Indole compounds as cell necrosis inhibitors. RU patent 2477282.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indole compounds of formula:

wherein A means 5-member heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms specified in N, O and S, R¹ means R⁵ -X-B-X'-, R² means -(CR⁸ R⁹ )p-Y-R⁷, R³ means hydrogen, C₁-C₆-alkyl or -(CH₂)_q-C₃-C₆-cycloalkyl, R⁴ means C₃-C₆-cycloalkyl (the other radical values are presented in cl.1 of the patent claim), their pharmaceutically acceptable salts or isomers which may be used for preventing or treating cell necrosis and necrosis-related diseases.

EFFECT: preparing the compounds to be used for preventing or treating cell necrosis and necrosis-related diseases.

34 cl, 2 tbl, 263 ex

The technical field

The present invention relates to compounds indole formula (1), their pharmaceutically acceptable salts or isomers and to method and composition for prevention or treatment of cell necrosis and associated with necrosis of diseases, including these compounds as the active ingredient.

The level of technology

Most of the researches, connected with the death of cells, was focused on the apoptosis of cells, also known as programmed cell death (PCD). With the opening of the enzyme caspase during the last 10 years a number of pharmaceutical companies involved in drug development, which used caspase inhibitors. However, the current situation is that only some of these drugs have been approved by the FDA. The reason for this is that the apoptosis of cells is cell death that occurs at physiological circumstances, and that such death of cells is probably the result of a protective mechanism to maintain homeostasis in the body. On the contrary, necrosis is the death of cells, which mainly occurs in pathological circumstances, and in most cases it is characterized by a concomitant inflammatory response. Necrosis been known for a long time as uncontrolled cell death, but in a recent study (Proskurykakov S.Y. et al. 2002, Biochemistry) necrosis has been described as active/controlled cell death. Typical of the disease caused by necrosis, include ischemic (such as myocardial infarction, stroke, heart attack, kidney), degenerative and inflammatory diseases. As it is believed that necrosis is uncontrolled, accidental death of cells in pathological circumstances, a study on the functional mechanism, molecular targets, systems of transduction of signals etc. were seldom. Thus, there is a serious need for the discovery and development of inhibiting necrosis substances for the treatment of ischemic, neurodegenerative and inflammatory disease caused necrosis, and in the explanation of biological, pathological causes necrosis.

Indole derivatives according to the present invention are very useful patterns from a medical point of view, and in many publications reported about the results of the research in respect of these structures. Among the results of the research the following is the most representative: in the patent application WO 2006/112549 reported about some of indole derivatives, have activity against glucokinase, in the patent application WO95/07276 reported about the connections that can be used as antitumor agents and as inhibitors against the products of the cardiovascular system, and in the patent application WO 2004/018428 reported about the connections that can be used as antibiotics.

Detailed description of the invention

Solved the technical problem

Thus, the authors of the present invention carried out extensive studies in this area to develop new compounds that exercise effect regarding prevention or treatment and improvement in the case of cellular necrosis and associated with necrosis diseases, particularly suitable for the prevention or treatment of diseases of the liver. As a result, they confirmed that indole derivatives of the formula (1)disclosed below are superior to the effect in the prevention and treatment of cell necrosis and associated with necrosis diseases, through which carried out the present invention.

The objective of the present invention is to get new indole derivatives of the formula (1).

Another aim of the present invention is a composition for prophylaxis and treatment of cellular necrosis and associated with necrosis of diseases, in particular for , functional improvement of the state of the liver and the prevention or treatment of acute/chronic liver diseases, which contains, as active ingredient compounds of formula (1), their pharmaceutically acceptable salts of isomers or together with a pharmaceutically acceptable carrier or diluent, and a way of its reception.

Another objective of the present invention is a method of prevention or treatment of cell necrosis and associated with necrosis of diseases, in particular , functional improvement of the state of the liver and the prevention or treatment of acute/chronic liver disease, using the specified composition.

To solve these problems, the present invention relates to compounds indole the following formula (1):

in which

n represents a number from 0 to 3,

And denotes the 5-membered ring or heterocycle, each of which has from 1 to 3 heteroatoms selected of N, O and S,

R 1 indicates R 5-X-B-X',

B indicates a direct link, or indicates 3 of 10-membered heterocycle or , each of which has from 1 to 4 heteroatoms selected of N, O and S,

X and X' independently from each other indicate a direct link, or selected from the group consisting of NR 6 -, CO-, -CONR 6 -, -CO 2 -, -OC(O)-, -S(O) m -, -O-(CH 2 ) m -, -(CH 2 ) m-O-, -(CH 2 ) m -, -NR 6 CO-, -(R 6 O) 2 P(O)- and -NHCO 2 -, where m is a number from 0 to 3, and R 6 indicates hydrogen alkyl or cycloalkyl,

R 5 indicates hydrogen, nitrile, hydroxy, alkyl, alkoxy, cycloalkyl, or aryl, or indicates 3 of 10-segmented or condensed cyclic heterocycle or , each of which has from 1 to 3 heteroatoms selected of N, O and S, and may be replaced oxo or , or

R 5 and R 6 may together to form with 4-8-membered cycle,

R 2 means -(CR 8 R 9 ) p-Y-e 7 ,

p is a number from 0 to 2,

R 8 and R 9 independently one from another represent hydrogen or an alkyl, or can together to form with 4-8-membered cycle,

Y indicates a direct link, or selected from the the group consisting of O-, S-, -NR 6 -, -NR 6 C(O)-, -CO 2-a, -C(O)-, -C(O)NR 6 -, -S(O) q - and-S(O) q NR 6-where q denotes the number from 0 to 2,

R 7 indicates hydrogen, halogen, cyano, hydroxy, nitro, alkyl, cycloalkyl or aryl, or indicates 3 of 10-membered heterocycle or , each of which has from 1 to 3 heteroatoms selected of N, S, and O, and, if necessary, contains oxo,

R 3 represents hydrogen alkyl, -(CH 2 ) q-cycloalkyl or(CH 2 ) q-heterocycle,

R 4 means -(CH 2 ) p-D-R 10 ,

D indicates a direct link, indicates cycloalkyl, if necessary contains oxo, indicates aryl, or indicates 3 of 10-membered heterocycle or , each of which has from 1 to 3 heteroatoms selected of N, S, and O,

R 10 indicates hydrogen, halogen, amino, cyano, nitro, hydroxy, alkyl, , alkylsulfonyl or(CH 2 ) p-NR 8 R 9 ,

where alkyl, alkoxy, aryl, cycloalkyl, heterocycle and can be if necessary, replaced, and deputies represent one or more deputies, selected from the group consisting of hydroxy, halogen, nitrile, amino, , , alkyl, , alkylsulfonyl, , , , , , and oxo, and to their pharmaceutically acceptable salts or isomers.

In the above definitions for the compounds of formula (1), the term 'alkyl' means aliphatic hydrocarbon radical. Alkyl may be saturated , which does not include or group, or unsaturated , which includes at least one or group. "" means a group that contains at least one carbon-carbon double bond, and “” means a group that contains at least one carbon-carbon triple bond. Alkyl may be branched or direct circuit when used individually or in a complex form, such as alkoxy.

An alkyl group can have from 1 to 20 carbon atoms, unless otherwise specified. An alkyl group can be having from 1 to 10 carbon atoms. Otherwise an alkyl group may be lower having from 1 to 6 carbon atoms. Typical examples include, but are not limited to, methyl, ethyl, propyl, isopropyl n-butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, , etc. for Example, C 1-C 4-alkyl has 1 to 4 carbon atoms in an alkyl chain and is selected from the group consisting of methyl, ethyl, cut, isopropyl nitrate, n-butyl, , sec-butyl and tert-butyl.

The term 'alkoxy' means having from 1 to 10 carbon atoms, unless otherwise specified.

The term 'cycloalkyl' means saturated aliphatic 3 of 10-membered cycle, unless otherwise specified. Typical examples include, but are not limited to, , , , cyclohexyl etc.

The term 'aryl' includes at least one ring, having covalent π electronic system, for example, monocyclic or condensed polycyclic (i.e. loops with the same pair of adjacent carbon atoms) group. In the present description «aryl» means aromatic 4 of 10-segmented, preferably 6 of 10-segmented, or cycle, including phenyl, naphthyl etc. unless otherwise specified.

The term '' means aromatic 3 of 10-segmented, preferably with 4-8-membered ring, preferably 5 of about 6-membered cycle, which is from 1 to 4 heteroatoms selected of N, O and S, and which can be with benzo or C 3-C 8 , unless otherwise specified. includes, but is not limited to, , , thiophene, furan, pyrrol, imidazol, isoxazole, isothiazol, pyrazole, triazole, triazine, thiadiazole, , oxidiazol, pyridine, , pyrimidine, pyrazin etc. Б includes, but is not limited to, indole, , , , benzimidazole, , , benzothiazole, , , chinoline, isoquinoline, purine, etc.

The term 'heterocycle' means 3 of 10-segmented, preferably with 4-8-membered ring, preferably 5 of about 6-membered cycle, which is from 1 to 4 heteroatoms selected of N, O and S, which can be with benzo or C 3-C 8 and is saturated or contains 1 or 2 dual communication, unless otherwise specified. Heterocycle includes, but is not limited to, pyrrolin, pyrrolidine, , , pyrazolin, , Piran, piperidine, morpholine, , piperazine, etc.

Other terms and abbreviations this description have values that are commonly used specialist in this area, unless otherwise specified.

The preferred compounds among the compounds of formula (1)above, are compounds in which

n represents a number from 0 to 3,

And denotes the 5-membered ring or heterocycle, each of which has from 1 to 3 heteroatoms selected of N, O and S,

R 1 R denotes 5-X-B-X',

B indicates a direct link, or indicates 3 of 10-membered heterocycle or , each of which has from 1 to 4 heteroatoms selected of N, O and S,

X and X' independently from each other indicate a direct link, or selected from the group consisting of NR 6 -, CO-, -CONR 6 -, -CO 2 -, -OC(O)-, -S(O) 2 -, -O-(CH 2 ) m -, -(CH 2 ) m-O-, -(CH 2 ) m -, -NR 6 CO-, -(R 6 O) 2 P(O)- and -NHCO 2 -, where m is a number from 0 to 3, and R 6 indicates hydrogen, C 1-C 6-alkyl or C 3-C 6-cycloalkyl,

R 5 indicates hydrogen, nitrile, hydroxy, C 1-C 6-alkyl, halogen-C 1-C 6-alkyl, hydroxy-C 1-C 6-alkyl, C 4-C 6-cycloalkyl, phenyl or , or indicates 5 of 10-segmented or condensed cyclic heterocycle or , each of which has from 1 to 3 heteroatoms selected of N, O and S, and may be replaced oxo or halogen-C 1-C 6-, or

R 5 and R 6 may together to form with 4-8-membered cycle,

R 2 means -(CR 8 R 9 ) p-Y-e 7 ,

p is a number from 0 to 2,

R 8 and R 9 independently one from another represent hydrogen or C 1-C 6-alkyl, or can together to form 5 of about 6-membered cycle,

Y indicates a direct link, or selected from the group consisting of O-, -NR 6 -, -NR 6 C(O)-, -C(O)-, -CO 2-a, -C(O)NR 6 - and-S(O) q, where q denotes the number from 0 to 2,

R 7 indicates hydrogen, halogen, cyano, hydroxy, C 1-C 6-alkyl, hydroxy-C 1-C 6-alkyl or halogen-C 1-C 6-alkyl, indicates phenyl, if necessary, replacing C 1-C 6-, or indicates 5 of about 6-membered heterocycle or , each of which has from 1 to 3 heteroatoms selected of N and O,

R 3 indicates hydrogen, C 1-C 6-alkyl, -(CH 2 )-C 3-C 6-cycloalkyl or(CH 2 )-heterocycle, and heterocycle is a 5 VAC 6-membered cycle, having 1 or 2 heteroatoms selected of N, O and S,

R 4 means -(CH 2 ) p-D-R 10 ,

D indicates a direct link, denotes C 3-C 6-cycloalkyl, if necessary, containing oxo, or indicates 5 of about 6-membered heterocycle or , each of which has 1 or 2 heteroatoms selected of N, O and S,

R 10 indicates hydrogen, halogen, amino, C 1-C 6-alkyl, C 1-C 6-, halogen-C 1-C 6-, C 1-C 6-alkylsulfonyl or -(CH 2 ) p-NR 8 R 9 .

In the compounds of formula (1) according to the present invention, And, preferably indicates a cycle that can be represented by one of the following formulas (i)-(viii)where R stands for hydrogen, or indicates C 1-C 4-alkyl, if necessary, replacing hydroxy or amino.

A most preferably selected from the group consisting of 4,5-dihydro-thiazole, thiazole, , and .

In the formula R 5-X-B-X'- R 1 B is more preferable means direct communication, indicates imidazol or oxidiazol, or indicates 5 of about 6-membered heterocycle, having 1 or 2 heteroatoms selected of N and O, and it is most preferable means a structure that can be represented by one of the following formulas (ix) (xii).

X is more preferable indicates a direct link or selected from the group consisting of the CO-, -CONR 6 -, -CO 2 -, -SO 2 -, -(CH 2 ) m - O-(CH 2 ) m, where m is a number from 0 to 2, and R 6 indicates hydrogen, C 1-C 6-alkyl or C 3-C 6-cycloalkyl. It is most preferable to X selected from the group consisting of the CO-, -CONH-, -CO 2 -, -SO 2 -, -(CH 2 ) 2 -, -O - O-CH 2.

X' is more preferable indicates a direct link, or selected from the group consisting of -(CH 2 ) 2 -, -NH-, -CO, CO 2 -, -CONH-, -S(O) 2 -, -(R 6 O) 2 P(O)-, -NHC(O)- and-NHCO 2 -.

R 5 more preferable means hydrogen, nitrile, hydroxy, C 1-C 6-alkyl, halogen-C 1-C 6-alkyl, hydroxy-C 1-C 6-alkyl, C 4-C 6-cycloalkyl, phenyl or , or indicates or condensed cyclic 5~9-membered heterocycle or 5 of about 6-membered ring , each of which has from 1 to 3 heteroatoms selected of N, O and S, and may be replaced oxo or . The most preferable R 5 selected from the group consisting of hydrogen, nitrile, hydroxy, methyl, ethyl, isopropyl nitrate, , , , , , , pyrrolidine, piperidine, 2-, 2-, tetrahydrofuran, , , morpholine, furan, pyridine, 1,3-, 1,1-dioxo-, , imidazole, pyrazole and 3-trifluoromethyl-5,6,7,8-tetrahydro-2H-[1,2,4]triazolo[4,3-a].

In formula(CR 8 R 9 ) p-Y-R 7 R 2 , R 8 and R 9 , each more preferable means hydrogen.

Y preferably selected from the group consisting of O-, -NR 6 -, -NR 6 C(O)-, -C(O)-, -C(O)NR 6 - and-S(O) 2 -, where R 6 has value, as defined above, the preferred values. Most preferably, Y is selected from the group consisting of O-, -NH-, -NHC(O)-, -SO 2 - and-C(O)-.

R 7 more preferable means hydrogen, halogen, hydroxy, C 1-C 6-alkyl, hydroxymethyl or halogen-C 1-C 6-alkyl, indicates phenyl, if necessary, replacing C 1-C 6-, or indicates 5 of about 6-membered heterocycle or , each of which has 1 or 2 heteroatoms selected of N and O. it is Most preferable, R 7 selected from the group consisting of hydrogen, bromine, fluorine, chlorine, methyl, ethyl, cut, , , , 4--, piperidine, pyrrolidine, furan, pyrrole, pyrazole and pyridine.

R 3 is more preferable means hydrogen, or methyl isobutyl.

R 4 more preferable means-R 10 , -D-R 10 , or-CH 2-D-R , 10-D is C 3-C 6-cycloalkyl, if necessary, containing oxo, denotes 5 of about 6-membered heterocycle, having 1 or 2 heteroatoms selected of N, O and S, or indicates 5 of about 6-membered ring having 1 or 2 heteroatoms selected of N and S, and R 10 indicates hydrogen, halogen, amino, C 1-C 6 -alkyl, C 1-C 3-, halogen-C 1-C 3-, C 1-C 3-alkylsulfonyl or(CH 2 ) p-NR 8 R 9 , where p, R 8 and R 9 have the meanings given above in your preferred values. The most preferable R 4 is selected from the group consisting of hydrogen, isopropyl nitrate, , , , , , , 4-methyl-, 4,4-, 4-oxo-, -4 ILA (-4-yl)methyl, (-2-yl)methyl, tetrahydrofuran-3-sludge, piperidine-4-sludge, , 1-acetyl-piperidine-4-sludge, 1--piperidine-4-sludge, 1-TRIFLUOROACETYL-piperidine-4-sludge, 1-acetyl-pyrrolidine-3-sludge, -4-sludge, thiophene-3-sludge and 5-amino-pyridine-2-sludge.

The compounds of formula (1) according to the present invention can also form a pharmaceutically acceptable salt. Such “pharmaceutically acceptable salt” includes non-toxic salt accession acid-containing pharmaceutically acceptable anion, for example, salt with inorganic acids such as sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid, Hydrobromic acid, acid etc.; salt with organic carbonic acids, such as citric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; or salt with acids such as acid, acid, acid, p- acid, acid etc. The compounds of formula (I) can also form a pharmaceutically acceptable salt of accession with the basis, for example, salt with alkali metals or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium etc; salt with amino acids such as lysine, arginine, guanidine etc.; or organic salt with , N-methyl-D-, Tris(hydroxymethyl), , choline, etc. The compounds of formula (I) according to the present invention may be converted into their salts under any of the usual ways, and education salt can easily be done by specialist on the basis of the formula (1) without further explanation.

The term 'isomer' in this description refers to those that have the same chemical or molecular formula of the compound of formula (1), but optical or spatially different from the compounds of formula (1) or salts. The compounds of formula (1) according to the present invention may be asymmetric carbon centre (centers) in the structure, and thus may exist in the form of an optical isomer (isomer R or S), racemate, mixture of diastereomers, or individual etc. When joints have double bond, they can exist in the form of a geometric isomer (TRANS or CIS-isomer). All isomers and their mixtures are also covered by the present invention.

In the further description of the connection formula (1) include their pharmaceutically acceptable salt and isomers, unless otherwise specified. It should be understood that salt and isomers covered by the present invention. For convenience, they are specified in this description as the compounds of formula (1).

Typical connections among the compounds of formula (1) selected from the following connections:

-[2-(4,5-dihydro-1,3--2-yl)-1H-indol-7-yl]amine;

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro-1,3--4-yl]methanol;

methyl [(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

(R)-2-[7--5-(hydroxymethyl)-1H-indole-2-yl]-4,5-dihydro--4-;

[2-(4,5-Dihydro--2-yl)-1H-indol-7-yl]piperidine-4-ylamine;

[(R)-2-(5-methyl-7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7-(1--4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

2-[(S)-2-(7-(-2-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7-(1--3-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-phenoxy-7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-phenoxy-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7-(4,4--4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

[(S)-2-(5-methyl-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

(thiophen-3-yl)methyl-[2-(4,5-dihydro-1,3--2-yl)-1H-indol-7-yl]amine;

(3-tetrahydrofuran)-[2-(4,5-dihydro-1,3--2-yl)-1H-indol-7-yl]amine;

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro-1,3--4-yl]methanol;

3-[(R)-2-(7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro-1,3--4-yl]methanol;

(-4-yl)-[2-(4,5-dihydro-4-methyl--2-yl)-1H-indol-7-yl]amine;

[(R)-2-(5-(morpholine-4-yl)methyl-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-(dimethylamino)methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-(pyrrol-3-yl)methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-(1,3-imidazol-1-yl)methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-(pyrazol-1-yl)methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-acetylamino-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

methyl [(R)-2-(5-(pyrrolidine-1-yl)methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

-[5-chloro-2-(R)-4-isobutyl-4,5-dihydro--2-yl)-1H-indol-7-yl)amine;

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid ethyl ester;

{(R)-2-[7-((3R)-1--3-yl)amino-1H-indole-2-yl]-4,5-dihydro-1,3--4-yl}methanol;

-[5-fluoro-2-(R)-4-ethyl-4,5-dihydro--2-yl)-1H-indol-7-yl]amine;

{(R)-2-[7-(methyl-)amino-5-fluoro-1H-indole-2-yl]-4,5-dihydro-1,3--4-yl}methanol;

methyl [(S)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

ether ethyl [(R)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]carboxylic acid;

[(S)-2-(5-phenoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(7-(tetrahydrofuran-3-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(7-(1-()pyrrolidine-3-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-fluoro-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

[(R)-2-(5-chloro-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-bromo-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-bromo-7-(-4-yl)-1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-methoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-(pyridine-3-yl)hydroxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-(pyridine-3-yl)hydroxy-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[(R)-2-(5-(-1,3-dione-2-yl)methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

methyl [(R)-2-(5-chloro-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-chloro-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-chloro-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

[(R)-2-(5-bromo-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-bromo-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

[(R)-2-(5-bromo-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

ether ethyl [(R)-2-(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

[(R)-2-(5-fluoro-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

ether ethyl [(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

[(R)-2-(7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]carboxylic acid;

[(R)-2-(7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

methyl [(R)-2-(5-methoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-methoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-methoxy-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-propyloxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-phenoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-phenoxy-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

methyl [(R)-2-(5-(pyridine-3-yl)hydroxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-(pyridine-3-yl)hydroxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

methyl [(R)-2-(5-(pyridine-3-yl)hydroxy-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-(pyridine-3-yl)hydroxy-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

methyl [(R)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-methyl-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5-(4-()phenoxy)-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

methyl [(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

methyl [(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

methyl [(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl];

3-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propanol;

3-[(R)-2-(5-chloro-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(5-chloro-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]propanol;

ethyl ester 3-[(R)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(5-phenoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

ethyl ester 3-[(R)-2-(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

ethyl ester 3-[(R)-2-(5-bromo-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(5-bromo-7--1H-indole-2-Il)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(5-methoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

ethyl ester 3-[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

ethyl ester 3-[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

3-[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]propionic acid;

[(R)-2-(5-methyl-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

[(S)-2-(5-methyl-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-methyl-7-(-4-yl)amino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[(S)-2-(5-chloro-7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[2-((4S,5R)-5--4-benzyl-dihydro--2-yl)-5-chloro-1H-indol-7-yl]-amine;

{2-[(R)-5-(S)-1-amino-2-phenyl-ethyl)-4,5-dihydro--2-yl]-5-chloro-1H-indol-7-yl}-amine;

(-4-yl)-[2-(4,5-dihydro--2-yl)-1H-indol-7-yl]amine;

[2-(7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid;

[2-(7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol;

-[2-(4,5-dihydro-oxidiazol-2-yl)-1H-indol-7-yl]amine;

[2-(5-methyl-7--1H-indole-2-yl)-4-yl]methanol;

[2-(5-methyl-7--1H-indole-2-yl)-5-yl]methanol;

ether ethyl [2-(5-methyl-7--1H-indole-2-yl)-4-yl]carboxylic acid;

[2-(5-methyl-7--1H-indole-2-yl)-4-yl]carboxylic acid;

[2-(7--1H-indole-2-yl)-4-yl]methanol;

methyl ether [2-(7--1H-indole-2-yl)-4-yl]carboxylic acid;

{(R)-2-[5-methyl-7-(4-oxo-)-1H-indole-2-yl]-4,5-dihydro--4-yl}acetic acid;

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-morpholine-4-;

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(morpholine-4-yl)-;

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(morpholine-4-yl)-;

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-metilamino-;

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-dimethylamino-;

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-[4-(methyl)piperazine-1-Il];

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(3--1-Il);

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(piperidine-4-yl);

2-[(R)-2-(5-chloro-7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]-1-metilamino-;

2-[(R)-2-(5-chloro-7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(morpholine-4-yl);

2-[(R)-2-(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(4-methyl)piperazine-1-Il);

2-[(R)-2-(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(morpholine-4-yl)-;

2-[(R)-2-(5-methoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(metilamino)-4-;

2-[(R)-2-(5-methoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(morpholine-4-yl);

2-[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-metilamino-;

2-[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(morpholine-4-yl);

2-[(R)-2-(7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]-1-metilamino-;

2-[(R)-2-(7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(morpholine-4-yl);

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(morpholine-4-yl)-;

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-(4-methyl)piperazine-1-Il);

-{5--2-[(R)-4-(2-morpholine-4-yl-ethyl)-4,5-dihydro--2-yl]-1H-indol-7-yl}Amin;

1-(4-{2-[(R)-2-(7--5--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-Il);

-[2-(R)-4-pyrrolidine-1--4,5-dihydro--2-yl)-1H-indol-7-yl]amine;

{5-chloro-2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro--2-yl]-1H-indol-7-yl}-amine;

{5-chloro-2-[(R)-4-(2-piperazine-1-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-amine;

(5-chloro-2-{(R)-4-[2-(4--piperazine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

1-(4-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-;

{5-chloro-2-[(R)-4-(2-pyrazol-1-yl-ethyl)-4,5-dihydro--2-yl]-1H-indol-7-yl}-amine;

(S)-1-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}pyrrolidine-2-carboxylic acid;

{5-chloro-2-[(R)-4-(2--ethyl)-4,5-dihydro--2-yl]-1H-indol-7-yl}-amine;

ethyl ester 3-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}-5-methyl-3H-imidazol-4-carboxylic acid;

3-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}-5-methyl-3H-imidazol-4-carboxylic acid;

1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl) - piperidine-3-carboxylic acid;

tert-butyl ether [(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl)pyrrolidine-3-yl] acid;

(2-{(R)-4-[2-(S)-3-amino-pyrrolidine-1-yl)ethyl]-4,5-dihydro--2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

N-[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl)pyrrolidine-3-yl];

-{2-[(R)-4-(2-methoxy-ethyl)-4,5-dihydro--2-yl]-1H-indol-7-Il}Amin;

[2-(R)-4--4,5-dihydro--2-yl)-1H-indol-7-yl]-amine;

{2-[(R)-4-((R)-3-amino-pyrrolidine-1-)-4,5-dihydro--2-yl]-5-chloro-1H-indol-7-yl}-amine;

4-[(R)-2-(7--5--1H-indole-2-yl)-4,5-dihydro--4-]piperazine-2-on;

{2-[(R)-4-((S)-3-amino-pyrrolidine-1-)-4,5-dihydro--2-yl]-5-chloro-1H-indol-7-yl}-amine;

(5-chloro-2-{(S)-4-[2-(3-dimethylamino-phenyl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

1-(4-{2-[(S)-2-(7--5-chloro-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-Il);

1-(4-{2-[(S)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-Il);

(5-methoxy-2-{(R)-4-[2-(pyrrolidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(2-{(R)-4-[(pyrrolidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(2-{(S)-4-[(2--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5--2-{(S)-4-[(2--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-methyl-2-{(S)-4-[(morpholine-4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

1-(4-{2-[(R)-2-(7--5-chloro-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-Il);

(5-chloro-2-{(R)-4-[4-methyl-piperazine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(R)-4-[4-(hydroxy)piperidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(R)-4-[2--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(R)-4-[(piperidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(R)-4-[(1,1-dioxo--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(R)-4-[(2--1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(R)-4-[(3S)-3-()piperidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-chloro-2-{(R)-4-[(piperazine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

1-(4-{2-[(R)-2-(5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-;

(5-chloro-2-{(R)-4-[(1-(TRIFLUOROACETYL)piperazine-4-yl)ethyl]4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-chloro-2-{(R)-4-[(1-[(furan-2-yl)carbonyl]piperazine-4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-chloro-2-{(R)-4-[(1,4-pyrazin-2-yl)piperazine-4-yl-ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-chloro-2-{(R)-4-[(1,3-pyrazin-2-yl)piperazine-4-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-Fluoro-2-{(R)-4-(2-aminoethyl)-4,5-dihydro--2-yl}-1H-indol-7-Il)-amine;

1-(4-{2-[(R)-2-(5-fluoro-7-)-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-;

(5-Fluoro-2-{(R)-4-[(morpholine-4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-Fluoro-2-{(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-Fluoro-2-{(R)-4-[(pyrrolidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-Fluoro-2-{(R)-4-[(1,1-dioxo--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-Fluoro-2-{(R)-4-[(2--1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

1-(4-{2-[(5-fluoro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-;

(5-Fluoro-2-{(R)-4-[-ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-Fluoro-2-{(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-Fluoro-2-{(R)-4-[(pyrrolidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-Fluoro-2-{(R)-4-[(morpholine-4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

1-(4-{2-[(R)-2-(7-(tetrahydro-PYRAN-4-)-5-fluoro-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-Il);

(5-Fluoro-2-{(R)-4-[(1,1-dioxo--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-Fluoro-2-{(R)-4-[2--ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

(5-Fluoro-2-{(R)-4-[2--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

1-(4-{2-[(R)-2-(5-fluoro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-;

(2-{(R)-4-[2-dimethylamino-ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(2-{(R)-4-[(piperidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

2-{(R)-4-[2--ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine;

1-(4-{2-[(R)-2-(5-methoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-;

1-(4-{2-[(R)-2-(7-)-5-chloro-1H-indole-2-yl)-4,5-dihydro--4-yl]propyl}piperazine-1-Il);

2-{(R)-4-[(morpholine-4-yl)methyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(R)-4-[(morpholine-4-yl)propyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(2-{(R)-4-[2-dimethylamino-methyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(S)-4-[(morpholine-4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

{5-methyl-2-[(R)-4-(2-morpholine-4-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-(-4-yl)amine;

{5-methyl-2-[(S)-4-(2-morpholine-4-yl-ethyl)-4,5-dihydro--2-yl]-1H-indol-7-yl}-(tetrahydro-PYRAN-4-)amine;

1-(4-{2-[(S)-2-(5-phenoxy-7,7-)-1H-indole-2-yl)-4,5-dihydro--4-Il]ethyl}piperazine-1-Il);

(5-Phenoxy-2-{(S)-4-[(pyrrolidine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

1-(4-{2-[(S)-2-(5-phenoxy-7-)-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-;

(5-Phenoxy-2-{(S)-4-[(piperazine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

tert-butyl-(4-{2-[(S)-2-(5-phenoxy-7-)-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-carboxylate;

-(5-phenoxy-2-{(S)-4-[2-(3--5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)amine;

(5-Phenoxy-2-{(S)-4-[2--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(4-{2-[(S)-2-(5-phenoxy-7-)-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)--2-Il-;

(5-Phenoxy-2-{(S)-4-[(pyridin-2-yl)piperazine-ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-Phenoxy-2-{(S)-4-[(2-fluorophenyl)piperazine-ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-chloro-2-{(S)-4-[2--4-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-Phenoxy-2-{(S)-4-[(3S)-3-(amino)pyrrolidine-1-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

1-(4-{2-[(S)-2-(5-phenoxy-7-)-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-Il);

(5-methyl-2-{(S)-4-[2-()pyrrolidine-1-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(-4-yl)methylamine;

(5-methyl-[(S)-2-(7-(-4-yl)metilamino-1H-indole-2-yl)-4,5-dihydro--4-yl])pyrrolidine-2-;

(5-chloro-[(S)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl])pyrrolidine-3-;

(5-Phenoxy-2-{(S)-4-[4-(benzyl)piperazine-1-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-methyl-2-{(S)-4-[2--ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(-4-yl)methylamine;

(5-methyl-2-{(S)-4-[morpholine-4-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(-4-yl)methylamine;

(5-Phenoxy-2-{(R)-4-[pyrrolidine-1-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-Phenoxy-2-{(S)-4-[morpholine-4-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(-4-yl)methylamine;

(5-Phenoxy-2-{(S)-4-[pyrrolidine-1-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-amine;

(5-methyl-2-{(S)-4-[2--4-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-4,4--amine;

(5-methyl-2-{(S)-4-[morpholine-4-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-4,4--amine;

(-4-yl)-(5-methyl-2-{(S)-4-[2-(3--5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)amine;

(5-methyl-2-{(S)-4-[2--4-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(-4-yl)methylamine;

(5-chloro-2-{(S)-4-[1-(pyridin-2-yl)piperazine-4-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(-4-yl)amine;

(4-{2-[(S)-2-(5-chloro-7-(-4-yl)amino)-1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-Il)-2-;

(5-methoxy-2-{(R)-4-[2--4-]-4,5-dihydro--2-yl}-1H-indol-7-yl)-(-4-yl)amine;

1-(4-{2-[(R)-2-(5-methoxy-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-;

[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol;

[7--2-(R)-4-hydroxymethyl-4,5-dihydro--2-yl)-1H-indole-5-]amide furan-2-carboxylic acid;

methyl [(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-]acetic acid;

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-]acetic acid;

-{2-[(R)-4-(3--[1,2,4]oxidiazol-5-)-4,5-dihydro--2-yl]-1H-indol-7-yl}Amin; and

-{2-[(R)-4-(3-piperidine-1-yl-[1,2,4]oxidiazol-5-)-4,5-dihydro--2-yl]-1H-indol-7-yl}Amin.

The present invention also relates to a method of obtaining the compounds of formula (1). Further ways of obtaining the compounds of formula (1) illustrates for a better understanding of schemes examples of reactions. However, the expert in the field that is the present invention can get the compounds of formula (1) in different ways depending on their structures, and such methods should be considered as included in the scope of the present invention. In other words, the compounds of formula (1) can be obtained, if necessary to combine different ways of synthesis, which are described in the present description or disclosed in the prior art. Methods of obtaining the compounds of formula (1) to cover even such processes are not limited unexplained below.

First of all, the compounds of formula (1) can be obtained by the reaction of the amide of the combination or the reaction of alkylation of compounds (2) and (3) according to the following reaction scheme (1).

The reaction scheme 1

in the above reaction scheme (1)

A, R 1 , R 2 , R 3 , R 4 and n have the meanings given above, and

W denotes carboxylic acid used in the reaction of the amide combination, or halo, etc. used in combination reaction.

In particular, R 1 in the above Reaction scheme (1) preferably denotes a group containing amine or reactions a nucleophilic carbon.

Reaction amidation can be accomplished with the agent combinations, such as, for example, (DCC), EDC, N-[dimethylamino-1H-1,2,3-triazole[4,5-b]pyridine-1-]-N- (HATU), etc. together with HOBT. The reaction is carried out in DMF or DCM in the presence of a base Et 3 N DIPEA etc., within 4-12 hours and the ambient temperature. In the case of nucleophile reaction centre containing nitrogen atom of the reaction of alkylation can be done using various grounds, such as Et 3 N, K 2 CO 3 , NMPA, DBU, etc. in a solvent such as acetonitrile, THF or DMF, at a temperature of 25 to 80 C and for 4-24 hours. The majority of the compounds (3) commercially available.

In the following reaction scheme (2) connection (2-1) and (2-2), where A denotes the 4,5-dihydro- can be obtained by hydrolysis of complex (4,5-dihydro--4-yl)-EW ethers compounds (4)or may be obtained synthesis of alcohols by reconstruction and introduction of halogen or group as a deleted group.

The reaction scheme 2

in the above reaction scheme (2)

n, R 2 , R 3, and R 4 have the meanings given above,

Q denotes removable group, preferably halogen or , and

R' denotes alkyl, preferably methyl, ethyl, isopropyl, etc.

In particular, the connection carboxylic acid (2-1) can be obtained by hydrolysis broadcasting connection (4), where from 2 to 10 EQ. NaOH, LiOH, KOH etc. use as a base, and use one or more solvents, selected from the water, methanol, THF and dioxane. This reaction of hydrolysis performed for 30 minutes to 12 hours at a temperature from the ambient temperature to 100 degrees C.

Alcohol compound (5) can also be obtained restoration of essential compounds (4)where NaBH 4 , LiBH 4 , LAH etc. use as a reducing agent, and alcohol, such as methanol, THF, dioxane, etc., used as a solvent. This reaction recovery is carried out in the period from 30 minutes to 24 hours at a temperature from the ambient temperature to 100 degrees C. the Restorer is typically used in an amount of from 3 to 5 EQ., but can be used in excess of approximately 10 EQ., if you want to.

