: 430,1 [M+H]+

Example 59

Hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-bromothiophene-2-sulfonic acid

59.1. Dimethyl ether (S)-2-phenylethanol acid

5 g of (S)-2-Phenylethanol acid (25,75 mmol) is dissolved in 50 ml of methanol. At a temperature of 4°C is added dropwise to 4.7 ml of thionyl chloride (64,37 mmol). The reaction mixture was stirred at room temperature for 2 hours, the solvents evaporated under reduced pressure. The remaining residue is dissolved in diethyl ether, washed the once saturated aqueous NaHCO 3re-extracted with diethyl ether and the combined organic layers are dried over magnesium sulfate, filtered and evaporated to dryness to obtain at the output of 5.8 g of the desired product.

ESI-MS: 223,1 [M+H]+

59.2. (S)-2-Phenylbutane-1,4-diol

of 2.54 g of sociallyengaged (66,95 mmol) is suspended under ice cooling in 25 ml of tetrahydrofuran. Slowly add 5.8 g (S)-2-phenylethanol acid dimethyl ester (25,75 mmol)dissolved in 25 ml of tetrahydrofuran at a temperature of 5-10°C. Stirring is continued for 15 minutes and then added dropwise 15 ml of a mixture of tetrahydrofuran/water (1:1). The pH value of the suspension was adjusted to 3-4 with concentrated hydrochloric acid, filtered and the filter washed with dichloromethane. The filtrate is evaporated to dryness, transferred into diethyl ether, washed with saturated sodium hydrogen carbonate solution, re-extracted with diethyl ether and the combined organic layers are dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output of 4.2 g of diol.

ESI-MS: 189,1 [M+Na]+

1H-NMR (CDCl3): δ [h/million] 7,25 to 7.4 (m, 2H), 7,15-to 7.3 (m, 3H), 4,2-of 4.35 (m, 2H), 3,2 (m, 1H), 3,1 (m, 1H), to 2.1-2.3 (m, 3H).

59.3. (S)-4-methanesulfonate-3-privately ether methanesulfonate acid

4,19 g (S)-2-Phenylbutane-1,4-diol (25,21 mmol) is dissolved in 50 ml of dichloromethane. Add Aut 10,53 ml of triethylamine (75,6 mmol) and under ice cooling, 5 ml of methanesulfonanilide (64,34 mmol). Stirring is continued for 15 minutes and then add 40 ml of water. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic layers are dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output of 8.37 g of the product.

59.4. (S)-3-Phenyl-1-propylpyrrolidine

2.0 g (S)-4-methanesulfonate-3-phenylbutyramide ether methanesulfonate acid (5.51 mmol) dissolved in 5 ml of n-Propylamine (60,82 mmol). The reaction mixture is stirred for 15 hours at room temperature, add diethyl ether, the organic phase is washed twice with water. The aqueous phase is re-extracted once with diethyl ether, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output of 1.09 g of product.

ESI-MS: 190,1 [M+H]+

59.5. (S)-3-(4-Nitrophenyl)-1-propylpyrrolidine

0.3 g (S)-3-phenyl-1-propylpyrrolidine (1.48 mmol) dissolved in 2 ml of concentrated sulfuric acid in an argon atmosphere and ice cooling. Add small portions 165,16 mg of potassium nitrate (1,63 mmol). The reaction mixture is stirred for 15 minutes under ice cooling for 15 hours at room temperature and poured on rezmelts the config ice. The aqueous solution is alkalinized with 25% sodium hydroxide solution, extracted three times with diethyl ether, the aqueous phase is re-extracted once with diethyl ether, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output 0,326 g of brownish oil. The second response provides a more 0,919 g of the desired product.

ESI-MS: 235,1 [M+H]+

1H-NMR (CDCl3): δ [h/million] of 8.15 (d, 2H), 7,45 (d, 2H), 3,4-3,5 (m, 1H), of 2.9-3.0 (m, 1H), 2,75 (m, 1H), 2,3-2,6 (m, 4H), 1,8-1,9 (m, 1H), 1,5-of 1.65 (m, 3H), of 0.95 (m, 3H).

59.6. (S)-3-(4-AMINOPHENYL)-1-propylpyrrolidine

0,907 g (S)-3-(4-Nitrophenyl)-1-propylpyrrolidine (3,59 mmol) was dissolved in 20 ml of methanol, add 7.0 g of tin dichloride (31,02 mmol) and the reaction mixture is stirred at the boiling temperature under reflux for one hour. The methanol evaporated, add 60 ml of 1 N sodium hydroxide solution and dichloromethane and the phases are separated after extensive mixing. The aqueous phase is extracted twice with dichloromethane, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain at the output 0,744 g of crude amino compounds.

ESI-MS: 205,2 [M+H]+

1H-NMR (DMSO-d6): δ [h/million] of 6.9 (d, 2H), 6,45 (d, 2H), 4,7 (users, 2H), 3,1 (m, 1H), 2,85 (m, 1H), 2,65 (m, 1H), to 2.55 (m, 1H), 2,25-2.45 m, 3H), 2,1 (m, 1H), 1,65 (m, 1H), 1,4-1,5 (m, 2H), 0,85 (m, 3H).

59.7. Hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-bromothiophene-2-sulfonic acid

400 mg of the hydrochloride of (S)-3-(4-AMINOPHENYL)-1-propylpyrrolidine (of 1.66 mmol) and 435 mg (0.33 mmol) of 5-bromothiophene-2-sulphonylchloride (of 1.66 mmol) dissolved in 15 ml of tetrahydrofuran. Add 1.2 ml of triethylamine (8.3 mmol) and the reaction mixture is stirred for 15 hours at room temperature. The solvents are evaporated under reduced pressure, the residue is treated with water and the pH adjusted to an alkaline value by using sodium hydroxide solution. The aqueous layer was extracted three times with diethyl ether, the organic layers combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude product is purified by chromatography on silica gel with a mixture ethyldichlorosilane/methanol (0-6%) as eluent, obtaining at the output 45 mg of the pure product. The specified product is dissolved in 10 ml of diethyl ether and add to 0.055 ml of 1 N HCl in diethyl ether and after the formation of the precipitate, the suspension is evaporated under reduced pressure, to obtain at the output 50 mg white precipitate.

ESI-MS: 431,0 [M+H]+

1H-NMR (DMSO): δ [h/million] of 11.2 and 11.0 (2C, user., 1H), 10,65 (m, 1H), 7,2-7,4 (several m, 4H), and 7.1 (m, 2H), 3,0-3,8 (several m, 7H), 2,3 (m, 1H), 1.85 to 2.0 (m, 1H), 1,7 (m, 2H), and 0.9 (m, 3H).

Example 60

[4-((S)-1-about iparralde-3-yl)phenyl]amide 5-propylthiophene-2-sulfonic acid

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using a 5-propylthiophene-2-sulphonylchloride, which, in turn, is obtained from commercially available 2-propylthiophene through reaction with chlorosulfonic acid.

ESI-MS: 393,1 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] of 7.3 (d, 1H), 7,2 (d, 2H), 7,05 (d, 2H), of 6.65 (d, 1H), 3,35 (m, 1H), 3,1 (m, 1H), 2,9 (m, 1H), 2,75 (m, 3H), 2,5 (m, 3H), 2,3 (m, 1H), of 1.85 (m, 1H), 1.5 and 1.7 (m, 4H), and 0.9 (m, 6H).

Example 61

The hydrochloride of 3-bromo-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]-4-triftormetilfullerenov

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 3-bromo-4-triftormetilfullerenov.

ESI-MS: 507,05/509,05 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] to 11.1 11.4 in (user., 1H), 10,6 (user., 1H), 8,15 (s, 1H), 7,9 (d, 1H), 7.7 (d, 1H), 7,35 (d, 1H), and 7.3 (d, 1H), and 7.1 (d, 2H), 3,2-3,8 (several m, 4H), 2.95 and-3,15 (several m, 3H), 2,8 (m, 1H), 1,95 (m, 1H), 1,7 (m, 2H), and 0.9 (t, 3H).

Example 62

[4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-chlorothiophene-2-sulfonic acid

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercial access the first 5-chlorothiophene-2-sulphonylchloride.

ESI-MS: 385,0 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] of 7.25 (d, 1H), 7,2 (d, 2H), 7,0 (d, 2H), 6,8 (d, 1H), 5,1 (users, 1H), 3,3 (m, 1H), 3,05 (m, 1H), 2,85 (m, 1H), and 2.7 (m, 1H), 2,4-2,6 (several m, 3H), 2,3 (m, 1H), 1.8 m (m, 1H), 1.55V (m, 2H), and 0.9 (t, 3H).

Example 63

The hydrochloride of N-(3-piperidine-3-ylphenyl)-3-triftormetilfullerenov

ESI-MS: 401,0 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,55 (user., 1H), 9,35 (user., 1H), 9,2 (user., 1H), and 7.8 (d, 1H), and 7.7 (m, 1H), 7,65 (m, 2H), 7,2 (t, 1H), 7,0 (m, 3H), of 3.25 (m, 1H), 3,2 (m, 1H), 2.8 to 3.0 (m, 3H), 1.7 to 1.9 (m, 3H), 1,5-of 1.65 (m, 1H).

Example 64

Hydrochloride 3-cyano-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 3-cyanobenzenesulfonyl.

ESI-MS: 370,4 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,8 (user., 2H), and 8.2 (s, 1H)and 8.1 (d, 1H), with 8.05 (d, 1H), and 7.8 (t, 1H), 7,25 (d, 2H), and 7.1 (d, 2H), 3,0-3,8 (several m, 7H), 2,3 (m, 1H), 1,95 (m, 1H), 1,7 (m, 2H), and 0.9 (t, 3H).

Example 65

N-[3-((S)-1-Benzylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 3-triftoratsetilatsetonom.

ESI-MS: 461,1 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] to 8.0 (s, 1H), 7,9 (d, 1H), of 7.75 (d, 1H), 7,55 (t, 1H), 7,2-7,4 (several m, 6H), to 7.15 (m, 1H), 7,05 (d, 1H), 6,95 (s, 1H), 6,9 (d, 1H), the 3.65 (s, 2H), 3,25 (m, 1H), 2.95 and (m, 1H), 2,75 (m, 2H), 2,45 (m, 1H, in), 2.25 (m, 1H), 1,75 (m, 1H).

Example 66

Hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-pyridin-2-althofen-2-sulfonic acid

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 5-pyridin-2-althofen-2-sulphonylchloride.

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] to 10.8 to 11.2 (user., 1H), 10,6 (m, 1H), 8,55 (d, 1H), 8.0 a (d, 1H), 7,9 (t, 1H), and 7.8 (d, 1H), and 7.6 (d, 1H), 7.3 to 7.4 (m, 2H), and 7.3 (d, 1H), 7,15 (m, 2H), and 3.8 (m, 1H), 3,65 (m, 1H), 3,6 (m, 1H), 3,3-3,5 (m, 1H), 3,25 (m, 1H), 3.0 to 3.15 in (m, 2H), 2,35 (m, 1H), 2.0 (m, 1H), 1,7 (m, 2H), and 0.9 (t, 3H).

Example 67

N-[3-((S)-Pyrrolidin-3-yl)phenyl]-3-triftoratsetilatsetonom

A solution of N-[3-((S)-1-benzylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom (620 mg, of 1.34 mmol) (example 65) in methanol (30 ml) hydronaut using the hydrogenation reactor ThalesNano H-Cube®, using a catalytic cartridge with 10% palladium-on-charcoal grill. After concentrating the solution under reduced pressure the crude product is purified by chromatography on silica gel with a mixture of ethyl acetate/methanol (1:1; 0:1) as eluent, obtaining at the output of 328 mg of the pure product.

ESI-MS: 371,0 [M+H]+

1H-NMR (MeOD, 400 MHz): δ [h/million] to 7.9 (m, 2H), and 7.7 (m, 1H), 7,55 (m, 1H), 7,0 (m, 1H), 6,7-6,85 (m, 3H), 3,2-3,3 (m, 2H), 3,05 is 3.15 (m, 2H), 3.0 a (m, 1H), and 2.7 (m, 1H), 2,1 (m, 1H), 1,7 (m, 1H).

Example 68

Hydrochloride [4-((S)-1-arylpyrimidine-3-yl)phenyl]amide 5-pyridin-2-althofen-2-sulfonic acid

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-bromothiophene-2-sulfonic acid (example 59), using commercially available 5-pyridin-2-althofen-2-sulphonylchloride and 4-((S)-1-arylpyrimidine-3-yl)phenylamine.

ESI-MS: 426,1 [M+H]+

Example 69

Hydrochloride ((S)-4-pyrrolidin-3-ylphenyl)amide 5-pyridin-2-althofen-2-sulfonic acid

36 mg Pd2(dba)3 (0.04 mmol) and 24 mg of 1,4-bis-(diphenylphosphino)butane (0.06 mmol) dissolved in 10 ml of tetrahydrofuran. After stirring for 20 minutes add [4-((S)-1-arylpyrimidine-3-yl)phenyl]amide 5-pyridin-2-althofen-2-sulfonic acid (235 mg, 0.55 mmol) (example 68) and 2-mercaptobenzoic acid (160 mg, 1.04 mmol), each in the form of a solution in 3 ml of tetrahydrofuran. The reaction mixture is stirred for 20 hours at room temperature. The solvents are evaporated under reduced pressure, the residue is dissolved in ethyl acetate and extracted with 0.5 N HCl. the pH of the aqueous phase adjusted to an alkaline value by using the solution of the sodium hydroxide and then extracted three times with dichloromethane. The organic layers are combined, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude product is purified using chromatography (Chromabond-C18) with a mixture of H2O/acetonitrile(95:5; 0:100; 95:5)/0,1% acetic acid as eluent. To the solution thus obtained oil in 2-propanol added HCl in diethyl ether. The formed solid is filtered off and dried in a vacuum oven, to obtain 8 mg specified in the connection header.

ESI-MS: 386,0 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] of 8.5 (d, 1H), 7,95 (d, 1H), a 7.85 (t, 1H), 7.7 (d, 1H), and 7.4 (d, 1H), and 7.3 (m, 1H), and 7.1 (d, 2H), 7,0 (d, 2H), 3,4 (m, 1H), 3,2-3,3 (m, 2H), 3,1 (m, 1H), 2,85 (m, 1H), 2,2 (m, 1H), 1,7-of 1.85 (m, 1H).

Example 70

3-Bromo-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 3-bromobenzonitrile.

ESI-MS: 423,0/425,0 [M+H]+

Example 71

N-[4-((S)-1-Propylpyrrolidine-3-yl)phenyl]-3-pyrrolidin-1-albenzaalbenza

0.4 g of 3-Bromo-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide (0,94 mmol), 0,156 ml pyrrolidine (1,89 mmol), 160 mgtert-butyl sodium(from 1.66 mmol) and 540 mg of sodium sulphate is dissolved in 15 ml of tetrahydrofuran and heated to a temperature of 50°Stabilat 120 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0,19 mmol) and 85 mg three(dibenzylideneacetone)diplegia(0) (0.09 mmol) and the reaction mixture is stirred for 4 hours at boiling temperature under reflux. After processing the partially entered into the initial reaction product interacts again in the same reaction conditions until the reaction is completed. The solvents are evaporated under reduced pressure, the residue is treated with dichloromethane and water, the organic layers dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude product is purified by chromatography on silica gel with a mixture of dichloromethane/methanol (0-20%) as eluent, using a semi-automatic device ISCO Companion, receiving the output 0,309 g of the pure product.

ESI-MS: 414,1 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] to 7.2 (m, 1H), 7,15 (d, 2H), 7,0 (m, 3H), 6,8 (s, 1H), 6,65 (d, 1H), 3,3 (m, 1H), 3,2 (m, 4H), 3.0 a (m, 1H), 2,8 (m, 1H), and 2.6 (m, 1H), 2,3-2,5 (several m, 3H), of 2.25 (m, 1H), 2,0 (m, 4H), of 1.75 (m, 1H), 1,5 (m, 2H), and 0.9 (t, 3H).

Example 72

Hydrochloride 3-(2-methylpyrrolidine-1-yl)-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

is 0.023 g of the desired product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 71.

ESI-MS: 428,2/443,0 [M+H]+

1H-NMR (DMSO-d6): δ [h/million] to 10.8 to 11.2 (user., 1H), 10,2 (m, 1H), 7,2-7,35 (several m, 3H), and 7.1 (m, 2H), 6,95 (d, 1H), 6,8 (s, 1H), 6,7 (d, 1H), 2,9-3,9 (several m, 8H), 2,3 (m, 1H), 1,8-2,1 (several m, 4H), 1,6-1,75 (several m, 3H), and 1.0 (d, 3H), and 0.9 (t, 3H).

Example 73

Hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)FeNi is]amide 5-pyrazole-1-althofen-2-sulfonic acid

0.2 g of [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-bromothiophene-2-sulfonic acid (0.47 mmol), 0,038 g of pyrazole (0,56 mmol), 0.005 g of Cu2O (0.03 mmol), 0.015 g salicylaldoxime (0.11 mmol) and 0.3 g of cesium carbonate (0,93 mmol) dissolved in 3 ml of acetonitrile and heated in the system of microwave irradiation (CEM) at a temperature of 120°C for 4 hours. The reaction mixture was filtered through celite, the filtrate evaporated under reduced pressure, the residue is treated with dichloromethane and water and the organic layer was washed with saturated aqueous sodium chloride. The organic phase is evaporated under reduced pressure and the crude product purified using preparative HPLC, which in turn yields 0.02 g of the pure product.

ESI-MS: 417,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,65-11,0 (user., 1H), 10,55 (s, 1H), 8,55 (s, 1H), and 7.8 (s, 1H), and 7.5 (s, 1H), 7,35 (d, 2H), and 7.3 (m, 1H), 7,15 (d, 2H), and 6.6 (s, 1H), 2,9-3,85 (several m, 7H), 2.3 to 2.4 (m, 1H), 1.85 to 2.1 a (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 74

Hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 4,5-dichlorothiophene-2-sulfonic acid

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 4,5-dichlorothiophene-2-sulphonylchloride.

ESI-MS: 419/421 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] to 10.9 to 11.2 (user., 1H), and 10.8 (1H), to 7.7 (s, 1H), and 7.4 (d, 1H), and 7.3 (d, 1H), 7,2 (d, 2H), and 3.8 (m, 1H), 3,2-3,7 (several m, 3H), 2.95 and-3,2 (m, 3H), 2,35 (m, 1H), 1,9-2,1 (m, 1H), of 1.6-1.8 (m, 2H), and 0.9 (t, 3H).

Example 75

Hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-[1,2,3]thiadiazole-4-althofen-2-sulfonic acid

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 5-[1,2,3]thiadiazole-4-althofen-2-sulphonylchloride.

ESI-MS: 435,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,55-10,85 (user., 1H), a 10.6 (s, 1H), and 9.7 (s, 1H), and 7.8 (d, 1H), 7,65 (d, 1H), 7.3 to 7.4 (m, 2H), 7,2 (d, 2H), 3,2-3,8 (several m, 4H), 2.95 and-3,2 (m, 3H), 2,35 (m, 1H), 1.85 to 2.1 a (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 76

Hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-triptorelin-2-sulfonic acid

5-Triptorelin-2-sulphonylchloride obtained from commercially available 2-triptorelin through reaction with chlorosulfonic acid in dichloromethane followed by chromatography on a column of silica gel (1H-NMR sulphonylchloride (CDCl3, 400 MHz): δ [h/million] of 7.9 (1H, d), and 7.5 (1H, d)).