Halogenation reaction alcoholic compounds (5) can be made using the agent selected from iodine, bromine, N- (NIS), N- (NBS), carbon tetrachloride (CCl 4 ), carbon (CBr 4 ) etc., in the presence of a base, such as imidazol, (DMAP) etc. and phosphine, such as triphenylphosphine (Ph 3 P), (Bu 3 P), etc. Each reagent, grounds and phosphine is typically used in an amount of from 1 up to 10 EQ. regarding connection (5). The reaction may proceed in a solvent chosen from the ethers, such as tetrahydrofuran, simple diethyl ether etc., dichloromethane, chloroform, and etc., at temperatures from 0 to 50 degrees C for 10 minutes to 12 hours.

Reaction alcoholic compounds (5) can be performed using the agent selected from , p- etc. in the amount from 1 to 10 EQ. In the presence of organic bases, such as pyridine, triethylamine, etc. This reaction can take place in a solvent, selected from dichloromethane, dichlorethane, etc., at temperatures from 0 to 50 degrees C for 10 minutes to 12 hours.

Connection indole-4,5-dihydro-thiazole (4') can be obtained as shown in the following reaction scheme (3), i.e. the introduction of 4,5-dihydro-thiazole in the original connection of ester 7-, restoration of nitro and restorative reaction amination with the introduction of the R 3 and R 4 .

The reaction scheme 3

in the above reaction scheme (3)

R 2 has the values defined above,

R” denotes the p- (p-MeOBn) or (Ph 3 C), and

R"' denotes R 1 or protected R 1 , and usually denotes (alkyl-OC(O)) or alkyl carboxylate (alkyl-CO 2 -).

Reaction of hydrolysis in the reaction scheme (3) conduct the same way, as explained for the reaction scheme (2), and the reaction of the amide combination of conduct, as explained schemes for Reaction (1). Cyclization reaction can be carried out through phosphorus (PCl 5 ) in dichloromethane as a solvent, when R is p-, or using anhydride acid (Tf 2 O) and (Ph 3 PO) in dichloromethane as a solvent, when R is .

Restoration of nitrogroup in 7- connection (10) can be done using an acid catalyst and metal or using a metal catalyst in the atmosphere of hydrogen gas. In reaction with the use of acid catalyst as metals can be used iron, zinc, lithium, sodium or tin (usually, tin chloride), and as an acid catalyst can be used inorganic acids, such as hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, etc; organic carboxylic acids such as acetic acid, acid etc.; acid salts Amin, such as ammonium chloride, etc., preferably hydrochloric acid, acetic acid or ammonium chloride. In addition, the reduction reaction with the use of a metal catalyst in the atmosphere of hydrogen gas, as a metal catalyst, which can be used, can be called palladium, Nickel, platinum, ruthenium, rhodium, etc., preferably palladium or Nickel.

The reaction of rehabilitation amination exercise using compound containing group (ketone or aldehyde). As a reducing agent that can be used, can be called sodium borohydride sodium, sodium etc. The reaction can be alleviated by using acid as a catalyst. As an acid catalyst that can be used, can be called inorganic acids, such as hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, etc; organic carboxylic acids such as acetic acid, acid etc.; acid salts Amin, such as ammonium chloride, etc. more preferable hydrochloric acid or acetic acid.

In the following reaction scheme (4) connection (11) and connection indole (7) is subjected to a combination reaction, getting connection (9-1), which then in the acidic environment and hydrolyzing, getting connection (2-3), in which R' is alcohol. In addition, the connection (2-4), which is produced by replacing the spirit connection group (2-3) to be removed as a group, can be entered into a reaction with the connection Amin (14) obtaining the compounds amine (2-5).

The reaction scheme 4

in the above reaction scheme (4)

Q, R 2 , R-5 , R 6 and R” have the meanings given above.

The reaction of the amide combination and cyclization can be held in the same conditions as explained schemes for reaction (1) and (3).

Reaction of hydrolysis to obtain connection (2-3) is carried out in a mixture of water and organic solvent and in the presence of a base, where as organic solvent can be used THF, methanol, dioxane and etc, and as a basis can be used LiOH, KOH, NaOH, etc.

7- connection (6) commercially available or can be obtained according to the following reaction scheme (5).

The reaction scheme 5

in the above reaction scheme (5) R 2 has the values defined above.

Connection Nitra- (15) commercially available or can be obtained according to the method, known from Heterocycles, 68(11), 2285-99, 2006, or Bioorganic & Medicinal Chemistry Letters, 14(19), 4903-4906, 2004.

connection (16) commercially available or can be obtained by modification of amino compounds (15) in group according to the method, known from the Journal of the America Chemical Society, 198(48), 15374-75, 2006.

Connection of hydrazine (18) can be obtained by a combination of connection ketone (17) with connection (16). The base is not used when connection (16) is a neutral form, but should be used when the connection is a form of acid salt, to put it in a neutral form. As the base can be called metal hydroxides such as sodium hydroxide, lithium hydroxide, etc., metal carbonates, such as sodium bicarbonate, potassium carbonate, etc., acetates metals, such as sodium acetate, etc., organic bases, such as triethylamine, pyridine, etc., preferably sodium acetate, sodium bicarbonate, and etc.

Connection of hydrazine (18) can be obtained by the reaction of diazonium salts with the connection ketone (19) in the presence of grounds under way rearrangement Japp-Klingemann, known from the Organic Process Research & Development, 2, 1988, 214-220.

Cyclization reaction connection (18) may be performed according to the method, known from the Journal of Organic Chemistry, 68(24), 2003, 9506~9509, Tetrahedron, 55(34), 1999, 10271-10282, etc. Acid, which can be used in this reaction can be acid, hydrochloric acid, p- acid, sulphuric acid, acetic acid, etc., In the case of acid it can be used individually or together with aromatic hydrocarbon, selected from benzene, toluene, etc.

A connection that's modified in position 5 ring can be obtained from the connection (6'), as shown in the following reaction scheme (6).

The reaction scheme 6

in the above reaction scheme (6)

R, R' and R 7 have the meanings given above.

Connection (20) can be obtained by joining the protective group to amino methyl ester (5-methyl-7-nitro-1H-indole-2-yl)carboxylic acid (6') using the Boc 2 O in the presence of a base and transformation of a methyl group at position 5 in group using agent.

Subsequent acetylation on the connection (20) with the use of sodium acetate, removing the protective group from the group VOS and hydrolysis reaction can give alcoholic connection (22).

Cyclization reaction can be made using the phosphorus on the connection (9-2), which is obtained by the reaction of the amide combination between connections (22) and (8), as explained for the reaction scheme (3), obtaining connection (2-6), in which alcohol replaced chloride, and connection (2-6) can be converted to a connection (2-7) the introduction of group R 7 .

Connection (1-2), having amino-group in position 5 rings may be obtained through a connection (24) of connection (23) and acylation of amino compounds (1-1), which is obtained from the connection (24), as shown in the following reaction scheme (7).

The reaction scheme 7

R 4 , R, R' and R 10 have the meanings given above.

potassium, used in the reaction of alkylation for the introduction of group, is commercially available, and this reaction can be carried out in the presence of tetrahydrofuran, N,N-dimethylformamide, N- etc. Hydrolysis can be made the same way as a way to obtain a connection (2-3) on the reaction scheme (4). combination of connection (23), cyclization and recovery and reductive amination of connection (24) can also be performed in the same way as explained above. Reaction removal connection group (24) can be made using the hydrazine. Connection (1-2) can be obtained compounds amine (1-1) communication using the acetyl chloride acid (25), where the base of the selected from the Et 3 N DIPEA, DMAP, pyridine, etc. is used usually in the amount of 2 EQ. or more to the connection Amin.

In the following reaction scheme (8) connection (8-1) and (8-2) receive, protecting group of amino acids, such as cysteine, or by group in derivatives of amino acids, obtained from glutamic acid, aspartic acid, etc.

The reaction scheme 8

in the above reaction scheme (8)

R has the values defined above, and

R”” indicates alkyl, preferably methyl, ethyl, isopropyl or cyclohexyl.

Connection (8-1) can be obtained by the reaction of protected Amin connection amino acids (28) with obtaining azo compounds, an extension of one carbon atom with the use of silver ions, such as sodium benzoate silver, esterification of acid group and removing the protective amino group. In particular, the reaction of the lengthening of one carbon atom can be carried out by means of introduction into the reaction of the connection (28) with (EtOCOCl) or (iBuOCOCl) in the presence of the reasons [for example, N- (NMM), triethylamine, etc.] solvent, which is a tetrahydrofuran, at an ambient temperature according to the method, known from Helvetica Chimica Acta, 87, 2004, 3131~3159, obtaining anhydride, the introduction of the received dioxide reacts with water solution of sodium hydroxide, in a simple diethyl ether as a solvent in the 0 C and then with the ion Ag [for example, silver (CF 3 CO 2 Ag), silver etc.] and alcohol (e.g., methanol, ethanol, etc) in the dark with obtaining connections complex ether.

In the above reaction diazomethane can be obtained by the reaction of Diazald, N-methyl-N-nitrozoguanidine mutagenesis, or N-methyl-N- in the presence of a base KOH according to known from the prior art to the usual method. Essential compound that one additional carbon atom can be obtained from the diazocompounds introduction of it in the reaction with silver in an alcohol solvent, where appropriate reaction temperature is around -15 C completion of the reaction, the reaction mixture after adding benzoate silver heated up to the temperature of the environment. As a solvent can be used methanol or ethanol. Group VOS can be deleted with acid or 4 Mr. solution hydrochloric acid/ether or hydrochloric acid/dioxane.

Connection amino acids (28), in which the amino group is protected by a group of VOS may be obtained protection group cysteine in the principal terms of the protection of the amino group of VOS. In particular, the protection group can be made using the p- (PMBCl) or (TrCl) in the presence of a base, selected from NaOH, NaH etc. Protection group VOS amino groups can be made using the (RE) 2 O in the basic environment where the base can include NaOH, Et 3 N, NaHCO 3, etc. and can be used solvent selected from the DCM, dioxane, water etc.

Connection (8-2) can be obtained by introducing group in connection (31) and remove the group VOS. In particular, adding group can be performed using PMB-SH () in the presence of a base, selected from NaH, CeCO 3 , K 2 CO 3 etc. On the other hand, the connection (31) can be obtained protection alcoholic compounds (29) using in the presence of a base Et 3 N or DIPEA.

Connection (29) can be synthesized from the source of glutamic acid compounds or aspartic acid according to the method, known from Synlett, 15, 2005, 2397~2399 or Journal of Organic Chemistry, 66(5), 2001,1919~1923, etc.

In the following Reaction scheme (9) group, a carboxylic acid derivative cysteine (28) modify, getting connection (11).

The reaction scheme 9

in the above reaction scheme (9) R has the values specified above.

Protection of amino compounds (28) can be done with the (RE) 2 O, acylation can be performed using chloroacetyl ISO-butyrate acid, acid chloride tert-butyric acid etc. in the presence of a base, and recovery can be accomplished using NaBH 4 .

Acylation connection (32) carry out, using in the presence of a base, and remove VOS carried out, as explained above.

Compounds, methods of production which does not specifically explained in this description, known per se , or can be obtained from the known connections according to the known method or like him way.

In ways according to the present invention, the mixture is usually shared by chromatography on your speakers. In the case of the final product, it can be separated after the reaction by recrystallization or normal or HPLC HPLC phase (Waters, Delta Pack, 300 x 50 mm inner diameter, C18 5 microns, 100A). When the product is purified by recrystallization or HPLC, the connection can be obtained in the form of salts with acid. When it is desirable to have salt with hydrochloric acid may be used ion-exchange resin.

As explained above, the compounds according to the present invention, raw materials, intermediate compounds etc. for their receipt, may be obtained in different ways, and such methods of obtaining the compounds of formula (1) should be considered as included in the scope of the present invention.

Effect

The present invention also relates to a composition for prophylaxis and treatment of necrosis and related diseases, which contains a therapeutically efficient quantity of the compounds of formula (1), their pharmaceutically acceptable salts of isomers or as active ingredient together with a pharmaceutically acceptable carriers or diluents.

Necrosis and related disorders that can be treated and/or prevention according to the present invention, include acute/chronic liver disease (for example, hepatitis, liver fibrosis, cirrhosis of the liver), a neurodegenerative disease (for example, dementia, Parkinson's disease, Huntington's disease), ischemic heart disease, reperfusion injury, cerebral infarction or ischemic damage, pancreatitis, bacterial/viral pneumonia, diabetes or diabetic complications, diabetic vascular disease [in particular, these types of diabetes are caused by substances that destroy pancreatic cells, and mediated by the virus, hyperglycemia, fatty acid, diet, toxins, etc.], necrotizing , cystic fibrosis, rheumatoid arthritis, degenerative arthritis, nephropathy, bacterial infection, viral infection (e.g., HIV), multiple sclerosis, leukemia, lymphoma, respiratory distress syndrome of the newborn asphyxia, tuberculosis, endometriosis, , psoriasis, frostbite, complications of treatment with steroids, gangrene, decubitus, , burns, pyrexia, Crohn's disease, disease, embarrassment syndrome, spinal cord injury, glomerulonephritis, muscular dystrophy, hereditary metabolic disease, disease, anthrax, a disease Andersen, innate disease, phenylketonuria, myocardial placenta, syphilis, aseptic necrosis, etc. in addition, necrosis and related disorders caused by drugs and toxic substances, selected from the group consisting of necrosis associated with chronic alcoholism, contact with, and/or the introduction and/or , cocaine, drugs (such as ), antibiotics, anti-cancer products, adriamycin, puromycin, bleomycin, NSAID, cyclosporine, chemical toxins (e.g., carbon tetrachloride, cyanide, methanol, ethylene glycol), poison gas, agrochemicals, heavy metals (e.g. cadmium, mercury, lead), or damage due to contact with radiation/UV and associated necrosis.

In particular, the composition according to the present invention, illustrates not only the effects on and functional improvement of the state of the liver, but also preventive and therapeutic effects against chronic liver disease, such as obesity liver, liver fibrosis, cirrhosis of the liver, etc. and acute/chronic liver disease such as hepatitis, etc. caused by viruses or drugs. Therefore, complications of liver disease, including, but not limited to her, portal hypertension may also be subject to preventive or treatment. More specifically, medical composition according to the present invention also effective for the treatment or prevention of diseases of liver, selected from the transplantation of the liver, alcoholic or non-alcoholic fatty liver disease, liver fibrosis, cirrhosis and induced hepatitis or drugs, and is effective in respect of alcohol acute/chronic liver disease.

Further, the composition according to the present invention is effective for the treatment and prevention of diseases caused by fatty acid fatty liver disease or acute/chronic liver disease that is caused by the degeneration of the liver.

In the framework of the invention "treatment" means an interruption or delay the onset of disease in relation to the patient, which is shown by the emergence of symptoms, and "prevention" means an interruption or delay the onset of signs of the onset of the disease in relation to the patient, which is not shown, but there is a risk of occurrence of symptoms of disease.

The specified “pharmaceutical composition can include a pharmaceutically acceptable carriers, diluents, or a combination thereof, if necessary, together with the compounds according to the present invention. Pharmaceutical composition facilitates the introduction of a connection in a living organism. There are many techniques of introduction of a connection, and they include, but are not limited to, oral, injection, aerosol, parenteral and introduction.

In the framework of the invention of "carrier" means a substance which makes it easy to enable connection in cells or tissues. For example, dimethyl sulfoxide (DMSO) is a typical carrier which is used to facilitate the introduction of various organic compounds in cells or tissues of living organisms.

In the framework of the invention "thinner" is defined as a substance that is diluted in water which dissolves connection and stabilizes the biologically active form which connection to use. Salt dissolved in a buffer solution, used in the art as dilutants. Usually used with the buffer is phosphate buffered saline solution which simulates the salt form environment of the human body. Buffer thinners rarely alter the biological activity of the connection, because the buffer salts can control the pH of the solution in low concentration.

Connection according to the present invention can be made as a variety of pharmaceutical dosage forms, depending on the desired goal. To obtain a pharmaceutical composition according to the present invention, the active ingredient, in particular, to the compounds of formula (1), their pharmaceutically acceptable salts of isomers or mixed together with various pharmaceutically acceptable carriers that can be selected depending on the volume of the composition. For example, pharmaceutical composition according to the present invention can be written as a drug for injection, oral, etc. depending on the desired goal.

Connection according to the present invention can be made in ways known from the prior art, using pharmaceutical carriers and , known from the prior art, and can be enclosed in containers for pharmaceutical form as a single dose or forms for many doses. Form of the drug can represent itself solutions, suspensions and emulsions in oil or water environments and can include normal dispersing agents, agents or stabilizers. Further, for example, it may be a form of dry powder, which is used to recover by dissolution in a sterile, pyrogen-free water before use. Connection according to the present invention may be composed in form of the suppositories, using a normal basis suppositories, such as cocoa butter or other glycerides. As solid dosage forms for oral administration may be obtained capsules, tablets, pills, powder and granules, and particularly preferred capsules and tablets. Preferably, pills and tablets receive in moulds with coverage. Solid dosage forms are available, mixing compounds according to the present invention, together with carriers such as one or more inert diluent such as sucrose, lactose, starch, etc., , such as magnesium stearate, , resins, etc.

If necessary, the compounds according to the present invention, or containing pharmaceutical composition can also be given in combination with other active means, including funds with different mechanisms of action of different types, particularly the existing means used for , functional improvement of the state of the liver and the prevention or treatment of liver - the promoters of the regeneration of hepatocytes, functional hepatic adjuvant, antiviral, immunosuppressive drugs, inhibitors fibrosis etc.

Connection according to the present invention, or pharmaceutical compositions containing them can be used together with prophylactic or therapeutic agents for the prevention or treatment of any caused by drug necrosis and related diseases. These medicines include drugs for any disease, such as antibiotics, anti-cancer products, antiviral agents, anti-infective products, anti-inflammatories, tools that improve the lipid profile, inhibitors of cell death antihypertensive agents, anti-diabetic/anti-obesity products, therapeutic products for the treatment of cardiovascular disease, therapeutic tools for the treatment of neurodegenerative diseases, tools, slowing down aging, therapeutic tools for the treatment of metabolic diseases etc.

Connection according to the present invention, or pharmaceutical compositions containing them can prevent cell damage and subsequent necrosis and related diseases caused by various reasons, such as toxins, and these causes include reactive oxygen species (ROS), heavy metals, alcohol, food additives, radiation, diet etc.

Dosage of compounds of formula (1) depends on the doctor's orders, taking into account such factors as body weight, gender, age, state of health and diet of the patient, the specific nature of the disease, the administration tools, method of administration, the ratio of the mixture and the seriousness of the disease and etc, However the dose necessary for the treatment of adult, usually from approximately 1.0 mg to 2000 mg / day, depending on the intensity and frequency of injection. With the introduction of adult intramuscular or intravenous routes, full dose of approximately 1.0 mg to 300 mg per day, it will usually be sufficient for a separate introduction in the form of a single dose, but for some patients it may be desirable higher daily dose.

The present invention also relates to a method of obtaining a composition for prophylaxis and treatment of necrosis and related diseases, which includes the stage of mixing compounds of formula (1), their pharmaceutically acceptable salts of isomers or as active ingredient together with a pharmaceutically acceptable carriers or diluents.

The best way of carrying out the invention

The following Examples obtain explain in more detail the receipt of intermediate compounds, which are needed for the synthesis of compounds of the examples. Abbreviations used in the following examples, the receipt and examples are as follows.

Ac: acetyl

AIBN: 2,2'-(2-)

BOC: tert-

Bu: butyl

Bn: benzyl

c-Pen:

c-Hex: cyclohexyl

CBZ(Cbz):

DME:

DCM: dichloromethane

DIPEA:

DMAP: 4-

DMF: N,N-dimethylformamide

EDC: 1-(3-)-3-, hydrochloride

Et: ethyl

EtOAC: ethyl acetate

Hex: n-hexane

HOBT: hydroxybenzotriazole

HBTU: 2-(1H--1-Il)-1,1,3,3-

i-Pr: isopropyl

i-Pen:

Me: methyl

Ph: phenyl

Pid: piperidine

Piz: piperazine

Pyd: pyrrolidine

PMB:

TEA: triethylamine

TFA: acid

THF: tetrahydrofuran

THP:

t-Bu: tert-butyl

Example 1

4-(Pyridine-3-)phenylamine

Phase A: 4-(Pyridine-3-yl)hydroxy-1-nitrobenzene

1-chloro-4-nitrobenzene (40 g of 0.25 mol) and 3- (36 g, 0,38 mol) was dissolved in N,N-dimethylformamide (100 ml). Added potassium carbonate (52,6 g 0,38 mol), and the mixture was stirred for 20 hours at 100 degrees C. Once the reaction is added to the water. The reaction mixture is extracted , washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, receiving the target connection.

Stage B: 4-(Pyridine-3-)phenylamine

4-(Pyridine-3-yl)hydroxy-1-nitrobenzene, obtained for A stage, was dissolved in a mixture of water (100 ml), tetrahydrofuran (100 ml) and methanol (100 ml). Added iron powder (103 g, 1,84 mol) and ammonium chloride (99 g, 1,84 mol), and the mixture was stirred for 3 hours at 80 C, using the drive stirrer. After the reaction, the reaction mixture was filtered through celite, was rinsed with methanol and concentrated under reduced pressure. Thus obtained solid filtered off, washed with ether and dried, receiving the target connection (17 g, exit 36%).

Weight [M+H]: 186 (M+1).

Example 2

4-(4--phenoxy)phenylamine

Phase A: 1-(4-)-4-nitrobenzene

1-chloro-4-nitrobenzene (15 g, 95 mmol) and 4()phenol (13.3 g, 95 mmol) was dissolved in dimethyl sulfoxide (100 ml). Added potassium carbonate (15,8 g, 134 mmol)and the mixture was stirred for 12 hours at 100 degrees C. After the reaction, added with an excess of water to besiege the solid, which is then filtered and dried, receiving the target connection.

Stage B: 4-(4--phenoxy)nitrobenzene

1-(4-)-4-nitrobenzene (86 g, 330 mmol)obtained on A stage, was dissolved in methylene chloride; (500 ml). Added mCPBA (3- acid) (83 g, 330 mmol)and the mixture was stirred for 2 hours at the temperature from 0 C up to ambient temperature. Once the reaction is added to the excess of 6 N. aqueous solution of sodium hydroxide. The reaction mixture is extracted and dichloromethane, washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, receiving the target connection (28 g, Exit 100%).

Stage C: 4-(4--phenoxy)phenylamine

4-(4--phenoxy)nitrobenzene (28 grams, 95 mmol)obtained on the stage B, dissolved in methanol (500 ml) and added ethyl acetate (500 ml). 10%Pd/C (1.0 g), and the mixture was stirred in the atmosphere of gaseous hydrogen at atmospheric pressure within 3 hours. After the reaction, the reaction mixture was filtered through celite, washed methanol, was concentrated under reduced pressure, and dried over anhydrous magnesium sulfate, receiving the target connection (25 g, exit 100%).

Weight [M+H]: 263 (M+1).

Example 3

4--2-nitro-phenylamine

Phase A: 4--1-

4- (40 g, 0,29 mol) and triethylamine (61 ml, 0,44 mol) was dissolved in methylene chloride; (200 ml). Added dropwise acetic anhydride (30 ml, 0,32 mol), and the mixture was stirred for 1 h at the temperature from 0 C up to ambient temperature. Added 1 N. solution of hydrochloric acid, and the reaction mixture is extracted , washed with a solution of sodium chloride and dried over anhydrous magnesium sulfate, receiving the target connection.

Stage B: 4--2-nitro-1-phenylamine

4--1- (51, the 0,29 mol)obtained on A stage, was dissolved in methylene chloride; (200 ml). nitric acid (13 ml, 0,29 mol) was added dropwise at 0 C, and the mixture was stirred for 1 h at the temperature from 0 C up to ambient temperature. The reaction mixture was added saturated aqueous solution of sodium bicarbonate, then extracted , washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. Received dissolved in methanol (100 ml) and tetrahydrofuran (100 ml). 6 N. sodium hydride added dropwise, and the mixture was stirred for 6 hours at the ambient temperature. After the reaction, the reaction mixture was neutralized to approximately pH 7 using 6 N. hydrochloric acid is extracted , washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, receiving the target connection (44 g, exit 83%).

Weight [M+H]: 182 (M+1).

Examples of obtaining 4-13:

Connection received in examples 1 and 2, and commercially available anilines injected into the reaction according to the same procedure as in example 3, for the synthesis of compounds receipt of the examples shown in the following table.

An example of obtaining

R

2

Weight [M+H]

4

-O-(pyridine-3-yl)

231

5

-O-(4-)

308

6

methoxy

168

7

phenoxy

231

8

fluorine

156

9

bromine

217

10

NAc

195

11

-O-(n-Pr)

196

12

-O-CF3

222

13

chlorine

172

Example 14

Methyl 5-chloro-7-nitro-1H-indole-2-carboxylic acid

<Method A>

Phase A: (4-chloro-2-nitro-phenyl)hydrazine chloride

4-Chloro-2-nitroaniline (40 g, 0,23 mol), resulting in the example of obtaining 13, was dissolved in 12 G. hydrochloric acid (100 ml). Sodium nitrite (16 g, 0,23 mol)dissolved in water (50 ml), slowly added dropwise at 0 C, and the mixture was stirred for 30 minutes at a temperature from 0 C up to ambient temperature. The reaction mixture was cooled to 0 C, slowly added dropwise tin chloride (II) (132 g, to 0.70 mol), dissolved in 12 G. hydrochloric acid (100 ml)and the mixture was stirred for 3 hours at a temperature from 0 C up to ambient temperature. The resulting solid yellow filtered off, washed with a small amount of 6 N. HCl, and dried it, getting the target connection (30 g, exit 63%).

1 H-NMR (400 MHz, DMSO-d 6 ); δ 9,21 (1H), 7,98 (d, J=2,4 Hz, 1H), compared to 7.66 (d, J=9,6 Hz, 1H), 7,55 (DD, J=2,4, 9,6 Hz, 1H), 4,74 (., 2H).

Stage B: methyl ether 2-[(4-chloro-2-nitro-phenyl)]propionic acid

(4-Chloro-2-nitro-phenyl)hydrazine chloride (30 g, 0,14 mol)obtained on A stage, and (14,4 ml, 0,16 mol) was dissolved in methanol (300 ml) and added sodium acetate (14.2 g, 0,17 mol). The reaction solution was stirred for 8 hours at ambient temperature, and the resulting solid yellow filtered off, washed with water and methanol, and dried, receiving the target connection (30 g, exit 82%).

1 H-NMR (400 MHz, CDCl 3 ); δ 10,88 (1H), 8,21 (d, J=2,4 Hz, 1H), 8,01 (d, J=9.2 Hz, 1H), 7,56 (DD, J=2,4, 9.2 Hz, 1H), 3,90 (C, 3H), 2,23 (c, 3H).

Stage C: methyl 5-chloro-7-nitro-1H-indole-2-carboxylic acid

To methyl ether 2-[(4-chloro-2-nitro-phenyl)]propionic acid (13 g, 46 mmol), received on stage B, added acid (100 ml), and the mixture was heated up to 4 hours at 100 degrees C. After the reaction to the reaction mixture with 0 C added water. The resulting mixture was stirred for 2 hours, and filtered to collect solid. This solid is washed with water and dried, receiving the target connection (6,0 g, exit 49%).

1 H-NMR (400 MHz, CDCl 3 ); δ 10,32 (., 1H), 8,29 (d, 1H), 8,03 (d, J=2,4 Hz, 1H), 7,31 (d, J=2.0 Hz, 1H), and 4.01 (C, 3H).

<Method B>

Phase A: methyl ether 2-[(4-chloro-2-nitro-phenyl)]propionic acid

4-Chloro-2-nitro-phenylamine (11,0 g, 64,05 mmol), resulting in the example of obtaining 13, was dissolved in concentrated hydrochloric acid (32 ml) in A flask, and cooled to 10 degrees C. Added ice (90 g), slowly added sodium nitrite (4.42 g, 64,05 mmol)dissolved in water (50 ml), and the mixture was stirred until she became transparent.

Methyl ether 2-methyl-3-oxo-butyric acid (8.32 grams, 64,05 mmol) was dissolved in ethanol (76 ml) in a flask B and cooled to 10 degrees C. Added potassium hydroxide (19,05 ml)dissolved in water (19 ml), which at 10oC added to the solution obtained in the flask. The mixture was stirred for 1 hour. The resulting solid red color was filtered, receiving the target connection (7,54 g, exit 49%).

Stage B: Methyl 5-chloro-7-nitro-1H-indole-2-carboxylic acid

Methyl ether 2-[(4-chloro-2-nitro-phenyl)]propionic acid, obtained for A stage, introduced in reaction according to the same procedure as at the stage of C <Ways A> example 14, receiving the target connection.

1 H-NMR (400 MHz, CDCl 3 ); δ 10,32 (., 1H), 8,29 (d, 1H), 8,03 (d, J=2,4 Hz, 1H), 7,31 (d, J=2.0 Hz, 1H), and 4.01 (C, 3H).

Examples of obtaining 15-26

Connection of the examples receiving injected into the reaction with , , methyl ether 2-methyl-3-oxo-butyric acid or ethyl ether 2-methyl-3-oxo-butyric acid according to the mode A or B sample receipt of 14 to synthesize compounds examples obtain shown in the following table.

An example of obtaining

R

R

2

1

H-NMR

15

methyl

methyl

(500 MHz, DMSO-d 6 ); δ 11,25 (., 1H), of 8.08 (3, 1H), 7,96 (1H), 7,32 (1H), 3,87 (C, 3H), 2,44 (C, 3H).

16

methyl

methoxy

(400 MHz, DMSO-d 6 ); δ 11,26 (., 1H), to 7.84 (1H), 7,80 (, 1H), 7,35 (1H), 3,91 (C, 3H), 3,89 (C, 3H).

17

methyl

hydrogen

1 H-NMR (500 MHz, DMSO-d 6 ); δ 11,36 (., 1H), 8,23 (d, 1H), 8,17 (d, 1H), 7,42 (1H), 7,32 (t, 1H), 3,88 (C, 3H).

18

ethyl

fluorine

(400 MHz, DMSO-d 6 ); δ 11,55 (., 1H), 8,16 (m, 1H), 8,10 (m, 1H), 7,42 (1H), 4,40 (kV, 2H), 1,36 (t, 3H).

19

ethyl

(400 MHz, DMSO-d 6 ); δ 10,20 (., 1H), 7,86 (1H), 7,51 (1H), 7,26 (1H), 4,13 (m, 2H), 3,98 (C, 3H), 1,47 (m, 3H).

20

methyl

bromine

(400 MHz, CDCl 3 ); δ 10,33 (., 1H), to 8.41 (1H), 8,18 (1H), a 7.30 (d, J=4.0 Hz, 1H), and 4.01 (C, 3H).

21

methyl

phenoxy

(400 MHz, CDCl 3 ); δ 10,26 (., 1H), 8,05 (1H), 7,69 (1H), 7,39 (m, 2H), 7,26 (1H), 7,15 m, 1H), 7,01 (m, 2H), 4,00 (C, 3H).

22

ethyl

-O-(4-methane )

(400 MHz, DMSO-d 6 ); δ 8,09 (1H), and 10.20 (., 1H), 7,86 (1H), 7,51 (1H), 7,26 (1H), 4,13 (m, 2H), 3,98 (C, 3H), 1,47 (m, 3H).

23

ethyl

-O-(pyridine-3-yl)

1 H-NMR (400 MHz, CDCl 3 ); δ 10,32 (., 1H), 8,51~of 8.47 (m, 2H), with 8.05 (d, J=2,4 Hz, 1H), 7,73 (d, J=2.0 Hz, 1H), 7,42~7,35 (m, 2H), 7,31 (d, J=2,4 Hz, 1H), 4,48 (kV, 2H), 1,47 (t, 3H).

24

ethyl

-O-(n-Pr)

(400 MHz, DMSO-d 6 ); δ 10,12 (., 1H), 7,92 (1H), 7,51 (1H), 7,24 (1H), 4,44 (m, 2H), and 4.01 (m, 2H), 1,91 m 2H), 1.44MB (m, 3H), from 1.08 (m, 3H).

25

ethyl

-O-CF 3

(400 MHz, DMSO-d 6 ); δ 10,34 (., 1H), one-7.91 (1H), 7,80 (1H), 7,45 (1H), 4,34 (m, 2H), 1,45 (m, 3H).

26

ethyl

NAc

(400 MHz, DMSO-d 6 ); δ 11,26 (1H), 10,31 (1H), 8,55 (1H)and 8.44 (1H), 7,45 (1H), 4,40 (kV, 2H), 2,11 (C, 3H), 1,36 (t, 3H).

An example of obtaining 27

Methyl (R)-3-amino-4-(4-methoxy-)butyric acid hydrochloride

Phase A: (R)-2-amino-3-(4-methoxy-)propionic acid

4- alcohol (280 g, 1780 mmol), dissolved in a simple diethyl ether (400 ml)was added dropwise to a mixture of simple diethyl ether (400 ml) and concentrated hydrochloric acid (400 ml) for 2 hours, and the mixture was stirred for 1 hour. The organic layer is separated and added to solution obtained by dissolving L-cysteine (197 g, 1625 mmol) and 2 N. aqueous solution sodium hydroxide (980 ml) in ethanol (1890 ml). The mixture was stirred for 2 hours at the ambient temperature. After the reaction, the reaction mixture was cooled to 0 C and neutralized to a pH of 7 using 3 N. aqueous solution of hydrochloric acid. The resulting solid filtered and dried, receiving the target connection (250 g, exit 64%).

Stage B: (R)-2-BOC-amino-3-(4-methoxy-)propionic acid

(R)-2-Amino-3-(4-methoxy-)propionic acid (30,7 g, 127,3 mmol), obtained at the stage of A, dissolved in tetrahydrofuran (150 ml) and water (150 ml). Added potassium carbonate (26,4 g, 190 mmol) and (VOS) 2 O (27,7 g, 127,3 mmol)and the mixture was stirred for 2 hours at the ambient temperature. After the reaction, the reaction mixture was distilled at low pressure to remove tetrahydrofuran. The remainder was cooled to 0 C and acidified to pH 3, using 3 N. aqueous solution of hydrochloric acid. The resulting solid is washed with water and dried, receiving the target connection (43 g, exit 99%).

Stage C: tert-butyl ether [(R)-3-diazo-1-(4-methoxy-)-2-oxo-propyl] acid

(R)-2-BOC-amino-3-(4-methoxy-)propionic acid (43, 132 mmol)obtained at stage B, 1- (14,5 ml, 132 mmol) and (14,1 ml, 132 mmol) was dissolved in tetrahydrofuran (500 ml), and the mixture was stirred for 1 h at 25 degrees C. At the same time potassium hydroxide (75 g, 1336 mmol) dissolved in water (75 ml) and simple diethyl ether (750 ml), 2 hours at 0 degrees C was added dropwise N-methyl- (26 g, 252 mmol)and the mixture was stirred for 30 minutes These two thus obtained solution mixed together and stirred for 3 hours at temperature from -25 C to ambient temperature. Once the reaction is the reaction mixture was added water, washed saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of ammonium chloride, in that order. The organic layer is centered, getting the target connection (46,0 g, exit 95%).

1 H-NMR (400 MHz, CDCl 3 ); δ 7,25 (d, J=8,8 Hz, 2H), 6,86 (d, J=8,8 Hz, 2H), 5,48 (., 1H), 5,29 (m, 1H), 4,31 (m, 1H), with 3.79 (C, 3H), of 3.69 (C, 2H), 2,76 (d, J=6.0 Hz, 2H), 1,45 (9H).