ESI-MS: 419,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10.8V-11.1V (user., 2H), and 7.8 (d, 1H), 7,65 (d, 1H), 7,25 to 7.4 (osirm, 2H), 7,1-7,2 (d, 2H), 3,2-3,9 (several m, 4H), 2,9-3,2 (m, 3H), 2,35 (m, 1H), 1.85 to 2.1 a (m, 1H), of 1.6-1.8 (m, 2H), of 0.95 (t, 3H).

Example 77

The hydrochloride of N-[3-((S)-1-methylp Raiden-3-yl)phenyl]-3-triftoratsetilatsetonom

The product is obtained after reductive amination of N-[3-((S)-pyrrolidin-3-yl)phenyl]-3-triftoratsetilatsetonom (example 67) with formaldehyde and triacetoxyborohydride sodium in dichloromethane in the presence of acetic acid.

ESI-MS: 385,0 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,5-11,0 (user., 2H), and 7.9 to 8.1 (m, 3H), and 7.8 (m, 1H), 7,25 (m, 1H), and 7.1 (m, 1H), and 7.1 (s, 1H), 6,95 (d, 1H), 3,0-3,8 (m, 5H), 2,85 (s, 3H), 2,3 (m, 1H), 1.85 to 2.05 is (m, 1H).

Example 78

[4-((S)-1-Propylpyrrolidine-3-yl)phenyl]amide 5-(2-methylthiazole-4-yl)thiophene-2-sulfonic acid

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 5-(2-methylthiazole-4-yl)thiophene-2-sulphonylchloride.

ESI-MS: 448,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] a 9.7-11,0 (user., 1H), and 8.0 (s, 1H), 7.5 (d, 1H), 7,45 (d, 1H), 7,2 (d, 2H), and 7.1 (d, 2H), 3,25 (m, 1H), 2,84 (m, 1H), and 2.7 (s, 3H), 2,6-2,7 (m, 2H), 2,3-2,5 (m, 3H), 2,1-2,2 (m, 1H), 1.6 to 1.7 (m, 1H), 1,4-1,5 (m 2N), to 0.8-0.9 (t, 3H).

Example 79

N-[3-((S)-pyrrolidin-3-yl)phenyl]-2-fluoro-5-triftoratsetilatsetonom

The product is obtained as described for the synthesis of N-[3-((S)-pyrrolidin-3-yl)phenyl]-3-triftoratsetilatsetonom (example 67). Removing protection from N-benzyl derivative can be achieved by hydrogenation in the H-cube™.

ESI-MS: 389,1 [M+H]+

Example 80

N-[3-((S)-Pierre is lidin-3-yl)phenyl]-3-fluoro-5-triftoratsetilatsetonom

The product is obtained as described for the synthesis of N-[3-((S)-pyrrolidin-3-yl)phenyl]-3-triftoratsetilatsetonom (example 67). Removing protection from N-benzyl derivative can be achieved by hydrogenation in the H-cube™.

ESI-MS: 389,0 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] of 7.8 (s, 1H), 7,7-7,8 (m, 2H), 6,95 (t, 1H), 6,8 (s, 1H), 6.75 in (d, 1H), and 6.6 (d, 1H), 5,8 (very broad, 2H), 3.45 points (m, 1H), 3,3 (m, 1H), 3,1-of 3.25 (m, 2H), 2,85 (m, 1H), 2,2 (m, 1H), of 1.75 (m, 1H).

Example 81

N-[3-((S)-pyrrolidin-3-yl)phenyl]-4-fluoro-5-triftoratsetilatsetonom

The product is obtained as described for the synthesis of N-[3-((S)-pyrrolidin-3-yl)phenyl]-3-triftoratsetilatsetonom (example 67). Removing protection from N-benzyl derivative can be achieved by hydrogenation in the H-cube™.

ESI-MS: 389,0 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] with 8.05 (m, 1H), 8.0 a (m, 1H), and 7.6 (t, 1H), 7,0 (m, 2H), 6,85 (s, 1H), 6,8 (d, 1H), 6,7 (d, 1H), 5,8 (very broad, 2H), 3,4 (m, 1H), 3,2 (m, 2H), 3,1 (m, 1H), 2,85 (m, 1H), 2,2 (m, 1H), a 1.75 (m, 1H).

Example 82

N-[3-((S)-pyrrolidin-3-yl)phenyl]-2-methoxy-5-triftoratsetilatsetonom

The product is obtained as described for the synthesis of N-[3-((S)-pyrrolidin-3-yl)phenyl]-3-triftoratsetilatsetonom (example 67). Removing protection from N-benzyl derivative can be achieved by hydrogenation in the H-cube™.

ESI-MS: 401,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] to 8.0 (s, 1H), 7,9 (m, 1H), 7,35 (d, 1H), and 7.1 (m, 1H), 7,0 (m, 1H), 6,85-to 6.95 (m, 2H), 3,9(s, 3H), of 3.0-3.4 (several m, 4H), to 2.65 (m, 1H), 2,1 (m, 1H), 1,6 (m, 1H).

Example 83

3,5-Dibromo-4-(2-floratone)-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

The corresponding sulphonylchloride obtained from commercially available 2,6-dibromophenol through reaction with 1-bromo-2-floridanum and cesium carbonate and subsequent formation sulphonylchloride through reaction with chlorosulfonic acid (1H-NMR (CDCl3, 400 MHz) 3,5-dibromo-4(2-floratone)phenylsulfonylacetate: δ [h/million] of 8.2 (s, 2H), 4,9 (m, 1H), and 4.8 (m, 1H), 4,45 (m, 1H), 4,4 (m, 1H)).

ESI-MS: 565,0 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] a 7.85 (s, 2H), 7,2 (d, 2H), 7,0 (d, 2H), around 4.85 (m, 1H), 4,7 (m, 1H), 4,35 (m, 1H), 4,25 (m, 1H), 3,35 (m, 1H), 3,1 (m, 1H), 2,9 (m, 1H), 2,8 (m, 1H), 2,45 of 2.6 (m, 3H), 2,3 (m, 1H), of 1.85 (m, 1H), 1,6 (m, 2H), of 0.95 (t, 3H).

Example 84

Hydrochloride 3-deformedarse-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 3-deformatsiyalanuvchi.

ESI-MS: 411,5 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,2-11,1 (very broad, 2H), 7,65 (m, 2H), and 7.5 (s, 1H), 7,45 (m, 1H), 7,25 (m, 2H), and 7.1 (m, 2H), 3,1-3,8 (m, 5H), 3,1 (m, 2H), 2,3 (m, 1H), 1,9-2,0 (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 85

5-Bromo-2,4-debtor-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]baselslt the amide

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 5-bromo-2,4-differentialalgebraic.

ESI-MS: 459,0/461,0 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,9 (very wide)and 8.1 (t, 1H), of 7.75 (t, 1H), and 7.3 (d, 2H), and 7.1 (d, 2H), 3,15 to 3.8 (m, 5H), 3,1 (m, 2H), 2,35 (m, 1H), 1,9-2,0 (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 86

The hydrochloride of 3-bromo-2,4-debtor-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 3-bromo-2,4-differentialalgebraic.

ESI-MS: 459,4/461,4 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,9 (very wide), 7,9 (square, 1H), 7,45 (t, 1H), and 7.3 (d, 2H), and 7.1 (d, 2H), 3,15 to 3.8 (m, 5H), 3,1 (m, 2H), 2,3 (m, 1H), 1,9-2,0 (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 87

The hydrochloride of N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl] - for 3,5-bis-triftoratsetilatsetonom

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 3,5-bis-triftormetilfullerenov.

ESI-MS: 481,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,8 (of all the ü wide), of 8.5 (s, 1H), 8,25 (s, 2H), and 7.3 (d, 2H), and 7.1 (d, 2H), 3,15 to 3.7 (m, 5H), 3,1 (m, 2H), 2,3 (m, 1H), 1,9-2,0 (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 88

The hydrochloride of 3-bromo-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]-5-triftoratsetilatsetonom

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 3-bromo-5-triftoratsetilatsetonom.

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] to 10.7 (very wide), and 8.3 (s, 1H), 8,15 (s, 1H), 7,95 (s, 1H), and 7.3 (d, 2H), and 7.1 (d, 2H), 3,15 to 3.7 (m, 5H), 3,1 (m, 2H), 2,25-2,4 (m, 1H), 1.85 to 2.05 is (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 89

The hydrochloride of N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]-2,5-bis-triftoratsetilatsetonom

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 2,5-bis-triftoratsetilatsetonom.

ESI-MS: 481,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,5-11,0 (very wide), 8,35 (s, 1H), 8,25 (s, 2H), 7,3 (user., 2H), and 7.1 (d, 2H), and 3.2 to 3.8 (m, 4H), 2,9-3,1 (m, 3H), 2,25-2,4 (m, 1H), 1,8-2,05 (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 90

Hydrochloride [4-((S)-1-propylpyrrolidine-3-yl)phenyl]amide 5-methylthiophene-2-sulfonic acid

Specified in the header of the product is obtained by following the method of synthesis, similar to what I described to obtain the compound from example 59, using commercially available 5-methylthiophene-2-sulphonylchloride.

ESI-MS: 365,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] of 11.1 to 11.2 (very wide), 10,85-11,0 (very wide), 10,4 (m, 1H), and 7.4 (d, 1H), and 7.3 (d, 1H), 7,25 (d, 1H), and 7.1 (d, 2H), 6,8 (s, 1H), and 3.2 to 3.8 (m, 4H), 2.95 and-3,2 (m, 3H), of 2.45 (s, 3H), 2,25-2,4 (m, 1H), 1.85 to 2.1 a (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 91

2-Methoxy-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]-5-triftoratsetilatsetonom

Specified in the header of the product is obtained by following the procedure of synthesis similar to that described to obtain the compound from example 59, using commercially available 2-methoxy-5-triftoratsetilatsetonom.

ESI-MS: 443,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,9 (very wide), of 10.25 (very wide), to 7.95 (m, 2H), and 7.4 (d, 1H), and 7.3 (d, 2H), and 7.1 (d, 2H), 3,95 (s, 3H), of 2.9 to 3.8 (several m, 7H), of 2.25 to 2.35 (m, 1H), 1,8-2,0 (m, 1H), 1,6-of 1.75 (m, 2H), and 0.9 (t, 3H).

Example 92

N-((R)-3-Pyrrolidin-3-ylphenyl)-3-triftoratsetilatsetonom

The product is obtained as described for the synthesis of N-[3-((S)-pyrrolidin-3-yl)phenyl]-3-triftoratsetilatsetonom (example 67). Removing protection from N-benzyl derivative can be achieved by hydrogenation in the H-cube™.

ESI-MS: 371,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] to 8.0 (m, 2H), a 7.85 (d, 1H), and 7.7 (m, 1H), 7,0 (t, 1H), 6,85 (s, 1H), 6,8 (d, 1H), 6,7 (d, 1H), 3,35 (m, 1H), 3,0-3,2 (m, 3H), of 2.75 (m, 1H), 2,05-2,2 (m, 1H), 1,6-of 1.75 (m, 1H).

Example 93

3-(2-Methylthiazole-4-yl)-N-((S)-3-pyrrolidin-3-ylphenyl)benzosulfimide

The product is obtained as described for the synthesis of N-[3-((S)-pyrrolidin-3-yl)phenyl]-3-triftoratsetilatsetonom (example 67). Removing protection from N-benzyl derivative is achieved through the hydrogenation ammonitrates and 10% Pd/C.

ESI-MS: 400,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] and 8.4 (s, 1H)and 8.1 (d, 1H), and 8.0 (s, 1H), 7,65 (d, 1H), 7,55 (t, 1H), and 7.1 (t, 1H), 7,0 (s, 1H), 6.8 or 6.9 (m, 2), 3,2 (m, 1H), 2,85-3,1 (m, 3H), and 2.7 (s, 3H), by 2.55 (m, 1H), 2,0-2,1 (m, 1H), 1,5-of 1.65 (m, 1H).

Example 94

The hydrochloride of N-[4-((3S,5R)-5-methyl-1-propylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom

The product is obtained through the following intermediate compounds:

94.1. 1-tert-Butyl ester 2-methyl ester (2S,4S)-4-phenylpyrrolidine-1,2-dicarboxylic acid

4,48 g of a commercially available (2S,4S)-Boc-4-phenylpyrrolidine-2-carboxylic acid (shed 15.37 mmol) is dissolved in 50 ml of dimethylformamide. Add 2,59 g of potassium carbonate (18,76 mmol) and 2.66 g under the conditions (18,76 mmol) and the reaction mixture is stirred for 48 hours at room temperature. Standard treatment with ethyl acetate gives the output of 5.3 g of the product.

ESI-MS: 206,1 (-Boc), 250,1 (-tBu) [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] a 7.2 to 7.35 (m, 5H), 4,4-4,55 (m, 1H), 3,9-4,1 (m, 1H, in), 3.75 (s, 3H), 3,55 (m, 1H), 3,4 (m, 1H), 2,35 (m, 2H), 1,45 (m, 9H).

94.2.tert-Butyl e is Il (2S,4S)-2-hydroxymethyl-4-phenylpyrrolidine-1-carboxylic acid

of 4.2 g of 1-tert- Butyl ester 2-methyl ester (2S,4S)-4-phenylpyrrolidine-1,2-dicarboxylic acid (of 13.75 mmol) in 30 ml of tetrahydrofuran is added slowly to a suspension of 0.27 g of sociallyengaged in 50 ml of tetrahydrofuran. Stirring is continued for 5 hours at a temperature of 0-5°C for 14 hours at room temperature. For processing to the reaction mixture slowly add a mixture of tetrahydrofuran/water (1:1) at 0°C. the solvent is Then evaporated under reduced pressure, water is added and the pH was adjusted to approximately 5 with 20% aqueous citric acid solution. The aqueous phase is extracted four times with ethyl acetate, the organic layers combined, dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure, to obtain at the output of 3.85 g of the product.

ESI-MS: 222,1 (-tBu) [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] of 7.2 to 7.4 (m, 5H), to 4.15 (m, 1H), 3,65 to 3.8 (m, 3H), at 3.35 to 3.5 (m, 2H), 3,1 (user., 1H), 2,15 (m, 1H), 2.05 is (m, 1H), and 1.5 (s, 9H).

94.3.tert-Butyl ester of (2S,4S)-2-methanesulfonylaminoethyl-4-phenylpyrrolidine-1-carboxylic acid

To 2.5 gtert-butyl ester (2S,4S)-2-hydroxymethyl-4-phenylpyrrolidine-1-carboxylic acid (9,01 mmol) in 70 ml of dichloromethane added 1.92 g of triethylamine (18,02 mmol) and 1.03 g of methanesulfonamide (9,01 mmol)dissolved in 5 ml of dichloromethane. The reaction mixture was peremeci is up for 16 hours at room temperature and get the output of 3.4 g of the product after standard processing.

ESI-MS: 300,1 (-tBu) [M+H]+

94.4.tert-Butyl ester (2R,4S)-2-methyl-4-phenylpyrrolidine-1-carboxylic acid

3.4 gtert-butyl ester (2S,4S)-2-methanesulfonylaminoethyl-4-phenylpyrrolidine-1-carboxylic acid (9,56 mmol) is dissolved in 50 ml of tetrahydrofuran. After addition of 15.1 ml ltigkeitsbereich (14,34 mmol; 1 M in tetrahydrofuran) is added 1,93 ml of triethylborane (1M in tetrahydrofuran) and the reaction mixture is stirred at the boiling temperature under reflux for 20 minutes. Standard processing gives 2.7 g of crude product which is purified by chromatography on silica gel using ISCO Companion device, receiving the output 1,69 g of the pure product.

ESI-MS: 206,1 (-tBu) [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] a 7.2 to 7.35 (m, 5H), 3,9-4,0 (m, 1H), 3,7 (m, 1H), 3,5 (m, 1H), 3.15 in (m, 1H), 2,3 (d, 3H), of 2.15 (m, 1H), and 1.9 (m, 1H), and 1.4 (s, 9H).

94.5. (2R,4S)-2-Methyl-4-phenylpyrrolidine

1.68 gtert-Butyl ester (2R,4S)-2-methyl-4-phenylpyrrolidine-1-carboxylic acid (6.42 per mmol) was dissolved in 40 ml dichloromethane and added dropwise to 19.2 ml (38,56 mmol) of 2 N HCl in diethyl ether. After stirring at room temperature for 16 hours, the solvent evaporated, the residue is dissolved in water, the pH adjusted to pH 9 with aqueous sodium hydroxide solution and the aqueous phase is shaken out three times with ethyl acetate. The organic phases are combined the comfort, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure, to obtain at the output of 1.05 g of the product.

ESI-MS: 162,2 [M+H]+

94.6. (2R,4S)-2-methyl-4-phenyl-1-propylpyrrolidine

of 1.05 g of (2R,4S)-2-Methyl-4-phenylpyrrolidine (6,51 mmol) dissolved in 30 ml of dichloromethane, of 0.58 g of acetic acid, 0.56 g of propionic aldehyde (9,76 mmol) and slowly add portions 2,07 g triacetoxyborohydride sodium (9,76 mmol). After stirring at room temperature for 90 minutes, the solvent is evaporated, water is added and the pH adjusted to 6. The aqueous phase is shaken out three times with ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure, to obtain at the output of 1.48 g of product.

ESI-MS: to 204.1 [M+H]+

Nitration and subsequent reduction of the nitro group with tin dichloride and binding of aniline with 3-triftormetilfullerenov performed, as already described for the compounds according to other examples, to obtain the output 0,088 g of the hydrochloride of N-[4-((3S,5R)-5-methyl-1-propylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom.

ESI-MS: 427,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,65 (user., 1H), and 10.5 (1H), 7.95 is to 8.1 (m, 3H), and 7.8 (t, 1H), 7,25 (d, 2H), 7,15 (d, 2H), and 3.8 (m, 1H), 3,65 (m, 1H), 3,5 (m, 1H), 3,25 (m, 1H), 3.0 a (m, 1H), 2.95 and (m, 1H), 2,2 (m, 1H), 2,1 (m, 1H), 1,7 (m, 2H)and 1.4 (d, 3H), and 0.9 (t, 3H).

the example 95

N-[4-(TRANS-4-Vermeil-1-propylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom

The product is obtained through the following intermediate compounds:

95.1.tert-Butyl ether TRANS-3-vermeil-4-phenylpyrrolidine-1-carboxylic acid

1.5 gtert-butyl ether TRANS-3-hydroxymethyl-4-phenylpyrrolidine-1-carboxylic acid (5.41 mmol) was dissolved in 20 ml dichloromethane and added 1.31 g diethylaminosulfur (DAST, 8.1 mmol) in 2 ml dichloromethane at 0°C. the Reaction mixture is stirred for 72 hours at room temperature, then add dichloromethane and water, the organic phase is separated, dried over magnesium sulfate, filtered and evaporated to dryness to obtain at the output of 1.7 g oil light yellowish color. The crude product is purified by chromatography on silica gel using a mixture of n-heptane/ethyl acetate (6:4) as eluent, to obtain at the output of 1.08 g of the product.