Stage D: (R)-3-tert--4-(4-methoxy-)butyric acid methyl ester

Tert-butyl ether [(R)-3-diazo-1-(4-methoxy-)-2-oxo-propyl] acid (40 g, 109 mmol)obtained on the stage of C, was dissolved in methanol (600 ml), and the mixture was cooled to 25 degrees C. Added silver, and the mixture slowly heated. After the reaction solid portion removed by filtration through celite. Added saturated aqueous solution NH 4 Cl, and the mixture is extracted EtOAc and dried over MgSO 4 . Solvent was removed under reduced pressure, and the residue was purified chromatography on your speakers (eluent: EtOAc/n-Hex=1/3), receiving the target connection (30,6 g, exit 76%).

1 H-NMR (500 MHz, CDCl 3 ); δ 7,24 (d, J=8.6 Hz, 2H), 6,83 (d, J=8.6 Hz, 2H), 5,09 (m, 1H), 4,08 (m, 1H), with 3.79 (c, 3H), 3,68 (c, 2H), 3,66 (c, 3H), 2,70-2,52 (m, 4H), 1.44MB (c, 9H).

Stage E: methyl (R)-3-amino-4-(4-methoxy-)butyric acid

Methyl (R)-3-tert--4-(4-methoxy-)-butyric acid (30 g, 81,3 mmol)obtained on the stage D, dissolved in dichloromethane (70 ml). Solution was added 4 N. hydrochloric acid 1,4-dioxane (71 ml), and the mixture was stirred for 2 hours at the ambient temperature. Once the reaction is the reaction solution was concentrated under reduced pressure. To the residue added dichloromethane (30 ml) and simple diethyl ether (150 ml). The resulting solid filtered and dried, receiving the target connection (19.2 g, exit 87%).

1 H NMR (400 MHz, DMSO-d 6 ); δ 8,21 (., 3H), 7,25 (d, 2H), 6,83 (d, 2H), 3,78 (C, 3H), 3,68 (C, 2H), 3,65 (C, 3H), 3,29 (m, 1H), 2,51-2,48 (m, 2H), 2,35-2,31 (m, 2H).

An example of obtaining 28

(R)-3-Amino-4-(4-methoxy-) hydrochloride

Tert-butyl ether [(R)-3-diazo-1-(4-methoxy-)-2-oxo-propyl] acid, obtained at the stage of C example of obtaining 27, and ethanol were administered in reaction according to the same procedures as at the stages of D and E example of obtaining 27, consistently receiving the target connection.

Commercially available 5-ethyl-1-methyl (R)-2-BOC- acid (57,8 g, 200 mmol) was dissolved in methanol (200 ml). Added LiBH 4 (1H. solution in THF, 400 ml)and the mixture was stirred for 2 hours, maintaining a temperature of 10 C or below. After the reaction, the reaction mixture was cooled to 0 C and slowly added water to complete the reaction. Methanol was removed under reduced pressure, and the remainder were saturated with water solution of NaHCO 3 . The mixture is extracted EtOAc and dried over MgSO4. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (39 g, exit 75%).

Stage B: ethyl ester (R)-4-BOC-amino-5--pentanoic acid

Ethyl ester (R)-4-BOC-amino-5-hydroxy-pentanoic acid (36 g, 137,8 mmol)obtained on A stage, and triethylamine (38,4 ml, 275,5 mmol) was dissolved in methylene chloride; (200 ml). (11.7 ml, 151,5 mmol) was added dropwise, and the mixture was stirred for 1 h at the temperature from 0 C up to ambient temperature. Once the reaction is added 1 N. solution of hydrochloric acid, then extracted , washed saturated with water solution of sodium chloride and dried over anhydrous magnesium sulfate, receiving the target connection.

Stage C: ethyl ester (R)-4-BOC-amino-5-(4-methoxy-), valerianic acid

Sodium hydride (5.5 g, 137,8 mmol) and 4- (15.4 ml, 110,2 mmol) was dissolved in N,N-dimethylformamide (150 ml), and the mixture was stirred for 10 minutes at 0 degrees C. To this solution was added dropwise ethyl ester (R)-4-BOC-amino-5--pentanoic acid (46,7 g, 137,8 mmol)obtained at stage B, and the mixture was stirred for 4 hours at 0 degrees C. Added water to complete the reaction, and the reaction mixture is extracted , washed saturated with water solution of sodium chloride and dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection.

1H-NMR spectrum (400 MHz, CDCl 3 ); δ 7,25 (d, J=8,8 Hz, 2H), 6,85 (d, J=8,8 Hz, 2H), 4,56 (m, 1H), 4,12 (m, 2H), with 3.79 (c, 3H), of 3.69 (c, 2H), 2,53 (m, 2H), 2,33 (t, 2H), 1,93 (m, 1H), 1,70 m, 1H), 1.44MB (c, 9H), 1,25 (t, 3H).

Stage D: ethyl ester (R)-4-amino-5-(4-methoxy-), valerianic hydrochloride acid

Ethyl ester (R)-4-BOC-amino-5-(4-methoxy-), valerianic acid (11 g, 62,7 mmol)obtained on the stage of C, was dissolved in methylene chloride; (200 ml). Solution was added 4 G. hydrochloric acid ethyl acetate (20 ml), and the mixture was stirred for 2 hours at the ambient temperature. Once the reaction is fully solvent was removed under reduced pressure. The residue was recrystallized from simple diethyl ether (150 ml) and dried, receiving the target connection (20 g, exit 96%).

1 H NMR (400 MHz, DMSO-d 6 ); δ of 8.69 (., 3H), 7,29 (d, J=8.0 Hz, 2H), 6,89 (d, J=8.0 Hz, 2H), 4,08 (m, 2H), 3,74 (m, 5H), 3,26 (m, 1H), 2,76~2,63 m, 2H), 2,49~2,40 m 2H), 1,89 (m, 2H), 1,20 (t, 3H).

An example of obtaining 30

Isopropyl ether (S)-3-amino-4-(methoxy-)butyric acid

Phase A: 4-isopropyl-1-methyl (S)-2-BOC-amino-succinic acid

Commercially available 1-methyl (S)-2-BOC-amino-succinic acid (2,4 g, 10 mmol) was dissolved in DCM (30 ml) and added triethylamine (2,8 ml, 20 mmol). To a mix added isopropanol (660 mg, 11 mmol), EDC (2.5 g, 26 mmol) and HOBt (2.3 g, 30 mmol)and the mixture was stirred for 4 hours at the ambient temperature. The reaction mixture was extinguished saturated aqueous solution of NaHCO 3 . The reaction mixture is extracted EtOAc, washed saturated with water solution of sodium chloride and dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (2.5 g, exit 87%).

Stage B: isopropyl ether (S)-3-amino-4-(methoxy-)butyric acid

4-Isopropyl-1-methyl (S)-2-BOC-amino-succinic acid, obtained for A stage, introduced in reaction according to the same procedure as in the example of obtaining 29, receiving the target connection.

Weight [M+H]=397.

An example of obtaining 31

(R)-2-amino-3-(4-methoxy-)propyl ether 2,2- acid

Phase A: methyl (R)-2-amino-3-(4-methoxy-)propionic acid

(R)-2-BOC-amino-3-(4-methoxy-)propionic acid, obtained at the stage of the B sample receipt of 27, and methanol were introduced into the reaction according to the same procedure as in the example of obtaining 30, receiving the target connection.

1 H NMR (400 MHz, DMSO-d 6, salt HCl); δ 8,81 (., 3H), 7,29 (d, J=8,4 Hz, 2H), 6,91 (d, J=8,4 Hz, 2H), 4,28 (m, 1H), 3,18 (., 8H), 2,95 m, 2H).

Stage B: methyl (R)-2-BOC-amino-3-(4-methoxy-)propionic acid

Methyl (R)-2-amino-3-(4-methoxy-)propionic acid (30,7 g, 127,3 mmol)obtained on A stage, was dissolved in DCM. Added Et 3 N (26,4 g, 190 mmol) and (VOS) 2 O (27,7 g, 127,3 mmol)and the mixture was stirred for 2 hours at the ambient temperature. After the reaction, the reaction mixture was distilled at low pressure to remove DCM, and used in the following reaction without further purification.

Stage C: tert-butyl ether [(R)-2-hydroxy-1-(4-methoxy-)ethyl] acid

Tert-butyl ether [(R)-2-hydroxy-1-(4-methoxy-)ethyl] acid (71,3 g, 227,9 mmol)obtained on the stage of C, was dissolved in methylene chloride; (300 ml). Added triethylamine (58 ml, 414,4 mmol) and chloride acid (28 ml, 227,9 mmol)and the mixture was stirred for 6 hours at 0 degrees C. Added water to complete the reaction. The reaction mixture is extracted , washed saturated with water solution of sodium chloride and dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (81,0 g, exit 95%).

1 H NMR (400 MHz, CDCl 3 ); δ 7,25 (d, J=8,8 Hz, 2H), 6,85 (d, J=8,8 Hz, 2H), 4,71 (m, 1H), 4,11 (m, 2H), with 3.79 (c, 3H), 3,70 (c, 2H), 2,55 (d, J=6,4 Hz, 2H), 1,52 (c, H), of 1.27 (c, 9H).

Stage E: (R)-2-amino-3-(4-methoxy-)propyl ether 2,2- acid

(R)-2-tert--3-(4-methoxy-)propyl ether 2,2- acid (81 g, 196 mmol)obtained on the stage D, dissolved in methylene chloride; (300 ml). Solution was added 4 G. hydrochloric acid 1,4-dioxane (100 ml)and the mixture was stirred for 8 hours at the ambient temperature. Once the reaction is fully solvent was removed under reduced pressure. The residue was recrystallized from simple diethyl ether and dried, receiving the target connection (68 g, exit 95%).

1 H NMR (400 MHz, DMSO-D6 , the free form); δ 7,24 (d, J=12.0 Hz, 2H), 6,85 (DD, J=a 4.0 8.0 Hz, 2H), of 4.04 (m, 1H), 3,95 (m, 1H), 3,80 (c, 3H), 3,68 (c, 2H), 3,10 m, 1H), 2,60 m, 1H), a 2.36 (m, 1H), 1.18 in (c, 9H).

Example 32

(S)-2-amino-3-(4-methoxy-)propyl ether 2,2- acid

Phase A: methyl (S)-2-BOC-amino-3--propionic acid

Commercially available methyl (S)-2-BOC-amino-3-hydroxy-propionic acid and injected into the reaction according to the same procedure as at the stage of the B sample receipt 29, receiving the target connection.

Stage B: methyl (S)-2-BOC-amino-3-(4-methoxy-)propionic acid

Methyl (S)-2-BOC-amino-3--propionic acid, obtained for A stage, and 4-methoxy-benzyl-thiol injected into the reaction according to the same procedure as at the stage of C example of obtaining 29, receiving the target connection.

Stage C: (S)-2-tert--3-(4-methoxy-)propanol

Methyl (S)-2-BOC-amino-3-(4-methoxy-)propionic acid, obtained at stage B, and LiBH 4 injected into the reaction according to the same procedure as on the stage As an example of obtaining 29, receiving the target connection.

Stage D: (R)-2-amino-3-(4-methoxy-)propyl ether 2,2- acid

(S)-2-tert--3-(4-methoxy-)propanol, received on stage C, and HCl (4 N. solution in dioxane) were introduced in the reaction according to the same procedures as at the stages of D and E example of receipt 31, consistently receiving the target connection.

Weight [M+H]=397.

An example of obtaining 33

Methyl 2-amino-3-(4-methoxy-)propionic acid

Commercially available BOC-Ser-OMe were introduced into the reaction according to the same procedures as at stages B, C and D example of obtaining 29, consistently receiving the target connection.

Weight [M+H]=255 (M+1).

An example of obtaining 34

2-[(4-Methoxy-)ethylamine

Commercially available BOC-amino ethanol was administered in reaction according to the same procedures as at stages B and C example of obtaining 29 and at the stage of E example of receipt 31, consistently receiving the target connection.

Weight [M+H]=197 (M+1).

An example of obtaining 35

(R)-1-[(4-Methoxy-)methyl]Propylamine

Commercially available (R)-2-BOC-amino-1-butanol was injected into the reaction according to the same procedures as at stages B and C example of obtaining 29 and at the stage of E example of receipt 31, consistently receiving the target connection.

Weight [M+H]=225 (M+1).

An example of obtaining 36

(R)-1-[(4-Methoxy-)methyl]-2-methyl-1-Propylamine

Commercially available methyl ether 2-BOC-amino-3-methyl-butyric acid was injected into the reaction according to the same procedures as stages A, B and C example of obtaining 29 and at the stage of E example of receipt 31, consistently receiving the target connection.

Weight [M+H]=239 (M+1).

An example of obtaining 37

Methyl 5-bromomethyl-7-nitro-indole-2-carboxylic acid

Phase A: methyl 1-BOC-5-methyl-7-nitro-indole-2-carboxylic acid

Methyl 5-methyl-7-nitro-1H-indole-2-carboxylic acid (24,0 g, 100 mmol), resulting in the example of obtaining 15, was dissolved in methylene chloride; (500 ml), added triethylamine (84 ml, 601 mmol) and 4-(dimethylamino)pyridine (600 mg, 5 mmol). Added dropwise (VOS) 2 O (43,7 g, 200 mmol), dissolved in dichloromethane (100 ml)and the mixture was stirred for 8 hours at the ambient temperature. Once the reaction is added to the water. The reaction mixture is extracted , washed saturated with water solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, receiving the target connection (34,0 g, exit 100%).

1 H-NMR (500 MHz, CDCl 3 ); δ 7,80 (1H), 7,67 (1H), 7,15 (1H), 3,93 (C, 3H), 2,51 (C, 3H), 1,62 (9H).

Stage B: methyl 1-BOC-5-methyl bromide-7-nitro-indole-2-carboxylic acid

Methyl 1-BOC-5-methyl-7-nitro-indole-2-carboxylic acid (34 g, 101,7 mmol)obtained on A stage, was dissolved in (100 ml). Added N- (27,2 g, 152,6 mmol) and AIBN (1.7 g, 10,2 mmol)and the mixture was stirred for 5 hours at 80 degrees C. After the reaction, the reaction mixture was distilled at low pressure and purified chromatography columns on getting the target connection (48,0 g, exit 100%).

1 H-NMR (500 MHz, CDCl 3 ); δ 8,01 (1H), 7,90 (1H), 7,21 (1H), 4,60 (C, 2H), 3,93 (C, 3H), 1,62 (9H).

Stage C: methyl 5-Bromomethyl-7-nitro-indole-2-carboxylic acid

Methyl 1-BOC-5-methyl bromide-7-nitro-indole-2-carboxylic acid, obtained at stage B, introduced in reaction according to the same procedure as at the stage of E example of receipt of 31 receiving the target connection.

Weight [M+H]=313 (M+1).

An example of obtaining 38

5-Hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid

Phase A: methyl 1-BOC-5--7-nitro-indole-2-carboxylic acid

Methyl 1-BOC-5-methyl bromide-7-nitro-indole-2-carboxylic acid (10,0 g, 24,2 mmol)obtained on the stage of the B sample receipt 37, was dissolved in N,N-dimethylformamide (50 ml). Added sodium acetate (2.4 g, 29,0 mmol)and the mixture was stirred for 4 hours at the ambient temperature. After the reaction solvent was removed by distillation under reduced pressure. The residue extracted , washed saturated with water solution of sodium chloride and dried over anhydrous magnesium sulfate. The residue was purified chromatography columns on getting the target connection (4.7 g, exit 50%).

1 H-NMR (500 MHz, CDCl 3 ); δ 7,99 (1H), 7,90 (1H), 7,21 (1H), 5,22 (C, 2H), 3.94 in (C, 3H), 2,12 (C, 3H), 1,63 (9H).

Stage B: methyl 5--7-nitro-1H-indole-2-carboxylic acid

Methyl 1-BOC-5--7-nitro-indole-2-carboxylic acid (4.7 grams 12.0 mmol)obtained on A stage, was dissolved in dichloromethane (50 ml). Added 2 N. solution of hydrochloric acid (30 ml, 60 mmol)and the mixture was stirred for 12 hours at the ambient temperature. The reaction mixture was distilled at low pressure, getting a solid target connection (3.5 g, output 100%).

1 H-NMR (500 MHz, CDCl 3 ); δ 10,33 (., 1H), 8,32 (1H), 8,06 (1H), 7,34 (1H), 5,24 (C, 2H), 3,99 (C, 3H), 2,12 (C, 3H).

Stage C: 5-Hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid

Methyl 5--7-nitro-1H-indole-2-carboxylic acid (3.5 g, 12.0 mmol)obtained on the stage B, dissolved in a mixture of tetrahydrofuran, methanol and water (1:1:1, 100 ml). Added hydrate lithium hydroxide (1.5 g, 35,9 mmol)and the mixture was stirred for 3 hours at the ambient temperature. After the reaction of methanol and tetrahydrofuran removed by distillation under reduced pressure. To the residue added 1 N. hydrochloric acid. The reaction mixture is extracted , dried over anhydrous magnesium sulfate and distilled at low pressure to remove the solvent. The residue was purified chromatography columns on getting the target connection (2.3 g, exit 81%).

1 H-NMR (500 MHz, DMSO-d 6 ); δ 11,02 (., 1H), 8,21 (c, 1H), 8,10 (c, 1H), 7,34 (c, 1H), 5,43 (., 1H), to 4.64 (c, 2H).

An example of obtaining 39

Methyl 5-(1,3-Dioxo-1,3-dihydro--2-)-7-nitro-1H-indole-2-carboxylic acid

Phase A: methyl 1-BOC-5-(1,3-dioxo-1,3-dihydro--2-)-7-nitro-1H-indole-2-carboxylic acid

Methyl 1-BOC-5-methyl bromide-7-nitro-indole-2-carboxylic acid (4.9 g of 11.4 mmol)obtained on the stage of the B sample receipt 37, was dissolved in N,N-dimethylformamide (50 ml). Added potassium (2.7 g 14.8 per mmol), and the mixture was stirred for 4 hours at the ambient temperature. Added water to complete the reaction. The reaction mixture is extracted , washed saturated with water solution of sodium chloride and dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the residue was purified chromatography columns on getting the target connection (3.6 g, exit 66%).

1 H-NMR (500 MHz, CDCl 3 ); δ of 8.04 (c, 1H), 7,98 (c, 1H), the 7.85 (m, 2H), 7,71 (m, 2H), 7,17 (c, 1H), 4,96 (c, 2H), 4,37 (kV, 2H), 1,59 (c, 9H), 1,39 (t, 3H).

Stage B: methyl 5-(1,3-Dioxo-1,3-dihydro--2-)-7-nitro-1H-indole-2-carboxylic acid

Methyl 1-BOC-5-(1,3-dioxo-1,3-dihydro--2-)-7-nitro-1H-indole-2-carboxylic acid, obtained for A stage, introduced in reaction according to the same procedure as at the stage of the B sample receipt 38, receiving the target connection.

Weight [M+H]=379 (M+1).

Example of getting 40

(R)-2-(7-nitro-1H-indole-2-yl)-4,5-dihydro--4- ether 2,2- acid

Stage A: 7-Nitro-1H-indole-2-carboxylic acid

Methyl 7-Nitro-1H-indole-2-carboxylic acid (13 d, 59 mmol), resulting in the example of a 17, was dissolved in a mixture of tetrahydrofuran and water (1:1, 300 ml), added 1 N. aqueous solution sodium hydroxide (180 ml, 177 mmol). The mixture was stirred for 3 hours at ambient temperature, and added an excess of 6 N. solution of hydrochloric acid. The reaction mixture is extracted . Extract washed saturated with water solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Solvent was removed by distillation under reduced pressure, and the residue was dried, receiving the target connection (12 g, exit 99%).

Stage B: (R)-3-(4-methoxy-)-2-[(7-nitro-1H-indole-2-carbonyl)amino]propyl ether 2,2- acid

7-Nitro-1H-indole-2-carboxylic acid (8.2 g, 22,7 mmol), obtained at the stage of A, and (R)-2-amino-3-(4-methoxy-)propyl ether 2,2- acid (13.2 g, 27,2 mmol), resulting in the example of obtaining 31, dissolved in N,N-dimethylformamide (100 ml). Added EDC (6.6 g, 25,0 mmol) and HOBT (4.6 g, 25,0 mmol)and the mixture was stirred for 8 hours at the ambient temperature. To a mix added saturated aqueous solution of sodium bicarbonate to complete the reaction. The reaction mixture is extracted , dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified chromatography columns on getting the target connection (8,1 g, exit 71%).

1 H-NMR (400 MHz, CDCl 3 ); δ 10,47 (., 1H), of 8.27 (d, J=8.0 Hz, 1H), 8,01 (d, J=8.0 Hz, 1H), 7,26 (m, 2H), 6,93 (d, J=4.0 Hz, 1H), 6,83 (m, 2H), 6,74 (d, J=8.0 Hz, 1H), 4,56 (m, 1H), 4,44 (m, 1H), 4,24 (m, 1H), 3,74 (m, 5H), 2,77 (m, 1H), 2,62 (m, 1H), 1,18 (9H).

Stage C: [(R)-2-(7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid

(R)-3-(4-methoxy-)-2-[(7-nitro-1H-indole-2-carbonyl)amino]propyl ether 2,2- acid (1.6 g, 3.2 mmol)obtained on the stage B, dissolved in dichloromethane (50 ml). Added phosphorus (1.3 g of 6.4 mmol)and the mixture was stirred for 5 hours at the ambient temperature. To a mix added saturated aqueous solution of sodium bicarbonate to complete the reaction. The reaction mixture is extracted , dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. The residue was purified chromatography columns on getting the target connection (0.8 g, exit 69%).

1 H-NMR (400 MHz, CDCl 3 ); δ 10,53 (., 1H), of 8.26 (d, J=8.0 Hz, 1H), 7,99 (d, J=8.0 Hz, 1H), 7,04 (d, J=2.0 Hz, 1H), 6,90 (d, J=7.6 Hz, 1H), 4,78 (m, 1H), 4,46 (m, 1H), 4,30 (m, 1H), 3,59 (m, 1H), 3,36 (m, 1H), 1,20 (9H).

An example of obtaining 41

(R)-2-[(5-chloromethyl-7-nitro-1H-indole-2-yl)-(4,5-dihydro--4-yl)methyl ether 2,2- acid

Phase A: (R)-2-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)amino]-3-(4-methoxy-)propyl ether 2,2- acid

5-Hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid, resulting in the example of obtaining 38, and (R)-2-amino-3-(4-methoxy-)propyl ether 2,2- acid, resulting in the example of obtaining 31, introduced in reaction according to the same procedure as at the stage of the B sample receipt 40, receiving the target connection.

Stage B: (R)-2-[(5-chloromethyl-7-nitro-1H-indole-2-yl)-(4,5-dihydro--4-yl)methyl ether 2,2- acid

(R)-2-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)amino]-3-(4-methoxy-)propyl ether 2,2- acid, obtained for A stage, introduced in reaction according to the same procedure as at the stage of C example getting 40, receiving the target connection.

Weight [M+H]=395 (M+1).

An example of obtaining 42

Methyl (R)-2-[(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid

5-Hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid, resulting in the example of obtaining 38, and methyl ester hydrochloride (R)-3-amino-4-(4-methoxy-)butyric acid, resulting in the example of obtaining 27, introduced in reaction according to the same procedures as at stages B and C example getting 40, receiving the target connection.

Weight [M+H]=353 (M+1).

An example of obtaining 43

(R)-2-[5-(2,2-dimethyl-)-7-nitro-1H-indole-2-yl]-4,5-dihydro--4- ether 2,2- acid

Phase A: (R)-2-{[5-(2,2-dimethyl-)-7-nitro-1H-indole-2-carbonyl]amino}-3-(4-methoxy-)propyl ether 2,2- acid

(R)-2-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)amino]-3-(4-methoxy-)propyl ether 2,2- acid (3.1 g, 6,01 mmol)obtained on the stage As an example of obtaining 41, was dissolved in DCM, adding Et 3 N (1,68 ml, 12,02 mmol). Added (0,92 ml, 6,61 mmol)and the mixture was stirred for 12 hours at the ambient temperature. After the reaction, the solvent was removed under reduced pressure, and the residue was purified chromatography on your speakers (eluent: EtOAc/n-Hex=1/1), receiving the target connection.

Stage B: (R)-2-{[5-(2,2-dimethyl-)-7-nitro-1H-indole-2-yl]-4,5-dihydro--4- ether 2,2- acid

(R)-2-{[5-(2,2-dimethyl-)-7-nitro-1H-indole-2-carbonyl]amino}-3-(4-methoxy-)propyl ether 2,2- acid, obtained for A stage, introduced in reaction according to the same procedure as at the stage of C example getting 40, receiving the target connection.

Weight [M+H]=475 (M+1).

An example of obtaining 44

(R)-2-{[5--7-nitro-1H-indole-2-yl]-4,5-dihydro--4- ether 2,2- acid

Phase A: methyl ether (5--7-nitro-1H-indole-2-yl)carboxylic acid

Methyl 5-Bromomethyl-7-nitro-indole-2-carboxylic acid (251 mg, 0,805 mmol), resulting in the example of obtaining 37, added to DMF (8 ml). Added NaSO 2 Me (290 mg, 2,415 mmol)and the mixture was stirred for 2 hours at the ambient temperature. The reaction mixture was extinguished saturated aqueous solution of NaHCO 3 . The reaction mixture is extracted EtOAc and dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure, and the remainder used in the following reaction without further purification.

Methyl ether (5--7-nitro-1H-indole-2-yl)carboxylic acid, obtained for A stage, and (R)-2-amino-3-(4-methoxy-)propyl ether 2,2- acid, resulting in the example of obtaining 31, introduced in reaction according to the same procedure as in the example of getting 40, receiving the target connection.

Weight [M+H]=453 (M+1).

An example of obtaining 45

Methyl (R)-2-[5--7-nitro-1H-indole-2-yl]-4,5-dihydro--4- acid

Methyl ether (5--7-nitro-1H-indole-2-yl)carboxylic acid, obtained on the stage As an example of obtaining 44, and methyl ester hydrochloride (R)-3-amino-4-(4-methoxy-)butyric acid, resulting in the example of obtaining 27, introduced in reaction according to the same procedure as in the example of getting 40, receiving the target connection.

Weight [M+H]=411 (M+1).

Examples of obtaining 46-91

Connection of the examples obtain 14-26, 38 and 39, and with the connection of the examples obtain 27-36 selectively used for the synthesis of compounds receipt of the examples shown in the following table, according to the mode selected examples of receipt of 40-45.

Example recip.

R

1

*

n

R

2

Weight [M+H]

46

MeO 2 C-

R

1

(pyridine-3-yl)oxy

412

47

(t-Bu)C(O)O

R

1

(pyridine-3-yl)oxy

454

48

MeO 2 C-

R

1

4-()phenoxy

489

49

MeO 2 C-

R

1

methoxy

347

50

MeO 2 C-

R

2

methoxy

361

51

MeO 2 C-

R

1

methoxy

347

52

(i-Pr)O 2 C-

S

1

methyl

361

53

(t-Bu)C(O)O

R

1

methyl

375

54

EtO 2 C-

R

1

methyl

347

55

EtO 2 C-

S

2

methyl

361

56

EtO 2 C-

R

2

methyl

361

57

EtO 2 C-

R

2

bromine

412

58

MeO 2 C-

R

1

bromine

386

59

(t-Bu)C(O)O

R

1

bromine

440

60

(t-Bu)C(O)O

R

1

acetylamino

418

61

MeO 2 C-

S

1

363

62

EtO 2 C-

R

2

391

63

MeO 2 C-

R

1

363

64

EtO 2 C-

R

1

chlorine

367

65

(t-Bu)C(O)O

R

1

chlorine

395

66

(i-Pr)O 2 C-

S

1

chlorine

381

67

MeO 2 C-

R

1

chlorine

353

68

MeO 2 C-

R

2

chlorine

367

69

isobutyl

R

0

chlorine

323

70

MeO 2 C-

R

1

phenoxy

411

71

(i-Pr)O 2 C-

S

1

phenoxy

439

72

MeO 2 C-

R

2

phenoxy

425

73

MeO 2 C-

R

1

424

74

ethyl

R

0

fluorine

293

75

EtO 2 C-

R

1

fluorine

351

76

EtO 2 C-

R

2

fluorine

365

77

(t-Bu)C(O)O

R

1

fluorine

379

78

(t-Bu)C(O)O

R

1

CH 2 -(-1,3-dione-1-Il)

520

79

MeO 2 C-

R

1

CH 2 -(-1,3-dione-1-Il)

478

80

(t-Bu)C(O)OCH 2

R

1

H

361

81

MeO 2 C-

R

1

H

319

82

(i-Pr)O 2 C-

S

1

H

347

83

EtO 2 C-

R

2

H

347

84

(t-Bu)C(O)OCH 2

S

1

H

361

85

methyl

R

0

H

261

86

ethyl

R

0

H

275

87

MeO 2 C-

R

0

H

305

88

(t-Bu)C(O)O

R

2

H

375

89

MeO 2 C-

R

1

O(n-Pr)

363

90

EtO 2 C-

R

2

OCF 3

417

91

t-BuC(O)O

R

2

OCH 3

391

An example of obtaining 92

[(R)-2-(5--7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid

[(R)-2-(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl] methyl ether 2,2- acid (1,0 g, 2.4 mmol), resulting in the example of obtaining 41, was dissolved in dimethyl sulfoxide (15 ml). Added (0.6 g, 4.9 mmol) and dimethylamine (0.2 g, 4.9 mmol)and the mixture was stirred for 6 hours at the ambient temperature. Once the reaction is added to the water. The reaction mixture is extracted , dried over anhydrous magnesium sulfate and filtered. The filtrate were driven under reduced pressure and purified chromatography columns on getting the target connection (0.7 g, exit 71%).

Weight [M+H]=418 (M+1).

An example of obtaining 93

{(R)-2-[5-(morpholine-4-yl)methyl-7-nitro-1H-indole-2-yl]-4,5-dihydro--4-yl}methyl ether 2,2- acid

[(R)-2-(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid, resulting in the example of obtaining 41, and morpholine was injected into the reaction according to the same procedure as in the example of obtaining 92, except that DMF used as a solvent instead of DMSO, receiving the target connection.

Weight [M+H]=460 (M+1).

An example of obtaining 94

{(R)-2-[5-(pyrazol-1-yl)methyl-7-nitro-1H-indole-2-yl]-4,5-dihydro--4-yl}methyl ether 2,2- acid

[(R)-2-(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid, resulting in the example of obtaining 41, and pyrazole injected into the reaction according to the same procedure as in the example of obtaining 92, except that DMF used as a solvent instead of DMSO, receiving the target connection.

Weight [M+H]=441 (M+1).

An example of obtaining 95

{(R)-2-[5-(1,3-imidazol-1-yl)methyl-7-nitro-1H-indole-2-yl]-4,5-dihydro--4-yl}methyl ether 2,2- acid

[(R)-2-(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid, resulting in the example of obtaining 41, and 1,3-imidazol injected into the reaction according to the same procedure as in the example of obtaining 92, except that DMF used as a solvent instead of DMSO, receiving the target connection.

Weight [M+H]=441 (M+1).

An example of obtaining 96

{(R)-2-[5-(1,2,4-triazole-1-yl)methyl-7-nitro-1H-indole-2-yl]-4,5-dihydro--4-yl}methyl ether 2,2- acid

[(R)-2-(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid, resulting in the example of obtaining 41, and 1,2,4-triazole injected into the reaction according to the same procedure as in the example of obtaining 92, except that DMF used as a solvent instead of DMSO, receiving the target connection.

Weight [M+H]=442 (M+1).

Example of getting 97

[(R)-2-(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid, resulting in the example of obtaining 41, and pyrrol injected into the reaction according to the same procedure as in the example of obtaining 92, except that DMF used as a solvent instead of DMSO, receiving the target connection.

Weight [M+H]=440 (M+1).

An example of obtaining 98

Methyl [(R)-2-(7-nitro-5--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid

Phenol (192 mg, 2,04 mmol) was dissolved in DMF. Added NaH (60% in mineral oil, 82 mg, 2,04 mmol), and the reaction solution was cooled to 0 C). Slowly added methyl (R)-2-(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4- acid 500 mg, 1,36 mmol), resulting in the example of obtaining 42, which was dissolved in DMF. The reaction solution was heated up to the temperature of the environment and stirred for 4 hours. After adding the saturated aqueous solution NH4Cl for completion of the reaction, the reaction mixture is extracted EtOAc, dried over MgSO4 and filtered. Solvent was removed under reduced pressure, and the residue was purified chromatography on your speakers (eluent: EtOAc/n-Hex=1/2), receiving the target connection.

Weight [M+H]=425 (M+1).

Example of getting 99

{(R)-2-[7-nitro-5-(phenylamino)methyl-1H-indole-2-yl]-4,5-dihydro--4-yl}methyl ether 2,2- acid

Methyl (R)-2-(5-chloromethyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4- acid, resulting in the example of obtaining 42, and phenylamine injected into the reaction according to the same procedure as in the example of obtaining 98, receiving the target connection.

Weight [M+H]=466 (M+1).

An example of obtaining 100

{(R)-2-[7-nitro-5-(pyrrolidine-1-yl)methyl-1H-indole-2-yl]-4,5-dihydro--4-yl}methyl ether 2,2- acid

(R)-2-[(5-chloromethyl-7-nitro-1H-indole-2-yl)-(4,5-dihydro--4-yl)methyl ether 2,2- acid, resulting in the example of obtaining 41, and pyrrolidine injected into the reaction according to the same procedure as in the example of obtaining 92, except that DMF used as a solvent instead of DMSO, receiving the target connection.

Weight [M+H]=444 (M+1).

Example of getting 101

2-(4,5-Dihydro--2-yl)-7-nitro-1H-indole

Stage A: 7-Nitro-1H-indole-2-carboxylic acid

Commercially available 7--2- (500 mg, 2,14 mmol) was dissolved in a mixture of tetrahydrofuran and water (1:1, 20 ml). Added hydrate lithium hydroxide (448 mg, 10.7 per mmol), and the mixture was stirred for 8 hours at the ambient temperature. Added 1 N. solution of hydrochloric acid, and the reaction mixture is extracted . Extract of dried over anhydrous magnesium sulfate and filtered. The filtrate were driven under reduced pressure, receiving the target connection.

Stage B: (2-chloroethyl)-amide 7-Nitro-1H-indole-2-carboxylic acid

7-Nitro-1H-indole-2-carboxylic acid (371 mg, 3.2 mmol)obtained on A stage, was dissolved in N,N-dimethylformamide (10 ml). Added triethylamine (0.6 ml, 4,3 mmol), EDC (614 mg, 3.2 mmol) and HOBT (433 mg, 3.2 mmol), added 2- (252,8 mg, 3.2 mmol)and the mixture was stirred for 8 hours at the ambient temperature. Added 1 N. solution of hydrochloric acid, and the reaction mixture is extracted , washed saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The filtrate were driven under reduced pressure, receiving the target connection.

1 H NMR (400 MHz, CDCl 3 ); δ 10,51 (., 1H), of 8.28 (d, J=6,4 Hz, 1H), of 8.02 (d, J=6,4 Hz, 1H), 7,27 (t, 1H), 7.03 is (with, 1H), 6,62 (., 1H), 3,86 (m, 2H), 3,77 (m, 2H).

Stage C: 2-(4,5-Dihydro--2-yl)-7-nitro-1H-indole

(2-Chloroethyl)-amide 7-Nitro-1H-indole-2-carboxylic acid (267 mg, 1 mmol)obtained on the stage B, dissolved in ethylene dichloride (10 ml) and toluene (10 ml) and added reagent (1,29 g, 3.2 mmol). The mixture was heated under reflux for 4 hours and distilled under reduced pressure. Added water, and the reaction mixture is extracted , dried over anhydrous magnesium sulfate and filtered. The filtrate distilled at low pressure and concentrate chromatography purified on your speakers, getting the target connection as a reaction product of cyclization (148 mg, exit 60%).