ESI-MS: 224,1 (-Boc) [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] of 7.2 to 7.4 (m, 5H), of 4.45 (m, 0,5H), 4,35 (m, 1H), 4,25 (m, 0,5H), to 3.9 (m, 1H), and 3.8 (m, 1H), 3,3-3,5 (m, 2H), 3,2 (m, 1H), 2.5 and 2.7 (m, 1H), 1,45 (s, 9H).

95.2 TRANS-3-Vermeil-4-phenylpyrrolidine

ESI-MS: 180,1 [M+H]+

95.3 TRANS-3-Vermeil-4-phenyl-1-propylpyrrolidine

ESI-MS: 222,1 [M+H]+

95.4 TRANS-3-Vermeil-4-(4-nitrophenyl)-1-propylpyrrolidine

ESI-MS: 267,1 [M+H]+/p>

95.5 TRANS-3-Vermeil-4-(4-AMINOPHENYL)-1-propylpyrrolidine

ESI-MS: 237,1 [M+H]+

Binding of TRANS-3-vermeil-4-(4-AMINOPHENYL)-1-propylpyrrolidine with 3-triftormetilfullerenov using the methods previously described for the other examples, provides a 0,155 g of N-[4-(TRANS-4-vermeil-1-propylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom.

ESI-MS: 445,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,6 (user., 1H), and 8.0 to 8.1 (m, 2H), 7,95 (s, 1H), and 7.8 (t, 1H), 7,25 (d, 2H), 7,05 (d, 2H), 4,4 (m, 1H), 4,3 (m, 1H), 3,3 (m, 1H), 3,2 (m, 1H), 3,1 (m, 1H), 2,9 (m, 2H), 2,75 (m, 2H), by 2.55 (m, 1H), 1,5-1,6 (m, 2H), and 0.9 (t, 3H).

Example 96

Hydrochloride 3-(5-methyl-[1,3,4]oxadiazol-2-yl)-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

0,047 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide (example 1), using commercially available 3-(5-methyl-[1,3,4]oxadiazol-2-yl)benzosulphochloride.

ESI-MS: 427,0 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] and 8.4 (s, 1H), and 8.2 (d, 1H), 7,9 (d, 1H), 7,55 (t, 1H), 7,15 (d, 2H), 7,0 (d, 2H), 3,35 (m, 1H), 3,1 (m, 1H), 2,9 (m, 1H), 2,8 (m, 1H), and 2.6 (s, 3H), by 2.55 (m, 3H), 2,3 (m, 1H), of 1.85 (m, 1H), 1,6 (m, 2H), of 0.95 (t, 3H).

Example 97

3-Fluoro-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide triptorelin

0,0065 g of the desired product is obtained by following the methodology with which NASA, similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide (example 1), using commercially available 3-forbindelsesfaneblad.

ESI-MS: 363,1 [M+H]+

Example 98

3-Chloro-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

amount of 0.118 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide using commercially available 3-chlorobenzenesulfonamide.

ESI-MS: 379,1 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] of 7.75 (s, 1H), and 7.6 (d, 1H), 7.5 (d, 1H), 7,35 (m, 1H), 7,15 (d, 2H), 7,0 (d, 2H), 3,3 (m, 1H), 3.0 a (m, 1H), 2,8 (m, 1H), and 2.7 (m, 1H), 2,4-by 2.55 (m, 3H), 2,3 (m, 1H), 1.8 m (m, 1H), 1.55V (m, 2H), of 0.95 (t, 3H).

Example 99

3-(2-Methylthiazole-4-yl)-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

0,113 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide (example 1), using commercially available 3-(2-methylthiazole-4-yl)benzosulphochloride.

ESI-MS: 442,0 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] and 8.4 (s, 1H), with 8.05 (d, 1H), 7.7 (d, 1H), and 7.4 (m, 2H), 7,15 (d, 2H), 7,05 (d, 2H), 3,55 (m, 2H), 3,2-3,5 (osirm, 2H), of 2.9-3.0 (m, 3H), and 2.7 (s, 3H), 2,35 (m, 1H), 2,0-2,1 (m, 1H), of 1.75 to 1.9 (m, 2H), of 0.95 (t, 3H).

Por the measures 100

N-[4-((S)-1-Arylpyrimidine-3-yl)phenyl]-3-triftoratsetilatsetonom

0.01 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide (example 1), using commercially available 3-triftoratsetilatsetonom.

ESI-MS: 411,1 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] of 7.95 (s, 1H), 7,9 (d, 1H), and 7.8 (d, 1H), and 7.6 (t, 1H), 7,15 (d, 2H), 6,95 (d, 2H)and 5.9 (m, 1H), and 5.2 (d, 1H), 5,1 (d, 1H), 3,3 (m, 1H), 3,1-3,2 (m, 2H), 3.0 a (m, 1H), 2,8 (m, 1H), 2,65 (m, 1H), 2,45 (m, 1H), 2,3 (m, 1H), 1.8 m (m, 1H).

Example 101

N-((S)-4-Pyrrolidin-3-ylphenyl)-3-triftoratsetilatsetonom

0,071 g of Tris-(dibenzylideneacetone)diplegia(0) (0.08 mmol) and 0,033 g of 1,3-bis(diphenylphosphino)butane (0.08 mmol) was dissolved in 20 ml of tetrahydrofuran and stirred for 30 minutes. To the resulting solution was added 0.32 g of N-[4-((S)-1-arylpyrimidine-3-yl)phenyl]-3-triftoratsetilatsetonom (0.78 mmol)dissolved in 5 ml of tetrahydrofuran, and then 0,129 g 2-mercaptobenzoic acid (0.84 mmol). The reaction mixture was stirred at room temperature for 72 hours, the solvent evaporated and add dichloromethane and 1 N aqueous solution of hydrochloric acid. The pH value of the aqueous phase is brought to a basic, extracted with dichloromethane and the combined organic layers washed with water concrete is sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The crude product is purified by chromatography on silica gel using ISCO Companion device to receive the output 0.01 g of product.

ESI-MS: 371,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] to 8.0 (d, 1H), 7,95 (s, 1H), and 7.8 (d, 1H), and 7.7 (t, 1H), 6,95 (d, 2H), 6,85 (d, 2H), 3,3 (m, 1H), 3,05-3,2 (m, 2H), 3.0 a (m, 1H), and 2.7 (m, 1H), 2,1 (m, 1H), 1,7 (m, 1H).

Example 102

4-Fluoro-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom

0,253 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide (example 1), using commercially available 3-trifluoromethyl-4-forbindelsesfaneblad.

ESI-MS: 431,2 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,5 (user., 1H), 8,1 (m, 1H), with 8.05 (d, 1H), of 7.75 (t, 1H), 7,25 (d, 2H), 7,05 (d, 2H), 3,2-3,6 (m, 5H), 3.0 a (m, 2H), 2,3 (m, 1H), and 1.9 (m, 1H), 1,65 (m, 2H), and 0.9 (t, 3H).

Example 103

Hydrochloride 3-fluoro-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]-5-triftoratsetilatsetonom

0,080 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide (example 1), using commercially available 3-fluoro-5-triftoratsetilatsetonom.

ESI-MS: 431,4 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,55 (OSiR.), of 8.1 (d, 1H), 7,9 (d, 1H), and 7.8 (s, 1H), and 7.3 (d, 2H), and 7.1 (d, 2H), 3,2-3,6 (m, 5H), 3,1 (m, 2H), 2,3 (m, 1H), 1,95 (m, 1H), 1,7 (m, 2H), and 0.9 (t, 3H).

Example 104

2-Fluoro-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]-5-triftoratsetilatsetonom

0,103 g of the desired product is obtained by following the procedure of synthesis similar to that described for the preparation of 3-triptoreline-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide (example 1), using commercially available 2-fluoro-5-triftoratsetilatsetonom.

ESI-MS: 431,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] to 10.7 (very broad, 1H), 8,1 (m, 1H), with 8.05 (d, 1H), and 7.7 (t, 1H), 7,25 (d, 2H), 7,05 (d, 2H), 3,1-3,6 (m, 5H), of 2.9-3.0 (m, 2H), 2,3 (m, 1H), of 1.85 (m, 1H), 1,6 (m, 2H), and 0.9 (t, 3H).

Example 105

3-Morpholine-4-yl-N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]benzosulfimide

0,033 g of the desired product is obtained by following the procedure of synthesis similar to that described to obtain N-[4-((S)-1-propylpyrrolidine-3-yl)phenyl]-3-pyrrolidin-1-albenzaalbenza (example 71), using morpholine as the amine.

ESI-MS: 430,5 [M+H]+

1H-NMR (CDCl3, 400 MHz): δ [h/million] a 7.2 to 7.35 (m, 2H), 7,1-7,2 (m, 3H), 6,95-7,05 (m, 3H), and 3.8 (t, 4H), 3,3 (m, 1H), 3,1 (t, 4H), 3,05 (m, 1H), 2,85 (m, 1H), and 2.7 (m, 1H), 2,4-2,6 (m, 3H), 2,3 (m, 1H), 1.8 m (m, 1H), 1.55V (m, 2H), of 0.95 (t, 3H).

Example 106

The hydrochloride of N-[4-(CIS-2-methyl-1-propylpyrrolidine-3 is)phenyl]-3-triftoratsetilatsetonom

0.015 g of product is obtained, as described for the synthesis of N-[4-((3S,5R)-5-methyl-1-propylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom (example 94) from commercially available Boc-CIS-3-phenylpyrrolidine-2-carboxylic acid:

106.1. 1-tert-Butyl ester 2-methyl ester CIS-3-phenylpyrrolidine-1,2-dicarboxylic acid

ESI-MS: 206,1 (-Boc), 250,1 (-tBu) [M+H]+

106.2.tert-Butyl ether CIS-2-hydroxymethyl-3-phenylpyrrolidine-1-carboxylic acid

ESI-MS: 222,1 (-tBu) [M+H]+

106.3.tert-Butyl ether CIS-2-methanesulfonylaminoethyl-3-phenylpyrrolidine-1-carboxylic acid

ESI-MS: 256,2 (-Boc), 299,9 (-tBu) [M+H]+

106.4.tert-Butyl ether CIS-2-methyl-3-phenylpyrrolidine-1-carboxylic acid

ESI-MS: 206,1 (-tBu) [M+H]+

106.5. CIS-2-Methyl-3-phenylpyrrolidine

ESI-MS: 162,1 [M+H]+

106.6. CIS-2-Methyl-3-phenyl-1-propylpyrrolidine

ESI-MS: to 204.1 [M+H]+

106.7. CIS-2-Methyl-3-(4-nitro)phenyl-1-propylpyrrolidine

ESI-MS: 249,1 [M+H]+

106.8. CIS-2-Methyl-3-(4-amino)phenyl-1-propylpyrrolidine

ESI-MS: 219,1 [M+H]+

Binding of aniline with 3-triftormetilfullerenov performed, as already described for the compounds according to other examples, to obtain at the output of 0.015 g of the final product.

ESI-MS: 427,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,3 (very Shir.), to 8.0 (d, 1H), 7,95 (d, 1H), a 7.85 (s, 1H), of 7.75 (t, 1H), 7,15 (d, 2H), 7,0 (d, 2H), and 3.8 (m, 1H), 3,65 (m, 1H), 3,33,6 (m, 2H), 3,1 (m, 1H), 2,9 (m, 1H), 2,2 (m, 2H), 1,65 (m, 2H), of 0.85 (t, 3H), and 0.7 (d, 3H).

Example 107

The hydrochloride of N-[4-((3S,5S)-5-methyl-1-propylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom

0,053 g of product is obtained, as described for the synthesis of N-[4-((3S,5R)-5-methyl-1-propylpyrrolidine-3-yl)phenyl]-3-triftoratsetilatsetonom (example 94) from commercially available (2R,4S)-Boc-4-phenylpyrrolidine-2-carboxylic acid:

107.1. 1-tert-Butyl ester 2-methyl ester (2R,4S)-4-phenylpyrrolidine-1,2-dicarboxylic acid

ESI-MS: 206,0 (-Boc), 250,0 (-tBu) [M+H]+

107.2.tert-Butyl ester (2R,4S)-2-hydroxymethyl-4-phenylpyrrolidine-1-carboxylic acid

ESI-MS: 222,1 (-tBu) [M+H]+

107.3.tert-Butyl ester (2R,4S)-2-methanesulfonylaminoethyl-4-phenylpyrrolidine-1-carboxylic acid

ESI-MS: 256,1 (-Boc), 300,1 (-tBu) [M+H]+

107.4.tert-Butyl ester of (2S,4S)-2-methyl-4-phenylpyrrolidine-1-carboxylic acid

ESI-MS: 206,1 (-tBu) [M+H]+

107.5. (2S,4S)-2-Methyl-4-phenylpyrrolidine

ESI-MS: 162,1 [M+H]+

107.6. (2R,4S)-2-Methyl-4-phenyl-1-propylpyrrolidine

ESI-MS: to 204.1 [M+H]+

107.7. (2S,4S)-2-Methyl-4-(4-nitro)phenyl-1-propylpyrrolidine

ESI-MS: 249,1 [M+H]+

107.8. (2S,4S)-Methyl-4-(4-amino)phenyl-1-propylpyrrolidine

ESI-MS: 219,1 [M+H]+

Binding of aniline with 3-triftormetilfullerenov performed, as already described for the compounds according to other examples, to obtain the output 0,053 the final product.

ESI-MS: 427,1 [M+H]+

1H-NMR (DMSO-d6, 400 MHz): δ [h/million] 10,6 (very Shir.), with 8.05 (m, 1H), 8.0 a (m, 2H), and 7.8 (m, 1H), and 7.3 (m, 2H), 7,05 (m, 2H), 3,3-3,6 (m, 4H), 3,2 (user., 1H), 2,9 (user., 1H), 2,4 (user., 1H), 1,75 (user., 2H), 1,65 (user., 1H), 1,4 (user., 3H), and 0.9 (user., 3H).

III. Examples of galenic dosage forms

A) Tablets

Tablets of the following composition is pressed using a tablet press according to traditional methods:

40 mg of the product from example 8

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg Aerosil® (chemically pure silicic acid fine submicroscopic form)

of 6.75 mg of potato starch (6% paste)

B) Covered sugar pills

20 mg of the substance from example 8

60 mg the core of the composition

70 mg Osharova composition

The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of 60:40 vinyl pyrrolidone/vinyl acetate copolymer. Osharova composition consists of 5 parts sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. Covered sugar pills, which were prepared in this way, then cover resistant to gastric juice by the shell.

IV. Biological studies

Studies of the binding of the receptor

The test substance was dissolved in methanol/Chremophor® (BASF AG) or dimetilan is oxide and then diluted with water to the desired concentration.

Human 5HT6receptor

The description of the compounds of the present invention relative to the human 5-HT6receptor in the study of binding and functional study of adenylylcyclase.

Connections bring the solution up to a concentration of 10-2M or 10-3M in DMSO. Further dilutions were made in incubation buffer.

Research associate

Research methodology binding based on the way Monsma et al. (1993) Mol. Pharmacol. 43: 320-327. The binding reaction was performed in a total volume of 0.250 ml for 60 min at 37°C. the Membranes of cells HEK-293 stably expressing the human 5-HT6receptors, incubated with 2 nm3H-LSD in the presence or absence of various concentrations of test compounds for 60 min at 37°C. Nonspecific binding is determined using 100 μm serotonin (5-HT). Studies conducted twice. Bound and free radioligand separated by filtration and the associated radioactivity was determined by scintillation counter.

Assessment

Specific binding of the ligand with the receptor was defined as the difference between total binding and nonspecific binding determined in the presence of excess unlabeled 5-HT. The results are expressed as percent of control specific binding obtained in the presence of soybean is inane. The values of the IC50(concentration causing half maximal inhibition of control specific binding) and hill coefficients (nH) is determined using nonlinear regression analysis of competing curves using hill equation curve approximation.

The inhibition constants (Ki) calculate the equation of Cheng Prusoff (Ki=IC50/(1+(L/KD)), where L = concentration of radioligand in the study, and KD = affinity of radioligand to the receptor).

Functional study of adenylylcyclase

Membrane of a human cell line Hela stably expressing the human 5-HT6 receptors, incubated for 20 min at 37°C in HBSS, 1 mm MgCl2, 1 mm CaCl2, 100 mm IBMX, pH 7.4 in the presence and in the absence of test compounds. For agonistic activity of a compound is incubated for themselves. For the antagonistic effects of the inhibition of the increase in camp caused 0.3 μm serotonin (5-HT)was defined.

Assessment: the accumulation of camp was determined using the quantitative analysis of EIA.

Dopamine D3receptor

The analyzed mixture of 0.250 (ml) consists of membranes obtained from ~106cells HEK-293 having stably expressed human dopamine D3receptors, 0.1 nm [125I]-iodoantipyrine and incubation buffer (total binding) or, chrome is in the test substance (inhibition curve) or 1 μm of spiperone (nonspecific binding). Each study mixtures spend three times.

The incubation buffer contained 50 mm Tris, 120 mm NaCl, 5 mm KCl, 2 mm CaCl2, 2 mm MgCl2and 0.1% bovine serum albumin, 10 μm quinolone and 0.1% ascorbic acid (every day we get fresh). The buffer was brought to a pH of 7.4 by addition of HCl.

Dopamine D2Lreceptor

Mixture studies (1 ml) consisted of membranes obtained from ~106cells HEK-293 with stably expressed human dopamine D2Lreceptors (long isoform) and 0.01 nm [125I]ispiron and incubation buffer (total binding) or, in addition, the test substance (inhibition curve) or 1 μm haloperidol (nonspecific binding). Each study mixtures spend three times.

The incubation buffer contained 50 mm Tris, 120 mm NaCl, 5 mm KCl, 2 mm CaCl2, 2 mm MgCl2and 0.1% bovine serum albumin. The buffer was brought to a pH of 7.4 by addition of HCl.

Measurement and analysis

After incubation at 25°C for 60 minutes mix, focusing filtered through glass fiber filter Whatman GF/B under vacuum using a cell harvester. The filters are transferred into scintillation vials using a transfer system filters. After adding 4 ml of Ultima Gold®(Packard), the samples were shaken for 1 hour and then measured the radioactivity in the counter Beta-Counter (Packard, Tricarb 2000 or 2200CA). The cpm values were then converted to dpm using the standard series to be converted and the program supplied with the instrument.

Curves of inhibition was analyzed using repeated non-linear regression analysis using the Statistical Analysis System (SAS), which is similar to the program “LIGAND”as described by Munson and Rodbard.

The results of studies of the binding of the receptor expressed in the form of a binding constant of receptor Ki(5HT6), Ki(D3and Ki(D2), respectively, as described previously and shown in table 6.

In these tests, the compounds according to the invention show a very good affinity for 5HT6receptor (<50 nm, or <10 nm, often <5 nm). Some of these compounds, in particular, have as 1,4-phenylene, as a group And also have a very good affinity for D3receptor (<50 nm, or <10 nm, often <5 nm) and bind selectively with D3receptor, compared with the affinity for D2the receptor.

The test results of binding are shown in table 6.