1 H-NMR (400 MHz, CDCl 3 ); δ 10,49 (., 1H), 8,24 (d, J=8.0 Hz, 1H), 7,98 (d, J=7.6 Hz, 1H), 7,23 (t, 1H), 7,02 (1H), 4,47 (t, 2H), 3,51 (t, 2H).

Example of getting 102

Isopropyl ether [(S)-2-(5-chloro-7-nitro-1H-indole-2-yl)-4,5--4-yl]-carboxylic acid

Phase A: isopropyl ether (S)-3-amino-4-hydroxy butyric acid

4-Isopropyl-1-methyl (S)-2-BOC-amino-succinic acid, obtained on the stage As an example of obtaining 30, introduced in reaction according to the same procedures as the stages A-D example of obtaining 29, consistently receiving the target connection.

Stage B: isopropyl ether [(S)-3-(5-chloro-7-nitro-1H-indole-2-carbonyl)amino]-4-hydroxybutiric acid

5-Chloro-7-nitro-1H-indole-2-carboxylic acid, obtained by hydrolysis of methyl ether 5-chloro-7-nitro-1H-indole-2-carboxylic acid, resulting in the example of a 14 according to the stage As an example of getting 40, and isopropyl ether (S)-3-amino-4-hydroxy butyric acid, obtained for A stage, introduced in reaction according to the same procedure as at the stage of the B sample receipt 40, receiving the target connection.

Stage C: isopropyl ether [(S)-3-(5-chloro-7-nitro-1H-indole-2-carbonyl)amino]-4--butyric acid

Stage D: isopropyl ether [(S)-2-(5-chloro-7-nitro-1H-indole-2-yl)-4,5--4-yl]carboxylic acid

Isopropyl ether [(S)-3-(5-chloro-7-nitro-1H-indole-2-carbonyl)amino]-4--butyric acid (930 mg, 2 mmol)obtained on the stage of C added to the THF (10 ml). Added K 2 CO 3 (330 mg, 10 mmol)and the mixture was stirred for 2 hours at 80 degrees C. Added water to complete the reaction. The reaction mixture is extracted EtOAc and dried over MgSO 4 . Solvent was removed under reduced pressure, and the residue was purified chromatography on your speakers (eluent: EtOAc/n-Hex/DMC=1/4/1), receiving the target connection (445 mg, exit 61%).

Weight [M+H]=365 (M+1).

Example of getting 103

tert-Butyl ether (1S,2R)-(3-amino-1-benzyl-2-hydroxy-propyl) acid

Phase A: tert-butyl ether (1S,2R)-(3--1-benzyl-2-hydroxy-propyl) acid

Commercially available tert-butyl ether (1--2-phenyl-ethyl) acid (2.6 g, 10 mmol) was dissolved in DMF (30 ml). Added sodium azide (655 mg, 10 mmol)and the mixture was stirred for 12 hours at 80 degrees C. Added water to complete the reaction. The reaction mixture is extracted EtOAc and dried over MgSO 4 . Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (2,75 g, exit 90%).

Stage B: tert-butyl ether (1S,2R)-(3-amino-1-benzyl-2-hydroxy-propyl) acid

Tert-butyl ether (1S,2R)-(3--1-benzyl-2-hydroxy-propyl) acid (2.5 g, 8,17 mmol)obtained on A Stage, was dissolved in methanol (15 ml), added Pd/C (100 mg). The mixture is injected into the reaction within 12 hours in hydrogen reactor (50 psi), and filtered through Celite. Solvent was removed under reduced pressure, and the remainder used in the following reaction without further purification.

Weight [M+H]=280 (M+1).

An example of obtaining 104

tert-Butyl ether [(1S,2R)-1-benzyl-3-(1,3-dioxo-1,3-dihydro--2-yl)-2-hydroxypropyl] acid

Tert-butyl ether (1R,2S)-(3-amino-1-benzyl-2-hydroxy-propyl) acid (1.4 g 5 mmol), resulting in the Example of getting 103, was dissolved in DMF (20 ml), added phthalic anhydride (735 mg, 5 mmol). Added Et 3 N (of 1.4 ml, 10 mmol)and the mixture was stirred for 24 hours at 80 degrees C. The reaction mixture was extinguished with water, and the reaction mixture is extracted EtOAc and dried over MgSO 4 . Solvent was removed under reduced pressure, and the residue was dissolved in DCM. Added TFA, and the mixture was stirred for 2 hours at the ambient temperature. After the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM/Hex, receiving the target connection (1.18 g, exit 71%).

Weight [M+H]=410 (M+1).

Examples of obtaining 105-109

Esters indole-2-carboxylic acid, obtained in the examples, 14, 15 and 17, and derivative aminoethanol derivatives have broad application, which are commercially available or can be obtained in the examples obtain 103 and 104, introduced in reaction according to the same procedure as in the example of getting 101 to synthesize compounds example of receipt in the following table.

Example

receiving

R

1

R

1a

*

**

n

R

3

Weight [M+H]

105

MeO 2 C

H

S

-

1

methyl

317

106

isobutyl

H

R

-

0

Cl

321

107

H

(S)-Ph-CH 2-CH(NH2 )-

_

R

0

Cl

384

108

Ph-CH 2 -

S

R

1

Cl

514

109

H

H

-

-

0

H

231

An example of obtaining 110

2-(-2-yl)-7-nitro-1H-indole

Phase A: amide 7-Nitro-1H-indole-2- acid

7-Nitro-1H-indole-2-carboxylic acid, obtained on the stage As an example of obtaining 101, and ammonium chloride was injected into the reaction according to the same procedures as at stages B and C example obtain 101, receiving the target connection.

Stage B: 2-(-2-yl)-7-nitro-1H-indole

Amide 7-Nitro-1H-indole-2- acid (1,15 g, 5 mmol)obtained on A stage, was dissolved in DMF (15 ml). Added 2-bromo-1,1- (985 mg, 5 mmol), and the mixture was stirred under reflux for 2 hours at 100 degrees C. the Reaction mixture was extinguished with water, and the reaction mixture is extracted EtOAc and dried over MgSO 4 . Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (612 mg, exit 65%).

Weight [M+H]=245 (M+1).

Example of getting 111

Methyl 2-(7-nitro-1H-indole-2-yl)-4-carboxylic acid

Methyl 3-chloro-2-oxo-propionic acid and amide 7-nitro-1H-indole-2- acid, obtained on the stage As an example of obtaining 110, introduced in reaction according to the same procedure as in the example of obtaining 110, receiving the target connection.

Weight [M+H]=303 (M+1).

Example of getting 112

[2-(7-nitro-1H-indole-2-yl)-4-yl]methanol

Methyl 2-(7-nitro-1H-indole-2-yl)-4-carboxylic acid, resulting in the example of getting 111, introduced in reaction according to the same procedures as at the stage As an example of obtaining 29, receiving the target connection.

Weight [M+H]=275 (M+1).

Example of getting 113

Ethyl ester of 2-(5-methyl-7-nitro-1H-indole-2-yl)-4-carboxylic acid

Phase A: amide (5-methyl-7-nitro-1H-indole-2-yl)

(5-Methyl-7-nitro-1H-indole-2-yl)carboxylic acid was injected into the reaction according to the same procedure as on the stage As an example of obtaining 110, receiving the target connection.

Stage B: ethyl ester of 2-(5-methyl-7-nitro-1H-indole-2-yl)--4-carboxylic acid

Amide (5-methyl-7-nitro-1H-indole-2-yl) obtained at the stage of A, and ethyl ester 3-chloro-2-oxo-propionic acid was injected into the reaction according to the same procedure as at the stage of the B sample receipt 110, receiving the target connection.

Weight [M+H]=331 (M+1).

Example of getting 114

[2-(5-methyl-7-nitro-1H-indole-2-yl)-4-yl]methanol

Methyl 2-(5-methyl-7-nitro-1H-indole-2-yl)-4-carboxylic acid, resulting in the example of getting 113, introduced in reaction according to the same procedure as on the stage As an example of obtaining 29, receiving the target connection.

Weight [M+H]=289 (M+1).

Example of getting 115

Methyl ether [5-(7-nitro-1H-indole-2-yl)-[1,2,4]oxidiazol-3-yl]acetic acid

Phase A: methyl ester of 2-(N-)acetic acid

Methyl ether 2- acid (990 mg, 10 mmol) was dissolved in THF (30 ml). Added (690 mg HCl salt, 10 mmol)and the mixture was stirred for 2 hours at 80 degrees C. After the reaction was added 1H. HCl. The reaction mixture is extracted EtOAc and dried over MgSO 4 . Solvent was removed under reduced pressure, and the remainder used in the following reaction without further purification.

Stage B: methyl 3-()-3-[(7-nitro-1H-indole-2-carbonyl)amino]propionic acid

Methyl 2-(N-)acetic acid, obtained for A stage, and 7-nitro-1H-indole-2-carboxylic acid, obtained on the stage As an example of obtaining 101, introduced in reaction according to the same procedure as at the stage of the B sample receipt 101, receiving the target connection.

Stage C: methyl ether 2-[5-(7-nitro-1H-indole-2-yl)-[1,2,4]oxidiazol-3-yl]acetic acid

Methyl 3-()-3-[(7-nitro-1H-indole-2-carbonyl)amino]propionic acid (960 mg, 1 mmol)obtained on the stage B, dissolved in DMF (10 ml). Added pyridine (1 ml), and the mixture was stirred for 4 hours at 80 degrees C. the Reaction mixture was extinguished by water solution of NH 4 Cl. The reaction mixture is extracted EtOAc and dried over MgSO 4 . Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (830 mg, exit 90%).

Weight [M+H]=302 (M+1).

Example of getting 116

2-[5-(7-nitro-1H-indole-2-yl)-[1,2,4]oxidiazol-3-yl]ethanol

Methyl ether 2-[5-(7-nitro-1H-indole-2-yl)-[1,2,4]oxidiazol-3-yl]acetic acid, resulting in the example of getting 115, introduced in reaction according to the same procedure as on the stage As an example of obtaining 29, receiving the target connection.

Weight [M+H]=274 (M+1).

An example of obtaining 117

5-methyl-7-nitro-2-[1,3,4]oxidiazol-2-Il-1H-indole

Methyl 5-methyl-7-nitro-1H-indole-2-carboxylic acid (234 mg, 1 mmol), resulting in the example of obtaining 15, was dissolved in methanol (10 ml), added hydrazine (3 ml). The reaction solution was heated under reflux for 3 hours and concentrated under reduced pressure. Added to the concentrate (10 ml), and the mixture was heated under reflux for 8 hours. The reaction mixture distilled under reduced pressure and the solid is washed , receiving the target connection (49 mg, exit 20%).

Example 1

-[2-(4,5-dihydro-1,3--2-yl)-1H-indol-7-yl]Amin

Phase A: [2-(4,5-Dihydro-1,3--2-yl)-1H-indol-7-yl]Amin

2-(4,5-Dihydro--2-yl)-7-nitro-1H-indole, resulting in the example of getting 101, introduced in reaction according to the same procedure as at the stage of the B sample 1, getting the target connection.

Stage B: -[2-(4,5-dihydro-1,3--2-yl)-1H-indol-7-yl]Amin

[2-(4,5-Dihydro-1,3--2-yl)-1H-indol-7-yl]Amin (15 mg of 0.07 mmol)obtained on A stage, was dissolved in 1,2-ethylene dichloride (10 ml). Added Cyclopentanone (12 mg, or 0.14 mmol) and sodium (29 mg, or 0.14 mmol)and the mixture was stirred for 3 hours at the ambient temperature. The reaction mixture was extinguished with water, and the reaction mixture is extracted , dried over anhydrous magnesium sulfate and filtered. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (6.7 mg, exit 34%).

1 H-NMR (400 MHz, CDCl 3 ); δ 10,27 (c, 1H), 7,06 (d, J=8.0 Hz, 1H), 7,00 (t, J=7.6 Hz, 1H), 6,92 (c, 1H), 6,52 (d, J=7,2 Hz, 1H), 4,42 (m, 2H), 4,38 (m, 1H), 4,35 (m, 2H), 2,00 m 2H), 1,64 (m, 4H), 1,46 (m, 2H).

Example 2

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro-1,3--4-yl]methanol

Phase A: [(R)-2-(7-)-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid

(R)-2-(7-amino-1H-indole-2-yl)-4,5-dihydro--4- ether 2,2- acid, resulting in the example of getting 40, was injected into the reaction according to the same procedure as in stage B of the sample 1, getting the target connection.

Stage B: [(R)-2-(7--1H-indole-2-yl)-4,5-dihydro-1,3--4-yl]methanol

[(R)-2-(7-)-1H-indole-2-yl)-4,5-dihydro--4-yl]methyl ether 2,2- acid, obtained for A stage, introduced in reaction according to the same procedure as on the stage As an example of obtaining 29, receiving the target connection.

1 H-NMR (500 MHz, CDCl 3 ); δ 11,17~11,08 (m, 1H), 7,09 (m, 1H), 6,99 (t, 1H), 6,96 (c, 1H), 6,52 (m, 1H), 4,72 (m, 1H), of 4.04 (m, 1H), to 3.75 (m, 1H), 3,65 (m, 1H), 3,51 (m, 1H), 3,40 (m, 1H), 1,90 m, 2H), 1,60~1,49 (m, 4H), 1,41~1,24 (m, 2H).

Example 3

Methyl [(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid

1 H NMR (DMSO-D6 , ppm); δ 11,51 (c, 1H), 6,79 (c, 1H), 6,79 (c, 1H), 6,16 (c, 1H), 6,13 (d, 1H), 4,85 (m, 1H), 3,80 m, 1H), 3,62 (m, 1H), to 3.58 (c, 3H), 3,19 (m, 1H), 2,71 (m, 1H), 2,63 m, 1H), 1,93 m, 2H), 1,69 (m, 2H), and 1.56 (m, 4H).

Example 4

[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid

Methyl [(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid, resulting in example 3, introduced in reaction according to the same procedure as on the stage As an example of obtaining 29, receiving the target connection.

1 H NMR (DMSO-D6 , ppm); δ 12,51 (., 1H), 11,51 (c, 1H), 6,79 (c, 1H), 6,79 (c, 1H), 6,16 (c, 1H), 6,14 (d, 1H), 4,87 (m, 1H), 3,80 m, 1H), 3,61 (m, 1H), 3,19 (m, 1H), 2,72 (m, 1H), 2,64 (m, 1H), 1,93 m, 2H), 1,69 (m, 2H), and 1.56 (m, 4H).

Example 5

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol

[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-acetic acid (391 mg, 1 mmol)obtained in example 4, was dissolved in DCM (10 ml). Added triethylamine (280 ml 2 mmol) and chloroacetyl ISO-butyrate acid (106 mg, 1 mmol)and the mixture was stirred for 30 minutes at 0 degrees C. After the reaction solvent was removed under reduced pressure. Balance diluted THF. Added NaBH 4 (74 mg, 2 mmol)and the mixture was stirred for 12 hours. The reaction mixture to extinguish a small amount of water. The reaction mixture is again added to the excess water, then the mixture was stirred for 30 minutes, extracted EtOAc, dried over MgSO 4 and filtered. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (272 mg, exit 72%).

1 H NMR (400 MHz, DMSO-d 6 ); δ 11,47 (1H), 6,79 (1H), 6,67 (1H), 6,11 (1H), 6,09 (m, 1H), 4,65 (t, 1H), 4,54 (m, 1H), 3,80 m, 2H), 3,61 (m, 2H), 3,52 (m, 1H), 3,15 (m, 1H), 2,47 (m, 1H), 1,97 (m, 2H), by 1.68 (m, 2H), the 1.54 (m, 4H).

Example 6

(R)-2-[7--5-(hydroxymethyl)-1H-indole-2-yl]-4,5-dihydro--4-

Phase A: (R)-2-[7--5-(2,2-dimethyl-)-1H-indole-2-yl]-4,5-dihydro--4- ether 2,2- acid

(R)-2-[5-(2,2-dimethyl-)-7-nitro-1H-indole-2-yl]-4,5-dihydro--4- ether 2,2- acid, resulting in the example of obtaining 43, Cyclopentanone and injected into the reaction according to the same procedure as in example 1, getting the target connection.

Stage B: (R)-2-[7--5-(hydroxymethyl)-1H-indole-2-yl]-4,5-dihydro--4-

(R)-2-[7--5-(2,2-dimethyl-)-1H-indole-2-yl]amino}-4,5-dihydro--4- ether 2,2- acid, obtained for A stage, introduced in reaction according to the same procedure as on the stage As an example of obtaining 29, receiving the target connection.

1 H-NMR (400 MHz, CDCl 3 ); δ 9,63 (., 1H), yield of 7.40 (c, 1H), 7,18 (c, 1H), 6,90 (c, 1H), 4,80 m, 1H), 4,73 (c, 2H), of 4.06 (m, 1H), 3,84 (m, 1H), 3,66 (m, 2H), 3,48 (m, 1H), 3,31 (m, 1H), 1,79 (m, 2H), 1,43 (m, 4H), 1,26 (m, 2H).

Example 7

[2-(4,5-Dihydro--2-yl)-1H-indol-7-yl]piperidine-4-ylamine

Phase A: [2-(4,5-Dihydro--2-yl)-1H-indol-7-yl]-(1-BOC-piperidine-4-yl)amine

2-(4,5-Dihydro--2-yl)-7-nitro-1H-indole, resulting in the example of getting 101, and 1-BOC-4- injected into the reaction according to the same procedure as in example 1, getting the target connection.

Stage B: [2-(4,5-Dihydro--2-yl)-1H-indol-7-yl]piperidine-4-ylamine

[2-(4,5-Dihydro--2-yl)-1H-indol-7-yl]-(1-BOC-piperidine-4-yl)amine, received on A stage, introduced in reaction according to the same procedure as at the stage D example of obtaining 29, receiving the target connection.

1 H-NMR (400 MHz, CDCl 3 , MeOH-d 4 ); δ 7,39 (c, 1H), 7,07 (d, J=8.0 Hz, 1H), 6,99 (t, J=8.0 Hz, 1H), 6,93 (c, 1H), 6,47 (d, J=7.6 Hz, 1H), 4,41 (m, 2H), 3,77 (m, 1H), 3,48 (m, 4H), 3,11 (m, 2H), to 2.29 (m, 2H), to 1.87 (m, 2H).

Examples 8-117

Compounds produced in the examples getting 40, 48-100, introduced in response to synthesize compounds from the examples shown in the following table, according to the mode selected examples of 1-7.

Example

R

1

∗

n

R

2

R

3

R

4

1 H NMR data

8

R

1

methyl

H

(THP-4-yl)methyl

(400 MHz, CDCl 3 ); δ 11,54 (., 1H), 7,11 (1H), 6,80 (1H), 6,22 (1H), 5,29 (m, 1H), 3,92 (m, 2H), 3,68 (m, 1H), 3,35 (m, 2H), 3,21-3,04 m, 3H), 2,84-2,52 (m, 2H), 2,32 (C, 3H), 1,90 m, 1H), 1,74 m, 2H), 1,35 (m, 2H).

9

S

1

methyl

H

1-(TRIFLUOROACETYL)piperidine-4-yl

(400 MHz, CDCl 3 ); δ 11,94 (., 1H), 6,98 (1H), 6,78 (1H), 6,25 (1H), 5,33 (m, 1H), 4,13 (m, 1H), 3,76-3,68 (m, 5H), 3,47-3,41 (m, 3H), 2,74-2,63 m, 2H), a 2.36 (C, 3H), 2,04 (m, 2H), and 1.56 (m, 2H).

10

S

1

H

H

(THP-2-yl)methyl

(400 MHz, CDCl 3 ); δ 11,68 (., 1H), 7,06-6,98 (m, 3H), 6,45 (with, 1H), 5,32 (m, 1H), 3,96 (m, 1H), 3,77-3,61 (m, 2H), 3,43 (m, 1H), 3,28-3,21 (m, 3H), 2,80 m, 1H), 2,65 m, 1H)and 1.83 (m, 1H), 1,71 (m, 1H), 1,62-1,42 (m, 4H).

11

S

1

H

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,87 (., 1H), 7,15 (c, 1H), 7.03 is (m, 2H), 6,50 (m, 1H), 5,39 (m, 1H), of 4.06 (m, 2H), 3,80-3,62 (m, 2H), 3,57 (m, 2H), 3,29 (m, 1H), 2,83 (m, 1H), 2,69 (m, 1H), 2,11 (m, 2H), 1,64 (m, 2H).

12

S

1

H

H

(THP-4-yl)methyl

(400 MHz, CDCl 3 ); δ us $ 11.89 (., 1H), 7,13 (c, 1H), 7,04 (m, 2H), 6,44 (m 1H), 5,39 (m, 1H), 3,98 (m, 2H), 3,77 (m, 1H), 3,41 (m, 2H), 3,25 (m, 1H), 3,13 (m, 2H), 2,78 (m, 1H), 2,64 (m, 1H), 2,00 m, 1H), 1,79 (m, 2H), 1.44MB (m, 2H).

13

S

1

methyl

H

1-acetyl-pyrrolidine-3-yl

(400 MHz, CDCl 3 ); δ 10,13 (., 1H), 6,93 (c, 1H), PC 6.82 (c, 1H), 6,38 (c, 1H), 5,09 (m, 1H), 4,16 (m, 1H), 3,67 (m, 2H), 3,52 (m, 2H), 3,38 (m, 1H), 3,25 (m, 1H), 2,91 (m, 1H), 2,66 (m, 1H), 2,48 (c, 3H), 2,23 (m, 1H), 2,00 m, 1H).

14

S

1

H

H

c-Pen

(400 MHz, CDCl 3 ); δ 11,74 (., 1H), 7,06 (c, 1H), 6,99 (m, 2H), 6,45 (c, 1H), 5,48 (m, 1H), 3,90 (m, 1H), 3,71 (m, 1H), 3,23 (m, 1H), 2,75 m, 1H), 2,67 m, 1H), 2,04 (m, 2H), 1.75 in (m, 2H), 1,61-1,48 (m, 4H).

15

R

1

phenoxy

H

(THP-4-yl)methyl

(400 MHz, CDCl 3 ); δ 11,96 (., 1H), 7,30 (m, 2H), 7.03 is (m, 4H), 6,60 (c, 1H), 6,20 (c, 1H), and 5.36 (m, 1H), 3,93 (m, 1H), the 3.73 (m, 1H), 3,35 (m, 2H), 3,23 (m, 1H), 3,06 (m, 2H), 2,72 (m, 1H), 2,62 (m, 1H), 1,92 (m, 1H), 1,73 (m, 2H), of 1.40 (m, 2H).

16

S

1

phenoxy

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,95 (., 1H), 7,28 (m, 2H), 7,06-6,96 (m, 4H), 6,58 (c, 1H), 6,24 (c, 1H), 5,33 (m, 1H), 3,98 (m, 2H), to 3.75 (m, 1H), to 3.58-3,47 (m, 3H), 2,23 (m, 1H), 2,78-2,62 (m, 2H), 2,04 (m, 2H), 1,26 (m, 2H).

17

S

2

methyl

H

4,4-

(400 MHz, CDCl 3 ); δ 11,94 (., 1H), 7,00 (c, 1H), 6,78 (c, 1H), of 6.26 (c, 1H), 5,35 (m, 1H), 3,71 (m, 1H), 3,63 (m, 1H), 3,22 (m, 1H), 2,75 m, 1H), 2,62 (m, 1H), 2,37 (c, 3H), of 2.25 m, 1H), 2,09-1,73 m 7H).

18

S

1

chlorine

H

(THP-4-yl)methyl

(400 MHz, DMSO-d 6 ); δ of 11.61 (., 1H), 6,85 (c, 1H), a 6.75 (c, 1H), 6,21 (c, 1H), 6,15 (c, 1H), of 4.91(t, 1H), 3,90 (m, 2H), 3,65 (m, 1H), 3,41~3,20 m, 4H), 3,05 m 2H), 2,80~2,66 (m, 2H), a 1.88 (m, 1H), 1,76 (m, 2H), 1,31 (m, 2H), 1,09 (m, 1H).

19

S

1

methyl

H

(400 MHz, CDCl 3 ); δ 11,21 (., 1H), 6,66 (c, 1H), 6,61 (c, 1H), 6,00 (c, 1H), 4,89 (., 1H), 3,95 (m, 1H), 3,63 (m, 1H), 3,35 (m, 2H), 2,67 m, 2H), 2,50 (c, 3H), 2,42 (m, 2H), 1,80 m, 4H).

20

S

1

methyl

H

tetrahydrofuran-3-yl

(400 MHz, CDCl 3 ); δ 11,82 (d, 1H), to 6.95 (c, 1H), 6,79 (c, 1H), 6,20 (d, 1H), 5,30 (., 1H), and 4.15 (m, 1H), 4,05~of 3.75 (m, 5H), 3,66 (m, 1H), 3,19 (c, 1H), 2,79~2,61 (m, 2H), 2,37 (c, 3H), 2,23 (m, 1H), 1,98 (m, 1H).

21

S

1

methyl

H

(400 MHz, CDCl 3 /MeOH-d 4 ); δ 11,24 (., 1H), 6,84 (c, 1H), 6,77 (c, 1H), 6,25 (c, 1H), 5,05 (m, 1H), 3,56 (m, 1H), 3,15 (m, 2H), to 3.03 (m, 2H), 2,78 (m, 1H), 2,63 m, 1H), 2,34 (c, 3H), 1,23 m, 1H), 1,18 (m, 1H), 0,52 (m, 2H), 0,24 (m, 2H).

22

S

1

methyl

H

(THP-4-yl)methyl

(400 MHz, CDCl 3 ); δ averaged 11.92 (., 1H), 6,98 (c, 1H), 6,77 (c, 1H), 6,22 (c, 1H), 6,29 (., 1H), 3,96 (m, 2H), 3,70 (m, 1H), 3,37 (m, 2H), 3,18 (m, 1H), 3,08 (m, 2H), 2,72 (m, 1H), 2,56 (m, 1H), 2,37 (c, 3H), 1,91 (m, 1H), 1.75 in (m, 2H), 1,41 (m, 2H).

23

S

1

methyl

H

(c-Pen)methyl

(400 MHz, DMSO-d 6 ); δ 11,35 (., 1H), 6,67 (c, 1H), 6,61 (c, 1H), 6,09 (c, 1H), 5,81 (., 1H), 4,90 (m, 1H), 3,64 (m, 1H), 3,21 (m, 1H), 3,05 m 2H), 2,77~2,69 (m, 2H), 2,28 (c, 3H, c,23 (m, 1H), 1,85 (m, 2H), 1,65~1,58 (m, 4H)1,32 (m, 2H).

24

HO-

S

2

methyl

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,37 (., 1H), 6,84 (c, 1H), PC 6.82 (c, 1H), 6,32 (c, 1H), to 4.64 (m, 1H), 4,00 (m, 4H), 3,63~3,51 (m, 4H), 3,11 (t, 1H), 2,38 (c, 3H), of 2.05 (m, 4H)and 1.51 (m, 2H).

25

S

1

methyl

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 11,77 (., 1H), 6,98 (see, 2H), 6,67 (c, 1H), 4,95 (m, 1H), of 4.02 (m, 2H), 3.72 points m, 2H), 3,42~3,29 (m, 3H), 2,86~2,69 (m, 2H), 2,50 (c, 1H), 1,94 (m, 2H), 162 (m, 2H).

26

S

1

methyl

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,88 (., 1H), 7,09 (c, 1H), 7,04 (c, 1H), 6,74 (c, 1H), 4,94 (m, 1H), 3,98 (m, 1H), the 3.73 (m, 1H), 3,47 (m, 1H), 2,87~2,70 m, 2H), 2,51 (c, 3H), 1,93 (m, 2H), 1,76~1,56 (m, 6H).

27

H

-

0

H

H

(thiophen-3-yl)methyl

(400 MHz, CDCl 3 ); δ 9,67 (c, 1H), 7,32 (DD, 1H), 7,21(m, 1H), 7,13 (d, J=8.0 Hz, 1H), 7,07 (d, J=5,2 Hz, 1H), 7,02(t, J=8.0 Hz, 1H), 6,91 (c, 1H), 6,56 (d, J=7.6 Hz, 1H), 4,42 (c, 2H), 4,36 (m, 2H), 3,36 (m, 2H).

28

H

-

0

H

H

tetrahydrofuran-3-yl

(400 MHz, CDCl 3 ); δ 10,36 (c, 1H), 7,10 (d, J=8.0 Hz, 1H), 7,00 (t, J=8.0 Hz, 1H), 6,99 (c, 1H), 6,45 (d, J=7.6 Hz, 1H), 4,41 (m, 2H), 4,18 (c, 1H), 3,98~of 3.73 (m, 4H), 3,47 (m, 2H), 2,28 (m, 1H), 1,90 m, 1H).

29

HO-

R

1

H

H

cyclohexyl

(500 MHz, CDCl 3 ); δ 11,17~11,08 (m, 1H), 7,09 (m, 1H), 6,99 (t, 1H), 6,96 (c, 1H), 6,52 (m, 1H), 4,72 (m, 1H), of 4.04 (m, 1H), to 3.75 (m, 1H), 3,65 (m, 1H), 3,51 (m, 1H), 3,40 (m, 1H), 1,90 m, 2H), 1,60~1,49 (m, 4H), 1,41~1,24 (m, 2H).

30

R

2

H

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 12,42 (., 1H), 11,34 (c, 1H), 6,80 (d, 1H), 6,72 (c, 1H), 6,33 (d, 1H), 5,79 (d, 1H), 4,86 (square, 1H), 3,88 (m, 2H), 3,60-3,52 (m, 2H), 3,42 (t, 2H), 3,17 (m, 1H), 2,74 (m, 1H), 2,59 (m, 1H), 1,94 (m, 2H), 1,39 (m, 2H).

31

HO-

R

1

chlorine

H

isopropyl

(400 MHz, CDCl 3 ); δ 10,89 (., 1H), 7,00 (c, 1H), 6,83 (c, 1H), 6,43 (c, 1H), 4,75 (m, 1H), of 4.04 (DD, 1H), 3,71 (DD, 1H), 3,61 (m, 1H), 3,43 (DD, 1H), 1,09 (t, 6H).

32

methyl

R

0

H

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,13 (., 1H), 7,08~6,99 (m, 3H), 6,53 (d, 1H), 4,76 (m, 1H), of 4.09 (m, 2H), 3.72 points m, 1H), 3,63 (m, 3H), 3,12 (m, 1H), 2,13 (m, 2H), by 1.68 (m, 2H), 1,48 (d, 3H).

33

HO-

R

1

(morpholine-4-yl)methyl

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,77 (., 1H), 7,06 (c, 1H), to 6.95 (c, 1H), 6,62 (c, 1H), 4,80 m, 1H), 4,11 (m, 1H), 3,99 (m, 2H), 3,76 (m, 1H), to 3.75 (m, 4H), 3,51 (c, 2H), 3,45 (m, 5H), 2,51 (., 4H)2,00 m 2H), 1,45 (m, 2H).

34

HO-

R

1

(dimethylamino)methyl

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,86 (., 1H), 6,96 (c, 1H), 6,88 (c, 1H), 6,51 (c, 1H), 4,75 (m, 1H), 4,37 (m, 2H), 3,85 (m, 1H), 3,71 (m, 1H), 3,50 (c, 2H), 3,42 (m, 2H), and 2.27 (c 6H), 1,96 (m, 2H), 1,59 (m, 4H), 1,39 (m, 2H).

35

HO-

R

1

(pyrrol-3-yl)methyl

H

c-Pen

(400 MHz, CDCl 3 ); δ 11.04 per (1H, ), the 7.85 (1H, ), 6,90~6,85 (2H, m), 6,62 (1H, c), of 6.36 (1H, c), 6,13 (1H, m), at 6.01 (1H, c), 4,77~4,67 (1H, m), 4,08~4,01 (1H, m), 3,99 (2H, c), 3,78~3,65 (2H, m), 3,52~3,38 (2H, m), 1,98~1,85 (2H, m), 1,65~1,47 (4H, m), 1,42~of 1.33 (1H, m), 1,33~1,26 (1H, m).

36

HO-

R

1

(1,3-imidazol-1-yl)methyl

H

c-Pen

(400 MHz, CDCl 3 ); δ 11,10 (1H, ), 8,21 (1H, c), of 7.25 (1H, c), of 7.23 (1H, c), and 6.87 (3H, ), 6,16 (1H, c), of 5.05 (2H, c), 4,81~4,73 (1H, m), 4,00~3,93 (1H, m), with 3.79~1,73 (1H, m), 3,73~to 3.67 (1H, m), 3,49~3,37 (2H, m), 1,98~1,88 (2H, m), 1,66~1,53 (4H, m), 1,43~of 1.37 (2H, m).

37

HO-

R

1

(pyrazol-1-yl)methyl

H

c-Pen

(500 MHz, CDCl 3 ); δ of 11.11 (1H, ), 7,52 (1H, d, J=1,85 Hz), 7,34 (1H, d, J=2,45 Hz), 6,93 (1H, c), 6,88 (1H, c), 6,34 (1H, c), 6,22 (1H, m), 5,31 (2H, c), 4,75~4,67 (1H, m), 4,02~3,95 (1H, m), 3,70~3,61 (2H, m), 3,47~3,38 (2H, m), 1,92~1,81 (2H, m), 1,60~1,46 (4H, m), 1,33~1,20 (2H, m).

38

HO-

R

1

acetylamino

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,71(., 1H), 7,26 (c, 1H), of 7.23 (c, 1H), 6,88 (c, 1H), 4,77 (m, 1H), of 4.02 (m, 1H), 3,80 m, 1H), the 3.73 (m, 1H), 3,47 (m, 2H), 2,20 (c, 3H), 2,04 (m, 2H), 1,60 m, 4H), 1.44MB (m, 2H).

39

R

1

H

c-Pen

(500 MHz, CDCl 3 ); δ to 11.79 (1H, ), 7,29~7,26 (2H, m), 7.03 is~7,00 (3H, m), 6,99 (1H, c), 6,93 (1H, m), 6,48 (1H, m), 5,39~5,30 (1H, m), 5,07 (2H, c), 3,94~3,86 (1H, m), 3,75~3,68 (1H, m), 3,24~3,18 (1H, m), 2,78~2,70 (1H, m), 2,68~2,61 (1H, m), 2,05~1,96 (2H, m), 1,79~1,70 (2H, m), 1,66~1,56 (4H, m).

44

ethyl

R

0

fluorine

H

c-Pen

(500 MHz, CDCl 3 ); δ 11,22 (., 1H), 6,88 (c, 1H), 6,63 (d, 1H), 4,65 m, 1H), 3,99 (., 1H), to 3.75 (m, 1H), 3,53 (m, 1H), 3,117 (m, 1H), 2,02~1,94 (m, 2H), 1,77 (m, 1H), 1,63 (m, 5H), 1.44MB (m, 1H), 1,28 (m, 1H), 0,94 (m, 3H).

45

HO-

R

1

fluorine

Me

c-Pen

(500 MHz, CDCl 3 ); δ 10,28 (., 1H), 6,92 (d, 1H), 6,70 (d, 1H), 6,59 (c, 1H), 4,71 (m, 1H), 4,22 (DD, 1H), to 3.75 (DD, 1H), of 3.69 (m, 1H), 3,59 (t, 1H), 3,35 (t, 1H), 2,68 (c, 3H), 1,82 m, 1H), 1,72 (m, 1H), 1,62~of 1.40 (m, 6H).

46

MeO 2 C-

S

1

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,66 (., 1H), PC 6.82 (c, 1H), 6,41 (c, 1H), 6,17 (c, 1H), to 5.08 (m, 1H), and 4.01 (m, 2H), 3,80 m, 1H), 3,67 (m, 1H), 3,49 (c, 3H), 3,20 (DD, 1H), 2,85 (DD, 1H), 2,65 (DD, 1H), 2,02 (m, 1H), 1,66~1,53 (m, 4H), 1,45~of 1.33 (m, 5H).

47

S

1

H

c-Pen

NMR (400 MHz, CDCl 3 ); δ 11,99 (., 1H), to 6.95 (c, 1H), 6,34 (c, 1H), is 6.11 (c, 1H), 5,33 (m, 1H), of 4.04 (m, 2H), 3,83 (m, 1H), of 3.69 (m, 1H), 3,18 (d, 1H), 2,73 (m, 1H), 2,59 (m, 1H), 2,00 m 2H), 1,73 (m, 2H), 1,59 (m, 4H), 1,43 (m, 3H).

48

HO-

S

2

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,64 (., 1H), PC 6.82 (c, 1H), 6,39 (d, 1H), 6,15 (d, 1H), 4,69 (., 1H), 4,60 (m, 1H), 4,06~of 3.84 (m, 5H), 3,54 (m, 1H), 3,10 m, 1H), 2,08~1,94 (m, 4H), 1,70 m, 2H), was 1.58 (m, 4H), of 1.40 (m, 3H).

49

EtO 2 C-

R

0

methyl

H

c-Pen

(400 MHz, CDCl 3 ); δ 9,74 (., 1H), 6,85 (d, J=4 Hz, 2H), 6,37 (c, 1H), 5,33 (t, 1H), 4,23 (m, 2H), 3,87 (m, 1H), 3,71 (m, 2H), 2,39 (c, 3H), up 2.03 (m 2N), by 1.68 (m, 2H), 1,61 (m, 2H), 1,47 (m 2N), 1,26 (t, 3H).

50

S

1

phenoxy

H

c-Pen

(400 MHz, DMSO-d 6 , salt Na); δ 11,85 (., 1H), 7,31 (t, 2H), 7,01 (t, 1H), 6,93 (d, J=8 Hz, 2H), 6,64 (c, 1H), 6,48 (d, J=4 Hz, 1H), 6,39 (c, 1H), 5,97 (c, 1H), 4,93 (m, 1H), to 3.75 (m, 1H), 3,55 (t, 1H), 3,20 (kV, 1H), 2,62 (DD, 1H), 2,15 (kV, 1H), 1,90 m, 2H), 1,72 (m, 2H), 1,60 m, 4H).

51

HO-

R

1

H

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,91 (., 1H), 7,01~6,91 (m, 3H), 6,48 (d, J=7,2 Hz, 1H), 4,86 (m, 1H), 4,34 (m 2H), 4,00 (m, 2H), 3,61 (m, 1H), 3,54 (m, 3H), 3,31 (m, 1H), of 2.05 (m, 2H), 1,55 (m, 2H), to 1.16 (c, 9H).

52

HO-

R

1

H

H

THF-3-yl

(500 MHz, CDCl 3 ); δ of 10.58 (., 1H), 7,14 (d, J=7,95 Hz, 1H), 7,00 (m, 1H), 6,94 (m, 1H), 6,48 (d, J=7,35 Hz, 1H), 4,79 (m, 1H), 4,15~3,95 (m, 3H), 3,90~3,65 (m, 4H), 3,50~3,39 (m, 2H), 2,20 m, 1H)and 1.83 (m, 1H).

53

HO-

R

1

H

H

1-()pyrrolidine-3-yl

(500 MHz, CDCl 3 ); δ 10,50 (., 1H), 7,15 (d, J=7,95 Hz, 1H), 7,00 (DD, 1H), 6,93 (c, 1H), of 6.46 (d, J=7,35 Hz, 1H), 4,77 (m, 1H), 4,18 (m, 1H), 4,08 (DD, 1H), to 3.75 (DD, 1H), 3,59~3,36 (m, 6H), 3,48 (c, 3H), 2,27 (m, 1H), 1,95 (m, 1H).

54

HO-

R

1

fluorine

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,73 (., 1H), 6,91 (c, 1H), 6,72 (m, 1H), 6,33 (m, 1H), 4,78 (m, 1H), 4,12 (m, 1H), 3,97 (., 1H), with 3.79 (m, 1H), to 3.75 (m, 1H), 3,49 (m, 2H), a 2.01 (m, 2H), 1,62 (m, 4H), 1,41 (m, 2H).

55

HO-

R

1

fluorine

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,45 (., 1H), 6,90 (c, 1H), a 6.75 (m, 1H), 6,34 (m, 1H), 4,82 (m, 1H), 4,12 (m, 1H), and 4.01 (m, 2H), 3.94 in (m, 1H), 3,78 (m, 1H), 3,54~3,43 (m, 5H), up 2.03 (m, 2H), 1,50 m, 2H).

56

HO-

R

2

chlorine

H

c-Pen

(500 MHz, CDCl 3 ); δ 10,53 (., 1H), from 7.24 (c, 1H), 6,84 (d, 1H), 6,45 (c, 1H), 4,74 (m, 1H), of 4.06 (m, 1H), 3,81 (m, 1H), 3,71 (m, 1H), 3,45 (DD, 2H), 1,99 (m, 2H), 1,60 m, 4H), of 1.37 (m, 2H)

57

HO-

R

1

chlorine

H

(400 MHz, CDCl 3 ); δ 10,87 (., 1H), 7,01 (c, 1H), 6,89 (c, 1H), 6,40 (c, 1H), 4,80 m, 1H), 4,10 (m, 1H), 3,80 m, 1H), 3,50 (m, 2H), 3,32 (m, 1H), 2,76 m, 4H), to 2.29 (m, 2H), and 1.56 (m, 2H).

58

HO-

R

1

bromine

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,59 (., 1H), of 7.23 (c, 1H), 6,88 (c, 1H), 6,64 (d, 1H), 4,77 (m, 1H), 4,14 (m, 1H), 3,82 (m, 1H), 3,76 (m, 1H), 3,49 (DD, 2H), 2,04 (m, 2H), 1,65 m, 4H), 1,41 (m, 2H).

59

HO-

R

1

bromine

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,53 (., 1H), 7,25 (c, 1H), and 6.87 (c, 1H), 6,63 (d, 1H), 4,80 m, 1H), 4,14 (m, 1H), 4,03 (m, 2H), with 3.79 (m, 1H), 3,56-3,44 (m, 4H), 2,02 (m, 2H), 1,45 (m, 2H).

60

HO-

R

1

methoxy

H

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,23 (., 1H), 6,60 (c, 1H), 6,23 (c, 1H), 5,89 (m, 1H), 5,84 (m, 1H), 4,96 (m, 1H), 4,65 m, 1H), 3,77 (m, 1H), 3,70 (m, 1H), 3,45 (m, 1H), 3,33 m, 1H), 3,29 (c, 3H), 1,91 m 2H), 1,67 (m, 2H), 1,53 (m, 4H).

61

HO-

R

1

(pyridine-3-yl)oxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 11,16 (., 1H), to 8.42 (d, 1H), of 8.28 (m, 1H), 7,30 (m, 1H), 7,22 (m, 1H), 6,88 (1H), 6,67 (d, 1H), 6,28 (d, 1H), 4,83 (m, 1H), of 4.02 (m, 1H), to 3.75 (m, 2H), of 3.46 (m, 2H), 1,97 (m, 2H), 1,63 (m, 4H), 1,43 (m, 2H).

62

HO-

R

1

(pyridine-3-yl)oxy

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,96 (., 1H), of 8.36 (d, J=2,4 Hz, 1H), of 8.26 (m, 1H), 7,27 (m, 1H), 7,19 (m, 1H), 6,83 (1H), 6,63 (d, J=1.6 Hz, 1H), 6,24 (d, J=1.6 Hz, 1H), 4,81 (m, 1H), 4,01~3.94 in (m, 3H), to 3.75 (m, 1H), 3,47(C, 3H), 3,48~3,29 (m, 5H), 1,93 (m, 2H), 1,52 (m, 2H).

63

HO-

R

1

-methyl

H

c-Pen

(500 MHz, CDCl 3 ); δ 11,10 (., 1H), 7,01 (1H), 6,88 (m, 1H), 6,49 (1H), 4,76 (m, 1H), 4,26 (C, 2H), 3,99 (m, 1H), with 3.79 (m, 1H), 3,68 (m, 1H), 3,43 (m, 2H), 2,73 (C, 3H), 1,96 (m, 2H), 1.57 in (m, 4H), 1,35 (m, 2H).

64

HO-

R

1

(-1,3-dione-2-yl)methyl

H

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,30 (., 1H), 8,83 (., 1H), 7,69 (m, 1H), 7,51 (m, 1H), 7,44 (m, 2H), 6,78 (1H), 6,67 (d, 1H), 6,28 (1H), 5,81 (1H), 4,96 (., 1H), 4,67 (m, 1H), 4,37 (d, 2H), 3,83 (m, 1H), 3,70 (m, 1H), 3,52 (m, 1H), of 3.46 (m, 1H), 1,94 (m, 2H), by 1.68 (m, 2H), the 1.54 (m, 4H).

65

MeO 2 C-

R

1

chlorine

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ to 11.52 (1H), 6,81 (1H), of 6.71 (1H), 6,28 (1H), 6,07 (d, 1H), 4,90 (m, 1H), 3,86 (m, 2H), 3,64 (C, 3H), 3,62 (m, 2H), 3,44 (t, 2H), 2,82-2,71 (m, 2H), 1,94 (m, 2H), of 1.40 (m, 2H).

66

R

1

chlorine

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 12,43 (., 1H), 11,53(1H), 6,81 (1H), of 6.71 (1H), 6,28 (1H), the 6.06 (d, 1H), 4,87 (m, 1H), 3,87 (m, 2H), 3,62 (m, 2H), 3,44 (t, 2H), 3,19 (m, 1H), 3,74 (m, 1H), 2,63 m, 1H), 1,94 (m, 2H), 1,41 (m, 2H).

67

HO-

R

2

chlorine

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 11,48 (1H), 6,81(1H), 6,68 (1H), 6,28 (1H), 6,05 (d, 1H), 4,66 (kV, 1H), 4,54 (t, 1H), 3,87 (m, 2H), 3,61-3,54 (m, 3H), 3,44 (t, 2H)and 3.15 (m, 1H), 1,99-1,93 (m, 3H), 1,73 (m, 1H), of 1.40 (m, 2H), 1,20 m, 1H).

68

R

1

bromine

H

c-Pen

(400 MHz, CDCl 3 ); δ 12,50 (., 1H), 7,10 (see 1H), 7,06 (1H), 6,56 (1H), 5,31 (m, 1H), 3,89 (m, 2H), 3,40 (m, 1H), 2,99 (m, 1H), 2,83 (m, 1H), 2,08 (m, 2H), 1,86 (m, 2H), of 1.66 (m, 4H).

74

R

1

fluorine

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 11,45 (1H), a 6.75 (d, 1H), 6,22 (DD, 1H), 6,16 (d, J=6,8 Hz, 1H), of 4.91 (m, 1H), 3,88 (m, 2H), 3,66 (m, 1H), 3,61 (m, 1H), 3,48 (m, 2H), 3,22 (m, 1H), 2,80 m, 1H), 2,65 m, 1H), 2,99 (m, 2H), of 1.40 (m, 2H).

75

R

1

H

H

c-Pen

(400 MHz, CDCl 3 ); δ 11,77 (., 1H), 7,04 (d, 1H), 6,97 (m, 2H), 6,43 (d, 1H), 5,34 (m, 1H), 3,88 (m, 1H), of 3.69 (m, 1H), 3,19 (m, 1H), 2,72 (m, 1H), 2,60 m, 1H), a 2.01 (m, 2H), 1,74 (m, 2H), 1,59 (m, 4H).

76

EtO 2 C-

R

1

H

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,12 (., 1H), 7,05 (m, 1H), 6,99 (m, 1H), 6,91 (d, 1H), 6,51 (d, 1H), 5,07 (m, 1H), of 4.09 (kV, 2H), 3,87 (m, 1H), 3,65 (m, 1H), 3,21 (m, 1H), 2,86 (m, 1H), 2,65 m, 1H), a 2.01 (m, 2H), 1,74 (m, 2H), 1,62 (m, 4H), 1,46 (m, 2H), 1,81 (t, 3H).

77

HO-

R

2

H

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,28 (1H), 6,77-6,74 (m, 2H), 6,69 (1H), 6,25 (d, 1H), 5,78 (d, 1H), 4,65 (kV, 1H), 4,53 (t, 1H), 3,82 (m, 1H), 3,60 m 2H), 3,51 (m, 1H), 3,11 (m, 1H), 1,99-1,91 (m, 3H), 1,75-1,67 (m, 3H), 1.56 to the 1.54 (m, 4H).

78

R

0

H

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 12,42 (., 1H), 11,34 (1H), 6,80 (d, 1H), 6,72 (1H), 6,33 (d, 1H), 5,79 (d, 1H), 4,86 (kV, 1H), 3,88 (m, 2H), 3,60-3,52 (m, 2H), 3,42 (t, 2H), 3,17 (m, 1H), 2,74 (m, 1H), 2,59 (m, 1H), 1,94 (m, 2H), 1,39 (m, 2H).

79

HO-

R

2

H

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ of 11.29 (1H), 6,79 (m, 2H), 6,70 (1H), 6,33 (d, 1H), 5,76 (d, 1H), 4,66 (kV, 1H), 4,54 (t, 1H), 3,88 (m, 2H), 3,62-3,59 (m, 3H), 3,53 (t, 1H), 3,43 (m, 2H), 3,12 (m, 1H), 1,96 (m, 3H), 1.75 in (m, 1H), of 1.40 (m, 2H).

80

MeO 2 C-

R

1

methoxy

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,24 (1H), 6,62 (1H), 6,22 (1H), 5,89 (d, 1H), 5,84 (1H), 4,83 (kV, 1H), 3,77 (m, 1H), 3,64 (C, 3H)and 3.59 (C, 3H), 3,56 (m, 1H), 3,15 (m, 1H), 2,69 (m, 1H), 2,58 (m, 1H), 1,90 m, 2H), 1,67 (m, 2H)and 1.51 (m, 4H).

81

R

1

methoxy

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 12,54 (., 1H), 11,21 (1H), 6,63 (1H), 6,23 (1H), 5,89 (d, 1H), 5,84 (1H), 4,84 (kV, 1H), 3,77 (m, 1H), 3,64 (C, 3H), 3,56 (m, 1H), 3,15 (m, 1H), 2,69 (m, 1H), 2,58 (m, 1H), 1,90 m, 2H), 1,67 (m, 2H), 1,52 (m, 4H).

82

R

1

methoxy

H

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,21 (., 1H), 6,64 (m, 1H), of 6.26 (m, 1H), 5,95 (m, 1H), 5,84 (m, 1H), 4,85 (m, 1H), 3,85 (m, 1H), 3,64 (C, 3H), 3,63-3,49 (m, 2H), 3,43 (m, 2H), 3,17 (m, 1H), 2,73 (m, 1H), 2,62 (m, 1H), 1,94 (m, 2H), 1,72 (m, 1H), 1,38 (m, 2H).

83

R

1

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,24 (., 1H), 6,65 (d, J=2.0 Hz, 1H), of 6.26 (d, J=2.0 Hz, 1H), 5,92 (d, J=6.0 Hz, 1H), 5,88 (d, J=2.0 Hz, 1H), 4,89 (m, 1H), 3.94 in (kV, 2H), 3,81 (m, 1H), 3,65 (m, 1H), 3,20 m, 1H), 2,74 (m, 1H), 2,62 (m, 1H), 1,94 (m, 2H), 1,72 (m, 2H), 1,61 (m, 4H), 1,31 (t, 3H).

84

R

1

O(n-Pr)

H

c-Pen

(500 MHz, CDCl 3 ); δ 12,79 (., 1H), 7,05 (, 1H), of 6.26 (C, 1H), 6,22 (1H), 5,14 (., 1H), 3,88 (m, 3H), 3,41 (m, 2H), 3,07 (m, 1H), 2,83 (m, 1H), up 2.03 (m, 2H), 1,82 m, 3H), 1,69 (m, 2H), 1,60 m 2H), of 1.04 (t, 3H).

85

R

1

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ averaged 11.92 (., 1H), 7,28 (m, 2H), 7,00 (m, 4H), 6,56 (1H), 6,22 (1H), 5,34 (., 1H), 3,81 (., 1H), 3,70 (m, 1H), 3,22 (d, J=12.0 Hz, 1H), 2,76~2,62 (m, 2H), 1,96 (m, 2H), 1,73 (m, 2H), 1,58 (m, 4H).

86

R

1

phenoxy

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,98 (., 1H), 7,28 (m, 2H), 7,00 (m, 4H), 6,58 (1H), 6,22 (, 1H), 5,34 (., 1H), 3,98 (., 2H), 3,70 (m, 1H), 3,50 (m, 3H), 3,21 (m, 2H), 2,74 (m, 1H), 2,66 (m, 1H), of 2.05 (m, 2H), was 1.58 (m, 2H).

87

MeO 2 C-

R

1

(pyridine-3-yl)oxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,89 (., 1H), to 8.41 (d, 1H), of 8.26 (m, 1H), 7,27 (m, 1H), 7,19 (m, 1H), 6,85 (1H), 6,62 (d, 1H), 6,22 (m, 1H), 5,04 (m, 1H), 4,13 (., 1H), 3,78 (m, 1H), 3,65 (m, 1H), 3,59 (C, 3H), 3,20 m, 1H), 2,83 (m, 1H), 2,67 m, 1H), 1,98 (m, 2H), 1,61 (m, 4H), 1,46 (m, 2H).

88

R

1

(pyridine-3-yl)oxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 11,86 (., 1H), 8,40 (d, 1H), 8,26 (m, 1H), 7,25 (m, 1H), 7,17 (m, 1H), 6,96 (1H), 6,57 (d, 1H), 6,18 (d, 1H), 5,33 (., 1H), 3,80 (., 1H), 3,70 (m, 1H), 3,21 (m, 1H), 2,73 (m, 1H), 2,65 m, 1H), 1,96 (m, 2H), 1,72 (m, 2H), was 1.58 (m, 4H).

89

MeO 2 C-

R

1

(pyridine-3-yl)oxy

H

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 11,48 (., 1H), 8,30 (d, 1H), 8,25 (m, 1H), 7,34 (m, 1H), 7,29 (m, 1H), 6,76 (d, 1H), of 6.46 (d, 1H), 6,18 (d, 1H), 4,93 (m, 1H), 3,87 (m, 3H), 3,66 (C, 3H)and 3.59 (m, 1H), 3,44 (m, 2H), 3,23 (m, 1H), 2,81 (m, 2H), 1,95 (m, 2H), 1,43 (m, 2H).

90

R

1

(pyridine-3-yl)oxy

H

THP-4-yl

(400 MHz, MeOH-d 4 ); δ 8,14 (1H), 8,07 (1H), 7,25 (m, 2H), 6,76 (1H), 6,45 (with, 1H), 6,12 (d, 1H), 4,84 (m, 1H), 3,85 (m, 1H), 3,83 (m, 1H), 3,53 (m, 1H), 3,40 (m, 2H), 3,21 (m, 2H), 3,12 (m, 1H), 2,73 (m, 1H), 2,59 (m, 1H), 1,93 (m, 2H), 1,46 (m, 2H).

91

MeO 2 C-

R

1

methyl

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,19 (1H), 6,62 (1H), 6,55 (1H), 6,07 (1H), 5,75 (d, 1H), 4,88 (kV, 1H), with 3.79 (m, 1H), 3,63 is 3.57 (m, 5H), 3,17 (m, 1H), 2,82-2,73 (m, 2H), 2,23 (C, 3H), 1,94 (m, 2H), 1,68 (m, 2H), 1,55 (m, 3H).

92

R

1

methyl

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 12,42 (., 1H), 11,21 (1H), 6,61 (1H), 6,54 (1H), of 6.02 (C, 1H), 5,76 (d, 1H), 4,87 (kV, 1H), 3,77 (m, 1H), 3,62 (t, 2H)at 3.16 (m, 1H), 2,81-2,72 (m, 2H), 2,23 (C, 3H), 1,94 (m, 2H), by 1.68 (m, 2H), 1.55V (m, 3H).

93

R

1

methyl

H

THP-4-yl

(500 MHz, CDCl 3 ); δ 11,85 (., 1H), 6,97 (d, 1H), 6,76 (1H), of 6.26 (C, 1H), 5,32 (m, 1H), 3,99 (m, 2H), 3,71 (m, 1H), 3,65 (m, 1H), 3,54 (m, 2H), 3,23 (m, 1H), 2,76 m, 1H), 2,64 (m, 1H), 2,31 (C, 3H), 2,06 (m, 2H), was 1.58 (m, 2H).

94

R

1

4-()-phenoxy

H

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,71 (., 1H), 7,81 (d, 2H), 7,05 (m, 2H), 6,65 (1H), 6,49 (1H), 6.35mm (m, 1H), 5,96 (1H), 4,86 (m, 1H), to 3.75 (m, 1H), 3,52 (m, 1H), 3,17 (m, 1H), 3,12(C, 3H), to 1.87 (m, 2H), 1,67 (m, 2H), 1,53 (m, 4H).

95

MeO 2 C-

R

1

H

c-Pen

(500 MHz, CDCl 3 ); δ 9,49 (., 1H), 7,27 (m, 2H), 7,10 (1H), 7,01 (m, 2H), 6,93 (m, 1H), 6,89 (1H), 6,59 (1H), 5,07 (C, 2H), 5,02 (m, 1H), 3,93 (m, 1H), 3,71 (C, 3H), 3,65 (m, 1H), 3,21 (m, 1H), 2,88 (m, 1H), 2,68 (m, 1H), 2,04 (m, 2H), 1.75 in (m, 2H), was 1.58 (m, 4H).

96

MeO 2 C-

R

1

H

c-Pen

(500 MHz, CDCl 3 ); δ 9,47 (., 1H), 7,21 (DD, 2H), 7,07 (1H), 6,88 (1H), a 6.75 (m, 3H), 6,57 (1H), to 5.08 (m, 1H), 4,35 (C, 2H), 3.94 in (m, 1H), 3.72 points C, 3H), 3,68 (m, 1H), 3,23 (m, 1H), 2,92 (m, 1H), 2,10~1,30 (m, 8H).

97

MeO 2 C-

R

1

-

H

c-Pen

(500 MHz, CDCl 3 ); δ 10,22 (., 1H), 7,00 (1H), and 6.87 (1H), 6,50 (1H), 5,05 (m, 1H), 4,27(C, 2H), 3,87 (m, 1H), 3,61 (C, 3H), 3,22 (m, 1H), 2,83 (m, 1H), 2,72 (C, 3H), 2,66 (m, 1H), up 2.03 (m, 2H), 1,64 (m, 4H), 1,46 (m, 2H).

98

R

1

-

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,68 (., 1H), 6,85 (1H), of 6.71 (1H), 6,33 (1H), 6,18 (m, 1H), 4,88 (m, 1H), 4,35 (C, 2H), 3,84 (m, 1H), 3,56 (m, 1H), 3,20 m, 1H), 2,84 (C, 3H), 2,55 m, 1H), 2,09 (m, 1H), 1,97 (m, 2H), 1,73 (m, 2H), was 1.58 (m, 4H).

99

HO-

R

2

-

H

c-Pen

(500 MHz, CDCl 3 ); δ 10,41 (., 1H), 6,98 (1H), 6,90 (1H), 6,49 (1H), 4,68 (m, 1H), 4,28 (C, 2H), 3,96 (m, 3H)and 3.59 (m, 1H), 3,13 (m, 1H), of 2.05 (m, 4H)1,72 (m, 2H), 1,60 m, 4H).

100

EtNHC(O)-

R

1

H

H

c-Pen

(400 MHz, CDCl 3 ); δ 9,66, 7,08~6,99 (m, 2H), 6,92 (d, 1H), 6,55 (d, J=7,2 Hz, 1H), 5,88 (m, 1H), 5,02 (m, 1H), 4,13 (m, 1H), 3,61 (m, 1H), 3,32~3,18 (m, 3H), 2,67(1H, m), 2,52 (m, 1H), 2,04 (m, 1H), 1,72~1,53 (m, 6H), from 1.08 (m, 3H).

101

R

2

chlorine

H

c-Pen

(400 MHz, DMSO-d 6 , salt Na); δ of 11.69 (., 1H), PC 6.82 (d, J=4.0 Hz, 1H), 6,68 (1H), 6,27 (1H), 6,18 (1H), 4,63 (m, 1H), 3,83 (m, 1H), 3,50 (m, 1H), 3,13 (m, 1H), 2,08~1,96 (m, 6H), 1,72 (m, 2H), was 1.58 (m, 4H).

102

HO-

R

3

chlorine

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,42 (., 1H), 6,94 (, 1H), PC 6.82 (1H), 6,37 (1H), 4,58 (m, 1H), 4,56 (m, 1H), to 3.75 (m, 2H), 3,65 (m, 1H), 1,95 (m, 7H)and 1.51 (m, 4H), 1,31 (m, 2H).

103

R

2

chlorine

H

THP-4-yl

(400 MHz, DMSO-d 6 , salt Na); δ 11,53 (., 1H), 6,86 (1H), 6,76 (1H), 6,34 (1H), 4,67 (m, 1H), 3,91 (m, 2H), 3,49 (m, 4H), 3,21 (m, 1H), 2,50 (m, 2H), a 2.01 (m, 4H), 1,43 (m, 2H).

104

HO-

R

3

chlorine

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,00 (., 1H), 6,93 (1H), PC 6.82 (1H), 6,31 (1H), 4,89 (., 1H), 4,56 (m, 1H), 3,95 (m, 1H), 3,85 (m, 1H), 3,77 (m, 1H), 3,65 (m, 1H), 3,51 (m, 4H), 3,10 m, 1H), 1,97 (m, 2H)and 1.83 (m, 3H), 1,74 (m, 1H), 1.44MB (m, 1H), of 1.40 (m, 1H).

105

EtO 2 C-

R

2

methyl

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,75 (., 1H), PC 6.82 (d, 2H), 6,32 (1H), 4,71 (m, 1H), and 4.01 (kV, 2H), 3,83 (m, 1H), 3,53 (m, 1H), 3,11 (m, 1H), 2,44 m 2H), 2,37 (C, 3H), a 2.01 (m, 4H)1,64 (m, 4H), of 1.40 (m, 2H).

106

R

2

methyl

H

c-Pen

(400 MHz, CDCl 3 ); δ 11,34 (., 1H), 6,56 (1H), 6,54 (1H), the 6.06 (1H), 5,05 (., 1H), 4,60 (m, 1H), 3,81 (m, 1H), 3,45 (m, 1H), 3,06 (m, 1H), 2,28 (C, 3H), 2,09~1,93 (m, 5H), 1,78~of 1.54 (m, 7H).

107

R

2

phenoxy

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,59 (., 1H), 7,29 (m, 2H), 7,01 (m, 1H), 6,92 (m, 2H), 6,67 (1H), 6,40 (d, 1H), 6,21 (d, 1H), 5,99 (d, 1H), 4,63 (m, 1H), to 3.75 (m, 1H), 3,50 (m, 1H), 3,11 (m, 1H), 2,08 (m, 2H), 2,03 (m, 1H), 1,90 m, 2H), 1,81 (m, 1H), 1,71 (m, 2H), and 1.56 (m, 4H).

108

EtO 2 C-

R

2

fluorine

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,48 (., 1H), 6,91 (1H), 6,69 (m, 1H), 6,30 (m, 1H), 4,77 (m, 1H), 4,19~of 4.02 (m, 3H), 3,84 (m, 1H), 3,60 (m, 1H), 3,18 (m, 1H), 2,51 (m, 2H), of 2.07 (m, 4H), 1,74~1,46 (m, 6H), 1,21 (m, 3H).

109

R

2

fluorine

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,63 (., 1H), 6,49 (m, 1H), 6,33 (m, 1H), 6,09 (m, 1H), 6,66 (m, 1H), 4,61 (m, 1H), 3,85 (m, 1H), 3,52 (m, 1H), 3,11 (m, 1H), 2,09~1,74 (m, 12H).

110

EtO 2 C-

R

2

bromine

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,02 (., 1H), 7,16 (1H), 6,81 (1H), 6,57 (1H), 4,74 (m, 1H), 4,11 (m, 2H), of 4.02 (m, 2H)and 3.59 (kV, 1H), 3,16 (kV, 1H), 2,52 (m, 2H), from 2.06 (m, 4H)1,72 (m, 3H), 1,49 (m, 2H), 1,19 (t, 3H).

111

R

2

bromine

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,77 (., 1H), 6,96 (1H), 6,68 (1H), 6,31 (m, 1H), 6,29 (1H), to 4.64 (m, 1H), 3,82 (m, 1H), 3,53 (m, 1H), 3,13 (m, 1H), of 2.05 (m, 2H), 1,97 (m, 2H), 1,77 (m, 3H), was 1.58 (m, 4H).

112

R

2

H

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,46 (., 1H), 6,85 (m, 2H), 6,70 (1H), 6,27 (d, J=4.0 Hz, 1H), 5,94 (d, J=8.0 Hz, 1H), 4,65 m, 1H), 3,86 (m, 1H), 3,52 (m, 1H), 3,11 (m, 1H), of 2.05 (m, 2H), 1,97 (m, 3H), 1,78 (m, 3H), 1,56 (m, 4H).

113

R

2

methoxy

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,28 (., 1H), 6,61 (1H), 6,27 (1H), 5,97 (m, 1H), 5,88 (1H), 4,59 (m, 1H), to 3.75 (m, 1H), 3,68 (C, 3H), 3,48 (m, 2H), 3,08 (m, 1H), 2,00 m, 5H), 1.75 in (m, 3H), 1.57 in (m, 4H).

114

EtO 2 C-

R

2

H

c-Pen

(500 MHz, CDCl 3 ); δ 9,79 (., 1H), 6,80 (1H), 6,44 (1H), 6,19 (1H), 4,69 (m, 1H), 4,11 (kV, 2H), 4,03 (kV, 2H), 3,83 (m, 1H), 3,54 (m, 1H), 3,11 (m, 1H), 2,49 (m, 2H), 2,02 (m, 4H), 1,69 (m, 2H), 1,60 m 2H), 1,48 (m, 2H), 1,25 (t, 3H), 1,19 (t, 3H).

115

R

2

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,37 (., 1H), 6,78 (1H), 6,30 (1H), 5,94 (1H), to 4.64 (m, 1H), 3,93 (kV, 2H), 3,82 (m, 1H), 3,60 (m, 1H), 3,21 (m, 1H), 2,44 m 2H), 1,97 (m, 4H), 1,71 (m, 2H), 1.57 in (m, 4H), 1,32 (t, 3H).

116

EtO 2 C-

R

2

OCF 3

H

c-Pen

(500 MHz, CDCl 3 ); δ 10,97 (., 1H), 6,93 (1H), 6,86 (1H), 6,30 (1H), 4,76 (m, 1H), 4,05-3,89 (m, 3H), 3,78 (m, 1H), 3,57 (m, 1H), 3,16 (m, 2H), 2,42 (m, 2H), 2,00 m, 4H), 1,63 (m, 2H), 1,45 (m, 1H), to 1.34 (m, 1H).

117

R

2

OCF 3

H

c-Pen

(40 MHz, DMSO-d 6 ) of 11.61 (., 1H), 6,85 (d, 1H), 6,77 (1H), 6,16 (1H), 4,66 (m, 1H), 3,85 (m, 1H), 3,60 m 2H), 3,20 m, 1H), 2,42 (m, 2H), 1,99 (m, 4H), 1,71 (m, 2H), was 1.58 (m, 4H).

Examples 118-123

Compounds produced in the examples obtain 102 and 105-109, introduced in response to synthesize compounds from the examples shown in the following table, according to the mode selected examples of 1-7.

Example

R 1

*

n

R 2

R 4

Data 1 H NMR

118

hydroxy

S

2

methyl

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,11 (., 1H), 6,91 (c, 1H), 6,86 (c, 1H), 6,34 (c, 1H), 4,60 (t, 1H), 4,48 (m, 1H), 4,10~3,93 (m, 5H), 3,63~3,52 (m, 3H), 2,39 (c, 3H), of 2.07 (d, 2H), 1,94 (m, 2H), was 1.58 (m, 2H).

119

S

1

methyl

c-Pen

(400M Hz, CDCl 3 /MeOH-d 4 ); δ 6,97 (c, 1H), 6,79 (c, 1H), 6,33 (c, 1H), 4,86 (m, 1H), 4,62 (DD, 1H), 4,35 (DD, 1H), 3,95 (m, 1H), 2,94 (DD, 1H), 2,67 (DD, 1H), 2,39 (c, 3H), of 2.07 (m, 2H), 1,78 (m, 2H), 1,65 m, 4H).

120

S

1

methyl

THP-4-yl

(400 MHz, CDCl 3 /MeOH-d 4 ); δ 6,94 (c, 1H), 6,81 (c, 1H), 6,32 (c, 1H), 4,87 (m, 1H), 4,59 (DD, 1H), 4,34 (DD, 1H), of 4.02 (d, 1H), 3,68~to 3.58 (m, 3H), 2,92 (DD, 1H), 2,68 (DD, 1H), 2,38 (c, 3H)by 2.13 (d, 2H), 1.57 in (m, 2H).

121

S

1

Cl

c-Pen

(400 MHz, CDCl 3 /MeOH-d 4 ); δ 6,89 (c, 1H), 6,85 (c, 1H), 6,30 (c, 1H), 4,79 (m, 1H), 4,55 (DD, 1H), 4,30 (DD, 1H), 3,82 (m, 1H), 2,86 (DD, 1H), 2,264 (DD, 1H), a 2.01 (m, 2H), 1,71 (m, 2H), 1.57 in (m, 4H).

122

S

1

Cl

(THP-4-yl)methyl

(400 MHz, MeOH-d 4 ); δ of 6.96 (c, 1H), 6,84 (c, 1H), 6,27 (c, 1H), 4,78 (m, 1H), 4,60 (DD, 1H), 4,31 (DD, 1H), 3.94 in (DD, 2H), 3,40 (m, 2H), 3,08 (d, 2H), 2,98 (DD, 2H), 2,64 (DD, 2H), 1,94 (m, 1H), 1.75 in (m, 2H), to 1.37 (m, 2H).

(400 MHz, MeOH-d 4 ); δ of 7.36-7,18 (6H, m), to 6.95 (1H, c), of 6.75 (1H, c), 6,27 (1H, d, J=1,2 Hz), 3,84 (1H, .), 3,77 (1H, .), 3,66 of 3.56 (1H, m), 3,34 (1H, .), 2,77 (2H, .), 1,93 (2H, .), 1,54-1,48 (6H, m).

123

N

-

0

H

THP-4-yl

(500 MHz, CDCl 3 ); δ and 11.38 (., 1H), 7,10 (d, J=8 Hz, 1H), 7,00~6,98 (m, 2H), 6,52 (d, J=8.0 Hz, 1H), 4,50 m 2H), 4,12 (m, 2H), 4,00 (m, 2H), to 3.58 (m, 1H), 3,50 (m, 2H), 2,04 (m, 2H), 1,47 (m, 2H).

Example 124

[2-((4S,5R)-5--4-benzyl-dihydro--2-yl)-5-chloro-1H-indol-7-yl]-Amin

Phase A: 2-[(4S,5R)-benzyl-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--5-]-1,3-dione

2-[(4S,5R)-benzyl-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--5-]-1,3-dione (50 mg, 1 mmol)obtained on A stage, was dissolved in ethanol (10 ml). Added hydrazine chloride (1.8 ml, 0.33 mmol)and the mixture was stirred for 4 hours at 80 degrees C. After the reaction, the solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (16 mg, exit 39%).

1 H-NMR (400 MHz, MeOH-d 4 ); δ of 7.36-7,18 (6H, m), to 6.95 (1H, c), of 6.75 (1H, c), 6,27 (1H, d, J=1,2 Hz), 3,84 (1H, .), 3,77 (1H, .), 3,66 of 3.56 (1H, m), 3,34 (1H, .), 2,77 (2H, .), 1,93 (2H, .), 1,54-1,48 (6H, m).