+++
Table 6
ExampleKi(5HT6)* [nm]Ki(D3)* [nm]Ki(D2)/Ki(D3)
1++
3++++++++
4++++++
6+++
7+++
8++
9+++
10+++
11+++
12++
13++
14
15+++
16+++
17++++
18+++
19+++
20++++
21+
22+++
23++
24+
25+++
26+++
31+++

32+++
34++
40+
42+
43++
44+
45++
46+
47++
48++
49++
50+
51+
52++
54+
59+++++++++
60+++++++
61+++++++
62++++++++++
63 ++
64+
65++
66+++++++++
67+++
69+++++++
70++++++++
71++++++
73+++++++
74+++++++
75+++++
76 +++++++++
77+++
78+++++++
86+++++++
90++++++++++
91++
94++
95++++++
97+++++++
98++++++
99+++++

100++++++++
101++
102++++++
103+++++
104++
*The binding constant of the receptor, obtained according to the research, described in this description earlier.

Explanation

Ki(D3)* and Ki(5HT6)*Ki(D2)*/Ki(D3)*
+between 50 and 150 nmbetween 10 and 50
++between 10 and 50 nmbetween 50 and 100
+++between 1 and 10 nmbetween 10 and 150
++++<1 nm>150

A study testing the compatibility of the ligands of the dopamine D3and 5HT6receptors

Microdialysis studies

Enhancing cholinergic function, according to widespread opinion, improves cognitive function, increased cortical content of extracellular acetylcholine (ACh) can be considered as a biochemical marker of potential procognitive effects.

Thus were produced microdialysis studies in freely moving rats. We studied the effects of ligands of 5-HT6receptors, selective D3ligands or their combinations on acetylcholine release in the medial prefrontal cortex and in the hippocampus: one guide cannula was implanted in the medial prefrontal cortex (AP=2,5; ML=0,6; DV=-0,2), the second in the hippocampus (AP=-5,5; ML=4,5; DV=-4,5). 5-7 days after surgery 2 microdialysis probe (CMA/12, the length of the membrane 3 mm) were slowly lowered to the end position. On the day of the experiment, the test compound or its vehicle (2 ml/kg) was administered intraperitoneally injected. Microdialysate fraction (six 20-minute fractions before and six fractions after the introduction of compounds) were analyzed for the presence of acetylcholine using high-performance liquid is ostroy chromatography in combination with electrochemical definition (description of the methods see in Fox et al., J. Phamacol. Exp. Ther. 2005, 313, 176-190 and detailed description below).

The ligands of 5-HT6receptors and selective ligands D3receptors were increased dose-dependent manner extracellular ACh levels in the medial prefrontal cortex and in the hippocampus. The combination of ligands of 5-HT6receptors and ligands D3receptors led at least to the additive effect of both of the above agents in the medial prefrontal cortex and in the hippocampus, suggesting that their combination can provide therapeutic benefit in disorders of the CNS, characterized by impaired cognitive functions, including dementia and schizophrenia.

Moreover, the mixed ligands D3/5-HT6receptors also increase microdialysate ACh levels in the medial prefrontal cortex and in the hippocampus. Based on a comparison of the doses of compounds, combining the D3/5-HT6inside the molecule, are more potent in increasing cortical cholinergic function in comparison with "pure" antagonist D3receptors.

Microdialysis experiments

Operation

To prevent pain before surgery was administered Rimadyl® (3 mg/kg, administered intraperitoneally). In male rats, line Sprague-Dawley (weight 290-320 g) was obezbolivatmi pentobarbital (60 mg/kg, administered intraperitoneally, Narcoren®, Rhone-Merieux GmbH, France) and were placed in a stereotactic frame is at KOPF and implanted two microdialysis guide cannula (CMA/12, Axel Semrau GmbH, Germany) in selected brain areas of the same animal: one guide cannula was implanted in the medial prefrontal cortex (AP=2,5; ML=0,6; DV=-0,2)and the second in the hippocampus (AP=-5,5; ML=4,5; DV=-4.5). The guide cannula was attached by a dental cement (Technovit powder, Product No. 5071, Technovit polymerization starter fluid, Product No. 2060, Kulzer GmbH, Germany) and 4 anchor screws to the skull. The rats were allowed to recover from surgery for 5-7 days. The day before the experiment, each animal was transferred into a system that allows free movement (CMA/120 Axel Semrau GmbH, Germany, consisting of a plastic tank, wire mount, counterweight, swivel connection connecting input/output probe with a perfusion pump). Then microdialysis probe CMA/12 (the length of the membrane 3 mm) was slowly lowered to the end position. The probe was perfesional ringer's solution (147 mm NaCl, 4.0 mm KCl, and 2.4 mm CaCl2containing 1 μm of neostigmine), for approximately one hour (CMA/102 microdialysis pump, Axel Semrau GmbH, Germany; 1,5 µl/min). The probe was perfesional again after 24 hours, at least 1 hour before collecting every 20 minutes microdialysate fractions. Six fractions before and six fractions after intraperitoneal the introduction of the test compounds or media were analysed for levels microdialysate acetylcholine by HPLC with electrochemical detection.

Issledovaniia microdialysate acetylcholine

10 ál of each microdialysate fractions were injected with column reverse phase (MF-8908 Acetylcholine SepStik Kit; microcolony, particle size 10 μm, 530×1.0 mm, coupled with immobilized enzyme reactor 50×1.0 mm, particle size 10 μm, containing acetylcholinesterase and cholinesterase; BAS, U.S.A.) using a refrigerated automatic sampler (HTC PAL dual injection sampling system, Axel Semrau, Germany). The mobile phase consisted of 50 mmol/l Na2HPO4(pH 8.5) and 5 ml/l Kathon. The flow rate was 0.14 ml/min (Flux Rheos pump, Axel Semrau GmbH, Germany), and the processing time of the sample was less than 15 minutes. Acetylcholine and choline were measured by an electrochemical detector (LC-4C, BAS, U.S.A.) with a platinum working electrode set at + 500 mV compared with the Ag/AgCl reference electrode. The system was calibrated with standard solutions (acetylcholine, choline), containing 1 pmol/10 ál injections. Acetylcholine identified by its retention period and peak height with the external standard method, using the software for chromatography (Chrom Perfect®, version 4.4.22, Justice Laboratory Software, U.S.A.).

Data were synthesized (area under the curve 0-120 min) were evaluated for accuracy using single-factor analysis of variance (ANOVA), then using a post hoc test with datachecker comparison by Dunnett using the program GraphPad Prism v 4.0.

1. Connect four is ula (I)

where
n is 0, 1 or 2;
G represents CH2or CHR3;
R1represents H, C1-C6-alkyl, C3-C6alkenyl or benzyl;
R2, R3and R4independently of one another represent H, methyl, vermeil, deformity or trifluoromethyl;
And represents 1,4-phenylene or 1,3-phenylene, which is optionally substituted one, two, three or four substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4-alkoxy;
E represents NR5where R5represents N or C1-C3-alkyl;
Ar represents a radical of the formula A, F, and G

where
Rarepresents halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenylsulfonyl, CN, -NR6R7where R6and R7form together with the N atom a 5 - or 6-membered saturated ring, or represents a 5-membered saturated or unsaturated aromatic or non-aromatic heterocyclic ring comprising as ring members 1, 2 is 3 heteroatoms, selected from N, O and S, where the heterocyclic ring may carry 1, 2 or 3 substituent selected from halogen and C1-C6-alkyl, or represents a 6-membered saturated heterocyclic ring comprising as ring members one nitrogen atom and one oxygen atom;
Rband Rcindependently of one another represent H, a halogen, CH3The co3CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2CH2CF3or OCH2CF3;
Rddefined as Raor represents 5 - or 6-membered heteroaromatic ring comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S, where the heteroaromatic ring may carry 1 Deputy selected from C1-C6-alkyl and C1-C6-alkylthio;
Rerepresents H or defined as Ra;
Rfdefined as Ra;
k is 0, 1, 2 or 3; and
j is 0, 1, 2, 3 or 4;
provided that Rais not F, CH2F, CHF2, CF3or OCF3if a represents 1,4-phenylene, Ar is a radical of formula (a) and Rband Rcrepresent H or halogen;
with the exception of compounds where R1represents about the sludge, G represents CH2, n is 1, And represents 1,4-phenylene, E represents NH, Ar is a radical of formula (F) and Rdrepresents halogen, C1-C6-alkyl, C2-C6alkenyl or 5-membered heteroaromatic ring;
and its physiologically acceptable acid additive salt.

2. The compound of formula (I) according to claim 1, where Ar represents a radical of the formula A.

3. The compound of formula (I) according to claim 1 or 2, where
R1represents H, C1-C6-alkyl or C3-C6alkenyl;
Ar represents a radical of the formula A;
Rarepresents halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenylsulfonyl, CN, -NR6R7where R6and R7form together with the N atom a 5 - or 6-membered saturated ring, or represents a saturated or unsaturated 5-membered heterocyclic ring comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S, where the heterocyclic ring may carry 1, 2 or 3 substituent selected from halogen and C1-C6-alkyl, or represents a 6-membered saturated heterocyclic ring comprising as ring member of one atom of nitrogen and one atom of oxygen; the
Rband Rcindependently of one another represent H, a halogen, CH3The co3, CHF2, OCHF2, CF3or OCF3;
provided that Rais not F, CH2F, CHF2, CF3or OCF3if a is a 1,4-phenylene and Rband Rcrepresent H or halogen;
and their physiologically acceptable acid additive salt.

4. The compound according to claim 1, where Ar represents a radical of formula (F), or formula (G).

5. The compound according to claim 4, where Rdselected from halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl, phenylsulfonyl and 5 or 6-membered heteroaromatic ring comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S, where the heteroaromatic ring may carry 1 Deputy selected from C1-C6-alkyl and C1-C6-alkylthio.

6. The compound according to claim 5, where Rdselected from halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl, phenylsulfonyl and 5 or 6-membered heteroaromatic ring comprising as ring members 1 nitrogen atom and optionally one or two additional heteroatoms selected from N, O and S, where the heteroaromatic ring may carry 1 Deputy selected from C1-C6-alkyl and C1-C6-alkylthio.