Example 125

{2-[(R)-5-(S)-1-amino-2-phenyl-ethyl)-4,5-dihydro--2-yl]-5-chloro-1H-indol-7-yl}-Amin

Tert-butyl ether {(S)-1-[(R)-2-(5-chloro-7-nitro-1H-indole-2-yl)-4,5-dihydro--5-yl]-2-phenylethyl} acid, resulting in the example of getting 107, introduced in reaction according to the same procedure as in example 1, and the product thus obtained (50 mg, 1 mg) dissolved in the DCM (2 ml). Added TFA (2 ml)and the mixture was stirred for 2 hours. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (38 mg, exit 92%).

1 H-NMR (400 MHz, MeOH-d 4 ); δ of 10.4 (1H, .), 7,34-7,31 (2H, m), 7,27-7,20 (3H, m), 7.03 is (1H, d, J=1.6 Hz), to 6.95 (1H, c), of 6.46 (1H, d, J=1.6 Hz), the 4.65-4,59 (1H, m), 4,25-4,04 (2H, m), 3,92-3,83 (2H, m), 3,15-3,07 (1H, m), 2,90-2,85 (1H, m), 2,72-2,64 (1H, m), 2,05-2,00 (2H, m), was 1.58 (2H, .), 1,68-1,63 (4H, m), 1,49 to 1.47 (2H, m).

Examples 126-134

Compounds produced in the examples obtain 110-117, introduced in response to synthesize compounds of the examples shown in the following table, according to the mode selected examples of 1-7.

Example

A

R

1

n

R

2

R

4

1 H NMR data

126

-3-yl

5-

1

H

THP-4-yl

(500 MHz, CDCl 3 , MeOH-d 4 ); δ 7,20 (1H), 6,96 (d, J=8.0 Hz, 1H), 6,92 (t, J=8.0 Hz, 1H), 6.42 per (d, J=7,4 Hz, 1H), 3,96 (m, 2H), 3,83 (C, 2H), 3,57 (m, 1H), 3,49 (m, 2H), 2,02 (m, 2H), the 1.54 (m, 2H).

127

-3-yl

5-hydroxy

2

H

THP-4-yl

(400 MHz, CDCl 3 ); δ the 10.40 (., 1H), 7,27 (1H), 7,08(d, J=8.0 Hz, 1H), 7,04 (t, J=8.0 Hz, 1H), 6,55 (d, J=7,4 Hz, 1H), 4,11 (m, 4H), 3,70 (m, 1H), 3,61 (t, 2H), 3,06 (m, 2H), and 2.14 (m, 2H), of 1.66 (m, 2H).

128

oxidiazol-2-yl

H

0

methyl

c-Pen

(400 MHz, CDCl 3 ); δ 9,97 (., 1H), 8,43 (1H), 7,10 (1H), 6,81 (1H), 6,40 (1H), and 4.15 (., 1H), 3.94 in (m, 1H), 2,42 (C, 3H), 2,04 (m, 2H), 1,73 (m, 2H), 1,63 (m, 2H), the 1.54 (m, 2H).

129

-2-yl

4-hydroxy

1

methyl

c-Pen

(400 MHz, CDCl 3 ); δ 10,42 (., 1H), 7,14 (1H), 6,88 (d, J=4 Hz, 1H), 6,86 (1H), 6,36 (1H), 4,70 (C, 2H), 3,86 (m, 1H), of 3.69 (., 1H), 2,39 (C, 3H), 1,95 (m, 2H), of 1.37 (m, 4H), 1,26 (m, 2H).

130

-2-yl

5-hydroxy

1

methyl

c-Pen

(400 MHz, DMSO-d 6 ); δ is 11.39 (1H), 7,70 (1H), 6,78 (1H), 6,60 (1H), 1H), 5,72 (d, J=8 Hz, 1H), 5,62 (m, 1H), 4,72 (d, J=4 Hz, 2H), 3,88 (m, 1H), 2,30 (C, 3H), 1,99 (m, 2H), 1,74 (m, 2H), 1.57 in (m, 4H).

131

-2-yl

4-EtO 2 C-

0

methyl

c-Pen

(400 MHz, CDCl 3 ); δ 9,36 (., 1H), 8,07 (1H), 6,91 (d, J=4 Hz, 1H), 6,84 (1H), 6,37 (1H), 4,37 (kV, 2H), 3,95 (m, 1H), 3,64 (., 1H), 2,40 (C, 3H), 2,04 (m, 2H), 1,76 (m, 2H), 1,65 m, 2H), 1,55 (m, 2H), 1,33 (t, 3H).

132

-2-yl

4-

0

methyl

c-Pen

(400 MHz, DMSO-d 6 , salt Na); δ 7,89 (1H), 6,81 (1H), 6,65 (., 1H), 6,59 (1H), 6,13 (1H), 3,87 (m, 1H), 2,31 (C, 3H), a 2.01 (m, 2H), 1.75 in (m, 4H), 1,55 (m, 2H).

133

-2-yl

4-hydroxy

1

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,60 (., 1H), 7,14 (1H), 6,99 (m, 3H), 6,53 (d, J=8 Hz, 1H), 4,71 (C, 2H), 3,87 (m, 1H), 3,74 (m, 1H), 1,96 (m, 2H), 1,59 (m, 4H), of 1.37 (m, 2H).

134

-2-yl

4-MeO 2 C-

0

H

c-Pen

(400 MHz, CDCl 3 ); δ 9,31 (., 1H), of 8.08 (1H), 7,05 (m, 3H), 6,56 (e, j+8 Hz, 1H), 3,96 (C, 3H), the 3.73 (m, 1H), of 2.07 (m, 2H), 1,80 m 2H), 1,67 (m, 4H).

Example 135

{(R)-2-[5-methyl-7-(4-oxo-)-1H-indole-2-yl]-4,5-dihydro--4-yl}acetic acid

Phase A: ethyl ester {(R)-2-[7-(1,4-dioxa-Spiro[4,5]Dec-8-)-5-methyl-1H-indole-2-yl]-4,5-dihydro--4-yl}acetic acid

Ether ethyl [(R)-2-(5-methyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid, resulting in the example of obtaining 54, and 1,4-dioxa-Spiro[4,5]Dean-8-he was injected into the reaction according to the same procedure as in example 1, getting the target connection.

Stage B: {(R)-2-[5-methyl-7-(4-oxo-)-1H-indole-2-yl]-4,5-dihydro--4-yl}acetic acid

Ethyl ester {(R)-2-[7-(1,4-dioxa-Spiro[4,5]Dec-8-yl)amino-5-methyl-1H-indole-2-yl]-4,5-dihydro--4-yl}acetic acid (177 mg, 4 mmol)obtained on A stage, was dissolved in methanol (10 ml). Added HCl (conc. 2 ml), and the mixture is injected into the reaction in for 6 hours at 60 C. the Solvent was removed under reduced pressure, and to the remnant of the added water. The reaction mixture is extracted EtOAc, dried, concentrated and purified HPLC, receiving the target connection (76 mg, exit 50%).

1 H-NMR (500 MHz, CDCl 3 ); δ 11,99 (., 1H), 7,00 (c, 1H), 6,79 (c, 1H), 6,30 (c, 1H), 5,34 (m, 1H), 3,89 (m, 1H), 3,71 (m, 1H), 3,21 (m, 1H), 2,66 (m, 2H), 2,59 (m, 2H), 2,43 to 2.35 (m, 5H), a 2.26 (m, 2H), 1,97 (m, 2H).

Example 136

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-1-morpholine-4-

[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]-acetic acid, obtained in example 4, and introduced morpholine in reaction according to the same procedure as at the stage of the B sample receipt 101, receiving the target connection.

1 H-NMR (500 MHz, DMSO-d 6 ); δ to 11.52 (., 1H), 6,80 (c, 1H), 6,69 (c, 1H), 6,16 (c, 1H), 6,12 (m, 1H), 4,95 (m, 1H), 3,81 (m, 1H), 3,63 (m, 1H), 3,41 (m, 8H), 3,12 (m, 1H), 2,85 (m, 1H), 2,69 (m, 1H), 1,93 (m, 2H), by 1.68 (m, 2H), and 1.56 (m, 4H).

Examples 137-155

Compounds produced in the examples 4, 11, 66, 71, 75, 81 and 101, and commercially available amines have introduced in reaction to synthesize compounds of the examples shown in the following table, according to the same procedure as at the stage of the B sample receipt of 101.

Example

R

1'

*

n

R

2

R

4

1 H NMR data

137

1-(morpholine-4-yl)

R

1

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,53 (., 1H), one-7.91 (m, 1H), 6,80 (1H), 6,70 (1H), 6,16 (1H), 6,12 (m, 1H), 4,93 (m, 1H), 3,80 m, 1H), 3,53 (m, 5H), 3,20 m, 3H), 2,60 m, 1H), 2,32 (m, 7H), 1,93 (m, 2H), by 1.68 (m, 2H), 1,53 (m, 4H).

138

1-(morpholine-4-yl)

R

1

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ to 11.52 (., 1H), 7,94 (m, 1H), 6,79 (1H), 6,70 (1H), 6,16 (1H), 6,12 (m, 1H), 4,93 (m, 1H), 3,80 m, 1H), 3,51 (m, 5H), 3,10 m, 3H), 2,59 (m, 1H), 2,37 (m, 1H), of 2.25 m, 6H), 1,93 (m, 2H), by 1.68 (m, 2H), 1,53 (m, 6H).

139

Metilamino

R

1

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ to 11.52 (., 1H), 7,90 (m, 1H), 6,80 (1H), 6,69 (1H), 6,16 (1H), 6,13 (m, 1H), 4,93 (m, 1H), 3,80 m, 1H), 3,55 (m, 1H), 3,15 (m, 1H), 2,58 (m, 4H), 2,39 (m, 1H), 1,93 (m, 2H), by 1.68 (m, 2H), and 1.56 (m, 4H).

140

Dimethylamino

R

1

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,53 (., 1H), 6,79 (1H), 6,69 (1H), 6,16 (1H), 6,12 (m, 1H), 4,93 (m, 1H), 3,81 (m, 1H), 3,63 (m, 1H), 3,15 (m, 1H), 2,95 (C, 3H), 2,87 (m, 1H), 2,83 (C, 3H), 2,65 (m, 1H), 1,93 (m, 2H), 1,69 (m, 2H), 1,53 (m, 4H).

141

4-methyl)piperazine-1-Il

R

1

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ to 11.52 (., 1H), 6,80 (c, 1H), 6,69 (c, 1H), 6,16 (c, 1H), 6,12 (m, 1H), 4,94 (m, 1H), 3,80 m, 1H), 3,62 (m, 1H), 3,42 (m, 4H), 3,35 (m, 1H), 3,15 (m, 1H), 2,85 (m, 1H), 2,66 (m, 1H), 2,24 (m, 4H)by 2.13 (c, 3H), 1,93 (m, 2H), by 1.68 (m, 2H), 1,55 (m, 4H).

142

3--1-Il

R

1

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,53(., 1H), 6,80 (1H), 6,69 (1H), 6,16 (1H), 6,12 (m, 1H), 4,94 (m, 1H), 3,81 (m, 1H), 3,62 (m, 3H), 3,30 m, 1H), 3,17 (m, 2H), 2,78 (m, 1H), 2,53 (m, 2H), 2,11 (C, 3H), of 2.07 (C, 3H), 1,93 (m, 2H), 1,69 (m, 3H), 1,59 (m, 5H).

143

piperidine-1-yl

R

1

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ to 11.52 (., 1H), 6,80 (1H), 6,69 (1H), 6,16 (1H), 6,12 (m, 1H), 4,94 (m, 1H), 3,81 (m, 1H), 3,63 (m, 1H), 3,45 (m, 1H), 3,38 (m, 3H), 3,14 (m, 1H), 2,85 (m, 1H), 1,93 (m, 2H), by 1.68 (m, 2H), 1,48 (m, 10H).

144

Metilamino

R

1

chlorine

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,54 (., 1H), one-7.91 (m, 1H), 6,81 (1H), 6,70 (1H), 6,28 (1H), between 6.08 (m, 1H), 4,93 (m, 1H), 3,85 m 2H), 3,56 (m, 2H), 3,44 (m, 2H)and 3.15 (m, 1H), from 2.06 (m, 4H), 2,37 (m, 1H), 1,93 (m, 2H), 1,39 (m, 2H).

145

morpholine-4-yl

R

1

chlorine

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,53 (., 1H), 6,81 (1H), 6,70 (1H), 6,28 (1H), between 6.08 (m, 1H), 4,96 (m, 1H), 3,86 (m, 2H), 3,47 (m, 12H)and 3.15 (m, 1H), 2,85 (m, 1H), 2,69 (m, 1H), 1,94 (m, 2H), 1,39 (m, 2H).

146

4-methyl)piperazine-1-Il

R

1

fluorine

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,44 (., 1H), of 6.73 (1H), 6,52 (DD, 1H), 6,19 (d, J=1,2 Hz, 1H), 6,07 (DD, 1H), 4,99 (m, 1H), 3,84 m 2H), 3,65 (m, 1H), 3,49 (m, 4H), 3,20 m, 1H), 2,88 (m, 1H), 2,71 (m, 1H), 2.28 in (m, 4H), which is 2.17 (C, 3H), 1,98 (m, 2H), 1,72 (m, 2H), was 1.58 (m, 4H).

147

(morpholine-4-yl)

R

1

fluorine

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,46 (., 1H), 7,95 (m, 1H), a 6.75 (c, 1H), of 6.73(DD, 1H), 6,18 (d, J=4.0 Hz, 1H), 6,07 (DD, 1H), 5,00 (m, 1H), 3,84 (m, 1H), to 3.58 (m, 1H), 3,53 (m, 4H), 3,20 m, 3H), 2,73 (m, 1H), 2,45 m, 3H), 2,34 (m, 4H), 1,98 (m, 2H), 1,72 (m, 2H), 1,59 (m, 4H).

148

Metilamino

R

1

methoxy

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,22 (., 1H), 7,90 (m, 1H), 6,61 (c, 1H), 6,23 (c, 1H), 5,87 (m, 1H), 5,85 (c, 1H), 4,90 (m, 1H), 3,76 (m, 1H), 3,64 (c, 3H), 3,52 (m, 1H), 3,12 (m, 1H), 2,58 (m, 4H), 2,35 (m, 1H), 1,91 m 2H), 1,67 (m, 2H), 1,53 (m, 4H).

149

morpholine-4-yl

R

1

methoxy

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,21 (., 1H), 6,62 (c, 1H), 6,24 (c, 1H), 5,87 (m, 1H), 5,85 (c, 1H), 4.92 in (m, 1H), 3,77 (m, 1H), 3,65 (c, 3H), 3,60 (m, 1H), to 3.58-3,33 (m, 8H), 3,13 (m, 1H), 2,84 (m, 1H), 2,66 (m, 1H), 1,91 m 2H), 1,67 (m, 2H), 1,53 (m, 4H).

150

Metilamino

R

1

H

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,33 (., 1H), 7,90 (m, 1H), 6,78 (m, 1H), of 6.71 (c, 1H), 6,24 (c, 1H), 5,80 (m, 1H), 4,93 (m, 1H), 3,81 (m, 1H), 3,54 (m, 1H), 3,14 (m, 1H), 2,62 (m, 1H), 2,58 (m, 3H), 2,38 (m, 1H), 1,93 (m, 2H), 1,69 (m, 2H), the 1.54 (m, 4H).

151

morpholine-4-yl

R

1

H

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,32 (., 1H), 6,78 (m, 1H), of 6.71 (1H), 6,24 (1H), 5,81 (m, 1H), 4,95 (m, 1H), 3,81 (m, 1H), 3,61 (m, 1H), 3,59-3,39 (m, 8H)and 3.15 (m, 1H), 2,87 (m, 1H), 2,68 (m, 1H), 1,93 m, 2H), by 1.68 (m, 2H), the 1.54 (m, 4H)

152

Metilamino

R

1

H

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,34 (., 1H), 7,90 (m, 1H), 6,79 (m, 1H), 6,72 (c, 1H), 6,33 (m, 1H), 5,76 (m, 1H), 4,93 (m, 1H), 3,86 (m, 1H), 3,54 (m, 2H), 3,43 (m, 2H), 3,14 (m, 1H), 2,61 (m, 1H), 2,59 (m, 3H), 2,38 (m, 1H), 1,95 (m, 2H), of 1.40 (m, 2H).

153

morpholine-4-yl

R

1

H

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,34 (., 1H), 6,79 (m, 1H), 6,72 (1H), 6,33 (m, 1H), 5,77 (m, 1H), 4,95 (m, 1H), 3,87 (m, 1H), 3,61 (m, 1H), 3,57-3,38 (m, 11H)and 3.15 (m, 1H), 2,87 (m, 1H), 2,68 (m, 1H), 1,95 m, 2H), of 1.40 (m, 2H).

154

(morpholine-4-yl)

R

2

chlorine

c-Pen

(400 MHz, CDCl 3 ); δ 11,13 (., 1H), 7,06 (., 1H), 6,93 (c, 1H), PC 6.82 (c, 1H), 6,39 (c, 1H), 4,61 (m, 1H), 3,88 (m, 2H), 3,77 (c 4H), 3,45 (m, 2H), 3,07 (m, 1H), 2,70 m, 6H), 2,44 m 2H), 2,10 m, 3H), 1,95 (m, 1H), 1,71 (m, 2H), 1,64 (m, 2H), the 1.54 (m, 2H).

155

4-methyl)piperazine-1-Il

R

2

chlorine

c-Pen

(400 MHz, CDCl 3 ); δ 10,33 (., 1H), 6,97 (c, 1H), 6,81 (c, 1H), 6.42 per (c, 1H), to 4.64 (m, 1H), 3,85 (m, 1H), 3,65 m 2H), 3,56 (m, 1H), 3,45 (m, 2H), 3,13 (m, 1H), 2,43 (m, 6H), 2,04 (m, 2H), 1,72 (m, 8H), the 1.54 (m, 2H).

Example 156

-{5--2-[(R)-4-(2-morpholine-4-)-4,5-dihydro--2-yl]-1H-indol-7-yl}Amin

Phase A: -{2-[(R)-4-(2-)-4,5-dihydro--2-yl]-5--1H-indol-7-yl}Amin

2-[(R)-2-(7--5--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol (178 mg, 0,42 mmol), resulting in the example of 99, was dissolved in tetrahydrofuran (10 ml). Added iodine (161 mg, 0,63 mmol), triphenylphosphine (166 mg, 0,63 mmol) and imidazol (86 mg, 1,23 mmol)and the mixture was stirred for 8 hours at the ambient temperature. The reaction mixture was extinguished with water, and the reaction mixture is extracted . Extract washed saturated with water solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (120 mg, exit 54%).

Stage B: -{5--2-[(R)-4-(2-morpholine-4-)-4,5-dihydro--2-yl]-1H-indol-7-yl}Amin

-{2-[(R)-4-(2-)-4,5-dihydro--2-yl]-5--1H-indol-7-yl}Amin, received on stage As an example 156, and injected into the reaction according to the same procedure as at the stage of the B sample 156, receiving the target connection.

1 H-NMR (500 MHz, CDCl 3 ); δ to 10.62 (., 1H), 6,99 (c, 1H), 6,89 (c, 1H), of 6.46 (c, 1H), 4,77 (m, 1H), 4,26 (c, 2H), 3,87 (m, 1H), 3,57 (m, 1H), 3,30 m, 2H)at 3.16 (m, 1H), 2,72 (c, 3H), 2,46 (m, 2H), 2,31 (m, 2H), 2,21 (m, 2H), 2,04 (c, 3H), up 2.03 (m, 2H), 1,79 (m, 2H), 1,64 (m, 4H), 1,45 (m, 2H).

Example 158

-[2-(R)-4-pyrrolidine-1--4,5-dihydro--2-yl)-1H-indol-7-yl]Amin

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]methanol obtained in example 2, and pyrrolidine injected into the reaction according to the same procedure as in the example 156, receiving the target connection.

1 H-NMR (400 MHz, DMSO-d 6 ); δ 11,37 (., 1H), 6,83 (m, 1H), a 6.75 (d, J=2.0 Hz, 1H), 6,29 (d, J=8.0 Hz, 1H), 5,86 (d, J=8.0 Hz, 1H), 4,80 m, 1H), 3,87 (m, 1H), 3,52 (m, 1H), 3,43 (m, 1H), 3,33 m 2H), 2,78 (m, 2H), 2,61 (m, 2H), 1,99 (m, 2H), 1,72 (m, 6H), 1,60 m, 4H).

Example 159

{5-chloro-2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol produced in example 5, and dimethylamine injected into the reaction according to the same procedure as in the example 156, receiving the target connection.

1 H-NMR (500 MHz, CDCl 3 ); δ 10,07 (., 1H), 6,99 (, 1H), 6,80 (1H), 6.42 per (1H), 4,67 (m, 1H), 3,54 (m, 1H), 3,16 (m, 1H), 2,46 (m, 1H), 2,37 (m, 1H), 2,19 (6H), 2,02 (m, 3H), 1,81 (m, 4H), 1,69 (m, 4H).

Example 160

{5-Chloro-2-[(R)-4-(2-piperazine-1-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin

Phase A: {5-chloro-2-[(R)-4-(2-1-BOC-piperazine-4-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol produced in example 5, and 1-BOC-piperazine injected into the reaction according to the same procedure as in the example 156, receiving the target connection.

Stage B: {5-chloro-2-[(R)-4-(2-piperazine-1-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin

{5-chloro-2-[(R)-4-(2-1-BOC-piperazine-4-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin, obtained at the stage of A, dissolved in dichloromethane (50 ml). Added 4 N. hydrochloric acid solution in ethyl acetate (1.3 ml, 5,28 mmol)and the mixture was stirred for 4 hours at the ambient temperature. After the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM and simple ethyl ether, receiving the target connection (125 mg, exit 55%).

1 H NMR (DMSO-D6 , ppm); δ 11,48 (1H, s), 6,79 (1H, s), 6,67 (1H, s), 6,11 (1H, s), 6,10 (1H, d), 4,61 (1H, m), 3,80 (1H, m), 3,54 (1H, m)and 3.15 (1H, m), 2,93 (2H, m), 2,50-2,41 (2H, m), 2,31 (3H, m), 1,95 (4H, m), 1,79 (1H, m), 1,68 (3H, m), 1,57-1,50 (4H, m), 1,20 (1H, m).

FAB MC (m/e)=432.

Example 161

(5-chloro-2-{(R)-4-[2-(4--piperazine-1-yl)ethyl]-4,5-dihydro--2-yl}-1H-indol-7-yl)-Amin

{5-chloro-2-[(R)-4-(2-piperazine-1-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin, resulting in the example 160, and injected into the reaction according to the same procedure as at the stage of the B sample receipt 29, receiving the target connection.

1 H-NMR (500 MHz, CDCl 3 ); δ of 11.29 (., 1H), 6,97 (1H), 6,86 (1H), 6,37 (1H), 4,93 (m, 1H), 3,92 (., 1H), 3,77 (m, 1H), 3,57 (m, 1H), 3,16 (m, 1H), 2,95 m, 2H), 2,80 m, 4H), 2,42-2,28 (m, 4H), 2,03 (m, 4H), 1,74 (m, 3H), 1,63 (m, 4H), 1,43 (m, 1H), 1,32 (t, 3H).

Example 162

1-(4-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}piperazine-1-yl)-2-hydroxy-

{5-chloro-2-[(R)-4-(2-piperazine-1-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin, resulting in the example 160, and glycolic acid was injected into the reaction according to the same procedure as at the stage of the B sample receipt 101, receiving the target connection.

1 H-NMR (500 MHz, DMSO-d 6 ); δ 11,47 (., 1H), 6,79 (1H), 6,68 (1H), 6,16 (1H), 6,10 (m, 1H), 4,63 (m, 1H), 4,50 m, 1H), of 4.04 (m, 2H), 3,81 (m, 1H), 3,55 (m, 1H), 3,43 (m, 2H)at 3.16 (m, 1H), 2,52 (m, 2H), 2,35 (m, 4H), 1,95 (m, 3H), 1,81 (m, 1H), by 1.68 (m, 2H), 1,53 (m, 4H).

Example 163

{5-chloro-2-[(R)-4-(2-pyrazole-1-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol (81 mg, 0.11 mmol)obtained in example 5, was dissolved in tetrahydrofuran (4 ml). Added iodine (13.2 mg, 0.11 mmol) and imidazol (to 9.7 mg of 0.14 mmol)and the mixture was stirred for 2 hours at the ambient temperature. After the reaction, the reaction mixture was filtered to remove the stain. Solvent was removed under reduced pressure, and to the residue added tetrahydrofuran (4 ml). Added pyrazol (58 mg, 0,85 mmol) and sodium hydride (60% in mineral oil, 21 mg, 0,85 mmol)and the mixture was stirred for 8 hours at the ambient temperature. The reaction mixture was extinguished with water, and the reaction mixture is extracted , dried over anhydrous magnesium sulfate and filtered. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (24 mg, exit 34%).

1 H NMR (DMSO-D6 , ppm); δ 11,50 (1H, s), 7,76 (1H, s), 7,42 (1H, s), 6,80 (1H, s), 6,70 (1H, s), 6,22 (1H, s), 6,17 (1H, s), 6,11 (1H, d), 4,49 (1H, kV), 4,32 (2H, m), 3,80 (1H, m), 3,53 (1H, t), 3,12 (1H, t), 2,38 (1H, m), 2,14 (1H, m), with 1.92 (2H, m), 1,68 (2H, m), 1,59-1,50 (4H, m).

Example 164

(S)-1-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}pyrrolidine-2-carboxylic acid

Phase A: methyl ether 2-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}pyrrolidine-2-carboxylic acid

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol produced in example 5, and methyl (S)-pyrrolidine-2- acid was injected into the reaction according to the same procedure as in the example 156, receiving the target connection.

Stage B: (S)-1-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}pyrrolidine-2-carboxylic acid

Methyl ether 2-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}pyrrolidine-2-carboxylic acid, obtained for A stage, hydrolyzed according to the same procedure as on the stage As an example of obtaining 101, receiving the target connection.

1 H NMR (CDCl 3 , ppm); δ of 12.04 (1H, s), 11,02 (1H, s), 6,85 (1H, s), 6,69 (1H, s), 6,31 (1H, s), 6,24 (1H, m), 4,37 (1H, m), 4,10 (1H, m), 3,86 (1H, m), with 3.79 (1H, m)and 3.59 (1H, m), 3,28 (1H, m), 3,17 (1H, m), 2,88 (2H, m), 2,59 (1H, m), 2,21 (1H, m), 2.06 to 1,59 (11H, m), 1,23 (1H, m).

Example 165

{5-chloro-2-[(R)-4-(2--ethyl)-4,5-dihydro--2-yl]-1H-indol-7-yl}-Amin

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol (50 mg, 0.11 mmol)obtained in example 5, was dissolved in N,N-dimethylformamide (2 ml). Added methanesulfonate sodium (54 mg, 0,55 mmol)and the mixture was stirred for 8 hours at the ambient temperature. The reaction mixture was extinguished by water. The reaction mixture is extracted , dried over anhydrous magnesium sulfate and filtered. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (19 mg, exit 45%).

1 H-NMR (400 MHz, CDCl 3 ); δ accounted for 10.39 (., 1H), 7.03 is (c, 1H), 6,89 (c, 1H), 6,48 (c, 1H), 6,17 (c, 1H), 4,77 (m, 1H), 3,87 (m, 1H), 3,59 (m, 1H), 3,29 (m, 1H), 3,17 (m, 2H), 2,86 (c, 3H), a 2.26 (m, 2H), 2,10 m, 2H), 1,70 m, 4H)and 1.51 (m, 2H).

Example 166

Ethyl ester 3-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}-5-methyl-3H-imidazol-4-carboxylic acid

2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol produced in example 5, and ethyl ester 5-methyl-3H-imidazol-4-carboxylic acid was injected into the reaction according to the same procedure as in the example 156, receiving the target connection.

1 H-NMR (500 MHz, DMSO-d 6 ); δ 11,49 (., 1H), 7,71 (c, 1H), 6,80 (c, 1H), 6,72 (c, 1H), 6,17 (c, 1H), between 6.08 (m, 1H), 4,56 (m, 1H), 4,16 (m, 4H), 3,81 (m, 1H), to 3.58 (m, 1H), 3,18 (m, 1H), 2,46 (c, 3H), 2,11 (m, 2H), 1,95 (m, 2H), by 1.68 (m, 2H), 1,53 (m, 4H), 1,22 m, 3H).

Example 167

3-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}-5-methyl-3H-imidazol-4-carboxylic acid

Ethyl ester 3-{2-[(R)-2-(5-chloro-7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethyl}-5-methyl-3H-imidazol-4-carboxylic acid, resulting in the example 166, introduced in reaction according to the same procedure as on the stage As an example of obtaining 101, receiving the target connection.

1 H NMR (DMSO-D6 , ppm); δ 11,50 (1H, s), 7,71 (1H, s), 6,80 (1H, s), 6,72 (1H, s), 6,17 (1H, s), between 6.08 (1H, m), 4,55 (1H, m), 4,13 (2H, m), 3,80 (1H, m), 3,55 (2H, m), 2,19-2,15 (2H, m), 1,95 (3H, m), 1,68 (3H, m)and 1.51 (5H, m).

Example 168

1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl) - piperidine-3-carboxylic acid

Phase A: ethyl ester 1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl) - piperidine-3-carboxylic acid

2-{2-[(R)-5-chloro-7-(-4-yl)amino-1H-indole-2-yl]-4,5-dihydro--4-yl]}the ethanol produced in the example 67, and ethyl ether piperidine-3-carboxylic acid was injected into the reaction according to the same procedure as in the example 156, receiving the target connection.

1 H NMR (DMSO-d 6 , ppm); δ 11,48 (1H, s), PC 6.82 (1H, s), 6,67 (1H, s), 6,29 (1H, s), 6,04 (1H, d), 4,61 (1H, Queen), 4,47 (1H, m), a 3.87 (2H, m), 3,62 (2H, kV), 3,56 (2H, m), 3,44-3,39 (4H, m), 3,14 (2H, m), 2,52 (1H, m), 2,37-2,30 (6H, m), a 1.96-1,92 (3H, m), 1,81 (1H, m), 1,42 (2H, m), 1,28 (3H, t).

Stage B: 1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl) - piperidine-3-carboxylic acid

Ethyl ester 1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl) - piperidine-3-carboxylic acid, obtained for A stage, introduced in reaction according to the same procedure as on the stage As an example of obtaining 101, receiving the target connection.

1 H NMR (DMSO-D6 , ppm); δ 13,17 (1H, c), 11,94 (1H, c), 6,80 (1H, c), 6,68 (1H, c), 6,28 (1H, c), 6,04 (1H, d), 4,62 (1H, Queen), 4,47 (1H, m), a 3.87 (2H, m), 3,56 (2H, m), 3,44-3,39 (4H, m), 3,14 (2H, m), 2,52 (1H, m), 2,37-2,30 (6H, m), a 1.96-1,92 (3H, m), 1,80 (1H, m), 1,40 (2H, m).

Example 169

tert-Butyl ether [(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl)pyrrolidine-3-yl] acid

2-{2-[(R)-5-chloro-7-(-4-yl)amino-1H-indole-2-yl]-4,5-dihydro--4-yl]}the ethanol produced in the example 67, and (S)-3-BOC-amino-pyrrolidine injected into the reaction according to the same procedure as in the example 156, receiving the target connection.

1 H-NMR (500 MHz, DMSO-d 6 ); δ 11,48 (., 1H), 6,92 (m, 1H), 6,81 (c, 1H), 6,68 (c, 1H), 6,28 (m, 1H), 6,05 (m, 1H), 4,63 (m, 1H), 3,86 (m, 3H)and 3.59 (m, 1H), 3,54 (m, 1H), 3,44 (m, 2H), 3,14 (m, 1H), 2,71-2,58 (m, 2H)by 2.25 (m, 1H), 1,95 (m, 4H), 1.75 in (m, 1H), 1,52 (m, 1H), 1,39 (m, 2H), 1,37-1,32 (m, 11H).

Example 170

(2-{(R)-4-[2-(S)-3-amino-pyrrolidine-1-yl)ethyl]-4,5-dihydro--2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine

Tert-butyl ether [(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl)pyrrolidine-3-yl] acid 150 mg, and 0.27 mmol), resulting in the example 169, was dissolved in dichloromethane (30 ml). Added 4 N. solution of hydrochloric acid in dioxane (0,34 ml, 1,35 mmol)and the mixture was stirred for 4 hours at the ambient temperature. After the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from a mixture of DCM/simple ethyl ester, receiving the target connection (92 mg, exit 75%).

1 H NMR (DMSO-D6 , ppm); δ 10,92 (1H, s), 8,63 (2H, with, .), 6,86 (1H, s), 6,83 (1H, s), 6,43 (1H, s), 6,11 (1H, m), 4,72 (1H, m), 3,65 (5H, m), 3,45 (5H, m), 3,22 (3H, m), 2,37 (2H, m), 2,19 (3H, m), 1,90 (2H, m), 1,49 (2H, m).

Example 171

N-[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-PYRAN-4-)-1H-indole-2-yl]-4,5-dihydro--4-yl}ethyl)pyrrolidine-3-yl]

(2-{(R)-4-[2-(S)-3-amino-pyrrolidine-1-yl)ethyl]-4,5-dihydro--2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydro-PYRAN-4-yl)amine (85 mg, the 0.19 mmol), resulting in the example 170, was dissolved in methylene chloride; (10 ml). Added (0.13 ml, 0.75 mmol) and acetyl chloride (0,013 ml of 0.19 mmol)and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was extinguished with water, and the reaction mixture is extracted , dried over anhydrous magnesium sulfate and filtered. Solvent was removed under reduced pressure, and the residue was purified chromatography columns on getting the target connection (39 mg, exit 42%).

1 H NMR (DMSO-D6 , ppm); δ 11,49 (1H, s), 7,97 (1H, s), for 6.81 (1H, s), 6,69 (1H, s), 6,28 (1H, s), 6,05 (1H, d), to 4.64 (1H, KVINT, 4,12 (1H, m), 3,85 (2H, m), 3,53 (2H, m), 3,44 (2H, t), 3,34 (2H, m)and 3.15 (1H, t), 2,72-2,60 (3H, m), 2,39 (1H, m), 2,05-1,87 (4H, m), 1,80-1,72 (4H, m), 1,53 (1H, m), to 1.37 (2H, m).

Example 172

-{2-[(R)-4-(2-methoxy-ethyl)-4,5-dihydro--2-yl]-1H-indol-7-yl}Amin

2-[2-(7--1H-indole-2-yl)-4,5-dihydro--4-yl]ethanol produced in the example of 77 and sodium methylate injected into the reaction according to the same procedure as in the example 165, receiving the target connection.

1 H-NMR (500 MHz, DMSO-d 6 ); δ to 10.62 (., 1H), 7.03 is (d, J=7,95 Hz, 1H), 6,99 (t, 1H), 6,93 (1H), 6,48 (d, J=7,35 Hz, 1H), 4,83 (m, 1H), 3,83 (m, 1H), 3,56 (m, 1H), of 3.46 (m, 2H), 3,20 m, 4H), 2,05~1,87 m, 4H), 1,70~1,38 (m, 6H).

Examples 173-224

Compounds produced in the examples 2, 5, 24, 56, 67, 73, 77, 79, 99 and 102, and commercially available amines or methanesulfonate sodium was administered in response to synthesize compounds of the examples shown in the following table, according to the mode selected examples of 156-172.

Example

R

1

∗

n

R

2

R

4

1 H NMR data

173

Amino

R

1

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 6,92 (c, 1H), 6,86 (m, 2H), 6,28 (d, J=6 Hz, 1H), 5,84 (m, 1H), 4,24 (m, 1H), 3,86 (m, 2H), 3,56 (m, 1H), 2,75 m, 2H), 1,97 (m, 2H), 1,72 (m, 2H), and 1.56 (m, 4H).

174

(3R)-3-(amino)pyrrolidine-1-Il

R

2

chlorine

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,24 (1H), 6,62 (1H), 6,22 (1H), 5,89 (d, 1H), 5,84 (1H), 4,83 (kV, 1H), 3,77 (m, 1H), 3,64 (C, 3H)and 3.59 (C, 3H), 3,56 (m, 1H), 3,15 (m, 1H), 2,69 (m, 1H), 2,58 (m, 1H), 1,90 m, 2H), 1,67 (m, 2H)and 1.51 (m, 4H).

175

2--4-yl

R

2

methoxy

c-Pen

(400 MHz, CDCl 3 ); δ 10,75 (., 1H), 7,11 (., 1H), PC 6.82 (c, 1H), 6,39 (d, J=4 Hz, 1H), 6,13 (d, J=4 Hz, 1H), 4,71 (m, 1H), 3,84 (m, 1H), 3,81 (c, 3H), 3,50 (m, 1H), 3,28 (m, 2H)at 3.16 (m, 2H), 3,08 (m, 1H), to 2.57 (m, 4H), a 2.01 (m, 2H), 1,95 (m, 1H), 1,84 (m, 1H), 1,71 (m, 2H), 1.57 in (m, 4H).

176

(3S)-3-(amino)pyrrolidine-1-Il

S

2

chlorine

c-Pen

(400 MHz, MeOD); δ 7,51 (1H), 7,28 (1H), 7,06 (1H), 4,27 (m, 1H), and 4.15 (m, 1H), 3,95-3,8 (m, 5H), 3,67 (m, 3H), 3,44 (DD, 1H), 2,70 m, 1H), 2,40-2,25 (m, 3H), 2,10 m 2H), 1,91 (m, 4H), 1,71 (m, 2H).

177

(3S)-3-(dimethylaminophenyl)--1-Il

S

2

chlorine

c-Pen

(500 Hz, CDCl 3 ); δ 7,16 (t, 1H), 6,89 (1H), 6,74 (1H), 6,61 (m, 3H), 6,34 (1H), to 4.64 (m, 1H), 3,86 (m, 1H), 3,66 (m, 2H), 3,51 (m, 2H), a 3.45-3,25 (., 2H), 3.25 to 3,05 (., 2H), to 3.03 (t, 1H), 3,05-2,95 (., 1H), 2,92 (6H), 2,38 (., 1H), 2,05-1,85 (m, 5H), 1,80-1,65 m, 4H), was 1.58 (m, 1H).

178

1-(acetyl)piperazine-4-yl

S

2

chlorine

c-Pen

(500 Hz, CDCl 3 ); δ 10,17 (., 1H), 7,00 (1H), 6,83 (1H), 6,43 (1H), 4,75 (m, 1H), 3,83 (m, 2H), to 3.58 (m, 1H), 3,56 (DD, 1H), 3,48 (m, 1H), 3,32 (m, 1H), 3,25 (m, 1H), 3,15 (DD, 1H), 2,46 (m, 2H), 2,36 (m, 1H), a 2.26 (m, 2H), 2,20 m, 1H), of 2.05 (C, 3H), 2,04 (m, 2H), 1,96 (m, 1H), 1,80 m, 1H), of 1.66 (m, 3H), 1,48 (m, 2H).

179

1-(acetyl)piperazine-4-yl

S

2

chlorine

H

(500 Hz, DMSO); δ 11,70 (., 1H), 10,41 (1H), one-7.91 (1H), 7,78 (d, 1H), 7,58 (1H), 7,46 (C, 2H), crude 7.36 (m, 3H), 7,09 (t, 1H), 7,05 (1H), 6,97 (d, 2H), 3,86 (C, 2H), 2,90 (., 2H).

180

pyrrolidine-1-Il

R

2

methoxy

c-Pen

(500 MHz, CDCl 3 ); δ 10,11 (., 1H), PC 6.82 (c, 1H), 6,44 (c, 1H), 6,16 (c, 1H), 4,72 (m, 1H), 3,81 (c, 3H), 3,74 (m, 1H), 3,54 (DD, 1H), 3,15 (DD, 1H), 2,62 (m, 1H), 2,46 (m, 1H), 2,42 (m, 4H), a 2.01 (m, 4H), 1,84 (m, 1H), 1,73-1,64 (m, 3H), was 1.58 (m, 2H), 1,50 m, 1H), 1,42 (m, 1H).

181

pyrrolidine-1-Il

R

2

H

THP-4-yl

(500 MHz, CDCl 3 ); δ 7,80 for 7.78 (2H, m), 7,51-7,47 (2H, m), 4,79-4,66 (4H, m), of 4.39 (4H, .), the 3.73-3,55 (6H, m), 3,42-3,33 (6H, m), 3,04-2,98 (2H, m).

182

2--4-yl

S

2

methyl

THP-4-yl

(500 MHz, CDCl 3 ); δ 11,05 (c, 1H), 7,72 (c, 1H), PC 6.82 (c, 1H), 6,78 (c, 1H), 6,27 (c, 1H), 4,71-4,67 (m, 1H), 4,03-4,01 (m, 2H), 3,62-3,47 (m, 4H), 3,30-3,20 m 2H)and 3.15 (d, 2H), 3,11-3,08 (m, 1H), 2,59 of $ 2.53 (m, 4H), 2,42-2,36 (m, 3H), 2,09-2,04 (m, 2H), 1,95-1,92 (m, 1H), 1,84-1,81 (m, 1H), 1,59-1,51 (m, 2H).

183

2--4-yl

R

2

methane -methyl

c-Pen

(400 MHz, CDCl 3 ); δ 10,61 (., 1H), 6,97 (c, 1H), 6,85 (c, 1H), 6,72 (c, 1H), 6,48 (c, 1H), the 4.75-4,69 (m, 2H), 4,28 (c, 2H), 3,93 (m, 1H), to 3.58 (m, 1H), 3,42-3,23 (m, 3H), 3,19-3,10 m, 2H), the 2.75-2,52 (m, 6H), from 2.06 (m, 2H), 1,93 (m, 2H), 1,74 (m, 2H), 1,68-1,53 (m, 6H).

184

morpholine-4-yl

S

2

methyl

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,91 (1H), 6,85 (1H), 6,83 (1H), 6,28 (1H), 4,81 (m, 1H), 3,96 (m, 2H), 3,60~3,41 (m, 7H), 3,17(, 1H), 2,40 m 2H), a 2.36 (C, 3H), to 2.29 (m, 2H), 2,18 (m, 2H), 2,04~1,79 (m, 4H), 1,39 (m, 2H).

185

1-(acetyl)piperazine-4-yl

R

2

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,47 (., 1H), 6,79 (1H), 6,68 (1H), 6,16 (1H), 6,11 (m, 1H), 4,62 (m, 1H), 3,80 (m, 1H), 3,55 (m, 1H), 3,39 (m, 4H)and 3.15 (m, 1H), 2,46 (m, 1H), 2,32 (m, 4H), 1,95 (m, 4H), 1,80 m, 1H), by 1.68 (m, 2H), 1,53 (m, 4H).

186

4-methyl-piperazine-1-Il

R

2

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,47 (., 1H), 6,79 (1H), 6,67 (1H), 6,16 (1H), 6,10 (m, 1H), 4,59 (m, 1H), 3,80 m, 1H), 3,54 (m, 1H), 3,15 (m, 1H), 2,40 (m, 10H)by 2.13 (C, 3H), 1,95 (m, 3H), 1,78 (m, 1H), by 1.68 (m, 2H), 1,53 (m, 4H).

191

2--1-Il

R

2

chlorine

c-Pen

(500 MHz, DMSO-d 6 ); δ 11,49 (., 1H), 6,80 (c, 1H), 6,69 (c, 1H), 6,16 (c, 1H), 4,51 (m, 1H), 3,80 m, 1H), 3,57 (m, 1H), of 3.46 (m, 1H), 3,32 (m, 1H), 3,15 (m, 1H), 2,18 (m, 2H), 1,91 (m, 5H), 1,80 m, 1H), by 1.68 (m, 2H), 1,53 (m, 4H).

192

(3S)-3-()piperidine-1-yl

R

2

chlorine

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 11,48 (c, 1H), 6,81 (c, 1H), 6,69 (c, 1H), 6,28 (c, 1H), 6,04 (d, 1H), 4,60 (kV, 1H), 3,87 (m, 2H), 3,56 (m, 2H), 3,44 (t, 2H)at 3.16 (m, 1H), 2,97 (c, 3H), 2,95 m, 1H), 2,88-2,76 m, 2H), 2,74 (m, 5H), 1,96 (m, 4H), 1,80 m 2H), of 1.66 (m, 2H), 1,50 to 1.37 (m, 3H), 1,23 m, 1H).

193

piperazine-1-Il

R

2

chlorine

THP-4-yl

(400 MHz, DMSO-d 6 ); δ 11,42 (c, 1H), 6,83 (c, 1H), 6,74 (c, 1H), 6,30 (c, 1H), of 6.02 (d, 1H), 4,69 (m, 1H), 3,85 (m, 1H), 3,52-3,42 (m, 6H), 3,35 (m, 3H), 3,20 m 2H), 2,16 (m, 2H), 1,92 (m, 3H), 1,42 (m, 3H).

194

1-()piperazine-4-yl

R

2

chlorine

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,48 (., 1H), 6,81 (1H), 6,69 (d, J=1,8 Hz, 1H), 6,29 (1H), 6,05 (d, J=7,4 Hz, 1H), 4,62 (m, 1H), 4,49 (t, 1H), of 4.04 (m, 2H), 3,87 (m, 2H), 3,56 (m, 1H), 3,45 (m, 4H), 3,29 (m, 4H)at 3.16 (m, 1H), a 2.36 (m, 4H), 1,96 (m, 3H), 1,80 m, 1H), of 1.40 (m, 2H).

195

1-(TRIFLUOROACETYL)piperazine-4-yl

R

2

chlorine

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,47 (c, 1H), 6,81 (c, 1H), 6,69 (c, 1H), 6,28 (c, 1H), 6,09 (d, 1H), 4,62 (kV, 1H), 3,87 (m, 2H), 3,56 (m, 4H), 3,47-3,38 (m, 7H)at 3.16 (m, 1H), 2,53 (m, 1H), 2,37~2,30 (m, 4H), 1,94 (m, 3H), 1,81 (m, 1H), of 1.40 (m, 2H).

196

1-[(furan-2-yl)carbonyl]piperazine-4-yl

R

2

chlorine

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,48 (., 1H), 7,79 (c, 1H), 6,81 (c, 1H), 6,69 (c, 1H), 6,59 (m, 1H), 6,28 (c, 1H), 6,05 (m, 1H), 4,63 (m, 1H), 3,86 (m, 2H), 3,57 (m, 6H), 3,44 (m, 2H)at 3.16 (m, 2H), 2,56 (m, 1H), 1,96 (m, 3H)and 1.83 (m, 1H), 1,41 (m, 2H).

197

1-(1,4-pyrazin-2-yl)piperazine-4-yl

R

2

chlorine

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,48 (., 1H), of 8.27 (c, 1H), of 8.04 (c, 1H), 7,80 (c, 1H), 6,81 (c, 1H), 6,69 (c, 1H), 6,29 (c, 1H), 6,05 (m, 1H), to 4.64 (m, 1H), 3,86 (m, 2H), 3,57 (m, 2H), 3,53 (m, 4H), 3,18 (m, 1H), to 2.57 (m, 1H), 1,99 (m, 1H), 1,95 (m, 2H)and 1.83 (m, 1H), of 1.40 (m, 2H).

198

1-(1,3-pyrazin-2-yl)piperazine-4-yl

R

2

chlorine

THP-4-yl

(500 MHz, DMSO-d 6 ); δ 11,49 (., 1H), 8,31 (m, 1H), 6,81 (1H), 6,69 (1H), 6,58 (m, 1H), 6,28 (1H), the 6.06 (m, 1H), 4,65 m, 1H), 3,86 (m, 2H), of 3.69 (m, 4H), to 3.58 (m, 2H), 3,45 (m, 2H), 3,35 (m, 1H), 3,18 (m, 1H), 2,56 (m, 1H), 2,43 (m, 3H), from 2.00 (m, 1H), 1,96 (m, 2H), of 1.40 (m, 2H).

199

Amino

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 /DMSO-d 6 ); δ 11,28 (., 1H), 6,80 (., 2H), 6,80 (d, J=2.0 Hz), 6,50 (DD, 1H), 6,16 (DD, 1H), 4,58 (m, 1H), 3,81 (m, 1H), 3,54 (m, 1H), 3,24 (m, 2H), 3,02 (m, 1H), 2,13~1,55 (m, 10H).

200

1-(acetyl)piperazine-4-yl

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 ); δ 10,47 (., 1H), and 6.87 (c, 1H), 6,66 (d, J=8.0 Hz, 1H), of 6.26 (d, J=12.0 Hz, 1H), 4,80 m, 1H), 3,92 (m, 1H), 3,81 (m, 1H), 3,59 (m, 2H), 3,49 (m, 1H), 3,28 (m, 1H), 3,18 (m, 1H), 2,44 m 2H), 2,34 (m, 1H), 2,23 (m, 2H), and 2.14 (m, 1H), a 2.05 (c, 3H), 1,93 (m, 1H), 1,81 (m, 1H), 1,71 (m, 5H), 1,48 (m, 2H).

201

morpholine-4-yl

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 ); δ 10,92 (., 1H), and 6.87 (1H), 6,64 (d, J=8.0 Hz, 1H), 6,24 (d, J=12.0 Hz, 1H), 4,83 (m, 1H), 3,93 (m, 1H), 3,77 (m, 1H), 3,54 (m, 4H), 3,47 (m, 1H), 3,17 (m, 1H), 2,38 (m, 1H), 2,33 (m, 2H), 2,16 (m, 2H), 2,04 (m, 3H), 1,77 (m, 1H), 1,65 m, 4H), 1,47 (m, 1H), 1,35 (m, 1H).

202

Dimethylamino

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 ); δ 10,99 (., 1H), 6,80 (c, 1H), 6,60 (d, J=8.0 Hz, 1H), 6,22 (d, J=12.0 Hz, 1H), 4,59 (m, 1H), 4,13 (m, 1H), 3,47 (m, 1H), to 3.03 (m, 1H), 2,90 (m, 1H), 2,55 m, 1H), 2,42 (c 6H), a 2.01 (m, 3H), 1,81 (m, 1H), 1,62 (m, 2H), 1,55 (m, 4H).

203

pyrrolidine-1-Il

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 ); δ is 11.39 (., 1H), 6,81 (c, 1H), 6,63 (DD, 1H), 6,25 (DD, 1H), 4,59 (m, 1H), to 4.17 (m, 1H), 3,89 (m, 1H), 3,32 (m, 1H), 3,07 (m, 3H), 2,71 (m, 1H), 2,09 (m, 2H), 1,95 (m, 4H), 1,77 (m, 2H), 1,65 m, 4H).

204

1,1-dioxo--4-yl

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 ); δ 11,05 (., 1H), 6,94 (c, 1H), 6,60 (d, J=8.0 Hz, 1H), of 6.26 (d, J=12.0 Hz, 1H), 4,74 (m, 1H), 3,85 (m, 1H), 3,62 (t, 1H), 3,49 (kV, 1H), 3,18 (kV, 1H), 3,00 (m, 8H), 2,74 m 2H), of 2.05 (m, 3H), 1,79 (m, 2H), 1,63 (m, 4H).

205

2--4-yl

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 ); δ 11,26 (., 1H), 7,26 (., 1H), and 6.87 (1H), 6,58 (d, J=8.0 Hz, 1H), 6,22 (d, J=12.0 Hz, 1H), 4,73 (m, 1H), 3,84 (m, 1H), 3,53 (t, 1H), 3,19 (m, 5H), to 2.57 (m, 4H), 2,04 (m, 3H), 1,95 (m, 1H), 1,74 (m, 2H), 1,62 (m, 2H).

206

1-()piperazine-4-yl

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 ); δ 11,26 (., 1H), 6,89 (1H), 6,63 (d, J=8.0 Hz, 1H), 6,22 (d, J=12.0 Hz, 1H), 4,85 (m, 1H), 4,10 (C, 2H), 3,77 (m, 1H), 3,57 (m, 2H), 3,41 (m, 1H), 3,14 (kV, 1H), 3,00 (m, 1H), 2,91 (m, 1H), 2,38 (m, 3H), 2,12 (m, 2H), 2,02 (m, 4H), 1,85 (m, 1H), 1,77 (m, 1H), 1,63 (m, 4H), 1,36 (m, 1H), 1,26 (m, 1H).

207

R

2

fluorine

c-Pen

(400 MHz, CDCl 3 ); δ of 9.89 (., 1H), and 6.87 (1H), 6,67 (DD, 1H), 6,28 (DD, 1H), 4,77 (m, 1H), 3,83 (t, 1H), 3,59 (m, 1H), 3,31 (m, 1H), 3,13 (m, 2H), 2,84 (C, 3H), 2,27 (m, 2H), 2,04 (m, 2H), by 1.68 (m, 6H)and 1.51 (m, 2H).

208

Dimethylamino

R

2

fluorine

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,27 (., 1H), 6,79 (c, 1H), 6,60 (d, J=8.0 Hz, 1H), 6,22 (d, J=12.0 Hz, 1H), 4,61 (m, 1H), 4,13 (m, 2H)and 3.59 (m, 4H), 3,04 (m, 1H), 2,55 (c 4H), 2,04 (m, 6H), 1,65 m, 2H), 1,26 (m, 2H).

209

pyrrolidine-1-Il

R

2

fluorine

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,16 (., 1H), and 6.87 (c, 1H), 6,68 (d, J=8.0 Hz, 1H), of 6.26 (d, J=12.0 Hz, 1H), 4,69 (m, 1H), to 4.17 (d, J=8.0 Hz, 2H), 3,60 (m, 5H), 3,17 (m, 1H), 2,90 (m, 1H), 2,67 m, 5H), 2,09 (m, 3H), 1,90 m, 4H), 1.57 in (m, 2H).

210

morpholine-4-yl

R

2

fluorine

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,16 (., 1H), 6,86 (1H), 6,64 (d, J=8.0 Hz, 1H), 6,23 (d, J=12.0 Hz, 1H), 4,75 (m, 1H), of 4.02 (m, 1H), 3,66 (m, 4H), 3,51 (m, 4H), 3,18 (m, 1H), 2,60 m, 1H), 2,49 (m, 4H), of 2.07 (m, 4H), 1,80 m, 1H), the 1.54 (m, 2H).

211

1-(acetyl)piperazine-4-yl

R

2

fluorine

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,20 (., 1H), and 6.87 (1H), 6,68 (d, J=8.0 Hz, 1H), 6,27 (d, J=12.0 Hz, 1H), 4,76 (m, 1H), and 4.01 (m, 3H), 3,61 (m, 4H), 3,30 m, 2H), 3,20 m, 1H), 2,51 (m, 2H), 2,33 (m, 4H), from 2.06 (m, 7H), 1,99 (m, 1H), 1,49 (m, 2H).

212

1,1-dioxo--4-yl

R

2

fluorine

THP-4-yl

(400 MHz, CDCl 3 ); δ 6,93 (1H), 6,64 (d, J=8.0 Hz, 1H), 6,28 (d, J=12.0 Hz, 1H), 4,68 (m, 1H), 4,03 (m, 2H), 3,55 (m, 3H), 3,26 (m, 2H), 3,17 (m, 3H), 3,05 (m, 4H), 2,95 m, 1H), 2,82 (m, 1H), 2,09 (m, 4H), 1,82 m, 1H), 1,65 m, 2H).

213

R

2

fluorine

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,15 (., 1H), 6,86 (1H), 6,65 (DD, 1H), of 6.26 (DD, 1H), 4,77 (m, 1H), 4,05 (m, 1H), 3,56 (m, 4H), 3,36 (m, 1H), 3,24 (m, 2H), 3,12 (m, 1H), 2,91 (C, 3H), 2,32 (m, 1H), 2,22 (m, 1H), 2,13 (m, 1H), 2,02 (m, 1H), the 1.54 (m, 2H).

214

2--4-yl

R

2

fluorine

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,07 (., 1H), 7,70 (., 1H), 6,83 (1H), 6,61 (d, J=8.0 Hz, 1H), 6,22 (d, J=12.0 Hz, 1H), 5,19 (m, 1H), 4,71 (m, 1H), 4,05 (d, J=12.0 Hz, 2H), 3,55 (m, 4H), 3,33 m, 3H), 3,14 (m, 1H), 2,73 (m, 4H), 2,10 m 2H), 1,98 (m, 2H), was 1.58 (m, 4H).

215

1-()piperazine-4-yl

R

2

fluorine

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,19 (., 1H), 6,89 (1H), 6,65 (d, J=8.0 Hz, 1H), 6,23 (d, J=12.0 Hz, 1H), 4,82 (m, 1H), 4,20 m, 1H), 4,18 (C, 2H), 3,98 (m, 2H), 3,61 (m, 2H), 3,47 (m, 4H)at 3.16 (m, 3H), 2,42 (m, 3H), 2,17 (m, 5H), 1,90 m, 2H), of 1.40 (m, 2H).

216

Dimethylamino

R

2

H

c-Pen

(500 MHz, DMSO-d 6 ); δ to 10.62 (., 1H), 7.03 is (d, J=7,95 Hz, 1H), 6,99 (t, 1H), 6,93 (1H), 6,48 (d, J=7,35 Hz, 1H), 4,83 (m, 1H), 3,83 (m, 1H), 3,56 (m, 1H), of 3.46 (m, 2H), 3,20 m, 4H), 2,05~1,87 (m, 4H), 1,70~1,38 (m, 6H).

217

piperidine-1-yl

R

2

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,34 (., 1H), 7,04 (d, 1H), 6,99 (t, 1H), 6,49 (d, 1H), 4,72 (m, 1H), 3,86 (m, 1H), 3,51 (m, 1H), 3,15 (m, 1H), 2,30~2,00 m, 8H), 2,69~of 1.40 (m, 14H)

218

R

2

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,02 (., 1H), 7,08 (d, 1H), 7,00 (t, 1H), to 6.95 (c, 1H), 6,54 (d, 1H), 4,78 (m, 1H), and 4.01 (m, 2H), 3,61-3,47 (m, 4H), 3,33 m, 1H), 3,15 (m, 2H), 2,85 (c, 3H), of 2.25 m, 2H), of 2.05 (m, 2H)and 1.51 (m, 2H).

219

1-()piperazine-4-yl

R

2

methoxy

c-Pen

(400 MHz, CDCl 3 ); δ 11,13 (., 1H), 6,98 (c, 1H), 6.42 per (c, 1H), 6,13 (d, 1H), 4,85 (m, 1H), of 4.07 (c, 2H), 3,81 (m, 8H), 3,55 (m, 2H), 3,39 (m, 1H), 3,13 (m, 1H), 2,96 (m, 1H), 2,90 (m, 1H), 2,35 (m, 3H), 2,10 m 2H), 1,99 (m, 3H), 1,84 (m, 1H), 1.75 in (m, 1H), 1,62 (m, 4H), 1.44MB (m, 1H), 1,35 (m, 1H).

220

1-(acetyl)piperazine-4-yl

R

3

chlorine

c-Pen

(400 MHz, CDCl 3 ); δ 10,33 (., 1H), 6,97 (1H), 6,81 (c, 1H), 6.42 per (c, 1H), to 4.64 (m, 1H), 3,85 (m, 1H), 3,65 m 2H), 3,56 (m, 1H), 3,45 (m, 2H), 3,13 (m, 1H), 2,43 (m, 6H), 2,04 (m, 2H), 1,72 (m, 8H), the 1.54 (m, 2H).

221

morpholine-4-yl

R

1

H

c-Pen

(400 MHz, DMSO-d 6 ); δ 11,37 (., 1H), 6,83 (m, 1H), a 6.75 (m, 1H), 6,29 (d, J=8.0 Hz, 1H), 5,85 (d, J=8.0 Hz, 1H), 4,87 (m, 1H), 3,87 (m, 1H), 3,61 (m, 4H), 3,35 (m, 3H), 2,71 (m, 1H), 2,54 (m, 2H), 2,44 (m, 2H), 1,99 (m, 2H), 1,74 (m, 6H), 1,59 (m, 4H).

222

morpholine-4-yl

R

3

chlorine

c-Pen

(400 MHz, CDCl 3 ); δ 11,07 (., 1H), 6,90 (c, 1H), 6,74 (c, 1H), 6,36 (c, 1H), 4,61 (m, 1H), 3.94 in (m, 4H), 3,55 (m, 1H), 3,04 (m, 3H), 2,04 (m, 7H), 1,71 (m, 3H), 1,61 (m, 4H), 1,26 (m, 3H).

223

Dimethylamino

R

1

H

c-Pen

(400 MHz, CDCl 3 ); δ 9,87 (, 1H), 7,05 (d, J=8.0 Hz, 1H), 6,99 (t, 1H), 6,89 (c, 1H), 6,52 (d, J=8.0 Hz, 1H), 4,83 (m, 1H), 3,91 (m, 1H), 3,50 (t, 1H), 3,29 (t, 1H), 2,63 m, 1H), 2,44 (m, 1H), to 2.29 (6H), 2,04 (m, 2H), 1,70 m, 2H), 1,50 m, 4H).

224

morpholine-4-yl

R

2

chlorine

c-Pen

(DMSO-D6 , ppm); δ 11,46 (1H, c), 6,79 (1H, c), 6,68 (1H, c), 6,11 (1H, c), 6,09 (1H, d), 4,61 (1H, Queen), 3,81 (1H, m), 3,57(4H, m)and 3.15 (1H, m), 2,50-2,43(3H, m), 2,35(4H, m), 1,95 (2H, m), 1,80 (1H, m), 1,68 (2H, m), 1,57-1,49(4H, m), 1,21 (1H, m).

Example 225

{5-methyl-2-[(R)-4-(2-morpholine-4-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-(-4-yl)amine

2-[(R)-2-(5-methyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid, resulting in the example 104, -4-one and morpholine consistently introduced in reaction according to the same procedures as in example 1 on the stage As an example of obtaining 29 and in the example 156, receiving the target connection.

1 H NMR (400 MHz, CDCl 3 ); δ 10,11 (., 1H), 6,91 (c, 1H), 6,86 (c, 1H), 6,34 (c, 1H), 4,60 (t, 1H), 4,48 (m, 1H), 4,10~3,93 (m, 5H), 3,63~3,52 (m, 3H), 2,39 (c, 3H), of 2.07 (d, 2H), 1,94 (m, 2H), was 1.58 (m, 2H).

Example 226

{5-methyl-2-[(S)-4-(2-morpholine-4-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-(tetrahydro-PYRAN-4-)amine

Phase A: isopropyl ether ((S)-2-{5-methyl-7-[(tetrahydro-PYRAN-4-)amino]-1H-indole-2-yl}-4,5-dihydro--4-yl) - acetic acid

Isopropyl ether [(5-methyl-7-nitro-1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid, resulting in the example of getting 52, and -4- injected into the reaction according to the same procedure as in example 1, getting the target connection.

Stage B: 2-(R)-2-{5-methyl-7-[(tetrahydro-PYRAN-4-)amino]-1H-indole-2-yl}-4,5-dihydro--4-yl)ethanol

Isopropyl ether ((S)-2-{5-methyl-7-[(tetrahydro-PYRAN-4-)amino]-1H-indole-2-yl}-4,5-dihydro--4-yl) - acetic acid, obtained for A stage, introduced in reaction according to the same procedure as in example 5, receiving the target connection.

Stage C: {5-methyl-2-[(S)-4-(2-morpholine-4-)-4,5-dihydro--2-yl]-1H-indol-7-yl}-(tetrahydro-PYRAN-4-)amine

2-(R)-2-{5-methyl-7-[(tetrahydro-PYRAN-4-)amino]-1H-indole-2-yl}-4,5-dihydro--4-yl)ethanol at stage B, and morpholine was injected into the reaction according to the same procedure as in the example 156, receiving the target connection.

1 H NMR (500 MHz, CDCl 3 ); δ 11,13 (c, 1H), PC 6.82 (d, 2H), 6,24 (c, 1H), 4,81-4,78 (m, 1H), 3,88-3,81 (m, 2H), 3,60-of 3.46 (m, 5H), 3,35-3,30 m, 2H), 3,19-3,17 (m, 1H), 3,01 (, 2H), 2,38-2,26 (m, 7H), 2,14 (c, 2H), 1,91-1,88 (m, 1H), a 1.75-1,71 (m, 2H), 1,53~1,47 (m, 2H), 1,28-1,16 (m, 2H).

Examples 227-257

Connection of the examples 10, 22, 51, 66 and 82 were introduced into the reaction according to the same procedure as in the example 226, or the connection of the examples of receipt of 52 and 71 and commercially available aldehydes or ketones and amines selectively introduced in reaction according to the same procedure as in the example of 226 to synthesize compounds of the examples shown in the following table.

Example

R

1

*

n

R

2

R

3

R

4

1 H NMR data

227

1-(acetyl)piperazine-4-yl

S

2

phenoxy

isobutyl

isobutyl

(400 MHz, CDCl 3 ); δ 9,56 (1H, .), 7,30-7,24 (2H, m), 7,04-7,00 (1H, m), 6,96-6,94 (3H, m), 6,84 (1H, d, J=2,4 Hz), 6,63 (1H, d, J=2.0 Hz), 4,79-4,72 (1H, m), 3,64-3,52 (3H m), a 3.45-3,34 (2H, m), 3,17-3,00 (5H, m), 2,64-2,52 (2H, m), 2,44 to 2.35 (1H, m), 2,08 (1H, c), 2.06 to 1,99 (1H, m), 1,91-1,82 (1H, m), 1,50 1,40 in (2H, m), 1,38-1,26 (4H, m), 0,82-0,79 (12H, m).

228

pyrrolidine-1-Il

S

2

phenoxy

isobutyl

isobutyl

(400 MHz, CDCl 3 ); δ of 9.24 (1H, .), 7,31-7,27 (2H, m), 7,05-7,02 (1H, m), 6,97-6,95 (3H, m), 6,86 (1H, d, J=2.0 Hz), 6,68 (1H, d, J=2.0 Hz), 4,77-4,70 (1H, m), 3,63-3,58 (1H, m), 3,41 at 3.28 (6H, m), 3,19-3,05 (5H, m), 2,52-2,46 (1H, m), and 2.26-2,20 (1H, m), 2,16-2,13 (4H, m), 1,56 of 1.46 (2H, m), 1,38-1,33 (4H, m), 0,85-0,83 (12H, m).

229

1-()-piperazine-4-yl

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,7 (1H, .), 7,30-7,27 (2H, m), 7,04-6,97 (3H, m), 6,86 (1H, c), of 6.62 (1H, d, J=2.0 Hz), 6,28 (1H, d, J=2.5 Hz), 4,87-4,80 (1H, m), 3,80 of 3.75 (1H, m)and 3.59-3,55 (2H, m), 3,49-3,45 (1H, m), 3,18-3,08 (2H, m), 3,03-3,01 (1H, m), 2,47-2,38 (3H, m), 2,24-2,14 (3H, m), 2,05-1,88 (4H, m), 1,84-1,55 (8H, m), 1,49 to 1.39 (2H, m).

230

piperazine-1-Il

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 7,40 of 7.36 (4H, m), 7,16-7,12 (1H, m), 7,04-7,02 (2H, m), 6,94 (1H, s), 4,20-4,15 (1H, m), 3,99-3.94 in (1H, m), 3,91-3,80 (5H, m), 3,75-3,63 (6H, m), to 3.58-3,48 (1H, m), 2,44-2,40 (2H, m), 2,09-2,07 (2H, m), 1,91-1,89 (4H, m), 1,71 to 1.69 (2H, m).

231

1-BOC-piperazine-4-yl

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,7 (1H, c), 7,30-7,26 (2H, m), 7.03 is-6,98 (3H, m), 6,85 (1H, c), of 6.62 (1H, d, J=2.0 Hz), of 6.26 (1H, d, J=2,4 Hz), 4,82-4,77 (1H, m), a 3.87 (1H, .), 3,78-3,74 (1H, m)and 3.59-3,54 (1H, m), 3,31 (4H, .), 3,19-3,14 (1H, m), 2,48 to 2.35 (2H, m), a 2.26 (1H, .), 2,17 (1H, .), 2,03-1,91 (4H, m), 1,84-1,75 (1H, m), 1,67-1,53 (4H, m), 1,45 (9H, c), of 1.42-1,35 (1H, m).

232

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,9 (1H, .), 7,32-7,28 (2H, m), 7,05-6,99 (3H, m), 6,90 (1H, s), 6,59 (1H, d, J=1.6 Hz), 6,29 (1H, d, J=2.0 Hz), 4,77-4,74 (1H, m), of 4.06-3,99 (1H, m), 3.95 to 3,82 (4H, m), 3,62 is 3.57 (1H, m), 3,18-3,14 (1H, m), 2,87-2,80 (3H, m), 2,77-2,74 (1H, m), 2.00 in 1,98 (4H, m), 1,69 (2H, .), 1,60-1,56 (6H, m).

233

2--4-yl

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,7 (1H, .), 7,30-7,26 (2H, m), 7.03 is-7,00 (3H, m), PC 6.82 (1H, s), 6,60 (1H, d, J=2.0 Hz), 3,25 (1H, d, J=2.0 Hz), 4,74-4,71 (2H, m), 3,83 (1H, .), 3,56-3,52 (1H, m), 3,50-3,26 (2H, m), 3,20-3,10 (2H, m), 2,68-2,61 (4H, m), 2,01-1,86 (4H, m), 1,73-1,58 (8H, m).

234

1-[(tetrahydrofuran-2-yl)carbonyl]piperazine-4-yl

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,67-of 10.58 (1H, m), 7,30-7,27 (2H, m), 7,04-6,98 (m, 3H), 6,85 (1H, d, J=1,2 Hz), 6,62 (1H, d, J=2.0 Hz), 6,27 (1H, .), 4,84-4,78 (1H, m), 4,58-4,54 (m, 1H), 3,96-3,91 (1H, m), a 3.87-3,71 (3H, m)and 3.59-3,42 (3H, m), 3,19-3,14 (1H, m), 2,47-2,37 (2H, m), 2,33-2,16 (4H, m), 2,07-1,87 (6H, m)and 1.83-1,75 (4H, m), 1,68 was 1.56 (1H, m), 1,49-1,40 (2H, m).

235

1-(pyridine-2-yl)piperazine-4-yl

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,3 (1H, s), 8,19-8,18 (1H, m), 7,49-7,45 (1H, m), 7,29-7,25 (2H, m), 7.03 is-6,98 (3H, m), 6,85 (1H, s), 6,64-6,60 (3H, m), 6,28 (1H, d, J=2,4 Hz), 4,82-4,78 (1H, m), with 3.79 (1H, .), 3,60-3,55 (1H, m), 3,49-3,45 (4H, m), 3,21-3,17 (1H, m), 2,55-2,41 (6H, m), 1,99 (3H, .), 1,88 is 1.86 (1H, m), 1,70 (3H, .), 1,61 to 1.47 (3H m).

236

1-(2-fluorophenyl)piperazine-4-yl

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,7 (1H, s), 7,29-7,25 (2H, m), 7,07-6,98 (5H, m), 6,95-6,88 (2H, m), 6,86 (1H, s), 6,23 (1H, d, J=1,6 Hz), 6,28 (1H, d, J=1.6 Hz), 4,88-4,81 (1H, m), 3,89 (1H, .), 3,60 of 3.56 (1H, m), 3,23-3,18 (1H, m), 2,99 (4H, .), 2,54-2,43 (5H, m), 2,04-1,94 (3H, m), 1,98-1,82 (2H, m), 1,68 to 1.37 (6H, m).