7. Connect the Addendum according to claim 4, where Rerepresents H, halogen, C1-C4-alkyl or fluorinated C1-C4-alkyl, Rfrepresents a C1-C4-alkyl or fluorinated C1-C4-alkyl and j is 0 or 1.

8. The compound according to claim 1, where n is 0 or 1.

9. The compound according to claim 1, where R1represents hydrogen, methyl, ethyl, n-propyl, allyl or benzyl.

10. The connection according to claim 9, where R1represents hydrogen, n-propyl or allyl.

11. The compound according to claim 1, where R2, R3and R4represent N.

12. The compound according to claim 1, where E represents NH.

13. The compound according to any one of claims 1 to 3 and 8 to 12, where Raselected from radicals of the formula Ra'

where
Y represents N, CH or CF,
where in the case when Y represents CH or CF, Ra1and Ra2independently from each other selected from C1-C2-alkyl, fluorinated C1-C2-alkyl and C1-C2-alkoxy, or one of the radicals Ra1or Ra2may also be hydrogen or fluorine, or
where in the case when Y is N, Ra1and Ra2together form a radical (CH2)mwhere 1 of the hydrogen atoms may be replaced by C1-C2-alkyl, where one CH2the residue may be replaced by Oh, and where m has a value of 4 or 5.

14. With the Association according to claim 1, where the radical Raselected from halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, CN or saturated or unsaturated 5-membered heterocyclic ring comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S, where the heterocyclic ring may carry 1, 2 or 3 substituent selected from halogen and C1-C6-alkyl, and 6-membered saturated heterocyclic ring comprising as ring member of one atom of nitrogen and one atom of oxygen.

15. The compound according to claim 1, where the absolute configuration at the carbon atom having the group a, is a (S).

16. The compound according to claim 1, where a represents a 1,3-phenylene, which is optionally substituted by one or more substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4-alkoxy.

17. The compound according to claim 1, where a represents 1,4-phenylene, which is optionally substituted by one or more substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4-alkoxy.

18. The connection 17, where Rarepresents a C 1-C6-alkyl, C1-C6-alkoxy, phenylsulfonyl, CN, -NR6R7where R6and R7form together with the N atom a 5 - or 6-membered saturated ring, or represents a saturated or unsaturated 5-membered heterocyclic ring comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S, where the heterocyclic ring may carry 1, 2 or 3 substituent selected from halogen and C1-C6-alkyl, or represents a 6-membered saturated heterocyclic ring comprising as ring member of one atom of nitrogen and one atom of oxygen.

19. The compound according to claim 1, where a saturated or unsaturated heterocyclic ring, Raselected from pyrrolidinyl, morpholinyl, pyrrolyl, furanyl, teinila, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, triazolyl, oxadiazolyl, furazane and thiadiazolyl, where in the case of 5-membered ring heterocyclic radical may be unsubstituted or may carry 1 to 3 substituents selected from halogen and C1-C4-alkyl.

20. The connection according to claim 19, where the saturated or unsaturated heterocyclic ring, Raselected from pyrrolidinyl, morpholinyl, furanyl, teinila, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole and thiadiazolyl, where in the case of 5-membered stake the heterocyclic radical may be unsubstituted or may carry 1 to 3 substituents, selected from halogen and C1-C4-alkyl.

21. The compound according to any one of p or 20, where a saturated or unsaturated heterocyclic ring contains as ring member, at least one nitrogen atom.

22. The compound according to claims 1-3, 8-21, where Raselected from halogen, C1-C4-alkyl, fluorinated C1-C4-alkyl, CN, 5-membered heteroaromatic ring comprising as ring members one nitrogen atom and optionally one or two additional heteroatoms selected from N, O, S, and where the heteroaromatic ring may carry 1, 2 or 3 substituent selected from halogen or C1-C4-alkyl and 5 - or 6-membered saturated heterocyclic ring bound through the nitrogen atom, where in the case of 6-membered rings it contains in addition to the nitrogen atom and one additional heteroatom selected from O, where the 5-membered heterocyclic radical may have 1, 2 or 3 substituent selected from C1-C4-alkyl.

23. Pharmaceutical composition for modulating the activity T6receptors containing at least one compound according to any one of the preceding paragraphs, optionally together with at least one physiologically acceptable carrier or auxiliary substance.

24. Method of modulating activity T6receptors, where specified the manual includes an introduction to the patient, in need, an effective amount of at least one of the compounds of formula (I), as defined according to any one of claims 1 to 22, and/or at least one of its physiologically acceptable acid additive salt.

25. The use of the compounds of formula (I)as defined in any one of claims 1 to 22, and/or its physiologically acceptable acid additive salts to obtain pharmaceutical compositions for modulating the activity T6the receptors.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) X represents NH, n means a number equal to 0-3, Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-, p means a number equal to 0-2, q means a number equal to 1-3, R1 represents hydrogen, -(CR4R5)P-A-R6 or -(CR4R5)q-R6, R2 represents halogen, C1-C3-alkyl or trifluoromethyl, or represents 5~6-member heteroaryl or heterocyclyl each of which has 1 -3 heteroatoms selected from N and O, or represents optionally substituted C1-C3-alkylsulphonyl 6~12-member aryl, R3 represents R7-X-B-X'-, B represents a direct bond or represents 5~6-member heterocyclyl or heteroaryl each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S. Also the invention refers to a pharmaceutical composition for glucokinase activation and a method for preparing it.

EFFECT: use of the compounds of formula (I) as glucokinase activators.

22 cl, 11 dwg, 3 tbl, 222 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2-piperidino-5-(thienyl-2)-6H-1,3,4-thiadiazines, hydrobromides (of general formula I) and 2-piperidino-5-(thienyl-3)-6H-1,3,4-thiadiazines, hydrobromides (of general formula II) which possess antiaggregant action. wherein R=H; Cl; Br R1=H; Cl.

EFFECT: given compounds may be used for preparing cardiologic drugs and enable better treatment of various cardiovascular diseases, including myocardial infarction and thrombotic apoplexy.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel purified compound PM 181104 of formula I

(with molecular weight 1514 and molecular formula C69H66N18O13S5), pharmaceutically acceptable salts thereof, methods for synthesis via fermentation of a microorganism of the type Kocuria (ZMA B-1 / MTCC 5269), as well as pharmaceutical compositions.

EFFECT: high efficiency of using the composition to produce a medicinal agent for treating bacterial infections.

20 cl, 4 dwg, 4 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or tautomer thereof

or enantiomer or physiologically acceptable salt, where R1 is o-bromo, R2 is n-fluoro, R3 is C1-C4 alkyl, R6 is thiazolyl-2-yl, X is methylene and Z is morpholinyl. The invention also relates to methods of producing (versions) compounds of formula (I) and (Ia). The compound of formula (I) or (Ia) is used to prepare a pharmaceutical composition for treating or preventing HBV infections and HBV-induced diseases such as hepatitis B.

EFFECT: bromophenyl substituted thiazolyl dihydropyrimidines for HBV infection control.

20 cl, 7 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds specified in cl. 1, and also to a pharmaceutical composition possessing binding activity with respect to Bcl proteins, to applying the declared compounds for preparing a drug for treating cancer and for treating a bcl-mediated disorder.

EFFECT: use of the compounds as Bcl protein inhibitors.

18 cl, 2 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an immunodepressant based on a heterocyclic compound of formula

or to its pharmaceutically acceptable salt where X represents a nitrogen atom or CH, both or one of R1 or R2 represents a hydrogen atom, hydroxyl, a halogen atom, an amino group, C1-C6 alkoxy or C1-C6 alkyl: R3 represents a hydrogen atom, difluoromethyl, an amino group, methyl or hydroxymethyl; R4 or R5 represents a hydrogen atom or C1-C6 alkyl; R6 represents morpholino (optionally substituted by one or two C1-C6 alkyl groups), pyrrolidinyl (optionally substituted by hydroxy C1-C6 alkyl), piperidine (which is optionally substituted by an oxygen atom, hydroxyl, formyl or C1-C6 alkyl), piperazinyl (optionally substituted by one or two oxygen atoms, where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a groups consisting of formyl, C1-C6 hydroxyalkyl, C1-C6 alkoxycarbonyl, C1-C6 oxoalkyl, furoyl, benzoyl, methoxybenzoyl, benzylcarbonyl, dimethylcarbamoyl, diethylcarbamoyl, morpholinocarbonyl and methoxyacetyl) or 1,4-diazepano (optionally substituted by one oxygen atom where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a group consisting of formyl, C1-C6 oxoalkyl). Also, the invention refers to a heterocyclic compound of general formula

and to an anticancer drug based on the compound of formula (II).

EFFECT: there are produced new immunodepressant based on the compound of formula (I) and compound of formula (II) which can be used as anticancer drugs.

12 cl, 8 tbl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula in which: X denotes S, N-R5 or O; R denotes H; alkyl; heteroaryl, which is a thienyl optionally substituted with alkyl; R1 denotes alkyl; aryl, optionally substituted with a halogen; heteroaryl which is a thienyl optionally substituted with an alkyl, a a halogen, a methoxy group; R2 denotes heteroaryl which is 2-, 3- or 4-pyridyl; R3 denotes H; aryl, optionally substituted with a halogen, a methoxy group; heteroaryl, which is a thienyl optionally substituted with a halogen; alkyl, optionally substituted with oxytetrahydropyranyl; R4 denotes H; R5 denotes H; alkyl; or salt thereof.

EFFECT: invention also relates to a method of producing said compounds, which can be used as antifungal agents for crops, as well as agents against other pests, such as insects or mites and weeds which can harm crops.

10 cl, 7 ex

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