237

2--4-yl

S

2

H

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,23 (., 1H), 7,00 (m, 2H), 6,89 (1H), 6,48 (1H), 4,72 (m, 1H), 3,92 (m, 1H), 3,54 (m, 1H), 3,38-3,11 (m, 5H), 2,73-2,58 (m, 4H), 2,11 is 1.96 (m, 4H), 1,74-1,55 (m, 6).

238

(3S)-3-(amino)pyrrolidine-1-Il

S

2

phenoxy

H

c-Pen

(400 Hz, CDCl 3 ); δ 9,97 (., 1H), 7,32 (m, 1H), 7,01-6,95 (m, 6H), 6,93 (m, 3H), 6,69 (c, 1H), 6,34 (m, 1H), 4,83 (m, 1H), 3,85 (m, 1H), 3,62 (DD, 1H), 3,24 (DD, 1H), 3,10 m, 4H), 2,58 (m, 6H), of 2.05 (m, 3H), 1,92 (m, 1H), 1,70 m, 6H), 1,53 (m, 2H).

239

1-(acetyl)piperazine-4-yl

S

2

phenoxy

H

c-Pen

(400 MHz, CDCl 3 ); δ 10,6 (1H, s), 7,31-7,27 (2H, m), 7,04-6,98 (3H, m), 6,84 (1H, s), 6,60 (1H, d, J=2.0 Hz), 6,27 (1H, d, J=1.6 Hz), 4,77-4,72 (1H, m), 4,30 (1H, .), 3,81 (1H, .), 3,74 (1H, .), 3,64-3,55 (2H, m), 3,41 (1H, .), 3,17-3,10 (2H, m), 2,89 (1H, .), 2,68-2,63 (3H, m), 2,56-2,48 (2H, m), from 2.06 (3H, C), 2,03-1,90 (4H, m)1,72 (2H, .), 1,60-1,56 (4H, m).

240

(2R)-2-()pyrrolidine-1-Il

S

2

methyl

H

(THP-4-yl)methyl

(CDCl 3 , 400 MHz) δ 11,31 (1H), 8,18 (, 1H), 7,24 (d, 1H), 6,83 (1H), a 6.75 (1H), 6,22 (1H), 5,50 (, 1H), 4,71 with 4.64 (m, 1H), 4,07-3,99 (m, 2H), 3,57-3,38 (m, 3H), 3,28-3,25 m, 1H), 3,19-3,06 (m, 4H), 2,88-2,81 (m, 1H), the 2.75-2,70 m, 1H), 2,49-2,41 (m, 1H), 2,39 (C, 3H) 2,25 of 2.12 (m, 1H), 2,08-2,04 (m, 1H), 1,99-1,95 (m, 2H)and 1.83-1,80 m, 4H), 1,53-1,40 m 2H).

241

(2R)-2-(hydroxymethyl)pyrrolidine-1-Il

S

2

methyl

H

(THP-4-yl)methyl

(CDCl 3 , 400 MHz) δ of 10.25 (1H), 6,76 (1H), 6,74 (1H), 6,23 (1H), 4,67-4,58 m 2H), 4,16-of 4.09 (m, 1H), 4,00-3.94 in (m, 2H), the 3.73-3,68 (m, 1H), 3,50-3,36 (m, 2H), 3,11 (d, 2H), 2,99-2,94 (m, 2H), 2,32 (C, 3H), 2,15-2,07 (m, 2H), 2,02-1,92 (m, 3H), 1,76-1,73 m 2H), 1,42-1,36 (m, 2H), 1,14-1,08 (m, 2H)of 0.86-0,81 (m, 2H), 0,73-0,68 (m, 2H).

242

(3R)-3-(acetylamino)pyrrolidine-1-Il

S

2

phenoxy

H

c-Pen

(500 Hz, CDCl 3 ); δ 11,45 (., 1H), 8,14 (., 1H), 6,90 (1H), 6,77 (1H), 6,37 (1H), 4,83 (m, 1H), 4,66 (m, 1H), 4,05 (m, 1H), 3,91 (m, 1H), 3,77 (m, 1H), 3,62-3,52 (m, 2H), 3,13 (m, 1H), 3,08-3,00 (m, 2H), 2,84 (m, 1H), 2,43 (m, 1H), 2,23 (m, 1H), of 2.05 (m, 4H), from 2.00 (C, 3H), 1,80 m 2H), 1,71 (m, 2H), 1,63 (m, 2H).

243

4-(benzyl)piperazine-1-Il

S

2

phenoxy

H

c-Pen

(500 Hz, CDCl 3 ); δ 7,32-7,24 (m, 7H), 7,01 (m, 3H), 6,77 (c, 1H), 6,59 (c, 1H), 6,29 (c, 1H), 4,71 (m, 1H), 3,87 (m, 1H), 3,56 (DD, 1H), 3,50 (c, 2H), 3,08 (DD, 1H), 2,80 (., 8H), 2,60 (., 2H), 2,11 of 1.99 (m, 4H), 1,80 m 2H), 1,71 (m, 2H), 1,61 (m, 2H).

244

S

2

methyl

H

(THP-4-yl)methyl

(400 MHz, CDCl 3 ); δ 10,08 (1H), PC 6.82 (1H), 6,80 (1H), 6,29 (1H), 4,66 (1H), 4,10-3,90 (m, 6H), 3,52 (DD, 1H), 3,40 (m, 2H), 3,10 m, 2H), 2,39 (C, 3H), 2,10-1,95 (m, 3H), 2,95-2,85 m 2H), 2,72 (d, 2H), 1,42-1,30 m 2H), 1,25 (kV, 6H).

245

morpholine-4-yl

S

2

methyl

H

(THP-4-yl)methyl

(500 MHz, CDCl 3 ); δ 11,13 (c, 1H), 6,84 (c, 1H), 6,81 (c, 1H), 6,24 (c, 1H), 4,81-4,78 (m, 1H), 3,87 (d, 2H), 3,60-of 3.46 (m, 5H), 3,35-3,30 m, 2H), 3,19-3,17 (m, 1H), 3,01 (, 2H), 2,38-2,36 (m, 7H), 2,14 (, 2H), 1,91-1,88 (m, 1H), a 1.75-1,71 (m, 2H), 1,28-1,21 (m, 2H).

246

pyrrolidine-1-Il

R

2

phenoxy

H

c-Pen

(500 MHz, CDCl 3 ); δ 7,26-7,23 (2H, m), 6,98-6,95 (1H, m), 6,91-6,90 (2H, m), 6,74 (1H, c), of 6.46-6,45 (1H, m), 6,12 (1H, .), 4,60-4,58 (1H, m), 3,82-3,80 (2H, m), 3,60-3,50 (2H, m), 3,33 at 3.28 (5H, m), 3,14-3,10 (1H, m), 2,14-2,03 (6H, m), 2.00 in 1,94 (2H, m), 1,78 (2H, .), 1,66-1,60 (4H, m).

247

morpholine-4-yl

S

2

phenoxy

H

(THP-4-yl)methyl

(400 MHz, CDCl 3 ); δ 10,19 (., 1H), 7,29 (m, 2H), 7,01 (m, 3H), 6,84 (d, 1H), 6,65 (d, 1H), 6,27 (d, 1H), 4,77 (m, 1H), 3,93 (m, 2H), 3,83 (m, 1H), 3,63-3,55 (m, 6H), 3,35 (m, 6H), 3,19 (m, 1H), 3,04 m 2H), 2,46 (m, 2H), 2,34 (m, 4H)2,00 m, 1H), 1,83 m 2H), 1,60 m 2H), 1,30 (m, 2H).

248

2--4-yl

S

2

phenoxy

H

(THP-4-yl)methyl

(400 MHz, CDCl 3 ); δ 10,7 (., 1H), 7,28 (m, 2H), 7,00 (m, 3H), 6,85 (., 1H), 6,81 (d, 1H), 6,60 (d, J=1.6 Hz, 1H), 6,20 (d, J=2.0 Hz, 1H), of 5.03 (m, 1H), 4,70 (m, 1H), 3,98 (m, 2H), 3,56 (m, 1H), 3,49-3,36 (m, 6H)and 3.15-3,06 (m, 4H), 2,80 m, 1H), 2,71 (m, 3H), 1,95-1,91 (m, 3H), 1,72 (m, 2H), 1,42 (m, 2H).

253

2--4-yl

S

2

methyl

H

(THP-4-yl)methyl

(500 MHz, CDCl 3 ); δ 11,03 (c, 1H), 8,19 (., 1H), PC 6.82 (c, 1H), 6,79 (c, 1H), 6,31 (c, 1H), 4,84-4,65 m, 3H), 4,24 (m, 1H), 3,91 (m, 2H), 3,82-3,55 (m, 4H), 3,31 (m, 2H), 3,19 (m, 1H), 3,14 (m, 2H), 2,95 m, 2H), 2,69 (m, 1H), 2,20 m, 1H), 1,98 (m, 1H), is 1.81 (d, 2H), 1,39 (m, 2H).

254

1-(pyridin-2-yl)piperazine-4-yl

S

2

chlorine

H

THP-4-yl

(400 MHz, CDCl 3 ); δ UAH 9.71 (., 1H), 8,17 (c, 1H), 7,47 (m, 1H), 7.03 is (c, 1H), PC 6.82 (c, 1H), 6,62 (m, 1H), 6,45 (c, 1H), 4,73 (m, 1H), and 4.01 (m, 2H), 3,61-3,49 (m, 8H), 3,20 m, 1H), 2,69-2,50 (m, 6H), 2,11 is 2.01 (m, 3H), 1,92 (m, 1H), 1,52 (m, 2H).

255

1-[(tetrahydrofuran-2-yl)carbonyl]piperazine-4-yl

S

2

chlorine

H

THP-4-yl

(400 MHz, CDCl 3 ); δ of 9.89 (,c, 1H), 7,02 (c, 1H), PC 6.82 (c, 1H), 6,45 (c, 1H), 4,73 (m, 1H), 4,57 (m, 1H), and 4.01 (m, 2H), 3.94 in (m, 1H), 3,85 (m, 1H), 3,78-3,49 (m, 8H)and 3.15 (m, 2H), 2,64-2,21 (m, 7H), 2,11-1,81 (m, 7H), 1,48 (m, 1H).

256

2--4-yl

R

2

methoxy

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 10,75 (., 1H), 7,02 (., 1H), 6,83 (c, 1H), 6,41 (c, 1H), 6,14 (c, 1H), 4,70 (m, 1H), and 4.01 (d, J=12 Hz, 2H), to 3.58 (c, 3H), 3,54 (m, 4H), 3,11~3,36 (m, 5H), 2,66 (m, 4H), 2,12 (m, 2H), 1,97 (m, 1H), a 1.88 (m, 1H), 1,56 (m, 2H).

257

1-()-piperazine-4-yl

R

2

methoxy

H

THP-4-yl

(400 MHz, CDCl 3 ); δ 11,13 (., 1H), 6,91 (1H), 6,47 (1H), 6,17 (1H), 4,86 (m, 1H), 4,13 (m, 2H), 3,97 (m, 3H), 3,84 (m, 3H), 3,62 (m, 2H), 3,47 (m, 4H), to 3.03 (m, 3H), 2,43 (m, 3H), 2,17 (m, 5H), 1,98 (m, 3H), 1.44MB (m, 2H).

Example 258

[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]-methanol

2-[7--2-(R)-4-hydroxymethyl-4,5-dihydro--2-yl)-1H-indole-5-]-1,3-dione (27 mg, of 0.07 mmol), resulting in the example, 64, was dissolved in ethanol (3 ml). Added hydrazine hydrate (0.6 ml, 0.11 mmol)and the mixture was stirred for 3 hours at 80 degrees C. After the reaction, the reaction mixture was distilled at low pressure and purified chromatography columns on getting the target connection (7 mg, exit 37%).

1 H-NMR (500 MHz, CDCl 3 ); δ 10,50 (., 1H), 6,98 (1H), 6,88 (1H), of 6.46 (1H), 4,72 (m, 1H), 4,40 (m, 1H), 3,86 (C, 2H), 3,81 (m, 1H), 3,70 (m, 1H), 3,44 (m, 2H), 1,97 (m, 2H), 1,59 (m, 4H), 1,41 (m, 2H).

Example 259

[7--2-(R)-4-hydroxymethyl-4,5-dihydro--2-yl)-1H-indole-5-]amide furan-2-carboxylic acid

[(R)-2-(5--7--1H-indole-2-yl)-4,5-dihydro--4-yl]-methanol, resulting in the example 258 and furan-2-carboxylic acid was injected into the reaction according to the same procedure as at the stage of the B sample receipt 101, receiving the target connection.

1 H-NMR (CDCl 3 ); δ 11,01 (1H, ), 7,38 (1H, s), 7,12 (1H, d, J=3,7 Hz), 7.03 is (1H, s), 6,90 (1H, s), 6,58 (1H, ), 6,49~6,45 (2H, m), 4,76~4,67 (1H, m), 4,60 (2H, d, J=Hz 5,5), 4,06~4,01 (1H, m), 3,80~of 3.73 (1H, m), 3,70~3,64 (1H, m), 3,52~of 3.46 (1H, m), 3,45~3,38 (1H, m), 1,99~1,86 (2H, m), 1,62~1,46 (4H, m), 1,41~1,32 (1H, m), 1,32~1,24 (1H, m).

Example 260

Methyl [(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-]acetic acid

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro-1,3--4-yl]-methanol obtained in example 2, and injected into the reaction according to the same procedure as at the stage of the B sample receipt 29, receiving the target connection.

1 H-NMR (400 MHz, CDCl 3 ); δ 10,16 (., 1H), and 6.87 (c, 1H), 6,66 (DD, J=2,4, 9.2 Hz, 1H), 6,30 (DD, J=2,4, 11,8 Hz, 1H), 4,94 (m, 1H), 4,25 (kV, 2H), 4,13 (d, J=5,6 Hz, 2H), 3,87 (m, 1H), 3,76 (d, J=6,4 Hz, 2H), 3,56 (m, 1H), 3,44 (m, 1H), of 2.07 (m, 2H), 1,67 (m, 4H)and 1.51 (m, 2H), 1,30 (t, 3H).

Example 261

[(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-]acetic acid

Methyl [(R)-2-(7--1H-indole-2-yl)-4,5-dihydro--4-]acetic acid, resulting in the example 260, introduced in reaction according to the same procedure as on the stage As an example of obtaining 101, receiving the target connection.

1 H-NMR (400 MHz, DMSO-d 6 ); δ of 12.70 (., 1H), 7,07 (1H), 6,57 (d, J=8,8 Hz, 1H), 6,23 (d, J=12 Hz, 1H), 5,13 (m, 1H), 4,34 (m, 1H), 4,07 (m, 2H), 3,89 (m, 1H), 3,63 (m, 3H), up 2.03 (m, 2H), was 1.58 (m, 6H).

Example 262

-{2-[(R)-4-(3--[1,2,4]oxidiazol-5-)-4,5-dihydro--2-yl]-1H-indol-7-yl}Amin

[(7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid (140 mg, 0,41 mmol)received example, 75, was dissolved in N,N-dimethylformamide (5 ml). Added 1,1'- (73 mg, 0,45 mmol)and the mixture was stirred for 30 minutes at room temperature. Added N-hydroxy- (260 mg, 2,03 mmol)and the mixture was stirred for 5 hours at 80 degrees C. Once the reaction is added to the water. The reaction mixture is extracted , dried over anhydrous magnesium sulfate and filtered. The filtrate were driven under reduced pressure, and the residue was purified chromatography columns on getting the target connection (100 mg, exit 56%).

1 H-NMR (400 MHz, CDCl 3 ); δ to 10.62 (., 1H), 7,04 (d, 1H), 6,97 (t, 1H), 6,92 (d, 1H), 6,49 (d, 1H), 5,20 (m, 1H), 3,83 (m, 2H), 3,64 (m, 1H), 3,39 (m, 1H), 3,31 (m, 1H), 3,17 (m, 1H), 3,01 (m, 1H), 1,97 (m, 4H), 1,73 (m, 4H), 1,60 m, 6H), 1,46 (m, 2H), to 1.34 (m, 2H).

Example 263

-{2-[(R)-4-(3-piperidine-1-yl-[1,2,4]oxidiazol-5-)-4,5-dihydro--2-yl]-1H-indol-7-yl}Amin

[(7--1H-indole-2-yl)-4,5-dihydro--4-yl]acetic acid, resulting in the example 75, and N- injected into the reaction according to the same procedure as in the example 262, receiving the target connection.

1 H-NMR (400 MHz, CDCl 3 ); δ 10,56 (., 1H), 7,01 (d, 1H), 6,96 (t, 1H), 6,90 (d, 1H), of 6.46 (d, 1H), 5,23 (m, 1H), 3,83 (m, 2H), 3,64 (m, 1H), 3,36 (m, 1H), 3,31 (m, 1H), 3,17 (m, 2H), 3,01 (m, 1H), 1,95 m, 2H), 1,68-1,43 (m, 11H), 1,35 (m, 1H).

Experimental example 1. Measurement and analysis of connections of the examples for the effect of the protection of hepatocytes against the toxicity of hepatocytes, caused by the substances.

Various endogenous/exogenous attack on the cells of the trigger mechanisms of cell death, which are usually divided into two types, i.e. apoptosis or necrosis. Using these mechanisms of cell death, and in this pilot example, primary hepatocytes, obtained from rats treated with drugs that have been clinically shown to lead to serious side effects for toxicity for hepatocytes, or by different chemical compounds that lead to cell death, and compounds synthesized in the Examples evaluated on their protective effects against hepatocytes after 24-48 hours. Substances used to cause the death of hepatocytes, include CCl 4 , ActD, H 2 O 2 , doxorubicin, anti-Fas Ab/Actinomycin D, acetaminophen, EtOH, CdCl 2 , palmitate, stearate, cyclophosphamide, terfenadine, , simvastatin and adefovir. Primary hepatocytes allocated using the method Seglen PO (Experimental Cell Research 74(1972) pp.450-454). Briefly, hepatocytes allocated according to a two-step method perfusion collagenase, and dead cells are removed, low-speed centrifugation (500 rpm) for 10 minutes, using a gradient (Kreamer B.L. etc, In Vitro Cellular & Developmental Biology 22(1986) pp.201-211). During this phase, the viability of cells was maintained at a level of 90 percent or higher. Cells suspended in a medium HepatoZYME (Gibco BRL), and counted the number of cells. 1.5 x 10 4 cells in 100 ml placed in covered collagen 96-well plate (BD biocoat), and leave for 3-4 hours for their adhesion to the bottom.

To evaluate the protective effect against hepatocytes, the above adhesive cells pre-processed within 30 min connections according to sample. At this time, the concentration of compounds of the examples consistently diluted in 2 or 3 times in 5 stages, starting with 30 microns 10 microns or 1 microns depending on the experiment, and final concentration DMSO have established equal to 0.2%. 30 minutes after handling compounds cells were processed substances, causing the death of hepatocytes, or gepatotoksicnami drugs in concentrations shown in table 1. In 24-48 hours determined the viability of cells for evaluation of the protective effects against hepatocytes. Cell viability was determined using the method WST-1 (MK-400, Takeda) on the basis of light absorption at 440 nm. Protective effects of compounds in accordance with the Examples in respect of hepatocytes presented as “EC 50 ”, which is calculated based on the measured values. “EC 50 ” here means the concentration of compounds in which the experiment was observed 50% of the maximum protective effect.

Preferably, EC 50 connections according to sample is 30 microns or less, preferably, to 10 microns or less, and especially preferably 1.0 microns or less.

Table 1 shows the concentration of various chemicals used, causing hepatotoxicity, and the protective effect connections from example 4 in respect of hepatocytes. Table 2 shows the protective effects of compounds in accordance with the examples in respect of hepatocytes against doxorubicin as a substance that causes hepatotoxicity.

Table 1

Protective effect connections from example 4 in the cells against substances, cause hepatotoxicity

Chemicals that are toxic to hepatocytes

Concentration for processing

EC

50

(microns)

An explanation for substances with toxic for hepatocytes

Terfenadine

10 microns

0,4

Anti-allergic agent

Simvastatin

16 microns

<10 microns

A means of lowering the level of lipids

Diclofenac

350 mm

40% viability at 3-100 microns

Non-steroidal anti-inflammatory drug (NSAID)

Adefovir

100 microns

50% viability at 3-30 microns

Antiviral agent

Table 2

Protective effects against hepatocytes against doxorubicin

Example

EC

50

, micron

Example

EC

50

, micron

Example

EC

50

, micron

Example

EC

50

, micron

1

>1

38

2,0

109

0,61

229

0,25

2

0,1

40

15,58

115

<1

230

>0,32

4

0,3

43

1 of 10

117

<0,5

231

0,2

6

4,93

45

1,32

118

0,41

232

0,24

7

1,17

46

0,4

119

0,17

233

0,27

8

0,41

47

0,36

120

1,12

234

0,09

9

>2

48

0,2

121

0,47

235

>0,54

10

0,6

50

0,25

122

0,96

236

0,16

11

2,8

51

0,6

127

1,18

237

0,2

12

3,25

52

0,75

128

0,2

238

0,33

13

1,13

61

0,78

130

0,1

239

0,83

14

0,19

62

3,77

133

0,31

240

0,28

15

0,6

64

0,54

134

0,51

241

0,21

16

1,29

67

>1

135

1,26

244

0,195

17

V 0.315

68

0,49

158

0,91

246

0,35

18

2,42

71

1,1

173

1,98

247

0,86

19

0,35

78

29,44

176

>1

249

0,11

20

5,77

83

0,6

177

>1

250

0,09

21

0,3

84

1,6

178

0,23

251

0,3

22

0,25

85

0,4

182

0,375

252

0,51

23

0,14

88

1,87

184

0,18

253

0,2

24

0,13

90

7,92

193

0,65

254

1,0

25

0,76

93

0,55

201

0,33

257

<0,4

26

0,2

94

28,14

205

0,34

32

2,12

97

4,1

218

0,26

33

4,04

101

1 of 10

222

0,18

34

5,58

108

<0,5

228

0,13

Experimental sample 2: protective effects when processing hepatocytes and other cells obtained from various tissues, tBHP (tert-; t-BuOOH)

1) Protective effect in processing of primary hepatocytes tBHP

Preferably, EC 50 connections according to sample is 30 microns or less, preferably, to 10 microns or less, and especially preferably 1.0 microns or less.

2) Protective effect when processing pancreatic cells (Linm5F) tBHP

To determine the protective effect on pancreatic cells, the cells Linm5F, a kind of beta cells, distributed plate with 96 hole in the amount of 2 x 10 4 cells/well and incubated for 24 hours. Connection according to sample successively 3-fold diluted to a final concentration of 30, 10, 3, 1, 0,3, 0,1 mkm, which each well treated for 1 hour. Cells were treated tBHP at a final concentration of 400 microns, and further incubated for 5 hours. The protective effects were determined using the method SRB ( B-protein), which is painted with a total number of cellular protein. Briefly, cells were incubated for 5 hours, to each hole added 50ul of 4%solution of formaldehyde to fix the cells, and kept for about 30 minutes at the temperature of the environment. After discarding environment each of the wells were washed with distilled water 2-3 times, and the tablet is dried in a drying case at 50 C. For each hole added a 50 ml solution of SRB and left about 30 minutes at ambient temperature. After removal solution SRB, tablet washed 2-3 times a 1%solution of acetic acid. After drying the tablet in a drying case at 50 C added 100 MKL of 10 mm Tris, to eluted SRB, which intracellular protein. Absorbance was measured at 590 nm and 650 nm, using SpectrMax, and absorption at 650 nm subtracted from absorption at 590 nm, in order to calculate the value of EC 50 .

Preferably, EC 50 connections according to sample is 30 microns or less, preferably, to 10 microns or less, and especially preferably 1.0 microns or less. So, EC 50 connections from the Example 14 was 0,15 micron, and EC 50 connections from the example 22 was 0,20 microns.

3) a Protective effect when processing the cells of the heart (H9C2, a white rat cardiomyocytes) tBHP

To evaluate the protective effect on the cells of the heart, H9C2 cells distributed in the amount of 1.5 x 10 4 cells/well and incubated for 24 hours. Connection according to sample successively 3-fold diluted to a final concentration of 30, 10, 3, 1, 0,3, 0,1 mkm, which each well treated for 45 min Cells were treated tBHP at a final concentration of 400 microns and were incubated for 2 hours. Protective effect of each connection is determined using the same method SRB, as in the case of Linm5F in the above described test 2.

Preferably, EC 50 connections according to sample is 30 microns or less, preferably, to 10 microns or less, and especially preferably 1.0 microns or less. Values EC 50 representative connections according to sample were as follows: example 22: 0.17? m and an example of 85: 0.7 micrometers.

4) Protective effect when processing kidney cells (LLC-PK1) tBHP

To determine the protective effect on the kidney cells, 4 x 10 4 cells distributed to each well and incubated for 24 hours. Cells were treated connections according to sample at a final concentration of 30, 10, 3, 1, 0,3, 0,1 mkm and incubated for 30 min Cells were treated to 400 microns tBHP and further incubated within 6 hours. Protective effect of each connection is determined using the same method SRB, as in the case of Linm5F in the above described test 2.

Preferably, EC 50 connections according to sample is 30 microns or less, preferably, to 10 microns or less, and especially preferably 1.0 microns or less.

5) Protective effect, while processing chondrocytes tBHP

To determine the protective effect on the chondrocytes, chondrocytes, isolated from the 2 rear limbs 16 rats SD weeks of age (weight: 450-460 g). Isolation method was as follows. Cartilage isolated from the knee areas hind limbs rats upon the tablet 100 pi containing PBS (+1X antibiotics). PBS supported at 4 OC C in an ice bath. PBS replaced fresh and centrifuged at 1000 rpm/min After the removal of the PBS added to 3 ml of 1X trypsin (Gibco) at a temperature of 37 C, and were treated for 15 minutes after centrifugation cast and again washed with PBS. after centrifugation is discarded. After adding 0.2% of collagenase (Worthington, type II) cells isolated incubation during the night in a rotating the incubator supported the temperature of 37 deg C. Filtered solution cells were centrifuged, and discarded. After washing PBS cells suspended in 10 ml DMEM/F-12 (Gibco, 10% FBS). 2 x 10 4 cells distributed to each well and incubated for 24 hours. Connection according to sample successively 3-fold diluted to a final concentration of 30, 10, 3, 1, 0,3, 0,1 mkm, which each well treated for 1 hour. Cells were treated tBHP at a final concentration of 500 microns and incubated for 3 hours. Protective effect of each connection is determined using the same method of coloring SRB, as in the case of Linm5F in the above described test 2.

Preferably, EC 50 connections according to sample is 30 microns or less, preferably, to 10 microns or less, and especially preferably 1.0 microns or less.

6) Protective effect when processing brain cells (SK-N-MC) tBHP

To evaluate the protective effect on the cells of the brain, 2 x 10 4 brain cells distributed plate with 96 hole, using a medium DMEM (Gibco, 10% FBS)and incubated for 24 hours. Connection according to sample successively 3-fold diluted to a final concentration of 30, 10, 3, 1, 0,3, 0,1 mkm, which each well treated for 1 hour. Cells were treated tBHP at a final concentration of 400 microns and incubated for 6 hours. 50ul of environment were taken from each well, to carry out a test LDH (Promega). In the test LDH 50ul of environment mixed with 50 ul of the test solution. After the reaction within 30 minutes at an ambient temperature of measured the absorption of light at 490 nm, using SpectraMax Molecular Device).

Preferably, EC 50 connections according to sample is 30 microns or less, preferably, to 10 microns or less, and especially preferably 1.0 microns or less. So, the connection from example 4, for example, showed excellent activity in this experiment, and its value EC 50 was 0,1 microns or less.

Industrial applicability

As demonstrated above results, new compounds according to the present invention, not only show the effects and functional improvement of the state of the liver, but can also be used for prevention and treatment of chronic liver diseases, such as obesity liver, liver fibrosis, cirrhosis of the liver, etc. and acute/chronic liver diseases such as hepatitis, etc. caused by a virus or drugs. Connection according to the present invention also show necrosis overwhelming efficiency in the cells of the pancreas, kidney, brain, cartilage and heart.

Thus, the compounds according to the present invention can be used in the prevention and treatment of necrosis and related diseases.

Technician is able to make a variety of application and modification are not stepping back from the volume of the present invention.

1. Compounds indole the following formula (I):

where n represents a number from 0 to 3, And denotes the 5-membered ring or heterocycle, each of which has from 1 to 3 heteroatoms selected from N, O and S, R 1 R denotes 5-X-B-X', indicates a direct link or 3 indicates about 10-membered heterocycle or , each of which has from 1 to 4 heteroatoms selected of N, O and S, X and X' independently from each other indicate a direct link, or selected from the group consisting of NR 6 -, -,- CONR 6 -, -2, -OC(O)-, -S(O) m -, -O-(CH 2 ) m -, -(CH 2 ) m-O-, -(CH 2 ) m -, -NR 6 CO-, -(R 6 O) 2 P(O)- and-NHCO 2 -, where m is a number from 0 to 3 and R 6 indicates hydrogen or C 1-C 6-alkyl, R 5 indicates hydrogen, hydroxy, C 1-C 6-alkyl, 1 C -10-alkoxy, 4-6 -cycloalkyl or phenyl or indicates 3 of 10-segmented or condensed cyclic heterocycle or , each of which has from 1 to 3 heteroatoms selected of N, O and S, and may be replaced oxo or C 1-C 6-, R 2 means -(CR 8 R 9 )p-Y-R 7 , p is a number from 0 to 2, R 8 and R 9 independently of one another represent hydrogen or C 1-6 alkyl, Y denotes the direct link, or selected from the group consisting of O-, S-, -NR 6 -, -NR 6 C(O)-, -C(O)NR 6 - and-S(O) q, where q denotes the number from 0 to 2, R 7 indicates hydrogen, halogen, hydroxy, C 1-6 alkyl or phenyl or indicates 3 of 10-membered heterocycle or , each of which has from 1 to 3 heteroatoms selected of N, S, O and, if necessary, contains oxo, R 3 represents hydrogen, C 1-C 6-alkyl or(CH 2 ) q-3-6-cycloalkyl, R 4 denotes With 3-6-cycloalkyl, where alkyl, alkoxy, phenyl, cycloalkyl, heterocycle and can be in case of need replaced and deputies represent one or more deputies, selected from the group consisting of hydroxy, halogen, amino, With 1-6 alkyl, halogen-1-6 alkyl, With 1-6 -, and oxo, and their pharmaceutically acceptable salts or isomers.

2. Connection according to claim 1, where n represents a number from 0 to 3, And denotes the 5-membered ring or heterocycle, each of which has from 1 to 3 heteroatoms selected of N, O and S, R 1 R denotes 5-X-B-X', indicates a direct link or 3 indicates about 10-membered heterocycle or , each of which has from 1 to 4 heteroatoms selected of N, O and S, X and X' independently from each other indicate a direct link, or selected from the group consisting of NR 6 -, CO-, -CONR 6 -, -CO 2 -, -OC(O)-, -S(O) 2 -, -O-(CH 2 ) m -, -(CH 2 ) m-O-, -(CH 2 ) m -, -NR 6 CO-, -(R 6 O) 2 P(O)- and-NHCO 2 -, where m is a number from 0 to 3 and R 6 indicates hydrogen or C 1-C 6-alkyl, R 5 indicates hydrogen, hydroxy, C 1-C 6-alkyl, halogen-1-6 alkyl, hydroxy-C 1-C 6-alkyl, 4-6-cycloalkyl, phenyl or or indicates 5 of 10-segmented or condensed cyclic heterocycle or , each of which has from 1 to 3 heteroatoms selected of N, O and S, and may be replaced oxo or halogen-C 1-6-, R 2 means -(CR 8 R 9 ) p-Y-R 7 , p is a number from 0 to 2, R 8 and R 9 independently from each other denote hydrogen or C 1-6 alkyl, Y denotes a direct link, or selected from the group consisting of, -NR 6 -, -NR 6 C(O)-, -C(O)NR 6 - and-S(O) q, where q denotes the number from 0 to 2, R 7 indicates hydrogen, halogen, hydroxy, C 1-C 6-alkyl, hydroxy-C 1-6 alkyl or halo-1-6 -alkyl, indicates phenyl, if necessary, replacing C 1-C 6-, or indicates 5 of about 6-membered heterocycle or , each of which has from 1 to 3 heteroatoms selected of N and O, R 3 represents hydrogen, C 1-C 6-alkyl or(CH 2 )-With 3-6-cycloalkyl, R 4 denotes With 3-6 -cycloalkyl, which may contain .

3. Connection of claim 2, which indicates a cycle presented by one of the following formulas (i)-(viii):

where n and R 1 are the values defined in clause 2, R denotes hydrogen or .

4. Connection of claim 3, which is selected from the group consisting of 4,5-dihydro-thiazole, thiazole, , and .

5. Connection of claim 2, which indicates a direct link, indicates imidazol or oxidiazol or indicates 5 of about 6-membered heterocycle, having 1 or 2 heteroatoms selected of N and O.

6. Connection of claim 5, which refers to the structure presented one of the following formulas (ix) (xii):

where R 5 has the values defined in section 2.

7. Connection of claim 2, where X denotes the direct link or selected from the group consisting of-THE-, -CONR 6 -, -CO 2 -, -SO 2 -, -(CH 2 ) m - O-(CH 2 ) m, where m is a number from 0 to 2 and R 6 indicates hydrogen or C 1-C 6-alkyl.

8. Connection in paragraph 7, in which X is selected from the group consisting of-THE-, -CONH-, -CO 2 -, -SO 2 -, -(CH 2 ) 2 -, -O - O-CH 2.

9. Connection of claim 2, where X' indicates a direct link or selected from the group consisting of -(CH 2 ) 2 -, -NH -, -,- 2, -CONH-, -S(O) 2 -, -(R 6 O) 2 P(O)-, -NHC(O)- and-NHCO 2 -, and R 6 has the values defined in section 2.

10. Connection of claim 2, where R 5 indicates hydrogen, hydroxy, C 1-C 6-alkyl, halogen-1-6 alkyl, hydroxy-1-6 alkyl, 4-6-cycloalkyl, phenyl or or indicates or condensed cyclic 5~9-membered heterocycle or 5 of about 6-membered ring , each of which has from 1 to 3 heteroatoms selected of N, O and S, and may be replaced oxo or .

11. Connection to 10, where R 5 selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, isopropyl nitrate, , , , , , , pyrrolidine, piperidine, 2-, 2-, tetrahydrofuran, , , morpholine, furan, pyridine, 1,3-, 1,1-dioxo-, , imidazole, pyrazole and 3-trifluoromethyl-5,6,7,8-tetrahydro-2H-[1,2,4]triazolo[4,3-a].

12. Connection of claim 2, in which each of the R 8 and R 9 indicates hydrogen.

13. Connection of claim 2, where Y is selected from the group consisting of, -NR 6 -, -NR 6(O)-, -C(O)NR 6 - and-S(O) 2 -, and R 6 has the values defined in section 2.

14. Connection 13, in which Y is selected from the group consisting of-The-, -NH-, -NHC(O)- and-SO 2 -.

15. Connection of claim 2, where R 7 indicates hydrogen, halogen, hydroxy, C 1-C 6-alkyl, hydroxymethyl or halo-1-6 alkyl, indicates phenyl, if necessary, replacing C 1-C 6-, or indicates 5 of about 6-membered heterocycle or , each of which has 1-2 heteroatoms selected of N and O.

16. Connection according to item 15 of which R 7 selected from the group consisting of hydrogen, bromine, fluorine, chlorine, methyl, ethyl, cut, , , , 4--, piperidine, pyrrolidine, furan, pyrrole, pyrazole and pyridine.

17. Connection of claim 2, where R 3 represents hydrogen, or methyl isobutyl.

18. Connection of claim 2, where R 4 is selected from the group consisting of , , , 4-methyl- 4,4-.